Lower-Dose Schizophrenia Medication Increases Risk of Relapse or Discontinuation

A serious young man looks down at an open bottle of prescription drugs he is holding.
The researchers compared the risks and benefits of reduced vs standard doses of antipsychotics for patients with schizophrenia.

During maintenance treatment for multi-episode schizophrenia, reducing antipsychotic medication dose may increase risk of relapse and all-cause discontinuation, according to a review published in The Lancet Psychiatry.

Current treatments differ in the length of maintenance treatment and whether acute treatment doses are reduced or remain the same. Reducing the dose has the advantage of potentially reducing side effects, but this literature review shows it may not be worth the risk.

The researchers searched Medline, Embase, PsycINFO, and Cochrane Library for articles published from database inception to June 17, 2020. They also searched reference lists for randomized controlled trials. After identifying 7853 potentially relevant records, the researchers found 22 studies that met their inclusion criteria.

The study participants were 65.9% men and 34.0% women with a median age of 38 years.

The researchers found low-dose treatment was associated with a 44% increased risk of relapse (risk ratio [RR], 1.44; 95% CI, 1.10-1.87; I²=46%; number needed-to-harm [NHH]=15), and a 12% increased risk of all-cause discontinuation (RR, 1.12; CI, 1.03-1·22; I²=0%; NNH=24) compared with standard dose.

Relapse risk was significantly higher with low-dose first-generation antipsychotics than with low-dose second-generation antipsychotics (RR, 2.08; 95% CI, 1.49-2.90 vs RR, 1.23, CI, 0.88-1.70; P =.026), and with low-dose long-acting injectable antipsychotics than with low-dose oral antipsychotics (RR, 2.13, CI, 1.44-3.14 vs RR, 1.29; CI, 0.96-1.72; P =.043).

All-cause discontinuation was significantly higher with low-dose first-generation antipsychotics than with low-dose second-generation antipsychotics (RR, 1.34, 95% CI, 1.11–1.63 vs RR, 1.07; CI, 0.97-1.18; P =.036), but there was no significant difference between low-dose long-acting injectable antipsychotics and low-dose oral antipsychotics (RR, 1.35; CI, 1.09-1.66 vs RR, 1.08; CI, 0.98-1.18; P =.058).

Compared with standard dose, very-low-dose was associated with a 72% increased risk of relapse.

One limitation is that the researchers analyzed only 22 studies. Several of the trials included had small sample sizes. Analysis of secondary outcomes was “inadequately powered,” the researchers reported.

“Our findings should inform future clinical practice guidelines, which substantially vary on their recommendations in this area,” the researchers concluded. “However, our findings are restricted to patients with multi-episode schizophrenia. Additional high-quality randomized controlled trials are required to examine the effect of dose reduction during maintenance treatment.”

They added, “The need for additional high-quality randomized controlled trials applies particularly to dopamine partial agonists because only one study of such a drug was included in our review.”


Højlund M, Kemp AF, Haddad PM, Neill JC, Correll CU. Standard versus reduced dose of antipsychotics for relapse prevention in multi-episode schizophrenia: a systematic review and meta-analysis of randomised controlled trials. Lancet Psychiatry. 2021;8(6):471-486. doi:10.1016/S2215-0366(21)00078-X