Cognitive Deficits in Schizophrenia: Which Antipsychotics Should Be Avoided?

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A new study indicated that patients with schizophrenia who have cognitive deficit concerns should avoid antipsychotics, particularly dopamine antagonists and clozapine, as they are not precognitive drugs.¹

Although molindone and thioridazine ranked the highest at improving cognition, the studies evaluating the cognition impact of these antipsychotics had too small of a sample size and only based cognition on the speed of processing domain. Therefore, this recent study does not support molindone and thioridazine for improving cognition.

“The development of drugs that specifically target cognition, such as iclepertin, is needed,” wrote investigators, led by Lena Feber, MSc, from the Technical University of Munich in Germany.

Many people with schizophrenia have cognitive deficits, and although antipsychotic drugs do not enhance cognition, investigators theorized that the receptor-binding profiles of various antipsychotics may have differing effects on cognition. Previous meta-analyses have examined this topic but had many limitations, such as not including newer medications and only including second-generation antipsychotics or oral antipsychotics.^2,3,4 The analyses also had poor methodological quality in terms of risk-of-bias assessment and other areas and did not differentiate between antipsychotics and placebo.

Feber and colleagues conducted their own systematic review and network meta-analysis that assessed the link between cognition and treatment with various antipsychotics in patients with schizophrenia spectrum disorder.¹ Investigators leveraged randomized clinical trials assessing the effects on cognition of psychiatric drugs or placebo from Cochrane Schizophrenia Trials Register from June 25, 2023.

The analysis included 68 studies, published between 1958 to 2022, involving 9525 participants (70% male) with a mean age of 35.1 years. The primary outcome was a change in overall cognition score. Secondary outcomes included cognitive domains, quality of life, and functioning.

The antipsychotics haloperidol (standardized mean difference [SMD], 0.04; 95% confidence interval [CI] −0.25 to 0.33), fluphenazine (SMD, 0.15; 95% CI, −0.39 to 0.69), and clozapine (SMD, 0.12; 95% CI, −0.23 to 0.48) were the worst when it came to cognition. Investigators wrote this may be the case since haloperidol and clozapine are dopamine blockers and clozapine may have negative effects on cognition due to its anticholinergic and histaminergic profile.

“These findings contradict earlier publications that suggested potential cognitive benefits with clozapine,” investigators wrote.

The antipsychotics that had the best impact on cognition were molindone and thioridazine, but the studies had a small sample size (n = 15 – 22) and were based on only 1 cognitive domain (speed of processing). Chlorpromazine also ranked high as having an impact on cognition but had a small number of participants (n = 101). Sertindole (SMD, −0.43; 95% CI, −0.93 to 0.08) and paliperidone (SMD, −0.57; 95% CI, −1.03 to −0.11) were associated with a better cognitive outcome than haloperidol, fluphenazine, and clozapine.

The post hoc analysis which grouped the antipsychotics according to their receptor affinity found a small benefit in cognition compared with placebo (mean SMDs: adrenergic/low dopamine, 0.21; serotonergic/dopaminergic, 0.26; muscarinic, 0.28; dopaminergic, 0.40).

When assessing for secondary outcomes, investigators found brexpiprazole was linked to a small positive effect compared to placebo in visual learning. This was based on 2 studies with 148 total participants. Additionally, the analysis revealed paliperidone could be linked to better cognitive performance than placebo for verbal learning (SMD, −0.69; 95% CI, −1.39 to 0.02) and working memory (SMD, −0.45; 95% CI, −0.94 to 0.03). Haloperidol, fluphenazine, and clozapine consistently scored the worst in different cognition domains.

“…we cannot recommend a specific antipsychotic for treating the cognitive symptoms of [schizophrenia spectrum disorder],” investigators concluded. “Nevertheless, the findings suggest that first-generation dopamine blockers, such as haloperidol or fluphenazine, and clozapine should be avoided based on their low ranking in the hierarchies and theoretical considerations.”

References

1. ^{Feber, L, Peter, N, Chiocchia, V. Antipsychotic Drugs and Cognitive Function: A Systematic Review and Pairwise Network Meta-Analysis. JAMA Psychiatry. 2024. doi:10.1001/jamapsychiatry.2024.2890}
2. ^{Nielsen RE, Levander S, Kjaersdam Telléus G, Jensen SO, Østergaard Christensen T, Leucht S. Second-generation antipsychotic effect on cognition in patients with schizophrenia--a meta-analysis of randomized clinical trials. Acta Psychiatr Scand. 2015;131(3):185-196. doi:10.1111/acps.12374}
3. ^{Baldez DP, Biazus TB, Rabelo-da-Ponte FD, et al. The effect of antipsychotics on the cognitive performance of individuals with psychotic disorders: Network meta-analyses of randomized controlled trials. Neurosci Biobehav Rev. 2021;126:265-275. doi:10.1016/j.neubiorev.2021.03.028}
4. ^{Désaméricq G, Schurhoff F, Meary A, et al. Long-term neurocognitive effects of antipsychotics in schizophrenia: a network meta-analysis. Eur J Clin Pharmacol. 2014;70(2):127-134. doi:10.1007/s00228-013-1600-y}