Drugs and the Treatment of Psychiatric Disorders: Psychosis and Mania

Several classes of drugs are effective in the symptomatic treatment of psychiatric disorders. They are most appropriately used in the therapy of schizophrenia, the manic phase of bipolar (manic-depressive) illness, and other acute idiopathic psychotic illnesses or conditions marked by severe agitation. They also are used as an alternative to electroconvulsive therapy (ECT) in severe depression with psychotic features and sometimes in the management of patients with organic psychotic disorders.

Effective antipsychotic agents include phenothiazines, structurally similar thioxanthenes, and benzepines; butyrophenones (phenylbutylpiperidines) and diphenylbutylpiperidines; and indolones and other heterocyclic compounds. Since these chemically dissimilar drugs share many properties, information about their pharmacology and clinical uses is presented for the group as a whole. Particular attention is paid to chlorpromazine, the oldest representative of the phenothiazinethioxanthene group of antipsychotic agents, and haloperidol, the original butyrophenone and representative of several related classes of aromatic butylpiperidine derivatives.

Many patients have been treated with the antipsychotic agents since their introduction in the 1950s. Although they have had a revolutionary, beneficial impact on medical and psychiatric practice, their liabilities, especially the almost relentless association of older, typical or 'neuroleptic' agents with extrapyramidal neurological effects, also must be emphasized. Newer antipsychotics are atypical in having less risk of extrapyramidal side effects, but some of them produce hypotension, seizures, weight gain, diabetes, hyperprolactinemia, and other adverse effects.

Tricyclic Antipsychotic Agents

Antipsychotic agents are used primarily in the management of patients with psychotic or other serious psychiatric illnesses marked by agitation and impaired reasoning. Several dozen antipsychotic drugs are used in psychiatric conditions worldwide; still others are marketed primarily for other uses, including antiemetic and antihistaminic effects. The term neuroleptic has taken on connotations, at least in the United States, of relatively prominent experimental and clinical antagonism of D₂-dopamine receptor activity, with substantial risk of extrapyramidal side effects. The term atypical antipsychotic has been used to describe agents that are associated with substantially lower risks of adverse extrapyramidal effects. Representative examples include clozapine, olanzapine, quetiapine, and low doses of risperidone (Blin, 1999; Markowitz et al., 1999).

History

The history of the antipsychotic agents is well summarized by Swazey (1974) and Caldwell (1978). In the early 1950s, some antipsychotic effects were obtained with extracts of the Rauwolfia plant and then with large doses of the purified active alkaloid reserpine, which was later chemically synthesized by Woodward. Although reserpine and related compounds that share its ability to deplete monoamines from their vesicular storage sites in neurons exert antipsychotic effects, these are relatively weak and are typically associated with severe side effects, including sedation, hypotension, diarrhea, anergy, and depressed mood. Thus, the clinical utility of reserpine primarily has been as an antihypertensive agent (seeChapter 33: Antihypertensive Agents and the Drug Therapy of Hypertension).

Phenothiazine compounds were synthesized in Europe in the late nineteenth century as part of the development of aniline dyes such as methylene blue. In the late 1930s, a phenothiazine derivative, promethazine, was found to have antihistaminic and sedative effects. Attempts to treat agitation in psychiatric patients with promethazine and other antihistamines followed in the 1940s, but with little success.

Meanwhile, the ability of promethazine to prolong barbiturate sleeping time in rodents was discovered, and the drug was introduced into clinical anesthesia as a potentiating and autonomic stabilizing agent (Laborit et al., 1952). This work prompted a search for other phenothiazine derivatives with anesthesia-potentiating actions, and in 19491950 Charpentier synthesized chlorpromazine. Soon thereafter, Laborit and his colleagues described the ability of this compound to potentiate anesthetics and produce 'artificial hibernation.' Chlorpromazine by itself did not cause a loss of consciousness but diminished arousal and motility, with some tendency to promote sleep. These central actions became known as ataractic or neuroleptic soon thereafter.

The first attempts to treat mental illness with chlorpromazine were made in Paris in 1951 and early 1952 by Paraire and Sigwald (seeSwazey 1974). In 1952, Delay and Deniker became convinced that chlorpromazine achieved more than symptomatic relief of agitation or anxiety and that it had an ameliorative effect upon psychotic processes in diverse disorders. In 1954, Lehmann and Hanrahan in Montreal, followed by Winkelman in Philadelphia, reported the initial use of chlorpromazine in North America for the treatment of psychomotor excitement and manic states as well as schizophrenia (seeSwazey, 1974). Clinical studies soon revealed that chlorpromazine was effective in the treatment of psychotic disorders of various types.

Chemistry and StructureActivity Relationships

This topic is reviewed in detail elsewhere (Baldessarini, 1985; Neumeyer and Booth, 2001). Phenothiazines have a three-ring structure in which two benzene rings are linked by a sulfur and a nitrogen atom (seeTable 201). If the nitrogen at position 10 is replaced by a carbon atom with a double bond to the side chain, the compound is a thioxanthene.

Substitution of an electron-withdrawing group at position 2 increases the efficacy of phenothiazines and other tricyclic congeners (e.g., chlorpromazinevs.promazine). The nature of the substituent at position 10 also influences pharmacological activity. As can be seen in Table 201, the phenothiazines and thioxanthenes can be divided into three groups on the basis of substitution at this site. Those with an aliphatic side chain include chlorpromazine and triflupromazine among the phenothiazines; these compounds are relatively low in potency (but not in clinical efficacy). Those with a piperidine ring in the side chain include thioridazine and mesoridazine. There is a somewhat lower incidence of extrapyramidal side effects with this substitution, possibly due to increased central antimuscarinic activity. Several potent phenothiazine antipsychotic compounds have a piperazine group in the side chain; fluphenazine and trifluoperazine are examples. Use of these potent compounds, most of which have relatively weak anticholinergic activity, entails a greater risk of inducing extrapyramidal side effects but less tendency to produce sedation or autonomic side effects, such as hypotension, unless unusually large doses are employed. Several piperazine phenothiazines have been esterified at a free hydroxyl group with long-chain fatty acids to produce slowly absorbed and hydrolyzed, long-acting, highly lipophilic prodrugs. The decanoates of fluphenazine and haloperidol and enanthate of fluphenazine are used commonly in the United States, and several others are available internationally.

Thioxanthenes also have aliphatic or piperazine side-chain substituents. The analog of chlorpromazine among the thioxanthenes is chlorprothixene. Piperazine-substituted thioxanthenes include clopenthixol, flupentixol, piflutixol, and thiothixene; they are all potent and effective antipsychotic agents, although only thiothixene is available in the United States. Since thioxanthenes have an olefinic double bond between the central-ring carbon atom at position 10 and the side chain, geometric isomers exist; the cis (or ) isomers are the more active.

The antipsychotic phenothiazines and thioxanthenes have three carbon atoms interposed between position 10 of the central ring and the first amino nitrogen atom of the side chain at this position; the amine is always tertiary. Antihistaminic phenothiazines (e.g., promethazine) or strongly anticholinergic phenothiazines (e.g., ethopropazine, diethazine) have only two carbon atoms separating the amino group from position 10 of the central ring. Metabolic N-dealkylation of the side chain or increasing the size of amino N-alkyl substituents reduces antipsychotic activity.

Additional tricyclic antipsychotic agents are the benzepines, containing a seven-member central ring, of which loxapine (a dibenzoxazepine; seeTable 201) and clozapine (a dibenzodiazepine) are available in the United States. Loxapine-like agents include potent and typical neuroleptics with prominent antidopaminergic activity (e.g., clothiapine, metiapine, loxapine, zotepine, and others). They have an electron-withdrawing moiety at position 2, relatively close to the side-chain nitrogen atoms.

Clozapine-like agents either lack a ring substituent (e.g., quetiapine, a dibenzothiazepine), have an analogous methyl substituent (notably olanzapine, a thienobenzodiazepine; seeTable 201), or have an electronegative substituent at position 8, away from the side-chain nitrogen atoms (e.g., clozapine, fluperlapine, and others). In addition to dopamine receptors, clozapine-like agents interact at several other classes of receptors with varying affinities ( - and -adrenergic, serotonin 5-HT_2A and 5-HT_2C, muscarinic cholinergic, histamine H₁, and others). Some are highly effective antipsychotic agents, and clozapine, in particular, has proved effective even in chronically ill patients who respond poorly to standard neuroleptics. The basic and clinical pharmacology of clozapine is reviewed elsewhere (Baldessarini and Frankenburg, 1991; Wagstaff and Bryson, 1995; Worrell et al., 2000).

Clozapine strongly stimulated searches for additional, safer agents with antipsychotic activity and an atypically low risk of extrapyramidal neurological side effects. This search led to a series of atypical antipsychotic agents with some pharmacological similarities to clozapine. These include the structurally similar olanzapine and quetiapine, and the mixed antidopaminergic-antiserotonergic agent risperidone (a benzisoxazole; seeTable 201; Owens and Risch, 1998; Waddington and Casey, 2000).

The butyrophenone (phenylbutylpiperidine) neuroleptics include haloperidol (Janssen, 1974). Other experimental heterocyclic-substituted phenylbutylpiperidines include the spiperones. An analogous compound, droperidol, is a very short-acting, highly sedative neuroleptic that is used almost exclusively in anesthesia (seeChapter 14: General Anesthetics) but sometimes also in psychiatric emergencies. Additional analogs in the diphenylbutylpiperidine series include fluspirilene, penfluridol, and pimozide (seeTable 201 and Neumeyer and Booth, 2001). These are potent neuroleptics with prolonged action. In the United States, pimozide is indicated for the treatment of Tourette's syndrome of severe tics and involuntary vocalizations, although it also is an effective antipsychotic.

Several other classes of heterocyclic compounds have antipsychotic effects, but too few are available or sufficiently well characterized to permit conclusions regarding structureactivity relationships (seeNeumeyer and Booth, 2001). These include several indole compounds [notably, molindone (seeTable 201) and oxypertine]. Another experimental compound, butaclamol, is a potent antidopaminergic agent that has a pentacyclic structure with a dibenzepine core and structural and pharmacological similarity to loxapine-like rather than clozapine-like dibenzepines. Its active (dextrorotatory) and inactive enantiomeric forms have been useful in characterizing the stereochemistry of sites of action of neuroleptics at dopamine receptors.

Risperidone (seeTable 201) has prominent antiserotonergic (5-HT₂) as well as antidopaminergic (D₂) and antihistaminic (H₁) activity. Although risperidone and clozapine share those receptor affinities, risperidone is a much more potent antidopaminergic agent and, unlike clozapine, can induce extrapyramidal symptoms as well as prominent hyperprolactinemia. Nevertheless, risperidone can be considered a 'quantitatively atypical' antipsychotic agent in that its extrapyramidal neurological side effects are limited at low daily doses (6 mg or less).

A growing series of heterocyclic antipsychotic agents are the enantiomeric, substituted benzamides. These include the gastroenterologic agents metoclopramide and cisapride, which have antiserotonergic as well as antiD₂-dopaminergic actions. In addition, several benzamides, like the butyrophenones and their congeners, are relatively selective antagonists at central D₂dopamine receptors, and many have neuroleptic-antipsychotic activity. Experimental examples include epidepride, eticlopride, nemonapride, raclopride, remoxipride, and sultopride; sulpiride is employed clinically in other countries, mainly as a sedative.

Pharmacological Properties

Antipsychotic drugs share many pharmacological effects and therapeutic applications (seeBaldessarini, 1985; Marder, 1998; Owens and Risch, 1998). Chlorpromazine and haloperidol are commonly taken as prototypes for the older, standard neuroleptic-type agents; newer agents can be compared and contrasted to them. Many antipsychotic drugs, especially chlorpromazine and other agents of low potency, have a prominent sedative effect. This is particularly conspicuous early in treatment, although tolerance to this effect is typical; sedation may not be noticeable when very agitated psychotic patients are treated. Despite their sedative effects, neuroleptic drugs generally are not used to treat anxiety disorders, largely because of their autonomic and neurological side effects, which paradoxically can include severe anxiety and restlessness (akathisia). The risk of developing extrapyramidal side effects including tardive dyskinesia following long-term administration of neuroleptic drugs makes these agents less desirable than others for the treatment of anxiety.

The term neuroleptic was introduced to denote the effects of chlorpromazine and reserpine on the behavior of laboratory animals and in psychiatric patients and was intended to contrast their effects to those of sedatives and other CNS depressants. The neuroleptic syndrome involves suppression of spontaneous movements and complex behaviors, while spinal reflexes and unconditioned nociceptive-avoidance behaviors remain intact. In human beings, neuroleptic drugs reduce initiative and interest in the environment as well as manifestations of emotion or affect. Such effects led to their being considered 'tranquilizers' before their unique antipsychotic effects were well established. In their clinical use, there may be some initial slowness in response to external stimuli and drowsiness. However, subjects are easily aroused, can answer questions, and retain intact cognition. Ataxia, incoordination, or dysarthria do not occur at ordinary doses. Typically, psychotic patients soon become less agitated, and withdrawn or autistic patients sometimes become more responsive and communicative. Aggressive and impulsive behavior diminishes. Gradually (usually over a period of days), psychotic symptoms of hallucinations, delusions, and disorganized or incoherent thinking tend to disappear. Neuroleptic agents also exert characteristic neurological effectsincluding bradykinesia, mild rigidity, some tremor, and subjective restlessness (akathisia)that resemble the signs of Parkinson's disease.

Although early use of the term neuroleptic appears to have encompassed the whole unique syndrome just described and neuroleptic still is used as a synonym for antipsychotic, there now is a tendency to use the term neuroleptic to emphasize the more neurological aspects of the syndrome (i.e., the parkinsonian and other extrapyramidal effects). Except for clozapine and perhaps olanzapine and quetiapine, all antipsychotic drugs available in the United States also have effects on movement and posture and can thus be called neuroleptic. However, the more general term antipsychotic is preferable. Introduction of atypical drugs such as clozapine, olanzapine, and quetiapine that are antipsychotic and have little extrapyramidal action has reinforced this trend.

General Psychophysiological and Behavioral Effects

In laboratory animals and in human beings, the most prominent observable effects of many antipsychotic agents are strikingly similar (Fielding and Lal, 1978). In low doses, operant behavior is reduced but spinal reflexes are unchanged. In laboratory animals, exploratory behavior is diminished, and responses to a variety of stimuli are fewer, slower, and smaller in magnitude, although the ability to discriminate stimuli is retained. Conditioned avoidance behaviors are selectively inhibited, whereas unconditioned escape or avoidance responses are not. Highly reinforcing self-stimulation of the animal brain (commonly induced with electrodes placed in the monoamine-rich medial forebrain bundle) is blocked, although capacity to press the stimulation-inducing lever is not lost. Behavioral activation, stimulated environmentally or pharmacologically (particularly by stimulants and dopaminergic agonists), is blocked. Feeding is inhibited. Most neuroleptics block the emesis, hyperactivity, and aggression induced by apomorphine and other dopaminergic agonists. In high doses, most neuroleptics induce characteristic cataleptic immobility that allows an animal to be placed in abnormal postures that persist. Muscle tone is increased, and ptosis is typical. The animal appears to be indifferent to most stimuli, although it continues to withdraw from those that are noxious or painful. Many learned tasks still can be performed if sufficient stimulation and motivation are provided. Even very high doses of most neuroleptics do not induce coma, and the lethal dose is extraordinarily high.

Effects on Motor Activity

Nearly all antipsychotic agents diminish spontaneous motor activity in laboratory animals and in human beings. However, one of the more disturbing clinical side effects of these agents is akathisia, which is manifest by an increase in restless activity that is not readily mimicked by animal behavior. The cataleptic immobility of animals treated with neuroleptics resembles the catatonia seen in some psychotic patients as well as in association with a variety of metabolic and neurological disorders affecting the central nervous system (CNS). In patients, catatonic signs, along with other features of psychotic illnesses, are sometimes relieved by antipsychotic agents. However, rigidity and bradykinesia, which mimic catatonia, can be induced in patients, especially by large doses of potent neuroleptics, and reversed by removal of the offending drug or the addition of an antiparkinsonian agent (seeFielding and Lal, 1978; Janssen and Van Bever, 1978). Theories concerning the mechanisms underlying these extrapyramidal reactions, as well as descriptions of their clinical presentations and management, are given below.

Effects on Sleep

Antipsychotic drugs have inconsistent effects on sleep patterns, but tend to normalize sleep disturbances characteristic of many psychoses and mania. Ability to prolong and enhance the effect of opioid and hypnotic drugs appears to parallel the sedative rather than the neuroleptic potency of a particular agent. Thus, the more potent neuroleptic agents that do not cause drowsiness also do not enhance hypnosis produced by other drugs.

Effects on Conditioned Responses

Chlorpromazine and other neuroleptics impair the ability of animals to make a conditioned avoidance response to a learned sensory cue that signals the onset of punishing shock avoidable by moving to a safe place in an experimental chamber. Under the influence of small doses of these drugs, animals ignore the warning signal but still attempt to escape once the shock is applied. General CNS depressants affect both avoidance (the conditioned response) and escape (the unconditioned response) to approximately the same extent, but suppression of unconditioned escape occurs only with doses of neuroleptics that produce ataxia or hypnosis. Passive avoidance behavior, requiring immobility, also is suppressed by neuroleptic drugs, in contrast to what might be expected of drugs that suppress locomotion.

Since correlations between antipsychotic effectiveness and conditioned avoidance tests are good for many types of neuroleptic agents, they have been important in pharmaceutical screening procedures. However, despite their empirical utility and quantitative characteristics, effects on conditioned avoidance have not provided important insights into the basis of clinical antipsychotic effects. For example, the effects of neuroleptic drugs on conditioned avoidance, but not their clinical antipsychotic actions, are subject to tolerance and are blocked by anticholinergic agents. Moreover, the extraordinarily close correlation between the potencies of drugs in conditioned avoidance tests and their ability to block the behavioral effects of dopaminergic agonists such as amphetamine or apomorphine suggests that such avoidance tests may be selective for drugs with extrapyramidal and other neurological effects. The ability of the atypical antipsychotic drugs, such as clozapine and olanzapine, to antagonize dopamine agonists and to block conditioned avoidance responses in animal behavioral tests also supports this interpretation (seeFielding and Lal, 1978; Janssen and Van Bever, 1978; Arnt and Skarsfeldt, 1998).

Effects on Complex Behavior

Antipsychotic drugs can impair vigilance or motor responses in human subjects performing a variety of tasks, such as continuous rotor-pursuit and tapping-speed tests. The drugs produce relatively little impairment of digitsymbol substitution, a test of intellectual functioning. In contrast, barbiturates cause greater impairment in performance in digitsymbol substitution than in continuous performance and other vigilance tests. Moreover, most antipsychotic agents can improve cognitive functioning in psychotic patients with symptomatic improvement.

Effects on Specific Areas of the Nervous System

Effects of antipsychotic drugs are apparent at all levels in the nervous system. Although knowledge of the actions underlying the antipsychotic and many of the neurological effects of neuroleptic drugs remains incomplete, theories based on their ability to antagonize the actions of dopamine as a neurotransmitter in the basal ganglia and limbic portions of the forebrain have become most prominent and are supported by a large body of data.

Cerebral Cortex

Since psychosis involves a disorder of higher functions and thought processes, cortical effects of antipsychotic drugs are of great interest. Antipsychotic drugs interact with dopaminergic projections to the prefrontal and deep-temporal (limbic) regions of the cerebral cortex with relative sparing of these areas from adaptive changes in dopamine metabolism that would suggest tolerance to the actions of neuroleptics (Bunney et al., 1987).

Seizure Threshold

Many neuroleptic drugs can lower the seizure threshold and induce discharge patterns in the electroencephalogram (EEG) that are associated with epileptic seizure disorders. Clozapine as well as aliphatic phenothiazines with low potency (such as chlorpromazine) seem particularly able to do this, while the more potent piperazine phenothiazines and thioxanthenes (notably fluphenazine and thiothixene), as well as risperidone, seem much less likely to have this effect (Itil, 1978; Baldessarini and Frankenburg, 1991). The butyrophenones have variable and unpredictable effects that cause seizure activity; molindone may have the least activity of this type. Clozapine has a clearly dose-related risk of inducing seizures in nonepileptic patients (Baldessarini and Frankenburg, 1991), and clozapine and olanzapine are associated with more EEG abnormalities than are many high-potency neuroleptics, including risperidone (Centorrino et al., 2001). Antipsychotic agents, especially clozapine and low-potency phenothiazines and thioxanthenes, should be used with extreme caution, if at all, in untreated epileptic patients and in patients undergoing withdrawal from central depressants such as alcohol, barbiturates, or benzodiazepines. Most antipsychotic drugs, especially the piperazines, as well as the novel atypical agents quetiapine and risperidone, can be used safely in epileptic patients if moderate doses are attained gradually and if concomitant anticonvulsant drug therapy is maintained (seeChapter 21: Drugs Effective in the Therapy of the Epilepsies).

Basal Ganglia

Because the extrapyramidal effects of most clinically used antipsychotic drugs are prominent, a great deal of interest has centered on the actions of these drugs in the basal ganglia, notably the caudate nucleus, putamen, globus pallidus, and allied nuclei, which play a crucial role in the control of posture and the extrapyramidal aspects of movement. The critical role of a deficiency of dopamine in this region in the pathogenesis of Parkinson's disease, the potent activity of neuroleptics as antagonists of dopamine receptors, and the striking resemblance between clinical manifestations of Parkinson's disease and the neurological effects of neuroleptic drugs all have focused attention on the role of a deficiency of dopaminergic activity in some of the neuroleptic-induced extrapyramidal effects (Carlsson, 1990).

The hypothesis that interference with the transmitter function of dopamine in the mammalian forebrain might contribute to the neurological and possibly also the antipsychotic effects of the neuroleptic drugs arose from the observation that neuroleptic drugs consistently increased the concentrations of the metabolites of dopamine but had variable effects on the metabolism of other neurotransmitters. The importance of dopamine also was supported by histochemical studies, which indicated a preferential distribution of dopamine-containing fibers between midbrain and the basal ganglia (notably, the nigrostriatal tract), and within the hypothalamus (seeChapter 12: Neurotransmission and the Central Nervous System). Other dopamine-containing neurons project from midbrain tegmental nuclei to forebrain regions associated with the limbic system as well as to temporal and prefrontal cerebral cortical areas closely related to the limbic system. A simplistic but attractive concept arose: many extrapyramidal neurological effects of the antipsychotic drugs might be mediated by antidopaminergic effects in the basal ganglia. Their antipsychotic effects might be mediated by modification of dopaminergic neurotransmission in the limbic, mesocortical, and hypothalamic systems.

Antagonism of dopamine-mediated synaptic neurotransmission is an important action of neuroleptic drugs (Carlsson, 1990). Thus, drugs with neuroleptic actions, but not their inactive congeners, initially increase the rate of production of dopamine metabolites, the rate of conversion of the precursor amino acid tyrosine to dihydroxyphenylalanine (DOPA) and its metabolites, and the rate of firing of dopamine-containing cells in the midbrain. These effects usually have been interpreted to represent adaptive responses of neuronal systems that tend to reduce the impact of interrupting synaptic transmission at dopaminergic terminals in the forebrain.

Supporting evidence for such an interpretation includes the observation that small doses of neuroleptic drugs block behavioral or neuroendocrine effects of systemically administered or intracerebrally injected dopaminergic agonists. An example is stereotyped gnawing behavior in the rat induced by apomorphine. Many neuroleptic drugs (except the butyrophenones, their congeners, and the benzamides) also block the effects of agonists on dopamine-sensitive adenylyl cyclase associated with D₁-dopamine receptors in forebrain tissue (Figure 201). Atypical antipsychotic drugs such as clozapine and quetiapine are characterized by their low affinity or weak actions in such tests (Campbell et al., 1991). Whereas the initial effect of neuroleptics is to block D₂ receptors and stimulate increased firing and metabolic activity in dopamine neurons, these responses eventually are replaced by diminished activity ('depolarization inactivation'), particularly in the extrapyramidal basal ganglia (Bunney et al., 1987). The timing of these adaptive changes correlates well with the gradual evolution of parkinsonian bradykinesia over days in the clinical application of neuroleptics (Tarsy et al., 2001).

Radioligand-binding assays for dopamine receptor subtypes have been used to define more precisely the mechanism of action of neuroleptic agents (seeCivelli et al., 1993; Baldessarini and Tarazi, 1996; Neve and Neve, 1997; seeTable 202 and Figure 201). Estimates of the clinical potency of most types of antipsychotic drugs correlate well with their relative potency in vitro to inhibit binding of these ligands to D₂-dopamine receptors (seeChapter 12: Neurotransmission and the Central Nervous System). This correlation is obscured to some extent by the tendency of neuroleptics to accumulate in brain tissue to different degrees (Tsuneizumi et al., 1992; Cohen et al., 1992). Nevertheless, almost all clinically effective antipsychotic agents (with the notable exception of clozapine and quetiapine) have characteristically high affinity for D₂ receptors. Although some antipsychotics (especially thioxanthenes, phenothiazines, and clozapine) bind with relatively high affinity to D₁ receptors, they also block D₂ receptors and other D₂-like receptors including the D₃- and D₄-receptor subtypes (Sokoloff et al., 1990; Van Tol et al., 1991; Baldessarini and Tarazi, 1996; Tarazi and Baldessarini, 1999). Butyrophenones and congeners (e.g., haloperidol, pimozide, N-methylspiperone) as well as experimental benzamide neuroleptics (e.g., eticlopride, nemonapride, raclopride, remoxipride) have relatively high selectivity as antagonists at D₂ and D₃ dopamine receptors, with variable D₄ affinity. The physiological and clinical consequences of selectively blocking D₁ or D₅ receptors remain obscure, although experimental benzazepines (e.g., SCH-23390 and SCH-39166 or ecopipam) with such properties, but apparently weak antipsychotic effects, are known (Daly and Waddington, 1992; Kebabian et al., 1997).

Atypical antipsychotic agents with a low risk of extrapyramidal side effects, such as clozapine and other benzepines, have low affinity for D₂-dopamine receptors and little propensity to produce extrapyramidal side effects. They are, however, active -adrenergic antagonists, as are many other antipsychotic agents (Baldessarini et al., 1992). This action may contribute to sedative and hypotensive side effects or might underlie useful psychotropic effects, although assessment of the psychotropic potential of centrally active antiadrenergic agents is limited. Many antipsychotic agents also have some affinity for 5-HT_2A-serotonin receptors, and this is particularly prominent in the case of clozapine, olanzapine, quetiapine, risperidone, and other investigational D₂/5-HT_2A antagonists (Chouinard et al., 1993; Leysen et al., 1994; see also Chapter 11: 5-Hydroxytryptamine (Serotonin): Receptor Agonists and Antagonists). This admixture of moderate affinities for several CNS receptor types (including also muscarinic acetylcholine and H₁-histamine receptors) may contribute to the virtually unique pharmacological profile of the atypical antipsychotic agent clozapine (Baldessarini and Frankenburg, 1991). Clozapine also has modest selectivity for dopamine D₄ receptors over other dopamine-receptor types. D₄ receptors, preferentially localized in cortical and limbic brain regions, are upregulated after repeated administration of clozapine and other typical and atypical antipsychotic drugs. These receptors may contribute to the clinical actions of antipsychotic drugs, although agents that are selective D₄ or mixed D₄/5-HT_2A antagonists have not proved effective in the treatment of psychotic patients (Baldessarini, 1997; Kramer et al., 1997; Tarazi and Baldessarini, 1999; Truffinet et al., 1999; see'Prospectus,' below).

Limbic System

Dopaminergic projections from the midbrain terminate on septal nuclei, the olfactory tubercle, the amygdala, and other structures within the temporal and prefrontal lobes of the cerebrum. Because of the dopamine hypothesis just reviewed, much attention also has been given to the mesolimbic and mesocortical systems as possible sites of mediation of some of the antipsychotic effects of these agents. Speculations about the pathophysiology of the idiopathic psychoses, such as schizophrenia, have for many years centered on the limbic system. Such speculation has been given indirect encouragement by repeated 'natural experiments' that have associated psychotic mental phenomena with lesions of the temporal lobe and other portions of the limbic system.

The finding that D₃ and D₄ receptors are preferentially expressed in limbic areas of the CNS has led to increased efforts to identify agents selective for these receptors that might have antipsychotic efficacy with a reduced tendency to cause extrapyramidal side effects, so far without success (Kebabian et al., 1997; Kramer et al., 1997; Lahti et al., 1998; Tarazi and Baldessarini, 1999). Moreover, long-term administration of typical and atypical antipsychotic drugs does not alter D₃ receptor levels in rat forebrain regions while increasing expression of D₂ and D₄ receptors (Tarazi et al., 1997). These findings suggest that D₃ receptors are unlikely to play a pivotal role in antipsychotic drug actions, perhaps due to their avid affinity for endogenous dopamine, which may prevent their interaction with antipsychotics (Levant, 1997).

Many of the behavioral, neurophysiological, biochemical, and pharmacological findings with regard to the properties of the dopaminergic system of the basal ganglia have been extended to mesolimbic and mesocortical tissue. Certain important effects of antipsychotic drugs are similar in extrapyramidal and limbic regions, including those on ligand-binding assays for dopaminergic receptors. However, the extrapyramidal and antipsychotic actions of antipsychotic agents differ in several ways. For example, while some acute extrapyramidal effects of neuroleptics tend to diminish or to disappear with time or when anticholinergic drugs are administered concurrently, this is not characteristic of the antipsychotic effects. Dopaminergic subsystems in the forebrain differ functionally and in the physiological regulation of their responses to drugs (seeBunney et al., 1987; Moore, 1987; Sulser and Robinson, 1978; Wolf and Roth, 1987). For example, anticholinergic agents block the increase in turnover of dopamine in the basal ganglia induced by neuroleptic agents but not in limbic areas containing dopaminergic terminals. Further, development of tolerance to enhancement of the metabolic turnover of dopamine by antipsychotics is much less prominent in limbic than in extrapyramidal areas (see Carlsson, 1990).

In Vivo Occupation of Cerebral Neurotransmitter Receptors

Levels of occupation of dopamine receptors and other receptors in human brain can be estimated with positron emission tomography (PET) in patients treated with antipsychotic drugs. Such analyses not only support conclusions arising from laboratory studies of receptor occupancy (seeTable 202) but also assist in predicting clinical efficacy and extrapyramidal side effects as well as clinical dosing, even in advance of controlled clinical trials (Farde et al., 1995; Waddington and Casey, 2000).

For example, occupation of more than 75% of D₂-like receptors in the basal ganglia is associated with risk of acute extrapyramidal side effects and is commonly found with clinical doses of typical neuroleptics (Farde et al., 1995). In contrast, therapeutic doses of clozapine usually are associated with lower levels of occupation of D₂ receptors (averaging 40% to 50%), but higher (70% to 90%) levels of occupation of cortical 5-HT₂ receptors (Kapur et al., 1999; Nordstrom et al., 1995).

Of the novel atypical antipsychotics, only quetiapine has a clozapine-like in vivo receptor-occupancy profile, resembling clozapine's levels of occupation of both D₂ (40% to 50%) and 5-HT₂ receptors (50% to 70%) (Gefvert et al., 1998). Olanzapine and risperidone also block cortical 5-HT₂ receptors at high levels (80% to 100%), with greater effects at D₂ sites (typically, 50% to 90%) than have clozapine or quetiapine (Farde et al., 1995; Nordstrom et al., 1998; Kapur et al., 1999). In addition to its relatively high levels of D₂-receptor occupation, olanzapine is more antimuscarinic than is risperidone, perhaps accounting for its lower risk of acute extrapyramidal effects (seeTables 201 and 202).

Hypothalamus and Endocrine Systems

In addition to neurological and antipsychotic effects that appear to be mediated in part by antidopaminergic actions of neuroleptic drugs, endocrine changes occur as a result of their effects on the hypothalamus or pituitary that also may involve dopamine. Prominent among these is the ability of most antipsychotic drugs to increase the secretion of prolactin.

This effect on prolactin secretion probably is due to a blockade of the pituitary actions of the tuberoinfundibular dopaminergic system that projects from the arcuate nucleus of the hypothalamus to the median eminence. D₂-dopaminergic receptors on mammotrophic cells in the anterior pituitary mediate the prolactin-inhibiting action of dopamine secreted at the median eminence into the hypophyseal portal system (seeBen-Jonathan, 1985; see alsoChapter 56: Pituitary Hormones and Their Hypothalamic Releasing Factors).

Correlations between the potencies of antipsychotic drugs in stimulating prolactin secretion and causing behavioral effects are excellent for many types of agents (Sachar, 1978). Clozapine and quetiapine are exceptional in having minimal effects on prolactin (Arvanitis et al., 1997; Sachar, 1978), and olanzapine produces only minor, transient increases in prolactin levels (Tollefson and Kuntz, 1999), whereas risperidone has an unusually potent prolactin-elevating effect (Grant and Fitton, 1994). The effects of neuroleptics on prolactin secretion tend to occur, however, at lower doses than do their antipsychotic effects; this may reflect their action outside the bloodbrain barrier in the adenohypophysis. Little tolerance develops to the effect of antipsychotic drugs on prolactin, even after years of treatment. However, the effect is rapidly reversible when the drugs are discontinued (Bitton and Schneider, 1992). This effect of antipsychotic agents is presumed to be responsible for the breast engorgement and galactorrhea that occasionally are associated with their use, sometimes even in male patients given high doses of neuroleptic agents. Because antipsychotic drugs are used chronically and thus cause prolonged hyperprolactinemia, there has been concern about their possible contribution to risk of carcinoma of the breast, although clinical evidence has not supported this concern (Dickson and Glazer, 1999; Mortensen, 1994). Nevertheless, neuroleptic and other agents that stimulate secretion of prolactin should be avoided in patients with established carcinoma of the breast, particularly with metastases. Some antipsychotic drugs reduce secretion of gonadotropins, estrogens, and progestins, possibly contributing to amenorrhea.

The effects of neuroleptics on other hypothalamic neuroendocrine functions are much less well characterized, although neuroleptics inhibit the release of growth hormone and may reduce the secretion of corticotropin-releasing hormone (CRH) that occurs in response to stress. Neuroleptics also interfere with secretion of pituitary growth hormone. Nevertheless, neuroleptics are poor therapy for acromegaly, and there is no evidence that they retard growth or development of children. In addition, chlorpromazine can decrease secretion of neurohypophyseal hormones. Weight gain and increased appetite occur with most neuroleptics, particularly clozapine, others of low potency, and olanzapine. Chlorpromazine also may impair glucose tolerance and insulin release to a clinically appreciable degree in some patients (Erle et al., 1977). In addition, several atypical antipsychotic agents (notably clozapine, olanzapine, and quetiapine) have been associated with risk of new-onset type 2 diabetes that may not be accounted for entirely by weight gain (Wirshing et al., 1998).

In addition to neuroendocrine effects, it is likely that other autonomic effects of antipsychotic drugs may be mediated by the hypothalamus. An important example is the poikilothermic effect of chlorpromazine and other neuroleptic agents, which impairs the body's ability to regulate temperature such that hypo- or hyperthermia may result, depending on the ambient temperature. Clozapine can induce elevations of body temperature.

Brainstem

Clinical doses of the antipsychotic agents usually have little effect on respiration. However, vasomotor reflexes mediated by either the hypothalamus or the brainstem are depressed by relatively low doses of chlorpromazine. This effect might occur at many points in the reflex pathway, and the net result is a centrally mediated fall in blood pressure. Even in cases of acute overdosage with suicidal intent, the antipsychotic drugs usually do not cause life-threatening coma or suppression of vital functions; this contributes importantly to their safety. In addition, haloperidol has been administered safely in doses exceeding 500 mg/24 hours intravenously to control agitation in delirious patients (Tesar et al., 1985).

Chemoreceptor Trigger Zone (CTZ)

Most neuroleptics protect against the nausea- and emesis-inducing effects of apomorphine and certain ergot alkaloids, all of which can interact with central dopaminergic receptors in the CTZ of the medulla. The antiemetic effect of most neuroleptics occurs with low doses. Drugs or other stimuli that cause emesis by an action on the nodose ganglion or locally on the gastrointestinal tract are not antagonized by antipsychotic drugs, but potent piperazines and butyrophenones are sometimes effective against nausea caused by vestibular stimulation.

Autonomic Nervous System

Since various antipsychotic agents have antagonistic interactions at peripheral, -adrenergic, serotonin (5-HT_2A), and histamine (H₁) receptors, their effects on the autonomic nervous system are complex and unpredictable. Chlorpromazine, clozapine, and thioridazine have particularly significant -adrenergic antagonistic activity. The potent piperazine tricyclic neuroleptics (e.g., fluphenazine, trifluoperazine), as well as haloperidol and risperidone, have antipsychotic effects even when used in low doses and show little antiadrenergic activity in patients.

The muscarinic-cholinergic blocking effects of antipsychotic drugs are relatively weak, but the blurring of vision commonly experienced with chlorpromazine may be due to an anticholinergic action on the ciliary muscle. Chlorpromazine regularly produces miosis, which can be due to -adrenergic blockade. Other phenothiazines can cause mydriasis; this is especially likely to occur with clozapine or thioridazine, which are potent muscarinic antagonists. Chlorpromazine can cause constipation and decreased gastric secretion and motility, and clozapine can decrease the efficiency of clearing saliva and induce severe impairment of intestinal motility (Rabinowitz et al., 1996; Theret et al., 1995). Decreased sweating and salivation are additional manifestations of the anticholinergic effects of such drugs. Acute urinary retention is uncommon but can occur in males with prostatism. Anticholinergic effects are least frequently caused by the potent neuroleptics, including haloperidol and risperidone. The phenothiazines inhibit ejaculation without interfering with erection. Thioridazine produces this effect with some regularity, sometimes limiting its acceptance by male patients. Attribution of this effect to adrenergic blockade is logical but unsubstantiated, inasmuch as thioridazine is less potent than chlorpromazine in its antiadrenergic effects.

Kidney and Electrolyte Balance

Chlorpromazine may have weak diuretic effects in animals and human beings because of a depressant action on the secretion of antidiuretic hormone (ADH), inhibition of reabsorption of water and electrolytes by a direct action on the renal tubule, or both. The slight fall in blood pressure that occurs with chlorpromazine is not associated with a significant change in glomerular filtration rate; indeed, renal blood flow tends to increase. The syndrome of idiopathic polydipsia with potential hyponatremia has been improved with clozapine, presumably through CNS mechanisms (Siegel et al., 1998).

Cardiovascular System

The actions of chlorpromazine on the cardiovascular system are complex because the drug produces direct effects on the heart and blood vessels and also indirect actions through CNS and autonomic reflexes. Chlorpromazine and other low-potency or atypical antipsychotic agents can cause orthostatic hypotension, systolic blood pressure being affected more than diastolic. Tolerance usually develops to the hypotensive effect over several weeks. However, some degree of orthostatic hypotension may persist indefinitely, especially in elderly patients (Ray et al., 1987).

Chlorpromazine and other phenothiazines with low potency can have a direct negative inotropic action and a quinidine-like antiarrhythmic effect on the heart. Electrocardiographic (ECG) changes include prolongation of the QT and PR intervals, blunting of T waves, and depression of the ST segment. Thioridazine, in particular, causes a high incidence of QT- and T-wave changes and may very rarely produce ventricular arrhythmias and sudden death. These effects are uncommon when potent antipsychotic agents are administered. Clozapine has been associated with rare cases of early carditis and later-appearing cardiomyopathy (Killian et al., 1999).

Miscellaneous Pharmacological Effects

Interactions of antipsychotic drugs with central neurohumors other than dopamine may contribute to their antipsychotic effects or other actions. For example, many antipsychotics enhance the turnover of acetylcholine, especially in the basal ganglia, perhaps secondary to the blockade of inhibitory dopamine heteroceptors on cholinergic neurons. In addition, as discussed above, there is an inverse relationship between antimuscarinic potency of antipsychotic drugs in the brain and the likelihood of extrapyramidal effects (Snyder and Yamamura, 1977). Chlorpromazine and low-potency antipsychotic agents including clozapine have antagonistic actions at histamine receptors that probably contribute to their sedative effects. Antagonistic interactions also occur at serotonin-5-HT_2A receptors in the forebrain. The significance of this effect is not certain, but several antipsychotic agentsnotably risperidone, olanzapine, quetiapine, sertindole, and ziprasidonewere developed in part to mimic the relatively potent and selective antagonistic activity of clozapine at serotonin-5-HT_2A receptors (Ichikawa and Meltzer, 1999; Meltzer and Nash, 1991).

Absorption, Distribution, Fate, and Excretion

Some antipsychotic drugs tend to have erratic and unpredictable patterns of absorption, particularly after oral administration and even when liquid preparations are used. Parenteral (intramuscular) administration increases the bioavailability of active drug by four to ten times. The drugs are highly lipophilic, highly membrane- or protein-bound, and accumulate in the brain, lung, and other tissues with a high blood supply; they also enter the fetal circulation and breast milk. It is virtually impossible (and usually not necessary) to remove these agents by dialysis.

The usually stated elimination half-lives with respect to total concentrations in plasma are typically 20 to 40 hours, but complex patterns of delayed elimination may occur with some agents, particularly the butyrophenones and their congeners (Cohen et al., 1992). The biological effects of single doses of most neuroleptics usually persist for at least 24 hours; this encourages the common practice of giving the entire daily dose at one time, once the patient has accommodated to the initial side effects of the drug. Elimination from the plasma may be more rapid than from sites of high lipid content and binding, notably in the CNS, but direct pharmacokinetic studies on this issue are few and inconclusive (Sedvall, 1992). Metabolites of some agents have been detected in the urine for as long as several months after administration of the drug has been discontinued. Slow removal of drug may contribute to the typically slow rate of exacerbation of psychosis after stopping drug treatment. Repository ('depot') preparations of esters of neuroleptic drugs are absorbed and eliminated much more slowly than are oral preparations. For example, whereas half of an oral dose of fluphenazine hydrochloride is eliminated in about 20 hours, the elimination of the decanoate ester following a depot intramuscular injection has a nominal half-life of 7 to 10 days, although the overall clearance of fluphenazine decanoate and normalization of hyperprolactinemia following repeated dosing can require 6 to 8 months (Sampath et al., 1992).

The main routes of metabolism of the antipsychotic drugs are oxidative processes mediated largely by genetically controlled hepatic cytochrome-P450 (CYP) microsomal oxidases and by conjugation processes. 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, but a few are not (notably, 7-hydroxychlorpromazine, mesoridazine, and several N-demethylated metabolites of phenothiazines as well as 9-hydroxyrisperidone) and may contribute to the biological activity of the parent substance as well as complicate the problem of correlating assays of drug in blood with clinical effects. The less potent antipsychotic drugs may weakly induce their own hepatic metabolism, since concentrations of chlorpromazine and other phenothiazines in blood are lower after several weeks of treatment with the same dosage; it also is possible that alterations of gastrointestinal motility are partially responsible. The fetus, the infant, and the elderly have diminished capacity to metabolize and eliminate antipsychotic agents, but children tend to metabolize these drugs more rapidly than do adults (Kutcher, 1997).

Bioavailability of several antipsychotic agents is somewhat increased by the use of liquid concentrates. Peak serum concentrations of chlorpromazine and other phenothiazines are attained within 2 to 4 hours. Their intramuscular administration avoids much of the first-pass metabolism in the liver (and possibly also the gut) and provides measurable concentrations in plasma within 15 to 30 minutes. Bioavailability of chlorpromazine may be increased up to tenfold with injections, but the clinical dose usually is decreased by three- to fourfold. Gastrointestinal absorption of chlorpromazine is modified unpredictably by food and probably is decreased by antacids. Concurrent administration of anticholinergic antiparkinsonian agents probably does not appreciably diminish the intestinal absorption of neuroleptic agents (Simpson et al., 1980). Chlorpromazine and other antipsychotic agents bind significantly to membranes and to plasma proteins. Typically, more than 85% of the drug in plasma is bound to albumin. Concentrations of some neuroleptics (e.g., haloperidol) in brain can be more than ten times those in the blood (Tsuneizumi et al., 1992), and their apparent volume of distribution may be as high as 20 liters per kilogram.

Disappearance of chlorpromazine from plasma includes a rapid distribution phase (half-life about 2 hours) and a slower elimination phase (half-life about 30 hours), but markedly variable values have been reported; the half-life of elimination from human brain is not known but may be determined using modern brain-scanning technologies (Sedvall, 1992). Approximate elimination half-life of commonly clinically employed antipsychotic agents is provided in Table 203.

Attempts to correlate plasma concentrations of chlorpromazine or its metabolites with clinical responses have not been successful (seeBaldessarini et al., 1988; Cooper et al., 1976). Studies have revealed wide variations (at least tenfold) in plasma concentrations among individuals. Although it appears that plasma concentrations of chlorpromazine below 30 ng/ml are not likely to produce an adequate antipsychotic response and that levels above 750 ng/ml are likely to be associated with unacceptable toxicity (seeRivera-Calimlim and Hershey, 1984), it is not yet possible to state with confidence the concentrations in plasma that are associated with optimal clinical responses.

At least 10 or 12 metabolites of chlorpromazine occur in human beings in appreciable quantities (Morselli, 1977). Quantitatively, the most important of these are nor₂-chlorpromazine (doubly demethylated), chlorophenothiazine (removal of the entire side chain), methoxy and hydroxy products, and glucuronide conjugates of the hydroxylated compounds. In the urine, 7-hydroxylated and N-dealkylated (nor₂) metabolites and their conjugates predominate. Chlorpromazine and other phenothiazines are metabolized extensively through CYP2D6.

The pharmacokinetics and metabolism of thioridazine and fluphenazine are similar to those of chlorpromazine, but the strong anticholinergic action of thioridazine on the gut may modify its own absorption. Major metabolites of thioridazine and fluphenazine include N-demethylated, ring-hydroxylated, and S-oxidized products (Neumeyer and Booth, 2001). Concentrations of thioridazine in plasma are relatively high (hundreds of nanograms per milliliter), possibly because of its relative hydrophilicity. Thioridazine is prominently converted to the active product mesoridazine, a drug in its own right, and probably an important contributor to the neuroleptic activity of thioridazine.

The biotransformation of the thioxanthenes is similar to that of the phenothiazines except that metabolism to sulfoxides is common and ring-hydroxylated products are uncommon. Piperazine derivatives of the phenothiazines and thioxanthenes also are handled much like chlorpromazine, although metabolism of the piperidine ring itself occurs.

Elimination of haloperidol and chemically related agents from human plasma is not a log-linear function, and the apparent half-life increases with time, with a very prolonged terminal half-life of approximately 1 week (Cohen et al., 1992). Haloperidol and other butyrophenones are metabolized primarily by an N-dealkylation reaction; the resultant inactive fragments can be conjugated with glucuronic acid. The metabolites of haloperidol are inactive, with the possible exception of a hydroxylated product formed by reduction of the keto moiety that may be reoxidized to haloperidol (Korpi et al., 1983). A potentially neurotoxic derivative of haloperidol, a substituted phenylpiperidine, analogous to the parkinsonism-inducing agent methylphenyltetrahydropyridine (MPTP), has been described and found in nanomolar quantities in postmortem brain tissue of persons who had been treated with haloperidol (Eyles et al., 1997; Castagnoli et al., 1999). Typical plasma concentrations of haloperidol encountered clinically are about 5 to 20 ng/ml, and these correspond to 80% to 90% occupancy of D₂-dopamine receptors in human basal ganglia, as demonstrated by PET brain scanning (Baldessarini et al., 1988; Wolkin et al., 1989).

Typical peak serum concentrations of clozapine after a single oral dose of 200 mg (100 to 770 ng/ml) are reached at 2.5 hours after administration, and typical serum levels during treatment are about 300 to 500 nanograms per milliliter. Clozapine is metabolized preferentially by CYP3A4 into pharmacologically inactive demethylated, hydroxylated, and N-oxide derivatives before excretion in urine and feces. The elimination half-life of clozapine varies with dose and dosing frequency, but average about 12 hours (seeTable 203).

Risperidone is well absorbed, and it is metabolized in the liver preferentially by isozyme CYP2D6 to a major and active circulating metabolite, 9-hydroxyrisperidone. Since this metabolite and risperidone are nearly equipotent, the clinical efficacy of the drug reflects both compounds. Following oral administration of risperidone, peak plasma concentrations of risperidone and of its 9-hydroxy metabolite occur at 1 and 3 hours, respectively. The mean half-life of both compounds is about 22 hours (Table 203).

Olanzapine is also well absorbed, but about 40% of an oral dose is metabolized before reaching the systemic circulation. Plasma concentrations of olanzapine peak at about 6 hours after oral administration, and its elimination half-life ranges from 20 to 54 hours (Table 203). The major, readily excreted metabolites of olanzapine are the inactive 10-N-glucuronide and 4'-nor derivatives, formed mainly by the action of CYP1A2 with CYP2D6 as a minor alternative pathway (United States Pharmacopoeia, 2000).

Quetiapine fumarate is readily absorbed after oral administration and reaches peak plasma levels after 1.5 hours, with a mean half-life of 6 hours (Table 203). It is highly metabolized by hepatic CYP3A4 to inactive and readily excreted sulfoxide and acidic derivatives (United States Pharmacopoeia, 2000).

Tolerance and Physical Dependence

The antipsychotic drugs are not addicting, as the term is defined in Chapter 24: Drug Addiction and Drug Abuse. However, some degree of physical dependence may occur, with malaise and difficulty in sleeping developing several days after their abrupt discontinuation.

Tolerance usually develops to the sedative effects of neuroleptics over a period of days or weeks. Tolerance to antipsychotic drugs and cross-tolerance among the agents also are demonstrable in behavioral and biochemical experiments in animals, particularly those directed toward evaluation of the blockade of dopaminergic receptors in the basal ganglia (seeBaldessarini and Tarsy, 1979). This form of tolerance may be less prominent in limbic and cortical areas of the forebrain. One correlate of tolerance in forebrain dopaminergic systems is the development of disuse supersensitivity of those systems, probably mediated by changes in the receptors for the neurotransmitter. This mechanism may underlie the clinical phenomenon of withdrawal-emergent dyskinesias (choreoathetosis on abrupt discontinuation of antipsychotic agents, especially following prolonged use of high doses of potent agents) (Baldessarini et al., 1980).

Although cross-tolerance for some effects may occur among neuroleptic drugs, clinical problems occur in making rapid changes from high doses of one type of agent to another; sedation, hypotension, and other autonomic effects or acute extrapyramidal reactions can result. Worsening of the clinical condition that routinely follows discontinuation of maintenance treatment with antipsychotic agents appears to be dependent on the rate of drug discontinuation (Viguera et al., 1997). Clinical worsening of psychotic symptoms is particularly likely after rapid discontinuation of clozapine, and it is difficult to control with alternative antipsychotics (Baldessarini et al., 1997).

Preparations and Dosage

The number of agents with known neuroleptic or antipsychotic effects is large. Table 201 summarizes only those that are currently marketed in the United States for the treatment of psychotic disorders.

Several available agents are excluded, such as promazine hydrochloride (SPARINE) and reserpine and other rauwolfia alkaloids that have inferior antipsychotic effects or that are no longer commonly used for psychiatric patients. Prochlorperazine (COMPAZINE) has questionable utility as an antipsychotic agent and frequently produces acute extrapyramidal reactions; it is thus not commonly employed in psychiatry, although it is used as an antiemetic. Thiethylperazine (TORECAN), marketed only as an antiemetic, is a potent dopaminergic antagonist with many neuroleptic-like properties; at high doses it may be an efficacious antipsychotic agent (Rotrosen et al., 1978). Several other thioxanthenes, butyrophenones, diphenylbutylpiperidines, benzamides, and long-acting repository preparations of neuroleptic agents are available in other countries.

Toxic Reactions and Side Effects

Antipsychotic drugs have a high therapeutic index and generally are safe agents. Furthermore, most phenothiazines and haloperidol have a relatively flat doseresponse curve and can be used over a wide range of dosages. Although occasional deaths from overdosage have been reported, this is rare if the patient is given medical care and if an overdosage is not complicated by the concurrent ingestion of alcohol or other drugs. Based on animal data, the therapeutic index is lower for thioridazine and chlorpromazine than for the more potent agents (Janssen and Van Bever, 1978). Adult patients have survived doses of chlorpromazine up to 10 grams, and deaths from an overdose of haloperidol alone appear to be unknown, although the neuroleptic malignant syndrome and dystonic reactions that compromise respiration can be lethal.

Side effects often are extensions of the many pharmacological actions of these drugs. The most important are those on the cardiovascular system, central and autonomic nervous systems, and on endocrine functions. Other dangerous effects are seizures, agranulocytosis, cardiac toxicity, and pigmentary degeneration of the retina, all of which are rare (see below).

Therapeutic doses of phenothiazines may cause faintness, palpitation, and anticholinergic effects including nasal stuffiness, dry mouth, blurred vision, constipation, and, in males with prostatism, urinary retention. The most common troublesome cardiovascular side effect is orthostatic hypotension, which may result in syncope and falls. A fall in blood pressure is most likely to occur from administration of the phenothiazines with aliphatic side chains and of the atypical antipsychotics. Potent neuroleptic agents generally produce less hypotension.

Neurological Side Effects

A variety of neurological syndromes, involving particularly the extrapyramidal motor system, occur following the use of almost all antipsychotic drugs. These reactions are particularly prominent during treatment with the high-potency agents (tricyclic piperazines and butyrophenones). There is less likelihood of acute extrapyramidal side effects with clozapine, quetiapine, olanzapine, thioridazine, or low doses of risperidone. The neurological effects associated with antipsychotic drugs have been reviewed in detail (Baldessarini and Tarsy, 1979; Baldessarini et al., 1980; Baldessarini, 1984; Baldessarini et al., 1990; Kane et al., 1992; Tarsy et al., 2001).

Six varieties of neurological syndromes are characteristic of antipsychotic drugs. Four of these (acute dystonia, akathisia, parkinsonism, and the rare neuroleptic malignant syndrome) usually appear soon after administration of the drug, and two (rare perioral tremor and tardive dyskinesias or dystonias) are late-appearing syndromes that evolve during prolonged treatment. The clinical features of these syndromes and guidelines for their management are summarized in Table 204.

Acute dystonic reactions commonly occur with the initiation of antipsychotic drug therapy, particularly with agents of high potency, and may present as facial grimacing, torticollis, or oculogyric crisis. These syndromes may be mistaken for hysterical reactions or seizures, but they respond dramatically to parenteral administration of anticholinergic antiparkinsonian drugs. Oral administration of anticholinergic agents also can prevent dystonia, particularly in young male patients who have been given a high-potency neuroleptic drug (Arana et al., 1988). Although treated readily, acute dystonic reactions are terrifying to patients; sudden death has occurred in rare instances, perhaps due to the impaired respiration caused by dystonia of pharyngeal, laryngeal, and other muscles.

Akathisia refers to strong subjective feelings of distress or discomfort, often referred to the legs, as well as to a compelling need to be in constant movement rather than to follow any specific movement pattern. Patients feel that they must get up and walk or continuously move about and may be unable to keep this tendency under control. Akathisia often is mistaken for agitation in psychotic patients; the distinction is critical, since agitation might be treated with an increase in dosage. Because the response of akathisia to antiparkinsonian drugs frequently is unsatisfactory, treatment typically requires reduction of antipsychotic drug dosage or a change of drug. Antianxiety agents or moderate doses of propranolol may be beneficial (Lipinski et al., 1984). This common syndrome often interferes with the acceptance of neuroleptic treatment but frequently is not diagnosed.

A parkinsonian syndrome that may be indistinguishable from idiopathic parkinsonism commonly develops gradually during administration of antipsychotic drugs. Its incidence varies with different agents (seeTables 201 and 204). Clinically, there is a generalized slowing of volitional movement (akinesia) with mask facies and a reduction in arm movements. The syndrome characteristically evolves gradually over days to weeks. The most noticeable signs are slowing of movements, sometimes rigidity and variable tremor at rest, especially involving the upper extremities. 'Pill-rolling' movements may be seen, although they are not as prominent in neuroleptic-induced as in idiopathic parkinsonism. Parkinsonian side effects may be mistaken for depression, since the flat facial expression and retarded movements may resemble signs of depression. This reaction usually is managed by use of either antiparkinsonian agents with anticholinergic properties or amantadine (seeChapter 22: Treatment of Central Nervous System Degenerative Disorders); the use of levodopa or a directly acting dopamine agonist incurs the risk of inducing agitation and worsening the psychotic illness. Antipsychotic agents sometimes are required in the clinical management of patients with idiopathic Parkinson's disease with spontaneous psychotic illness or psychotic reactions to dopaminergic therapy (seeChapter 22: Treatment of Central Nervous System Degenerative Disorders); clozapine and perhaps quetiapine are least likely to worsen the neurological disorder itself (Menza et al., 1999; Parkinson Study Group, 1999).

A rare disorder, neuroleptic malignant syndrome, resembles a very severe form of parkinsonism with coarse tremor and catatonia, fluctuating in intensity, as well as signs of autonomic instability (labile pulse and blood pressure, hyperthermia), stupor, elevation of creatine kinase in serum, and sometimes myoglobinemia. In its most severe form, this syndrome may persist for more than a week after stopping the offending agent. Because mortality is high (more than 10%), immediate medical attention is required. This reaction has been associated with various types of neuroleptics, but its prevalence may be greater when relatively high doses of the more potent agents are used, especially when they are administered parenterally. Aside from immediate cessation of neuroleptic treatment and provision of supportive care, specific treatment is unsatisfactory; administration of dantrolene or the dopaminergic agonist bromocriptine may be helpful (Addonizio et al., 1987; Pearlman, 1986). Although dantrolene also is used to manage the syndrome of malignant hyperthermia induced by general anesthetics, the neuroleptic-induced form of catatonia and hyperthermia probably is not associated with a defect in Ca²⁺ metabolism in skeletal muscle.

A rare movement disorder that can appear late in the treatment of chronically ill patients with antipsychotic agents is perioral tremor, often referred to as the 'rabbit syndrome' (Jus et al., 1974) because of the peculiar movements that characterize this condition. While sometimes categorized with other tardive (late or slowly evolving) dyskinesias, this term usually is reserved for choreoathetotic or dystonic reactions that develop after prolonged therapy. The rabbit syndrome, in fact, shares many features with parkinsonism, because the tremor has a frequency of about 5 to 7 Hz and there is a favorable response to anticholinergic agents and to the removal of the offending agent.

Tardive dyskinesia is a late-appearing neurological syndrome (or syndromes) associated with the use of neuroleptic drugs. It occurs more frequently in older patients, and risk may be greater in patients with mood disorders than in those with schizophrenia. Prevalence averages 15% to 25% in chronically psychotic young adults, with an annual incidence of 3% to 5% and a somewhat smaller annual rate of spontaneous remission, even with continued neuroleptic treatment. The risk is much lower with clozapine, but that of other recently developed atypical antipsychotic agents is not established (Tarsy et al., 2001). 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. There are varying degrees of slower athetosis (twisting movements) and sustained dystonic postures, which are more common in young men and may be disabling. Late (tardive) emergence of possibly related disorders marked mainly by dystonia or akathisia (restlessness) also are seen. These movements all disappear in sleep (as in many other extrapyramidal syndromes), vary in intensity over time, and are dependent on the level of arousal or emotional distress.

Tardive dyskinetic movements can be suppressed partially by use of a potent neuroleptic, and perhaps with a dopamine-depleting agent such as reserpine or tetrabenazine, but such interventions are reserved for compellingly severe dyskinesia, particularly with continuing psychosis. Some dyskinetic patients, typically those with dystonic features, may benefit from use of clozapine, with which the risk of tardive dyskinesia is very low. Symptoms sometimes persist indefinitely after discontinuation of neuroleptic medication; more often, they diminish or disappear gradually over months of follow-up and are most likely to resolve spontaneously in younger patients (Gardos et al., 1994; Morgenstern and Glazer, 1993; Smith and Baldessarini, 1980). Antiparkinsonism agents typically have little effect on, or may exacerbate, tardive dyskinesia and other forms of choreoathetosis, such as in Huntington's disease; no adequate treatment of these conditions has yet been established (Adler et al., 1999; Soares and McGrath, 1999).

There is no established neuropathology in tardive dyskinesia, and its pathophysiological basis remains obscure. It has been hypothesized that compensatory increases in the function of dopamine as a neurotransmitter in the basal ganglia may be involved, including increased abundance and sensitivity of dopamine D₂-like receptors resulting from long-term administration of neuroleptic drugs (Baldessarini and Tarsy, 1979; Tarazi et al., 1997). This idea is supported by the dissimilarities of therapeutic responses in patients with Parkinson's disease and those with tardive dyskinesia and by the similarities in responses of patients with other choreoathetotic dyskinesias such as Huntington's disease (seeChapter 22: Treatment of Central Nervous System Degenerative Disorders). Thus, antidopaminergic drugs tend to suppress the manifestations of tardive dyskinesia or Huntington's disease, while dopaminergic agonists worsen these conditions; in contrast to parkinsonism, antimuscarinic agents tend to worsen tardive dyskinesia, but cholinergic agents usually are ineffective. Because supersensitivity to dopaminergic agonists tends not to persist for more than a few weeks after stopping exposure to antagonists of the transmitter, this phenomenon is most likely to play a role in variants of tardive dyskinesia that resolve rapidly; these usually are referred to as withdrawal-emergent dyskinesias. The theoretical and clinical aspects of this problem have been reviewed in detail elsewhere (Baldessarini and Tarsy, 1979; Baldessarini et al., 1980; Kane et al., 1992).

It is important to prevent the neurological syndromes that complicate the use of antipsychotic drugs. Certain therapeutic guidelines should be followed. Routine use of antiparkinsonian agents in an attempt to avoid early extrapyramidal reactions usually is unnecessary and adds complexity, side effects, and expense to the treatment regimen. Antiparkinsonian agents are best reserved for cases of overt extrapyramidal reactions that respond favorably to such intervention. The need for such agents for the treatment of acute dystonic reactions ordinarily diminishes with time, but parkinsonism and akathisia tend to persist. The thoughtful and conservative use of antipsychotic drugs in patients with chronic or frequently recurrent psychotic disorders almost certainly can reduce the risk of tardive dyskinesia. Although reduction of the dose of an antipsychotic agent is the best way to minimize its neurological side effects, this may not be practical in a patient with uncontrollable psychotic illness. The best preventive practice is to use the minimum effective dose of an antipsychotic drug for long-term therapy and to discontinue treatment as soon as it seems reasonable to do so or if a satisfactory response cannot be obtained. The use of clozapine, quetiapine, and other novel antipsychotic agents with a low risk of inducing extrapyramidal side effects represents an alternative for some patients, particularly those with continuing psychotic symptoms plus dyskinesia (Baldessarini and Frankenburg, 1991).

Jaundice

Jaundice was observed in patients shortly after the introduction of chlorpromazine. Commonly occurring during the second to fourth week of therapy, the jaundice generally is mild, and pruritus is rare. The reaction is probably a manifestation of hypersensitivity, because eosinophilic infiltration of the liver as well as eosinophilia occur, and there is no correlation with dose. Desensitization to chlorpromazine may occur with repeated administration, and jaundice may or may not recur if the same neuroleptic agent is given again. When the psychiatric disorder calls for uninterrupted drug therapy for a patient with neuroleptic-induced jaundice, it probably is safest to use low doses of a potent, dissimilar agent.

Blood Dyscrasias

Mild leukocytosis, leukopenia, and eosinophilia occasionally occur with antipsychotic medications, particularly with clozapine and less often with low-potency phenothiazines. It is difficult to determine whether a leukopenia occurring during the administration of a phenothiazine is a forewarning of impending agranulocytosis. This serious but rare complication occurs in not more than 1 in 10,000 patients receiving chlorpromazine or other low-potency agents other than clozapine; it usually appears within the first 8 to 12 weeks of treatment (Alvir et al., 1993).

Suppression of the bone marrow or, less commonly, agranulocytosis has been associated particularly with the use of clozapine; the incidence approaches 1% within several months of treatment, independent of dose, and close monitoring of the patient is required for its safe use. Because the onset of blood dyscrasia may be sudden, the appearance of fever, malaise, or apparent respiratory infection in a patient being treated with an antipsychotic drug should be followed immediately by a complete blood count. Risk of agranulocytosis has been greatly reduced, though not eliminated, by frequent white blood cell counts in patients being treated with clozapine.

Other Metabolic Effects

Weight gain and its common long-term complications commonly are associated with long-term treatment with most antipsychotic and antimanic drugs. Among newer antipsychotic agents, weight gain is especially prominent with clozapine and olanzapine and less so with risperidone and quetiapine (Allison et al., 1999). Associated adverse responses include new-onset or worsening of type 2 diabetes mellitus, hypertension, and hyperlipidemia. The anticipated long-term public health impact of these emerging problems is not yet well defined (Gaulin et al., 1999; Wirshing et al., 1998). In some patients with morbid increases in weight, the airway may be compromised, especially during sleep.

Skin Reactions

Dermatological reactions to the phenothiazines are common. Urticaria or dermatitis occurs in about 5% of patients receiving chlorpromazine. Several types of skin disorders may occur. Hypersensitivity reactions that may be urticarial, maculopapular, petechial, or edematous usually occur between the first and eighth weeks of treatment. The skin clears after discontinuation of the drug and may remain so even if drug therapy is reinstituted. Contact dermatitis may occur in personnel who handle chlorpromazine, and there may be a degree of cross-sensitivity to the other phenothiazines. Photosensitivity occurs that resembles severe sunburn. An effective sunscreen preparation should be prescribed for outpatients being treated with phenothiazines during the summer. Gray-blue pigmentation induced by long-term administration of low-potency phenothiazines in high doses is rare with current practices.

Epithelial keratopathy often is observed in patients on long-term therapy with chlorpromazine, and opacities in the cornea and in the lens of the eye also have been noted. The deposits tend to disappear spontaneously, although slowly, following discontinuation of drug administration. Pigmentary retinopathy has been reported, particularly following doses of thioridazine in excess of 1000 mg per day; a maximum daily dose of 800 mg currently is recommended.

Interactions with Other Drugs

The phenothiazines and thioxanthenes, especially those of low potency, affect the actions of a number of other drugs, sometimes with important clinical consequences (seeDeVane and Nemeroff, 2000; Goff and Baldessarini, 1993). Chlorpromazine originally was introduced to potentiate central depressants in anesthesiology. Antipsychotic drugs can strongly potentiate sedatives and analgesics prescribed for medical purposes, as well as alcohol, nonprescription sedatives and hypnotics, antihistamines, and cold remedies. Chlorpromazine increases the miotic and sedative effects of morphine and may increase its analgesic actions. Furthermore, the drug markedly increases the respiratory depression produced by meperidine and can be expected to have similar effects when administered concurrently with other opioids. Obviously, neuroleptic drugs inhibit the actions of dopaminergic agonists and of levodopa.

Other interactive effects can be manifest on the cardiovascular system. Chlorpromazine and some other antipsychotic drugs, as well as their N-demethylated metabolites, may block the antihypertensive effects of guanethidine, probably by blocking its uptake into sympathetic nerves. The more potent antipsychotic agents, as well as molindone, are less likely to cause this effect. Low-potency phenothiazines can promote postural hypotension, possibly due to their -adrenergic blocking properties. Thus, the interaction between phenothiazines and antihypertensive agents can be unpredictable.

Thioridazine, pimozide, and the experimental agents sertindole and ziprasidone can exert quinidine-like cardiac depressant effects, which can cause myocardial depression, decreased efficiency of repolarization, and increased risk of tachyarrhythmias. These effects may partially nullify the inotropic effect of digitalis. The antimuscarinic action of clozapine and thioridazine can cause tachycardia and enhance the peripheral and central effects (confusion, delirium) of other anticholinergic agents, such as the tricyclic antidepressants and antiparkinsonian agents.

Sedatives or anticonvulsants (e.g., carbamazepine, phenobarbital, and phenytoin but not valproate) that induce microsomal drug-metabolizing enzymes can enhance the metabolism of antipsychotic agents, sometimes with significant clinical consequences. Conversely, serotonin-reuptake inhibitors including fluoxetine (seeChapter 19: Drugs and the Treatment of Psychiatric Disorders: Depression and Anxiety Disorders) compete for hepatic oxidases and can elevate circulating levels of neuroleptics (Goff and Baldessarini, 1993).

Drug Treatment of Psychoses

The antipsychotic drugs are not specific for the type of psychosis to be treated. They are clearly effective in acute psychoses of unknown etiology, including mania, acute idiopathic psychoses, and acute exacerbations of schizophrenia; the greatest amount of controlled clinical data exists for the acute and chronic phases of schizophrenia and in acute mania. In addition, antipsychotic drugs are used empirically in many other neuromedical and idiopathic disorders in which psychotic symptoms and severe agitation are prominent.

The fact that neuroleptic agents are indeed antipsychotic was slow to gain acceptance. However, many clinical trials and five decades of clinical experience have established that these agents are effective and superior to sedatives such as the barbiturates and benzodiazepines, or alternatives such as electroconvulsive shock or other medical or psychological therapies (seeBaldessarini, 1984, 1985). The 'target' symptoms for which antipsychotic agents seem to be especially effective include agitation, combativeness, hostility, hallucinations, acute delusions, insomnia, anorexia, poor self-care, negativism, and sometimes withdrawal and seclusiveness; more variable or delayed are improvements in motivation and cognitive functions including insight, judgment, memory, and orientation. The most favorable prognosis is for patients with acute illnesses of brief duration who had functioned relatively well prior to the illness.

Despite the great success of the antipsychotic drugs, their use alone does not constitute optimal care of psychotic patients. The acute care, protection, and support of acutely psychotic patients, as well as mastery of techniques employed in their long-term care and rehabilitation, also are of critical importance. Detailed reviews of the clinical use of antipsychotic drugs are available (Baldessarini, 1984; Marder, 1998).

No one drug or combination of drugs has a selective effect on a particular symptom complex in groups of psychotic patients; although individual patients may appear to do better with one agent than another, this can be determined only by trial and error. Certain agents (particularly newer antipsychotic drugs) have been claimed to be specifically effective against 'negative' symptoms in psychotic disorders (abulia, social withdrawal, lack of motivation), but evidence supporting this proposal remains inconsistent, and such benefits usually are limited (Moller, 1999). Generally, 'positive' (irrational thinking, delusions, agitated turmoil, hallucinations) and negative symptoms tend to respond or not respond together. This trend is well documented with typical neuroleptics as well as modern atypical antipsychotic agents. It is clear that clozapine and other modern atypical antipsychotics induce less bradykinesia and other parkinsonian effects than do typical neuroleptics. Minimizing such side effects is sometimes interpreted clinically as a beneficial effect on impoverished affective responsiveness.

It is important to simplify the treatment regimen and to ensure that the patient is receiving the drug. In cases of suspected severe and dangerous noncompliance or with failure of oral treatment, the patient can be treated with injections of fluphenazine decanoate, haloperidol decanoate, or other long-acting preparations. Injectable and long-acting preparations of modern atypical antipsychotics currently are unavailable, but some are in development.

Because the choice of an antipsychotic drug cannot be made reliably on the basis of anticipated therapeutic effect, drug selection often depends on side effects or on a previous favorable response. If the patient has a history of cardiovascular disease or stroke and the threat from hypotension is serious, a potent neuroleptic should be used in the smallest dose that is effective (seeTable 201; DeBattista and Schatzberg, 1999). If it seems important to minimize the risk of acute extrapyramidal symptoms, quetiapine, a low dose of olanzapine or risperidone, or clozapine should be considered. If the patient would be seriously discomforted by interference with ejaculation or if there are serious risks of cardiovascular or other autonomic toxicity, low doses of a potent neuroleptic might be preferred. If sedative effects are undesirable, a potent agent is preferable. Small doses of antipsychotic drugs of high or moderate potency may be safest in the elderly. If the patient has compromised hepatic function or if there is a potential threat of jaundice, low doses of a high-potency agent may be used. The physician's experience with a particular drug may outweigh other considerations. Skill in the use of antipsychotic drugs depends on selection of an adequate but not excessive dose, knowledge of what to expect, and judgment as to when to stop therapy or change drugs.

Some patients do not respond satisfactorily to antipsychotic drug treatment, and many chronically ill schizophrenic patients, while helped during periods of acute exacerbation of their disease, may show unsatisfactory responses between the more acute phases of illness. Individual nonresponders cannot be identified beforehand with certainty, and a minority of patients do poorly or sometimes even become worse on medication. If a patient does not improve after a course of seemingly adequate treatment and fails to respond to another drug given in adequate dosage, the diagnosis should be reevaluated.

Usually 2 to 3 weeks or more are required to demonstrate obvious positive effects in schizophrenic patients. Maximum benefit in chronically ill patients may require several months. In contrast, improvement of some acutely psychotic patients can be seen within 48 hours. Aggressive dosing or parenteral administration of an antipsychotic drug at the start of an acute psychosis has not been found to increase the magnitude or the rate of appearance of therapeutic responses (Baldessarini et al., 1988). Sedatives, such as the potent benzodiazepines, can be used for brief periods during the initiation of antipsychotic therapy but are not effective in the long-term treatment of chronically psychotic and, especially, schizophrenic patients. After the initial response, drugs usually are used in conjunction with psychological, supportive, and rehabilitative treatments.

There is no convincing evidence that combinations of antipsychotic drugs offer consistent advantages. A combination of an antipsychotic drug and an antidepressant may be useful in some cases, especially in depressed psychotic patients or in cases of agitated major depression with psychotic features. However, antidepressants and stimulants are unlikely to reduce apathy and withdrawal in schizophrenia, and they may induce clinical worsening in some cases.

Optimal dosage of antipsychotic drugs requires individualization to determine doses that are effective, well tolerated, and accepted by the patient. Doseresponse relationships for antipsychotic and side effects overlap, and an end point of a desired therapeutic response can be difficult to determine (DeBattista and Schatzberg, 1999). Typical effective doses are approximately 300 to 500 mg of chlorpromazine, 5 to 15 mg of haloperidol, or their equivalent, daily. Doses of as little as 50 to 200 mg of chlorpromazine per day (or 2 to 6 mg of haloperidol or fluphenazine per day) may be effective and be better tolerated by many patients, especially after the initial improvement of acute symptoms (Baldessarini et al., 1988). Careful observation of the patient's changing response is the best guide to dosage.

In the treatment of acute psychoses, the dose of antipsychotic drug is increased during the first few days to achieve control of symptoms. The dose is then adjusted during the next several weeks as the patient's condition warrants. Parenteral medication sometimes is indicated for acutely agitated patients; 5 mg of haloperidol or fluphenazine or a comparable dose of another agent is given intramuscularly. The desired response usually can be obtained by administering additional doses at intervals of 4 to 8 hours for the first 24 to 72 hours, because the appearance of effects may be delayed for several hours. Rarely is it necessary to administer more than 20 to 30 mg of fluphenazine or haloperidol (or an equivalent amount of another agent) per 24 hours. Severe and otherwise poorly controlled agitation usually can be managed safely by use of adjunctive sedation (e.g., with a benzodiazepine such as lorazepam) and close supervision in a secure setting.

One must remain alert for acute dystonic reactions, which are especially likely early in the aggressive use of potent neuroleptics. Hypotension is most likely to occur if an agent of low potency, such as chlorpromazine, is given in a high dose or by injection and may occur with atypical antipsychotic agents early in treatment. Some antipsychotic drugs, including fluphenazine, other piperazines, and haloperidol, have been given in doses of several hundred milligrams a day without disaster, although such high doses of potent agents do not yield significantly or consistently superior results in the treatment of acute or chronic psychosis, and they may yield inferior antipsychotic effects as well as increasing risks of neurological and other side effects (Baldessarini et al., 1988). After an initial period of stabilization, regimens based on a single daily dose (typically 5 to 10 mg per day of haloperidol or fluphenazine, 2 to 4 mg of risperidone, 5 to 15 mg of olanzapine, or their equivalent) often are effective and safe; such dosing may allow some degree of selection of the time at which unwanted effects occur so as to minimize the patient's discomfort.

Table 201 gives the usual and extreme ranges of dosage for antipsychotic drugs used in the United States (see alsoDeBattista and Schatzberg, 1999). The ranges have been established for the most part in the treatment of schizophrenic or manic patients. Although acutely disturbed inpatients often require higher doses of an antipsychotic drug than do more stable outpatients, the concept that a low or flexible maintenance dose will suffice during follow-up care of a partially recovered or chronic psychotic patient is supported by several appropriately controlled trials (Baldessarini et al., 1988; Herz et al., 1991).

In reviews of nearly 30 controlled prospective studies involving several thousand schizophrenic patients, the mean overall relapse rate was 58% for those patients who were withdrawn from antipsychotic drugs and given a placebo, compared with only 16% of those who continued on drug therapy (Baldessarini et al., 1990; Gilbert et al., 1995; Viguera et al., 1997). Dosage in chronic cases often can be lowered to 50 to 200 mg of chlorpromazine (or its equivalent) per day without signs of relapse (Baldessarini et al., 1988), but rapid dose reduction or discontinuation appears to increase risk of exacerbation or relapse (Viguera et al., 1997). Flexible therapy in which dosage is adjusted to changing current requirements can be useful and can reduce the incidence of side effects. Maintenance with injections of the decanoate ester of fluphenazine or haloperidol every 2 to 4 weeks can be very effective (Kane et al., 1983).

The treatment of delirium or dementia is another accepted use of the antipsychotic drugs. They may be administered temporarily while a specific and correctable structural, infectious, metabolic, or toxic cause is vigorously sought. They sometimes are used for prolonged periods when no correctable cause can be found. Once again, there are no drugs of choice or clearly established dosage guidelines for such indications, although agents of high potency are preferred (seePrien, 1973). In patients with acute 'brain syndromes' without likelihood of seizures, frequent small doses (e.g., 2 to 6 mg) of haloperidol or another potent antipsychotic may be effective in controlling agitation. Agents with low potency should be avoided because of their greater tendency to produce sedation, hypotension, and seizures, and those with central anticholinergic effects may worsen confusion and agitation.

Most antipsychotics are effective in the treatment of mania and often are used concomitantly with the institution of lithium or anticonvulsant therapy (see below). In fact, it often is impractical to attempt to manage a manic patient with lithium alone during the first week of illness, when antipsychotic or sedative drugs usually are required. Adequate studies of possible long-term preventive effects of antipsychotic drugs in manic-depressive illness have not been conducted. Antipsychotic drugs also may have a limited role in the treatment of severe depression. Controlled studies have demonstrated the efficacy of several antipsychotic drugs in some depressed patients, especially those with striking agitation or psychotic delusions, and addition of an antipsychotic to an antidepressant in psychotic depression may yield results approaching those obtained with ECT (Brotman et al., 1987; Chan et al., 1987). Antipsychotic agents ordinarily are not used for the treatment of anxiety disorders.

The status of the drug treatment of childhood psychosis and other behavioral disorders of children is confused by diagnostic inconsistencies and a paucity of controlled studies. Antipsychotics can benefit children with disorders characterized by features that occur in adult psychoses or mania as well as those with Tourette's syndrome. Low doses of the more potent agents usually are preferred in an attempt to avoid interference with daytime activities or performance in school (Kutcher, 1997; Findling et al., 1998). Attention disorder, with or without hyperactivity, responds poorly to antipsychotic agents but often very well to stimulants and some antidepressants (Kutcher, 1997). Information on dosages of antipsychotic drugs for children is limited, as is the number of drugs currently approved in the United States for use in preadolescents. The recommended doses of antipsychotic agents for school-aged children with moderate degrees of agitation are lower than those for acutely psychotic children, who may require daily doses similar to those used in adults (Kutcher, 1997; see alsoTable 201).

Most relevant experience is with chlorpromazine, for which the recommended single dose is approximately 0.5 mg/kg of body weight given at intervals of 4 to 6 hours orally or 6 to 8 hours intramuscularly. Suggested dosage limits are 200 mg per day (orally) for preadolescents, 75 mg per day (intramuscularly) for children aged 5 to 12 years or weighing 23 to 45 kg, and 40 mg per day (intramuscularly) for children under 5 years of age or weighing less than 23 kg. Usual single doses for other agents of relatively low potency are thioridazine, 0.25 to 0.5 mg/kg, and chlorprothixene, 0.5 to 1.0 mg/kg, to a total of 100 mg/day (over the age of 6). For neuroleptics of high potency, daily doses are trifluoperazine, 1 to 15 mg (6 to 12 years of age) and 1 to 30 mg (over 12 years of age); fluphenazine, 0.05 to 0.10 mg/kg, up to 10 mg (over 5 years of age); and perphenazine, 0.05 to 0.10 mg/kg, up to 6 mg (over 1 year of age). Haloperidol and pimozide have been used in children, especially for Tourette's syndrome; haloperidol is recommended for use in a dosage of 2 to 16 mg per day in children over 12 years of age.

Poor tolerance of the side effects of the antipsychotic drugs often limits the dosage that can be given to elderly patients. One should proceed cautiously, using small, divided doses of agents with moderate or high potency, with the expectation that elderly patients will require doses that are one-half or less of those needed for young adults (Eastham and Jeste, 1997; Jeste et al., 1999a,b; Zubenko and Sunderland, 2000).

Miscellaneous Medical Uses for Antipsychotic Drugs

Antipsychotic drugs have a variety of uses in addition to the treatment of psychiatric patients. Predominant among these are the treatment of nausea and vomiting, alcoholic hallucinosis, certain neuropsychiatric diseases marked by movement disorders (notably, Tourette's syndrome and Huntington's disease), and occasionally pruritus (for which trimeprazine is recommended) and intractable hiccough.

Nausea and Vomiting

Many antipsychotic agents can prevent vomiting due to specific etiologies when given in relatively low, nonsedative doses. This use is discussed in Chapter 38: Prokinetic Agents, Antiemetics, and Agents Used in Irritable Bowel Syndrome.

Other Neuropsychiatric Disorders

Antipsychotic drugs are useful in the management of several syndromes with psychiatric features that also are characterized by movement disorders. These include, in particular, Tourette's syndrome (marked by tics, other involuntary movements, aggressive outbursts, grunts, and vocalizations that frequently are obscene) and Huntington's disease (marked by severe and progressive choreoathetosis, psychiatric symptoms, and dementia, with a clear genetic basis). Haloperidol currently is regarded as a drug of choice for these conditions, although it probably is not unique in its antidyskinetic actions. Pimozide, a diphenylbutylpiperidine, also is used (typically in daily doses of 2 to 10 mg). Pimozide carries some risk of impairing cardiac repolarization, and it should be discontinued if the QT interval exceeds 470 msec, especially in a child. Clonidine and certain antidepressants also may be effective in Tourette's syndrome (Spencer et al., 1993). Clozapine and quetiapine are relatively well tolerated in psychosis arising with dopamine-receptor agonist treatment in Parkinson's disease (Tarsy et al., 2001).

Withdrawal Syndromes

Antipsychotic drugs are not useful in the management of withdrawal from opioids, and their use in the management of withdrawal from barbiturates and other sedatives or alcohol is contraindicated because of the high risk of seizures. They can be used safely and effectively in psychoses associated with chronic alcoholismespecially the syndrome known as alcoholic hallucinosis (seeSadock and Sadock, 2000).