A comprehensive systematic review and network meta-analysis of 68 studies has concluded that no specific antipsychotic drug significantly improves cognitive function in patients with schizophrenia spectrum disorders (SSDs) when compared to placebo. The study, published in JAMA Psychiatry, highlights the limitations of current antipsychotic treatments in addressing cognitive deficits, a core aspect of SSDs.
Cognitive impairments, including difficulties with memory, attention, and overall cognitive performance, are central to SSDs. These deficits contribute significantly to the disease burden and are often more disabling than psychotic symptoms such as hallucinations and delusions. Although antipsychotics are effective in managing the primary symptoms of SSDs, such as hallucinations, delusions, and social withdrawal, their impact on cognitive function has been relatively understudied and is generally not considered a primary benefit.
The meta-analysis evaluated data from 9,525 participants across various randomized clinical trials. These trials used standardized cognitive assessment tools, such as the MATRICS Consensus Cognitive Battery, to measure the effects of different antipsychotic medications on cognitive performance. The researchers found that while antipsychotics as a group demonstrated slight cognitive improvements, no individual drug significantly outperformed placebo in enhancing cognitive function. Antipsychotic drugs treat schizophrenia by blocking dopamine D2 receptors, reducing symptoms like hallucinations. First-generation antipsychotics primarily target dopamine, which can cause motor side effects, while second-generation drugs also block serotonin 5-HT2A receptors, improving negative and cognitive symptoms with fewer side effects. These newer drugs modulate both dopamine and serotonin, enhancing efficacy and minimizing issues like sedation and weight gain.
First-generation antipsychotics, such as haloperidol and fluphenazine, and second-generation drugs like clozapine, ranked low in terms of cognitive outcomes. Some second-generation antipsychotics, including paliperidone and sertindole, showed marginally better cognitive performance, but these effects were not significant compared to placebo.The study also analyzed antipsychotics based on their receptor-binding profiles such as adrenergic, dopaminergic, serotonergic, and muscarinic properties but again found only minor improvements in cognitive function. Effect sizes, measured using standardized mean differences (SMD), ranged from 0.21 to 0.40, falling short of the 0.5 threshold for meaningful cognitive enhancement.
Furthermore, secondary analyses indicated that antipsychotic treatment had minimal impact on quality of life and social functioning. Drugs like molindone and thioridazine ranked slightly higher for cognitive benefits, but the findings were considered unreliable due to small sample sizes and the limited scope of cognitive metrics used.
The study underscores the need for new or adjunctive treatments that specifically target cognitive deficits in SSDs. The researchers suggest avoiding first-generation dopamine antagonists and clozapine when cognitive outcomes are a primary concern. They also recommend standardizing cognitive assessments across clinical trials to improve the comparability of future research. While antipsychotics are effective for managing the core symptoms of SSDs, their cognitive benefits remain limited, and more targeted therapies are urgently needed to address this unmet need.
References
- Feber L, Peter NL, Chiocchia V, Schneider-Thoma J, Siafis S, Bighelli I, et al. Antipsychotic Drugs and Cognitive Function: A Systematic Review and Pairwise Network Meta-Analysis. JAMA Psychiatry [Internet]. 2024 Oct 16 [cited 2024 Oct 21]; Available from: https://doi.org/10.1001/jamapsychiatry.2024.2890
- Chokhawala K, Stevens L. Antipsychotic Medications. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Oct 21]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK519503/