Strategies for Switching between Oral Postsynaptic Antidopaminergic Antipsychotics in Patients with Schizophrenia: A Systematic Review

Antipsychotic switching is common in the treatment of schizophrenia. Pharmacokinetic and pharmacodynamic properties of antipsychotics can inform switch strategies, as switching from shorter to longer half-life antipsychotics and switching from more antagonistic to less antagonistic or partial agonist agents at dopaminergic, histaminergic, and cholinergic receptors can lead to withdrawal or rebound symptoms, potentially complicating switch results. This systematic literature review of studies investigated switching strategies between oral antipsychotics. Pharmacokinetic and pharmacodynamic characteristics of antipsychotics that can influence switch outcomes were also extracted from publications and prescribing information. MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and PubMed databases were queried (last search 13 May 2024) for articles published from 1 June 2010 to 1 April 2024, with keywords (schizophr* OR schizoaff*) AND (antipsychotic*) AND (switch*). Randomized controlled trials, open-label studies, meta-analyses, and reviews of oral antipsychotic switching were included. Records were excluded if they investigated a disease other than schizophrenia or schizoaffective disorder or focused on long-acting injectable or non-approved antipsychotics. Data on switch strategies investigated and study outcomes were manually extracted from randomized controlled trials and open-label switch studies of oral antipsychotics in schizophrenia or schizoaffective disorder. Meta-analyses and review articles were summarized. There was no assessment for risk of bias or specific method to synthesize results. Of the 579 records identified during the systematic review, 80 articles investigated switching of oral antipsychotics in adult patients with schizophrenia, including 58 randomized and non-randomized studies (9 of which investigated ≥ 1 antipsychotic) and 22 review articles or meta-analyses. The antipsychotics investigated during this period were: aripiprazole (studies = 18); paliperidone, ziprasidone, olanzapine, and risperidone (studies = 7 each); brexpiprazole, clozapine and lurasidone (studies = 4 each); amisulpride, (studies = 3); quetiapine and iloperidone (studies = 2 each); and asenapine and lumateperone (1 study each). Most studies that reported a switch method employed cross-titration switching (studies = 39; 69.6%), while abrupt switching (studies = 10; 17.9%) and switching at investigator’s discretion (studies = 7; 12.5%) were rare. A total of 24 studies (N = 3440 patients) had statistical comparisons between treatment groups, but few studies specifically statistically compared outcomes between different switch strategies (1 trial each for aripiprazole, clozapine, iloperidone, and ziprasidone; N = 666 patients), with mixed outcomes. Frequencies of sedative rescue treatments, which could have attenuated potential withdrawal symptoms, were rarely disclosed. Despite the importance and frequency of antipsychotic switching, few studies have specifically investigated outcomes of different switch strategies. General clinical preference appears to utilize gradual switching approaches to avoid potential rebound symptoms. Future research with current and emerging antipsychotics is needed, especially for switching between antipsychotics with different receptor profiles and for switches that are potentially vulnerable to rebound and withdrawal symptoms. People with schizophrenia commonly switch between antipsychotics, but few studies give information about the best way to do this. This paper reviews antipsychotic qualities that can affect a person’s experience while switching antipsychotics, such as how antipsychotics pass through the body over time (called pharmacokinetics) and how they work in the body (called pharmacodynamics). Considering these antipsychotic qualities can help clinicians decide how to switch between antipsychotics to reduce the risk of worsening symptoms or side effects. This paper also reviews which switching methods are used most often. Studies published from 2010 to 2024 were found. Of 579 search results, 80 articles involving 13 different antipsychotics were summarized. In most studies (n = 39) the current antipsychotic was slowly stopped, and the new antipsychotic was slowly started over the same time period, called cross-titration. Fewer studies (n = 10) quickly stopped the current antipsychotic and started the new one, and some studies (n = 7) had prescribers decide switch timing. A total of 24 studies, including 3440 participants, reported on comparisons between study groups. However, only four trials (one trial each for aripiprazole, clozapine, iloperidone, and ziprasidone; 666 participants) reported on comparisons of outcomes of different switch strategies. Nevertheless, results of the reviewed studies are mostly in agreement that good practice consists of more gradual antipsychotic switching in people with stable schizophrenia. Unfortunately, comparisons between switching methods and details about medicines used to reduce side effects during the switch were rarely reported. More research is needed to understand the effects of antipsychotic switching methods in people with schizophrenia.