Some of the second-generation antipsychotic drugs produce more weight gain and increases in lipids than some first-generation drugs. A small percentage of patients develop diabetes mellitus, most often seen with clozapine and olanzapine. Ziprasidone is the second-generation drug causing the least weight gain. Risperidone, lurasidone, brexpiprazole, paliperidone, and aripiprazole usually produce small increases in weight and lipids. Asenapine and quetiapine have an intermediate effect. Clozapine and olanzapine frequently result in large increases in weight and lipids. Thus, these drugs should be considered as second-line drugs unless there is a specific indication. That is the case with clozapine, which at high doses (300–900 mg/d) is effective in the majority of patients with schizophrenia refractory to other drugs, provided that treatment is continued for up to 6 months. Case reports and several clinical trials suggest that high-dose olanzapine, ie, doses of 30–45 mg/d, may also be efficacious in refractory schizophrenia when given over a 6-month period. Clozapine is the only second-generation antipsychotic drug approved to reduce the risk of suicide in patients with history of schizophrenia. Patients with schizophrenia who have made life-threatening suicide attempts should be seriously evaluated for switching to clozapine.
New antipsychotic drugs have been shown in some trials to be more effective than older ones for treating negative symptoms. The floridly psychotic form of the illness accompanied by uncontrollable behavior probably responds equally well to all potent antipsychotics but is still frequently treated with older drugs that offer intramuscular formulations for acute and chronic treatment. Moreover, the low cost of the older drugs contributes to their widespread use despite their risk of adverse EPS effects. Several of the newer antipsychotics, including clozapine, risperidone, and olanzapine, show superiority over haloperidol in terms of overall response in some controlled trials. More comparative studies with aripiprazole are needed to evaluate its relative efficacy. Moreover, the superior adverse-effect profile of the newer agents and low to absent risk of tardive dyskinesia suggest that these should provide the first line of treatment. Generic forms of many second-generation drugs including clozapine, olanzapine, aripiprazole, risperidone, and quetiapine have become available, and cost of these drugs is much less of a consideration than it once was.
The best guide for selecting a drug for an individual patient is the patient history of past responses to drugs. At present, clozapine is limited to those patients who have failed to respond to substantial doses of conventional antipsychotic drugs. The agranulocytosis and seizures associated with this drug prevent more widespread use. Risperidone’s improved adverse-effect profile (compared with that of haloperidol) at dosages of 6 mg/d or less and the apparently lower risk of tardive dyskinesia have contributed to its widespread use. Olanzapine and quetiapine may have even lower risks and have also achieved widespread use. At this writing, aripiprazole is the most commonly prescribed second-generation antipsychotic in the USA due to a relatively favorable side effect profile and aggressive marketing.