The second caveat is the action of low D2 receptor affinity antipsychotics, such as clozapine and quetiapine. These agents generally achieve adequate D2 receptor occupancy for only a brief period of time.20 It has been suggested that continuous receptor occupancy at ≥65% may not be necessary to obtain antipsychotic control.21,22 There may also be specific limbic and cortical (vs striatal) D2 receptor selectivity by clozapine23 compared with other second-generation antipsychotics such as risperidone and olanzapine,24,25 although this point remains debatable.26 Furthermore, the antipsychotic efficacy of low D2 receptor affinity drugs is unreliable, even in controlled, blinded studies (eg, a failed large quetiapine study27). Thus far, the actual antipsychotic mechanism of these agents is yet to be fully understood.
Minimal effective dose achieves maximal response
An interesting aspect of the threshold phenomenon of drug response is that once the minimal effective dose is reached, maximal response is achieved. In other words, there is no additional efficacy with additional dose increases. This is readily demonstrated in some studies in which patients were randomly assigned to different fixed doses or dose ranges. In these studies, there was generally no difference in response rates of different doses, so that once 65% to 80% receptor occupancy is achieved, minimal and maximal clinical response is simultaneously reached.18,28,29
For example, in the original risperidone studies, 6 mg/d was essentially equivalent to 16 mg/d.28 Similarly, lurasidone, 40 mg/d, achieves approximately 65% D2 occupancy.30 When the daily dose is increased to 120 mg, there is no additional benefit in controlling psychosis in schizophrenia.29 This pattern is also seen in partial agonists, where there are no differences between lower and higher doses in terms of response.18
Upon reading this, many clinicians may think “I don’t care what the studies say, I have seen additional benefits with additional doses.” There are several explanations for this. One is that individual patients have genetic variants that may prevent them from responding in a typical fashion. Hints of this are seen in an apparent disconnect between dosage and drug levels, so that it is not surprising that drug levels are a much better predictor of receptor occupancy than dosage.31 Nonetheless, as previously pointed out, for a population, dosage does predict receptor occupancy and outcome. However, for individuals, genetic variations make dosages less reliable. For example, ultrarapid metabolizers of cytochrome P450 (CYP) 2D6 may discontinue risperidone due to nonresponse, or require a higher dose or longer time period to respond.32,33 Similarly, patients who smoke may require an increase in doses of CYP1A2 substrates such as clozapine and olanzapine.34
Alternatively, the clinician may note improvement in mood, sleep, appetite, or other symptoms at lower doses, and then note additional improvements in psychosis or mania at higher doses.3 This occurs due to the varying affinity of different receptors. For example, in bipolar depression trials that used quetiapine in a fixed-dose design, patients who received 300 or 600 mg/d responded in the same fashion, with no additional benefit in improving depression with the higher dose.35 Similarly, in a flexible dose range study that evaluated lurasidone in bipolar depression, an average dose of 34 mg/d (range 20 to 60 mg/d) and an average dose of 83 mg/d (range 80 to 120 mg/d) both resulted in the same response (a 15.4-point reduction in depression ratings and an effect size of 0.51).36 For both quetiapine and lurasidone, higher doses are generally required to control psychosis.29,37 Note that for lurasidone, agitation, but not psychosis, improves with higher doses, which suggests that recruitment of additional receptors results in improvement in a different set of symptoms.9
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