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Psychiatrist.comReviewing Non-Dopaminergic Mechanisms for Positive and Negative Schizophrenia Symptom Management

Is it time to go beyond dopamine signaling?

Traditional treatment for schizophrenia has focused on antipsychotics that reduce dopamine signaling, but this approach has limitations, including persistent negative symptoms and side effects. New research has revealed alternative mechanisms to reduce dopamine release, offering a different treatment approach that may lead to better outcomes for patients with schizophrenia.

Key Points:

  • Schizophrenia is characterized by hallucinations, delusions, apathy, and cognitive impairment, with somatic comorbidities like metabolic disturbances and cardiovascular issues.
  • Traditional treatment with antipsychotics (APs) targets dopamine signaling but only 1 out of 3 patients respond, and negative symptoms often persist.
  • New mechanisms, such as Muscarinic agonism and modulation of trace amine-associated receptor 1 (TAAR1), offer alternative treatment approaches.
  • Clinical trials of xanomeline-trospium (XT) and ulotaront (a TAAR1 agonist) have shown promising results, with improvements in Positive and Negative Syndrome Scale (PANSS) scores and fewer adverse effects.

Additional Points:

  • Second-generation APs have a lower propensity to cause drug-induced Parkinsonism than first-generation APs.
  • Agents like emraclidine that stimulate muscarinic receptors in the brain are under clinical investigation.
  • Phase 2 trials of emraclidine are expected in the first half of 2024.


  • The exploration of non-dopaminergic mechanisms for schizophrenia treatment offers hope for more effective and well-tolerated therapies, potentially improving patient outcomes and opening doors to rational polypharmacy.

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Did You Know?
Schizophrenia has a global prevalence of 1% and can shorten patients’ lifetime by decades, with a 2.5-fold greater mortality risk than the general population.

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