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 and relatively specific D1-, D3-, and D4-receptor antagonists have been tested repeatedly with no evidence of antipsychotic action. Most of the newer atypical antipsychotic agents and some of the traditional ones have a higher affinity for the 5-HT2A receptor than for the D2 receptor (Table 29–1), suggesting an important role for the serotonin 5-HT system in the etiology of schizophrenia and the action of these drugs.
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 among 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: α1 = 5-HT2A > D2 > D1
Haloperidol: D2 > α1 > D4 > 5-HT2A > D1 > H1
Clozapine: D4 = α1 > 5-HT2A > D2 = D1
Olanzapine: 5-HT2A > H1 > D4 > D2 > α1 > D1
Aripiprazole: D2 = 5-HT2A > D4 > α1 = H1 >> D1
Quetiapine: H1 > α1 > M1,3 > D2 > 5-HT2A
Thus, most of the second-generation and some first-generation antipsychotic agents are at least as potent in inhibiting 5-HT2 receptors as they are in inhibiting D2 receptors. Aripiprazole and brexpiprazole appear to be partial agonists of D2 receptors. Varying degrees of antagonism of α2 adrenoceptors are also seen with risperidone, clozapine, olanzapine, quetiapine, and aripiprazole.
TABLE 29–2 Adverse pharmacologic effects of antipsychotic drugs.
Current research is directed toward discovering novel 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—that have been proposed as new targets for antipsychotic action.
In contrast to the difficult search for receptors responsible for antipsychotic efficacy, the differences in receptor effects of various antipsychotics do explain many of their toxicities (Tables 29–1 and 29–2). In particular, extrapyramidal toxicity appears to be consistently associated with high D2 potency.
D. Psychological Effects
Most antipsychotic drugs cause unpleasant subjective effects in nonpsychotic individuals. The mild to severe EPS, including akathisia, sleepiness, restlessness, and autonomic effects are unlike any associated with more familiar sedatives or hypnotics. Nevertheless, low doses of some of these drugs, particularly quetiapine, are used to promote sleep onset and maintenance, although there is no approved indication for such usage.
People without psychiatric illness given antipsychotic drugs, even at low doses, 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. The ability of the second-generation anti-psychotic drugs to improve some domains of cognition in patients with schizophrenia and bipolar disorder is controversial. Some individuals experience marked improvement, and for that reason, cognition should be assessed in all patients with schizophrenia and a trial of an atypical agent considered, even if positive symptoms are well controlled by first-generation agents.
E. Electroencephalographic Effects