5-Minute Science: Schizophrenia is Not a Single Disease

Diana Kwon's recent article from Scientific American introduces a significant revision of our understanding of schizophrenia, highlighting its complexity and advocating a more nuanced view: rather than a single disease, schizophrenia represents multiple disorders—"schizophrenias"—each potentially with distinct biological underpinnings.

Reconceptualizing Schizophrenia as a Spectrum

Schizophrenia is increasingly understood as a spectrum of conditions rather than a singular disease entity, a shift that significantly alters both conceptual frameworks and therapeutic strategies. Historically, schizophrenia has been characterized primarily by psychosis—manifesting as delusions, hallucinations, and disordered thinking. These positive symptoms have traditionally guided treatment, dominated by dopamine-targeting antipsychotics. However, emerging research underscores schizophrenia's complexity, suggesting multiple biological pathways and mechanisms. These novel insights have substantial implications for diagnosis, treatment, and long-term management.

The Limitations of Dopamine Antagonists

The dopamine hypothesis, which posited excess dopamine activity as schizophrenia's primary cause, has driven the development of antipsychotics for decades. Drugs like chlorpromazine, first introduced in the 1950s, drastically improved psychotic symptoms by blocking dopamine receptors. However, despite their efficacy, these dopamine antagonists often result in severe side effects, including extrapyramidal symptoms such as tremors, movement disorders, sedation, significant weight gain, diabetes, and increased cardiovascular risk. Moreover, these drugs inadequately address negative and cognitive symptoms, such as emotional flatness, social withdrawal, and cognitive deficits, which profoundly impair daily functioning and quality of life.

KarXT: A Novel Muscarinic Receptor Agonist

Recent advancements in psychopharmacology introduce drugs targeting alternative neurotransmitter systems, notably acetylcholine and glutamate, reflecting schizophrenia's multifaceted neurochemistry. A significant breakthrough is the antipsychotic KarXT, which activates muscarinic acetylcholine receptors rather than inhibiting dopamine. KarXT has shown effectiveness not only against psychosis but also cognitive impairments, demonstrating fewer traditional side effects. This innovative pharmacological approach heralds a new era of antipsychotic medication, expanding therapeutic options beyond dopamine-focused treatments.

Abnormal Glutamate Signaling in the Schizophrenias

Parallel to these developments, glutamatergic pathways are gaining attention due to compelling genetic and pharmacological evidence. Altered glutamate signaling has been observed in many individuals with schizophrenia, suggesting that psychotic symptoms may also result from glutamatergic dysfunction. For instance, ketamine, a known NMDA receptor antagonist affecting glutamate neurotransmission, can induce psychosis in healthy individuals. Despite extensive efforts, effective glutamatergic-based medications have yet to emerge clinically, underscoring the complexity of targeting this neurotransmitter system.

Autoimmune Disorders May Cause Some Cases of Schizophrenia

Another profound shift arises from recognizing the immune system's involvement in schizophrenia. Autoimmune encephalitis, a condition in which the body's immune system mistakenly attacks brain tissues, offers an illustrative example. Individuals initially diagnosed with schizophrenia but later identified with autoimmune encephalitis demonstrate substantial recovery following immunotherapy treatments, radically transforming patient outcomes. This discovery highlights a previously underestimated inflammatory component within psychotic disorders. Clinicians increasingly advocate for comprehensive diagnostic assessments, including lumbar punctures to detect cerebrospinal fluid autoantibodies, as routine practice for new-onset psychosis.

Generalized Immune Dysfunction in the Schizophrenias

Current studies investigate broader immune system contributions beyond identifiable autoimmune diseases. Findings of immune-related genetic variants, abnormal microglial activity, and epidemiological associations between infections and psychosis suggest a generalized immune dysregulation in schizophrenia. Clinical trials exploring immunotherapies, such as rituximab, which targets B cells responsible for producing autoantibodies, reflect the expanding therapeutic landscape. Even moderate success in these trials could profoundly reshape treatment paradigms, emphasizing personalized medicine based on immunological profiles.

The Schizophrenias are Heterogeneous

The acknowledgment of schizophrenia's heterogeneity has encouraged research into biomarkers capable of distinguishing various disease subtypes or predicting disease onset. Ongoing initiatives, such as the Psychiatric Biomarker Network and the Accelerating Medicines Partnership for Schizophrenia, aim to identify cerebrospinal fluid markers and neuroimaging signatures indicative of early or prodromal phases. Early identification and intervention might prevent the onset of full psychosis, drastically improving prognoses. Recognizing subtle prodromal symptoms like the Truman sign, characterized by pervasive feelings of unreality, could facilitate timely interventions, potentially altering schizophrenia’s trajectory altogether.

The Promise of Complementary Interventions

Complementary interventions are also gaining prominence, addressing schizophrenia's cognitive, emotional, and behavioral dimensions inadequately served by pharmacological treatments alone. Dietary strategies, notably ketogenic diets high in fats and low in carbohydrates, have shown preliminary efficacy in mitigating schizophrenia symptoms, presumably by influencing metabolic and neuroinflammatory pathways. Concurrently, cognitive-behavioral therapy (CBT) provides substantial benefits, helping patients manage psychotic symptoms, cognitive distortions, and negative symptoms through structured psychological interventions.

Conclusion

Despite these promising advances, significant challenges remain. The stigma associated with schizophrenia continues to complicate diagnosis and patient acceptance of treatment, particularly regarding psychiatric versus neurological etiologies. Moreover, integrating comprehensive diagnostic evaluations, including lumbar punctures, neuroimaging, and immunological assessments, into routine psychiatric practice remains difficult due to practical, economic, and systemic barriers.

Ultimately, the evolving understanding of schizophrenia demands a precision medicine approach akin to oncology. Just as cancer treatments evolved from generic interventions to highly personalized therapies based on tumor biology, schizophrenia treatment must transition to individualized strategies guided by distinct biological markers, neurochemical profiles, and patient-specific factors. Such a shift holds tremendous potential for transforming schizophrenia management, substantially improving outcomes, and offering renewed hope to millions affected by this complex and profoundly impactful disorder.

Key Takeaways

Schizophrenia as “Schizophrenias”: schizophrenia comprises multiple distinct disorders with varied biological underpinnings, necessitating individualized treatment strategies rather than a one‑size‑fits‑all approach.
KarXT’s Novel Mechanism: KarXT, the first antipsychotic targeting muscarinic acetylcholine receptors instead of dopamine, effectively reduces both psychotic and cognitive symptoms with fewer traditional side effects.
Glutamatergic Involvement: evidence from ketamine‑induced psychosis and genetic studies implicating glutamate‑signaling genes highlights non‑dopaminergic neurotransmitter dysfunction as a key component of the disorder.
Immune‑Mediated Psychosis: autoimmune encephalitis and broader immune dysregulation (e.g., microglial overactivity) underlie a subset of psychosis cases, opening avenues for immunotherapies such as rituximab.
Precision Medicine via Biomarkers: initiatives like the Psychiatric Biomarker Network aim to identify cerebrospinal‑fluid markers and prodromal signs (e.g., the “Truman sign”) to enable early detection and tailored interventions.

Glossary

acetylcholine: a neurotransmitter involved in various functions including memory, learning, and muscle activation.

autoimmune encephalitis: a condition in which the immune system mistakenly attacks brain tissues, causing inflammation and neurological symptoms.

biomarkers: biological measures indicative of disease states or susceptibility.

cognitive‑behavioral therapy (CBT): a structured psychological intervention aiming to change maladaptive thought patterns and behaviors.

dopamine hypothesis: a theory suggesting that schizophrenia results primarily from excess dopamine activity in the brain.

extrapyramidal symptoms: movement disorders caused by antipsychotic drugs affecting the extrapyramidal motor system.

glutamate: a major excitatory neurotransmitter involved in synaptic plasticity and neuronal communication.

ketogenic diet: a high‑fat, low‑carbohydrate diet potentially influencing neuroinflammatory and metabolic pathways.

lumbar puncture: a medical procedure involving the extraction of cerebrospinal fluid for diagnostic purposes.

microglia: resident immune cells in the brain involved in immune responses and neuroinflammation.

muscarinic receptors: a type of acetylcholine receptor implicated in cognitive processes and targeted by certain antipsychotic drugs.

prodromal phase: the early stage preceding the full onset of schizophrenia symptoms, characterized by subtle signs of illness.

Rituximab: a monoclonal antibody medication targeting B cells, used in autoimmune diseases and tested in schizophrenia immunotherapy.

Truman sign: a prodromal symptom characterized by feelings of unreality, similar to experiences depicted in the film “The Truman Show.”

Reference

Kwon, D. (2025, March 18). New treatments are rewriting our understanding of schizophrenia. Scientific American. https://doi.org/10.1038/scientificamerican042025-1w2iS9iGamNrOUbaykJko9