What is it about?

Schizophrenia is a complex brain disease whose cause is only partially understood and is therefore very difficult to treat. Patients suffer from symptoms in primarily three domains that include positive symptoms (e.g., hallucinations, delusions, disordered thinking, and speech), negative symptoms (e.g., lack of motivation, lack of emotional expression or flat affect, social withdrawal), and cognitive symptoms (e.g., impaired attention, concentration, memory, and executive functions). The discovery and development of antipsychotic drugs spans over 70 years and unfortunately has yet to produce a highly effective medicine to control all symptoms. Current drugs primarily target dopamine D2 receptors, and while they generally control the positive symptoms, they have little to no impact on the negative or cognitive symptoms of schizophrenia. Consequently, the negative and cognitive symptoms of schizophrenia may be the most disabling for many patients. Current antipsychotics come with a significant side effect burden that greatly reduces tolerability and compliance. This review introduces a potentially novel approach for treating schizophrenia that targets specific members of the muscarinic acetylcholine family of receptors in the brain. The history and progress of this novel class of antipsychotic medications is described in detail and places their development in the context of existing as well as other novel treatment options.

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Why is it important?

Current medications for patients suffering from schizophrenia are inadequate in many, if not most, patients and have significant side effects resulting in an undesirable burden for patients, health care providers and family caregivers. Over the last 70+ years only modest improvements in symptom control have been achieved largely because the available medications are mechanistically similar. Novel approaches are needed and studies with muscarinic receptor activators look promising, with studies conducted to date suggesting that these treatments may help treat the symptoms of psychosis without the side effects typically associated with current standards of care.

Perspectives

Our review frames the current role of muscarinic acetylcholine receptors as promising potential drug targets for patients suffering from schizophrenia. Currently available medications often fail to provide adequate symptom relief and are often associated with troublesome side effects. For decades, many dedicated scientists and health professionals have applied their best efforts to discover and develop more effective and tolerable medicines for schizophrenia. As we describe in our manuscript, the development of muscarinic receptor-based approaches has been an equally long and challenging journey, yet there is growing evidence these non-D2 receptor “muscarinic” antipsychotics may produce tangible and meaningful benefits for many patients living with schizophrenia.

Christian Felder
Karuna Therapeutics

Read the Original

This page is a summary of: Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia, American Journal of Psychiatry, September 2022, American Psychiatric Association, DOI: 10.1176/appi.ajp.21101083.
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