What Does an Overactive Bladder Have to Do with Schizophrenia?

Years ago, scientists at Eli Lilly investigated the muscarinic system as a potential treatment for Alzheimer’s disease, since modulating it appeared to alleviate some symptoms of Alzheimer’s-related psychosis. During this research, they unexpectedly discovered that xanomeline, a compound they developed to activate the muscarinic system, also improved symptoms of schizophrenia. However, targeting brain-specific receptors was challenging, as muscarinic receptors are found throughout the body, including the bladder, gut, salivary glands, eyes, and heart. The resulting widespread side effects led Lilly to discontinue further exploration of xanomeline.

The developers of Cobenfy were intrigued by the muscarinic system’s potential and sought a way to activate it in the brain while limiting its effects elsewhere in the body. After testing 7,000 compounds, they combined xanomeline with an FDA-approved drug from the 1970s, initially used to treat overactive bladder, to inhibit muscarinic activity outside the brain. Although the bladder drug has no connection to psychiatry, and this approach diverged from typical drug development paths, the combination proved effective.

Treating the Symptom, Not the Cause

Because the causes of psychiatric disorders remain unknown, treatments are often discovered by accident. For example, the use of monoamine oxidase inhibitors (MAOIs) for depression emerged after the accidental observation that patients with hypertensive vascular disease treated with reserpine frequently became depressed. This led to the hypothesis that blocking monoamine oxidase could alleviate depression, resulting in the development of several drugs targeting this mechanism.

Tricyclic antidepressants like imipramine were also discovered by chance during research aimed at treating schizophrenia. While these drugs proved ineffective for the positive and negative symptoms of schizophrenia, they were found to relieve depressive symptoms.

The success of Cobenfy in treating schizophrenia underscores that, even in 2024, the underlying causes of psychiatric disorders remain elusive. Effective treatments must reduce suffering without causing side effects as severe as—or worse than—the conditions they aim to treat. This balance is particularly critical for diseases with unknown causes.

What Is Schizophrenia?

Schizophrenia is a chronic mental health disorder that affects how a person thinks, feels, and behaves. Individuals with schizophrenia often experience a distorted reality characterized by “positive” and “negative” symptoms. Positive symptoms include delusions (false beliefs not based in reality, such as believing they are being persecuted or have special powers), hallucinations (hearing or seeing things that are not present), and disorganized thinking (difficulty organizing thoughts or making logical connections). Negative symptoms involve a reduced ability to function normally, such as a lack of motivation, diminished emotional expression, or withdrawal from social activities.

The exact cause of schizophrenia is unknown, though several hypotheses exist regarding its development, suggesting it may result from genetic, brain chemistry, and environmental factors. The disorder typically emerges in late adolescence or early adulthood and requires long-term treatment, often involving antipsychotic medications and therapy. While schizophrenia can severely impact a person’s quality of life, proper management allows many individuals to lead functional lives.

How Is Schizophrenia Treated?

Schizophrenia is typically treated with a combination of medications, therapy, and support strategies. The goal is to manage symptoms, improve quality of life, and help individuals function. The following is an overview of the treatment approaches for schizophrenia.