Expanding therapeutic and clinical horizons in psychosis

Psychiatry stands at a pivotal moment. As Díaz-Marsá¹ has noted in this journal, the imperative to innovate in psychiatry extends beyond a strategic ambition and reflects a broader clinical and ethical responsibility. The considerable burden associated with schizophrenia that is manifested in disability, premature mortality, and substantial unmet needs, highlights the importance of continuing to refine and expand our therapeutic approaches beyond existing pharmacological paradigms.

This editorial accompanies the launch of the section Clinical and Translational Perspectives in Psychiatry, conceived as a forum for reflection on translational advances with potential relevance to contemporary psychiatric practice. The contributions gathered in this inaugural issue, focused on psychotic disorders, illustrate both the complexity of the challenges that remain and the growing sophistication of the scientific tools available to address them.

The section opens with a landmark review by Fernández-Egea and McCutcheon,² who map the pharmacological treatment landscape of psychosis with analytical rigour. Their work reaffirms that dopaminergic modulation remains central, and optimising antipsychotic engagement of the D2/D3 system continues to yield clinical gains, but argues compellingly that the therapeutic horizon must extend further. Muscarinic neurotransmission is emerging as a mechanistically distinct and clinically viable target. Glutamatergic modulation holds promise for symptom dimensions poorly served by conventional antipsychotics. Serotonergic fine-tuning, through receptor selectivity and partial agonism, offers new possibilities for tolerability and efficacy. And rational, evidence-driven combinations across these systems, distinct from empirical polypharmacy, represent perhaps the most promising strategy for patients with complex or refractory presentations. Crucially, Fernández-Egea and McCutcheon challenge the field to abandon positive symptom reduction as the primary yardstick of treatment response. Negative symptoms, cognitive impairment, and functional outcomes (employment, independent living, social participation) determine quality of life far more than the presence or absence of hallucinations. Any meaningful innovation must incorporate outcome measures commensurate with this broader reality.

The aspiration to personalise treatment is brought into concrete clinical focus by Martin da Silva and colleagues,³ who make the case for integrating pharmacogenetic counselling into routine clinical practice. Genetic variants in cytochrome P450 enzymes, particularly CYP2D6 and CYP2C19, substantially shape antipsychotic metabolism, placing poor metabolisers at heightened risk of adverse effects at standard doses and ultra-rapid metabolisers at risk of therapeutic failure. The barriers to pharmacogenomic-guided prescribing are no longer primarily scientific; they are organisational, educational, and systemic. Moving this precision medicine tool from research settings into everyday clinical decision-making is both feasible and necessary, and represents a direct translation of biological knowledge into patient benefit.

At the same time, innovation must be accompanied by careful reflection on how current treatments are being used in clinical practice. In this issue, Hurtado and colleagues⁴ report a substantial increase in antipsychotic prescribing among children and adolescents in Spain between 2015 and 2023, with prescriptions increasing by 61% and the number of treated patients by 50%. Particularly noteworthy were the marked increases among adolescents, very young children, and female patients, together with the growing use of compounds such as aripiprazole, quetiapine, olanzapine and lurasidone. Despite this expansion, treatment intensity per patient remained relatively stable, suggesting that antipsychotics are increasingly being used across a broader range of clinical situations. These findings raise important questions regarding indications, long-term safety, and the balance between pharmacological and non-pharmacological interventions in vulnerable populations. They also remind us that, while we strive to develop novel treatments, equal attention must be paid to ensuring the appropriate, evidence-based, and personalised use of those already available.

These concerns are contextualised by Madero and colleagues,⁵ whose analysis of mortality in psychotic disorders reveals a multifactorial and largely remediable picture. People with schizophrenia die prematurely, not solely from suicide or direct treatment effects, but from medical comorbidities exacerbated by socioeconomic disadvantage, fragmented care, and the persistent failure to integrate physical and mental health services. Although no direct causal chain between specific antipsychotic exposures and mortality is established in this study, the associations observed with treatment-related factors and chronic medical conditions underscore the imperative for vigilance. Excess mortality in psychotic disorders is not an unavoidable biological destiny; it is, in substantial part, a preventable clinical and social failure.

At the mechanistic frontier, the contributions of Llorca-Bofí and cols.⁶ and Pérez-Ramos and cols.⁷ chart two complementary pathways through which biological heterogeneity in schizophrenia may be operationalised for clinical benefit. Llorca-Bofí identifies immunological markers associated with functional outcomes, positioning neuroinflammation not as a pathophysiological curiosity but as a potential modulator of real-world recovery, and a candidate target for adjunctive therapeutic strategies. Pérez-Ramos investigates how premorbid environmental stress leaves epigenetic traces in the form of DNA methylation profiles that shape clinical trajectories. Together, these findings converge on a powerful message: the outcome of psychotic illness is biologically embedded but not biologically determined, and the intersecting signatures of environment, immunity, and epigenetics offer genuine leverage for future precision stratification.

The articles assembled in this inaugural section of Clinical and Translational Perspectives in Psychiatry compose a coherent and demanding vision. Addressing twenty-first century schizophrenia requires expanding the definition of therapeutic success to include negative symptoms and functional recovery; integrating pharmacogenetic intelligence into clinical routine; confronting the risks of rising antipsychotic exposure, especially in children; understanding premature mortality as a largely preventable failure; and translating immunological and epigenetic insights into clinical stratification tools. The complexity is real. But the path is discernible, and the field has both the scientific foundation and, with initiatives such as this section, the institutional will to follow it with rigour, ambition, and the patient at its centre.

Conflicts of interest

None declared.