Article: https://pmc.ncbi.nlm.nih.gov/articles/PMC12655517/

Citation: van Westrhenen R, Young AH. Recent Advances in Psychopharmacology. Pharmaceuticals (Basel). 2025 Oct 23;18(11):1602. doi: 10.3390/ph18111602. PMID: 41304850; PMCID: PMC12655517.

Title: Recent Advances in Psychopharmacology

This editorial analysis of recent advances in psychopharmacology highlights a critical shift from traditional “trial-and-error” prescribing toward precision psychiatry and novel neurobiological targets. For a psychiatrist, the following points represent the key takeaways and clinical applications.

  1. The Precision Psychiatry Paradigm: Beyond Trial-and-Error
  • The Clinical Gap: Currently, only one-third of patients respond well to initial psychiatric medication, and selection is largely based on physician experience.
  • Pharmacogenetics (PGx) Integration: The authors advocate for the use of PGx to identify person-specific genetic factors—such as variants in drug-metabolizing enzymes or drug targets—to predict clinical response and minimize side effects.
  • Prevalence of Metabolic Variants: Research from the UK Biobank shows that 62.9% of patients carry alleles associated with altered metabolism (on CYP2D6 or CYP3A4) for antipsychotic medications.
  • Clinical Application: Psychiatrists should consider early PGx testing, particularly for patients who fail their first line of treatment. For example, CYP2C19-poor metabolisers on escitalopram are significantly more likely to experience side effects, switch antidepressants, and discontinue treatment early.
  1. The Emergence of Neuroplastogens and NMDAR Modulators
  • The “Stinel” Class: Beyond ketamine, a novel class of neuroplastogens known as “stinels” (rapastinel, apimostinel, and zelquistinel) are being developed as positive allosteric modulators of the NMDA receptor (NMDAR).
  • Epigenetic Regulation: These treatments likely work by regulating Ca2+ influx via NMDARs, which activates enzymatic pathways that epigenetically regulate synaptic protein homeostasis and neural plasticity.
  • Esketamine: Preliminary reports continue to support the efficacy of esketamine nasal spray specifically for therapy-resistant depression (TRD).
  • Clinical Application: As these “neuroplastogens” move through the pipeline, clinicians should prepare for a shift in depression management that focuses on rapid-acting synaptic restoration rather than the delayed monoamine modulation of traditional SSRIs.
  1. Transdiagnostic and Adjunctive Strategies
  • Cariprazine’s Versatility: A systematic review of 30 studies suggests that cariprazine offers transdiagnostic efficacy, showing benefits for positive, negative, manic, and depressive symptoms, as well as preliminary benefits for hostility and cognitive symptoms across various disorders.
  • Vitamin D as Adjunct: Evidence demonstrates a clear inverse relationship between Vitamin D levels and depression. The authors suggest vitamin D supplementation as a viable adjunctive therapy in managing Major Depressive Disorder (MDD).
  • Clinical Application:
    • When treating complex patients with overlapping mood and psychotic symptoms, cariprazine may serve as a potent “all-in-one” option.
    • Routine screening of serum 25(OH)D levels should be integrated into the initial workup for MDD to identify patients who may benefit from adjunctive supplementation.
  1. Navigating the “Deadlock” of Drug Discovery
  • Low Success Rates: The likelihood of drug approval in psychiatry is only 6.2%, and the path to market takes nearly nine years. This has led several major pharmaceutical companies to scale back their research in this area.
  • Ongoing Pipeline: Despite these hurdles, there are still over 150 active phase 2 or 3 clinical trials across schizophrenia, bipolar disorder, MDD, anxiety, and substance use disorders.
  • Clinical Application: Psychiatrists should stay informed about digital phenotyping and new formulations of existing medications, as the current research trend focuses on identifying new molecules that minimize adverse effects and personalize treatment through these modern assessment tools.

Clinical Practice

The field is moving toward personalized pharmacotherapy. The primary goal for the modern psychiatrist is to refine assessments using pharmacogenetic data and digital phenotyping to move away from generic protocols and toward a “person-sensitive” treatment model that targets underlying pathological processes rather than just broad diagnostic categories.