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Year-End Review of Schizophrenia Treatment & Research in 2025

Schizophrenia: 2025 Progress in Negative Symptom Treatment, Coordinated Care, and Precision Approaches

Dr. Matcheri Keshavan

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Year-End Review of Schizophrenia Treatment & Research in 2025

It’s been a quietly important year – though not with a single breakthrough – but with multiple streams converging, reshaping how we think, diagnose, and treat schizophrenia. We are witnessing the end of the dopamine era, the rise of precision psychiatry, and – importantly – the expansion of real-world, scalable care models.

1. Beyond Dopamine

For over 60 years, virtually all antipsychotics shared a common denominator: D2 receptor blockade. 2025 marks something historic: the first truly viable non-dopaminergic antipsychotic in clinical use. Cobenfy™ – also known as xanomeline–trospium – a combined M1/M4 muscarinic agonist with peripheral blockade to reduce side effects. After its late 2024 approval, this year brought guidance on how to use it, who benefits most, and how to manage its GI side effects. What’s intriguing is that patients with prominent negative symptoms seem to respond particularly well. We’re seeing the first signs of treatment stratification – matching interventions to symptom profiles, perhaps even to biological signatures in the near future.

Ulotaront, a TAAR1 and 5-HT1A agonist: The results so far in 2025 confirm good tolerability and modest benefits – especially in those with milder psychosis or those who can’t tolerate dopamine blockers. It’s not widely approved yet, but remains very much alive.

These studies provide the proof of concept that schizophrenia can be effectively treated without dopamine antagonism. This opens the door toward mechanistically diverse antipsychotics, and possibly, symptom-specific treatment strategies.

  • Halassa, M.M. Preliminary real-world predictors of response to muscarinic targeting in psychosis. Nat. Mental Health (2025). https://doi.org/10.1038/s44220-025-00529-w

  • Hsu YC, Hung TY, Chen YB, Hung KC, Liang CS, Tseng PT, Tu YK, Correll CU, Hsu CW, Solmi M. Trajectory of efficacy and safety across ulotaront dose levels in schizophrenia: a systematic review and dose-response meta-analysis. Int J Neuropsychopharmacol. 2025 Sep 1;28(9):pyaf059. doi: 10.1093/ijnp/pyaf059. PMID: 40795331; PMCID: PMC12421877.

 

2. Long-Acting Injectables

Six-month paliperidone now has real-world 3-year follow-up data, demonstrating stable symptom control, lower hospitalization rates, and predictable tolerability. Olanzapine LAI – long delayed due to post-injection delirium risks – made a comeback. New Phase 3 data show no observed cases of PDSS across thousands of injections. If approved, this could finally make olanzapine, one of the most effective antipsychotics, practically available in LAI form.

Thus, practice guidelines are shifting: LAIs are no longer seen as “last-resort adherence tools” but increasingly as first-line maintenance options, especially when the goal is sustained functional recovery. In chronic psychosis, dosing every 6 months may soon become routine. We’re moving toward a future where non-adherence is treated as a medical risk factor – just like dropping out of insulin treatment for diabetes.

  • New Long-term Safety Data from the Completed Phase 3

  • Kane JM, Agid O, Castle DJ, Citrome L, Fagiolini A, Kishimoto T, Larrauri CA, Leucht S, Rubio JM, Sajatovic M, Schooler N, Correll CU. The Use of Long-Acting Injectables for People with Schizophrenia: Consensus Panel Recommendations for Overcoming Barriers and Implementing Treatment. Neurol Ther. 2025 Dec;14(6):2551-2581. doi: 10.1007/s40120-025-00838-3. Epub 2025 Oct 7. PMID: 41057718; PMCID: PMC12623523.

3. Digital Therapeutics (DTx)

One major development is CT-155, a smartphone-based prescription digital therapeutic targeting negative symptoms – particularly motivation and engagement. It met its primary endpoint in a Phase 3 trial and now has Breakthrough Device designation from the FDA. Other tools, such as SlowMo – a digital reasoning-based therapy for paranoia – have published high-quality RCT data demonstrating real-world improvements when added to treatment-as-usual. Moreover, apps using ecological momentary interventions – tiny push notifications with structured prompts, mindfulness cues, cognitive reframing – are being tested in several domains: motivation, social functioning, coping with hallucinations.

Digital interventions are no longer just “apps for wellness.” They are slowly becoming prescribable, evidence-based, reimbursable tools — especially for treating negative symptoms and social withdrawal, where medication alone is weak.

  • Lakhan SE, Dorner-Ciossek C, Besedina O, Dickerson F, Hastedt C, Isla R, Kahn RS, Lindenmayer JP, Mehta R, Snipes C, Speier A, Tang W, Willis B, Fernandez JW, von der Goltz C, Pratap A Effectiveness, Engagement, and Safety of a Digital Therapeutic (CT-155/BI 3972080) for Treating Negative Symptoms in People With Schizophrenia: Protocol for the Phase 3 CONVOKE Randomized Controlled Trial JMIR Res Protoc 2025;14:e81293
    doi:     10.2196/81293PMID: 41057039PMCID: 12541272

4. Brain Stimulation: A Growing Electroceutical Toolbox

Another major movement in 2025: accelerated TMS and theta-burst stimulation for negative symptoms. Intermittent theta-burst stimulation (iTBS) to the dorsomedial prefrontal cortex – especially using accelerated multi-session protocols – is showing clinically meaningful reductions in negative symptoms. Safety is no longer a major concern – 2025 meta-analyses confirm low seizure risk and good tolerability. The field is now asking: Which patients benefit most? Which brain targets? Which stimulation parameters? Precision is replacing general enthusiasm. This marks the beginning of an “electroceutical era” in schizophrenia care – still early, still mostly off-label – but increasingly structured, protocol-driven, and measurable.

  • Li J, Jiang D, Huang X, Wang X, Xia T, Zhang W. Intermittent theta burst stimulation for negative symptoms in schizophrenia patients with moderate to severe cognitive impairment: A randomized controlled trial. Psychiatry Clin Neurosci. 2025 Apr;79(4):147-157. doi: 10.1111/pcn.13779. Epub 2025 Jan 30. PMID: 39887864.

5. Biomarkers and Precision Psychiatry

Three trends dominate: Exosomal microRNAs – increasingly studied in relation to psychosis onset, cognitive deficits, and synaptic dysfunction. In AI-driven analyses — especially ensemble models — these miRNA signatures can discriminate risk states with growing accuracy. Polygenic risk scores – not clinically decisive yet — but when combined with clinical features or treatment trajectories, such as clozapine response, they begin to inform treatment stratification. Real-world data + clinical phenotyping – analyses of muscarinic agonist responses hint at early efforts to match treatment to patient phenotype, based on patterns like prominent negative symptoms or substance use history. Overall, psychiatry is edging closer to “precision psychiatry”, although this is not yet ready for routine care.

  • Adly NM, Khalifa D, Abdel-Ghany S, Sabit H. MicroRNAs as biomarkers and molecular mediators of cognitive dysfunction in schizophrenia. J Neural Transm (Vienna). 2025 Aug 8. doi: 10.1007/s00702-025-02993-1. Epub ahead of print. PMID: 40779062.

  • Năstase MG, Vasile AI, Pietreanu AC, Trifu S. Following the Action of Atypical Antipsychotic Clozapine and Possible Prediction of Treatment Response in Schizophrenia. Life (Basel). 2025 May 22;15(6):830. doi: 10.3390/life15060830. PMID: 40566484; PMCID: PMC12194553.

6. The Rise of Early Psychosis Programs

Coordinated Specialty Care – CSC – has now firmly established itself as the gold standard for first-episode psychosis. In 2025, the conversation moved from “Does this work?” to “How do we scale and sustain it?”. Policy frameworks now focus on: Financial models for sustained CSC funding, Training and retention of workforce, and Integration of family support, vocational therapy, and digital engagement. If implemented widely, CSC may improve outcomes, by catching psychosis early, shortening duration of untreated illness, and restoring role functioning.

Earlier Event: November 21
Catatonia

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