Antipsychotic Medications: Enhancing Use to Improve Outcomes

Hiroyoshi Takeuchi; Stefan Leucht; John M. Kane; Ofer Agid; Gary Remington


Schizophr Bull. 2021;47(5):1201-1204. 

In This Article

Antipsychotic Switching

Switching antipsychotics is routine as clinicians seek to achieve adequate response while minimizing associated side effects. Whether switching to another antipsychotic is superior to increasing antipsychotic dose in patients with schizophrenia not responding remains unknown as only 1 small RCT[36] was identified by a systematic review.[37] Surprisingly, work specific to this topic has been limited to date and various strategies are observed clinically.[38] In terms of existing antipsychotics, strategies can be classified as (1) abrupt or immediate discontinuation; (2) gradual discontinuation (ie, tapering over >1 d); and (3) wait-and-gradual discontinuation (ie, waiting >1 d after introduction of the new antipsychotic before tapering the existing antipsychotic over >1 d). Both gradual and wait-and-gradual discontinuation have been recommended when switching antipsychotics,[39] given concerns regarding, in particular, dopamine-related withdrawal phenomena.[40] At the same time, there is the evidence already noted indicating that reduction in central dopamine D2 receptor occupancy as a function of time is slower than what is observed with peripheral plasma levels,[25] calling into question the risk of adverse events such as dopamine supersensitivity psychosis in the face of immediate antipsychotic discontinaution.[25] In line with this, recent meta-analyses have demonstrated no significant differences in efficacy or effectiveness between immediate, gradual, and wait-and-gradual discontinuation in switching antipsychotics, except for all-cause study discontinuation, which favors wait-and-gradual versus immediate discontinuation.[38,41,42] In addition, there were no significant differences in any adverse events, not just dopamine-related withdrawal phenomena. In terms of the new antipsychotic (ie, the agent being started), a recent meta-analysis found that immediate introduction was inferior to gradual introduction in terms of all-cause study discontinuation when switching antipsychotics.[43] Summarizing, in switching antipsychotics the current antipsychotic can be immediately discontinued, particularly when it is necessary to undertake an urgent switch, while the next antipsychotic is gradually introduced. It should also be noted that there have been no RCTs to date comparing immediate versus gradual discontinuation of clozapine in switching antipsychotics.

We conclude with 2 final points. First, while evidence is critical in guiding treatment decision making, this is not an endorsement of "cookbook" medicine. The goal is personalized medicine, and good clinical practice calls for evidence to be integrated with a careful consideration of differences in pharmacological properties of antipsychotics as well as patients' clinical characteristics. For instance, clinicians should take into consideration individual factors that can affect plasma concentrations of antipsychotics such as pharmacogenetics and smoking. Second, we too embrace the notion that progress will bring significant advances in our understanding of schizophrenia, its complexity, and the varied approaches required to optimize both clinical and functional outcomes, including new drugs. Unfortunately, the nature of schizophrenia also translates to rates of progress that are slower than what we would wish. As we await these advances, it is no less important to ensure optimization of all treatments we currently have in hand. In the case of pharmacotherapy, decades of use may have lulled us into thinking that we know how to use these drugs, and this is not the case.