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Dr Stefan Leucht

A middle-of-the-road dose of an antipsychotic appears to be optimal for relapse prevention in stable schizophrenia, new research suggests.

Results of a meta-analysis show a 5-mg/day equivalent risperidone dose worked best. Higher doses were associated with more adverse events without showing substantial gains in relapse prevention, allis test and lower doses were associated with greater relapse risk.

“The safest approach is to just to carry on with 5 mg,” which in many cases represents a full dose, lead author Stefan Leucht, MD, professor, Department of Psychiatry and Psychotherapy, Technical University of Munich, School of Medicine, Germany, told Medscape Medical News.

However, he added, patient preferences and other factors should be considered in dosage decision-making.

The findings were published online August 18 in JAMA Psychiatry.

Unique Meta-Analysis

Antipsychotic drugs are effective for short-term treatment of schizophrenia and prevention of relapse, but are associated with movement disorders, weight gain, and other metabolic changes. They are also associated with even more severe adverse events including tardive dyskinesia and increased cardiovascular risk.

For years, researchers have tried to find the optimal dose of antipsychotic drugs to prevent relapse in patients with stable schizophrenia while mitigating adverse event risk.

For the meta-analysis, researchers searched for fixed-dose, randomized, blinded, or open trials that lasted longer than 3 months and compared two first-generation antipsychotics — haloperidol or fluphenazine — or a second-generation antipsychotic with placebo or a different dose of the same drug.

The analysis included 26 studies with 72 individual dose arms and 4776 participants with stable schizophrenia.  

Researchers used a dose-response meta-analysis. Unlike a simple meta-analysis that provides an “arbitrary” cut-off of superiority of one drug over placebo or another drug, a dose-response meta-analysis gives a plot or curve “that shows how this evolves with different doses,” Leucht noted.

The investigators estimated dose-response curves for each antipsychotic drug compared with placebo separately and as a group.

They did not have enough data for most of the single antipsychotics, so they converted doses to risperidone equivalents for a pooled analysis across drugs. They chose risperidone because its equivalents “are pretty well-defined,” said Leucht.

Go Slow to Go Low

For the primary outcome of relapse, the dose-response curve showed a hyperbolic shape with a clear plateau. Initially, the plot decreased sharply, but then flattened at about 5-mg/day risperidone equivalent (odds ratio [OR], 0.20; 95% CI, 0.13 – 0.31; relative risk (RR), 0.43; 95% CI, 0.31 – 0.57).

“We were a little disappointed because we hoped that a dose lower than 5 mg would be most efficacious in terms of relapse rate because this would have reduced the side-effect burden,” Leucht said.

Nevertheless, he emphasized that doses lower than 5 mg/day risperidone equivalent are not completely ineffective. For example, the 2.5-mg dose reduced risk to relapse in relative terms by about 40% (RR, 0.63).

Leucht pointed out there is “huge interindividual variability.” Therefore, 2.5 mg or even 1 mg may be sufficient for some patients. “It just means for the average patient it’s safest, let’s say, to keep her or him on 5 mg,” he said.  

When lowering the dose, Leucht noted clinicians should “be very careful and to do it very slowly. It should be very small reductions every 3 to 6 months.”

For the secondary endpoint of rehospitalizations, the shape of the curve was similar to the one for relapse, but with lower rates.

“If patients need to be rehospitalized, it usually means that the relapse was major and not only a minor increase in symptoms,” said Leucht.

The curves for all-cause discontinuation and reduction in overall symptoms were also similar to that of relapse.

However, the curve for dropouts because of adverse events showed that higher doses led to more adverse events. For example, with 5-mg/day dose, the OR was 1.4 (95% CI, 0.87 – 2.25) and the relative risk (RR) was 1.38 (95% CI, 0.87 – 2.15), but for the 15-mg/day dose, the OR was 2.88 (95% CI, 1.52 – 5.45) and the RR was 2.68 (95% CI, 1.49 – 4.62).

Patient Preference Key

The data were insufficient to assess differences between men and women, or between older and younger patients, Leucht noted.

However, post-hoc subgroup analyses turned up some interesting findings, he added. For example, patients who take high-potency first-generation antipsychotics such as haloperidol might do well on a lower dose, said Leucht.

“They may need a dose even lower than 5 mg, perhaps something like 2.5 mg, because these drugs bind so strongly to dopamine receptors,” he said.

He reiterated that patient preferences should always be considered when deciding on antipsychotic dosage.

“Many patients will say they don’t want to relapse anymore, but others will say these drugs have horrible side effects and they want to go on a lower dose,” said Leucht.

Clinicians should also factor in patient characteristics, such as comorbidities or substance abuse, as well as severity of past relapses and properties of individual drugs, he added.

Reflects Real-World Experience

Commenting on the findings for Medscape Medical News, Thomas Sedlak, MD, PhD, director, Schizophrenia and Psychosis Consult Clinic and assistant professor of psychiatry and behavioral sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, said the research “is a fine addition” to a previous analysis that explored dose-response relationships of antipsychotic drugs in the acute phase.

Crunching all the data from studies that have different types of patients and extracting a single dosage that provides maximum benefit is “a great challenge,” said Sedlak, who was not involved with the research.

The fact that most patients won’t get additional benefit above 5 mg, at which point they start getting more adverse events, and that 2.5 mg is sufficient for certain subgroups “agrees well with the experience of many who use these medications regularly,” Sedlak said.

However, he cautioned that psychiatrists “don’t always intuitively know which patients fall into which dose category, or who might require clozapine.”

“Clinicians need to be mindful that it’s easy to overshoot an optimal dose and elicit side effects,” said Sedlak.

He also noted severely ill patients are often under-represented in clinical trials because they are too impaired to participate, “so they may have a different optimal dosage,” he concluded.

Leucht has reported receiving personal fees for consulting, advising, and/or speaking outside the submitted work from Angelini, Boehringer Ingelheim, Geodon & Richter, Janssen, Johnson & Johnson, Lundbeck, LTS Lohmann, MSD, Otsuka, Recordati, Sanofi Aventis, Sandoz, Sunovion, Teva, Eisai, Rovi, and Amiabel. Sedlak has reported no relevant financial relationships.

JAMA Psychiatry. Published online August 18, 2021. Abstract

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