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No individual antipsychotic was associated with better cognitive outcomes than placebo in patients with schizophrenia spectrum disorders (SSD), according to a systematic review and network meta-analysis.

However, the study revealed that two first-generation dopamine antagonists -- haloperidol (standardized mean difference [SMD] 0.04, 95% CI −0.25 to 0.33) and fluphenazine (SMD 0.15, 95% CI −0.39 to 0.69) -- were connected with lower cognitive performance, Stefan Leucht, MD, of the Technical University of Munich School of Medicine and Health in Germany, and co-authors reported.

Clozapine (SMD 0.12, 95% CI −0.23 to 0.48) was also associated with lower cognitive performance, which contradicted earlier publications that suggested it offered potential benefits, they reported in .

All three ranked lowest among antipsychotics assessed for cognitive performance in SSDs when compared to placebo, the authors noted.

"Based on the evidence considered, no clear recommendation can be made for a specific antipsychotic medication," co-author Lena Feber, MSc, also of the Technical University of Munich School of Medicine and Health, told MedPage Today in an email. "However, antipsychotics as a group -- based on their receptor-binding profiles -- demonstrate more favorable effects on cognitive symptoms compared to placebo."

In fact, several antipsychotic drugs, grouped according to their receptor affinity, were associated with some benefit in a post-hoc analysis, with small effect sizes:

• Adrenergic/low dopamine: mean SMD -0.21 (95% CI -0.39 to -0.03)
• Serotonergic/dopaminergic: mean SMD -0.26 (95% CI -0.45 to -0.07)
• Muscarinic: mean SMD -0.28 (95% CI -0.46 to -0.10)
• Dopaminergic: mean SMD -0.40 (955 CI -0.70 to -0.09)

"Haloperidol, fluphenazine, and clozapine appear to be less suitable for the treatment of cognitive symptoms and should be used with caution in this context," Feber said. "In contrast, some antipsychotics, such as brexpiprazole [Rexulti], have demonstrated modest positive effects, warranting further research in this area."

Leucht and co-authors also explained the findings suggest a need for implementing a comprehensive standard for measuring cognitive function in future clinical trials to improve analysis of these drugs and their effects on cognition.

"To date, no gold standard for the assessment of cognitive symptoms within the context of schizophrenia has emerged," Feber noted.

Jacob Ballon, MD, MPH, of Stanford University in California, who was not involved in the study, said despite the lack of clear benefits for cognition among any individual antipsychotic, this analysis could still be useful in the clinical setting.

"When I am working with individuals who are students or engineers or folks for whom cognition is of paramount importance to them, having a drug that is less of a cognitive offender is really important for those patients," Ballon said.

He also emphasized that the analysis does not include some of the newest antipsychotic medications, such as xanomeline and trospium chloride (Cobenfy), which was approved last month and could potentially provide better cognitive outcomes than any previous antipsychotics.

Still, many of those also showed early potential for cognition, but Ballon noted this analysis shows none of them lived up to the hope.

"To some extent, I feel like we are getting excited in the way we had in the past about the newness of a drug," Ballon said. "But the difference here is that there is, at least mechanistically, reason for that conversation to be a little bit different than it was in the past."

Researchers conducted a systematic review and pairwise network meta-analysis by collecting data from 68 studies from the Cochrane Schizophrenia Trials Register through June 25, 2023; all studies were published from 1958 through 2022. The review included both blinded or unblinded randomized clinical trials that compared antipsychotics or antipsychotics versus placebo and were at least 3 weeks in duration. Ten studies in the review were open label, while more than half of the studies had an overall high risk of bias (n=40).

They included 9,525 participants with a mean age of 35.1 years. The majority were male (70%), but they noted some studies did not provide this information. The mean duration of illness was 10.5 years. In the 39 studies with race and ethnicity data, 54.7% of participants were white and 32.9% were Black.

The authors also noted that half of the studies involved participants with acute illness, and a quarter involved stable participants; the state of illness was not clear in the rest.

In total, 66 studies involving 18 different interventions were used to analyze the primary outcome, which was change in overall cognition score calculated for each study based on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery. When it was not reported, researchers chose other performance-based measures of cognition based on their similarity to MATRICS tests.

The study had several limitations. First, the authors used cognitive tests designed for cognition-enhancing drugs in stable patients in order to achieve standardization. Second, the wide variety of scales used in the studies made the calculation of an overall score necessary and researchers needed to make several assumptions. The authors also noted that the primary analysis included both stable and ill patients.

Correction: An earlier version of this story had incorrect mean SMD numbers based on the original numbers reported in the paper.

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