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