Antipsychotic Agents Lithium William Z.Potter,MD,PhD,Leo E.Hollister,MD ANTIPSYCHOTIC AGENTS Introduction The terms antipsychotic and neuroleptic have been used interchangeably to denote a group of drugs that have been used mainly for treating schizophrenia but are also effective in some other psychoses and agitated states. History Antipsychotic drugs have been used in Western medicine for more than 50 years.Reserpine and chlorpromazine were the first drugs found to be useful in schizophrenia.Although chlorpromazine is still sometimes used for the treatment of psychoses,these forerunner drugs have been superseded by many newer agents.Their impact on psychiatry,however respecially on the treatment of schizophrenia has been enormous:The number of patients hospitalized in mental institutions has markedly decreased,and schizophrenia is now recognized as a biologic illness. Nature of Psychosis Schizophrenia The term "psychosis"denotes a variety of mental disorders.Schizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking disturbance. The pathogenesis of schizophrenia is unknown.Largely as a result of research stimulated by the discovery of antipsychotic drugs,a genetic predisposition has been proposed as a necessary but not always sufficient condition underlying psychotic disorder.This assumption has been supported by the observed familial incidence of schizophrenia.At least one gene that encoding neuregulin 1 is associated with schizophrenia in Icelandic and northern European populations.Additional genes associated with schizophrenia continue to be identified that may contribute to understanding the molecular basis for schizophrenia.Based on the efficacy of antipsychotic drugs,efforts continue to link the disorder with abnormalities of amine neurotransmitter function,especially that of dopamine (see Box:The Dopamine Hypothesis of Schizophrenia).The defects of this hypothesis are significant,and it is now appreciated that schizophrenia is far more complex than originally supposed
Antipsychotic Agents & Lithium William Z. Potter, MD, PhD, & Leo E. Hollister, MD I. ANTIPSYCHOTIC AGENTS Introduction The terms antipsychotic and neuroleptic have been used interchangeably to denote a group of drugs that have been used mainly for treating schizophrenia but are also effective in some other psychoses and agitated states. History Antipsychotic drugs have been used in Western medicine for more than 50 years. Reserpine and chlorpromazine were the first drugs found to be useful in schizophrenia. Although chlorpromazine is still sometimes used for the treatment of psychoses, these forerunner drugs have been superseded by many newer agents. Their impact on psychiatry, however respecially on the treatment of schizophrenia has been enormous: The number of patients hospitalized in mental institutions has markedly decreased, and schizophrenia is now recognized as a biologic illness. Nature of Psychosis & Schizophrenia The term "psychosis" denotes a variety of mental disorders. Schizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking disturbance. The pathogenesis of schizophrenia is unknown. Largely as a result of research stimulated by the discovery of antipsychotic drugs, a genetic predisposition has been proposed as a necessary but not always sufficient condition underlying psychotic disorder. This assumption has been supported by the observed familial incidence of schizophrenia. At least one gene that encoding neuregulin 1 is associated with schizophrenia in Icelandic and northern European populations. Additional genes associated with schizophrenia continue to be identified that may contribute to understanding the molecular basis for schizophrenia. Based on the efficacy of antipsychotic drugs, efforts continue to link the disorder with abnormalities of amine neurotransmitter function, especially that of dopamine (see Box: The Dopamine Hypothesis of Schizophrenia). The defects of this hypothesis are significant, and it is now appreciated that schizophrenia is far more complex than originally supposed
THE DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA The dopamine hypothesis for schizophrenia is the most fully developed of several hypotheses and is the basis for much of the rationale for drug therapy. Several lines of circumstantial evidence suggest that excessive dopaminergic activity plays a role in the disorder:(1)many antipsychotic drugs strongly block postsynaptic D2 receptors in the central nervous system,especially in the mesolimbic-frontal system;(2)drugs that increase dopaminergic activity,such as levodopa (a precursor),amphetamines (releasers of dopamine),and apomorphine (a direct dopamine receptor agonist),either aggravate schizophrenia or produce psychosis de novo in some patients;(3)dopamine receptor density has been found postmortem to be increased in the brains of schizophrenics who have not been treated with antipsychotic drugs;(4) positron emission tomography(PET)has shown increased dopamine receptor density in both treated and untreated schizophrenics when compared with such scans of nonschizophrenic persons;and (5)successful treatment of schizophrenic patients has been reported to change the amount of homovanillic acid(HVA),a metabolite of dopamine,in the cerebrospinal fluid, plasma,and urine. The dopamine hypothesis is far from complete,however.If an abnormality of dopamine physiology were completely responsible for the pathogenesis of schizophrenia,antipsychotic drugs would do a much better job of treating patients%but they are only partially effective for most and ineffective for some patients.Moreover,it appears that antagonists of the NMDA receptor such as phencyclidine,when administered to nonpsychotic subjects,produce much more "schizophrenia-like"symptoms than do dopamine agonists.The cloning and characterization of multiple dopamine receptor types may permit more direct testing of the dopamine hypothesis if drugs can be developed that act more selectively on each receptor type.The traditional antipsychotics bind D2 50 times more avidly than Di or D3 receptors.Until recently,the main thrust in drug development was to find agents that were more potent and more selective in blocking D2 receptors.The fact that several of the atypical antipsychotic drugs have much less effect on D2 receptors and yet are effective in schizophrenia has redirected attention to the role of other dopamine receptors and to nondopamine receptors,especially serotonin receptor subtypes that may mediate synergistic effects or protect against the extrapyramidal consequences of D2 antagonism.As a result of these considerations,the direction of research has changed to a greater focus on compounds that may act on several transmitter-receptor systems.The great hope is to produce drugs with greater efficacy and fewer adverse effects,especially extrapyramidal toxicity
THE DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA The dopamine hypothesis for schizophrenia is the most fully developed of several hypotheses and is the basis for much of the rationale for drug therapy. Several lines of circumstantial evidence suggest that excessive dopaminergic activity plays a role in the disorder: (1) many antipsychotic drugs strongly block postsynaptic D2 receptors in the central nervous system, especially in the mesolimbic-frontal system; (2) drugs that increase dopaminergic activity, such as levodopa (a precursor), amphetamines (releasers of dopamine), and apomorphine (a direct dopamine receptor agonist), either aggravate schizophrenia or produce psychosis de novo in some patients; (3) dopamine receptor density has been found postmortem to be increased in the brains of schizophrenics who have not been treated with antipsychotic drugs; (4) positron emission tomography (PET) has shown increased dopamine receptor density in both treated and untreated schizophrenics when compared with such scans of nonschizophrenic persons; and (5) successful treatment of schizophrenic patients has been reported to change the amount of homovanillic acid (HVA), a metabolite of dopamine, in the cerebrospinal fluid, plasma, and urine. The dopamine hypothesis is far from complete, however. If an abnormality of dopamine physiology were completely responsible for the pathogenesis of schizophrenia, antipsychotic drugs would do a much better job of treating patients¾but they are only partially effective for most and ineffective for some patients. Moreover, it appears that antagonists of the NMDA receptor such as phencyclidine, when administered to nonpsychotic subjects, produce much more "schizophrenia-like" symptoms than do dopamine agonists. The cloning and characterization of multiple dopamine receptor types may permit more direct testing of the dopamine hypothesis if drugs can be developed that act more selectively on each receptor type. The traditional antipsychotics bind D2 50 times more avidly than D1 or D3 receptors. Until recently, the main thrust in drug development was to find agents that were more potent and more selective in blocking D2 receptors. The fact that several of the atypical antipsychotic drugs have much less effect on D2 receptors and yet are effective in schizophrenia has redirected attention to the role of other dopamine receptors and to nondopamine receptors, especially serotonin receptor subtypes that may mediate synergistic effects or protect against the extrapyramidal consequences of D2 antagonism. As a result of these considerations, the direction of research has changed to a greater focus on compounds that may act on several transmitter-receptor systems. The great hope is to produce drugs with greater efficacy and fewer adverse effects, especially extrapyramidal toxicity
*Deceased BASIC PHARMACOLOGY OF ANTIPSYCHOTIC AGENTS Chemical Types A number of chemical structures have been associated with antipsychotic properties. The drugs can be classified into several groups as shown in Figures 29-1 and 29-2 A.PHENOTHIAZINE DERIVATIVES Three subfamilies of phenothiazines,based primarily on the side chain of the molecule,were once the most widely used of the antipsychotics.Aliphatic derivatives (eg,chlorpromazine)and piperidine derivatives (eg,thioridazine)are the least potent.Piperazine derivatives are more potent (effective in lower doses)but not necessarily more efficacious.The piperazine derivatives are also more selective in their pharmacologic effects. B.THIOXANTHENE DERIVATIVES This group of drugs is exemplified primarily by thiothixene.In general,these compounds are slightly less potent than their phenothiazine analogs. C.BUTYROPHENONE DERIVATIVES This group,of which haloperidol is the most widely used,has a very different structure from those of the two preceding groups.Diphenylbutylpiperidines are closely related compounds.The butyrophenones and congeners tend to be more potent and to have fewer autonomic effects but greater extrapyramidal effects. D.MISCELLANEOUS STRUCTURES The newer drugs,not all of which are available in the USA,have a variety of structures and include pimozide,molindone,loxapine,clozapine,olanzapine, quetiapine,risperidone,ziprasidone,and aripiprazole(Figure 29-2)
*Deceased BASIC PHARMACOLOGY OF ANTIPSYCHOTIC AGENTS Chemical Types A number of chemical structures have been associated with antipsychotic properties. The drugs can be classified into several groups as shown in Figures 29-1 and 29-2. A. PHENOTHIAZINE DERIVATIVES Three subfamilies of phenothiazines, based primarily on the side chain of the molecule, were once the most widely used of the antipsychotics. Aliphatic derivatives (eg, chlorpromazine) and piperidine derivatives (eg, thioridazine) are the least potent. Piperazine derivatives are more potent (effective in lower doses) but not necessarily more efficacious. The piperazine derivatives are also more selective in their pharmacologic effects. B. THIOXANTHENE DERIVATIVES This group of drugs is exemplified primarily by thiothixene. In general, these compounds are slightly less potent than their phenothiazine analogs. C. BUTYROPHENONE DERIVATIVES This group, of which haloperidol is the most widely used, has a very different structure from those of the two preceding groups. Diphenylbutylpiperidines are closely related compounds. The butyrophenones and congeners tend to be more potent and to have fewer autonomic effects but greater extrapyramidal effects. D. MISCELLANEOUS STRUCTURES The newer drugs, not all of which are available in the USA, have a variety of structures and include pimozide, molindone, loxapine, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and aripiprazole (Figure 29-2)
PHENOTHIAZINE DERIVATIVES THIOXANTHENE DERIVATIVE Phenothiazine 21 nucleus 12 10) Substituting C for N in the nucleus Aliphatic side chain Chlorpromazine (2)-CI 10-CH2-CHa-CH2-N-(CH) Thiothixene (2)-S02NCH,12 Thioridazine 2-SCH-C4一CH2 9=CH-CH一CH CH CH3 Piperazine side chain BUTYROPHENONE Trifluoperazine (2)-CF3 (10)-CH2-CH2-CH2 C-CH2-CH2-CH2- Perphenazine (2)-CI (10)-CH2-CHz-CH2 -CH2-CH2-OH Haloperidol Fluphenazine (2)-CF3 (10)-CH2-CH2-CH2- CH2-CH2-0H Figure 29-1.Structural formulas of some older antipsychotic drugs:phenothiazines, thioxanthenes,and butyrophenones.Only representative members of each type are shown. Ziprasidone Olanzapine Aripiprazole Figure 29-2.Structural formulas of some newer antipsychotic drugs. Pharmacokinetics
Figure 29-1. Structural formulas of some older antipsychotic drugs: phenothiazines, thioxanthenes, and butyrophenones. Only representative members of each type are shown. Figure 29-2. Structural formulas of some newer antipsychotic drugs. Pharmacokinetics
A.ABSORPTION AND DISTRIBUTION Most antipsychotic drugs are readily but incompletely absorbed.Furthermore,many of these drugs undergo significant first-pass metabolism.Thus,oral doses of chlorpromazine and thioridazine have systemic availability of 25%to 35%,whereas haloperidol,which is less likely to be metabolized,has an average systemic availability of about 65%. Most antipsychotic drugs are highly lipid-soluble and protein-bound(92-99%).They tend to have large volumes of distribution(usually >7 L/kg).Probably because these drugs are sequestered in lipid compartments of the body and have a very high affinity for selected neurotransmitter receptors in the central nervous system,they generally have a much longer clinical duration of action than would be estimated from their plasma half-lives.This is paralleled by prolonged occupancy of dopamine D2 receptors in brain.Metabolites of chlorpromazine may be excreted in the urine weeks after the last dose of chronically administered drug.Similarly,full relapse may not occur until 6 weeks or more after discontinuation of many antipsychotic drugs. B.METABOLISM Most antipsychotic drugs are almost completely metabolized by a variety of processes. Although some metabolites retain activity,eg,7-hydroxychlorpromazine and reduced haloperidol,metabolites are not considered to be highly important to the action of these drugs.The sole exception is mesoridazine,the major metabolite of thioridazine, which is more potent than the parent compound and accounts for most of the effect. This compound has been marketed as a separate entity.Very little of these antipsychotic drugs is excreted unchanged,because they are almost completely metabolized to more polar substances. Pharmacologic Effects The first phenothiazine antipsychotic drugs,with chlorpromazine as the prototype, proved to have a wide variety of central nervous system,autonomic,and endocrine effects.These actions were traced to blocking effects at a wide range of receptors, including dopamine and a adrenoceptor,muscarinic,Hi histaminic,and serotonin (5-HT2)receptors.Dopamine receptor effects quickly became the major focus of interest. A.DOPAMINERGIC SYSTEMS Five important dopaminergic systems or pathways are now recognized in the brain. The first pathway%the one most closely related to behavior is the mesolimbic-mesocortical pathway,which projects from cell bodies near the substantia nigra to the limbic system and neocortex.The second system%the nigrostriatal pathwayconsists of neurons that project from the substantia nigra to the caudate and putamen;it is involved in the coordination of voluntary movement. The third pathwaythe tuberoinfundibular system'connects arcuate nuclei and
A. ABSORPTION AND DISTRIBUTION Most antipsychotic drugs are readily but incompletely absorbed. Furthermore, many of these drugs undergo significant first-pass metabolism. Thus, oral doses of chlorpromazine and thioridazine have systemic availability of 25% to 35%, whereas haloperidol, which is less likely to be metabolized, has an average systemic availability of about 65%. Most antipsychotic drugs are highly lipid-soluble and protein-bound (92-99%). They tend to have large volumes of distribution (usually > 7 L/kg). Probably because these drugs are sequestered in lipid compartments of the body and have a very high affinity for selected neurotransmitter receptors in the central nervous system, they generally have a much longer clinical duration of action than would be estimated from their plasma half-lives. This is paralleled by prolonged occupancy of dopamine D2 receptors in brain. Metabolites of chlorpromazine may be excreted in the urine weeks after the last dose of chronically administered drug. Similarly, full relapse may not occur until 6 weeks or more after discontinuation of many antipsychotic drugs. B. METABOLISM Most antipsychotic drugs are almost completely metabolized by a variety of processes. Although some metabolites retain activity, eg, 7-hydroxychlorpromazine and reduced haloperidol, metabolites are not considered to be highly important to the action of these drugs. The sole exception is mesoridazine, the major metabolite of thioridazine, which is more potent than the parent compound and accounts for most of the effect. This compound has been marketed as a separate entity. Very little of these antipsychotic drugs is excreted unchanged, because they are almost completely metabolized to more polar substances. Pharmacologic Effects The first phenothiazine antipsychotic drugs, with chlorpromazine as the prototype, proved to have a wide variety of central nervous system, autonomic, and endocrine effects. These actions were traced to blocking effects at a wide range of receptors, including dopamine and a adrenoceptor, muscarinic, H1 histaminic, and serotonin (5-HT2) receptors. Dopamine receptor effects quickly became the major focus of interest. A. DOPAMINERGIC SYSTEMS Five important dopaminergic systems or pathways are now recognized in the brain. The first pathway¾the one most closely related to behavior is the mesolimbic-mesocortical pathway, which projects from cell bodies near the substantia nigra to the limbic system and neocortex. The second system¾the nigrostriatal pathway¾consists of neurons that project from the substantia nigra to the caudate and putamen; it is involved in the coordination of voluntary movement. The third pathway¾the tuberoinfundibular system¾connects arcuate nuclei and
periventricular neurons to the hypothalamus and posterior pituitary.Dopamine released by these neurons physiologically inhibits prolactin secretion.The fourth dopaminergic system the medullary-periventricular pathway consists of neurons in the motor nucleus of the vagus whose projections are not well defined.This system may be involved in eating behavior.The fifth pathway the incertohypothalamic pathway%forms connections from the medial zona incerta to the hypothalamus and the amygdala.It appears to regulate the anticipatory motivational phase of copulatory behavior in rats. After dopamine was recognized as a neurotransmitter in 1959,investigators showed that its effects on electrical activity in central synapses and on production of cAMP by adenylyl cyclase could be blocked by most antipsychotic drugs.This evidence led to the conclusion in the early 1960s that these drugs should be considered dopamine antagonists.The antipsychotic action is now thought to be produced(at least in part) by their ability to block dopamine in the mesolimbic and mesocortical systems. Furthermore,the antagonism of dopamine in the nigrostriatal system explains the unwanted effect of parkinsonism produced by these drugs.The hyperprolactinemia that follows treatment with antipsychotics is caused by blockade of dopamine's tonic inhibitory effect on prolactin release from the pituitary.Thus,the same pharmacodynamic action may have distinct psychiatric,neurologic,and endocrinologic consequences. B.DOPAMINE RECEPTORS AND THEIR EFFECTS At present,five dopamine receptors have been described,consisting of two separate families,the Di-like and D2-like receptor groups.The Di receptor is coded by a gene on chromosome 5,increases cAMP by Gs-coupled activation of adenylyl cyclase,and is located mainly in the putamen,nucleus accumbens,and olfactory tubercle.The second member of this family,Ds,is coded by a gene on chromosome 4,also increases cAMP,and is found in the hippocampus and hypothalamus.The therapeutic potency of antipsychotic drugs does not correlate with their affinity for binding the D receptor(Figure 29-3,top)but for most,correlates strongly with D2 affinity.The D2 receptor is coded on chromosome 11,decreases cAMP(by Gi-coupled inhibition of adenylyl cyclase),and inhibits calcium channels but opens potassium channels.It is found both pre-and postsynaptically on neurons in the caudate-putamen,nucleus accumbens,and olfactory tubercle.A second member of this family,the D3 receptor, also coded by a gene on chromosome 11,is thought to decrease cAMP and is located in the frontal cortex,medulla,and midbrain.D4 receptors also decrease cAMP The activation of D2 receptors by a variety of direct or indirect agonists (eg, amphetamines,levodopa,apomorphine)causes increased motor activity and stereotyped behavior in rats,a model that has been extensively used for antipsychotic drug screening.When given to humans,the same drugs aggravate schizophrenia.The antipsychotic agents block D2 receptors stereoselectively for the most part,and their binding affinity is very strongly correlated with clinical antipsychotic and
periventricular neurons to the hypothalamus and posterior pituitary. Dopamine released by these neurons physiologically inhibits prolactin secretion. The fourth dopaminergic system the medullary-periventricular pathway¾consists of neurons in the motor nucleus of the vagus whose projections are not well defined. This system may be involved in eating behavior. The fifth pathway the incertohypothalamic pathway¾forms connections from the medial zona incerta to the hypothalamus and the amygdala. It appears to regulate the anticipatory motivational phase of copulatory behavior in rats. After dopamine was recognized as a neurotransmitter in 1959, investigators showed that its effects on electrical activity in central synapses and on production of cAMP by adenylyl cyclase could be blocked by most antipsychotic drugs. This evidence led to the conclusion in the early 1960s that these drugs should be considered dopamine antagonists. The antipsychotic action is now thought to be produced (at least in part) by their ability to block dopamine in the mesolimbic and mesocortical systems. Furthermore, the antagonism of dopamine in the nigrostriatal system explains the unwanted effect of parkinsonism produced by these drugs. The hyperprolactinemia that follows treatment with antipsychotics is caused by blockade of dopamine's tonic inhibitory effect on prolactin release from the pituitary. Thus, the same pharmacodynamic action may have distinct psychiatric, neurologic, and endocrinologic consequences. B. DOPAMINE RECEPTORS AND THEIR EFFECTS At present, five dopamine receptors have been described, consisting of two separate families, the D1-like and D2-like receptor groups. The D1 receptor is coded by a gene on chromosome 5, increases cAMP by Gs-coupled activation of adenylyl cyclase, and is located mainly in the putamen, nucleus accumbens, and olfactory tubercle. The second member of this family, D5, is coded by a gene on chromosome 4, also increases cAMP, and is found in the hippocampus and hypothalamus. The therapeutic potency of antipsychotic drugs does not correlate with their affinity for binding the D1 receptor (Figure 29-3, top) but for most, correlates strongly with D2 affinity. The D2 receptor is coded on chromosome 11, decreases cAMP (by Gi-coupled inhibition of adenylyl cyclase), and inhibits calcium channels but opens potassium channels. It is found both pre- and postsynaptically on neurons in the caudate-putamen, nucleus accumbens, and olfactory tubercle. A second member of this family, the D3 receptor, also coded by a gene on chromosome 11, is thought to decrease cAMP and is located in the frontal cortex, medulla, and midbrain. D4 receptors also decrease cAMP. The activation of D2 receptors by a variety of direct or indirect agonists (eg, amphetamines, levodopa, apomorphine) causes increased motor activity and stereotyped behavior in rats, a model that has been extensively used for antipsychotic drug screening. When given to humans, the same drugs aggravate schizophrenia. The antipsychotic agents block D2 receptors stereoselectively for the most part, and their binding affinity is very strongly correlated with clinical antipsychotic and
extrapyramidal potency (Figure 29-3,bottom).Continuous treatment with antipsychotic drugs has been reported in some studies to produce a transient increase in levels of a dopamine metabolite,homovanillic acid (HVA),in the cerebrospinal fluid,plasma,and urine. These findings have been incorporated into the dopamine hypothesis of schizophrenia However,many questions have not been satisfactorily answered,and many observations have not been fully confirmed.For example,dopamine receptors exist in both high-and low-affinity forms,and it is not known whether schizophrenia or the antipsychotic drugs alter the proportions of receptors in these two forms.With the introduction of aripiprazole,which in preclinical studies shows partial agonism at D2 and 5-HTIA receptors,the relevance of the proportion of receptors in various affinity states may prove especially important for understanding the degree of response to this agent. Furthermore,the drug-induced progression of extrapyramidal changes%from diminished function(resembling parkinsonism)to increased activity (manifested by dyskinesias)often occurs over a period of months to years.This time scale is much longer than that described for other drug-induced changes in receptor function.Of most importance,newer drugs clozapine,olanzapine,quetiapine,and aripiprazoledo not have very high affinity for the D2 receptor,which suggests that additional actions are critical to their antipsychotic effects. It has not been convincingly demonstrated that antagonism of any dopamine receptor other than the D2 receptor plays a role in the action of antipsychotic drugs.Selective D3-receptor antagonists may prove therapeutic but are not yet available.Most of the newer "atypical"antipsychotic agents and some of the traditional ones have significant affinity for the 5-HT2A receptor,suggesting an important role for the serotonin system.Participation of glutamate,GABA,and acetylcholine receptors in the pathophysiology of schizophrenia has also been proposed.Agents targeted at glutamatergic and cholinergic systems are just beginning to be evaluated in schizophrenia C.DIFFERENCES AMONG ANTIPSYCHOTIC DRUGS Although all effective antipsychotic drugs block D2 receptors,the degree of this blockade in relation to other actions on receptors varies considerably between drugs. Vast numbers of ligand-receptor binding experiments have been performed in an effort to discover a single receptor action that would best predict antipsychotic efficacy.A summary of the relative receptor-binding affinities of several key agents in such comparisons illustrates the difficulty in drawing simple conclusions from such experiments: Chlorpromazine:a1 5-HT2A D2>DI Haloperidol:D2>a1 D4>5-HT2A D1>HI
extrapyramidal potency (Figure 29-3, bottom). Continuous treatment with antipsychotic drugs has been reported in some studies to produce a transient increase in levels of a dopamine metabolite, homovanillic acid (HVA), in the cerebrospinal fluid, plasma, and urine. These findings have been incorporated into the dopamine hypothesis of schizophrenia. However, many questions have not been satisfactorily answered, and many observations have not been fully confirmed. For example, dopamine receptors exist in both high- and low-affinity forms, and it is not known whether schizophrenia or the antipsychotic drugs alter the proportions of receptors in these two forms. With the introduction of aripiprazole, which in preclinical studies shows partial agonism at D2 and 5-HT1A receptors, the relevance of the proportion of receptors in various affinity states may prove especially important for understanding the degree of response to this agent. Furthermore, the drug-induced progression of extrapyramidal changes¾from diminished function (resembling parkinsonism) to increased activity (manifested by dyskinesias) often occurs over a period of months to years. This time scale is much longer than that described for other drug-induced changes in receptor function. Of most importance, newer drugs clozapine, olanzapine, quetiapine, and aripiprazole¾do not have very high affinity for the D2 receptor, which suggests that additional actions are critical to their antipsychotic effects. It has not been convincingly demonstrated that antagonism of any dopamine receptor other than the D2 receptor plays a role in the action of antipsychotic drugs. Selective D3-receptor antagonists may prove therapeutic but are not yet available. Most of the newer "atypical" antipsychotic agents and some of the traditional ones have significant affinity for the 5-HT2A receptor, suggesting an important role for the serotonin system. Participation of glutamate, GABA, and acetylcholine receptors in the pathophysiology of schizophrenia has also been proposed. Agents targeted at glutamatergic and cholinergic systems are just beginning to be evaluated in schizophrenia. C. DIFFERENCES AMONG ANTIPSYCHOTIC DRUGS Although all effective antipsychotic drugs block D2 receptors, the degree of this blockade in relation to other actions on receptors varies considerably between drugs. Vast numbers of ligand-receptor binding experiments have been performed in an effort to discover a single receptor action that would best predict antipsychotic efficacy. A summary of the relative receptor-binding affinities of several key agents in such comparisons illustrates the difficulty in drawing simple conclusions from such experiments: Chlorpromazine: a1 = 5-HT2A > D2 > D1 Haloperidol: D2 > a1 > D4 > 5-HT2A > D1 > H1
Clozapine:D4=a1>5-HT2A>D2=D1 Olanzapine:5-HT2A>H1>D4>D2>a1>DI Aripiprazole:D2=5-HT2A>D4>a1 =HI>>DI Quetiapine:H1>a1>M13>D2>5-HT2A Thus,most of the atypical antipsychotic agents are at least as potent in inhibiting 5-HT2 receptors as they are in inhibiting D2 receptors.The newest,aripiprazole, appears to be a partial agonist of D2 receptors.Varying degrees of antagonism of az adrenoceptors are also seen with risperidone,clozapine,olanzapine,quetiapine,and aripiprazole.The clinical relevance of these actions remains to be ascertained. Current research is directed toward discovering atypical antipsychotic compounds that are either more selective for the mesolimbic system (to reduce their effects on the extrapyramidal system)or have effects on central neurotransmitter receptors%such as those for acetylcholine and excitatory amino acids%4that have been proposed as new targets for antipsychotic action. In contrast to the search for efficacy,such differences in the receptor effects of various antipsychotics do explain many of their toxicities.In particular,extrapyramidal toxicity appears to be associated with high D2 potency. D.PSYCHOLOGICAL EFFECTS Most antipsychotic drugs cause unpleasant subjective effects in nonpsychotic individuals;the combination of sleepiness,restlessness,and autonomic effects creates experiences unlike those associated with more familiar sedatives or hypnotics. Nonpsychotic persons also experience impaired performance as judged by a number of psychomotor and psychometric tests.Psychotic individuals,however,may actually show improvement in their performance as the psychosis is alleviated. E.ELECTROENCEPHALOGRAPHIC EFFECTS Antipsychotic drugs produce shifts in the pattern of electroencephalographic frequencies,usually slowing them and increasing their synchronization.The slowing (hypersynchrony)is sometimes focal or unilateral,which may lead to erroneous diagnostic interpretations.Both the frequency and the amplitude changes induced by psychotropic drugs are readily apparent and can be quantitated by sophisticated electrophysiologic techniques.Some of the neuroleptic agents lower the seizure threshold and induce EEG patterns typical of seizure disorders;however,with careful dosage titration,most can be used safely in epileptic patients. F.ENDOCRINE EFFECTS Older antipsychotic drugs produce striking adverse effects on the reproductive system. Amenorrhea-galactorrhea,false-positive pregnancy tests,and increased libido have been reported in women,whereas men have experienced decreased libido and gynecomastia.Some of these effects are secondary to blockade of dopamine's tonic
Clozapine: D4 = a1 > 5-HT2A > D2 = D1 Olanzapine: 5-HT2A > H1 > D4 > D2 > a1 > D1 Aripiprazole: D2 = 5-HT2A > D4 > a1 = H1 >> D1 Quetiapine: H1 > a1 > M1,3 > D2 > 5-HT2A Thus, most of the atypical antipsychotic agents are at least as potent in inhibiting 5-HT2 receptors as they are in inhibiting D2 receptors. The newest, aripiprazole, appears to be a partial agonist of D2 receptors. Varying degrees of antagonism of a2 adrenoceptors are also seen with risperidone, clozapine, olanzapine, quetiapine, and aripiprazole. The clinical relevance of these actions remains to be ascertained. Current research is directed toward discovering atypical antipsychotic compounds that are either more selective for the mesolimbic system (to reduce their effects on the extrapyramidal system) or have effects on central neurotransmitter receptors¾such as those for acetylcholine and excitatory amino acids¾that have been proposed as new targets for antipsychotic action. In contrast to the search for ef icacy, such differences in the receptor effects of various antipsychotics do explain many of their toxicities. In particular, extrapyramidal toxicity appears to be associated with high D2 potency. D. PSYCHOLOGICAL EFFECTS Most antipsychotic drugs cause unpleasant subjective effects in nonpsychotic individuals; the combination of sleepiness, restlessness, and autonomic effects creates experiences unlike those associated with more familiar sedatives or hypnotics. Nonpsychotic persons also experience impaired performance as judged by a number of psychomotor and psychometric tests. Psychotic individuals, however, may actually show improvement in their performance as the psychosis is alleviated. E. ELECTROENCEPHALOGRAPHIC EFFECTS Antipsychotic drugs produce shifts in the pattern of electroencephalographic frequencies, usually slowing them and increasing their synchronization. The slowing (hypersynchrony) is sometimes focal or unilateral, which may lead to erroneous diagnostic interpretations. Both the frequency and the amplitude changes induced by psychotropic drugs are readily apparent and can be quantitated by sophisticated electrophysiologic techniques. Some of the neuroleptic agents lower the seizure threshold and induce EEG patterns typical of seizure disorders; however, with careful dosage titration, most can be used safely in epileptic patients. F. ENDOCRINE EFFECTS Older antipsychotic drugs produce striking adverse effects on the reproductive system. Amenorrhea-galactorrhea, false-positive pregnancy tests, and increased libido have been reported in women, whereas men have experienced decreased libido and gynecomastia. Some of these effects are secondary to blockade of dopamine's tonic
inhibition of prolactin secretion;others may be due to increased peripheral conversion of androgens to estrogens.Absent or minimal increases of prolactin after some of the newer antipsychotics such as olanzapine,quetiapine,and aripiprazole may be a marker of diminished D2 antagonism and hence reduced risks of extrapyramidal system dysfunction and tardive dyskinesia as well as endocrine dysfunction. G.CARDIOVASCULAR EFFECTS Orthostatic hypotension and high resting heart rates frequently result from use of the low-potency phenothiazines.Mean arterial pressure,peripheral resistance,and stroke volume are decreased,and heart rate is increased.These effects are predictable from the autonomic actions of these agents.Abnormal ECGs have been recorded, especially with thioridazine.Changes include prolongation of QT interval and abnormal configurations of the ST segment and T waves.These changes are readily reversed by withdrawing the drug. Among the newest antipsychotics,prolongation of the QT or QTe intervalwith increased risk of dangerous arrhythmias%has been of such concern that the atypical drug sertindole was withdrawn shortly after being marketed.Ziprasidone carries a warning about the risk of significant QTe prolongation. H.ANIMAL SCREENING TESTS Inhibition of conditioned (but not unconditioned)avoidance behavior is one of the most predictive tests of antipsychotic action.Another is the inhibition of amphetamine-or apomorphine-induced stereotyped behavior.This inhibition is undoubtedly related to the D2 receptor-blocking action of the drugs,countering these two dopamine agonists.Other tests that may predict antipsychotic action are reduction of exploratory behavior without undue sedation,induction of a cataleptic state, inhibition of intracranial self-stimulation of reward areas,and prevention of apomorphine-induced vomiting.Most of these tests are difficult to relate to any model of clinical psychosis. The psychosis produced by phencyclidine (PCP)has been used as a model for schizophrenia.Because this drug is an antagonist of the NMDA glutamate receptor, attempts have been made to develop antipsychotics that work as NMDA agonists. Sigma opioid and cholecystokinin type b (CCKo)antagonism have also been suggested as potential targets.Thus far,NMDA receptor-based models have pointed to agents that modulate glutamate release as potential antipsychotics
inhibition of prolactin secretion; others may be due to increased peripheral conversion of androgens to estrogens. Absent or minimal increases of prolactin after some of the newer antipsychotics such as olanzapine, quetiapine, and aripiprazole may be a marker of diminished D2 antagonism and hence reduced risks of extrapyramidal system dysfunction and tardive dyskinesia as well as endocrine dysfunction. G. CARDIOVASCULAR EFFECTS Orthostatic hypotension and high resting heart rates frequently result from use of the low-potency phenothiazines. Mean arterial pressure, peripheral resistance, and stroke volume are decreased, and heart rate is increased. These effects are predictable from the autonomic actions of these agents. Abnormal ECGs have been recorded, especially with thioridazine. Changes include prolongation of QT interval and abnormal configurations of the ST segment and T waves. These changes are readily reversed by withdrawing the drug. Among the newest antipsychotics, prolongation of the QT or QTc interval¾with increased risk of dangerous arrhythmias¾has been of such concern that the atypical drug sertindole was withdrawn shortly after being marketed. Ziprasidone carries a warning about the risk of significant QTc prolongation. H. ANIMAL SCREENING TESTS Inhibition of conditioned (but not unconditioned) avoidance behavior is one of the most predictive tests of antipsychotic action. Another is the inhibition of amphetamine- or apomorphine-induced stereotyped behavior. This inhibition is undoubtedly related to the D2 receptor-blocking action of the drugs, countering these two dopamine agonists. Other tests that may predict antipsychotic action are reduction of exploratory behavior without undue sedation, induction of a cataleptic state, inhibition of intracranial self-stimulation of reward areas, and prevention of apomorphine-induced vomiting. Most of these tests are difficult to relate to any model of clinical psychosis. The psychosis produced by phencyclidine (PCP) has been used as a model for schizophrenia. Because this drug is an antagonist of the NMDA glutamate receptor, attempts have been made to develop antipsychotics that work as NMDA agonists. Sigma opioid and cholecystokinin type b (CCKb) antagonism have also been suggested as potential targets. Thus far, NMDA receptor-based models have pointed to agents that modulate glutamate release as potential antipsychotics
TTTr厂 所 10-5 Sulpiride 0 Clebopride Molindone 10-6 29998S-HE Chlorpromazine Spiperone 10-7 Clozapine Haloperidol (7ow) Thioridazine Fluphenazine Trifluperazine 10-8 Flupenthixol ⊥L4山L L⊥L⊥L ⊥LLLL 1LuUl 10 -7 TTTTT Promazine 02 Chlorpromazine Irazodone hondae Clozapine 10-8 Molindone Moperone Prochlorperazine Trifluperazine Thiothixene 10-9 Haloperidol Fluphenazine Droperidol (7/ow) Trifluperidol Pimozide Benperidol 10-10 Spiroperidol 0.1 10 100 1000 Range and average clinical dose for controlling schizophrenia(mg d-) Figure 29-3.Correlations between the therapeutic potency of antipsychotic drugs and their affinity for binding to dopamine Di (top)or D2 receptors (bottom).Potency is indicated on the horizontal axes;it decreases to the right.Binding affinity for Di receptors was measured by displacing the selective Di ligand SCH 23390;affinity for D2 receptors was similarly measured by displacing the selective D2 ligand haloperidol. Binding affinity decreases upward.(Modified and reproduced,with permission,from Seeman P:Dopamine receptors and the dopamine hypothesis of schizophrenia Synapse 1987;1:133.) CLINICAL PHARMACOLOGY OF ANTIPSYCHOTIC AGENTS
Figure 29-3. Correlations between the therapeutic potency of antipsychotic drugs and their affinity for binding to dopamine D1 (top) or D2 receptors (bottom). Potency is indicated on the horizontal axes; it decreases to the right. Binding affinity for D1 receptors was measured by displacing the selective D1 ligand SCH 23390; affinity for D2 receptors was similarly measured by displacing the selective D2 ligand haloperidol. Binding affinity decreases upward. (Modified and reproduced, with permission, from Seeman P: Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1987;1:133.) CLINICAL PHARMACOLOGY OF ANTIPSYCHOTIC AGENTS