Adverse effects of antipsychotics in the treatment of schizophrenia negatively affect cognitive functions
Schizophrenia is a severe psychiatric disorder characterized by a wide range of symptoms, with cognitive dysfunctions being one of its domains. Antipsychotics (APs) are used for treatment, but their effectiveness in improving cognitive functions is unclear, and they can simultaneously worsen cognition through their adverse metabolic effects, leading to a reduced lifespan for patients with schizophrenia.
Introduction
Cognitive dysfunction is one of the core symptom domains of schizophrenia. However, it is not entirely clear what effect antipsychotics — the primary group of drugs used to treat schizophrenia — have on it. Some research suggests that these drugs can partially improve cognitive functions and that this improvement varies by specific cognitive domain. However, the results can be confounded by age, stage of the disease, patient compliance with treatment, and extrapyramidal adverse effects (AEs).
Additionally, in about 50% of patients, antipsychotics (especially second-generation and atypical APs) negatively impact metabolism, promoting the development of obesity, dyslipidemia, and type 2 diabetes (DM2), diseases that are themselves associated with cognitive dysfunctions and, by negatively affecting the cardiovascular (CV) system, reduce the average lifespan of patients by 20 years.
Antipsychotics and metabolic dysregulation
Research shows that the use of antipsychotic therapy can be associated with significant early weight gain, especially in young patients being treated for the first time. First-generation antipsychotics, historically considered metabolically neutral, also have this effect; for instance, haloperidol causes a significant weight gain of an average of 3.8 kg during the first 3 months of treatment. A similar issue is prediabetes: It develops in more than 15% of patients during the first 6 months of antipsychotic treatment, and the cumulative risk and incidence of DM2 increase up to threefold. It appears that while overweight is the primary risk factor for the development of diabetes, antipsychotics can directly cause insulin resistance and dysregulation of glucose metabolism even in the absence of overweight.
Impact of metabolic syndrome on cognition
The term “metabolic syndrome” encompasses several interconnected risk factors for CV disease: abdominal obesity, elevated triglyceride levels, hyperglycemia, high blood pressure, and reduced HDL cholesterol levels. There is a link between metabolic syndrome and specific memory disorders, spatial orientation issues, executive function deficits, and slower information processing speed. For instance, patients with hypertension have been found to have a smaller frontal lobe volume and impaired glucocorticoid feedback, which correlates with poorer performance on tasks requiring executive function.
The decline in cognitive abilities, metabolic syndrome, DM, and Alzheimer’s disease could be caused by the same pathological mechanism—chronic inflammation. Besides the metabolic dysregulation caused by antipsychotic treatment, other lifestyle factors (smoking, poor diet, lack of physical activity) also contribute to the accumulation of metabolic risks in patients with schizophrenia, accelerating brain changes associated with aging.
Conclusion
The relationship between metabolic comorbidities and cognitive decline in patients with schizophrenia can probably be generalized, although based on current literature, causal links between well-known metabolic AEs of antipsychotics and cognitive decline cannot yet be established. It is likely that in the early stages of treatment, AEs of antipsychotics have minimal impact on cognition, but after crossing the
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