Vaughan & Asburys General Ophthalmology, 17th ed.

Chapter 5. Antipsychotic agents

   Conventional antipsychotics

    What makes an antipsychotic “conventional”?

    Neurolepsis

    Extrapyramidal symptoms and tardive dyskinesia

    Prolactin elevation

    The dilemma of blocking D2 dopamine receptors in all dopamine pathways

    Muscarinic cholinergic blocking properties of conventional antipsychotics

    Other pharmacologic properties of conventional antipsychotic drugs

   Atypical antipsychotics

    What makes an antipsychotic “atypical”?

    Serotonin synthesis and termination of action

    5HT2A receptors

    5HT1A partial agonism can also make an antipsychotic atypical

    5HT1B/D receptors

    5HT2C receptors

    5HT3 receptors

    5HT6 receptors

    5HT7 receptors

    D2 partial agonism (DPA) makes an antipsychotic atypical

   Links between antipsychotic binding properties and clinical actions

    Antidepressant actions in bipolar and unipolar depression

    Antimanic actions

    Anxiolytic actions

    Sedative-hypnotic and sedating actions

    Cardiometabolic actions

   Pharmacologic properties of individual antipsychotics: the pines, the dones, two pips and a rip, plus more

    The pines (peens)

    The dones

    Two pips and a rip

    The others

   Antipsychotics in clinical practice

    The art of switching antipsychotics

    Treatment resistance and violence

    Psychotherapy and schizophrenia

   Future treatments for schizophrenia

    Glutamate-linked mechanisms and new treatments for schizophrenia

    Treatments targeting cognitive symptoms in schizophrenia

    Presymptomatic and prodromal treatments for schizophrenia: putting the cart before the horse or preventing disease progression?

   Summary

This chapter will explore antipsychotic drugs, with an emphasis on treatments for schizophrenia. These treatments include not only conventional antipsychotic drugs, but also the newer atypical antipsychotic drugs that have largely replaced the older conventional agents. Atypical antipsychotics are really misnamed, since they are also used as treatments for both the manic and depressed phases of bipolar disorder, as augmenting agents for treatment-resistant depression, and “off-label” for various other disorders, such as treatment-resistant anxiety disorders. The reader is referred to standard reference manuals and textbooks for practical prescribing information, such as drug doses, because this chapter on antipsychotic drugs will emphasize basic pharmacologic concepts of mechanism of action and not practical issues such as how to prescribe these drugs (for that information see for example Stahl's Essential Psychopharmacology: the Prescriber's Guide, which is a companion to this textbook).

Antipsychotic drugs exhibit possibly the most complex pharmacologic mechanisms of any drug class within the field of clinical psychopharmacology. The pharmacologic concepts developed here should help the reader understand the rationale for how to use each of the different antipsychotic agents, based upon their interactions with different neurotransmitter systems (Figure 5-1). Such interactions can often explain both the therapeutic actions and the side effects of various antipsychotic medications and thus can be very helpful background information for prescribers of these therapeutic agents.



Figure 5-1. Qualitative and semi-quantitative representation of receptor binding properties. Throughout this chapter, the receptor binding properties of the atypical antipsychotics are represented both graphically and semi-quantitatively. Each drug is represented as a blue sphere, with its most potent binding properties depicted along the outer edge of the sphere. Additionally, each drug has a series of colored boxes associated with it. Each colored box represents a different binding property, and binding strength is indicated by the size of the box and the number of plus signs. Within the colored box series for any particular antipsychotic, larger boxes with more plus signs (positioned to the left) indicate stronger binding affinity, while smaller boxes with fewer plus signs (positioned to the right) represent weaker binding affinity. The series of boxes associated with each drug are arranged such that the size and positioning of a box reflect the binding potency for a particular receptor. The vertical dotted line cuts through the dopamine 2 (D2) receptor binding box, with binding properties that are more potent than D2 on the left and those that are less potent than D2 on the right. All binding properties are based on the mean values of published Ki (binding affinity) data (http://pdsp.med.unc.edu). The semi-quantitative depiction used throughout this chapter provides a quick visual reference of how strongly a particular drug binds to a particular receptor. It also allows for easy comparison of a drug's binding properties with those of other atypical antipsychotics.

Conventional antipsychotics

What makes an antipsychotic “conventional”?

In this section we will discuss the pharmacologic properties of the first drugs that were proven to effectively treat schizophrenia. A list of many conventional antipsychotic drugs is given in Table 5-1. These drugs are usually called conventional antipsychotics, but they are sometimes also called classical antipsychotics, or typical antipsychotics, or first-generation antipsychotics. The earliest effective treatments for schizophrenia and other psychotic illnesses arose from serendipitous clinical observations more than 60 years ago, rather than from scientific knowledge of the neurobiological basis of psychosis, or of the mechanism of action of effective antipsychotic agents. Thus, the first antipsychotic drugs were discovered by accident in the 1950s when a drug with antihistamine properties (chlorpromazine) was serendipitously observed to have antipsychotic effects when this putative antihistamine was tested in schizophrenia patients. Chlorpromazine indeed has antihistaminic activity, but its therapeutic actions in schizophrenia are not mediated by this property. Once chlorpromazine was observed to be an effective antipsychotic agent, it was tested experimentally to uncover its mechanism of antipsychotic action.

Table 5-1 Some conventional antipsychotics still in use


Generic name

Trade name

Comment

Chlorpromazine

Thorazine

Low potency

Cyamemazine

Tercian

Atypical at low doses; popular in France; not available in the US

Flupenthixol

Depixol

Depot; not available in the US

Fluphenazine

Prolixin

High potency; depot

Haloperidol

Haldol

High potency; depot

Loxapine

Loxitane

Atypical at low doses

Mesoridazine

Serentil

Low potency; QTc issues; second line

Perphenazine

Trilafon

High potency

Pimozide

Orap

High potency; Tourette's syndrome; QTc issues; second line

Pipothiazine

Piportil

Depot; not available in the US

Sulpiride

Dolmatil

May have some atypical properties; not available in the US

Thioridazine

Mellaril

Low potency; QTc issues; second line

Thiothixene

Navane

High potency

Trifluoperazine

Stelazine

High potency

Zuclopenthixol

Clopixol

Depot; not available in the US


Early in the testing process, chlorpromazine and other antipsychotic agents were all found to cause “neurolepsis,” known as an extreme form of slowness or absence of motor movements as well as behavioral indifference in experimental animals. The original antipsychotics were first discovered largely by their ability to produce this effect in experimental animals, and are thus sometimes called “neuroleptics.” A human counterpart of neurolepsis is also caused by these original (i.e., conventional) antipsychotic drugs and is characterized by psychomotor slowing, emotional quieting, and affective indifference.

D2 receptor antagonism makes an antipsychotic conventional

By the 1970s it was widely recognized that the key pharmacologic property of all “neuroleptics” with antipsychotic properties was their ability to block dopamine D2 receptors (Figure 5-2). This action has proven to be responsible not only for the antipsychotic efficacy of conventional antipsychotic drugs, but also for most of their undesirable side effects, including “neurolepsis.”



Figure 5-2. D2 antagonist. Conventional antipsychotics, also called first-generation antipsychotics or typical antipsychotics, share the primary pharmacological property of D2 antagonism, which is responsible not only for their antipsychotic efficacy but also for many of their side effects. Shown here is an icon representing this single pharmacological action.

The therapeutic actions of conventional antipsychotic drugs are hypothetically due to blockade of D2 receptors specifically in the mesolimbic dopamine pathway (Figure 5-3). This has the effect of reducing the hyperactivity in this pathway that is postulated to cause the positive symptoms of psychosis, as discussed in Chapter 4 (Figures 4-12 and 4-13). All conventional antipsychotics reduce positive psychotic symptoms about equally well in schizophrenia patients studied in large multicenter trials if they are dosed to block a substantial number of D2 receptors there (Figure 5-4). Unfortunately, in order to block adequate numbers of D2 receptors in the mesolimbic dopamine pathway to quell positive symptoms, one must simultaneously block the same number of D2 receptors throughout the brain, and this causes undesirable side effects as a “high cost of doing business” with conventional antipsychotics (Figures 5-5through 5-8). Although modern neuroimaging techniques are able to measure directly the blockade of D2 receptors in the dorsal (motor) striatum of the nigrostriatal pathway, as shown in Figure 5-4, for conventional antipsychotics it is assumed that the same number of D2 receptors is blocked in all brain areas, including the ventral limbic area of striatum known as the nucleus accumbens of the mesolimbic dopamine pathway, the prefrontal cortex of the mesocortical dopamine pathway, and the pituitary gland of the tuberoinfundibular dopamine pathway.



Figure 5-3. Mesolimbic dopamine pathway and D2 antagonists. In untreated schizophrenia, the mesolimbic dopamine pathway is hypothesized to be hyperactive, indicated here by the pathway appearing red as well as by the excess dopamine in the synapse. This leads to positive symptoms such as delusions and hallucinations. Administration of a D2 antagonist, such as a conventional antipsychotic, blocks dopamine from binding to the D2 receptor, which reduces hyperactivity in this pathway and thereby reduces positive symptoms as well.



Figure 5-4. Hypothetical thresholds for conventional antipsychotic drug effects. All known antipsychotics bind to the dopamine 2 receptor, with the degree of binding determining whether one experiences therapeutic and/or side effects. For most conventional antipsychotics, the degree of D2 receptor binding in the mesolimbic pathway needed for antipsychotic effects is close to 80%, while D2 receptor occupancy greater than 80% in the dorsal striatum is associated with extrapyramidal side effects (EPS) and in the pituitary is associated with hyperprolactinemia. For conventional antipsychotics (i.e,. pure D2 antagonists) it is assumed that the same number of D2 receptors is blocked in all brain areas. Thus, there is a narrow window between the threshold for antipsychotic efficacy and that for side effects in terms of D2 binding.



Figure 5-5. Mesocortical dopamine pathway and D2 antagonists. In untreated schizophrenia, the mesocortical dopamine pathways to dorsolateral prefrontal cortex (DLPFC) and to ventromedial prefrontal cortex (VMPFC) are hypothesized to be hypoactive, indicated here by the dotted outlines of the pathway. This hypoactivity is related to cognitive symptoms (in the DLPFC), negative symptoms (in the DLPFC and VMPFC), and affective symptoms of schizophrenia (in the VMPFC). Administration of a D2 antagonist could further reduce activity in this pathway and thus not only not improve such symptoms but actually potentially worsen them.



Figure 5-6. Nigrostriatal dopamine pathway and D2 antagonists. The nigrostriatal dopamine pathway is theoretically unaffected in untreated schizophrenia. However, blockade of D2 receptors, as with a conventional antipsychotic, prevents dopamine from binding there and can cause motor side effects that are often collectively termed extrapyramidal symptoms (EPS).



Figure 5-7. Tardive dyskinesia. Long-term blockade of D2 receptors in the nigrostriatal dopamine pathway can cause upregulation of those receptors, which may lead to a hyperkinetic motor condition known as tardive dyskinesia, characterized by facial and tongue movements (e.g., tongue protrusions, facial grimaces, chewing) as well as quick, jerky limb movements. This upregulation may be the consequence of the neuron's futile attempt to overcome drug-induced blockade of its dopamine receptors.



Figure 5-8. Tuberoinfundibular dopamine pathway and D2 antagonists. The tuberoinfundibular dopamine pathway, which projects from the hypothalamus to the pituitary gland, is theoretically “normal” in untreated schizophrenia. D2 antagonists reduce activity in this pathway by preventing dopamine from binding to D2 receptors. This causes prolactin levels to rise, which is associated with side effects such as galactorrhea (breast secretions) and amenorrhea (irregular menstrual periods).

Neurolepsis

D2 receptors in the mesolimbic dopamine system are postulated to mediate not only the positive symptoms of psychosis, but also the normal reward system of the brain, and the nucleus accumbens is widely considered to be the “pleasure center” of the brain. It may be the final common pathway of all reward and reinforcement, including not only normal reward (such as the pleasure of eating good food, orgasm, listening to music) but also the artificial reward of substance abuse. If D2 receptors are stimulated in some parts of the mesolimbic pathway, this can lead to the experience of pleasure. Thus, if D2 receptors in the mesolimbic system are blocked, this may not only reduce positive symptoms of schizophrenia, but also block reward mechanisms, leaving patients apathetic, anhedonic, lacking motivation, interest, and joy from social interactions, a state very similar to that of negative symptoms of schizophrenia. The near shutdown of the mesolimbic dopamine pathway necessary to improve the positive symptoms of psychosis (Figure 5-4) may contribute to worsening of anhedonia, apathy, and negative symptoms, and this may be a partial explanation for the high incidence of smoking and drug abuse in schizophrenia.

Antipsychotics also block D2 receptors in the mesocortical DA pathway (Figure 5-5), where DA may already be deficient in schizophrenia (see Figures 4-14 through 4-16). This can cause or worsen negative and cognitive symptoms even though there is only a low density of D2 receptors in the cortex. An adverse behavioral state can be produced by conventional antipsychotics, and is sometimes called the “neuroleptic-induced deficit syndrome” because it looks so much like the negative symptoms produced by schizophrenia itself, and is reminiscent of “neurolepsis” in animals.

Extrapyramidal symptoms and tardive dyskinesia

When a substantial number of D2 receptors are blocked in the nigrostriatal DA pathway, this will produce various disorders of movement that can appear very much like those in Parkinson's disease; this is why these movements are sometimes called drug-induced parkinsonism. Since the nigrostriatal pathway is part of the extrapyramidal nervous system, these motor side effects associated with blocking D2receptors in this part of the brain are sometimes also called extrapyramidal symptoms, or EPS (Figures 5-4 and 5-6).

Worse yet, if these D2 receptors in the nigrostriatal DA pathway are blocked chronically (Figure 5-7), they can produce a hyperkinetic movement disorder known as tardive dyskinesia. This movement disorder causes facial and tongue movements, such as constant chewing, tongue protrusions, facial grimacing, and also limb movements that can be quick, jerky, or choreiform (dancing). Tardive dyskinesia is thus caused by long-term administration of conventional antipsychotics and is thought to be mediated by changes, sometimes irreversible, in the D2 receptors of the nigrostriatal DA pathway. Specifically, these receptors are hypothesized to become supersensitive or to “upregulate” (i.e., increase in number), perhaps in a futile attempt to overcome drug-induced blockade of D2 receptors in the striatum (Figure 5-7).

About 5% of patients maintained on conventional antipsychotics will develop tardive dyskinesia every year (i.e., about 25% of patients by 5 years), not a very encouraging prospect for a lifelong illness starting in the early twenties. The risk of developing tardive dyskinesia in elderly subjects may be as high as 25% within the first year of exposure to conventional antipsychotics. However, if D2 receptor blockade is removed early enough, tardive dyskinesia may reverse. This reversal is theoretically due to a “resetting” of these D2 receptors by an appropriate decrease in the number or sensitivity of them in the nigrostriatal pathway once the antipsychotic drug that had been blocking these receptors is removed. However, after long-term treatment, the D2 receptors apparently cannot or do not reset back to normal, even when conventional antipsychotic drugs are discontinued. This leads to tardive dyskinesia that is irreversible, continuing whether conventional antipsychotic drugs are administered or not.

Is there any way to predict those who will be harmed with the development of tardive dyskinesia after chronic treatment with conventional antipsychotics? Patients who develop EPS early in treatment may be twice as likely to develop tardive dyskinesia if treatment with a conventional antipsychotic is continued chronically. Also, specific genotypes of dopamine receptors may confer important genetic risk factors for developing tardive dyskinesia with chronic treatment using a conventional antipsychotic. Risk of new cases of tardive dyskinesia, however, can diminish considerably after 15 years of treatment, presumably because patients who have not developed tardive dyskinesia despite 15 years of treatment with a conventional antipsychotic have lower genetic risk factors for it.

A rare but potentially fatal complication called the “neuroleptic malignant syndrome,” associated with extreme muscular rigidity, high fevers, coma, and even death, and possibly related in part to D2 receptor blockade in the nigrostriatal pathway, can also occur with conventional antipsychotic agents.

Prolactin elevation

Dopamine D2 receptors in the tuberoinfundibular DA pathway are also blocked by conventional antipsychotics, and this causes plasma prolactin concentrations to rise, a condition called hyperprolactinemia (Figure 5-8). This is associated with conditions called galactorrhea (i.e., breast secretions) and amenorrhea (i.e., irregular or lack of menstrual periods). Hyperprolactinemia may thus interfere with fertility, especially in women. Hyperprolactinemia might lead to more rapid demineralization of bones, especially in postmenopausal women who are not taking estrogen replacement therapy. Other possible problems associated with elevated prolactin levels may include sexual dysfunction and weight gain, although the role of prolactin in causing such problems is not clear.

The dilemma of blocking D2 dopamine receptors in all dopamine pathways

It should now be obvious that the use of conventional antipsychotic drugs presents a powerful dilemma. That is, there is no doubt that conventional antipsychotic medications exert dramatic therapeutic actions upon positive symptoms of schizophrenia by blocking hyperactive dopamine neurons in the mesolimbic dopamine pathway. However, there are several dopamine pathways in the brain, and it appears that blocking dopamine receptors in only oneof them is useful (Figure 5-3), whereas blocking dopamine receptors in the remaining pathways may be harmful (Figures 5-4 through 5-8). The pharmacologic quandary here is what to do if one wishes simultaneously to decreasedopamine in the mesolimbic dopamine pathway in order to treat positive psychotic symptoms theoretically mediated by hyperactive mesolimbic dopamine neurons and yet increase dopamine in the mesocortical dopamine pathway to treat negative and cognitive symptoms, while leaving dopaminergic tone unchanged in both the nigrostriatal and tuberoinfundibular dopamine pathways to avoid side effects. This dilemma may have been addressed in part by the atypical antipsychotic drugs described in the following sections, and is one of the reasons why the atypical antipsychotics have largely replaced conventional antipsychotic agents in the treatment of schizophrenia and other psychotic disorders throughout the world.

Muscarinic cholinergic blocking properties of conventional antipsychotics

In addition to blocking D2 receptors in all dopamine pathways (Figures 5-3 through 5-8), conventional antipsychotics have other important pharmacologic properties (Figure 5-9). One particularly important pharmacologic action of some conventional antipsychotics is their ability to block muscarinic M1-cholinergic receptors (Figures 5-9 through 5-11). This can cause undesirable side effects such as dry mouth, blurred vision, constipation, and cognitive blunting (Figure 5-10). Differing degrees of muscarinic cholinergic blockade may also explain why some conventional antipsychotics have a lesser propensity to produce extrapyramidal side effects (EPS) than others. That is, those conventional antipsychotics that cause more EPS are the agents that have only weak anticholinergic properties, whereas those conventional antipsychotics that cause fewer EPS are the agents that have stronger anticholinergic properties.



Figure 5-9. Conventional antipsychotic. Shown here is an icon representing a conventional antipsychotic drug. Conventional antipsychotics have pharmacological properties in addition to dopamine D2antagonism. The receptor profiles differ for each agent, contributing to divergent side-effect profiles. However, some important characteristics that multiple agents share are the ability to block muscarinic cholinergic receptors, histamine H1 receptors, and/or α1-adrenergic receptors.



Figure 5-10. Side effects of muscarinic cholinergic receptor blockade. In this diagram, the icon of a conventional antipsychotic drug is shown with its M1 anticholinergic/antimuscarinic portion inserted into acetylcholine receptors, causing the side effects of constipation, blurred vision, dry mouth, and drowsiness.

How does muscarinic cholinergic receptor blockade reduce the EPS caused by dopamine D2 receptor blockade in the nigrostriatal pathway? The reason seems to be based on the fact that dopamine and acetylcholine have a reciprocal relationship with each other in the nigrostriatal pathway (Figure 5-11). Dopamine neurons in the nigrostriatal dopamine pathway make postsynaptic connections with cholinergic neurons (Figure 5-11A). Dopamine normally inhibits acetylcholine release from postsynaptic nigrostriatal cholinergic neurons, thus suppressing acetylcholine activity there (Figure 5-11A). If dopamine can no longer suppress acetylcholine release because dopamine receptors are being blocked by a conventional antipsychotic drug, then acetylcholine becomes overly active (Figure 5-11B).



A. Reciprocal relationship of dopamine and acetylcholine. Dopamine and acetylcholine have a reciprocal relationship in the nigrostriatal dopamine pathway. Dopamine neurons here make postsynaptic connections with the dendrite of a cholinergic neuron. Normally, dopamine suppresses acetylcholine activity (no acetylcholine being released from the cholinergic axon on the right).



B. Dopamine, acetylcholine, and D2 antagonism. This figure shows what happens to acetylcholine activity when dopamine receptors are blocked. As dopamine normally suppresses acetylcholine activity, removal of dopamine inhibition causes an increase in acetylcholine activity. Thus if dopamine receptors are blocked at the D2 receptors on the cholinergic dendrite on the left, then acetylcholine becomes overly active, with enhanced release of acetylcholine from the cholinergic axon on the right. This is associated with the production of extrapyramidal symptoms (EPS). The pharmacological mechanism of EPS therefore seems to be a relative dopamine deficiency and a relative acetylcholine excess.



C. D2 antagonism and anticholinergic agents. One compensation for the overactivity that occurs when dopamine receptors are blocked is to block the acetylcholine receptors with an anticholinergic agent (M1 receptors being blocked by an anticholinergic on the far right). Thus, anticholinergics overcome excess acetylcholine activity caused by removal of dopamine inhibition when dopamine receptors are blocked by conventional antipsychotics. This also means that extrapyramidal symptoms (EPS) are reduced.

Figure 5-11

One compensation for this overactivity of acetylcholine is to block it with an anticholinergic agent (Figure 5-11C). Thus, drugs with anticholinergic actions will diminish the excess acetylcholine activity caused by removal of dopamine inhibition when dopamine receptors are blocked (Figures 5-10 and 5-11C). If anticholinergic properties are present in the same drug with D2 blocking properties, they will tend to mitigate the effects of D2 blockade in the nigrostriatal dopamine pathway. Thus, conventional antipsychotics with potent anticholinergic properties have lower EPS than conventional antipsychotics with weak anticholinergic properties. Furthermore, the effects of D2blockade in the nigrostriatal system can be mitigated by co-administering an agent with anticholinergic properties. This has led to the common strategy of giving anticholinergic agents along with conventional antipsychotics in order to reduce EPS. Unfortunately, this concomitant use of anticholinergic agents does not lessen the ability of the conventional antipsychotics to cause tardive dyskinesia. It also causes the well-known side effects associated with anticholinergic agents, such as dry mouth, blurred vision, constipation, urinary retention, and cognitive dysfunction (Figure 5-10).

Other pharmacologic properties of conventional antipsychotic drugs

Still other pharmacologic actions are associated with the conventional antipsychotic drugs. These include generally undesired blockade of histamine H1 receptors (Figure 5-9) causing weight gain and drowsiness, as well as blockade of α1-adrenergic receptors causing cardiovascular side effects such as orthostatic hypotension and drowsiness. Conventional antipsychotic agents differ in terms of their ability to block these various receptors represented in Figure 5-9. For example, the popular conventional antipsychotic haloperidol has relatively little anticholinergic or antihistaminic binding activity, whereas the classic conventional antipsychotic chlorpromazine has potent anticholinergic and antihistaminic binding. Because of this, conventional antipsychotics differ somewhat in their side-effect profiles, even if they do not differ overall in their therapeutic profiles. That is, some conventional antipsychotics are more sedating than others, some have more ability to cause cardiovascular side effects than others, some have more ability to cause EPS than others.

A somewhat old-fashioned way to subclassify conventional antipsychotics is “low potency” versus “high potency” (Table 5-1). In general, as the name implies, low-potency agents require higher doses than high-potency agents, but, in addition, low-potency agents tend to have more of the additional properties discussed here than do the so-called high-potency agents: namely, low-potency agents have greater anticholinergic, antihistaminic, and α1antagonist properties than high-potency agents, and thus are probably more sedating in general. A number of conventional antipsychotics are available in long-acting depot formulations (Table 5-1).

Atypical antipsychotics

What makes an antipsychotic “atypical”?

From a clinical perspective, an “atypical antipsychotic” is defined in part by the “atypical” clinical properties that distinguish such drugs from conventional antipsychotics. That is, atypical antipsychotics have the clinical profile of equal positive symptom antipsychotic actions, but low extrapyramidal symptoms and less hyperprolactinemia compared to conventional antipsychotics. Thus, they are “atypical” from what is expected from a classical, conventional, first-generation antipsychotic. Since almost all of the agents with this atypical profile came after the introduction of clozapine, sometimes the atypical antipsychotics are also called second-generation antipsychotics.

From a pharmacological perspective, the current atypical antipsychotics as a class are defined as serotonin–dopamine antagonists, with simultaneous serotonin 5HT2A receptor antagonism that accompanies D2antagonism (Figure 5-12). Pharmacologic actions in addition to 5HT2A antagonism that can hypothetically also mediate the atypical antipsychotic clinical profile of low EPS and less hyperprolactinemia with comparable antipsychotic actions include partial agonist actions at 5HT1A receptors and partial agonist actions at D2 receptors. Each of these mechanisms will be discussed here. In order to understand the mechanism of action of atypical antipsychotics and how this differs from conventional antipsychotics, it is necessary to have a somewhat detailed understanding of the neurotransmitter serotonin and its receptors; thus serotonin pharmacology will be discussed in detail throughout this chapter.



Figure 5-12. Serotonin–dopamine antagonist. The “atypicality” of atypical antipsychotics has often been attributed to the coupling of D2 antagonism with serotonin 5HT2A antagonism. On the right is an icon representing this dual pharmacological action.

Serotonin synthesis and termination of action

Serotonin is also known as 5-hydroxytryptamine and abbreviated as 5HT. Synthesis of 5HT begins with the amino acid tryptophan, which is transported into the brain from the plasma to serve as the 5HT precursor (Figure 5-13). Two synthetic enzymes then convert tryptophan into serotonin: firstly tryptophan hydroxylase (TRY-OH) converts tryptophan into 5-hydroxytryptophan, and then aromatic amino acid decarboxylase (AAADC) converts 5HTP into 5HT (Figure 5-13). After synthesis, 5HT is taken up into synaptic vesicles by a vesicular monoamine transporter (VMAT2) and stored there until it is used during neurotransmission.



Figure 5-13. Serotonin is produced. Serotonin (5-hydroxytryptamine [5HT]) is produced from enzymes after the amino acid precursor tryptophan is transported into the serotonin neuron. The tryptophan transport pump is distinct from the serotonin transporter. Once transported into the serotonin neuron, tryptophan is converted by the enzyme tryptophan hydroxylase (TRY-OH) into 5-hydroxytryptophan (5HTP), which is then converted into 5HT by the enzyme aromatic amino acid decarboxylase (AAADC). Serotonin is then taken up into synaptic vesicles via the vesicular monoamine transporter (VMAT2), where it stays until released by a neuronal impulse.

5HT action is terminated when it is enzymatically destroyed by monoamine oxidase (MAO), and converted into an inactive metabolite (Figure 5-14). Serotonergic neurons themselves contain MAO-B, which has low affinity for 5HT, so much of 5HT is thought to be enzymatically degraded by MAO-A outside of the neuron once 5HT is released. The 5HT neuron also has a presynaptic transport pump for serotonin called the serotonin transporter (SERT) that is unique for 5HT and that terminates serotonin's actions by pumping it out of the synapse and back into the presynaptic nerve terminal where it can be re-stored in synaptic vesicles for subsequent use in another neurotransmission (Figure 5-14).



Figure 5-14. Serotonin's action is terminated. Serotonin (5HT) action is terminated by the enzymes monoamine oxidase A (MAO-A) and MAO-B outside the neuron, and by MAO-B within the neuron when it is present in high concentrations. These enzymes convert serotonin into an inactive metabolite. There is also a presynaptic transport pump selective for serotonin, called the serotonin transporter or SERT, that clears serotonin out of the synapse and back into the presynaptic neuron.

5HT2A receptors

The key to understanding why antipsychotics are atypical is to understand the pharmacology of 5HT2A receptors, and the significance of what happens when they are blocked by atypical antipsychotics. All 5HT2A receptors are postsynaptic, and 5HT2A receptors are located in many brain regions. When they are located on cortical pyramidal neurons, they are excitatory (Figure 5-15A, box 1) and can thus enhance downstream glutamate release (Figure 5-15A, box 2). As discussed in Chapter 4, glutamate regulates downstream dopamine release, so stimulating (Figure 5-15A) or blocking (Figure 5-15B) 5HT2A receptors can therefore also regulate downstream dopamine release. Cortical 5HT1A receptors also regulate downstream dopamine release (Figure 5-15C, discussed below).



A. Cortical 5HT2A receptors decrease dopamine release. Shown here is the mechanism by which serotonin release in the cortex can lead to decreased dopamine release in the striatum. (1) Serotonin is released in the cortex and binds to 5HT2A receptors on glutamatergic pyramidal neurons, causing activation of those neurons. (2) Activation of glutamatergic pyramidal neurons leads to glutamate release in the brainstem, which in turn stimulates GABA release. GABA binds to dopaminergic neurons projecting from the substantia nigra to the striatum, inhibiting dopamine release (indicated by the dotted outline of the dopaminergic neuron).



B. Blocking cortical 5HT2A receptors increases dopamine release. (1) If 5HT2A receptors on glutamatergic pyramidal neurons are blocked, then these neurons cannot be activated by serotonin release in the cortex (indicated by the dotted outline of the glutamatergic neuron). (2) If glutamate is not released from glutamatergic pyramidal neurons into the brainstem, then GABA release is not stimulated and in turn cannot inhibit dopamine release from the substantia nigra into the striatum.



C. Cortical 5HT1A receptor stimulation increases dopamine release. Serotonin projections from the raphe nucleus to the cortex also make axoaxonic connections with glutamatergic pyramidal neurons. (1) Serotonin released at these synapses can bind to 5HT1A receptors, which causes inhibition of the glutamatergic neuron (indicated by the dotted outline of the glutamatergic neuron). (2) If glutamate is not released from glutamatergic pyramidal neurons into the brainstem, then GABA release is not stimulated and in turn cannot inhibit dopamine release from the substantia nigra into the striatum. Thus, cortical 5HT1A receptor stimulation is functionally analogous to cortical 5HT2Areceptor blockade, in that both lead to increased dopamine release in the striatum.

Figure 5-15

5HT2A receptors are brakes on dopamine release in the striatum

5HT2A stimulation of cortical pyramidal neurons by serotonin (Figure 5-15A, box 1) hypothetically blocks downstream dopamine release in the striatum. It does this via stimulation of glutamate release in the brainstem that triggers release of inhibitory GABA there (Figure 5-15A, box 2). Release of dopamine from neurons in the striatum is thus inhibited (Figure 5-15A).

5HT2A antagonism cuts the brake cable

5HT2A antagonism of cortical pyramidal neurons by an atypical antipsychotic interferes with serotonin applying its braking action to dopamine release via 5HT2A receptors (Figure 5-15B, box 1). Thus, 5HT2Aantagonism in the cortex hypothetically stimulates downstream dopamine release in the striatum (Figure 5-15B). It does this by reducing glutamate release in the brainstem, which in turn fails to trigger the release of inhibitory GABA at dopamine neurons there (Figure 5-15B, box 2). Release of dopamine from neurons downstream in the striatum is thus disinhibited, which should theoretically mitigate EPS.

5HT2A receptors in other brain areas are also a brake on dopamine release in the striatum

5HT2A receptors theoretically regulate dopamine release from nigrostriatal dopamine neurons by additional mechanisms in additional brain areas. That is, serotonin neurons whose cell bodies are in the midbrain raphe may innervate nigrostriatal dopamine neurons both at the level of the dopamine neuronal cell bodies in the substantia nigra (Figure 5-16A, box 2) and at the dopamine neuronal axon terminals in the striatum (Figure 5-16A, box 1). This innervation may be either via a direct connection between the serotonin neuron and the dopamine neuron, or via an indirect connection with a GABA interneuron. 5HT2A receptor stimulation by serotonin at either end of substantia nigra neurons hypothetically blocks dopamine release in the striatum (Figure 5-16A). On the other hand, 5HT2A receptor antagonism by an atypical antipsychotic at these same sites hypothetically stimulates downstream dopamine release in the striatum (Figure 5-16B). Such release of dopamine in the striatum should mitigate EPS, which is theoretically why antipsychotics with 5HT2A antagonist properties are atypical. 5HT1A receptors also regulate dopamine release in the striatum (Figure 5-16C, discussed below).



A. Nigral and striatal 5HT2A receptor stimulation decreases dopamine release. (1) In the striatum, serotonergic projections synapse directly with dopaminergic neurons and indirectly via GABAergic neurons. At GABAergic neurons, serotonin binding to 5HT2A receptors disinhibits GABA release, which in turn decreases release of dopamine (indicated by the dotted outline of the dopaminergic neuron). Similarly, when serotonin binds to 5HT2A receptors directly on dopamine neurons, this causes a decrease in dopamine release. (2) Serotonin can also decrease dopamine release in the striatum via 5HT2Abinding in the brainstem. That is, serotonin released in the raphe nucleus binds to 5HT2A receptors on GABAergic interneurons. This causes GABA to be released onto dopaminergic neurons in the substantia nigra, thus inhibiting dopamine release into the striatum (indicated by the dotted outline of the dopaminergic neuron).



B. Blocking nigral and striatal 5HT2A receptors increases dopamine release. (1) If 5HT2A receptors on GABAergic interneurons in the striatum are blocked, then serotonin is unable to stimulate these receptors to cause release of GABA (indicated by the dotted outline of the GABAergic neuron). Thus, GABA is unable to inhibit dopamine release. Likewise, blockade of 5HT2A receptors directly on striatal dopaminergic neurons prevents inhibition of dopamine release, thereby increasing striatal dopamine. (2) In the brainstem, blockade of 5HT2A receptors on GABAergic interneurons prevents GABA release onto dopaminergic neurons in the substantia nigra (indicated by the dotted outline of the GABAergic neuron). Thus, dopamine can be released into the striatum.



C. Raphe 5HT1A receptor stimulation increases dopamine release. Serotonin binding to 5HT1A receptors in the raphe nucleus inhibits serotonin release (indicated by the dotted outline of the serotonin neurons). (1) In the striatum, reduced serotonin release means that 5HT2A receptors on GABAergic and dopaminergic neurons are not stimulated, which in turn means that dopamine release is not inhibited. (2) Similarly, in the brainstem, reduced serotonin release means that 5HT2A receptors on GABAergic interneurons are not stimulated and therefore GABA is not released (indicated by the dotted outline of the GABAergic neuron). Thus, dopamine can be released into the striatum.

Figure 5-16

5HT2A receptor antagonism theoretically makes an antipsychotic atypical: low EPS

So, exactly how does this dopamine release by 5HT2A antagonism reduce EPS? The answer to this is shown in Figures 5-17 and 5-18. Normally, serotonin reduces dopamine release from the striatum by actions of serotonin at the various 5HT2A receptors discussed above (Figures 5-15A5-16A5-17). By contrast, the two actions of an atypical antipsychotic, namely blocking both D2 receptors and 5HT2Areceptors, are shown in Figure 5-18, one at a time. On the left, D2 receptors are blocked by the D2 antagonist actions of the atypical antipsychotic, just like a conventional antipsychotic (Figure 5-18A). If this were the only action of the drug, there would be EPS if occupancy of D2receptors reached 80% or more (Figure 5-18A). This is exactly what happens with a conventional antipsychotic. However, atypical antipsychotics have a second property, namely to block 5HT2A receptors, which as discussed above have multiple mechanisms by which they increase dopamine release in the striatum (Figures 5-15B5-16B5-18B). The result of this increased dopamine release is that dopamine competes with D2 receptor antagonists in the striatum, and reduces the D2 receptor binding there below 80% to more like 60%, enough to eliminate extrapyramidal symptoms (Figure 5-18B). This is the hypothesis most frequently linked to the explanation for the mechanism of the most important distinguishing clinical properties of atypical antipsychotics, namely low extrapyramidal symptoms (EPS) with comparable antipsychotic actions.



Figure 5-17. Enlarged view of serotonin (5HT) and dopamine (DA) interactions in the nigrostriatal DA pathway at axon terminals in the striatum. Normally, 5HT inhibits DA release. (A) DA is being released because no 5HT is stopping it. Specifically, no 5HT is present at its 5HT2A receptor on the nigrostriatal DA neuron. (B) Now DA release is being inhibited by 5HT in the nigrostriatal dopamine pathway. When 5HT occupies its 5HT2Areceptor on the DA neuron (lower red circle), this inhibits DA release, so there is no DA in the synapse (upper red circle).



Figure 5-18. Serotonin 2A antagonists in the nigrostriatal pathway. (A) Postsynaptic dopamine 2 (D2) receptors are being blocked by a serotonin–dopamine antagonist (SDA) in the nigrostriatal dopamine pathway. This shows what would happen if D2 blockade were the only active action of an atypical antipsychotic – the drug would only bind to postsynaptic D2 receptors and block them. In contrast, (B) shows the dual action of the SDAs, in which both D2 and 5HT2A receptors are blocked. The interesting thing is that the second action of 5HT2A antagonism actually reverses the first action of D2 antagonism. This happens because dopamine is released when serotonin can no longer inhibit its release. Another term for this is disinhibition. Thus, blocking a 5HT2A receptor disinhibits the dopamine neuron, causing dopamine to pour out of it. The consequence of this is that dopamine can then compete with the SDA for the D2 receptor and reverse the inhibition there. As D2 blockade is thereby reversed, SDAs cause little or no extrapyramidal symptoms (EPS) or tardive dyskinesia.

5HT2A receptor antagonism theoretically makes an antipsychotic atypical: low hyperprolactinemia

How do 5HT2A antagonist actions reduce hyperprolactinemia? Serotonin and dopamine have reciprocal roles in the regulation of prolactin secretion from the pituitary lactotroph cells. That is, dopamine inhibits prolactin release via stimulating D2 receptors (Figure 5-19), whereas serotonin promotes prolactin release via stimulating 5HT2A receptors (Figure 5-20). Thus, when D2 receptors alone are blocked by a conventional antipsychotic, dopamine can no longer inhibit prolactin release, so prolactin levels rise (Figure 5-21). However, in the case of an atypical antipsychotic, there is simultaneous inhibition of 5HT2A receptors, so serotonin can no longer stimulate prolactin release (Figure 5-22). This mitigates the hyperprolactinemia of D2 receptor blockade. Although this is interesting theoretical pharmacology, in practice, not all serotonin–dopamine antagonists reduce prolactin secretion to the same extent, and others do not reduce prolactin elevations at all.



Figure 5-19. Dopamine inhibits prolactin. Dopamine inhibits prolactin release from pituitary lactotroph cells in the pituitary gland when it binds to D2 receptors (red circle).



Figure 5-20. Serotonin stimulates prolactin. Serotonin (5HT) stimulates prolactin release from pituitary lactotroph cells in the pituitary gland when it binds to 5HT2A receptors (red circle). Thus, serotonin and dopamine have a reciprocal regulatory action on prolactin release.



Figure 5-21. Conventional antipsychotics and prolactin. Conventional antipsychotic drugs are D2 antagonists and thus oppose dopamine's inhibitory role on prolactin secretion from pituitary lactotrophs. Thus, these drugs increase prolactin levels (red circle).



Figure 5-22. Atypical antipsychotics and prolactin. This figure shows how 5HT2A antagonism reverses the ability of D2 antagonism to increase prolactin secretion. As dopamine and serotonin have reciprocal regulatory roles in the control of prolactin secretion, one cancels the other. Thus, stimulating 5HT2A receptors reverses the effects of stimulating D2 receptors. The same thing works in reverse, namely, blockade of 5HT2A receptors (shown here) reverses the effects of blocking D2 receptors (shown in Figure 5-21).

5HT2A receptor antagonism theoretically makes an antipsychotic atypical: comparable antipsychotic actions

Why doesn’t 5HT2A antagonism reverse antipsychotic actions? Although a conventional antipsychotic can only decrease dopamine, and will do this at D2 receptors throughout the brain, atypical antipsychotics with their additional 5HT2A antagonist properties have much more complicated net actions on dopamine activity, since they not only decrease dopamine activity by blocking D2 receptors but they can also increase dopamine release and thus increase dopamine activity by indirectly stimulating dopamine receptors. However, these actions seem to be very different in different parts of the brain. In the nigrostriatal dopamine pathway and in the tuberoinfundibular dopamine pathway, there is sufficient dopamine release by atypical antipsychotics to reverse, in part, the unwanted actions of EPS and hyperprolactinemia. This does not appear to occur in the mesolimbic dopamine pathway, as antipsychotic actions of atypical antipsychotics are just as robust as those of conventional antipsychotics, presumably due to regional differences in the way in which 5HT2A receptors can or cannot exert control over dopamine release. The trick has been to exploit these differing regional pharmacological mechanisms to get the best clinical results by simultaneous blockade of D2 receptors and 5HT2A receptors that can fortuitously have net blockade of differing amounts of D2 receptors in different areas of the same brain at the same time with the same drug! Although there are obviously many other factors at play here, and this is an overly simplistic explanation, it is a useful starting point for beginning to appreciate the pharmacological actions of serotonin–dopamine antagonists as a unique class of atypical antipsychotic drugs.

The making of a therapeutic window

One way to display this phenomenon of the atypical antipsychotics’ differing clinical actions is to contrast what happens to dopamine D2 binding in the striatum when a pure D2 antagonist is given (Figure 5-4) versus when an atypical antipsychotic that combines equal or greater potency for blocking 5HT2A receptors with D2 antagonism is given (Figure 5-23). In the case of a pure D2 antagonist like a conventional antipsychotic, the amount of D2 receptor antagonism shown in Figure 5-4 for the striatum is assumed to be the same amount in the limbic area and in the pituitary. This is why you get EPS and hyperprolactinemia at the same dose as you get antipsychotic actions, namely when all of these D2 receptors in all of these brain areas are blocked substantially (many estimate this to be approximately 80%). There is little if any wiggle room between therapeutic actions and side effects (Figure 5-4).



Figure 5-23. Hypothetical thresholds for atypical antipsychotic drug effects. All known antipsychotics bind to the dopamine 2 receptor, with the degree of binding determining whether one experiences therapeutic and/or side effects. For most atypical antipsychotics, D2 receptor occupancy greater than 80% in the mesolimbic pathway is needed for therapeutic effects, while D2 occupancy greater than 80% in the dorsal striatum is associated with extrapyramidal side effects (EPS) and D2 occupancy greater than 80% in the pituitary is associated with hyperprolactinemia. For conventional antipsychotics (i.e,. pure D2 antagonists) it is assumed that the same number of D2 receptors is blocked in all brain areas (see Figure 5-4). However, the 5HT2A and 5HT1A properties of atypical antipsychotics can presumably lower the amount of D2 antagonism in the dorsal striatum and in the pituitary but not in the limbic area; thus, there may be greater occupancy of D2 receptors in the limbic area of nucleus accumbens (not shown), perhaps up to 80% occupancy, while nigrostriatal and pituitary D2 receptors are only occupied at 60% due to the 5HT2A and 5HT1A properties of atypical antipsychotics.

However, in the case of an atypical antipsychotic, where essentially all of these drugs have an affinity for blocking 5HT2A that is equal to or greater than their affinity for blocking D2 receptors, the amount of D2 antagonism in the striatum is lowered at the same dose where the drugs have antipsychotic actions. This creates a window between the dose that exerts antipsychotic actions and the dose that causes EPS or elevated prolactin levels (Figure 5-23). While D2 receptors are assumed to be blocked by 80% in the limbic areas to cause antipsychotic actions, the D2 receptors in both the striatum and the pituitary are assumed to be blocked by only approximately 60%, below the threshold for side effects. Of course, if an atypical antipsychotic has its dose raised high enough, there will eventually be 80% blockade of even the striatum and pituitary, and the drug will lose its atypical properties. Thus, the drug is only “atypical” in the dosing window shown in Figure 5-23. This window is created by the fact that atypical antipsychotics almost always have higher affinity for 5HT2A receptors than they do for D2 receptors.

You can visualize the relative receptor actions of atypical antipsychotics on 5HT2A receptors versus D2 receptors by viewing simultaneously the relative potencies of the individual atypical antipsychotic drugs for binding 5HT2A receptors versus D2 receptors (Figure 5-24). The atypical antipsychotics can be categorized many ways, but for our discussion throughout this chapter, we will organize them as either the “pines” (peens) (Figure 5-24A), the “dones” (Figure 5-24B), or “two pips and a rip” (Figure 5-24C). Specifically, the pharmacologic binding properties of each drug are represented as a row of semi-quantitative and rank-order relative binding potencies at numerous neurotransmitter receptors. These figures are conceptual and not precisely quantitative, can differ from one laboratory to another, from species to species, and from method to method, and the consensus values for binding properties evolve over time. More potent binding (higher affinity) is shown to the left of the value for the D2 receptor, less potent binding (lower affinity) is shown to the right. Since these agents are all dosed to occupy about 60% or more of striatal D2 receptors (Figure 5-23), all receptors to the left of D2 in Figure 5-24 are occupied at the level of 60% or more at antipsychotic dosing levels. For these receptors to the left, there are also potentially clinically relevant receptor actions even at doses below those for treating psychosis. The receptors to the right of D2 in Figure 5-24 are occupied at a level of less than 60% at antipsychotic dosing levels. Only those receptors that are bound by drug within an order of magnitude of potency of D2 affinity are shown to the right of D2. These receptor actions have potentially relevant clinical actions despite lower levels of occupancy than D2 receptors, with dwindling occupancy levels as the receptor is listed further and further to the right, and also when given at lower doses than normal antipsychotic dosing levels.



Figure 5-24. 5HT2A binding by atypical antipsychotics. Shown here is a visual depiction of the binding profiles of atypical antipsychotics (see Figure 5-1). Each colored box represents a different binding property, with the size and positioning of the box reflecting the binding potency of the property (i.e., size indicates potency relative to a standard Ki scale, while position reflects potency relative to the other binding properties of that drug). The vertical dotted line cuts through the dopamine 2 (D2) receptor binding box, with binding properties that are more potent than D2 on the left and those that are less potent than D2 on the right. Interestingly, D2 binding is not the most potent property for any of the atypical antipsychotics. (A) The “pines” (clozapine, olanzapine, quetiapine, asenapine) all bind much more potently to the 5HT2A receptor than they do to the D2 receptor. (B) The “dones” (risperidone, paliperidone, ziprasidone, iloperidone, lurasidone) also bind more potently to the 5HT2A receptor than to the D2 receptor, or show similar potency at both receptors. (C) Aripiprazole and cariprazine both bind more potently to the D2receptor than to the 5HT2A receptor, while brexpiprazole has similar potency at both receptors.

The point is that although no two atypical antipsychotics have exactly the same pharmacologic binding profiles, it is easy to see that for the pines (Figure 5-24A) and for the dones (Figure 5-24B), 5HT2Areceptor binding is always to the left of D2 binding. This binding property of greater 5HT2A than D2 binding potency is what is widely thought to make these drugs “atypical” antipsychotics and to create the “window” of atypical antipsychotic action that is theoretically linked to low EPS as well as to low propensity to elevate prolactin. Note that for two pips and a rip, the 5HT2A binding potency is to the right of D2 binding, and thus less potent than D2 binding (Figure 5-24C). The fact that the two pips and a rip are still atypical antipsychotics in their clinical properties is attributed to other actions, as will be explained in the sections below on 5HT1A receptors and partial agonism of D2 receptors. Rather than having more potent 5HT2A than D2 binding, as is the case for the pines and the dones, binding at 5HT1A receptors and partial agonism of D2 receptors may account for the atypical properties of the two pips and a rip.

5HT1A partial agonism can also make an antipsychotic atypical

In order to understand how 5HT1A partial agonism can also reduce EPS, it is important to grasp how 5HT1A receptors function in various parts of the brain, and how they can regulate dopamine release in the striatum.

Postsynaptic 5HT1A receptors in prefrontal cortex are accelerators for dopamine release in striatum

If 5HT2A stimulation is the “brake” stopping downstream dopamine release (Figure 5-15A), and 5HT2A antagonism “cuts the brake cable,” enhancing dopamine release (Figure 5-15B), what is the accelerator for downstream dopamine release in the striatum? The answer is postsynaptic 5HT1A receptors on pyramidal neurons in the cortex (Figure 5-15C, box 1). 5HT1A receptor stimulation in the cortex hypothetically stimulates downstream dopamine release in the striatum, by reducing glutamate release in the brainstem, which in turn fails to trigger the release of inhibitory GABA at dopamine neurons there (Figure 5-15C, box 2). Dopamine neurons are thus disinhibited, just as they are by a 5HT2A antagonist. This would theoretically cause dopamine release in striatum, and mitigate EPS.

Presynaptic 5HT1A receptors in raphe are also accelerators for dopamine release in the striatum

5HT1A receptors can not only be postsynaptic throughout the brain (Figures 5-15C5-16B5-16C), but also they can be presynaptic on the dendrites and cell bodies of serotonin neurons in the midbrain raphe (Figure 5-25A). In fact, the only type of presynaptic 5HT receptor at the somatodendritic end of a serotonin neuron is a 5HT1A receptor (Figure 5-25A). When 5HT is detected at presynaptic somatodendritic 5HT1A receptors on neuronal dendrites and on the neuronal cell body, this activates an autoreceptor function that causes a slowing of neuronal impulse flow through the serotonin neuron and a reduction of serotonin release from its axon terminal (Figure 5-25B). Downregulation and desensitization of these presynaptic 5HT1A somatodendritic autoreceptors are thought to be critical to the antidepressant actions of drugs that block serotonin reuptake, and this is discussed in Chapter 7 on antidepressants.



Figure 5-25. 5HT1A autoreceptors. Presynaptic 5HT1A receptors are autoreceptors located on the cell body and dendrites, and are therefore called somatodendritic autoreceptors (A). When serotonin (5HT) binds to these 5HT1Areceptors, it causes a shutdown of 5HT neuronal impulse flow, depicted here as decreased electrical activity and a reduction in the release of 5HT from the synapse on the right (B).

When serotonin occupies a presynaptic 5HT1A somatodendritic autoreceptor in the midbrain raphe, where they are located (Figure 5-15C, box 2; Figure 5-16C, box 2), this turns off serotonin neurons. The serotonin pathways from raphe (Figure 5-16C, box 2) to substantia nigra (Figure 5-16C, box 2) and to striatum (Figure 5-16C, box 1) are thus “off” in the presence of serotonin at presynaptic 5HT1A receptors; as a consequence, serotonin is not released onto postsynaptic 5HT2A receptors on nigrostriatal neurons, activation of which would ordinarily inhibit dopamine release in the striatum (Figure 5-16A). Lack of serotonin release due to stimulation of presynaptic 5HT1A receptors thereby allows the nigrostriatal dopamine neurons to be active and thus to release dopamine in the striatum (Figure 5-16C). Pre- and postsynaptic 5HT1A receptors work together to enhance dopamine release in the striatum, and when both are stimulated by certain atypical antipsychotics, this theoretically mitigates EPS.

Some, but not all, atypical antipsychotics have potent 5HT1A partial agonist properties (Figure 5-26). In particular, the two pips and a rip, namely aripiprazole and the experimental antipsychotics brexpiprazole and cariprazine, all have 5HT1A partial agonist actions not only more potent than their 5HT2A antagonist actions, but comparable to their D2 antagonist actions (Figure 5-26C). The 5HT2A antagonist actions may also contribute to the atypical properties of these three agents (Figure 5-26C), but the reduction of EPS for these agents is likely given a major boost by the additional presence of potent 5HT1A partial agonist actions. In addition, note that potentially clinically relevant 5HT1A partial agonist actions are present for a few of the pines (especially clozapine and quetiapine) (Figure 5-26A) and some of the dones (especially lurasidone, iloperidone, and ziprasidone) (Figure 5-26B), with those binding properties further to the left being relatively more potent and thus potentially more clinically relevant as well at antipsychotic dosing levels.



Figure 5-26. 5HT1A binding by atypical antipsychotics. Shown here is a visual depiction of the binding profiles of atypical antipsychotics (see Figure 5-1). (A) Clozapine and quetiapine both bind more potently to the 5HT1Areceptor than they do to the D2 receptor, while asenapine binds less potently to the 5HT1A receptor and olanzapine does not bind to it at all. (B) All of the “dones” (risperidone, paliperidone, ziprasidone, iloperidone, lurasidone) bind to the 5HT1A receptor with less potency than they do to the D2 receptor. (C) Aripiprazole, brexpiprazole, and cariprazine each have similar relative potency for the D2 and 5HT1A receptors. 5HT1A binding is actually the most potent property of brexpiprazole.

The most dopamine release in striatum and fewest EPS may come when you take your foot off the brake and also step on the accelerator

If blocking 5HT2A receptors is like taking your foot off the brake, and if stimulating 5HT1A receptors is like stepping on the accelerator, this could account for why both of these actions that release dopamine from the striatum might be additive. It may also potentially explain why atypical antipsychotics with either potent 5HT2A antagonism (Figure 5-24) or potent 5HT1A agonist/partial agonist properties (Figure 5-26), or with both actions, have a reduced incidence of EPS. Thus, either pharmacologic action alone or both pharmacologic actions together seem to contribute to the atypical antipsychotic profiles of specific atypical antipsychotic drugs.

Not only do several atypical antipsychotics have 5HT1A partial agonist actions (Figure 5-26), but so do various agents with known or suspected antidepressant actions, from vilazodone to buspirone (augmentation of selective serotonin reuptake inhibitors [SSRIs]/serotonin–norepinephrine reuptake inhibitors [SNRIs]), to experimental agents with selective or mixed 5HT1A partial agonism (e.g., vortioxetine). This has led to speculation that those atypical antipsychotics with 5HT1A partial agonist actions that are proven antidepressants (such as quetiapine and aripiprazole) may be working in part through this mechanism, and that other atypical antipsychotics with 5HT1A partial agonist actions are also potential antidepressants (such as brexpiprazole, cariprazine, lurasidone, iloperidone, and others). The mechanism of how 5HT1A partial agonism exerts its possible antidepressant efficacy is unknown, but could be linked to release of dopamine and norepinephrine in prefrontal cortex or to the potentiation of serotonin levels in the presence of a serotonin reuptake inhibitor, which would be theoretically linked to antidepressant actions.

5HT1B/D receptors

Presynaptic 5HT receptors are autoreceptors, and detect the presence of 5HT, causing a shutdown of further 5HT release and 5HT neuronal impulse flow. Discussed above are the 5HT1A presynaptic receptors at the somatodendritic end of the serotonin neuron (Figure 5-25). There is also another type of presynaptic serotonin receptor, and it is located at the other end of the neuron, on the axon terminals (Figure 5-27). When 5HT is detected in the synapse by presynaptic 5HT receptors on axon terminals, it occurs via a 5HT1B/D receptor which is also called a terminal autoreceptor (Figure 5-27). In the case of the 5HT1B/D terminal autoreceptor, 5HT occupancy of this receptor causes a blockade of 5HT release (Figure 5-27B). On the other hand, drugs that block the 5HT1B/D autoreceptor can promote 5HT release, and this could hypothetically result in antidepressant actions, as for the experimental antidepressant vortioxetine discussed in Chapter 7. Among the atypical antipsychotics, only iloperidone, ziprasidone (Figure 5-28B), and asenapine (Figure 5-28A), unproven yet as antidepressants, have 5HT1B/D binding more potent than or comparably potent to D2 binding, although many other agents have low potency at this receptor (Figure 5-28), including the proven antidepressants olanzapine, quetiapine, and aripiprazole. However, the link of 5HT1B/D to the antidepressant actions of these agents, although plausible, remains unproven.



Figure 5-27. 5HT1B/D autoreceptors. Presynaptic 5HT1B/D receptors are autoreceptors located on the presynaptic axon terminal. They act by detecting the presence of serotonin (5HT) in the synapse and causing a shutdown of further 5HT release. When 5HT builds up in the synapse (A), it is available to bind to the autoreceptor, which then inhibits serotonin release (B).



Figure 5-28. 5HT1B/D binding by atypical antipsychotics. Shown here is a visual depiction of the binding profiles of atypical antipsychotics (see Figure 5-1). (A) Clozapine, olanzapine, and asenapine all bind relatively weakly to the 5HT1B receptor, while quetiapine and asenapine bind to the 5HT1D receptor. (B) Risperidone, paliperidone, ziprasidone, and iloperidone all have some affinity for the 5HT1B and 5HT1D receptors. In particular, ziprasidone binds more potently to the 5HT1B receptor than to the D2 receptor. Lurasidone does not bind to 5HT1B/D. (C) Aripiprazole and brexpiprazole each bind weakly to the 5HT1B receptor; aripiprazole also binds to the 5HT1D receptor; cariprazine does not bind to 5HT1B/D.

5HT2C receptors

5HT2C receptors are postsynaptic, and regulate both dopamine and norepinephrine release. Stimulation of 5HT2C receptors is one experimental approach to a novel antipsychotic, since this suppresses dopamine release, curiously more from the mesolimbic than from the nigrostriatal pathways, yielding an excellent preclinical profile: namely, an antipsychotic without EPS. One such agent, the 5HT2Cselective agonist vabacaserin, has entered clinical trials for the treatment of schizophrenia. Stimulating 5HT2C receptors is also an experimental approach to the treatment of obesity, since this leads to weight loss in both preclinical and clinical studies. Another 5HT2C selective agonist, lorcaserin, is now approved for the treatment of obesity. Psychopharmacological treatments for obesity, including lorcaserin, are discussed in Chapter 14.

Blocking 5HT2C receptors stimulates dopamine and norepinephrine release in prefrontal cortex, and has pro-cognitive but particularly antidepressant actions in experimental animals. Several known and experimental antidepressants are 5HT2C antagonists, ranging from certain tricyclic antidepressants to mirtazapine, to agomelatine, and these are discussed in Chapter 7 on antidepressants. Some atypical antipsychotics have potent 5HT2Cantagonist properties, especially the pines, including those with known antidepressant action, namely quetiapine and olanzapine (Figure 5-29A). Olanzapine is often combined with fluoxetine to boost olanzapine's antidepressant actions in treatment-resistant and bipolar depression. Fluoxetine is not only a well-known SSRI, but also has potent 5HT2C antagonist properties that may not only contribute to its antidepressant effects as monotherapy, but also add to the 5HT2C antagonist actions of olanzapine when an olanzapine–fluoxetine combination is given. For quetiapine, there is some evidence for pharmacologic synergism between its norepinephrine reuptake blocking properties and its 5HT2C antagonist properties (see NET for quetiapine in Figure 5-47, to the left and more potent than 5HT2C antagonism). These two mechanisms can each boost dopamine and norepinephrine release in prefrontal cortex, something theoretically linked to antidepressant actions. This is discussed as well in Chapter 7 on antidepressants. Potent 5HT2C antagonist actions suggests theoretical antidepressant effects for asenapine (Figure 5-29A), but there are only relatively weak 5HT2C binding potencies for most of the other atypical antipsychotics (Figure 5-29B and C).



Figure 5-29. 5HT2C binding by atypical antipsychotics. Shown here is a visual depiction of the binding profiles of atypical antipsychotics (see Figure 5-1). (A) All of the “pines” (clozapine, olanzapine, quetiapine, asenapine) bind more potently to the 5HT2C receptor than they do to the D2 receptor. (B) All of the “dones” (risperidone, paliperidone, ziprasidone, iloperidone, lurasidone) have some affinity for the 5HT2C receptor, though none with more potency than at the D2 receptor. (C) Aripiprazole, brexpiprazole, and cariprazine all have relatively weak affinity for the 5HT2C receptor.

5HT3 receptors

5HT3 receptors are postsynaptic and regulate inhibitory GABA interneurons in various brain areas that in turn regulate the release of a number of neurotransmitters, from serotonin itself to acetylcholine, norepinephrine, dopamine, and histamine. 5HT3 receptors are also involved in centrally mediated vomiting and possibly also in nausea. Peripheral 5HT3 receptors in the gut regulate bowel motility.

Blocking 5HT3 receptors in the chemoreceptor trigger zone of the brainstem is an established therapeutic approach to mitigating the nausea and vomiting caused by cancer chemotherapy. Blocking 5HT3receptors on GABA interneurons increases the release of serotonin, dopamine, norepinephrine, acetylcholine, and histamine in the cortex and is thus a novel approach to an antidepressant and to a pro-cognitive agent. The proven antidepressant mirtazapine and the experimental antidepressant vortioxetine are potent 5HT3 antagonists, and this may contribute to the antidepressant actions of such agents, especially in combination with inhibition of serotonin, norepinephrine, and/or dopamine reuptake. Antidepressant actions linked to 5HT3 receptors and other serotonin receptors are discussed in Chapter 7 on antidepressants. Among the atypical antipsychotics, only clozapine has 5HT3 binding potency comparable to its D2 binding potency, and the others have very weak or essentially no affinity for this receptor, so 5HT3 antagonism does not likely contribute to the clinical actions of atypical antipsychotics.

5HT6 receptors

5HT6 receptors are postsynaptic and may be key regulators of the release of acetylcholine and cognitive processes. Blocking this receptor improves learning and memory in experimental animals. 5HT6antagonists have been proposed as novel pro-cognitive agents for the cognitive symptoms of schizophrenia when added on to an atypical antipsychotic. Some atypical antipsychotics are potent 5HT6antagonists (clozapine, olanzapine, asenapine) relative to D2 binding (Figure 5-30A) and other atypical antipsychotics have moderate or weak binding to 5HT6 receptors relative to D2 binding (quetiapine, ziprasidone, iloperidone, aripiprazole, brexpiprazole) (Figure 5-30ABC), but it remains unclear how this action contributes to any of their clinical profiles.



Figure 5-30. 5HT6 and 5HT7 binding by atypical antipsychotics. Shown here is a visual depiction of the binding profiles of atypical antipsychotics (see Figure 5-1). (A) Clozapine, olanzapine, and asenapine each bind more potently to the 5HT6 receptor, whereas binding of quetiapine to 5HT6 receptors is relatively weak. Clozapine, quetiapine, and asenapine each have greater affinity for the 5HT7receptor compared to the D2 receptor. Olanzapine also binds to the 5HT7 receptor, but with relatively weak potency. (B) Of the dones, only ziprasidone and iloperidone bind to 5HT6, and in both cases this 5HT6 affinity is weaker than for the D2 receptor. Risperidone, paliperidone, and lurasidone have greater affinity for the 5HT7 receptor than for the D2 receptor. Ziprasidone also has relatively potent binding at the 5HT7 receptor, though with less affinity than for D2 receptors. (C) Aripiprazole and brexpiprazole have relatively weak affinity for 5HT6 receptors. Aripiprazole, brexpiprazole, and cariprazine all bind to the 5HT7 receptor, though none with more potency than for the D2 receptor.

5HT7 receptors

5HT7 receptors are postsynaptic and are important regulators of serotonin release. When blocked, serotonin release is disinhibited, especially when 5HT7 antagonism is combined with serotonin reuptake inhibition. This is discussed in further detail later in this chapter and also in Chapter 7 on antidepressants. Novel 5HT7-selective antagonists are thought to be regulators of circadian rhythms, sleep, and mood in experimental animals. Several proven antidepressants have at least moderate affinity for 5HT7 receptors as antagonists, including amoxapine, desipramine, imipramine, mianserin, fluoxetine, and the experimental antidepressant vortioxetine. Several of the pines and dones are potent 5HT7 antagonists relative to D2 binding (to the left of D2 for clozapine, quetiapine, and asenapine in Figure 5-30A, and to the left of D2 for risperidone, paliperidone, and lurasidone in Figure 5-30B). Other pines, dones, and the two pips and a rip have moderate affinities as well (to the right in Figure 5-30ABC) which are potentially clinically relevant.

It is plausible but unproven that 5HT7 antagonism contributes to the known antidepressant actions of quetiapine, especially in combination with SSRIs/SNRIs, and in combination with its other potential antidepressant mechanisms discussed above for quetiapine such as NET inhibition, 5HT2C antagonism, and 5HT1A partial agonism. It is also plausible but unproven that 5HT7 antagonism could contribute to the known antidepressant actions of aripiprazole, especially in combination with SSRIs/SNRIs and in combination with its 5HT1A partial agonism. This leads to speculation that lurasidone, asenapine, brexpiprazole, and others could have antidepressant potential in unipolar major depressive disorder, especially in combination with SSRIs/SNRIs, but more clinical trials are necessary at this time to prove this. Recent data already indicate antidepressant actions of lurasidone in bipolar depression.

D2 partial agonism (DPA) makes an antipsychotic atypical

Some antipsychotics act to stabilize dopamine neurotransmission in a state between silent antagonism and full stimulation/agonist action by acting as partial agonists at D2 receptors (Figure 5-31). Partial agonist actions at G-protein-linked receptors, which is how D2 receptors are categorized, are explained in Chapter 2 and illustrated in Figures 2-3 through 2-10. Dopamine partial agonists (DPAs) theoretically bind to the D2 receptor in a manner that is neither too antagonizing like a conventional antipsychotic (“too cold,” with antipsychotic actions but extrapyramidal symptoms: Figure 5-32A), nor too stimulating like a stimulant or dopamine itself (“too hot,” with positive symptoms of psychosis: Figure 5-32B). Instead, a partial agonist binds in an intermediary manner (“just right,” with antipsychotic actions but no extrapyramidal symptoms: Figure 5-32C). For this reason, partial agonists are sometimes called “Goldilocks” drugs if they get the balance “just right” between full agonism and complete antagonism. However, as we shall see, this explanation is an oversimplification and the balance is different for each drug in the D2 partial agonist class.



Figure 5-31. D2 partial agonism. A third property that may render an antipsychotic atypical is that of dopamine 2 partial agonism (DPA). These agents may stabilize dopamine neurotransmission in a state between silent antagonism and full stimulation.



Figure 5-32. Spectrum of dopamine neurotransmission. Simplified explanation of actions on dopamine. (A) Conventional antipsychotics bind to the D2 receptor in a manner that is “too cold”; that is, they have powerful antagonist actions while preventing agonist actions and thus can reduce positive symptoms of psychosis but also cause extrapyramidal symptoms (EPS). (B) D2 receptor agonists, such as dopamine itself, are “too hot” and can therefore lead to positive symptoms. (C) D2 partial agonists bind in an intermediary manner to the D2 receptor and are therefore “just right,” with antipsychotic actions but no EPS.

Partial agonists have the intrinsic ability to bind receptors in a manner that causes signal transduction from the receptor to be intermediate between full output and no output (Figure 5-33). The naturally occurring neurotransmitter generally functions as a full agonist, and causes maximum signal transduction from the receptor it occupies (Figure 5-33, top) whereas antagonists essentially shut down all output from the receptor they occupy and make them “silent” in terms of communicating with downstream signal transduction cascades (Figure 5-33, middle). Partial agonists cause receptor output that is more than the silent antagonist, but less than the full agonist (Figure 5-33, bottom). Thus, many degrees of partial agonism are possible between these two extremes. Full agonists, antagonists, and partial agonists may cause different changes in receptor conformation that lead to a corresponding range of signal transduction output from the receptor (Figure 5-34).



Figure 5-33. Dopamine receptor output. Dopamine itself is a full agonist and causes full receptor output (top). Conventional antipsychotics are full antagonists and allow little if any receptor output (middle). The same is true for atypical antipsychotics that are serotonin–dopamine antagonists. However, D2 partial agonists (DPAs) can partially activate dopamine receptor output and cause a stabilizing balance between stimulation and blockade of dopamine receptors (bottom).



Figure 5-34. Agonist spectrum and receptor conformation. This figure depicts changes in receptor conformation in response to full agonists versus antagonists versus partial agonists. With full agonists, the receptor conformation is such that there is robust signal transduction through the G-protein-linked second-messenger system of D2 receptors (on the left). Antagonists, on the other hand, bind to the D2receptor in a manner that produces a receptor conformation that is not capable of any signal transduction (middle). Partial agonists, such as a dopamine partial agonist (DPA), cause a receptor conformation such that there is an intermediate amount of signal transduction (on the right). However, the partial agonist does not induce as much signal transduction as a full agonist.

An amazing characteristic of D2 receptors is that it only takes a very small amount of signal transduction through D2 receptors in the striatum for a dopamine D2 receptor partial agonist to avoid extrapyramidal side effects. Thus a very slight degree of partial agonist property, sometimes called “intrinsic activity,” can have a very different set of clinical consequences compared to a fully silent and completely blocked D2 receptor, which is what almost all known conventional and atypical antipsychotics do. Those agents all lie to the far left on the D2 partial agonist spectrum in Figure 5-35. Partial agonists capable of treating schizophrenia lie far to the left on the D2 partial agonist spectrum, but not all the way to full antagonist. By contrast, dopamine itself, the naturally occurring full agonist, is all the way to the right on the D2partial agonist spectrum in Figure 5-35. Agents capable of treating Parkinson's disease (such as ropinirole and pramipexole) lie far to the right on the D2 partial agonist spectrum.



Figure 5-35. Spectrum of dopamine partial agonists. Dopamine partial agonists may themselves fall along a spectrum, with some having actions closer to a silent antagonist and others having actions closer to a full agonist. Agents with too much agonism may be psychotomimetic and thus not effective antipsychotics. Instead, partial agonists that are closer to the antagonist end of the spectrum (such as aripiprazole, cariprazine, or brexpiprazole, but not bifeprunox) seem to have favorable profiles. Amisulpride and sulpiride may be very partial agonists, with their partial agonist clinical properties more evident at lower doses.

What is so interesting is how very small movements off the far left and up the partial agonist spectrum in Figure 5-35 can have profound effects upon the clinical properties of an antipsychotic: just slightly too close to a pure antagonist (too far to the left), and it is just a conventional antipsychotic with EPS and akathisia unless it has other 5HT2A/5HT1A properties that compensate for being too far to the left (comparable to “too cold” in Figure 5-32A). On the other hand, just slightly too far to the right, and it is an atypical antipsychotic without EPS or akathisia, but one that is too activating, capable of worsening positive symptoms of schizophrenia and also causing intolerable nausea and vomiting (comparable to “too hot” in Figure 5-32B). The elusive Goldilocks solution of a drug that is a tolerable high-dose antipsychotic without EPS and a tolerable low-dose antidepressant is being sought empirically by iterative introduction of a series of partial agonists each differing in their intrinsic activity that demonstrate the consequences of being either too close to the antagonist end of the spectrum, or too far off that end of the spectrum. This is just a theory of how building tiny bits of partial agonism into a D2 antagonist can dramatically change its clinical properties, but there is some reasonable evidence for this possibility, given that there are several agents with significant clinical testing or experience that are available and that have tested this pharmacological concept in patients with schizophrenia.

For example, it is possible that the older agents sulpiride and amisulpride (not available in the US) are just barely off the antagonist part of the spectrum, without sufficient 5HT2A or 5HT1A actions to forgive this, and thus have low but not zero EPS with robust antipsychotic activities at high doses, plus anecdotal but not well-tested antidepressant and negative symptom clinical actions at low doses (Figure 5-35). Fairly extensive testing has been carried out of five other partial agonists shown in Figure 5-35, with progressively increasing amounts of partial agonist action as they go from left to right. The first dart thrown at the partial agonist spectrum was OPC4392 (structurally and pharmacologically related to both aripiprazole and brexpiprazole, which were tested later). OPC4392 landed too close to the agonist part of the curve, although it had relatively little intrinsic activity. This surprised investigators, who discovered that although OPC4392 improved negative symptoms of schizophrenia, it also activated rather than consistently improved positive symptoms of schizophrenia, and in balance did not have the profile of an acceptable antipsychotic so was never marketed.

However, investigators threw another dart closer to the antagonist part of the spectrum and it landed as aripiprazole. This agent is indeed an atypical antipsychotic in which the balance was improved so that it ameliorated positive symptoms without activating negative symptoms at higher antipsychotic doses, while proving to be an antidepressant at lower doses. Aripiprazole still has some akathisia, and some thought this was because it might be a bit too close to the antagonist end of the spectrum. Thus another dart, called bifeprunox, was aimed further up the spectrum, landing as more of an agonist than aripiprazole but less of an agonist than OPC4392, hoping for an improvement compared with aripiprazole, with less akathisia. What happened is that bifeprunox is too much of an agonist: it causes nausea and vomiting from dopamine agonist actions (and 5HT1A partial agonist actions), and bifeprunox's antipsychotic actions, although better than placebo, were not as robust as a full antagonist atypical antipsychotic, so the US Food and Drug Administration (FDA) did not approve it.

Two more agents with antagonist actions greater than aripiprazole are in late-stage clinical testing, namely a second “pip,” brexpiprazole, and the “rip” cariprazine (Figure 5-35). So far, both appear to have efficacy in schizophrenia, and clinical trials and dose finding in mania and depression are ongoing, but both agents, although having subtle pharmacologic differences, are looking as though they will have significant clinical differences not only from aripiprazole but also from each other. The take-away point here is that D2 partial agonism can make an antipsychotic atypical, and that subtle changes in the degree of intrinsic efficacy along the partial agonist scale at the full antagonist end of the spectrum can have profound clinical consequences.

Links between antipsychotic binding properties and clinical actions

Although D2 antagonist/partial agonist properties can explain the antipsychotic efficacy for positive symptoms as well as many side effects of antipsychotics, and the 5HT2A antagonist, 5HT1A partial agonist and muscarinic antagonist properties can explain the reduced propensity for EPS or elevating prolactin of various antipsychotics, there are many additional pharmacologic properties of these drugs. In fact, the atypical antipsychotics as a class have perhaps the most complicated pattern of binding to neurotransmitter receptors of any drug class in psychopharmacology, and no two agents have an identical portfolio of these additional properties (Figure 5-24). Binding properties of each individual atypical antipsychotic are discussed later in this chapter. In this section, we will review a number of other receptor interactions for the class of atypical antipsychotic drugs in general, and show where the potential links may exist between pharmacology and clinical actions. Although many of the actions of these drugs on the various receptors are fairly well established, the link between receptor binding and clinical actions remains hypothetical, with some links better established than others.

Antidepressant actions in bipolar and unipolar depression

Atypical antipsychotics are really misnamed, because they also have antidepressant actions alone and in combination with other antidepressants. It does not seem likely that D2 antagonism or 5HT2Aantagonism are the mechanisms for this, because agents with only those properties are not effective antidepressants, and antipsychotics with these properties often work at doses lower than those necessary for antipsychotic actions, perhaps due to other pharmacologic actions. The actions hypothetically linked to antidepressant effects are those that exist for proven antidepressants, although not every atypical antipsychotic with a potential antidepressant mechanism is proven to be an antidepressant in clinical trials. The hypothetical antidepressant actions of one or more of the atypical antipsychotics are shown in Figure 5-36, and each of these pharmacologic actions is discussed in more detail in Chapter 7. Numerous receptor binding properties linked to various serotonin receptors have already been mentioned, including 5HT1A partial agonist actions and antagonism of 5HT1B/D, 5HT2C, 5HT3, and 5HT7 receptors. Additional mechanisms linked to antidepressant actions that are shared by various atypical antipsychotics include:

·        Serotonin and/or norepinephrine reuptake inhibition – Only quetiapine has potency greater than its D2 binding, but ziprasidone and zotepine have weak binding at these sites.

·        Alpha-2 (α2) antagonism – The proven antidepressant mirtazapine is best known for α2 antagonism, but several atypical antipsychotics also have this action with variable degrees of potency, including essentially all the pines (higher potency especially for quetiapine and clozapine: Figure 5-37A) and dones (higher potency especially for risperidone: Figure 5-37B) as well as aripiprazole (Figure 5-37C).



Figure 5-36. Atypical antipsychotic binding properties. Atypical antipsychotics have some of the most complex mixtures of pharmacological properties in psychopharmacology. Beyond antagonism of 5HT2A and D2receptors, agents in this class interact with multiple other receptor subtypes for both dopamine and serotonin, and have effects on other neurotransmitter systems as well. Some of these multiple pharmacological properties can contribute to the therapeutic effects of atypical antipsychotics (e.g., antidepressant, antimanic, and anxiolytic effects), whereas others can contribute to their side effects (e.g,. sedative-hypnotic and cardiometabolic effects). No two atypical antipsychotics have identical binding properties, which probably helps to explain why they all have distinctive clinical properties.



Figure 5-37. Alpha-2 binding by atypical antipsychotics. Shown here is a visual depiction of the binding profiles of atypical antipsychotics (see Figure 5-1). (A) All of the “pines” (clozapine, olanzapine, quetiapine, asenapine) bind to α2 receptors to varying degrees. Clozapine and quetiapine in particular bind to some α2 receptor subtypes with greater potency than they do to the D2 receptor. (B) All of the “dones” (risperidone, paliperidone, ziprasidone, iloperidone, lurasidone) bind to α2 receptors to varying degrees. Risperidone binds to the α2C receptor with greater potency than it does to the D2 receptor. (C) Aripiprazole binds to α2 receptors with less potency than it does to the D2 receptor. Brexpiprazole and cariprazine do not bind to α2 receptors.

Antimanic actions

All antipsychotics are effective for psychotic mania, but atypical antipsychotics appear to have greater efficacy, or at least greater documentation of efficacy, for nonpsychotic mania, leading to the major hypothesis that it is the D2antagonism/partial agonism combined with 5HT2A antagonism that is the mechanism of this (Figure 5-36). However, proven for aripiprazole and with preliminary evidence of efficacy for cariprazine, agents with D2 partial agonism and with 5HT1A partial agonism more potent than 5HT2A antagonism are also effective for mania, so 5HT1A agonist/partial agonist actions may contribute to antimanic efficacy as well (Figure 5-36).

Anxiolytic actions

A somewhat controversial use of atypical antipsychotics is for the treatment of various anxiety disorders. Some studies suggest efficacy of various atypical antipsychotics for generalized anxiety disorder, and to augment other agents for other anxiety disorders, but perhaps more controversial is their use for posttraumatic stress disorder (PTSD). Furthermore, side effects and cost considerations and the lack of regulatory approval have tended to restrict this application of the atypical antipsychotics. It is possible that the antihistamine and anticholinergic sedative properties of some of these agents are calming in some patients and responsible for anxiolytic action in them (Figure 5-36). Agents with these properties are listed in the following section on sedation. Anecdotal use as well as clinical evidence for utility in various anxiety disorders is probably greatest for quetiapine.

Sedative-hypnotic and sedating actions

There has been a longstanding debate as to whether sedation is a good or a bad property for an antipsychotic. The answer seems to be that sedation is both good and bad. In some cases, particularly for short-term treatment, sedation is a desired therapeutic effect, especially early in treatment, during hospitalization, and when patients are aggressive, agitated, or needing sleep induction. In other cases, particularly for long-term treatment, sedation is generally a side effect to be avoided because diminished arousal, sedation, and somnolence can lead to cognitive impairment. When cognition is impaired, functional outcomes are compromised.

Blocking one or more of three particular receptors is held theoretically responsible for causing sedation: M1-muscarinic cholinergic receptors, H1-histaminic receptors, and α1-adrenergic receptors (Figures 5-36 and 5-38). Blocking central α1-adrenergic receptors is associated with sedation, and blocking peripheral α1-adrenergic receptors is associated with orthostatic hypotension. Central dopamine, acetylcholine, histamine, and norepinephrine are all involved in arousal pathways (Figure 5-38), so it is not surprising that blocking one or more of these systems can lead to sedation as well as to cognitive problems. Arousal pathways are discussed in detail in the chapters on sleep (Chapter 11) and cognition (Chapter 13). Pharmacologic evidence suggests that the best long-term outcomes in schizophrenia result when adequate D2/5HT2A/5HT1A receptor occupancy improves positive symptoms of psychosis, rather than from nonspecific sedation resulting from muscarinic, histaminic, and adrenergic receptor blockade. All atypical antipsychotics are not equally sedating because they do not all have potent antagonist properties at H1histamine, muscarinic cholinergic, and α1-adrenergic receptors. Obviously drugs that combine potent actions at all three receptors will be the most sedating:

·        Potent antihistamine actions – Clozapine, quetiapine, olanzapine, and iloperidone are all more potent H1 antagonists than D2 antagonists (all to the left in Figure 5-39A and B). All other antipsychotics have moderate potency, except lurasidone, which has essentially no binding to H1 (Figure 5-39).

·        Potent anticholinergic actions – Only the pines clozapine, quetiapine, and olanzapine have high potency for muscarinic receptors, whereas there is essentially no muscarinic cholinergic receptor binding for the other atypical antipsychotics, including asenapine (Figure 5-39A).

·        Potent α1-adrenergic antagonism – All atypical antipsychotics have at least moderate binding potency to α1-adrenergic receptors, but the most potent relative to their D2 binding are clozapine, quetiapine, risperidone, and iloperidone (Figure 5-40).



Figure 5-38. Neurotransmitters of cortical arousal. The neurotransmitters acetylcholine (ACh), histamine (HA), and norepinephrine (NE) are all involved in arousal pathways connecting neurotransmitter centers with the thalamus (T), hypothalamus (Hy), basal forebrain (BF), and cortex. Thus, pharmacological actions at their receptors could influence arousal. In particular, antagonism of M1-muscarinic, H1-histamine, and α1-adrenergic receptors are all associated with sedating effects.



Figure 5-39. Antihistamine/anticholinergic binding by atypical antipsychotics. Shown here is a visual depiction of the binding profiles of atypical antipsychotics (see Figure 5-1). (A) Clozapine, olanzapine, and quetiapine all have strong potency for histamine 1 and muscarinic receptors. Asenapine has some affinity for histamine 1 receptors and weak affinity for muscarinic receptors. (B) Risperidone, paliperidone, ziprasidone, and iloperidone all have some potency for histamine 1 receptors, though with less potency than for D2 receptors. Lurasidone does not bind to histamine 1 or muscarinic receptors. (C) Aripiprazole, brexpiprazole, and cariprazine all bind at the histamine 1 receptor with less potency than they do to the D2 receptor, and do not bind to muscarinic receptors.



Figure 5-40. Alpha-1 binding by atypical antipsychotics. Shown here is a visual depiction of the binding profiles of atypical antipsychotics (see Figure 5-1). (A) Clozapine and quetiapine each have greater potency for the α1receptor than for the D2 receptor, while olanzapine and asenapine each bind with similar potency to the α1 and the D2 receptors. (B) All of the “dones” (risperidone, paliperidone, ziprasidone, iloperidone, lurasidone) bind to the α1receptor. In particular, risperidone and iloperidone bind with greater potency than they do to the D2 receptor. (C) Aripiprazole, brexpiprazole, and cariprazine each have some binding potency at the α1 receptor.

Given this portfolio of findings, it is not surprising that in general the pines are more sedating than the dones, and furthermore, the presence of antihistamine and antimuscarinic binding has implications for how fast one can taper and switch these agents. Alpha-1 antagonist properties may have theoretical implications for lowering EPS by a novel mechanism. These points are discussed in further detail later in this chapter.

Cardiometabolic actions

Although all atypical antipsychotics share a class warning for causing weight gain and risks for obesity, dyslipidemia, diabetes, accelerated cardiovascular disease, and even premature death, there is actually a spectrum of risk among the various agents.

·        High metabolic risk – clozapine, olanzapine

·        Moderate metabolic risk – risperidone, paliperidone, quetiapine, iloperidone (weight only)

·        Low metabolic risk – ziprasidone, aripiprazole, lurasidone, iloperidone (low for dyslipidemia), asenapine, brexpiprazole?, cariprazine?

The pharmacologic mechanisms for what propels a patient taking an atypical antipsychotic along the “metabolic highway” (Figure 5-41) of these risks are only beginning to be understood. The “metabolic highway” begins with increased appetite and weight gain, and progresses to obesity, insulin resistance, and dyslipidemia with increases in fasting triglyceride levels (Figure 5-41). Ultimately, hyperinsulinemia advances to pancreatic β-cell failure, prediabetes and then diabetes. Once diabetes is established, risk for cardiovascular events is further increased, as is the risk of premature death (Figure 5-41). Receptors associated with increased weight are the H1 histamine receptor and the 5HT2C serotonin receptor, and when these receptors are blocked, particularly at the same time, patients can experience weight gain. Since weight gain can lead to obesity, and obesity to diabetes, and diabetes to cardiac disease along the metabolic highway (Figure 5-41), it seemed feasible at first that weight gain might explain all the other cardiometabolic complications associated with treatment with those atypical antipsychotics that cause weight gain. This may be true, but only in part, and perhaps mostly for those agents that have both potent antihistamine properties (Figure 5-39) and potent 5HT2C antagonist properties (Figure 5-29), notably clozapine, olanzapine, quetiapine, as well as the antidepressant mirtazapine (discussed in Chapter 7).



Figure 5-41. Monitoring on the metabolic highway. Where on the metabolic highway should psychopharmacologists monitor antipsychotics? Key stages along the metabolic highway where antipsychotics can produce cardiometabolic risks are the places where the actions of these drugs should be monitored. Thus, there are at least three “on” ramps where the cardiometabolic risk of some atypical antipsychotics can enter the metabolic highway, and they are all shown here. First, increased appetite and weight gain can lead to elevated body mass index (BMI) and ultimately obesity. Thus, weight and BMI should be monitored here. Second, atypical antipsychotics can cause insulin resistance by an unknown mechanism; this can be detected by measuring fasting plasma triglyceride levels. Finally, atypical antipsychotics can cause sudden onset of diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar syndrome (HHS) by unknown mechanisms, possibly including blockade of M3-cholinergic receptors. This can be detected by informing patients of the symptoms of DKA/HHS and by measuring fasting glucose levels.

However, it now appears that the cardiometabolic risk of certain atypical antipsychotics cannot simply be explained by increased appetite and weight gain, even though they certainly do represent the first steps down the slippery slope towards cardiometabolic complications. That is, some atypical antipsychotics can elevate fasting triglyceride levels and cause increased insulin resistance in a manner that cannot be explained by weight gain alone. When dyslipidemia and insulin resistance occur, this moves a patient along the metabolic highway towards diabetes and cardiovascular disease (Figure 5-41). Although this happens in many patients with weight gain alone, it also occurs in some patients who take atypical antipsychotics and prior to their gaining significant weight, as if there is an acute receptor-mediated action of these drugs on insulin regulation.

This hypothesized mechanism is indicated as receptor “X” on the drug icon in Figure 5-36 and on the icons for those agents hypothesized to have this action on insulin resistance and fasting triglycerides shown later in this chapter. To date, the mechanism of this increased insulin resistance and elevation of fasting triglycerides has been vigorously pursued but has not yet been identified. The rapid elevation of fasting triglycerides upon initiation of some antipsychotics, and the rapid fall of fasting triglycerides upon discontinuation of such drugs, is highly suggestive that an unknown pharmacologic mechanism causes these changes, although this remains speculative. The hypothetical actions of atypical antipsychotics with this postulated receptor action are shown in Figure 5-42, where adipose tissue, liver, and skeletal muscle all develop insulin resistance in response to administration of certain antipsychotic drugs (e.g., high-risk drugs but not “metabolically friendly” low-risk drugs) at least in certain patients. Whatever the mechanism of this effect, it is clear that fasting plasma triglycerides and insulin resistance can be elevated significantly in some patients taking certain antipsychotics, and that this enhances cardiometabolic risk, moves such patients along the metabolic highway (Figure 5-41), and functions as another step down the slippery slope towards the diabolical destination of cardiovascular events and premature death. This does not happen in all patients taking any antipsychotic, but the development of this problem can be detected by monitoring (Figure 5-43), and it can be managed easily when it does occur (Figure 5-44).



Figure 5-42. Insulin resistance, elevated triglycerides, and antipsychotics: caused by tissue actions at an unknown receptor? Some atypical antipsychotics may lead to insulin resistance and elevated triglycerides independently of weight gain, although the mechanism is not yet established. This figure depicts a hypothesized mechanism in which antipsychotic binds to receptor X at adipose tissue, liver, and skeletal muscle to cause insulin resistance.



Figure 5-43. Metabolic monitoring toolkit. The psychopharmacologist's metabolic monitoring toolkit includes items for tracking four major parameters: weight/body mass index (BMI), fasting triglycerides (TGs), fasting glucose (glu), and blood pressure (BP). These items are simply a flowchart that can appear at the beginning of a patient's chart with entries for each visit, a scale, a BMI chart to convert weight into BMI, a blood pressure cuff, and laboratory results for fasting triglycerides and fasting glucose.



Figure 5-44. Insulin resistance: what can a psychopharmacologist do? Several factors influence whether or not an individual develops insulin resistance, some of which are manageable by a psychopharmacologist and some of which are not. Unmanageable factors include genetic makeup and age, while items that are modestly manageable include lifestyle (e.g., diet, exercise, smoking). Psychopharmacologists exert their greatest influence on managing insulin resistance through selection of antipsychotics that either do or do not cause insulin resistance.

Another rare but life-threatening cardiometabolic problem is known to be associated with atypical antipsychotics: namely, an association with the sudden occurrence of diabetic ketoacidosis (DKA) or the related condition hyperglycemic hyperosmolar syndrome (HHS). The mechanism of this complication is under intense investigation, and is probably complex and multifactorial. In some cases, it may be that patients with undiagnosed insulin resistance, prediabetes or diabetes, who are in a state of compensated hyperinsulinemia on the metabolic highway (Figure 5-41), when given an atypical antipsychotic agent, become decompensated because of some pharmacologic mechanism associated with these drugs. Because of the risk of DKA/HHS, it is important to know the patient's location along the metabolic highway prior to prescribing an antipsychotic, particularly if the patient has hyperinsulinemia, prediabetes, or diabetes. It is also important to monitor (Figures 5-41 and 5-43) and manage (Figure 5-44) these risk factors.

Specifically, there are at least three stops along the metabolic highway where a psychopharmacologist should monitor a patient taking an atypical antipsychotic and manage the cardiometabolic risks of atypical antipsychotics (Figure 5-41). This starts with monitoring weight and body mass index to detect weight gain, and fasting glucose to detect the development of diabetes (Figures 5-41 and 5-43). It also means getting a baseline of fasting triglyceride levels and determining whether there is a family history of diabetes. The second action to monitor is whether atypical antipsychotics are causing dyslipidemia and increased insulin resistance, by measuring fasting triglyceride levels before and after starting an atypical antipsychotic (Figure 5-41). If body mass index or fasting triglycerides increase significantly, a switch to a different antipsychotic that does not cause these problems should be considered. In patients who are obese, with dyslipidemia, and either in a prediabetic or diabetic state, it is especially important to monitor blood pressure, fasting glucose, and waist circumference before and after initiating an atypical antipsychotic. Best practices are to monitor these parameters in anyone taking any atypical antipsychotic. In high-risk patients, it is especially important to be vigilant for DKA/HHS, and possibly to reduce that risk by maintaining the patient on an antipsychotic with lower cardiometabolic risk. In high-risk patients, especially those with pending or actual pancreatic β-cell failure as manifested by hyperinsulinemia, prediabetes, or diabetes, fasting glucose and other chemical and clinical parameters can be monitored to detect early signs of rare but potentially fatal DKA/HHS.

The psychopharmacologist's metabolic toolkit is quite simple (Figure 5-43). It involves a flowchart that tracks perhaps as few as four parameters over time, especially before and after switches from one antipsychotic to another, or as new risk factors evolve. These four parameters are weight (as body mass index), fasting triglycerides, fasting glucose, and blood pressure.

The management of patients at risk for cardiometabolic disease can be quite simple as well, although patients who already have developed dyslipidemia, hypertension, diabetes, and heart disease will likely require management of these problems by a medical specialist. However, the psychopharmacologist is left with a very simple set of options for managing patients with cardiometabolic risk who are prescribed an atypical antipsychotic (Figure 5-44). The major factors that determine whether a patient progresses along the metabolic highway to premature death include those that are unmanageable (e.g., the patient's genetic makeup and age), those that are modestly manageable (e.g., change in lifestyle such as diet, exercise, and stopping smoking), and those that are most manageable, namely the selection of antipsychotic and perhaps switching from one that is causing increased risk in a particular patient, to one that monitoring demonstrates reduces that risk.

Pharmacologic properties of individual antipsychotics: the pines, the dones, two pips and a rip, plus more

Here we will review some of the differences among 17 selected antipsychotic agents, based both on the art and the science of psychopharmacology. Further details on how to prescribe these individual drugs are available in the companion Stahl's Essential Psychopharmacology: the Prescriber's Guide and other standard references. The pharmacologic properties represented in the icons shown in the next section are conceptual and not precisely quantitative and are shown in two ways: a rank order of binding potencies in a strip below an icon containing the most important binding properties. For each individual drug, these are the same strips shown earlier in this chapter in several figures containing all the drugs in the various categories (e.g., Figure 5-24). As before, more potent binding is shown to the left of the value for the D2 receptor, less potent binding is shown to the right. As mentioned earlier, these agents are all dosed to treat psychosis in order to occupy about 60% or more of D2 receptors (Figure 5-23). Thus, all receptors to the left of D2 are occupied at the level of 60% or more at antipsychotic dosing levels. For those receptors to the left of D2, there are also potentially clinically relevant receptor actions even at doses below those for treating psychosis. The receptors to the right of D2 are occupied at a level of less than 60% at antipsychotic dosing levels. Those that are within an order of magnitude of potency of D2 are shown to the right of D2, and have potentially relevant clinical action despite lower levels of occupancy than D2 receptors, with declining occupancy levels as the receptor is listed further to the right, and also at lower than antipsychotic dosing levels. The point is really that no two atypical antipsychotics have exactly the same pharmacologic binding profiles, even though many of their properties overlap. The distinctive pharmacologic properties of each atypical antipsychotic are worth noting in order to match the best antipsychotic agent to each individual patient.

The pines (peens)

Clozapine

Clozapine, a serotonin 5HT2A–dopamine D2 antagonist or serotonin–dopamine antagonist (SDA) (Figure 5-45) is considered to be the “prototypical” atypical antipsychotic, and has one of the most complex pharmacologic profiles of any of the atypical antipsychotics. Although antipsychotics are generally dosed so that about 60% of D2 receptors are occupied (Figure 5-23), this may be lower for clozapine for unknown reasons. Clozapine was the first antipsychotic to be recognized as “atypical” and thus to cause few if any extrapyramidal side effects, not to cause tardive dyskinesia, and not to elevate prolactin. Despite its complex pharmacology, these atypical properties were linked particularly to the presence of serotonin 5HT2A antagonism added to the dopamine D2 antagonism of conventional antipsychotics, and this has become the prototypical binding characteristic of the entire class of atypical antipsychotics, namely 5HT2A antagonism combined with D2 antagonism. Interesting, however, is how complex the binding pattern is for all the various receptors for clozapine (Figure 5-45) and how clozapine actually has higher potency for so many of them than it even does for D2 receptors!



Figure 5-45. Clozapine's pharmacological and binding profile. The most prominent binding properties of clozapine are represented here; this is perhaps one of the most complex binding portfolios in all of psychopharmacology. Clozapine's binding properties vary greatly with technique and species and from one laboratory to another. This icon portrays a qualitative consensus of current thinking about the binding properties of clozapine, which are constantly being revised and updated. In addition to serotonin 5HT2A–dopamine D2 antagonism (SDA properties), numerous other binding properties have been identified for clozapine, most of which are more potent than its binding at the D2 receptor. It is unknown which of these contribute to clozapine's special efficacy or to its unique side effects.

Clozapine, however, is the one atypical antipsychotic recognized as particularly effective when other antipsychotic agents have failed, and is thus the “gold standard” for efficacy in schizophrenia. It may have a particular niche in treating aggression and violence in psychotic patients. It is unknown what pharmacologic property accounts for this gold-standard enhanced efficacy of clozapine, but it is unlikely to be simply 5HT2A antagonism, since clozapine can show greater efficacy than other atypical antipsychotics that share this pharmacologic property. Although patients treated with clozapine may occasionally experience an “awakening” (in the Oliver Sachs sense), characterized by return to a near-normal level of cognitive, interpersonal, and vocational functioning, and not just significant improvement in positive symptoms of psychosis, this is unfortunately rare. The fact that awakenings can be observed at all, however, gives hope for the possibility that a state of wellness might some day be achieved in schizophrenia by the right mix of pharmacologic mechanisms. Awakenings have been observed on rare occasions in association with treatment with other atypical antipsychotics, but almost never in association with conventional antipsychotic treatment.

Clozapine is also the only antipsychotic that has been documented to reduce the risk of suicide in schizophrenia. Clozapine may actually reduce tardive dyskinesia severity in some patients with this problem, especially over long treatment intervals. Although certainly a 5HT2A–D2 antagonist, the mechanism of clozapine's apparently enhanced efficacy profile compared to other antipsychotics remains the topic of vigorous debate. Obviously, it is beyond just the 5HT2A–D2 antagonism shared by many agents, but the question remains: is it the unique cluster of receptor binding properties of clozapine or some as yet unknown mechanism of clozapine that accounts for its robust efficacy?

Clozapine is also the antipsychotic associated with greatest risk of developing a life-threatening and occasionally fatal complication called agranulocytosis, in 0.5–2% of patients. Because of this, patients must have their blood counts monitored for as long as they are treated with clozapine. Clozapine also has an increased risk of seizures, especially at high doses. It can be very sedating, can cause excessive salivation, has an increased risk of myocarditis, and is associated with the greatest degree of weight gain and possibly the greatest cardiometabolic risk among the antipsychotics. Thus, clozapine may have the greatest efficacy but also the most side effects among the atypical antipsychotics.

Because of these side-effect risks, clozapine is not considered to be a first-line treatment, but is used when other antipsychotics fail. The mechanisms of clozapine's ability to cause agranulocytosis, myocarditis, and seizures are entirely unknown, although the weight gain may be associated with its blockade of both H1-histamine and 5HT2C receptors (Figures 5-29A5-365-39A). Sedation is probably linked to clozapine's potent antagonism of M1-muscarinic, H1-histaminic, and α1-adrenergic receptors (Figures 5-365-39A5-40A). Profound muscarinic blockade can also cause excessive salivation, especially at higher doses, as well as severe constipation, even leading to bowel obstruction from paralytic ileus. Clozapine is among the antipsychotics most notable for increasing cardiometabolic risks, including increases in fasting plasma triglyceride levels and increases in insulin resistance by an unknown but postulated pharmacologic mechanism (receptor X in Figure 5-42). Because of these side effects and the hassle of arranging for blood counts, the use of clozapine is low in clinical practice, perhaps too low. It is important not to lose the art of how to prescribe clozapine and for whom, as clozapine remains a powerful therapeutic intervention for many patients.

Olanzapine

Although this agent has a chemical structure related to clozapine and is also an antagonist at both serotonin 5HT2A and dopamine D2 receptors, olanzapine is more potent than clozapine, and has several differentiating pharmacologic (Figure 5-46) and clinical features. Olanzapine is “atypical” in that it generally lacks EPS not only at moderate antipsychotic doses, but usually even at higher antipsychotic doses. Olanzapine lacks the extreme sedating properties of clozapine, but can be somewhat sedating in some patients, as it does have antagonist properties at M1-muscarinic, H1-histaminic, and α1-adrenergic receptors (Figures 5-365-39A5-40A). Olanzapine does not often raise prolactin levels with long-term treatment. Olanzapine is consistently associated with weight gain, perhaps because of its antihistaminic and 5HT2C antagonist properties (Figures 5-36 and 5-46). It ranks among the antipsychotics with the greatest known cardiometabolic risks, as it robustly increases fasting triglyceride levels and increases insulin resistance by an unknown pharmacologic mechanism postulated to be active for some atypical antipsychotics in at least some patients (receptor X in Figures 5-42 and 5-46).



Figure 5-46. Olanzapine's pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about the binding properties of olanzapine. It has a complex pharmacology that somewhat overlaps with that of clozapine. Olanzapine binds at several receptors more potently than it does at the D2 receptor; in fact, it has strongest potency for the histamine H1 and serotonin 5HT2Areceptors. Olanzapine's 5HT2C antagonist properties may contribute to its efficacy for mood and cognitive symptoms, although together with its H1 antihistamine properties they could also contribute to its propensity to cause weight gain. As with all atypical antipsychotics discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated.

Olanzapine tends to be used in most patients in clinical practice in higher doses (> 15 mg/day) than originally studied and approved for marketing (10–15 mg/day), since there is the sense that higher doses might be associated not only with greater efficacy (i.e., improvement of clinical symptoms) but also with greater effectiveness (i.e., clinical outcome based upon the balance of safety and efficacy), especially in institutional settings where the dose can exceed 40 mg/day off-label. Olanzapine improves mood not only in schizophrenia but also in bipolar disorder and in treatment-resistant depression, particularly when combined with antidepressants such as fluoxetine. Perhaps the 5HT2C antagonist properties, with the weaker 5HT7 and α2 antagonist properties of olanzapine (Figures 5-36 and 5-46), especially when combined with the 5HT2C antagonist properties of the antidepressant fluoxetine (see Chapter 7), may explain some aspects of olanzapine's apparent efficacy for mood symptoms.

For patients with significant weight gain or who develop significant cardiometabolic risks, such as dyslipidemia (elevated fasting triglycerides) or diabetes, olanzapine may be considered a second-line agent. Olanzapine can, however, be considered an appropriate choice for patients when agents with lower propensity for weight gain or cardiometabolic disturbances fail to achieve sufficient efficacy, as olanzapine can often have greater efficacy than some other agents in some patients, particularly at higher doses and for patients seen in institutional settings. The decision to use any atypical antipsychotic requires monitoring not only of efficacy but also of risks, including cardiometabolic risks, and is a tradeoff between risks and benefits that must be determined for each individual patient and for each individual drug. Olanzapine is available as an oral disintegrating tablet, as an acute intramuscular injection, and as a long-acting 4-week intramuscular depot.

Quetiapine

Quetiapine also has a chemical structure related to clozapine, and is an antagonist at both serotonin 5HT2A and dopamine D2 receptors, but has several differentiating pharmacologic properties, especially at different doses and with different oral formulations (Figure 5-47). The net pharmacologic actions of quetiapine are actually due to the combined pharmacologic actions not only of quetiapine itself but also of its active metabolite, norquetiapine. Norquetiapine has unique pharmacologic properties compared to quetiapine, especially norepinephrine transporter (NET) inhibition (i.e., norepinephrine reuptake inhibition), but also 5HT7, 5HT2C, and α2 antagonism as well as 5HT1A partial agonist actions, all of which may contribute to quetiapine's overall clinical profile, especially its robust antidepressant effects (Figure 5-47). Quetiapine has an overall very complex set of binding properties to numerous neurotransmitter receptors, many of which have higher potency than to the D2 receptor, and this may account for why this drug appears to be far more than simply an antipsychotic.



Figure 5-47. Quetiapine's pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about the binding properties of quetiapine plus norquetiapine. Quetiapine does not actually have particularly potent binding at D2 receptors. Quetiapine's prominent H1 antagonist properties probably contribute to its ability to enhance sleep, and this may contribute as well to its ability to improve sleep disturbances in bipolar and unipolar depression as well as in anxiety disorders. However, this property can also contribute to daytime sedation, especially combined with M1antimuscarinic and α1-adrenergic antagonist properties. Recently, a potentially important active metabolite of quetiapine, norquetiapine, has been identified; norquetiapine may contribute additional actions at receptors, as noted in the binding profile with an asterisk. 5HT1A partial agonist actions, norepinephrine transporter (NET) inhibition, and 5HT2C antagonist actions may all contribute to mood-improving properties as well as to cognitive enhancement by quetiapine. However, 5HT2C antagonist actions combined with H1 antagonist actions may contribute to weight gain. Muscarinic cholinergic antagonist actions cause anticholinergic side effects. As with all atypical antipsychotics discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated.

Different drug with different formulations? Quetiapine is a very interesting agent, since it acts like several different drugs, depending upon the dose and the formulation. Quetiapine comes in an immediate-release (IR) formulation and in an extended-release (XR) formulation. The IR formulation has a relatively rapid onset and short duration of action, although most patients only need to take it once a day, and they usually take it at night because quetiapine is most sedating at its peak delivery shortly after taking it, due in large part to its antihistamine properties. In some ways, this makes an ideal hypnotic but not an ideal antipsychotic.

At 300 mg per day, probably the lowest effective antipsychotic dose, quetiapine IR rapidly occupies more than 60% of D2 receptors, sufficient for antipsychotic action, but then quickly falls below 60% D2receptor occupancy (Figure 5-48A). This means that the antipsychotic effect may wear off after a few hours, or require dosing more than once daily or very high doses to sustain adequate D2 receptor occupancy above 60% for a full day, as its plasma drug levels fall off rapidly (Figure 5-48A). By contrast, at 300 mg per day, the XR formulation of quetiapine more slowly hits its peak, yet has a rapid enough onset of 60% D2 occupancy to be effective without the same amount of sedation as quetiapine IR, and its duration of action above the 60% threshold is several hours longer than quetiapine IR (Figure 5-48A).



Figure 5-48. Estimated striatal D2 receptor occupancy at different doses of quetiapine. The estimated striatal D2 receptor occupancy binding for quetiapine differs with both the dose and the formulation. (A) At 300 mg of the immediate-release (IR) formulation, D2 receptor occupancy peaks quickly at approximately 90% and then drops fairly rapidly. At 300 mg of the extended- release (XR) formulation, D2receptor occupancy peaks at approximately 80% after 6 hours, and then exhibits a more gradual decline of the next 18 hours. (B) At 800 mg of the IR formulation, D2 receptor occupancy peaks early at nearly 100% and then drops fairly rapidly, although not as drastically as at the lower dose. At 800 mg of the XR formulation, D2 receptor occupancy peaks above 90% after 6 hours and then exhibits a slow decline to approximately 70% over the next 18 hours.

At the maximum dose of quetiapine generally used except for treatment-resistant cases, 800 mg of quetiapine IR still only occupies D2 receptors for about 12 hours above the 60% threshold, risking breakthrough symptoms at the end of the day, but quetiapine XR maintains fully effective D2 occupancy until the next dose 24 hours later (Figure 5-48B). The XR formulation is thus ideal for an antipsychotic, with less peak-dose sedation but duration of action lasting all day; however, the XR formulation is not ideal for a hypnotic, because the peak is much delayed from the time when the patient takes the pill, delaying sleep onset, with a good deal of residual drug present when the patient wakes up, increasing the chances of causing hangover effects.

Different drug at different doses? If the pharmacology of D2 partial agonists such as aripiprazole is the tale of Goldilocks, as discussed above, then the story of quetiapine dosing is the story of the three bears (Figure 5-49). The antipsychotic quetiapine is an 800 mg Papa Bear, ideally in the XR formulation. The antidepressant quetiapine is a 300 mg Mama Bear, also ideally in the XR formulation. The sedative hypnotic quetiapine is a 50 mg Baby Bear, ideally in the IR formulation. Higher and higher doses not only occupy more and more D2 receptors, but also recruit the blockade of additional receptors, moving to the right along the line of receptors at the bottom of Figure 5-47 as the dose goes up. The lowest doses act at the receptors that have the highest affinity for quetiapine (to the left in the line of receptors at the bottom of Figure 5-47).



Figure 5-49. Binding profile of quetiapine at different doses. The binding properties of quetiapine vary depending on the dose used. At antipsychotic doses (i.e., up to 800 mg/day), quetiapine has a relatively wide binding profile, with actions at multiple serotonergic, muscarinic, and α-adrenergic receptors. Histamine 1 receptor blockade is also present. At antidepressant doses (i.e., approximately 300 mg/day), the binding profile of quetiapine is more selective and consists primarily of actions at D2, 5HT2A, 5HT2C, and 5HT1A receptors as well as inhibition of the norepinephrine transporter. At sedative-hypnotic doses (i.e., 50 mg/day), the most prominent pharmacological property of quetiapine is histamine 1 antagonism.

Starting with Baby Bear, only the most potent binding properties of quetiapine to the far left in the strip at the bottom of Figure 5-47 are relevant, especially H1 antihistaminic properties. With the IR formulation, almost all H1receptors are blocked within minutes of oral administration (Figure 5-50A), increasing the chances of rapid onset of sleep, whereas with the XR formulation (Figure 5-50B), this peak is not reached until it is almost time to wake up, assuming quetiapine is taken at bedtime. Also, with the IR formulation, quetiapine rapidly declines in terms of H1 occupancy, diminishing the chances of a hangover (Figure 5-50A), but this is just the opposite for the XR formulation (Figure 5-50B). Baby Bear doses are not approved for use as a hypnotic, and this can be an expensive option with metabolic risks, so is not considered a first-line option for sleep. Note that with either formulation, only a very small number of the antidepressant-related receptors 5HT2C and norepinephrine transporter are blocked, theoretically insufficient for antidepressant efficacy. Also, the amount of D2 occupancy is far below the 60% threshold, so this is insufficient for antipsychotic efficacy as well.



Figure 5-50. Binding profile of quetiapine with different doses and formulations. (A, B) The estimated receptor occupancy for quetiapine IR and XR at 50 mg/day is shown here. Although quetiapine binds to multiple receptors at this dose, its most prominent action is at histamine 1 receptors, thus explaining its use as a sedative-hypnotic at this dose. (C, D) At antidepressant doses, histamine 1 and 5HT2Aantagonism are the most prominent binding properties of both quetiapine IR and XR, with additional binding at D2 receptors, the norepinephrine transporter, and 5HT2C receptors. (E, F) At antipsychotic doses, the strongest binding properties of quetiapine IR and XR are also histamine 1 and 5HT2A antagonism. However, occupancy at the D2 receptor, norepinephrine transporter, and 5HT2C receptor is greater than at lower doses.

Mama Bear is the surprise bear in many ways. Although developed as an antipsychotic, quetiapine was anecdotally observed to have antidepressant effects in bipolar and unipolar depressed patients, beyond helping them sleep, and in the absence of psychotic symptoms. Over time, clinical trials have repeatedly demonstrated that in the 300 mg range, quetiapine has some of the most robust antidepressant effects of any agent in bipolar depression. At first, this did not make any sense pharmacologically for a 5HT2A–D2 antagonist with antihistaminic properties, but then the active metabolite norquetiapine was discovered with its norepinephrine reuptake blocking and 5HT2Cantagonist properties, much greater than for the parent quetiapine itself. These two mechanisms can individually increase the release of both dopamine and norepinephrine, and together appear to have synergistic actions at doses below those that cause 60% D2 occupancy (Figure 5-50C and D). In addition, quetiapine has 5HT1A partial agonist, 5HT7, α2, and 5HT1B/D antagonist properties, also theoretically linked to antidepressant actions. These multiple concomitant pharmacological actions theoretically have accounted for ushering in the arrival of antidepressant quetiapine, a 300 mg Mama Bear. This constitutes a big paradigm shift for a drug originally developed as an antipsychotic for schizophrenia. Although both the IR (Figure 5-50C) and XR (Figure 5-50D) formulations appear to have antidepressant efficacy, the XR formulation has more consistent day-long receptor occupancy of both 5HT2Creceptors and norepinephrine transporters as well as other key receptors, and may thus be theoretically the preferred formulation for the treatment of depression. Quetiapine is approved both for bipolar depression and as an augmenting agent to SSRIs/SNRIs in unipolar depression that fails to respond sufficiently to SSRI/SNRI monotherapy. Thus, the combination of quetiapine with these other antidepressants in unipolar treatment-resistant depression would have the triple monoamine actions of increasing serotonin (via SSRI/SNRI actions), dopamine, and norepinephrine (the latter two neurotransmitters theoretically via quetiapine/norquetiapine 5HT2C antagonist actions plus both quetiapine and SNRI prefrontal cortex NET blockade), while simultaneously treating symptoms of insomnia and anxiety by antihistaminic action (Figure 5-50C and D).

Finally, Papa Bear is 800 mg quetiapine, which completely saturates both H1-histamine and 5HT2A receptors continuously in both cases, but has more consistent occupancy above 60% for D2 receptors with the XR formulation (compare Figure 5-50E and F). Substantial occupancy of the antidepressant-related receptors also occurs with either formulation, but this amount of 5HT2C and norepinephrine transporter blockade is not necessary for antidepressant actions, since most studies show that even 300 mg once a day has the same antidepressant efficacy as 600 mg. The 800 mg dose (Figure 5-50E and F) is really an antipsychotic dose, and potentially excessive and less well tolerated for the treatment of depression.

No matter what the dose or the formulation, quetiapine is “very atypical” in that it causes virtually no EPS at any dose, nor prolactin elevations. Thus, quetiapine tends to be a preferred atypical antipsychotic for patients with Parkinson's disease who require treatment for psychosis (as is clozapine). Quetiapine can cause weight gain, particularly when given in moderate to high doses, as it blocks histamine 1 receptors (Figure 5-47); the 5HT2C antagonist actions of its active metabolite norquetiapine may contribute to weight gain at moderate to high doses of quetiapine (Figure 5-47). Quetiapine can increase fasting triglyceride levels and insulin resistance, particularly at moderate to high doses, and with intermediate to high risk compared to other atypical antipsychotics, possibly via the same unknown pharmacologic mechanism postulated to be active for some other atypical antipsychotics (receptor X in Figures 5-42 and 5-47).

Asenapine

Asenapine is one of the newer atypical antipsychotics (Figure 5-51). It has a chemical structure related to the antidepressant mirtazapine and shares several of mirtazapine's pharmacological binding properties, especially 5HT2A, 5HT2C, H1, and α2 antagonism, plus many other properties that mirtazapine does not have, especially D2 antagonism, as well as actions upon many additional serotonin receptor subtypes (Figure 5-51). This suggests that asenapine would be an antipsychotic with antidepressant actions, but only antipsychotic/antimanic actions have been proven.



Figure 5-51. Asenapine's pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about the binding properties of asenapine. Asenapine has a complex binding profile, with more potent binding at multiple serotonergic and dopaminergic receptors than it has at D2 receptors. In particular, 5HT2C antagonist properties may contribute to its efficacy for mood and cognitive symptoms, while 5HT7 antagonist properties may contribute to its efficacy for mood, cognitive, and sleep symptoms. As with all atypical antipsychotics discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated.

Asenapine is unusual in that it is given as a sublingual formulation, because active drug is very poorly bioavailable if asenapine is swallowed, due to extensive first-pass metabolism. The surface area of the oral cavity for oral absorption may limit the size of the dose and the extent of drug absorption at high doses, so asenapine is generally taken twice a day despite a long half-life. Since asenapine is rapidly absorbed sublingually with rapid peak drug levels, unlike similar oral formulations of other antipsychotics such as olanzapine that simply dissolve rapidly in the mouth but are followed by delayed absorption, theoretical considerations and anecdotal observations suggest that asenapine can be used as a rapid-acting oral PRN (as needed) antipsychotic to “top up” some psychotic and disturbed patients rapidly without resorting to an injection. One side effect of sublingual administration in some patients is oral hypoesthesia; also, patients may not eat or drink for 10 minutes following sublingual administration, to avoid the drug being washed out of oral absorption sites and into the stomach, where extensive first-pass metabolism will cause minimal active drug bioavailability. Asenapine can be sedating, especially upon first dosing, but does not have a high propensity either for EPS or for weight gain/dyslipidemia despite its 5HT2C antagonist plus weaker antihistaminic properties.

The antagonist actions of asenapine at 5HT2C, 5HT7, 5HT1B/D, and α2 receptors with partial agonist actions at 5HT1A receptors, as well as anecdotal clinical reports, support the prospects of demonstrating antidepressant properties for asenapine. That is, antagonist action at 5HT2C receptors releases dopamine and norepinephrine in prefrontal cortex, which would hypothetically improve depression. The mechanism of this is shown in Figures 5-52Aand 5-52B. Serotonin input to 5HT2C receptors on GABA interneurons – both in the brainstem and in the prefrontal cortex – normally causes GABA release onto norepinephrine and dopamine neurons, which then inhibits the release of norepinephrine and dopamine out of these neurons in prefrontal cortex. These 5HT2C actions at the brainstem level are shown in Figure 5-52A. When these 5HT2C receptors are blocked, norepinephrine and dopamine release is disinhibited in prefrontal cortex, which theoretically has an antidepressant effect (Figure 5-52B). Established antidepressants such as agomelatine and mirtazapine and others have 5HT2C antagonist properties.



A. Serotonin inhibits norepinephrine and dopamine release. Normally, serotonin binding at 5HT2C receptors on γ-aminobutyric acid (GABA) interneurons (bottom red circle) inhibits norepinephrine and dopamine release in the prefrontal cortex (top red circles).



B. 5HT2C antagonist disinhibits norepinephrine and dopamine release. When a 5HT2C antagonist binds to 5HT2C receptors on γ-aminobutyric acid (GABA) interneurons (bottom red circle), it prevents serotonin from binding there and thus prevents inhibition of norepinephrine and dopamine release in the prefrontal cortex; in other words, it disinhibits their release (top red circles).

Figure 5-52

Not only does asenapine (like other atypical antipsychotics) have 5HT2C antagonist actions (Figure 5-51), it also has numerous other potent pharmacologic actions linked theoretically to antidepressant actions that are predicted to raise norepinephrine, serotonin, and dopamine levels via α2 antagonism (see Chapter 7) and to potentiate the elevation of serotonin levels in the presence of serotonin reuptake blockade by an SSRI/SNRI via 5HT1B/D as well as 5HT7 antagonism (see Chapter 7). These same binding properties and actions on monoamines of asenapine in preclinical models also suggest theoretical utility for negative symptoms of schizophrenia, and an early study in fact suggested better efficacy than a comparator for treatment of negative symptoms, but this has not been replicated. The compelling theoretical antidepressant pharmacologic profile of asenapine also remains to be studied adequately in patients with either treatment-resistant depression or bipolar depression.

Zotepine

Zotepine is an atypical antipsychotic available in Japan and Europe, but not in the US. Zotepine has a chemical structure related to clozapine, but with some distinguishing pharmacologic (Figure 5-53) and clinical properties. Although classified usually as an atypical antipsychotic, some EPS have nevertheless been observed, as have prolactin elevations. Like clozapine, there is an increased risk of seizures, especially at high doses, as well as weight gain and sedation. Zotepine probably increases risk for insulin resistance, dyslipidemia, and diabetes, but it has not been extensively studied for these side effects. Unlike clozapine, however, there is no clear evidence yet that zotepine is as effective for patients who fail to respond to conventional antipsychotics. Zotepine dose dependently prolongs QTc interval and is generally administered three times daily. Zotepine is a 5HT2C antagonist, an α2 antagonist, a 5HT7antagonist, and a weak partial agonist of 5HT1A receptors as well as a weak inhibitor of norepinephrine reuptake (NET or norepinephrine transporter) (Figure 5-53), suggesting potential antidepressant effects that have not been well established yet in clinical trials.



Figure 5-53. Zotepine's pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about the binding properties of zotepine. 5HT2C and histamine 1 antagonist properties can contribute to weight gain, H1 and α1-adrenergic antagonist properties can contribute to sedation, and 5HT2C and 5HT7 antagonist properties suggest possible efficacy for mood symptoms. As with all atypical antipsychotics discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated.

The dones

Risperidone

This agent is a “done” and thus has a different chemical structure and a different pharmacologic profile than the “pines” (compare Figure 5-24A and B; see Figure 5-54). Risperidone has atypical antipsychotic properties especially at lower doses, but can become more “conventional” at high doses in that EPS can occur if the dose is too high. Risperidone thus has favored uses in schizophrenia and bipolar mania at moderate doses, but also for other conditions where lower or moderate doses of antipsychotics can be used, such as for children and adolescents with psychotic disorders. Risperidone is approved for treatment of irritability associated with autistic disorder in children and adolescents (ages 5–16), including symptoms of aggression towards others, deliberate self-injury, tantrums, and quickly changing moods, for bipolar disorder (ages 10–17), and for schizophrenia (ages 13–17). Low-dose risperidone is occasionally used “off-label” for the controversial – due to a “black box” safety warning – treatment of agitation and psychosis associated with dementia. This occurs despite the fact that elderly patients with dementia-related psychosis treated with any atypical antipsychotic are at increased risk of death compared to placebo, even though that overall risk is low. Obviously, the risks versus benefits must be weighed for each patient carefully prior to prescribing an atypical antipsychotic for any use. Risperidone is available in a long-term depot injectable formulation lasting for 2 weeks. Such dosage formulations may improve treatment adherence, and if adherence is enhanced may lead to better long-term outcomes. There are also an orally disintegrating tablet and liquid formulation of risperidone.



Figure 5-54. Risperidone's pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about the binding properties of risperidone. Alpha-2 (α2) antagonist properties may contribute to efficacy for depression, but this can be diminished by simultaneous α1 antagonist properties, which can also contribute to orthostatic hypotension and sedation. As with all atypical antipsychotics discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated.

Although “atypical” in terms of reduced EPS at lower doses, risperidone does raise prolactin levels even at low doses. Risperidone has a moderate amount of risk for weight gain and dyslipidemia. Weight gain can be particularly a problem in children.

Paliperidone

Paliperidone, the active metabolite of risperidone, is also known as 9-hydroxy-risperidone, and it is an atypical antipsychotic with serotonin 5HT2A and dopamine D2 receptor antagonism (Figure 5-55). The binding profile of paliperidone (Figure 5-55) is similar to that of risperidone (Figure 5-54). One pharmacokinetic difference, however, between risperidone and paliperidone is that paliperidone is not hepatically metabolized; its elimination is based upon urinary excretion, and it thus has few pharmacokinetic drug interactions. Another pharmacokinetic difference is that the oral form of paliperidone is provided in a sustained-release formulation, which risperidone is not, and this actually changes some of the clinical characteristics of paliperidone compared to risperidone, a fact that is not always well recognized and can lead to underdosing of oral paliperidone. Oral sustained-release means that paliperidone only needs to be administered once a day, whereas risperidone, especially when treatment is initiated, and especially in children or the elderly, may need to be given twice daily to avoid sedation and orthostasis. Side effects of risperidone may be related in part to the rapid rate of absorption and higher peak doses with greater drug-level fluctuation leading to shorter duration of action, properties that are eliminated by the controlled-release formulation of paliperidone.



Figure 5-55. Paliperidone's pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about the binding properties of paliperidone, the active metabolite of risperidone. Paliperidone shares many pharmacological properties with risperidone. As with all atypical antipsychotics discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated.

Despite the similar receptor binding characteristics of paliperidone and risperidone, paliperidone tends to be more tolerable, with less sedation, less orthostasis, and fewer EPS, although this is based upon anecdotal clinical experience and not head-to-head clinical studies. Paliperidone may have weight gain, insulin resistance, and diabetes associated with its use as well as elevations of plasma prolactin, much the same risk as risperidone.

The fact that paliperidone is an active metabolite of a known antipsychotic in a controlled-release formulation may lead some clinicians to erroneously believe that there are only trivial differences between paliperidone and risperidone, that they are essentially the same drugs, and that they should be similarly dosed, with the same mg dosing and the same up-titration when initiated. When this is done in clinical practice, this can lead to the false perception that paliperidone is not as effective as risperidone, but that problem can often be alleviated by recognizing that 1 mg of paliperidone is not equal to 1 mg of risperidone. A common mistake is to start patients on 3 mg of paliperidone, incorrectly assuming that it requires up-titration like risperidone and that 3 mg of paliperidone is more or less the same as 3 mg of risperidone. Actually, 6 mg paliperidone is a better starting dose and is generally well tolerated. An increase to 9 mg starting the second week of treatment on day 8, or even to 12 mg starting the third week of treatment on day 15, can result in optimal efficacy for paliperidone. Additional dosing tips are possibly to start a higher dose of paliperidone (9 mg) if the patient is at imminent risk of relapse, or if the patient has always needed higher doses of antipsychotics, or if the patient has persistent troublesome symptoms despite relatively high doses of the previous antipsychotic. On the other hand, lower doses (e.g., 3 mg daily) may be useful if the patient is very sensitive to side effects, at least at the start of dosing.

A depot palmitate formulation of paliperidone for long-term administration every 4 weeks is available and has become popular as the currently preferred depot atypical antipsychotic without the need to have oral treatment at the beginning of injections plus an injection every 2 weeks like long-acting risperidone injectable. The depot formulation of paliperidone also lacks the potential problems with severe sedation and monitoring recommended for long-acting olanzapine 4-week injectable. Although depot antipsychotics have always been more popular in some European countries than in the US, now that atypical antipsychotics such as paliperidone are becoming available as depot formulations, US clinicians are beginning not only to utilize them more, but to change their targeted patient types, from only administering depots to the most chaotic, least adherent patients, to using them for patients early after the onset of psychosis. Assured adherence with a more tolerable depot atypical antipsychotic rather than a depot conventional antipsychotic early in the illness has the potential to lead to more favorable outcomes.

Ziprasidone

Ziprasidone is another atypical antipsychotic with a novel pharmacological profile (Figure 5-56). The major differentiating feature of ziprasidone is that it has little or no propensity for weight gain, despite its moderate 5HT2C and H1antagonist actions (Figure 5-56). Furthermore, there seems to be little association of ziprasidone with dyslipidemia, elevation of fasting triglycerides, or insulin resistance. In fact, when patients who have developed weight gain and dyslipidemia from high-risk antipsychotics are switched from those antipsychotics to ziprasidone, there can be weight loss, and often lowering of fasting triglycerides, while continuing to receive treatment with ziprasidone. The pharmacologic properties that make ziprasidone different in terms of its lower cardiometabolic risk are unknown, but could be explained if ziprasidone lacks the ability to bind to receptors postulated to mediate insulin resistance and hypertriglyceridemia.



Figure 5-56. Ziprasidone's pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about the binding properties of ziprasidone. This compound seems to lack the pharmacological actions associated with weight gain and increased cardiometabolic risk such as increasing fasting plasma triglyceride levels or increasing insulin resistance. Ziprasidone also lacks many of the pharmacological properties associated with significant sedation. As with all atypical antipsychotics discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated.

Ziprasidone is unusual as well because of the way it is dosed, namely twice a day and with food. Failure to give with about a 500 calorie meal can result in lowering oral absorption by half and inconsistent efficacy. Earlier concerns about dangerous QTc prolongation by ziprasidone now appear to be unjustified. Unlike iloperidone, zotepine, sertindole, and amisulpride, ziprasidone does not cause dose-dependent QTc prolongation, and few drugs have the potential to increase ziprasidone's plasma levels. Any antipsychotic that prolongs QTc interval – and this includes several conventional and atypical antipsychotics – should be given cautiously to patients receiving other drugs known to prolong QTc interval, but routine EKGs are generally not recommended. It is obviously prudent to be cautious when using any atypical antipsychotic or psychotropic drug in patients with cardiac problems, or in patients taking other drugs that affect cardiac function, or in those with a history of syncope or a family history of sudden death, and this is part of the routine risk–benefit calculation that is made for each individual patient prior to prescribing any of the atypical antipsychotic drugs. Ziprasidone has an intramuscular dosage formulation for rapid use in urgent circumstances.

Ziprasidone has several pharmacologic properties suggesting it might have antidepressant actions, including 5HT2C, 5HT7, 5HT1B/D, and α2 antagonism and 5HT1A partial agonism, and weak norepinephrine and serotonin reuptake blockade (Figure 5-56), but has never been proven to have antidepressant actions in large clinical trials.

Iloperidone

Iloperidone is one of the newer atypical antipsychotics with 5HT2A–D2 antagonist properties (Figure 5-57). Its most distinguishing clinical properties include a very low level of EPS, a low level of dyslipidemia, and a moderate level of weight gain associated with its use. Its most distinguishing pharmacology property is its potent α1 antagonism. As discussed earlier in this chapter, α1 antagonism is generally associated with the potential for orthostatic hypotension and sedation, especially if rapidly dosed. Although iloperidone has an 18- to 33-hour half-life that theoretically supports once-daily dosing, it is generally dosed twice daily and titrated over several days when initiated in order to avoid both orthostasis and sedation. Slow dosing can delay onset of antipsychotic effects, so iloperidone is often used as a switch agent in non-urgent situations.



Figure 5-57. Iloperidone's pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about the binding properties of iloperidone. Among the atypical antipsychotics, iloperidone has one of the simplest pharmacological profiles and comes closest to a serotonin–dopamine antagonist (SDA). Its other prominent pharmacological property is potent α1antagonism, which may be responsible for the risk of orthostatic hypotension but also may contribute to its low risk of EPS. As with all atypical antipsychotics discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated.

Although it is unknown why iloperidone, like quetiapine and clozapine, has such a low incidence of EPS, it may be in part due to the fact that all three of these agents have a high affinity for α1 receptors as well as for 5HT2Areceptors (Figure 5-40). Theoretically, low EPS has been linked to high affinity for 5HT2A (Figure 5-24), 5HT1A (Figure 5-26), and muscarinic cholinergic receptors (Figure 5-39), as discussed earlier in this chapter. Actions at α1receptors are correlated mostly with side effects such as sedation and orthostasis (Figures 5-38 and 5-40). More recently, however, central α1 receptors have been linked to potential therapeutic effects such as improvement in nightmares by the α1 antagonist prazosin in posttraumatic stress disorder (PTSD) (discussed in Chapter 9 on anxiety) and maybe even reduction of EPS. The latter possibility is suggested by the fact that preclinical studies show that norepinephrine acting at postsynaptic α1 receptors (Figure 5-58A) can stimulate the same pyramidal neurons in prefrontal cortex that serotonin acting at postsynaptic 5HT2A receptors stimulates (Figure 5-15A). By analogy, therefore, if blocking 5HT2A receptors reduces EPS by the downstream actions of such neurons (Figure 5-15B), it may be possible that blocking α1 receptors on these same neurons would also reduce EPS (Figure 5-58B). This possibility is supported by the fact that clozapine (Figure 5-45) and iloperidone (Figure 5-57) both have the highest binding potencies of α1 antagonism relative to D2 antagonism among all the atypical antipsychotics; quetiapine (Figure 5-47) also has potent α1 properties. All three of these agents exhibit few if any EPS in clinical use, although other atypical antipsychotics with higher EPS rates also have high α1 receptor binding (Figure 5-40). Perhaps the combination of high 5HT2A and α1 affinities is a plausible explanation in particular for the low EPS of iloperidone and clozapine, but this is unproven and requires further research. Clinical use of atypical antipsychotics with high binding to α1 receptors such as iloperidone for nightmares in PTSD is also theoretically appealing but requires much more clinical research.



A. Cortical α1 receptor stimulation may decrease dopamine release. (1) Noradrenergic projections from the locus coeruleus to the cortex synapse with glutamatergic pyramidal neurons, where norepinephrine binds to α1receptors on the cortical glutamate neuron. (2) This causes glutamate release in the brainstem, which in turn causes GABA release in the substantia nigra, inhibiting dopaminergic neurons and therefore decreasing dopamine release into the striatum (indicated by the dotted outline of the dopaminergic neuron).



B. Blocking cortical α1 receptors may increase dopamine release. (1) When α1 receptors on glutamatergic pyramidal neurons are blocked, this inactivates the glutamatergic neuron (indicated by the dotted outline of the glutamatergic neuron). (2) Glutamate release into the brainstem is therefore reduced and does not stimulate GABA release (indicated by the dotted outline of the GABA neuron). Without inhibitory input from GABA, dopaminergic neurons projecting from the substantia nigra to the striatum are activated and dopamine is released.

Figure 5-58

In addition to potent α1 antagonist properties, and very potent 5HT2A antagonism relative to D2 antagonism, iloperidone also has moderate α2, 5HT1B/D, and 5HT7 antagonist and 5HT1A partial agonist actions, suggesting potential antidepressant effects. However, there are no large-scale clinical studies of iloperidone yet in depression and it remains unproven as an antidepressant. Iloperidone exhibits dose-dependent QTc prolongation. There may be moderate weight gain with iloperidone but a low incidence of dyslipidemia. A 4-week depot preparation is in clinical testing.

Lurasidone

Lurasidone is one of the newer atypical antipsychotics with 5HT2A–D2 antagonist properties (Figure 5-59). This compound exhibits high affinity for both 5HT7 and 5HT2A receptors, as well as moderate affinity for 5HT1A and α2receptors, yet minimal affinity for H1-histamine and M1-cholinergic receptors, properties that may explain some of lurasidone's clinical profile. It is an effective antipsychotic generally without sedation (especially if dosed at night), and along with ziprasidone and aripiprazole, has little or no weight gain or dyslipidemia. In fact, as with these other drugs, when a patient is switched to lurasidone from a previous agent associated with weight gain and dyslipidemia, such side effects may reverse. For the usual patient, there is little or no sedation, so the starting dose of 40 mg is an effective antipsychotic dose, although studies suggest that for maximum long-term efficacy, doses up to 160 mg per day may be useful in some patients, and in certain cases may possibly be more effective than some other antipsychotics. There may be moderate EPS with lurasidone, but this is reduced if lurasidone is given at night. As with ziprasidone, absorption of lurasidone is much greater when it is taken with 500 calories of food, which is recommended for consistent results. There is no QTc prolongation. Large-scale clinical trials show robust antidepressant efficacy in bipolar depression, and in addition trials are ongoing in mixed depression (depression with subsyndromal symptoms of mania). The receptor binding profile of lurasidone at 5HT7, 5HT1A, and α2 receptors theoretically suggests why this drug has apparent antidepressant efficacy.



Figure 5-59. Lurasidone's pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about the binding properties of lurasidone. Among the atypical antipsychotics, lurasidone has a relatively simple pharmacological profile. It binds most potently to the D4 receptor, the effects of which are not well understood, and to the 5HT7 receptor, which may contribute to efficacy for mood, cognitive, and sleep symptoms. As with all atypical antipsychotics discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated.

The potential antidepressant effects of 5HT7 antagonism (Figures 5-60 and 5-61) may be theoretically relevant to several atypical antipsychotics including lurasidone. It may also be relevant to the action of several known antidepressants, as discussed in Chapter 7. Briefly, 5HT7 receptors are located both on GABA neurons in the raphe and in the prefrontal cortex (Figures 5-60A and 5-61A). In both brain regions, stimulation of 5HT7 receptors by serotonin is thought to release GABA (Figures 5-60B and 5-61B). In the brainstem, 5HT7 receptor stimulation serves as a negative feedback loop and turns off further serotonin release (Figure 5-60B). In the cortex, stimulation of 5HT7 receptors excites the GABA interneurons, and this in turn inhibits pyramidal neurons in the cortex, reducing their release of glutamate downstream (Figure 5-61B).



A. Function of 5HT7 receptors in the raphe nucleus. Shown here is a serotonergic neuron projecting from the raphe nucleus to the prefrontal cortex (PFC), where it releases serotonin. The release of serotonin is regulated in part by GABAergic neurons within the raphe nucleus that contain 5HT7 receptors.



B. Stimulation of 5HT7 receptors in the raphe nucleus reduces serotonin release. When serotonin binds to 5HT7 receptors on GABAergic interneurons within the raphe nucleus, this activates the GABA neuron (indicated by the red color of the neuron) to release GABA. GABA then inhibits serotonergic projections from the raphe nucleus to the prefrontal cortex, thus reducing serotonin release there (indicated by the dotted outline of the serotonin neuron).



C. Blockade of 5HT7 receptors in the raphe nucleus increases serotonin release. If 5HT7 receptors on GABAergic interneurons in the raphe nucleus are blocked, then GABA release is inhibited (indicated by the dotted outline of the GABA neuron). Without the presence of GABA, the serotonergic projection from the raphe nucleus to the prefrontal cortex can become overactivated (indicated by the red color of the neuron), leading to increased serotonin release in the prefrontal cortex.

Figure 5-60



A. Function of 5HT7 receptors in the prefrontal cortex. A major function of 5HT7 receptors may be to regulate serotonin–glutamate interactions. Serotonergic projections from the raphe nucleus to the prefrontal cortex synapse with GABAergic interneurons that contain 5HT7 receptors. The GABAergic neurons, in turn, synapse with glutamatergic pyramidal neurons.



B. Stimulation of 5HT7 receptors in the prefrontal cortex reduces glutamate release from pyramidal neurons. Serotonin binds to 5HT7 receptors on GABA interneurons in the prefrontal cortex. This stimulates GABA release (indicated by the red color of the neuron), which in turn inhibits glutamate release (indicated by the dotted outline of the glutamatergic neuron).



C. Blockade of 5HT7 receptors in the prefrontal cortex increases glutamate release from pyramidal neurons. If 5HT7 receptors on GABAergic interneurons in the prefrontal cortex are blocked, then GABA release is inhibited (indicated by the dotted outline of the GABA neuron). Without the presence of GABA, glutamatergic pyramidal neurons in the prefrontal cortex can become overactivated (indicated by the red color of the neuron), leading to increased glutamate release.

Figure 5-61

On the other hand, blocking 5HT7 receptors in the brainstem raphe prevents their inhibition by GABA, and thus leads to increased release of serotonin from those raphe neurons, wherever they project, theoretically causing an antidepressant action (Figure 5-60C). This enhancement of serotonin release is increased in the presence of serotonin reuptake blockade in animals, suggesting a role for 5HT7antagonists in augmenting SSRIs/SNRIs in depression/anxiety.

Blocking 5HT7 receptors in the prefrontal cortex causes less inhibition of certain populations of pyramidal neurons there and thus more downstream glutamate release from them (Figure 5-61C). There is potentially a wide variety of functional consequences of 5HT7 antagonism, which in experimental animals appear to be pro-cognitive, antidepressant, and synchronizing of circadian rhythms (Figure 5-61C). It is unknown yet whether these actions occur in human patients, as selective 5HT7 agents have not been widely tested in man, and the actions that many atypical antipsychotics with 5HT7 antagonist properties may have on mood and cognition in patients are only now being explored and are not yet proven. However, 5HT7 receptor antagonism remains a very plausible theoretical explanation for lurasidone's apparent antidepressant actions in bipolar depression, and suggests potential clinical efficacy in unipolar and treatment-resistant depression as well.

Two pips and a rip

Aripiprazole

This agent is a D2 dopamine receptor partial agonist (DPA, D2 partial agonist), a major differentiating pharmacologic feature compared to serotonin dopamine antagonists that are silent antagonists at D2receptors (Figures 5-35 and 5-62). Because of its D2 partial agonist actions, aripiprazole is theoretically an atypical antipsychotic with reduced EPS and hyperprolactinemia despite not having 5HT2Aantagonist properties at higher affinity than its affinity for D2receptors (i.e., 5HT2A lies to the right of D2, unlike almost every other atypical antipsychotic in Figure 5-24). In addition, aripiprazole has 5HT1Apartial agonist actions that are more potent than its 5HT2A antagonist actions, but less potent than its D2 binding affinity (Figure 5-62), and this property hypothetically contributes to its atypical antipsychotic clinical properties, as discussed earlier in this chapter.



Figure 5-62. Aripiprazole's pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about the binding properties of aripiprazole. Aripiprazole differs from most other antipsychotics in that it is a partial agonist at D2 receptors rather than an antagonist. Additional important pharmacological properties that may contribute to its clinical profile include 5HT2A antagonist actions, 5HT1A partial agonist actions, and 5HT7 antagonist actions. Aripiprazole lacks or has weak binding potency at receptors usually associated with significant sedation. Aripiprazole also seems to lack the pharmacologic actions associated with weight gain and increased cardiometabolic risk, such as increasing fasting plasma triglyceride levels or increasing insulin resistance. As with all atypical antipsychotics discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated.

Aripiprazole is effective in treating schizophrenia and mania, and is also approved for use in various child and adolescent groups, including schizophrenia (age 13 and older), acute mania/mixed mania (age 10 and older), and autism-related irritability in children ages 6–17. Aripiprazole lacks the pharmacologic properties normally associated with sedation, namely, M1-muscarinic cholinergic and H1-histaminic antagonist properties, and thus is not generally sedating. A major differentiating feature of aripiprazole is that it has, like ziprasidone and lurasidone, little or no propensity for weight gain, although weight gain without dyslipidemia can be a problem for some, including children and adolescents. Furthermore, there seems to be little association of aripiprazole with dyslipidemia, elevation of fasting triglycerides, or insulin resistance. In fact, as with ziprasidone and lurasidone, when patients with weight gain and dyslipidemia caused by other antipsychotics switch to aripiprazole, there can be weight loss and lowering of fasting triglyceride levels. The pharmacologic properties that make aripiprazole different in terms of its lower metabolic risk are unknown, but could be explained if aripiprazole lacks the ability to bind to postulated receptors that mediate insulin resistance and hypertriglyceridemia (Figure 5-42).

Aripiprazole is approved as an antidepressant for augmenting SSRIs/SNRIs in treatment-resistant major depressive disorder, and although not specifically approved, is often used as well in bipolar depression. How aripiprazole works in depression as compared to how it works in schizophrenia is of course unknown, but its potent 5HT1A partial agonist and 5HT7 antagonist properties are theoretical explanations for potential antidepressant actions, as these would be active at the low doses generally used to treat depression. It is also possible that partial agonist actions at both D2 and D3 receptors mean that aripiprazole could act more as an agonist than as an antagonist at dopamine receptors at low doses, in fact slightly boosting rather than blocking hypothetically deficient dopamine neurotransmission in depression, but this is unproven.

So, is aripiprazole the perfect “Goldilocks” D2 partial agonist? Some believe it is “too hot,” meaning that it is too much of an agonist and not enough of an antagonist, and that aripiprazole would thus be optimized if it were more of an antagonist, noting that aripiprazole can sometimes have dopamine agonist-like actions, such as being activating in some patients, causing mild agitation instead of tranquilization and antipsychotic actions, and can also cause nausea and occasionally vomiting. Also, high doses of aripiprazole sometimes do not seem to deliver sufficient antipsychotic efficacy in some very difficult-to-treat patients; in some psychotic cases, higher doses beyond a certain point are no more effective or even slightly less effective than somewhat lower doses. Such observations suggest that aripiprazole could be improved in those patients by greater antagonist actions, with closer placement towards the full antagonist part of the left hand of the spectrum shown in Figure 5-35.

On the other hand, some believe that aripiprazole is “too cold,” meaning that it is too much of an antagonist because it can have antagonist-like actions such as causing akathisia in some patients, which is often decreased by dose reduction or by administering an anticholinergic agent or a benzodiazepine. In this case, aripiprazole might be improved by closer placement towards the agonist part of the spectrum shown in Figure 5-35. The truth is that there is no Goldilocks drug that fits every patient. In late-stage clinical development are drugs that are both more antagonist on the spectrum than aripiprazole (see the discussions of brexpiprazole and cariprazine that follow, and Figure 5-35). Soon there may be a portfolio of partial agonist options to customize the needs of individual patients, since one size cannot fit all.

An intramuscular dosage formulation of aripiprazole for short-term use is available, as are an orally disintegrating tablet and a liquid formulation. A long-acting 4-week injectable is in the late stages of clinical development and is eagerly awaited as another potential atypical antipsychotic depot option for assuring adherence, especially in early-onset psychosis where aripiprazole's favorable tolerability profile may be particularly well received.

Brexpiprazole

Just as its name suggests, brexpiprazole is chemically related to aripiprazole. It differs from aripiprazole in several ways from a pharmacologic perspective (compare Figures 5-63 and 5-62). Brexpiprazole is still in late-stage clinical trials, so the clinical correlates of these pharmacological differences are only now being established. Firstly, brexpiprazole is more of a D2 antagonist than aripiprazole, moving it to the left towards the full antagonist part of the spectrum in Figure 5-35. Secondly, brexpiprazole has more potent 5HT2A antagonism, 5HT1A partial agonism, and α1 antagonism relative to its D2 partial agonism (Figure 5-63) than aripiprazole (Figure 5-62), which should theoretically enhance its atypical antipsychotic properties and reduce EPS despite its being more of a D2 antagonist than aripiprazole. Clinical trials in fact confirm this so far, as there is a very low incidence of EPS and only rare akathisia for brexpiprazole. This must be confirmed in large-scale trials now in progress. Brexpiprazole would be predicted to have antipsychotic and antimanic activity like aripiprazole, but with perhaps a more favorable tolerability profile. Its 5HT1A partial agonist and 5HT7 antagonist properties (Figure 5-63) also suggest antidepressant actions like aripiprazole. Finally, brexpiprazole is a potential treatment for agitation and psychosis in dementia, but a good deal of clinical testing will be necessary to confirm both its efficacy and its safety for this application.



Figure 5-63. Brexpiprazole's pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about the binding properties of brexpiprazole. Brexpiprazole has a pharmacological profile similar to that of aripiprazole: it is a partial agonist at D2 receptors rather than an antagonist, and also binds potently to 5HT2A, 5HT1A, and 5HT7 receptors. Brexpiprazole also seems to lack actions at receptors usually associated with significant sedation, weight gain, and increased cardiometabolic risk, although it is too early to evaluate the clinical profile of this medication. As with all atypical antipsychotics discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated.

Cariprazine

Cariprazine is another dopamine D2 partial agonist in late-stage clinical testing for schizophrenia, acute bipolar mania, bipolar depression, and treatment-resistant depression. Cariprazine is more of an antagonist at D2 receptors than aripiprazole, moving it towards the antagonist end of the spectrum in Figure 5-35. However, cariprazine is also less of an agonist than the related partial agonist bifeprunox, an agent that did not receive FDA approval as it had clinical effects consistent with being too much of an agonist – namely, less efficacy than comparator antipsychotics, too activating, too slow dose titration, and too much nausea and vomiting. In theory, cariprazine may be preferred at higher doses for mania and schizophrenia, to emphasize its antagonist actions, and at lower doses for depression, to emphasize its agonist actions and potentially its uniquely D3-preferring properties. Dosing, efficacy, and side effects are still under investigation, but little weight gain or metabolic problems have been identified thus far. This compound has two very long-lasting active metabolites with the novel and interesting potential for development as a weekly, biweekly, or even monthly “oral depot.”

Cariprazine so far shows a low incidence of EPS in clinical testing, perhaps because it has potent 5HT1A partial agonist actions and lesser 5HT2A antagonism (Figure 5-64). At higher doses cariprazine could potentially block 5HT7 and 5HT2C receptors for hypothetical antidepressant actions. At very low doses there are interesting theoretical possibilities suggested by cariprazine's unique D3-preferring over D2affinity, with both actions being partial agonist actions rather than antagonist actions (Figure 5-64). The role of D3 receptors is largely unknown but may be linked to cognition, mood, emotions, and reward/substance abuse. It has been difficult to dissect the role of D2receptors from D3 receptors, since essentially all antipsychotics act at both receptors, with the clinical effects attributed to their D2 actions. However, with cariprazine, there is a window of selectivity for D3 actions at low doses where D3 receptors are preferentially occupied (Figure 5-64), and this creates the theoretical opportunity to determine whether D3-preferring actions have a different clinical profile than the D2 (plus D3) actions of all other antipsychotics.



Figure 5-64. Cariprazine's pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about the binding properties of cariprazine. Cariprazine has potent actions at D3, 5HT2B, D2, and 5HT1A receptors, with relatively weaker affinity for 5HT2A and H1 receptors. As with all atypical antipsychotics discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated.

The others

Sulpiride

Sulpiride is an earlier compound structurally related to amisulpride that was developed as a conventional antipsychotic (Figure 5-65). Although it generally causes EPS and prolactin elevation at usual antipsychotic doses, it may be activating and have efficacy for negative symptoms of schizophrenia and for depression at low doses, where it is D3-preferring. This agent, if a D2 partial agonist, is likely to have pharmacologic properties very, very close to those of a silent antagonist and may only function as a partial agonist at low doses and as a more conventional D2 antagonist at higher, antipsychotic doses (Figure 5-35).



Figure 5-65. Sulpiride's pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about the binding properties of sulpiride. At usual doses, sulpiride has the profile of a conventional antipsychotic, but at low doses it may be a partial agonist at D2 receptors, though likely still closer to the antagonist end of the spectrum. As with all atypical antipsychotics discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated.

Amisulpride

Amisulpride, like sulpiride, was developed in Europe and elsewhere prior to full appreciation of the concept of dopamine partial agonism. Thus, it has not been tested in the same preclinical pharmacology systems as newer agents, but there are some clinical hints not only that amisulpride is an atypical antipsychotic, but that it has these clinical properties because it is a partial agonist very close to the full antagonist end of the D2 spectrum (Figure 5-35). Amisulpride has no appreciable affinity for 5HT2A or 5HT1A receptors to explain its low propensity for EPS and its observations of improvement of negative symptoms in schizophrenia and of depression, particularly at low doses, but it is an antagonist at 5HT7 receptors (Figure 5-66). Like all antipsychotics, it is not known how amisulpride's actions at D3 receptors may contribute to its clinical profile.



Figure 5-66. Amisulpride's pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about the binding properties of amisulpride. Amisulpride does not have affinity for 5HT2A or 5HT1A receptors, but it may be a partial agonist at D2 receptors rather than an antagonist. As with all atypical antipsychotics discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated.

Amisulpride's ability to cause weight gain, dyslipidemia, and diabetes has not been extensively investigated. It causes dose-dependent QTc prolongation. Since amisulpride can cause prolactin elevation, if it is appropriately classifiable as a partial agonist at all, it is likely closer to a silent antagonist than aripiprazole on the partial agonist spectrum, and it may only function as a partial agonist at low doses and a more conventional D2 antagonist at high doses (see Figure 5-35).

Sertindole

Sertindole is an atypical antipsychotic with serotonin 5HT2A–dopamine D2 receptor antagonist properties (Figure 5-67), originally approved in some European countries, then withdrawn for further testing of its cardiac safety and QTc-prolonging potential, and then reintroduced into certain countries as a second-line agent. It may be useful for some patients in whom other antipsychotics have failed, and who can have close monitoring of their cardiac status and drug interactions.



Figure 5-67. Sertindole's pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about the binding properties of sertindole. Potent antagonist actions at α1receptors may account for some of sertindole's side effects. As with all atypical antipsychotics discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated.

Perospirone

Perospirone is an atypical antipsychotic with 5HT2A and D2 antagonist properties available in Japan (Figure 5-68). 5HT1A partial agonist actions may contribute to its efficacy. Its ability to cause weight gain, dyslipidemia, insulin resistance, and diabetes are not well investigated. It is generally administered three times a day, with more experience in the treatment of schizophrenia than in the treatment of mania.



Figure 5-68. Perospirone's pharmacological and binding profile. This figure portrays a qualitative consensus of current thinking about the binding properties of perospirone. 5HT1A partial agonist actions may contribute to efficacy for mood and cognitive symptoms. As with all atypical antipsychotics discussed in this chapter, binding properties vary greatly with technique and from one laboratory to another; they are constantly being revised and updated.

Antipsychotics in clinical practice

Prescribing antipsychotics in clinical practice can be very different than studying them in clinical trials. Real patients are often more complicated, may have diagnoses that do not meet diagnostic criteria for the formally studied indications, and generally have much more comorbidity than patients studied in clinical trials. Thus, it is important for the practicing psychopharmacologist to appreciate that different atypical antipsychotics can have clinically distinctive effects in different patients in clinical practice and that these are not always well studied in randomized controlled trials. What this also means is that median clinical effects in clinical trials may not be the best indicator of the range of clinical responses possible for individual patients. Furthermore, optimal doses suggested from clinical trials often do not match optimal doses used in clinical practice (too high for some drugs, too low for others). Finally, although virtually all studies are head-to-head comparisons of monotherapies and/or placebo, many patients receive two antipsychotics or antipsychotics plus other psychotropic drugs in clinical practice settings. Sometimes this is rational and justified, but sometimes it is not. Here we will briefly discuss some of the issues that arise when trying to apply knowledge about the pharmacological mechanisms of action discussed so far in this chapter to the clinical utilization of atypical antipsychotics in clinical practice.

The art of switching antipsychotics

It might seem that it would be easy to switch from one antipsychotic to another, but this has proven to be problematic for many patients. Switching antipsychotics actually requires skill to convert patients from one agent to another. Otherwise, patients can develop agitation, activation, insomnia, rebound psychosis, and withdrawal effects, especially anticholinergic rebound, if it is done too quickly or without finesse, especially if one tries to precipitously stop one antipsychotic and start the other at full dose (Figure 5-69). Of course, this must occasionally be done under urgent circumstances when there is not the time to more carefully transition from one drug to another. Full doses can be given to patients who are not taking any antipsychotic at the time when one is started, but in a switch scenario, some form of transition is usually necessary in order for the clinical situation to stay stable or improve, and the best results are usually obtained by cross-titration over several days to weeks (Figure 5-70). This creates concomitant administration of two antipsychotics for a while as one goes up and the other goes down in dose, and this is acceptable and in fact desirable polypharmacy until the transition is complete (Figure 5-70).



Figure 5-69. How not to switch antipsychotics. Converting patients from one antipsychotic to another requires great care in order to ensure that they do not develop withdrawal symptoms, rebound psychosis, or aggravation of side effects. Generally, this means not precipitously discontinuing the first antipsychotic, not allowing gaps between the administration of the two antipsychotics, and not starting the second antipsychotic at full dose.



Figure 5-70. Switching from one antipsychotic to another. When switching from one antipsychotic to another, it is frequently prudent to “cross-titrate” – that is, to build down the dose of the first drug while building up the dose of the other over a few days to a few weeks. This leads to transient administration of two drugs but is justified in order to reduce side effects and the risk of rebound symptoms, and to accelerate the successful transition to the second drug.

Sometimes the transition between two similar agents can take a long time; nevertheless it is important to complete the transition and not get caught in cross-titration as shown in Figure 5-71. Sometimes as the dose of the second drug goes up and the dose of the first drug comes down, the patient begins to do better, and the clinician just stops without completing the transition to a full dose of the second agent and complete discontinuation of the first. That is not generally recommended, since a full trial on the second agent is the goal, and long-term polypharmacy of two agents is not well studied and can be quite expensive. If the second agent is not satisfactory, it is generally preferable to try a third (Figure 5-70) rather than use two agents together indefinitely in what can be unacceptable polypharmacy (Figure 5-71).



Figure 5-71. Getting trapped in cross-titration. When switching from one atypical antipsychotic to another, the patient may improve in the middle of cross-titration. Polypharmacy results if cross-titration is stopped at this point and the patient continues both drugs indefinitely. It is generally better to complete the cross titration as shown in Figure 5-70, with discontinuation of the first agent and an adequate monotherapy trial of the second drug before trying long-term polypharmacy.

Switching between two agents that have similar pharmacology is generally easiest, fastest, and has the fewest complications, namely a pine to a pine, or a done to a done, over as little as a week's time (Figure 5-72). However, problems can occur if the switch is too fast from a pine to a done (Figure 5-73). As discussed extensively in this chapter, the binding characteristics of pines and dones are different, the most striking difference being that the pines in general have more anticholinergic and antihistaminic actions (Figure 5-39), and more α1 antagonist actions (Figure 5-40), and thus are in general more sedating than the dones, which have less potent binding at these sites.



Figure 5-72. Switching from one pine or done to another. (A) When switching from one “pine” (clozapine, olanzapine, quetiapine, asenapine) to another, it is prudent to make the switch in as little as 1 week, while keeping estimated D2 receptor occupancy constant. (B) Likewise, when switching from one “done” (risperidone, paliperidone, ziprasidone, iloperidone, lurasidone) to another, it is prudent to make the switch in as little as 1 week, while keeping estimated D2 receptor occupancy constant.



Figure 5-73. Switching from a pine to a done. When switching from a “pine” (clozapine, olanzapine, quetiapine, asenapine) to a done (risperidone, paliperidone, ziprasidone, iloperidone, lurasidone), it is prudent to take at least 2 weeks to stop the pine, while keeping the estimated D2 receptor occupancy constant during the addition of the done.

Therefore, when switching from a pine to a done, it is generally a good idea to stop the pine slowly – over at least 2 weeks – to allow the patient to readapt to the withdrawal of blocking cholinergic, histaminic, and α1receptors, which makes the transition more tolerable without anticholinergic rebound, agitation, and insomnia (Figure 5-73). When stopping the specific pine clozapine, it should always be stopped very slowly, over 4 weeks or more if possible, to minimize the chances of rebound psychosis as well as anticholinergic rebound (Figure 5-74).



Figure 5-74. Stopping clozapine. When stopping clozapine, it is always necessary to do so slowly, with 4 weeks of down-titration prior to starting another antipsychotic.

When switching in the other direction, namely, from a done to a pine, it is generally best to titrate up the pine over 2 weeks or more, although the done can usually be stopped as quickly as over 1 week. This allows the patient to become tolerant to the sedating effects of most pines (Figure 5-75).



Figure 5-75. Switching from a done to a pine. When switching from a “done” (risperidone, paliperidone, ziprasidone, iloperidone, lurasidone) to a “pine” (clozapine, olanzapine, quetiapine, asenapine), tolerability may be best if the pine can be titrated up over the course of 2 weeks, while keeping the estimated D2 receptor occupancy constant as the done is stopped.

Switching to and from aripiprazole is a special case, in part because it has different pharmacologic properties, and in part because it has higher potency for the D2 receptor than many other drugs, meaning that its administration causes essentially immediate withdrawal of the first drug from D2 receptors. These principles are likely to be applicable to the new “pip and a rip” (namely, brexpiprazole and cariprazine), as they both have similar binding characteristics and D2 potencies, and are D2 partial agonists, but there is little experience as yet with switching to or from either brexpiprazole or cariprazine.

Switching to aripiprazole

Specifically, when switching to aripiprazole from a pine, it can be a good idea in many patients to start a middle, and not a low, dose when adding aripiprazole, building the aripiprazole dose up rapidly over 3–7 days while taking 2 weeks to taper the pine (Figure 5-76). The recommendation for fast up-titration of aripiprazole arises from the fact that it essentially replaces the first drug at the D2 receptor immediately, and it can be helpful therefore to get aripiprazole to its therapeutic dose rapidly. The slower down-titration of the pine allows readaptation of cholinergic and histaminergic receptors to minimize withdrawal, and the taper also allows slower offset of any sedating actions while the full dose of aripiprazole is being established (Figure 5-76). When switching to aripiprazole from a done (Figure 5-77), it can also be helpful to start a middle, not a low, dose of the aripiprazole, and build it up rapidly over 3–7 days, but it is possible to taper the done over 1 week, since the dones are less likely to be associated with anticholinergic and antihistaminic withdrawal symptoms.



Figure 5-76. Switching to aripiprazole from a pine. Aripiprazole has higher affinity for D2 receptors than most “pines” (clozapine, olanzapine, quetiapine, asenapine); thus, breakthrough symptoms may be more likely when switching from a pine to aripiprazole. A prudent approach, therefore, is to start aripiprazole at a middle dose, rather than a low dose, while down-titrating the pine slowly over 2 weeks.



Figure 5-77. Switching to aripiprazole from a done. When switching to aripiprazole from a “done” (risperidone, paliperidone, ziprasidone, iloperidone, lurasidone), it is recommended to start aripiprazole at a middle dose, rather than a low dose, while down-titrating the done over 1 week.

Switching from aripiprazole

In the other direction, when stopping aripiprazole and switching to a pine, consider immediately stopping the aripiprazole, which has not only high potency for D2 receptors but a very long half-life (more than 2 days), while starting a middle, and not a low, dose of the pine, tapered up over 2 weeks (Figure 5-78). When switching from aripiprazole to a done, also consider immediately stopping the aripiprazole, and starting a middle, and not a low, dose of the done, tapered up over 1 week (Figure 5-79).



Figure 5-78. Switching from aripiprazole to a pine. When switching from aripiprazole to a “pine” (clozapine, olanzapine, quetiapine, asenapine), it is recommended to stop aripiprazole immediately and start the pine at a middle, rather than a low, dose. The pine can be up-titrated over a period of 2 weeks.



Figure 5-79. Switching from aripiprazole to a done. When switching from aripiprazole to a “done” (risperidone, paliperidone, ziprasidone, iloperidone, lurasidone), it is recommended to stop aripiprazole immediately and start the done at a middle, rather than a low, dose. The done can be up-titrated over a period of 1 week.

These are very basic generalities that certainly do not apply in all situations for all antipsychotics discussed here, but may be useful guidelines based not only on receptor binding properties but also on empiric clinical experience. In many individual cases, switching may need to be even slower than illustrated here – but generally not faster, unless encountering clinically urgent circumstances.

Treatment resistance and violence

Although this chapter has discussed the well-researched and approved uses of antipsychotics in schizophrenia, namely as monotherapies at extensively studied doses with documented safety and efficacy in standard patient populations participating in clinical trials, what do you do when the antipsychotic is not working? This is often called treatment-resistant psychosis, and it can be characterized by delusions and hallucinations and thought disorder; that is, predominantly positive symptoms that do not respond to standard doses of several trials of individual conventional or atypical antipsychotics. Treatment guidelines suggest the use of clozapine at this point. However, what if clozapine does not work or you cannot prescribe it for medical reasons, or if the patient refuses it?

And what if the problem is aggressive symptoms, hostility, impulsivity, and even violence unresponsive to standard doses of several different antipsychotics or even clozapine? This is a common problem in institutional and forensic settings, and treatment guidelines from large-scale multicenter trials do not provide specific recommendations for these clinical scenarios. Principles of psychopharmacology coupled with case-based evidence do provide some potential solutions for treatment resistance with or without violence; however, these solutions are controversial to some experts and not based on traditional evidence since such patients for ethical and practical reasons (formal legal incompetence and institutionalization, etc.) cannot be studied in randomized controlled trials. Nevertheless, high dosing, use of two concomitant antipsychotics, and augmentation of an antipsychotic with a mood stabilizer are all commonly used in clinical practice as solutions for treatment resistance and violence. Is this rational or justified?

The rationale for treating violence when antipsychotic monotherapies fail is shown in Figure 5-80, and is based upon the specific hypothetical etiology of aggression and violence. Thus, violence that is linked to psychotic behavior despite standard antipsychotic dosing may be caused by inadequate occupancy of D2 receptors due to pharmacokinetic failure (Figures 5-80 and 5-81). That is, ideal pharmacokinetics are assumed at standard doses to attain 60% or more striatal D2 occupancy, but if drug is not adequately absorbed or is excessively metabolized, it can cause a pharmacokinetic failure (Figure 5-81). The formal diagnosis of this is possible by measuring therapeutic drug concentrations and documenting that they are low. The treatment solution is to raise the dose above the standard dose in order to compensate for the low amount of drug getting to D2 receptors. One can also document that plasma drug levels are increased to the normal range when this otherwise high dose is given (Figure 5-81). In the case of pharmacokinetic failures, a high dose is really a standard dose for such patients, as it just takes more peripherally administered oral antipsychotic to attain the standard amount of D2 occupancy (Figure 5-81).



Figure 5-80. Psychopharmacologic targeting of circuits associated with violence. Violent behavior can be associated with circuits that are relevant to schizophrenia, and may therefore be targeted by psychopharmacologic strategies that target those circuits. The mesolimbic and mesocortical pathways, which are thought to be responsible for positive and negative symptoms, may also be involved in aggression and violence. It is possible that agents targeting much more than 60% D2 receptor occupancy in these pathways could reduce these symptoms. Likewise, the orbitofrontal cortex and the amygdala may play a role in impulsive aggression, which could theoretically be alleviated by agents targeting much more than 60% D2 receptor occupancy. Affective symptoms that may contribute to violent behavior may be mediated by the ventromedial prefrontal cortex and could potentially be treated with mood stabilizers. Finally, instrumental aggression and violent sociopathy may be mediated by the dorsolateral prefrontal cortex, and may best be managed with behavioral strategies, including seclusion and incarceration.



Figure 5-81. Treatment resistance or pharmacokinetic failure. In general, D2 receptor occupancy greater than 80% is needed in the mesolimbic pathway for antipsychotic effects, while D2 occupancy greater than 80% in the dorsal striatum is associated with extrapyramidal side effects (EPS) and D2 occupancy greater than 80% in the pituitary is associated with hyperprolactinemia. However, although the majority of patients may achieve 80% D2 receptor occupancy in the mesolimbic pathway and 60% D2 receptor occupancy in the striatum with standard doses of antipsychotics, this may not be true for all patients. That is, pharmacokinetic factors may influence how much drug reaches the target receptor. For instance, individuals with certain CYP450 variants may be rapid metabolizers of certain medications, and thus never get adequate D2 receptor occupancy from standard doses. Low drug levels may also occur due to poor drug absorption, which may be the case for patients with gastric bypass, lap bands, ileostomies, colectomies, or for unknown reasons. Food can also affect the absorption of certain antipsychotics. If standard dosing attains less than 80% D2 receptor occupancy in the mesolimbic region or 60% D2 receptor occupancy in the striatum, then such doses may not be effective no matter how many drugs one tries. To that end, pharmacokinetic failure may be suspected for patients who do not respond to a sequence of monotherapies and also do not have side effects. This can be confirmed by measurement of therapeutic drug levels; if confirmed, higher than usual doses would be justified.

Although some patients have pharmacokinetic failures to explain their lack of treatment response, many have instead what can be called pharmacodynamic failures: that is, they fail to have adequate clinical responses despite attaining 60% or more striatal D2 receptor occupancy. Many potential causes of this are illustrated in Figure 5-80. For example, one cause of antipsychotic treatment failure despite attaining 60% or more striatal D2 occupancy can be that the patient has an affective disturbance that requires augmentation with a mood stabilizer, especially divalproex or lamotrigine, but even lithium or an antidepressant (Figure 5-80). Another cause of antipsychotic treatment failure in such cases can be that some patients are slow responders to 60% striatal D2 receptor occupancy (Figure 5-82). Evidence from long-term clinical trials is accumulating to show that many patients will respond with late onset of efficacy, particularly for remission of psychosis or for improvement of negative symptoms, and after many months of treatment (Figure 5-82). The solution for those patients able to wait for their clinical effects to “kick in” is to use “time as a drug” and treat for many weeks hoping to get a good outcome (Figure 5-83). There is no way to predict who will have such late-onset responses, so finding these patients is largely a matter of trial and error.



Figure 5-82. Time as a drug. It may be that maintaining a patient on the same medication over an extended period of time, rather than switching early, could lead to additional improvement in symptoms.



Figure 5-83. Nonresponse/violence: very long treatment using time as a drug. It is possible that some patients may experience pharmacodynamic failure. For such patients, it may be that the downstream effects of D2blockade take longer to manifest than the typical 6 weeks allotted for a drug trial. For these individuals, time itself may be a therapeutic treatment.

Another potential approach to pharmacodynamic antipsychotic treatment failures is to postulate that some patients require much more than 60% D2 occupancy to have an adequate treatment response (Figures 5-84 through 5-87). Such patients may have psychotic symptoms and/or impulsive symptoms associated with aggression and violence that can require urgent management to prevent harm to others (Figure 5-80). Empirically, patients like this can respond to very high doses associated with high plasma drug levels, and it can be assumed that drugs administered in high doses are occupying more than 60% of D2receptors (Figure 5-84). However, this has never been proven in randomized controlled trials nor quantitatively measured by PET scans. Usually these patients are too disturbed either to give informed consent or to cooperate with research studies, or to receive blinded treatments that may not work, so we only have case-based anecdotes to support this approach. To the extent that case-based evidence can be used to establish treatment recommendations in the absence of controlled trials, it does appear that some patients – those with psychotic or impulsive violence – do indeed respond to high-dose monotherapy (Figure 5-85), and that the tradeoff between side effects and therapeutic actions can be surprisingly in favor of continued high-dose treatment (Figures 5-84 and 5-85).



Figure 5-84. Nonresponse/violence: are hypothetical thresholds for drug effects altered? It is possible that some patients may experience pharmacodynamic failure. For such patients, it may be that they require more than 80% D2 receptor occupancy in the mesolimbic pathway in order to achieve therapeutic effects. This may be true particularly for patients who have failed to respond to multiple, adequately-dosed agents, and who still have aggression or violence. It is possible that, for these patients, using high doses that achieve 80–100% limbic D2 receptor occupancy may be necessary for therapeutic effects.



Figure 5-85. Nonresponse/violence: high to very high doses. Patients who have failed to respond to multiple, adequately dosed agents and who have aggression or violence may have pharmacodynamic failure and require doses that achieve 80–100% striatal D2 receptor occupancy. They may therefore require higher doses beyond the generally recommended range. The evidence base for high-dose monotherapy varies for the different atypical antipsychotics, and there are certain agents for which it may not be appropriate.



Figure 5-86. Nonresponse/violence: hypothetical thresholds for drug effects. Patients who have failed to respond to multiple, adequately-dosed agents and who have aggression or violence may have pharmacodynamic failure and require 80–100% limbic D2 receptor occupancy. This can potentially be achieved by adding a standard dose of a second antipsychotic to a standard dose of the first antipsychotic.



Figure 5-87. Nonresponse/violence: polypharmacy. Patients who have failed to respond to multiple, adequately dosed agents and who have aggression or violence may have pharmacodynamic failure and require 80–100% striatal D2 receptor occupancy. This can potentially be achieved by adding a standard dose of a second antipsychotic to a standard dose of the first antipsychotic. This strategy is not well studied and should truly be reserved for cases in which all else fails.

Another way to target greater than 60% D2 receptor occupancy is to use standard doses of two antipsychotics at the same time, sometimes called antipsychotic polypharmacy (Figures 5-86 and 5-87) rather than high doses of one antipsychotic (Figures 5-84 and 5-85). Because the curve of increasing D2 occupancy is very flat at the upper range of monotherapy dosing (Figure 5-84), it can actually be a more effective approach to give standard doses of two antipsychotics, as the receptor occupancy curve of the second antipsychotic may be steep (Figure 5-86). Some clinicians prefer augmenting clozapine for treatment-resistant cases, and this form of antipsychotic polypharmacy has been studied the most. Others try augmenting an atypical antipsychotic with a conventional antipsychotic, or giving two atypical antipsychotics together. All of these have empiric case-based evidence for improvement of psychosis, aggression, and violence in some patients with schizophrenia, but other patients can have intolerable side effects, most commonly sedation, EPS, and weight gain, but occasionally paralytic ileus (especially with very high-dose pines such as clozapine, quetiapine, and olanzapine), and cognitive dysfunction. Generally speaking, very-high-dose monotherapy or antipsychotic polypharmacy should be used sparingly and in selected cases of treatment resistance, violence, and aggression, and only “when all else fails” – and even in such cases only when demonstrated to be clearly beneficial. Another group of patients for whom pharmacodynamic antipsychotic treatment failures are a problem that should generally not be managed by high-dose monotherapy or antipsychotic polypharmacy consists of those with instrumental aggression related to sociopathy and antisocial personality disorder; no amount of D2 antagonism is likely to help such patients, who may instead need behavioral treatments, seclusion, or even incarceration (Figure 5-80).

Psychotherapy and schizophrenia

Although this is a psychopharmacology textbook, it is increasingly clear that psychotherapies can be combined with antipsychotics to leverage the effectiveness of these agents. Integrating psychopharmacology and psychotherapy in psychotic disorders is an area of growing interest and increasing research and is included in many treatment guidelines for schizophrenia. This includes adding cognitive behavioral psychotherapy to antipsychotics in order to strengthen the patient's capacity for normal thinking using mental exercises and self-observation. If patients can pay attention, learn, and remember, they are able to cope better with residual positive symptoms and are more likely to live an independent life. Patients who are stabilized on antipsychotics are often capable of being taught at that point in their illness to critically analyze hallucinations and examine any underlying beliefs in their hallucinations and delusions.

Family and outside support is critical to foster positive social interactions, which in turn may help to keep delusions under control. Family support is essential for encouraging patients to comply with their antipsychotics and to recognize early signs of relapse or side effects. It also helps family members understand the illness and reduce their own emotional reactions to the patient and this devastating illness, so that their own emotions do not trigger more acting-out by the patient.

Community treatment programs are highly beneficial, helping patients with vocational rehabilitation, finding paid work, enhancing self-esteem, and keeping a job if they have one, even though up to 90% of patients with severe symptoms are unemployed.

Motivational therapies, which assume that the mental health professional does not always know best and solicit active agreement and participation from the patient, have been shown to be effective in schizophrenia.

Cognitive remediation is a novel psychotherapy that is rapidly gaining popularity for the treatment of schizophrenia. It utilizes computerized therapies designed to improve neurocognition in such areas as attention, working memory, cognitive flexibility and planning, and executive capacity, which leads to improved social functioning.

Future treatments for schizophrenia

Glutamate-linked mechanisms and new treatments for schizophrenia

AMPAkines

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptors are one of the glutamate receptor subtypes, and they regulate ion flow and neuronal depolarization that can lead to NMDA (N-methyl-D-aspartate) receptor activation. A number of modulators of the AMPA receptor are under development, including those that do not act directly at the glutamate site of the AMPA receptor, but at positive allosteric modulating (i.e., PAM) sites on this receptor, e.g., CX 516 (Figure 5-88). Sometimes, these AMPA PAMs are also called AMPAkines. Preliminary evidence from animal studies suggests that AMPAkines might enhance cognition, but early results with CX516 in schizophrenia are somewhat disappointing. However, more potent AMPAkines are being developed (CX546, CX619/Org 24448, Org 25573, Org 25271, Org 24292, Org 25501, LY293558) and these might have more efficacy for cognitive symptoms in schizophrenia without showing activation of positive symptoms or neurotoxicity.



Figure 5-88. Novel glutamatergic treatments for schizophrenia: AMPA positive modulator. Positive modulation at postsynaptic AMPA receptors could help regulate ion flow and neuronal depolarization in postsynaptic neurons, leading to appropriate NMDA receptor activation. Also shown postsynaptically are NMDA receptors, kainate receptors, and postsynaptic metabotropic receptors, all for glutamate. Shown presynaptically are the presynaptic reuptake pump for glutamate, the excitatory amino acid transporter (EAAT), the presynaptic metobotropic autoreceptor mGluR2/3, and the synaptic vesicle transporter for glutamate or vGluT.

mGluR presynaptic antagonists/postsynaptic agonists

Another class of glutamate receptor, known as metabotropic glutamate receptors (mGluRs), regulates neurotransmission at glutamate synapses as well (discussed in Chapter 4 and illustrated in Figures 4-22and 4-23). Normally, presynaptic mGluRs act as autoreceptors to prevent glutamate release (Figure 4-23B). Thus, an agent acting at this site as a presynaptic mGluR2/3 agonist (Figure 5-89) could potentially prevent excessive glutamate release from glutamate neurons (Figures 5-90B and 5-91B), as is postulated to occur as the downstream consequence of NMDA hypoactivity (Figures 4-29B5-90A5-91A) and thereby improve the symptoms of schizophrenia. One such compound, LY2140023, has been tested with proof of concept of efficacy in schizophrenia but has been dropped from clinical development.



Figure 5-89. Novel glutamatergic treatments for schizophrenia: presynaptic agonist. Presynaptic metabotropic glutamate receptors (mGluR2/3) act as autoreceptors to prevent glutamate release. Thus, stimulating these receptors could block glutamate release, and thereby decrease activity at postsynaptic glutamate receptors.



A. Hypothetical glutamate signaling abnormality in schizophrenia. Shown here is a close-up of intracortical pyramidal neurons communicating via GABAergic interneurons in the presence of hypofunctional NMDA receptors. (1) Glutamate is released from an intracortical pyramidal neuron. However, the NMDA receptor that it would normally bind to is hypofunctional, preventing glutamate from exerting its effects at the receptor. (2) This prevents GABA release from the interneuron; thus, stimulation of α2 GABA receptors on the axon of another glutamate neuron does not occur. (3) When GABA does not bind to the α2 GABA receptors on its axon, the pyramidal neuron is no longer inhibited. Instead, it is disinhibited and overactive, releasing excessive glutamate into the cortex.



B. Hypothetical mechanism of action of mGluR2/3 agonists in schizophrenia. Metabotropic glutamate 2/3 receptors (mGluR2/3) are presynaptic autoreceptors that act to prevent glutamate release. Thus, mGluR2/3 agonists may be able to reduce excessive downstream glutamate release (3) even in the presence of reduced GABA inhibition of glutamatergic neurons (2) due to hypothetical NMDA receptor activation on GABAergic interneurons (1).



C. Hypothetical mechanism of action of selective glycine reuptake inhibitors (SGRI) in schizophrenia. Another mechanism to reduce excessive glutamate neurotransmission may be to enhance glycine action at hypofunctional NMDA receptors. Glycine is needed, in addition to glutamate, in order to activate NMDA receptors. By blocking its reuptake, more glycine will be available in the synapse to bind to NMDA receptors, which could theoretically enhance their function.

Figure 5-90



A. Hypofunctional NMDA receptors and positive symptoms of schizophrenia. If NMDA receptors on cortical GABA interneurons are hypoactive, then the cortical brainstem glutamate pathway to the ventral tegmental area (VTA) will be overactivated, leading to excessive release of glutamate in the VTA. This will lead to excessive stimulation of the mesolimbic dopamine pathway and thus excessive dopamine release in the nucleus accumbens (indicated by the red color of the dopaminergic neuron). This is the theoretical biological basis for the mesolimbic dopamine hyperactivity thought to be associated with the positive symptoms of psychosis.



B. Hypothetical mechanism of action of mGluR2/3 agonists in schizophrenia. Metabotropic glutamate 2/3 receptors (mGluR2/3) are presynaptic autoreceptors that act to prevent glutamate release. Thus, mGluR2/3 agonists may be able to reduce excessive glutamate release in the ventral tegmental area (VTA). This in turn would prevent excessive stimulation of the mesolimbic dopamine pathway.



C. Hypothetical mechanism of action of selective glycine reuptake inhibitors (SGRI) in schizophrenia. Another mechanism to reduce excessive glutamate neurotransmission may be to enhance glycine action at hypofunctional NMDA receptors. Glycine is needed, in addition to glutamate, in order to activate NMDA receptors. By blocking its reuptake, more glycine will be available in the synapse to bind to NMDA receptors, which could theoretically enhance their function. This would lead to enhanced GABAergic neurotransmission in the cortex, which in turn would reduce glutamatergic neurotransmission (indicated by the dotted outline of the glutamatergic neuron). Reduced glutamate release in the ventral tegmental area (VTA) would prevent excessive stimulation of the mesolimbic dopamine pathway.

Figure 5-91

Glycine agonists

In Chapter 4 we discussed the actions of coagonists at the glycine site of NMDA receptors and illustrated them in Figures 4-204-214-25, and 4-26. Agonists at the glycine site of NMDA receptors include the naturally occurring amino acids glycine and D-serine as well as an analogue of D-serine, called D-cycloserine, which is also active at the glycine coagonist site of NMDA receptors. All of these agents have been tested in schizophrenia, with evidence that they can reduce negative and/or cognitive symptoms (Figure 5-92). Further testing is in progress, and synthetic agonists with greater potency are in discovery. Perhaps stimulating the glycine site will boost NMDA receptor activity in a manner that is sufficient to overcome its hypothetical hypofunction (Figures 4-29B5-90A5-91A) and thereby reduce negative and cognitive symptoms, but possibly even positive symptoms in schizophrenia (Figure 5-92).



Figure 5-92. Novel glutamatergic treatments for schizophrenia: direct acting glycine site agonists. NMDA (N-methyl-D-aspartate) receptors require the presence of both glutamate and a coagonist at the glycine site in order to be fully active. Since schizophrenia may be linked to hypoactive NMDA receptors, agonists at the glycine coagonist site may enhance NMDA functioning. Several agonists at this coagonist site – including glycine, D-serine, and D-cycloserine – have been tested in schizophrenia and indeed show evidence that they can reduce negative and/or cognitive symptoms. Glycine agonists may thus be promising future treatments for negative and cognitive symptoms of schizophrenia without worsening positive symptoms.

GlyT1 inhibitors

In Chapter 4 we also discussed the role of glycine transporters on glial cells, known as GlyT1, in terminating the action of glycine released by glial cells into the synapses to act at the glycine site of NMDA receptors (Figure 4-20). Several GlyT1 inhibitors are now in clinical testing, including the natural agent N-methylglycine, also known as sarcosine, RG1678 (bitopertin), and Org 25935/SCH 900435, as well as others in preclinical testing such as SSR 504734, SSR 241586, and JNJ17305600. GlyT1 inhibitors, sometimes called selective glycine reuptake inhibitors or SGRIs, are analogous to drugs that inhibit reuptake of other neurotransmitters, such as the selective serotonin reuptake inhibitors (SSRIs) and their actions at the serotonin transporter or SERT. When GlyT1 pumps are blocked by a GlyT1 inhibitor, this increases the synaptic availability of glycine, and thus enhances NMDA neurotransmission (Figure 5-93). The downstream consequence of GlyT1 inhibition is to reverse the hypofunctional NMDA receptor (compare Figures 5-90A and 5-90C; also compare Figures 5-91A and 5-91C).



Figure 5-93. Novel glutamatergic treatments for schizophrenia: glycine transporter on glial cells inhibited. The glycine transporter 1 (GlyT1) normally terminates the actions of glycine at NMDA receptors in the glutamate synapse by transporting the glycine back up into glial cells as a reuptake pump. Thus, inhibitors at GlyT1 would increase availability of synaptic glycine, enhancing activity at NMDA receptors. This is analogous to the actions of an SSRI (selective serotonin reuptake inhibitor) at serotonin synapses. GlyT1 inhibition could potentially improve cognitive and negative symptoms of schizophrenia by enhancing the availability of glycine at hypofunctioning NMDA receptors. Preclinical evidence does suggest cognitive improvements with GlyT1 inhibition, and one such naturally occurring inhibitor, sarcosine, has been shown to improve the negative, cognitive, and depressive symptoms of schizophrenia, including symptoms such as alogia and blunted affect.

Sarcosine has been shown to improve negative, cognitive, and depressive symptoms, including symptoms such as alogia and blunted affect in schizophrenia. The SGRI RG1678 (bitopertin) also has reported proof of concept for reduction of both positive and negative symptoms in schizophrenia. The hope is that SGRI type GlyT1 inhibitors will be able to adequately reduce the hypofunctioning of NMDA receptors in order to lead to improvement, particularly in the negative and cognitive symptoms of schizophrenia, perhaps also augmenting the improvement in positive symptoms from treatment with atypical antipsychotics, and thus attain maximum overall efficacy in schizophrenia.

Treatments targeting cognitive symptoms in schizophrenia

Cognitive symptoms of course are not particularly amenable to treatment with the currently marketed antipsychotics, yet cognitive symptoms of schizophrenia are extremely important in determining long-term outcomes in this illness. Thus, a major unmet need in schizophrenia is for an agent that can improve cognitive symptoms and thereby improve functional outcome. There is a long list of agents with a wide variety of pharmacological mechanisms that have been added to antipsychotics in the hope that they would improve cognitive symptoms; to date the results have been largely disappointing. Nevertheless, the targeting of cognitive symptoms with novel therapeutics remains an area of considerable active investigation.

Presymptomatic and prodromal treatments for schizophrenia: putting the cart before the horse or preventing disease progression?

An emerging concept in psychopharmacology is the possibility that treatments that reduce symptoms could also be disease-modifying (Figure 5-94). In this chapter we have discussed almost entirely how atypical antipsychotics treat symptoms of schizophrenia after the illness has fully emerged. However, it is hypothesized that these same agents may also be able to prevent the emergence of schizophrenia when given to high-risk individuals who are either presymptomatic or in a state with only mild prodromal symptoms, and thus prevent or delay progression to schizophrenia.



Figure 5-94. Presymptomatic/prodromal treatment of schizophrenia. The stages of schizophrenia are shown here over a lifetime. The patient often has full functioning (100%) early in life and is virtually asymptomatic (stage I). However, during a prodromal phase (stage II) starting in the teens, there may be odd behaviors and subtle negative symptoms. The acute phase of the illness usually announces itself fairly dramatically in the twenties (stage III), with positive symptoms, remissions, and relapses but never a complete return to previous levels of functioning. This is often a chaotic stage of the illness, with a progressive downhill course. The final phase of the illness (stage IV) may begin in the forties or later, with prominent negative and cognitive symptoms and some waxing and waning during its course, but often more of a burnout stage of continuing disability. There may not necessarily be a continuing and relentless downhill course, but the patient may become progressively resistant to treatment with antipsychotic medications during this stage. An emerging concept in psychopharmacology is that the treatments that reduce symptoms could also be disease-modifying. That is, perhaps these agents given to high-risk individuals either in a presymptomatic (stage I) or prodromal (stage II) state could prevent or delay progression through the subsequent stages of schizophrenia.

Current concepts about the natural history of schizophrenia hypothesize that this illness progresses from a state of high risk without symptoms (presymptomatic), then to a prodrome with cognitive and negative but not psychotic symptoms, and ultimately to first-episode schizophrenia with psychotic symptoms (Figure 5-94). Throughout the field of psychiatry, it is being debated whether remission of symptoms of any psychiatric disorder with psychopharmacological treatments is able to prevent disease progression, possibly by preventing the plastic changes in brain circuits that fully establish and worsen psychiatric disorders. In schizophrenia, therefore the question is whether “prophylactic” antipsychotics can keep you from “catching” schizophrenia.

Pilot results from early intervention studies in first-episode cases of schizophrenia already suggest that treatment with atypical antipsychotics as soon as possible after the onset of first psychotic symptoms can improve outcomes (first-episode treatment in Figure 5-94). What if high-risk patients without any symptoms could be identified from genetic or neuroimaging techniques? How about patients with the prodromal cognitive and negative symptoms that frequently precede the onset of psychotic symptoms? Could treatment of patients at these points prevent the all-too-common long-term course of schizophrenia with waxing and waning positive symptoms and ever-worsening cognitive and negative symptoms (Figure 5-94)?

Early results with atypical antipsychotics are not definitive, although some suggest that treating prodromal symptoms with antipsychotics, antidepressants, or anxiolytics may delay onset of schizophrenia. Other studies do not confirm this, and of course treatments have costs in terms of both money and side effects and at this point cannot be recommended for either presymptomatic or prodromal treatment of psychosis. However, the promise of disease-modifying treatments for psychiatric disorders in general and for schizophrenia in particular is leading to studies that fully investigate this exciting possibility. The validation of diagnostic criteria for early-onset schizophrenia, prodromal schizophrenia, and ultra-high risk for schizophrenia could help determine not only who should be tested with novel potential therapeutic interventions, but also who should avoid high-risk behaviors such as use of marijuana and other drugs of abuse, sleep deprivation, and high-stress activities.

Summary

This chapter has reviewed the pharmacology of antipsychotic drugs, including conventional antipsychotics with dopamine D2 antagonist properties and atypical antipsychotic drugs with dopamine D2antagonist, 5HT2A antagonist, dopamine D2 partial agonist, and/or 5HT1A partial agonist properties. Multiple receptor binding properties are hypothesized to be linked to additional clinical actions of antipsychotics, from antimanic actions, to antidepressant effects, to cardiometabolic risk and sedation. The pharmacologic and clinical properties of more than a dozen specific atypical antipsychotics are discussed in detail. Use of these as a class in clinical practice settings is reviewed, including considerations on how to switch from one antipsychotic to another and how to use antipsychotics in difficult patients who are treatment-resistant or violent. Finally, several new treatments under development for schizophrenia are presented, particularly those targeting the glutamate system.