Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 29 Treatment of Psychotic Disorders

MAJOR DRUG CLASSES

Typical antipsychotics

Phenothiazines

Thioxanthines

Butyrophenones

Atypical antipsychotics

Therapeutic Overview

Psychotic behaviors are characterized by disturbances of reality and perception, impaired cognitive functioning, and disturbances of affect (mood). Psychotic disorders may have an organic basis (disease-induced) or may be idiopathic (schizophrenia). Schizophrenia is the most common psychotic disorder, affects 2.2 million Americans (1% of the population), and typically develops between 16 and 30 years of age. Schizophrenia interferes with a person’s ability to think clearly, manage emotions, make decisions, and relate to others. The symptoms of schizophrenia fall into two clusters, positive and negative.Positive symptoms are characterized by delusions and hallucinations and reality distortions, which include thought disorders and bizarre and agitated behaviors. Negative symptoms include a flattened affect and emotional and social withdrawal. In addition, many schizophrenics exhibit cognitive impairments manifest by attentional and short-term memory deficits.

Although schizophrenia is of unknown etiology, evidence supports a role for genetic and environmental factors, including neurodevelopmental abnormalities that may involve defects in the normal pattern of neuronal proliferation and migration, alterations in neurotransmitter receptor expression, and aberrant neuronal myelination. Evidence supporting a role for genetic factors includes findings that relatives of schizophrenics have a higher risk of illness as compared with the general population and that there is a higher concordance of schizophrenia in monozygotic (50%) as compared with dizygotic (15%) twins. In fact, a child born to two schizophrenic parents has a 40 times greater risk of developing the illness than the general population.

Structural studies have demonstrated that brains of schizophrenics have enlarged cerebral ventricles; atrophy of cerebral cortical layers; a decreased number of synaptic connections in the prefrontal cortex; and alterations in neocortical, limbic, and subcortical structures. Functional abnormalities include reduced cerebral blood flow and reduced glucose use in the prefrontal cortex.

Abbreviations

ACh

Acetylcholine

DA

Dopamine

5-HT

Serotonin

Although consistent neurochemical alterations have not been found in schizophrenia, studies have implicated changes in the expression or function of several neurotransmitter receptors including those for dopamine (DA), serotonin (5-HT), acetylcholine (ACh), and glutamate. Other studies have suggested that schizophrenia may involve alterations in signaling pathways, particularly those involving FOSand neuregulin, as well as a decreased expression of oligodendrocyte-associated genes, including proteolipid protein, the most abundant myelin-related protein.

Psychotic behaviors are treated pharmacologically with antipsychotic drugs, which have been classified into two categories, the typical and atypical compounds. The typical antipsychotics, often calledfirst-generation or traditional compounds, include the prototypes chlorpromazine and haloperidol, which were introduced in the 1950s. The atypical antipsychotics, referred to as second-generation ornovel antipsychotics, were developed recently and represent a more heterogeneous group that includes compounds such as clozapine and risperidone. The typical and atypical antipsychotics differ significantly with respect to their mechanisms of action, ability to relieve positive versus negative symptoms, and side effect profiles. Most importantly, many schizophrenic patients who fail to respond to the typical

Therapeutic Overview

Typical Antipsychotics

Alleviate positive symptoms

Bind to and block 70% to 80% of D2 receptors at clinically effective doses

Atypical Antipsychotics

Alleviate positive and may improve negative symptoms

May improve cognitive impairments

Bind to and block 40% to 60% of D2 receptors at clinically effective doses

Bind to and block 70% to 90% of 5-HT2A receptors at clinically effective doses

compounds show significant improvement after administration of atypical antipsychotics. It is also critical to understand that within the schizophrenic population, few patients achieve full recovery with or without medication. Approximately 30% exhibit good responses, 30% demonstrate partial improvement, and 20% to 25% are resistant to all drugs. Thus schizophrenia likely represents a heterogeneous disorder.

Therapeutic issues related to the treatment of psychotic disorders are summarized in the Therapeutic Overview Box.

Mechanisms of Action

Typical Antipsychotics

The typical antipsychotics comprised the first group of compounds developed for the treatment of schizophrenia. Based on chemical structure, these compounds fall into three groups (Fig. 29-1):

• Phenothiazines

• Thioxanthines

• Butyrophenones

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FIGURE 29–1 Structures of various antipsychotic agents.

Chlorpromazine was the first antipsychotic approved for use and is the prototypical phenothiazine, characterized by a three-ring structure. Thiothixene is representative of the thioxanthines, and haloperidol is representative of the butyrophenones.

The effects of the typical antipsychotics are due to blockade of postsynaptic DA receptors, specifically D2 receptors. Indeed, a positive linear correlation exists between the therapeutic potency of typical antipsychotics and their ability to bind to and block D2 receptors (Fig. 29-2). Inhibition of these receptors in mesolimbic and mesocortical regions (see Fig. 27-8) is believed to mediate the ability of these compounds to relieve some behavioral manifestations of schizophrenia. On the other hand, blockade of these receptors in the basal ganglia underlies the motor side effects of these compounds, and inhibition of these receptors in the tuberoinfundibular pathway in the hypothalamus leads to increases in prolactin secretion from the pituitary gland.

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FIGURE 29–2 Correlation between the therapeutic dose of antipsychotics and the concentration to block D2 receptors.

Acute administration of the typical antipsychotics increases the firing rate of both mesolimbic and nigrostriatal DA neurons as a compensatory response to DA receptor blockade. However, long-term administration inactivates these pathways via depolarization blockade. Because the therapeutic effects of the typical antipsychotics require several weeks to become apparent, it is believed that this inactivation of mesolimbic DA neurons mediates the time-dependent amelioration of psychotic symptoms. Long-term administration of antipsychotics also leads to an up regulation of DA receptors as a consequence of the depression of DA activity.

In addition to blocking DA receptors, the typical antipsychotics may also block muscarinic cholinergic receptors, α1 adrenergic receptors, histamine receptors, and serotonin (5-HT2) receptors. These actions underlie many of the side effects associated with these compounds.

The typical antipsychotics are of benefit primarily in alleviating the positive symptoms of schizophrenia.

Atypical Antipsychotics

The atypical antipsychotics represent a somewhat heterogeneous group of compounds with large differences in chemical structure (see Fig. 29-1), receptor antagonist activity, and therapeutic and side effect profiles. These compounds vary more in potency and range in treating specific symptoms as compared with the typical compounds. As heterogeneous as the group is, however, these compounds share several commonalities. They all occupy and block fewer D2 receptors than the typical antipsychotics (40% to 60% as compared with >70% to 80%), and they all block a high number (70% to 90%) of 5-HT2A receptors. Because of their lower occupancy of D2 receptors, the atypical antipsychotics have a lower propensity than the typical compounds to induce motor side effects. In addition, they may have an increased ability to alleviate the negative symptoms of schizophrenia, and the rate of relapse is lower than that after administration of typical antipsychotics.

Clozapine was the first atypical antipsychotic drug to be characterized and is effective in a significant population of schizophrenics who fail to respond to typical antipsychotic drugs. In addition to having a low affinity for D2 receptors, clozapine was the first antipsychotic demonstrated to have selective effects on specific DA pathways—that is, it produces a depolarization blockade of mesolimbic and mesocortical, but not nigrostriatal, DA neurons. Thus, in contrast to typical antipsychotics, clozapine does not disrupt DA function in the nigrostriatal pathway. Two of the newer compounds, olanzapine and quetiapine, both demonstrate similar anatomical specificity for DA pathways.

Clozapine also exhibits a high affinity for D4 receptors and for 5-HT2C receptors. The contribution of these effects to the actions of clozapine remains unknown. However, several other atypical antipsychotics, including olanzapine, risperidone, and ziprasidone, also have a very high affinity for 5-HT2A, 5-HT2C, and D4 receptors.

In addition to actions at these receptors, clozapine and olanzapine increase regional blood flow in cerebral cortex through an undefined mechanism, an action that may contribute to the beneficial effects of these compounds on cognitive functions such as working memory and attention.

A newer atypical drug, aripiprazole, is unlike others in this group, because it is a partial agonist at D2 and 5-HT1A receptors and a full antagonist at 5-HT2A receptors. Thus its therapeutic and side effect profile differs somewhat from other atypical antipsychotics.

Pharmacokinetics

The antipsychotics are readily but erratically absorbed after oral administration, and most undergo significant first-pass metabolism. Most of these compounds are highly lipophilic and protein bound, with variable half-lives after oral administration. In general, most antipsychotics are oxidized by hepatic microsomal enzymes to inactive metabolites and are excreted as glucuronides. Major exceptions are thioridazine and risperidone. Thioridazine is metabolized to the active product mesoridazine, which is more potent than the parent compound. Interestingly, the primary active metabolite of risperidone, paliperidone, was approved by the United States Food and Drug Administration in 2007 in an extended-release formulation.

Depot formulations of some antipsychotics (e.g., fluphenazine decanoate, haloperidol decanoate, and risperidone) are available and can be used for maintenance therapy administered intramuscularly at 2- to 4-week intervals. For patients who have difficulty taking oral medications, risperidone and olanzapine are available as rapidly dissolving oral wafers. In addition, for management of acute psychotic episodes, antipsychotics can be administered intramuscularly, although ziprasidone and olanzapine are currently the only atypical antipsychotics available in this formulation. The risperidone-dissolving wafer provides rapid relief of symptoms as well. Haloperidol is available in an intravenous form, which is commonly used in intensive care settings. However, because intravenous haloperidol bypasses first-pass metabolism, it is effectively twice as potent as oral haloperidol dosing. In general, once an effective dose is established, a regimen of single daily oral dosing is effective for symptomatic treatment. Pharmacokinetic parameters are summarized in Table 29-1.

TABLE 29–1 Selected Pharmacokinetic Parameters for Antipsychotics After Oral Administration

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Relationship of Mechanisms of Action to Clinical Response

The positive (hallucinations, delusions, paranoia, and thought disorders) and negative (depressive manifestations) symptoms and cognitive impairments characteristic of schizophrenia respond differently to currently available drugs. In addition, the intensity of these symptoms varies among patients and in particular patients over time, such that a patient may exhibit predominantly one set of symptoms at any particular time. However, in general, positive symptoms respond to both typical and atypical compounds, whereas the negative symptoms and cognitive impairments respond better to atypical than typical antipsychotics.

The DA hypothesis of psychotic behavior is based on findings that the chronic administration of amphetamine and other compounds that increase DA release leads to psychotic behaviors, the administration of compounds that enhance dopaminergic activity such as L-DOPA can induce psychotic behaviors, and a linear correlation exists between the therapeutic efficacy of the typical antipsychotics and their ability to block DA receptors (see Fig. 29-2). Similarly, a role for 5-HT in schizophrenia is based on evidence that many hallucinogens are structurally related to 5-HT. The newer atypical antipsychotics block 5-HT2 receptors with high potency, leading to a reduction or resolution of the hallucinations. Thus both DA and 5-HT clearly play a role in the manifestations of psychotic behavior.

The atypical antipsychotics block both 5-HT2 and D2 receptors and alleviate positive and decrease negative symptoms of schizophrenia, whereas the typical antipsychotics block only D2 receptors at therapeutic doses and alleviate only the positive symptoms. Therefore the idea has emerged that DA plays a major role in the manifestation of positive symptoms, whereas 5-HT plays a major role in the manifestation of negative symptoms.

It is critical to understand that DA receptor blockade occurs rapidly after initial antipsychotic treatment, whereas a maximal therapeutic response is not observed for several weeks and correlates with the induction of depolarization blockade of mesolimbic DA neurons. The long-term consequences of 5-HT receptor blockade are less well understood.

Based on evidence that the atypical antipsychotics may improve the cognitive impairment exhibited by schizophrenics, in concert with their ability to increase blood flow and enhance ACh release in prefrontal cortex, studies have suggested a role for altered cholinergic systems in the cognitive impairment in psychotic behavior. This idea is underscored by the vast literature supporting a role for ACh in learning and memory and the role of impaired cholinergic activity in Alzheimer’s disease (see Chapter 28).

The short-term goal of management of a psychotic episode is to reduce positive symptoms. The long-term goal includes the prevention of relapse, because it is believed that multiple psychotic episodes negatively affect the long-term outcome. Relapse of psychosis generally stems from noncompliance and not development of tolerance to the drug. Relapse is best prevented with continuous rather than intermittent drug therapy.

The choice of antipsychotic drug is based on the particular symptoms manifested by the patient as well as on sensitivity to undesirable side effects and previous therapeutic response to a particular agent. Although the typical antipsychotics have been first-line compounds, the use of atypicals is increasing because of their limited side effect profile, leading to better compliance. Although clozapine has not been considered a first-line drug because of multiple significant side effects (including agranulocytosis, seizures, and myocarditis), it is clearly of tremendous benefit for patients who fail to respond to other antipsychotics.

In addition to their use in schizophrenia, several antipsychotics have been of therapeutic benefit in other neuropsychiatric disorders. Many of the atypical antipsychotics (including risperidone, quetiapine, and olanzapine) are effective as the primary treatment or as an augmenting agent with mood stabilizers in the treatment of bipolar disorder, regardless of whether psychotic features were present at the time. The antipsychotics are often prescribed concomitantly with antidepressants and mood stabilizers for schizoaffective disorder (see Chapter 30). Haloperidol and pimozide are used to treat behavioral syndromes accompanied by motor disturbances, specifically Gilles de la Tourette’s syndrome.

Although the clinical outcome in schizophrenic patients is improved greatly with antipsychotic drug therapy, their quality of life is improved through the use of psychosocial interventions. Clinical outcomes appear to be more positive in patients who can engage in an occupation, maintain family contact, and function in a social environment.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

Although most antipsychotics are relatively safe, they can elicit a variety of neurological, autonomic, neuroendocrine, and metabolic side effects. Many side effects are an extension of the general pharmacological actions of these drugs and result from the blockade of receptors for several neurotransmitters (Table 29-2), whereas other side effects are specific to particular compounds.

TABLE 29–2 Side Effect Profile of Representative Antipsychotic Drugs

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Typical Antipsychotics

All typical antipsychotics block muscarinic cholinergic receptors, leading to dry mouth, urinary retention, and memory impairment (see Chapter 10). These effects are more common with the lower-potency agents such as chlorpromazine and thioridazine. They also block α1 adrenergic and histamine (H1) receptors, producing orthostatic hypotension and reflex tachycardia, and sedation, respectively. Blocking DA receptors in the pituitary gland results in elevated prolactin secretion, and this hyperprolactinemia may lead to menstrual irregularities in females and breast enlargement and galactorrhea in both sexes. In addition, thioridazine has a propensity to prolong the cardiac QT interval, predisposing to a risk for ventricular arrhythmias. High-dose thioridazine therapy (>800 mg/day) has been associated with the development of retinitis pigmentosa. Thioridazine should be used with caution at all times, whether it is used as monotherapy or with other agents. As thioridazine is metabolized by CYP2D6, using it concurrently with a CYP2D6 inhibitor (such as paroxetine or fluoxetine) could greatly increase serum thioridazine levels, leading to an increase in adverse events.

Blocking DA receptors in the basal ganglia leads to acute extrapyramidal symptoms including dystonia, parkinsonism, and akathisia. Acute dystonic reactions, characterized by spasms of the facial or neck muscles, may be evident, as well as a parkinsonian syndrome characterized by bradykinesia, rigidity, tremor, and shuffling gait. Akathisia or motor restlessness may also be apparent. These symptoms occur early (1 to 60 days) after initiation of drug treatment, improve if the antipsychotic is terminated, and if severe enough to cause noncompliance, may be treated with centrally active anticholinergic compounds such as those used for Parkinson’s disease (see Chapter 28).

In general, the high-potency butyrophenones such as haloperidol are associated with a greater incidence of extrapyramidal side effects, whereas the low-potency phenothiazines such as chlorpromazine are associated with a greater incidence of autonomic side effects and sedation.

After months to years of therapy, two late-onset effects may become apparent: perioral tremor, characterized by “rabbit-like” facial movements, and tardive dyskinesia, characterized by involuntary and excessive movements of the face and extremities. Severe tardive dyskinesia can be disfiguring and cause impaired feeding and breathing. There is no satisfactory treatment for tardive dyskinesia, and stopping drug treatment may unmask the symptoms, apparently exacerbating the condition. Tardive dyskinesia is thought to result from the hypersensitivity or up regulation of DA receptors that occurs after chronic DA receptor blockade induced by the antipsychotics. Together, clinician and patient must weigh the risks and benefits when considering whether to stop the antipsychotic medication or switch to another agent (i.e., from a typical to an atypical antipsychotic) once symptoms manifest themselves.

An idiosyncratic and potentially lethal effect of the typical antipsychotics is known as neuroleptic malignant syndrome, which occurs in 1% to 2% of patients and is fatal in almost 10% of those affected. It is most commonly seen in young males recently treated with an intramuscular injection of a typical antipsychotic agent. This syndrome is observed early in treatment and is characterized by a near-complete collapse of the autonomic nervous system, causing fever, muscle rigidity, diaphoresis, and cardiovascular instability. Immediate medical intervention with the DA receptor agonist bromocriptine (see Chapter 28) and the skeletal muscle relaxant dantrolene (see Chapter 12) is recommended to treat this condition.

Antipsychotics are not the only class of medications that can cause these types of side effects. In fact, any medication with significant D2 receptor blockade may induce extrapyramidal symptoms, akathisia, neuroleptic malignant syndrome, and other side effects normally associated with antipsychotics. Prochlorperazine, metoclopramide, promethazine, and trimethobenzamide are agents used in gastroenterology that can have similar side effects.

Atypical Antipsychotics

In general, the side effect profile of the atypical antipsychotics differs from that of typical antipsychotics. While the typical antipsychotics have a narrow therapeutic window in terms of acute extrapyramidal side effects, clozapine and the newer atypical compounds are associated with a very low incidence of these problems and most do not produce hyperprolactinemia. Risperidone has been associated with increased prolactin levels in some patients. Although these compounds are not devoid totally of the ability to induce tardive dyskinesia or neuroleptic malignant syndrome, their incidence is lower than with the typical antipsychotics.

The most prominent side effects of the atypical compounds are metabolic and cardiovascular. Many of these compounds cause substantial weight gain (particularly olanzapine and clozapine) and the development of insulin resistance, leading to the onset of diabetes mellitus. while

CLINICAL PROBLEMS

Typical Antipsychotics

High propensity to produce extrapyramidal symptoms and tardive dyskinesia

Hyperprolactinemia

Sedation

Moderate weight gain

Postural hypotension

Neuroleptic malignant syndrome

Prolnged QT interval, risk of ventricular arrhythmias (thioridazine)

Atypical Antipsychotics

Diabetes mellitus

Hypercholesterolemia

Sedation

Seizures and agranulocytosis (clozapine)

Hyperprolactinemia (risperidone)

Moderate to severe weight gain (clozapine, olanzapine)

Prolonged QT interval, risk of ventricular arrhythmias (ziprasidone)

the development of diabetes mellitus is believed to be caused by all atypical antipsychotics, it has been most commonly observed with olanzapine and clozapine. The atypical antipsychotics also cause increased plasma lipids, with as much as a 10% increase in cholesterol levels. Olanzapine and, to a lesser extent, quetiapine are the atypical agents most likely to induce hyperlipidemia. Like the typical antipsychotic thioridazine, the atypical compound ziprasidone can also increase the cardiac QT interval predisposing to arrhythmias. Quetiapine is very sedating and has also been associated with significant hypotension, especially during the titration phase of treatment.

Clozapine is the only atypical compound that causes agranulocytosis, characterized by leukopenia. Because this condition can be fatal, weekly blood cell counts must be performed for the first 6 months of treatment. After that time, if counts are stable, blood counts are done every other week. The incidence of agranulocytosis with the other atypical antipsychotics is minimal and is no greater than that associated with the use of typical antipsychotics.

The major problems associated with the use of the antipsychotics are listed in the Clinical Problems Box.

New Horizons

The development of new antipsychotic drugs is a major focus for research, especially because 20% to 25% of diagnosed schizophrenics are resistant to all currently available drugs. In addition, many schizophrenics are noncompliant because of the troublesome side effects associated with the use of currently available drugs. Thus there is a great need to develop newer compounds with efficacy for more patients and decreased side effects.

Although much attention has focused on the role of DA and 5-HT in schizophrenia, recent studies have begun to focus on glutamatergic neurotransmission. The glutamate N-methyl-D-aspartate receptor antagonist phencyclidine (“angel dust”) mimics schizophrenia more accurately than any other compound. The behavioral effects of phencyclidine prompted investigators to postulate a glutamatergic deficiency in the etiology of schizophrenia, and recent studies have demonstrated that partial deletion of the gene encoding these receptors leads to the same behavioral abnormalities observed after phencyclidine. Thus attempts to enhance the activity of the N-methyl-D-aspartate receptor in schizophrenics with glycine or serine, both of which stimulate allosteric sites on the receptor, have resulted in some symptomatic improvement. In addition, preliminary data from a recent clinical trial have suggested that glutamate metabotropic receptor agonists may also be of benefit.

The challenge remains to develop drugs that are effective in the schizophrenic population resistant to currently available antipsychotic agents and to improve side effect profiles to enhance patient compliance.

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

Typical Antipsychotics

Chlorpromazine (Thorazine)

Fluphenazine (Permitil, Prolixin)

Haloperidol (Haldol)

Perphenazine (Trilafon)

Pimozide (Orap)

Thioridazine (Mellaril)

Thiothixene (Navane)

Trifluoperazine (Stelazine)

Atypical Antipsychotics

Aripiprazole (Abilify)

Clozapine (Clozaril)

Olanzapine (Zyprexa)

Paliperidone (Invega)

Quetiapine (Seroquel)

Risperidone (Risperdal)

Ziprasidone (Geodon)

FURTHER READING

Anonymous. Drugs for psychiatric disorders. Treat Guidel Med Lett. 2006;4:35-46.

Javitt DC, Spencer KM, Thaker GK, et al. Neurophysiological biomarkers for drug development in schizophrenia. Nature Rev Drug Disc. 2008;7:68-83.

SELF-ASSESSMENT QUESTIONS

1. Which of the following side effects of antipsychotic drugs should be treated immediately?

A. Mild slowing of gait

B. Production of breast milk in a non-nursing woman

C. Neuroleptic malignant syndrome

D. Constipation

E. All of the above

2. Which of the following statements are correct regarding typical antipsychotic drugs?

A. Clinical potency correlates with binding to D2 receptors.

B. Long-term treatment increases the firing rate of dopamine neurons.

C. Long-term treatment results in the supersensitivity of dopamine receptors.

D. The drugs differ in efficacy and potency.

E. Both A and C are correct.

3. Tardive dyskinesia is thought to result from which of the following?

A. Dopamine receptor supersensitivity

B. Depolarization blockade of mesolimbic dopamine neurons

C. Blockade of serotonin receptors

D. Anticholinergic properties of the drugs

E. None of the above

4. Which of the following is considered the most serious side effect of clozapine?

A. Parkinsonian symptoms

B. Hyperprolactinemia

C. Tardive dyskinesia

D. Agranulocytosis

E. Akathisia

5. Which of the following actions distinguishes newer (atypical) antipsychotics from typical antipsychotics?

A. Low incidence of extrapyramidal effects

B. Selective effect on mesolimbic dopamine neurons

C. Little hyperprolactinemia

D. Lower incidence of sedation

E. AB, and C.