01. Switching Oral Antipsychotics: Six Strategies and Tips

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In this Quick Take today, I am going to discuss antipsychotic switching. Switching antipsychotics is something we do all the time. So when I saw that a colleague of mine, Christoph Correll wrote a piece in the journal CNS Drugs with the title, “Strategies for Switching between Oral Postsynaptic Antipsychotics in Patients with Schizophrenia: A Systematic Review”, my interest was piqued. What do we actually know about switching?

Switching Is Core Clinical Skill

Clinically, the issue is usually relevant as patients want to try a different antipsychotic all the time, at least in my practice, either because of side effects or insufficient efficacy. So switching antipsychotics is a critical clinical skill for psychiatrists. The manuscript provides a nice introductory section about the pharmacokinetics and pharmacodynamics of antipsychotics and also a discussion about rebound and withdrawal phenomena and different types of switches informed by pharmacokinetics and pharmacodynamics.

I think having some basic knowledge of a drug’s receptor profile, the degree of dopamine blockade and half-lives are important and helpful but the review wanted to examine what we actually know from clinical trials about different switching strategies. So let us go to this part of the manuscript.

Systematic Review Scope and Gaps

I will not bore you with the technical details of the manuscript other than to say that this was a standard systematic review of relevant data based on the English literature that netted 80 relevant articles. And of those 80, 58 were studies and 22 were reviews of meta-analyses. Now, this is important: Dr. Correll only included oral antipsychotics. So long-acting injectable antipsychotics were not covered. And the biggest gap in this review was that the newest approved antipsychotic in the United States, KarXT or xanomeline was not included. You may recall that this new medicine works at mechanisms other than primarily dopamine blockade.

Four Drugs Have Switch Data

Arguably, the main conclusion is that only four studies reported outcomes between different switch strategies. These studies specifically covered aripiprazole, clozapine, iloperidone, and ziprasidone. Put differently, for the majority of our medications, you will find very little guidance in the clinical trial literature.

Let me just add Dr. Correll’s two main conclusions about his review:

• Future research is needed particularly for switching between antipsychotics with different pharmacodynamic and pharmacokinetic characteristics and for antipsychotic switches that are potentially prone to rebound or withdrawal symptoms
• Gradual switching methods were preferred as they may improve tolerability and as they may reduce rebound phenomenon in patients with stable schizophrenia

Six Clinical Switching Tips

Unfortunately, I think the area of antipsychotic switching will always remain an orphan of clinical research. So you will have to come up with your own clinical expertise, how to switch antipsychotics.

And I do not want to leave you hanging but would like to offer my own six clinical points about switching on the outpatient side. Switching on the outpatient side may be different from the inpatient side where the outpatient side switching is usually not an emergency but an elective decision, if you will, that you can plan.

1. Switch Gradually But Switch

While I agree with the conclusion to switch antipsychotics gradually, I also want to caution against doing it too slowly which is a recipe for the so-called stalled taper, stalled taper resulting in no switch but polypharmacy.

The goal of a switch is to switch and not ending up on two antipsychotics. Set this as an expectation with your patient. And while you can show some flexibility, you always must keep this goal in mind.

For most patients, a switch can be accomplished in one or two months, maximum three, I would say. Once you go beyond that, you, I think you have real risk for a stalled taper or an eternal taper.

2. Consider Plateau Cross-Titration

Many drugs can be switched using a cross-titration, specifically a plateau cross-titration where you introduce the new antipsychotic gradually and only begin to reduce the old antipsychotic once you have achieved steady state with the new antipsychotic at a therapeutic dose.

This avoids leaving patients unprotected due to subtherapeutic antipsychotic blood levels and it also minimizes rebound phenomenon.

3. Manage Overlapping Side Effects

Be careful when using drugs with overlapping side effect profiles including QTc prolonging antipsychotics, antipsychotics that are sedating or antipsychotics that bind to dopamine tightly causing EPS or drugs that cause orthostatic hypotension.

In this case, when you do a cross-titration, you may want to begin reducing the old antipsychotic earlier before you reach the full target dose of the new antipsychotics to reduce the additive side effects.

4. Keep It Simple

Patients will find ways to mess up your cross-titration schedule if you make it too complicated.

And here’s a clinical corollary: see patients regularly during a switch, for example weekly and involve family or other so-called stakeholders to help you if applicable.

5. Prepare Patient Before Starting Switch

Prepare your patient prior to the switch, including reducing polypharmacy and high-dose antipsychotics before you officially begin the switch. I think this is time well spent to have a successful switch.

6. Clozapine Requires Careful Discontinuation

Be careful with stopping clozapine abruptly (which you may have to do if there’s a serious side effect like agranulocytosis), since you can cause a complex picture of cholinergic rebound and a withdrawal delirium psychosis. You may need to add an anticholinergic during this period.

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I hope my comments help you approach the next antipsychotic switch with some confidence, even if as we’ve seen the literature is somewhat limited.

Abstract

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

Christoph U. Correll

Background

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.

Methods

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.

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.

Conclusions

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.

Reference

Correll, C. Strategies for Switching between Oral Postsynaptic Antidopaminergic Antipsychotics in Patients with Schizophrenia: A Systematic Review. CNS Drugs 39, 913–935 (2025).