Vignesh Subramanian ’24
Schizophrenia is a psychotic disorder characterized by disorganized behavior, lack of emotional expression, and thoughts and experiences dissociated from reality. Patients who present such symptoms have elevated levels of the neurotransmitter dopamine, the ‘feel-good’ hormone responsible for mediating pleasure and stimulating neurons to carry out vital functions like concentration and motor control. Patients with schizophrenia are prescribed antipsychotic medications, which block binding to the D2 subtype of dopamine receptors and reduce the neuronal signaling contributing to “positive” symptoms, including hallucinations and uncontrolled repetitive movements, that make up the more exaggerated psychosis of the disease. However, recent evidence links the use of antipsychotics to an increased likelihood of these patients developing dementia, the progressive loss of memory, language, and executive function abilities to the point of cognitive impairment. To better characterize this relationship, a study led by Dr. Jonas of Stony Brook University theorizes the impact of antipsychotics’ side effects on recipients.
Researchers reviewed a meta-analysis of cross-sectional and longitudinal observational studies of patients recruited at various stages of treatment and adulthood to assess the prognosis of their dementia risk. These studies, which included two covering 5 and 8 million patients, respectively, demonstrated the expected increased likelihood of dementia in schizophrenic patients. One study even concluded that patients with schizophrenia exhibited dementia risk in their 60s comparable with that of the general populations of primarily first-world countries in their late 80s. The results of blood-based, neuroimaging, and postmortem biomarkers specifically linked antipsychotic use with decreased dopaminergic activity at D2 receptors and its effects: reduced signaling in the striatum of the brain while low activity was exacerbated elsewhere, and cortical thinning of gray matter associated with cognitive decline. Finally, the studies found that symptoms of metabolic syndrome such as obesity and hypertension are more prevalent in patients with schizophrenia, with antipsychotic use being linked to their greater incidence and risk of vascular dementia.
Researchers posited two hypotheses based on these results: that either long-term exposure to antipsychotics contributes to premature dementia or that metabolic dysfunction worsens dementia risk factors in patients with contributing psychotic disorders. Given that brain matter loss has been directly linked to cortical D2 receptor occupancy and that antipsychotics may alter insulin and glucagon release by acting on the pancreas’s own D2 receptors, either hypothesis may be true – and they are not mutually exclusive. Future research may determine which of these anticholinergic effects of antipsychotics most significantly foreshadows more destructive disease pathologies.
 K. Jonas, et al., Two hypotheses on the high incidence of dementia in psychotic disorders. JAMA Psychiatry, 1-2 (2021). doi: 10.1001/jamapsychiatry.2021.2584
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