In this article, we revise our previous hypothesis of the endogenous appearance of anticholinergic activity (AA) in schizophrenia and expand our commentary on the relationship between AA and schizophrenia. We speculate that the inflammatory system is upregulated in Alzheimer’s disease (AD) when the acetylcholine (ACh) downregulation reaches a critical level and then hyperactive inflammation generates cytokines with AA. We also speculated that the same mechanism might be active in schizophrenia; that is, downregulation of ACh or overloading of this system might already exist at even the preclinical stage (in those with a high-risk mental state) and when mental stress is added, the compensatory mechanism might fail, so AA might appear and psychotic symptoms develop. Recently, we reported the significant negative relationship between serum anticholinergic activity (SAA) and extrapyramidal symptom severity in patients with schizophrenia. These results support the theory of hyperactive ACh in schizophrenia. Accordingly, we re-hypothesize that there is a compensatory increase in the activity of the cholinergic system even in the prepsychotic phase. We also re-speculate that there might be an imbalance in not only the dopaminergic system, but also the cholinergic system in schizophrenia. Therefore, substantial levels of AA or antipsychotics with considerable AA might be needed in schizophrenia. Prescription of antipsychotics with AA might correct the imbalance in both dopamine and ACh and possibly achieve remission in patients with schizophrenia. Based on these speculations, we propose the use of SAA as a biological marker for evaluating the optimal dose of antipsychotics for patients with schizophrenia and suggest that, when the quantities of prescribed antipsychotics can be adjusted to achieve an SAA of slightly over 10 nM, the clinical symptoms (extrapyramidal motor symptoms and cognitive dysfunctions) might be minimized.
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