Goodman and Gilman Manual of Pharmacology and Therapeutics

Section II

chapter 16
Pharmacotherapy of Psychosis and Mania

Psychosis is a symptom of mental illnesses characterized by a distorted or nonexistent sense of reality. Common psychotic disorders include mood disorders (major depression or mania) with psychotic features, substance-induced psychosis, dementia with psychotic features, delirium with psychotic features, brief psychotic disorder, delusional disorder, schizoaffective disorder, and schizophrenia. Schizophrenia has a worldwide prevalence of 1%, but patients with schizophrenia exhibit features that extend beyond those seen in other psychotic illnesses. The positive symptoms of psychotic disorders include: hallucinations, delusions, disorganized speech, and disorganized or agitated behavior. Schizophrenia patients also suffer from negative symptoms (apathy, avolition, alogia), and cognitive deficits, particularly deficits in working memory, processing speed, and social cognition.

The dopamine (DA) hypothesis of psychosis was derived from the discovery that chlorpromazine and reserpine exhibited therapeutic antipsychotic properties in schizophrenia by decreasing dopaminergic neurotransmission. The DA overactivity hypothesis led to the development of the first therapeutic class of antipsychotic agents, now referred to as typical or first-generation antipsychotic drugs. The term “neuroleptic” refers to typical antipsychotic drugs that act through D2 receptor blockade but are associated with extrapyramidal side effects.

The DA hypothesis has its limitations: it does not account for the cognitive deficits associated with schizophrenia and does not explain the psychotomimetic effects of LSD (e.g., d-lysergic acid, a potent serotonin 5HT2 receptor agonist) or the effects of phencyclidine and ketamine, antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor. Advances in treatment have emerged from exploration of alternative (non-dopaminergic) mechanisms for psychosis and from experience with atypical antipsychotic agents such as clozapine. The newer atypical antipsychotics potently antagonize the 5HT2receptor, while blocking D2 receptors less potently than older typical antipsychotic agents, resulting in antipsychotic efficacy with limited extrapyramidal side effects. Promising medications target glutamate and 5HT7 receptor subtypes, receptors for γ-aminobutyric acid (GABA) and acetylcholine (both muscarinic and nicotinic), and peptide hormone receptors (e.g., oxytocin).


The 12th edition of the parent text reviews the relevant pathophysiology and the general goals of pharmacotherapy of psychosis and mania. Regardless of the underlying pathology, the immediate goal of antipsychotic treatment is a decrease in the acute symptoms that induce patient distress, particularly behavioral symptoms (e.g., hostility, agitation) that may present a danger to the patient or others. The dosing, route of administration, and choice of antipsychotic depend on the underlying disease state, clinical acuity, drug-drug interactions with concomitant medications, and patient sensitivity to short- or long-term adverse effects. With the exception of clozapine’s superior efficacy in treatment-refractory schizophrenia, neither the clinical presentation nor biomarkers predict the likelihood of response to a specific antipsychotic class or agent. As a result, avoidance of adverse effects based upon patient and drug characteristics and exploitation of certain medication properties (e.g., sedation related to histamine H1 or muscarinic antagonism) are the principal determinants for choosing initial antipsychotic therapy.

All commercially available antipsychotic drugs reduce dopaminergic neurotransmission (Figure 16–1). Chlorpromazine and other early low-potency typical antipsychotic agents are also profoundly sedating, a feature that used to be considered relevant to their therapeutic pharmacology. The development of the high-potency typical antipsychotic agent haloperidol, a drug with limited H1 and M1 affinity and significantly less sedative effect, demonstrate that sedation is not necessary for antipsychotic activity, although at times desirable.


Figure 16–1 Sites of action of antipsychotic agents and Li+. Following exocytotic release, DA interacts with both postsynaptic receptors and presynaptic autoreceptors. Termination of DA action occurs primarily by reuptake into presynaptic terminals via the DA transporter DAT, with secondary deamination by mitochondrial monoamine oxidase (MAO). Stimulation of postsynaptic D1 receptors activates the Gs-adenylyl cyclase-cAMP pathway. D2 receptors couple through Gi to inhibit adenylyl cyclase and through Gq to activate the PLC-IP3-Ca2+ pathway. Activation of the Gi pathway can also activate K+channels, leading to hyperpolarization. Li+ inhibits the phosphatase that liberates inositol (I) from inositol phosphate (IP). Li+ can also inhibit depolarization-evoked release of DA and NE, but not 5HT. D2-like autoreceptors suppress synthesis of DA by diminishing phosphorylation of rate-limiting tyrosine hydroxylase (TH), and by limiting DA release. In contrast, presynaptic A2 adenosine receptors (A2R) activate the AC-cAMP-PKA pathway, thereby enhancing TH activity. All antipsychotic agents act at D2 receptors and autoreceptors; some also block D1 receptors (see Table 16–2). Stimulant agents inhibit DA reuptake by DAT, thereby prolonging the dwell time of synaptic DA. Initially in antipsychotic treatment, DA neurons release more DA, but following repeated treatment, they enter a state of physiological depolarization inactivation, with diminished production and release of DA, in addition to continued receptor blockade. images, inhibition or blockade; +, elevation of activity; –, reduction of activity.


DELIRIUM AND DEMENTIA. Disease variables have considerable influence on selection of antipsychotic agents. Psychotic symptoms of delirium or dementia are generally treated with low medication doses, although doses may have to be repeated at frequent intervals initially to achieve adequate behavioral control. Despite widespread clinical use, not a single antipsychotic drug has received approval for dementia-related psychosis. Moreover, all antipsychotic drugs carry warnings that they may increase mortality in this setting. Because anticholinergic drug effects may worsen delirium and dementia, high-potency typical antipsychotic drugs (e.g., haloperidol) or atypical antipsychotic agents with limited antimuscarinic properties (e.g., risperidone) are often the drugs of choice.

The best tolerated doses in dementia patients are one-fourth of adult schizophrenia doses. Extrapyramidal neurological symptoms (EPSs), orthostasis, and sedation are particularly problematic in this patient population (see Chapter 22). Significant antipsychotic benefits are usually seen in acute psychosis within 60-120 min after drug administration. Oral dissolving tablet (ODT) preparations for risperidone, aripiprazole, and olanzapine, or liquid concentrate forms of risperidone or aripiprazole, are options for some patients. The dissolving tablets adhere to any moist tongue or oral surface, cannot be spit out, and are then swallowed along with oral secretions. Intramuscular (IM) administration of ziprasidone, aripiprazole, or olanzapine represents an option for treating agitated and minimally cooperative patients, and presents less risk for drug-induced parkinsonism than haloperidol. QTc prolongation associated with intramuscular droperidol and intravenous administration of haloperidol have curtailed use of those particular formulations.

MANIA. All atypical antipsychotic agents with the exception of clozapine and iloperidone have indications for acute mania, and doses are titrated rapidly to the maximum recommended dose over the first 24-72 h of treatment. Acute mania patients with psychosis require very high daily doses. Clinical response (decreased psychomotor agitation and irritability, increased sleep, and reduced or absent delusions and hallucinations) usually occurs within 7 days. Patients with mania may need to continue on antipsychotic treatment for many months after the resolution of psychotic and manic symptoms, typically in combination with a mood stabilizer such as lithium or valproic acid preparations. Combining an antipsychotic agent with a mood stabilizer often improves control of manic symptoms, and further reduces the risk of relapse. Weight gain from the additive effects of antipsychotic agents and mood stabilizers (lithium, valproic acid) presents a significant clinical problem.

MAJOR DEPRESSION. Patients with major depressive disorder with psychotic features require lower than average doses of antipsychotic drugs, given in combination with an antidepressant. Most antipsychotic drugs show limited antidepressant benefit as monotherapy agents. However, atypical antipsychotic agents are efficacious as adjunct therapy in treatment-resistant depression. Their clinical efficacy may be related to the fact that almost all atypical antipsychotic medications are potent 5HT2A antagonists (Figure 16–2).


Figure 16–2 Receptor occupancy and clinical response for antipsychotic agents. Typically, D2 receptor occupancy by the drug >60% provides antipsychotic effects; receptor occupancy >80% causes extrapyramidal symptoms (EPS). Atypical agents combine weak D2 receptor blockade with more potent 5HT2A antagonism/inverse agonism. Inverse agonism at 5HT2 receptor subtypes may contribute to the reduced EPS risk of olanzapine (Panel A) and risperidone (Panel B) and efficacy at lower D2 receptor occupancy (olanzapine, Panel A). Aripiprazole is a partial D2 agonist that can achieve only 75% functional blockade.

5HT2A and 5HT2C antagonism facilitates DA release and increases noradrenergic outflow from the locus coeruleus. Administration of 5HT2A and 5HT2C antagonists in the form of low doses of atypical antipsychotic agents, along with selective serotonin reuptake inhibitors (SSRIs), increases responses rates in SSRI nonresponders. A combination preparation of low-dose olanzapine and fluoxetine is approved for bipolar depression, and low-dose risperidone (i.e., 1 mg) increases clinical response rates when added to existing SSRI treatment in SSRI nonresponders. Aripiprazole is FDA-approved for adjunctive use in antidepressant nonresponders, again at low doses (2-15 mg). Aripiprazole and most other antipsychotic drugs are ineffective as monotherapy for bipolar depression, with quetiapine being the sole exception.

SCHIZOPHRENIA. Newer, atypical antipsychotic agents offer a better neurological side-effect profile than typical antipsychotic drugs. Atypical agents show markedly reduced EPS risk compared to typical antipsychotic agents. Excessive D2 blockade increases risk for motor neurological effects (e.g., muscular rigidity, bradykinesia, tremor, akathisia), slows mentation (bradyphrenia), and interferes with central reward pathways, resulting in patient complaints of anhedonia. In acute psychosis, sedation may be desirable, but the use of a sedating antipsychotic drug may interfere with a patient’s cognitive function and social reintegration.

Schizophrenia patients have a 2-fold higher prevalence of metabolic syndrome and type 2 diabetes mellitus (DM) and twice the rate of cardiovascular (CV) related mortality than the general population. Consensus guidelines recommend baseline determination of serum glucose, lipids, weight, blood pressure, and when possible, waist circumference and personal and family histories of metabolic and CV disease. Drug-induced parkinsonism can also occur, especially among elderly patients exposed to antipsychotic agents that have high D2 affinity (e.g., typical antipsychotic drugs); recommended doses are ~50% of those used in younger schizophrenia patients.


The choice of antipsychotic agents for long-term schizophrenia treatment is based primarily on avoidance of adverse effects and, when available, prior history of patient response. Because schizophrenia spectrum disorders are lifelong diseases, treatment acceptability is paramount to effective illness management. Atypical antipsychotic agents offer significant advantages related to reduced neurological risk, with long-term tardive dyskinesia rates <1%, or approximately one-fifth to one-tenth of that seen with typical antipsychotic drugs.

Antipsychotic treatments are associated with metabolic risks that include: weight gain, dyslipidemia (particularly hypertriglyceridemia), an adverse impact on glucose-insulin homeostasis, including new-onset type 2 DM, and diabetic ketoacidosis (DKA), with reported fatalities from the latter. Clozapine and olanzapine have the highest metabolic risk and are only used as last resort.

Acutely psychotic patients usually respond within hours after drug administration, but weeks may be required to achieve maximal drug response, especially for negative symptoms. Usual dosages for acute and maintenance treatment are noted in Table 16–1. Treatment-limiting adverse effects may include weight gain, sedation, orthostasis, and EPS, which to some degree can be predicted based on the potencies of the selected agent to inhibit neurotransmitter receptors (Table 16–2). The detection of dyslipidemia or hyperglycemia is based on laboratory monitoring (see Table 16–1). Certain adverse effects such as hyperprolactinemia, EPS, orthostasis, and sedation may respond to dose reduction, but metabolic abnormalities improve only with discontinuation of the drug and switching to a more metabolically benign medication. Patients with refractory schizophrenia on clozapine are not good candidates for switching because they are resistant to other medications (see the definition of refractory schizophrenia below).

Table 16–1

Drugs for Psychosis and Schizophrenia: Dosing and Metabolic Risk Profilea


Table 16–2

Potencies of Antipsychotic Agents at Neurotransmitter Receptorsa


The common problem of medication nonadherence among schizophrenia patients has led to the development of long-acting injectable (LAI) antipsychotic medications, often referred to as depot antipsychotics. There are currently 4 available LAI forms in the U.S.: decanoate esters of fluphenazine and haloperidol, risperidone-impregnated microspheres, and paliperidone palmitate. Patients receiving LAI antipsychotic medications show consistently lower relapse rates compared to patients receiving comparable oral forms and may suffer fewer adverse effects.

Lack of response to adequate antipsychotic drug doses for adequate periods of time may indicate treatment-refractory illness. Refractory schizophrenia is defined using the Kane criteria: failed 6-week trials of 2 separate agents and a third trial of a high-dose typical antipsychotic agent (e.g., haloperidol or fluphenazine 20 mg/day). In this patient population, response rates to typical antipsychotic agents, defined as 20% symptom reduction using standard rating scales (e.g., Positive and Negative Syndrome Scale [PANSS]), are 0%, and for any atypical antipsychotic except clozapine, are <10%. The therapeutic clozapine dose for a specific patient is not predictable, but various studies have found correlations between trough serum clozapine levels >327-504 ng/mL and likelihood of clinical response. When therapeutic serum concentrations are reached, response to clozapine occurs within 8 weeks.

Clozapine has numerous other adverse effects. These include agranulocytosis risk that mandates routine ongoing hematological monitoring, high metabolic risk, dose-dependent lowering of the seizure threshold, orthostasis, sedation, anticholinergic effects (especially constipation), and sialorrhea related to muscarinic agonism at M4 receptors. As a result, clozapine use is limited to refractory schizophrenia patients. Electroconvulsive therapy is considered a treatment of last resort in refractory schizophrenia and is rarely employed.


Tables 16–1 and 16–2 summarize the drug classes, dose ranges, severity metabolic side effects, and potencies at important CNS receptors for a variety of antipsychotic agents.

The introduction of clozapine stimulated research into agents with antipsychotic activity and low EPS risk. This search led to a series of atypical antipsychotic agents with certain pharmacological similarities to clozapine: namely lower affinity for D2 receptors than typical antipsychotic drugs and high 5HT2 antagonist effects. Currently available atypical antipsychotic medications include the structurally related olanzapine, quetiapine, and clozapine; risperidone, its active metabolite paliperidone, and iloperidone; ziprasidone; lurasidone; asenapine, and aripiprazole (see Table 16–1).

MECHANISM OF ACTION. All clinically available antipsychotics are antagonists at dopamine D2 receptors. This reduction in dopaminergic neurotransmission is achieved through D2 antagonism or partial D2 agonism (e.g., aripiprazole).

Aripiprazole has an affinity for D2 receptors only slightly less than DA itself, but its intrinsic activity is ~25% that of DA. That is, when DA is incubated with increasing concentrations of aripiprazole, maximal inhibition of D2 activity do not exceed 25% of the DA response, the level of agonism provided by aripiprazole. Aripiprazole’s capacity to stimulate D2 receptors in brain areas where synaptic DA levels are limited (e.g., PFC neurons) or decrease dopaminergic activity when DA concentrations are high (e.g., mesolimbic cortex) is thought to be the basis for its clinical effects in schizophrenia. Even with 100% receptor occupancy, aripiprazole’s intrinsic dopaminergic agonism can generate a 25% postsynaptic signal, implying a maximal 75% reduction in DA neurotransmission, below the 78% threshold that triggers EPS in most individuals.

The pharmacological basis for the clinical efficacy atypical antipsychotics without EPS induction results from a significantly weaker D2 antagonism, combined with potent 5HT2 antagonism. Clozapine possesses activity at other receptors including antagonism and agonism at various muscarinic receptor subtypes and antagonism at dopamine D4 receptors. However D4 antagonists that do not have D2antagonism lack antipsychotic activity. Clozapine’s active metabolite, N-desmethylclozapine, is a potent muscarinic M1 agonist.

The glutamate hypofunction hypothesis of schizophrenia has led to novel animal models that examine the influence of antipsychotic agents with agonist properties at metabotropic glutamate receptors mGlu2 and mGlu3 and other subtypes. Atypical antipsychotic drugs are better than typical antipsychotic medications at reversing the negative symptoms, cognitive deficits and social withdrawal induced by glutamate antagonists.

DOPAMINE RECEPTOR OCCUPANCY AND BEHAVIORAL EFFECTS. Excessive dopaminergic functions in the limbic system are central to the positive symptoms of psychosis. The behavioral effects and the time course of antipsychotic response parallel the rise in D2 occupancy and include calming of psychomotor agitation, decreased hostility, decreased social isolation, and less interference from disorganized or delusional thought processes and hallucinations. Occupation of ~78% of D2 receptors in the basal ganglia is associated with a risk of EPS across all DA antagonist antipsychotic agents, while occupancies in the range of 60-75% are associated with antipsychotic efficacy (see Figure 16–2). With the exception of aripiprazole, all atypical antipsychotic drugs at low doses have much greater occupancy of 5HT2A receptors (e.g., 75-99%) than typical agents (see Table 16–2).

D3 and D4 Receptors in the Basal Ganglia and Limbic System. D3 and D4 receptors are preferentially expressed in limbic areas. The D4 receptors, which are preferentially localized in cortical and limbic brain regions in low abundance, are upregulated after repeated administration of most typical and atypical antipsychotic drugs. These receptors may contribute to clinical antipsychotic actions, but agents that are D4 selective (e.g., sonepiprazole) or mixed D4/5HT2A antagonists (e.g., fananserin) lack antipsychotic efficacy in clinical studies.

D3 receptors are unlikely to play a pivotal role in antipsychotic drug actions. The subtle and atypical functional activities of cerebral D3 receptors suggest that D3 agonists rather than antagonists may have useful psychotropic effects, particularly in antagonizing stimulant-reward and dependence behaviors.

The Role of Non-Dopamine Receptors for Atypical Antipsychotic Agents. The concept of atypicality was initially based on clozapine’s absence of EPS within the therapeutic range, combined with a prominent role of 5HT2 receptor antagonism. As subsequent agents were synthesized using clozapine’s 5HT2/D2 ratio as a model, most of which possessed greater D2 affinity and EPS risk than clozapine, there has been considerable debate on the definition of an atypical antipsychotic agent and its necessary properties. Nonetheless, the term “atypical” persists in common usage and designates lesser (but not absent) EPS risk and other decreased effects of excessive D2 antagonism.

Antipsychotic agents with appreciable 5HT2 affinity have significant effects at both 5HT2A and 5HT2C receptors with individual medications varying in their relative potencies at each subtype. As discussed previously, atypical antipsychotic agents exhibit potent functional antagonism at both subtypes of 5HT2 receptors, but in vitro assays suggest that these effects result from inverse agonism at these G-coupled receptors.

TOLERANCE AND PHYSICAL DEPENDENCE. As defined in Chapter 24, antipsychotic drugs are not addicting; however, tolerance to the antihistaminic and anticholinergic effects of antipsychotic agents usually develops over days or weeks.

ABSORPTION, DISTRIBUTION, AND ELIMINATION. Most antipsychotic drugs are highly lipophilic, highly membrane- or protein-bound, and accumulate in the brain, lung, and other tissues with a rich blood supply. They also enter the fetal circulation and breast milk. Despite half-lives that may be short, the biological effects of single doses of most antipsychotic medications usually persist for at least 24 h, permitting once-daily dosing for many agents once the patient has adjusted to initial side effects.

Absorption for most agents is quite high, and concurrent administration of anticholinergic anti-parkinsonian agents does not appreciably diminish intestinal absorption. Most ODTs and liquid preparations provide similar pharmacokinetics. Asenapine remains the only exception; it is available only as an ODT preparation administered sublingually, and all absorption occurs via oral mucosa, with bioavailability of 35% by this route. If asenapine is swallowed, the first pass effect is >98%, indicating that drug swallowed with oral secretions is not bioavailable. IM administration avoids much of the first-pass enteric metabolism and provides measurable concentrations in plasma within 15-30 min. Most agents are highly protein bound, but this protein binding may include glycoprotein sites. Antipsychotic medications are predominantly highly lipophilic with apparent volumes of distribution as high as 20 L/kg.

Elimination from the plasma may be more rapid than from sites of high lipid content and binding, notably the CNS. Slow removal of drug may contribute to the typical delay of exacerbation of psychosis after stopping drug treatment. Depot decanoate esters of fluphenazine and haloperidol, paliperidone palmitate, as well as risperidone-impregnated microspheres, are absorbed and eliminated much more slowly than are oral preparations. For example, the t1/2 of oral fluphenazine is ~20 h, while the IM decanoate ester has a t1/2 of 14.3 days; oral haloperidol has a t1/2 of 24-48 h in CYP2D6-extensive metabolizers, while haloperidol decanoate has a t1/2 of 21 days; paliperidone palmitate has a t1/2 of 25-49 days compared to an oral paliperidone t1/2 of 23 h. Clearance of fluphenazine and haloperidol decanoate following repeated dosing can require 6-8 months. Effects of LAI risperidone (RISPERDAL CONSTA) are delayed for 4 weeks because of slow biodegradation of the microspheres and persist for at least 4-6 weeks after the injections are discontinued. The dosing regimen recommended for starting patients on LAI paliperidone generates therapeutic levels in the first week, obviating the need for routine oral antipsychotic supplementation.

With the exception of asenapine, paliperidone, and ziprasidone, all antipsychotic drugs undergo extensive phase I metabolism by CYPs and subsequent phase II glucuronidation, sulfation, and other conjugations. Hydrophilic metabolites of these drugs are excreted in the urine and to some extent in the bile. Most oxidized metabolites of antipsychotic drugs are biologically inactive; a few (e.g., P88 metabolite of iloperidone, hydroxy metabolite of haloperidol, 9-OH risperidone, N-desmethylclozapine, and dehydroaripiprazole) are active. These active metabolites may contribute to biological activity of the parent compound and complicate correlating serum drug levels with clinical effects. Table 16–3 in the 12th edition of the parent text outlines the metabolic pathways of selected agents in common use.

Table 16–3

Neurological Side Effects of Antipsychotic Drugs



Antipsychotic agents are also used in several nonpsychotic neurological disorders and as antiemetics.

ANXIETY DISORDERS. Adjunctive treatments with antipsychotic drugs are beneficial in obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD). Adjunctive low-dose quetiapine, olanzapine, and particularly risperidone significantly reduce the overall level of symptoms in SSRI-resistant PTSD, and OCD patients with limited response to the standard 12-week regimen of high-dose SSRI also benefit from adjunctive risperidone (mean dose 2.2 mg), even in the presence of comorbid tic disorders. For generalized anxiety disorder, double-blind placebo-controlled clinical trials demonstrate efficacy for quetiapine as monotherapy, and for adjunctive low-dose risperidone.

TOURETTE DISORDER. The ability of antipsychotic drugs to suppress tics in patients with Tourette disorder relates to reduced D2 neurotransmission in basal ganglia sites. While lacking FDA approval for tic disorders, risperidone and aripiprazole have indications for child and adolescent schizophrenia and bipolar disorder (acute mania) treatment, and these agents (as well as ziprasidone) have published data supporting their use for tic suppression.

HUNTINGTON DISEASE. Huntington disease is associated with basal ganglia pathology. DA blockade can suppress the severity of choreoathetotic movements, but is not strongly endorsed due to the risks associated of excessive DA antagonism that outweigh the marginal benefit. Inhibition of the vesicular monoamine transporter type 2 (VMAT2) with tetrabenazine has replaced DA receptor blockade in the management of chorea (see Chapter 22).

AUTISM. Risperidone has FDA approval for irritability associated with autism in child and adolescent patients ages 5-16, with common use for disruptive behavior problems in autism and other forms of mental retardation. Initial risperidone daily doses are 0.25 mg for patients weighing <20 kg, and 0.5 mg for others, with a target dose of 0.5 mg/day in those <20 kg weight, and 1.0 mg/day for other patients, with a range 0.5-3.0 mg/day.

ANTIEMETIC USE. Most antipsychotic drugs protect against the nausea- and emesis-inducing effects of DA agonists. Drugs or other stimuli that cause emesis by an action on the nodose ganglion, or locally on the GI tract, are not antagonized by antipsychotic drugs, but potent piperazines and butyrophenones are sometimes effective against nausea caused by vestibular stimulation. The commonly used antiemetic phenothiazines are weak DA antagonists (e.g., prochlorperazine) without antipsychotic activity, but can be associated with EPS or akathisia.


Dopamine D2 Receptor. With the exception of the D2 partial agonist aripiprazole, all other antipsychotic agents possess D2 antagonist properties, the strength of which determines the likelihood for EPS, akathisia, long-term tardive dyskinesia risk, and hyperprolactinemia. The manifestations of EPS are described in Table 16–3, along with the usual treatment approach. Acute dystonic reactions occur in the early hours and days of treatment with highest risk among younger patients (peak incidence ages 10-19), especially antipsychotic drug-naïve individuals, in response to abrupt decreases in nigrostriatal D2neurotransmission. The dystonia typically involves head and neck muscles, the tongue, and in its severest form, the oculogyric crisis, extraocular muscles, and is very frightening to the patient.

Parkinsonism resembling its idiopathic form occurs when striatal D2 occupancy exceeds 78%. Clinically, there is a generalized slowing and impoverishment of volitional movement (bradykinesia) with masked facies and reduced arm movements during walking. The syndrome characteristically evolves gradually over days to weeks as the risk of acute dystonia diminishes. The treatment of acute dystonia and antipsychotic-induced parkinsonism involves the use of antiparkinsonian agents, although dose reduction should be considered as the initial strategy for parkinsonism. Muscarinic cholinergic receptors modulate nigrostriatal DA release, with blockade increasing synaptic DA availability. Important issues in the use of anticholinergics include the negative impact on cognition and memory, peripheral antimuscarinic adverse effects (e.g., urinary retention, dry mouth, cycloplegia, etc.), and the relative risk of exacerbating tardive dyskinesia.

Amantadine (SYMMETREL), originally marketed as an antiviral agent toward influenza A, represents the most commonly used nonanticholinergic medication for antipsychotic-induced parkinsonism. Its mechanism of action is unclear but appears to involve presynaptic DA reuptake blockade, facilitation of DA release, postsynaptic DA agonism, and receptor modulation.

Tardive dyskinesia is a situation of increased nigrostriatal dopaminergic activity as the result of postsynaptic receptor supersensitivity and upregulation from chronically high levels of postsynaptic D2blockade (and possible direct toxic effects of high-potency DA antagonists). Tardive dyskinesia is characterized by stereotyped, repetitive, painless, involuntary, quick choreiform (tic-like) movements of the face, eyelids (blinks or spasm), mouth (grimaces), tongue, extremities, or trunk. The dyskinetic movements can be suppressed partially by use of a potent DA antagonist, but such interventions over time may worsen the severity. Switching patients from potent D2 antagonists to weaker agents, especially clozapine has at times proven effective. When possible, drug discontinuation may be beneficial, but usually cannot be offered to schizophrenia patients.

Akathisia is seen quite commonly during treatment with high doses of high potency typical antipsychotic drugs, but also can be seen with atypical agents, including those with weak D2 affinities (e.g., quetiapine), and aripiprazole. Despite the association with D2 blockade, akathisia does not have a robust response to antiparkinsonian drugs, so other treatment strategies must be employed, including the use of high-potency benzodiazepines (e.g., clonazepam), nonselective β-blockers with good CNS penetration (e.g., propranolol), and also dose reduction, or switching to another antipsychotic agent. That clonazepam and propranolol have significant cortical activity and are ineffective for other forms of EPS, points to an extrastriatal origin for akathisia symptoms.

The rare neuroleptic malignant syndrome (NMS) resembles a very severe form of parkinsonism, with signs of autonomic instability (hyperthermia and labile pulse, blood pressure, and respiration rate), stupor, elevation of creatine kinase in serum, and sometimes myoglobinemia with potential nephrotoxicity. The prevalence of this reaction is greater when relatively high doses of potent agents are used, especially when they are administered parenterally.

Hyperprolactinemia results from blockade of the pituitary actions of the tuberoinfundibular dopaminergic neurons that deliver DA to the anterior pituitary. D2 receptors on lactotropes in the anterior pituitary mediate the tonic prolactin-inhibiting action of DA. Correlations between the D2 potency of antipsychotic drugs and prolactin elevations are excellent. With the exception of risperidone and paliperidone, atypical antipsychotic agents show limited (asenapine, iloperidone, olanzapine, quetiapine, ziprasidone) to almost no effects (clozapine, aripiprazole) on prolactin secretion.

H1 Receptors. Central antagonism of H1 receptors is associated with 2 major adverse effects: sedation and weight gain via appetite stimulation. Examples of sedating antipsychotic drugs include low-potency typical agents such as chlorpromazine and thioridazine, and the atypical agents clozapine and quetiapine. The sedating effect is easily predicted by their high H1 receptor affinities (see Table 16–2). Some tolerance to the sedative properties will develop.

M1 Receptors. Muscarinic antagonism is responsible for the central and peripheral anticholinergic effects of medications. Most of the atypical antipsychotic drugs have no muscarinic affinity and no appreciable anticholinergic effects, while clozapine and low-potency phenothiazines have significant anticholinergic adverse effects (see Table 16–2). Quetiapine has modest muscarinic affinity, but its active metabolite norquetiapine is likely responsible for anticholinergic complaints. Clozapine is particularly associated with significant constipation. Routine use of stool softeners, and repeated inquiry into bowel habits are necessary to prevent serious intestinal obstruction from undetected constipation. Medications with significant anticholinergic properties should be particularly avoided in elderly patients, especially those with dementia or delirium.

α1 Receptors. α1 Adrenergic antagonism is associated with risk of orthostatic hypotension and can be particularly problematic for elderly patients who have poor vasomotor tone. Compared to high-potency typical agents, low-potency typical agents have significantly greater affinities for α1 receptors and greater risk for orthostasis. While risperidone has a Kithat indicates greater α1 adrenergic affinity than chlorpromazine, thioridazine, clozapine, and quetiapine, in clinical practice risperidone is used at 0.01-0.005 times the dosages of these medications, and thus causes a relatively lower incidence of orthostasis in nonelderly patients. Since clozapine-treated patients have few other antipsychotic options, the potent mineralocorticoid fludrocortisone is sometimes tried at the dose of 0.1 mg/day as a volume expander.


ADVERSE METABOLIC EFFECTS. Such effects have become the area of greatest concern during long-term antipsychotic treatment, paralleling the overall concern for high prevalence of prediabetic conditions and type 2 DM, and 2-fold greater CV mortality among patients with schizophrenia. Aside from weight gain, the 2 predominant metabolic adverse effects seen with antipsychotic drugs are dyslipidemia, primarily elevated serum triglycerides, and impairments in glycemic control.

Low-potency phenothiazines were known to elevate serum triglyceride values, but this effect was not seen with high-potency agents. As atypical antipsychotic drugs became more widely used, significant increases in fasting triglyceride levels were noted during clozapine and olanzapine exposure, and to a lesser extent, with quetiapine. Mean increases during chronic treatment of 50-100 mg/dL are common, with serum triglyceride levels exceeding 7000 mg/dL in some patients. Effects on total cholesterol and cholesterol fractions are significantly less, but show expected associations related to agents of highest risk: clozapine, olanzapine, and quetiapine. Risperidone and paliperidone have fewer effects on serum lipids, while asenapine, iloperidone, aripiprazole, and ziprasidone appear to have none. Weight gain in general may induce deleterious lipid changes, but there is compelling evidence to indicate that antipsychotic-induced hypertriglyceridemia is a weight-independent adverse event that temporally occurs within weeks of starting an offending medication, and which similarly resolves within 6 weeks after medication discontinuation.

In individuals not exposed to antipsychotic drugs, elevated fasting triglycerides are a direct consequence of insulin resistance since insulin-dependent lipases in fat cells are normally inhibited by insulin. Elevated fasting triglyceride levels thus become a sensitive marker of insulin resistance, leading to the hypothesis that the triglyceride increases seen during antipsychotic treatment are the result of derangements in glucose-insulin homeostasis. Analysis of the FDA MedWatch database found that reversibility was high upon drug discontinuation (~78%) for olanzapine- and clozapine-associated diabetes and ketoacidosis, supporting the contention of a drug effect. Comparable rates for risperidone and quetiapine were significantly lower. The mechanism by which antipsychotic drugs disrupt glucose-insulin homeostasis is not known.

Antipsychotics increase risk for metabolic disorders among patients with schizophrenia, and the medication itself seems to be the primary modifiable risk factor. As a result, all atypical antipsychotic drugs have a hyperglycemia warning in the drug label in the U.S., although there is essentially no evidence that asenapine, iloperidone, aripiprazole, and ziprasidone cause hyperglycemia. Clinicians should obtain baseline metabolic data, including fasting glucose, lipid panel, and also waist circumference, given the known association between central obesity and future type 2 diabetes risk. Ongoing follow-up of metabolic parameters is commonly built into psychiatric charts and community mental health clinic procedures to insure that all patients receive some level of metabolic monitoring.

ADVERSE CARDIAC EFFECTS. Ventricular arrhythmias and sudden cardiac death (SCD) are a concern with the use of antipsychotic agents.

Most of the older antipsychotic agents (e.g., thioridazine) inhibit cardiac K+ channels, and all antipsychotic medications marketed in the U.S. carry a class label warning regarding QTc prolongation. A black box warning exists for thioridazine, mesoridazine, pimozide, IM droperidol, and IV (but not oral or IM) haloperidol due to reported cases of torsade de pointes and subsequent fatal ventricular arrhythmias. Although the newer atypical agents are thought to have less effects on heart electrophysiology compared to the typical agents, a recent retrospective study found a dose-dependent increased risk for SCD among antipsychotic users of newer and older agents alike compared to antipsychotic nonusers, with a relative risk of 2.

Other Adverse Effects. Seizure risk is an unusual adverse effect of antipsychotic drugs. In the U.S., there is a class label warning for seizure risk on all antipsychotic agents, with reported incidences well below 1%. Among commonly used newer antipsychotic drugs, only clozapine has a dose-dependent seizure risk, with an incidence of 3-5% per year. Seizure disorder patients who commence antipsychotic treatment must receive adequate prophylaxis, with consideration given to avoiding carbamazepine and phenytoin due to their capacity to induce CYPs and P-glycoprotein. Carbamazepine is also contraindicated during clozapine treatment due to its bone marrow effects, particularly leukopenia. Redistribution and increased spacing of doses to minimize high peak serum clozapine levels can help, but patients may eventually require antiseizure medication. Valproic acid derivatives (e.g., divalproex sodium) are often used, but will compound clozapine-associated weight gain.

Clozapine possesses a host of unusual adverse effects aside from seizure induction, the most concerning of which is agranulocytosis. Clozapine’s introduction in the U.S. was based on its efficacy in refractory schizophrenia, but came with FDA-mandated CBC monitoring that is overseen by industry-created registries. Now that several generic forms of clozapine are available in addition to proprietary CLOZARIL, clinicians must verify with each manufacturer the history of prior exposure. Increased risk is associated with certain HLA types and advanced age.

While rarely used due to its risk of QTc prolongation, thioridazine is also associated with pigmentary retinopathy at daily doses ≥800 mg/day. Low-potency phenothiazines are associated with the development of photosensitivity, which necessitated warnings regarding sun exposure. Phenothiazines are also associated with development of a cholestatic picture on laboratory assessments (e.g., elevated alkaline phosphatase), and rarely elevations in hepatic transaminases.

Increased Mortality in Dementia Patients. All antipsychotic agents carry a mortality warning in the drug label regarding their use in dementia patients. Mortality is due to heart failure, sudden death, or pneumonia. Overdose with typical antipsychotic agents is of particular concern with low-potency agents (e.g., chlorpromazine) due to the risk of torsade de pointes, sedation, anticholinergic effects, and orthostasis. Patients who overdose on high-potency typical antipsychotic drugs (e.g., haloperidol) and the substituted benzamides are at greater risk for EPS due to the high D2 affinity, but also must be observed for ECG changes.

DRUG-DRUG INTERACTIONS. Antipsychotic agents are not significant inhibitors of CYP enzymes with a few notable exceptions (chlorpromazine, perphenazine, and thioridazine inhibit CYP 2D6). The plasma half-lives of a number of these agents are altered by induction or inhibition of hepatic CYPs and by genetic polymorphisms that alter specific CYP activities (Table 7–3see also Table 16–3 in the parent text, 12th edition). Smoking causes upregulation in CYP1A2 activity, and changes in smoking status can be especially problematic for clozapine-treated patients and will alter serum levels by 50% or more.

USE IN PEDIATRIC POPULATIONS. Both risperidone and aripiprazole have indications for child and adolescent bipolar disorder (acute mania) for ages 10-17, and for adolescent schizophrenia (ages 13-17). Risperidone and aripiprazole are FDA-approved for irritability associated with autism in child and adolescent patients ages 5-16. Antipsychotic drug-naïve patients and younger patients are more susceptible to EPS and to weight gain. Use of the minimum effective dose can minimize EPS risk.

USE IN GERIATRIC POPULATIONS. The increased sensitivity to EPS, orthostasis, sedation, and anticholinergic effects are important issues for the geriatric population, and often dictate the choice of antipsychotic medication. Avoidance of drug-drug interactions is also important, as older patients on numerous concomitant medications have multiple opportunities for interactions. Elderly patients have an increased risk for tardive dyskinesia and parkinsonism. Increased risk for cerebrovascular events and all-cause mortality is also seen in elderly patients with dementia. Compared to younger patients, antipsychotic-induced weight gain is lower in elderly patients.

USE DURING PREGNANCY AND LACTATION. Antipsychotic agents carry pregnancy class B or C warnings. Human data indicate no patterns of toxicity and no consistent increased rates of malformations. Haloperidol is often cited as the agent with the best safety record based on decades of accumulated human exposure reports. Antipsychotic drugs are designed to cross the blood-brain barrier, and all have high rates of placental passage. Use in lactation presents a separate set of concerns due to the low level of infant hepatic catabolic activity in the first 2 postpartum months. The inability of the newborn to adequately metabolize xenobiotics presents a significant risk for antipsychotic drug toxicity.


Mania is a period of elevated, expansive, or irritable mood with coexisting symptoms of increased energy and goal-directed activity, and decreased need for sleep. Mania represents 1 pole of what had been termed manic-depressive illness, but is now referred to as bipolar disorder. Mania may be induced by medications (e.g., DA agonists, antidepressants, stimulants) or substances of abuse, primarily cocaine and amphetamines, although periods of substance-induced mania should not be relied on solely to make a diagnosis of bipolar disorder.

Mania is distinguished from its less severe form, hypomania, by the fact that hypomania, by definition, does not result in functional impairment or hospitalization, and is not associated with psychotic symptoms. Patients who experience periods of hypomania and major depression have bipolar II disorder, those with mania at any time, bipolar I, and those with hypomania, but less severe forms of depression, cyclothymia. The prevalence of bipolar I disorder is roughly 1% of the population, and the prevalence of all forms of bipolar disorder 3-5%. Genetics studies of bipolar disorder have yielded several loci of interest associated with disease risk and predictors of treatment response, but the data are not yet at the phase of clinical application.

There is no medication designed to treat the full spectrum of bipolar disorder. While many classes of agents demonstrate efficacy in acute mania, including lithium, antipsychotic drugs, and certain anticonvulsants, no medication has surpassed lithium’s efficacy for prophylaxis of future manic and depressive phases of bipolar disorder, and no other medication has demonstrated lithium’s reduction in suicidality among bipolar patients.


ANTIPSYCHOTIC AGENTS. The chemistry and pharmacology of antipsychotic medications are addressed earlier in this chapter.

ANTICONVULSANTS. The pharmacology and chemistry of the anticonvulsants with significant data for acute mania (valproic acid compounds, carbamazepine) and for bipolar maintenance (lamotrigine) are covered in Chapter 21. These compounds are of diverse chemical classes, but share the common property of functional blockade of voltage-gated Na+channels, albeit with differing binding sites. These anticonvulsants have varying affinities for voltage-dependent Ca2+ channels, and differ in their ability to facilitate GABA-ergic (valproate) or inhibit glutamatergic neurotransmission (lamotrigine).

LITHIUM. Salts of the monovalent cation lithium (Li+) share some characteristics with those of Na+ and K+. Traces of the ion occur normally in animal tissues, but it has no known physiological role. Lithium carbonate and lithium citrate are used therapeutically in the U.S.

Hypotheses for the Mechanism of Action of Lithium, and Relationship to Anticonvulsants. In animal brain tissue, Li+ at concentrations of 1-10 mEq/L inhibits the depolarization-provoked and Ca++-dependent release of NE and DA, but not 5HT, from nerve terminals. Li+ may even transiently enhance release of 5HT. Li+ modifies some hormonal responses mediated by adenylyl cyclase or PLC in other tissues, including the actions of vasopressin and thyroid-stimulating hormone on their peripheral target tissues. Li+ can inhibit the effects of receptor-blocking agents that cause supersensitivity in such systems. In part, the actions of Li+ may reflect its ability to interfere with the activity of both stimulatory and inhibitory G proteins (Gs and Gi) by keeping them in their inactive αβγ trimeric states.

Lithium’s therapeutic efficacy may involve inhibition of inositol monophosphatase of the phosphatidylinositol pathway (see Figure 16–1), leading to decreased cerebral inositol concentrations (see Chapter 3). Further support for the role of inositol signaling in mania rests on the finding that valproate, and valproate derivatives, decrease intracellular inositol concentrations. Li+ treatment also leads to consistent decreases in the functioning of protein kinases in brain tissue, including PKC, particularly isoforms α and β. This effect is also shared with valproic acid (particularly for PKC) but not with carbamazepine. The impact of Li+ or valproate on PKC activity may secondarily alter the release of amine neurotransmitters and hormones as well as the activity of tyrosine hydroxylase. The proposed mechanism of PKC inhibition has been the basis for therapeutic trials of tamoxifen, a selective estrogen receptor modulator that is also a potent centrally active PKC inhibitor. In acutely manic bipolar I patients, tamoxifen has shown evidence of efficacy as adjunctive treatment.

Both Li+ and valproate treatment inhibit the activity of glycogen synthase kinase-3β (GSK-3β). GSK-3β inhibition increases hippocampal levels of β-catenin, a function implicated in mood stabilization. GSK-3β regulates mood stabilizer-induced axonal growth and synaptic remodeling and modulates brain-derived neurotrophic factor response. Li+ and valproate reduce arachidonic acid turnover in brain membrane phospholipids, and Li+ also decreases gene expression of PLA2 and decreases levels of COX-2.

ABSORPTION, DISTRIBUTION, AND ELIMINATION. Li+ is absorbed readily and almost completely from the GI tract. Peak plasma concentrations achieved 2-4 h after an oral dose. Slow-release preparations of lithium carbonate minimize early peaks in plasma concentrations, and may decrease local GI adverse effects, but the increased trough levels may increase the risk for nephrogenic diabetes insipidus. Li+ initially is distributed in the extracellular fluid, and gradually accumulates in various tissues. The concentration gradient across plasma membranes is much smaller than those for Na+ and K+. The final volume of distribution (0.7-0.9 L/kg) approaches that of total body water. Passage through the blood-brain barrier is slow, and at steady state, the concentration of Li+ in the cerebrospinal fluid and in brain tissue is ~40-50% of the concentration in plasma.

Approximately 95% of a single dose of Li+ is eliminated in the urine. From 33-66% of an acute dose is excreted during the first 6-12 h, followed by slow excretion over the next 10-14 days. The eliminationt1/2 averages 20-24 h. Steady state is achieved after ~5 half-lives. Loading with Na+ produces a small enhancement of Li+ excretion, but Na+ depletion promotes a clinically important degree of Li+retention. Li+ is completely filtered, and 80% is reabsorbed in the proximal tubules. Heavy sweating leads to a preferential secretion of Li+ over Na+; however, the repletion of excessive sweating using free water without electrolytes can cause hyponatremia, and promote Li+ retention. Thiazide diuretics deplete Na+ and reduce Li+ clearance that may result in toxic levels. The K+-sparing diuretics triamterene, spironolactone, and amiloride have modest effects on the excretion of Li+. Less than 1% of ingested Li+ leaves the human body in the feces; 4-5% is secreted in sweat. Li+ is secreted in saliva in concentrations about twice those in plasma, while its concentration in tears is about equal to that in plasma. Li+ is secreted in human milk, but serum levels in breast-fed infants are ~20% that of maternal levels, and are not associated with notable behavioral effects.

SERUM LEVEL MONITORING AND DOSE. Because of the low therapeutic index for Li+, periodic determination of serum concentrations is crucial.

Concentrations considered to be effective and acceptably safe are between 0.6 and 1.5 mEq/L. The range of 1.0-1.5 mEq/L is favored for treatment of acutely manic or hypomanic patients. Somewhat lower values (0.6-1.0 mEq/L) are considered adequate and are safer for long-term prophylaxis. Serum concentrations of Li+ have been found to follow a clear dose-effect relationship between 0.4 and 1.0 mEq/L, but with a corresponding dose-dependent rise in polyuria and tremor as indices of adverse effects. Nonetheless, patients who maintain trough levels of 0.8-1.0 mEq/L experience decreased relapse risk compared to those maintained at lower serum concentrations.


DRUG TREATMENT OF BIPOLAR DISORDER. Treatment with Li+ ideally is conducted in patients with normal cardiac and renal function. Li+ is the only mood stabilizer with data on suicide reduction in bipolar patients, and Li+ also has abundant efficacy data for augmentation in unipolar depressive patients who are inadequate responders to antidepressant therapy.

DRUG TREATMENT OF MANIA. While Li+, valproate, and carbamazepine have efficacy in acute mania, in clinical practice these are usually combined with atypical antipsychotic drugs, due to their delayed onset of action. Li+, carbamazepine, and valproic acid preparations are only effective with daily dosing that maintains adequate serum levels, and require serum level monitoring. Acute IM forms of olanzapine, ziprasidone, and aripiprazole can be used to achieve rapid control of psychosis and agitation. Benzodiazepines are often used adjunctively for agitation and sleep induction.

A 600-mg loading dose of Li+ can be given to hasten the time to steady state. Acutely manic patients may require higher dosages to achieve therapeutic serum levels, and downward adjustment may be necessary once the patient is euthymic.

The anticonvulsant sodium valproate provides more rapid antimanic effects than Li+, with therapeutic benefit seen within 3-5 days. The most common form of valproate in use is divalproex sodium, preferred over valproic acid due to lower incidence of GI and other adverse effects. Divalproex is initiated at 25 mg/kg once daily and titrated to effect or the desired serum concentration. Serum concentrations of 90-120 μg/mL show the best response in clinical studies. With immediate release forms of valproic acid and divalproex sodium, 12-h troughs are used to guide treatment. With the extended-release divalproex preparation, patients respond best when the 24-h trough levels are in the high therapeutic range.

Carbamazepine is effective for acute mania. Immediate release forms of carbamazepine cannot be loaded or rapidly titrated over 24 h due to the development of neurological adverse effects such as dizziness or ataxia. The extended-release form is better tolerated and effective as monotherapy with once-daily dosing. Carbamazepine response rates are lower than those for valproate compounds or Li+; nevertheless, certain individuals respond to carbamazepine after failing Li+ and valproate. Initial doses are 400 mg/day, with the larger dose given at bedtime due to the sedating properties of carbamazepine. Titration proceeds by 200-mg increments every 24-48 h based on clinical response and serum trough levels. Due to increased risk of Stevens-Johnson syndrome in Asian individuals, HLA testing must be performed prior to treatment in populations at risk.

PROPHYLACTIC TREATMENT OF BIPOLAR DISORDER. Both aripiprazole and olanzapine are effective as monotherapy for mania prophylaxis, but olanzapine use is eschewed out of concern for metabolic effects, and aripiprazole shows no benefit for prevention of depressive relapse. LAI risperidone is also approved for bipolar maintenance treatment to be used adjunctively with Li+ or valproate, or as monotherapy. Clozapine can be beneficial in refractory mania patients as adjunctive therapy and as monotherapy.

Bipolar disorder is a lifetime illness with high recurrence rates. Stopping mood stabilizer therapy can be considered in patients who have experienced only 1 lifetime manic episode, and who have been euthymic for extended periods. Discontinuation of maintenance Li+ treatment in bipolar I patients carries a high risk of early recurrence and of suicidal behavior over a period of several months. This risk may be moderated by slow, gradual removal of Li+, while rapid discontinuation should be avoided unless dictated by medical emergencies.

OTHER USES OF LITHIUM. Li+ has been shown to be effective as adjunct therapy in treatment-resistant major depression. Clinical data also support Li+ use as monotherapy for unipolar depression. Meta-analyses indicate that lithium’s benefit on suicide reduction extends to unipolar mood disorder patients. While maintenance Li+ levels of 0.6-1.0 mEq/L are used for bipolar prophylaxis, a lower range (0.4-0.8 mEq/L) is recommended for antidepressant augmentation.

INTERACTIONS WITH OTHER DRUGS. Interactions between Li+ and diuretics (especially thiazides spironolactone and amiloride), angiotensin-converting enzyme inhibitors, and nonsteroidal anti-inflammatory agents have been discussed earlier. Amiloride has been used safely to reverse the syndrome of nephrogenic diabetes insipidus associated with Li+ therapy, but requires careful monitoring and Li+ dosage reduction to prevent lithium toxicity.


CNS Effects. The most common CNS effect of Li+ in the therapeutic dose range is fine postural hand tremor. Severity and risk for tremor are dose-dependent, with incidence ranging from 15-70%. In addition to the avoidance of caffeine and other agents that increase tremor amplitude, therapeutic options include dose reduction (bearing in mind the increased relapse risk with lower serum Li+ levels), or β adrenergic blockade. Valproate treatment has a similar problem, and the approach to valproate-induced tremor is identical. At peak serum (and CNS) levels, some individuals may complain of incoordination, ataxia, or slurred speech, which can be avoided by dosing Li+ at bedtime. Li+ routinely causes EEG changes characterized by diffuse slowing, widened frequency spectrum, and potentiation with disorganization of background rhythm. Seizures have been reported in nonepileptic patients with therapeutic plasma concentrations of Li+. Li+ treatment has also been associated with increased risk of post-ECT confusion, and is generally tapered off prior to a course of ECT.

Li+ (and valproate) treatment results in significant weight gain, a problem that is magnified by concurrent use of antipsychotic drugs.

Renal Effects. The kidneys’ ability to concentrate urine decreases during Li+ therapy, and ~60% of individuals exposed to Li+ experience some form of polyuria and compensatory polydipsia. The mechanism of polyuria is unclear, but the result is decreased vasopressin stimulation of renal reabsorption of water, and the clinical picture of nephrogenic diabetes insipidus. Mean 24-h urinary volumes of 3 L/day are common among long-term Li+ users, but Li+ discontinuation or a switch to single daily dosing may reverse the effect on renal concentrating ability in patients with <5 years of Li+ exposure. Renal function should be monitored with biannual serum blood urea nitrogen and creatinine levels, calculation of estimated GFR using standard formulas, and annual measurement of 24-h urinary volume.

Thyroid and Endocrine Effects. A small number of patients on Li+ develop a benign, diffuse, nontender thyroid enlargement suggestive of compromised thyroid function, although many of these patients will have normal thyroid function. Measurable effects of Li+ on thyroid indices are seen in a fraction of patients: 7-10% develop overt hypothyroidism, and 23% have subclinical disease, with women at 3-9 times greater risk. Ongoing monitoring of TSH and free T4 is recommended throughout the course of Li+ treatment.

ECG Effects. The prolonged use of Li+ causes a benign and reversible T-wave flattening in ~20% of patients and the appearance of U waves, effects unrelated to depletion of Na+ or K+. Li+-induced effects on cardiac conduction and pacemaker automaticity become pronounced during overdose and lead to sinus bradycardia, atrioventricular blocks, and possible CV compromise. Routine ECG monitoring may be considered in older patients, particularly those with a history of arrhythmia or coronary heart disease.

Skin Effects. Allergic reactions such as dermatitis, folliculitis, and vasculitis can occur with Li+ administration. Worsening of acne vulgaris, psoriasis, and other dermatological conditions are usually treatable by topical measures, but in some may improve only upon discontinuation of Li+. Some patients on Li+ (and valproate) may experience alopecia.

PREGNANCY AND LACTATION. Li+ is classified as risk category D. The use of Li+ in early pregnancy may be associated with an increase in the incidence of CV anomalies of the newborn, especially Ebstein malformation. Although the anticonvulsants valproic acid and carbamazepine are also pregnancy risk category D, these agents are associated with irreversible neural tube defects. Potentially safer treatments for acute mania include antipsychotic drugs or ECT.

In pregnancy, maternal polyuria may be exacerbated by Li+. Concomitant use of Li+ with medications that waste Na+ or a low-Na+ diet during pregnancy can contribute to maternal and neonatal Li+intoxication. Li+ freely crosses the placenta, and fetal or neonatal Li+ toxicity may develop when maternal blood levels are within the therapeutic range. Fetal Li+ exposure is associated with neonatal goiter, CNS depression, hypotonia (“floppy baby” syndrome), and cardiac murmur. Most recommend withholding lithium therapy for 24-48 h before delivery.

Other Effects. A benign, sustained increase in circulating polymorphonuclear leukocytes (12,000-15,000 cells/mm3) occurs during the chronic use of Li+ and is reversed within a week after termination of treatment. Some patients complain of a metallic taste, making food less palatable. Myasthenia gravis may worsen during treatment with Li+.

ACUTE TOXICITY AND OVERDOSE. Acute intoxication is characterized by vomiting, profuse diarrhea, coarse tremor, ataxia, coma, and convulsions. Symptoms of milder toxicity include nausea, vomiting, abdominal pain, diarrhea, sedation, and fine tremor. The more serious effects involve the nervous system and include mental confusion, hyperreflexia, gross tremor, dysarthria, seizures, and cranial nerve and focal neurological signs, progressing to coma and death. Sometimes both cognitive and motor neurological damage may be irreversible, with persistent cerebellar tremor being the most common. Other toxic effects are cardiac arrhythmias, hypotension, and albuminuria.


Pediatric Use. Only Li+ has FDA approval for child/adolescent bipolar disorder for ages >12 years. Recently, aripiprazole and risperidone were FDA-approved for acute mania in children and adolescents ages 10-17. Children and adolescents have higher volumes of body water and higher GFR than adults. The resulting shorter t1/2 of Li+ demands dosing increases on a mg/kg basis, and multiple daily dosing is often required. As with adults, ongoing monitoring of renal and thyroid function is important. A number of studies suggest that valproate has efficacy comparable to that of Li+ for mania in children or adolescents. As with Li+, weight gain and tremor can be problematic. Ongoing monitoring of platelets and liver function tests, in addition to serum drug levels, is recommended.

Geriatric Use. The majority of older patients on Li+ therapy are maintained for years on the medication. Age-related reductions in total body water and creatinine clearance reduce the safety margin for Li+treatment in older patients. Li+ toxicity occurs more frequently in elderly patients, in part as the result of concurrent use of loop diuretics and angiotensin-converting enzyme inhibitors. Anticonvulsants, especially extended-release divalproex, are a reasonable alternative to Li+. Elderly patients who are drug-naïve may be more sensitive to CNS adverse effects.


FORMULATIONS. Most Li+ preparations currently used in the U.S. are tablets or capsules of lithium carbonate in strengths of 150, 300, and 600 mg. Slow-release preparations of lithium carbonate also are available in strengths of 300 and 450 mg, as is lithium citrate syrup (with 8 mEq of Li+/5 mL citrate liquid, equivalent to 300 mg of lithium carbonate). Because slow-release forms carry an increased risk for polyuria, their use should be limited to patients who experience GI side effects related to rapid absorption.