Recent issues and developments in antipsychotic use

A pharmacologically based evaluation of the newer atypical agents can facilitate the selection of best therapy for patients with schizophrenia. To illustrate, for negative symptoms, switching from a typical neuroleptic to an atypical agent or downward titration of typical antipsychotics towards the lowest possible dose should be considered. In the case of poor or inadequate negative symptom response: (1) consider if these are primary versus secondary (drug ADEs) negative symptoms; (2) choose a drug that minimizes the impact of EPS (e.g., low/intermediate affinity D2 antagonists), ameliorates depressive symptoms (ziprasidone, olanzapine, clozapine), or both; and (3) improve cortical and prefrontal function by selecting a medication that increases dopamine effects, glutamate effects, or both. This can be accomplished by selecting atypical antipsychotics with 5-HT2 activity (increased prefrontal dopamine), α2c antagonism (risperidone, clozapine, quetiapine), 5-HT1a agonist effects (ziprasidone, quetiapine), or all three; and (4) add an adjunctive drug with differing pharmacologic actions than the antipsychotic being used, which may yield an improvement in negative symptoms (e.g., SSRIs, bupropion, low dose psychostimulants, or psychosocial treatment).²⁴ Many of the adverse effects seen with atypical antipsychotics appear consistent with relative receptor affinities, as shown in Table 5. However, there are complexities in human responses to medications that are not completely modeled by in vitro data (i.e., the low rate of antimuscarinic effects with olanzapine). Additionally, despite risperidone's potent D2 blockade at appropriate low doses of 4 to 6 mg/d, this drug appears to exhibit equivalently low EPS potential when compared with other atypical agents. Therefore, clinical head-to-head trials such as the Clinical Antipsychotic Trials of Intervention Effectiveness NIMH funded studies are essential if we are to fully appreciate the differences between the increasing number of atypical antipsychotic therapies.