Characteristics of Antipsychotic Drugs

Chlorpromazine was the first compound identified to have therapeutic benefit for schizophrenia, and surprisingly it emerged from the field of antihistamine research.74 It has high affinity for adrenergic a-1A, -1B, -2B, and -2C, histamine H1, dopamine D2, D3, and D4, serotonin 5HT6 and 5HT7, and muscarinic M1, M3, and M5 receptors.75 It has strong sedative properties and was quickly superseded by drugs such as haloperidol and clozapine that maintained broad receptor interaction profiles and lower frequencies of adverse motor and cardiovascular effects. Compound structures are shown in Figure 7.2.

Haloperidol is considered a "typical" antipsychotic, showing efficacy in treating positive symptoms, e.g., delusions, paranoia, and hallucinations, in 70 to 80% of schizophrenic patients.76 It has high affinity for dopamine D2 and adrenergic a-1B receptors, with somewhat lower affinity for dopamine D3 and D4 and adrenergic a-1A receptors. Typical antipsychotics, including haloperidol, are still associated with sx

imipramine

aripiprazole

FIGURE 7.2 Selected structures of psychiatric drugs. Atypical antipsychotics include clozapine and its close analogs, quetiapine and olanzapine, plus the D2 partial agonist, aripiprazole. Haloperidol and chlorpromazine are typical antipsychotics, also known as neuroleptics. Imipramine, a derivative of chlorpromazine, is an antidepressant.

chlorpromazine imipramine

aripiprazole

FIGURE 7.2 Selected structures of psychiatric drugs. Atypical antipsychotics include clozapine and its close analogs, quetiapine and olanzapine, plus the D2 partial agonist, aripiprazole. Haloperidol and chlorpromazine are typical antipsychotics, also known as neuroleptics. Imipramine, a derivative of chlorpromazine, is an antidepressant.

high incidences of extrapyramidal symptoms (EPS), weight gain, sedation, hyper-prolactinemia, and impairment of cognitive function.77

Clozapine is different in that it is effective for positive disease symptoms as well as negative symptoms such as withdrawal, diminished emotions, and decreased social interaction, and it presents greatly reduced risks of movement disorders. The combination of efficacy in treating positive and negative disease symptoms and low incidences of EPS defines the class of "atypical" antipsychotic drugs, but the pharmacological basis for atypicality is still unclear.78

Interestingly, clozapine also has a broad receptor interaction profile, with lower affinity binding compared to haloperidol at most GPCRs. It has highest affinity overall for adrenergic a-1A and 1B, moderate affinity for the muscarinic Ml through M5 and serotonin 5HT2A, 5HT2C, 5HT6 and 5HT7 receptors, and 10-fold higher affinity for dopamine D4 versus dopamine Dl, D2, D3, and D5 receptors.75 Some experts believe that D2 receptor blockade may be sufficient for antipsychotic efficacy,79 whereas others propose that nonselective drugs with custom-designed receptor profiles will be required to treat complex psychiatric disorders.80

Despite the introduction of new atypical drugs, clozapine remains the "gold standard" of antipsychotic efficacy, as the only compound to show benefit for the population of patients (over 30%) who do not respond to other drug treatment options81 and for reducing emergent suicidal behavior82 — a major cause of death in schizophrenic patients. Interestingly, at efficacious doses of clozapine and its close

FIGURE 7.3 Dopaminergic pathways in a sagittal section of brain. The nigrostriatal pathway containing about 75% of the DA in the brain originates in the substantia nigra (SN) and projects primarily to the basal ganglia or striatum (ST), the center of movement control. This pathway is implicated in Parkinson's disease and in the extrapyramidal (short term) and tardive dyskinesia (long term) side effects observed during antipsychotic therapy. The mesolimbic pathway originates in the ventral tegmental area (VTA) and projects to the medial components of the limbic system such as the nucleus accumbens (NA) and anterior cingulated (AC) cortex. This pathway is implicated in emotion, memory, and the positive symptoms of schizophrenia. Neurons in the mesocortical pathway also originate in the VTA and project primarily to the PFC. This pathway is implicated in motivation and planning, attention, social behavior, and the negative symptoms of schizophrenia. The tuberoinfundibular pathway originates in the hypothalamus and projects to the pituitary gland where DA release controls prolactin secretion, influencing lactation and fertility.

FIGURE 7.3 Dopaminergic pathways in a sagittal section of brain. The nigrostriatal pathway containing about 75% of the DA in the brain originates in the substantia nigra (SN) and projects primarily to the basal ganglia or striatum (ST), the center of movement control. This pathway is implicated in Parkinson's disease and in the extrapyramidal (short term) and tardive dyskinesia (long term) side effects observed during antipsychotic therapy. The mesolimbic pathway originates in the ventral tegmental area (VTA) and projects to the medial components of the limbic system such as the nucleus accumbens (NA) and anterior cingulated (AC) cortex. This pathway is implicated in emotion, memory, and the positive symptoms of schizophrenia. Neurons in the mesocortical pathway also originate in the VTA and project primarily to the PFC. This pathway is implicated in motivation and planning, attention, social behavior, and the negative symptoms of schizophrenia. The tuberoinfundibular pathway originates in the hypothalamus and projects to the pituitary gland where DA release controls prolactin secretion, influencing lactation and fertility.

analog, quetiapine (Figure 7.2), only transient D2 receptor occupancy is observed in brain-imaging studies.83

The existence of multiple dopaminergic systems in the brain is key to understanding the pathology and current treatment strategies for schizophrenia (Figure 7.3). The dopamine hypothesis of schizophrenia, first proposed in 1965,84 now proposes that excess dopamine observed in the striatum leads to positive symptoms and a dopamine deficiency in prefrontal cortex contributes to negative symptoms. Whereas D2 receptor blockade in the mesolimbic pathway is believed to account for efficacy against positive symptoms, D2 blockade in the nigrostriatal pathway results in acute dyskinesia, akinesia, and tardive dyskinesia, motor side effects collectively referred to as EPS. Atypical antipsychotics selectively block dopamine receptors in limbic brain areas, consistent with their lower side-effect profiles.

Recent developments include identification of new modes of action for antipsychotics, including the launch of a dopamine D2 receptor partial agonist, aripipra-zole,85 and the finding that olanzapine and risperidone show inverse agonism at serotonin and/or dopamine receptors.86 Inverse agonist activity has not been shown to correlate with atypicality,87 but most atypical drugs have moderate to high affinity 5HT2A receptor antagonism, which is believed to facilitate dopaminergic transmission in the cortex.8889 A selective serotonin 5HT2A and 5HT2C receptor antagonist (SR46349B) and the neurokinin 3 (NK3) antagonist (SR142801) have shown antipsychotic efficacy in a first clinical trial.90 However, sonepiprazole, a D4-selective compound, failed to show efficacy in a separate placebo-controlled trial.91 5HT2 receptors are unique in that they are downregulated when chronically exposed to either agonists or antagonists,92 and 5HT2C transcripts are now known to undergo RNA editing that may be reduced in schizophrenic patients.93 RNA editing can produce up to 14 different receptor isoforms that vary with respect to receptor coupling to G proteins, agonist trafficking, and level of constitutive activity.94

Muscarinic receptors are also implicated in schizophrenia, based on the activity of the Ml and M4 agonist, xanomeline, in reducing psychotic and behavioral aspects of dementia.95

Cannabinoid receptors are localized in areas where they may indirectly modulate dopaminergic transmission relevant to both positive and negative symptoms.96 The CB1 receptor is reported to be upregulated in the prefrontal cortices of schizophrenic patients.97

One clinical trial with the SR141716A CB1 antagonist has been reported, but it did not demonstrate significant improvement in positive or negative symptoms of schizophrenia.90 The adenosine A2a receptor is also of interest based on the activity of CGS21680 in Cebus paella monkeys.98 Specifically, A2a-D2 heterodimers localized in the dendritic spines of the striatopallidal GABAergic neurons have been implicated as potential targets for schizophrenia and other disorders.99 Research related to finding novel antipsychotic drugs includes efforts aimed at GPCRs, ion channels, neurotrophic factors, and even cell-signaling mechanisms100 that may achieve better efficacy against positive and negative symptoms and therapeutic benefit for cognitive deficits such as reduced ability to focus attention and deficiencies in executive function. Preclinical models have implicated serotonin 5HT2A,101 5HT6,102 dopamine Dl103 and D2,104 and adrenergic a-2A105 receptors as targets to enhance cognitive function.

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