Standardisation and protocol-driven care

The shift toward evidence-based medicine and standardised treatment protocols has enhanced the overall quality and consistency of psychiatric care, but may have also narrowed the space for noticing unexpected treatment effects. Clinical guidelines and algorithms, designed to promote effective and reliable practice, focus attention on established interventions and anticipated outcomes. ^{Reference Sackett, Rosenberg, Gray, Haynes and Richardson25} Although these tools are invaluable, they can inadvertently discourage clinicians from pursuing observations that fall outside predefined parameters. Notably, the evidence-based framework already accommodates exploratory signals such as case reports, case series, registries and pragmatic data; the key challenge lies in building explicit mechanisms that can move credible anomalies into structured investigation, rather than dismissing them as statistical or clinical noise.

Similarly, the use of structured diagnostic interviews and standardised outcome measures has improved diagnostic reliability and the monitoring of treatment effects, but may constrain the breadth of clinical observation. As Andreasen has argued, an emphasis on checklist-based assessment risks overlooking subtle phenomenological details that could yield important insights into mental disorders and their treatment. ^{Reference Andreasen26}

Time constraints and productivity pressures

Modern clinical practice is frequently shaped by time pressures that limit opportunities for detailed observation and reflection. Economic and administrative demands often require clinicians to see more patients in less time, reducing the likelihood that unexpected findings will be noticed or explored. ^{Reference Mechanic27} In many settings, tightly constrained appointment lengths and insurance-driven efforts to reduce in-patient stays stand in marked contrast to the extended hospital observation common in the mid-20th century, leaving less scope for sustained, careful phenomenological assessment.

Research funding and design constraints

The organisation of modern research funding and clinical trial design can also constrain the scope for serendipitous discovery. Grant applications generally demand clearly defined hypotheses and predetermined outcome measures, leaving limited flexibility to follow unanticipated leads. ^{Reference Ioannidis28} Large, randomised controlled trials remain essential for establishing efficacy, but their scale and rigidity mean they are less likely to detect rare or unexpected effects that might emerge in smaller, more adaptable studies or through attentive clinical observation. In addition, the high costs and regulatory demands of drug development create strong incentives for pharmaceutical companies to prioritise incremental modifications of existing compounds over riskier ventures into novel mechanisms suggested by unexpected findings. ^{Reference Munos29} Although commercially understandable, this approach can result in missed opportunities for transformative advances.

One response to these constraints has been the development of innovative trial designs that may be particularly well-suited to evaluating signals arising from serendipitous observation. Adaptive platform and other master-protocol designs allow several candidate mechanisms, doses or combinations to be tested within a single overarching trial structure, adding or dropping arms over time as evidence accumulates. Rather than treating each new mechanistic hypothesis as a full standalone trial, these platforms can incorporate a novel arm based on an unexpected clinical signal, compare it head-to-head against relevant standards, and then either expand enrolment or close the arm according to prespecified decision rules.

Rapid-fail proof-of-concept programmes take a complementary approach by focusing on small, methodologically rigorous, early-phase studies that test whether a novel mechanism produces a clear signal on proximal targets (for example, pharmacodynamic biomarkers, task performance or short-term symptom change) before committing to larger, expensive phase 3 trials. In psychiatry, where many mechanistically promising agents have failed late in development, rapid-fail designs offer a way to recognise serendipitous observations while limiting opportunity cost and patient burden: signals that do not replicate or that lack convincing mechanistic engagement can be discontinued quickly, whereas promising effects can be escalated into larger, possibly platform-based trials for more definitive evaluation.

Specialisation and fragmentation

The growing specialisation within psychiatry and neuroscience has advanced understanding within specific domains, but may also limit the cross-disciplinary perspectives that have historically contributed to serendipitous discovery. Many past breakthroughs arose from clinicians whose work spanned different areas of medicine – surgeons noting psychiatric effects of anaesthetics, or internists observing mood changes in patients treated for tuberculosis. Today, the clearer separation between specialties may reduce opportunities for such cross-fertilisation of clinical observations. ^{Reference Fava30}

The limits of rational drug design

Although rational drug design grounded in disease mechanisms has driven important progress in many areas of medicine, its impact in psychiatry has been modest. Despite decades of work on the neurobiology of mental illness, most current psychiatric medications belong to chemical classes first identified through serendipitous discoveries many decades ago. ^{Reference Hyman31} The repeated failure of rationally designed agents in clinical trials underscores how incomplete our understanding of psychiatric neurobiology remains. The National Institute of Mental Health’s Research Domain Criteria initiative aims to move beyond traditional diagnostic categories, towards a dimensional view of psychopathology, ^{Reference Insel, Cuthbert, Garvey, Heinssen, Pine and Quinn32} offering a valuable framework for future research. Yet the limits of existing neurobiological models, combined with the potential rigidity of any predefined framework, underline the importance of remaining attentive to unexpected clinical observations, which can yield critical insights and open new therapeutic avenues.

Caveat: when serendipity misleads

The historical record also contains examples where promising signals from early open-label studies or case series failed to hold up in larger randomised trials. Instances such as the off-label use of certain agents as mood stabilisers, or adjunctive anti-inflammatory treatments that later produced mixed or null results, ^{Reference Deakin, Suckling, Barnes, Byrne, Chaudhry and Dazzan33} highlight the importance of disciplined follow-up. Preregistration, transparent reporting and rigorous evaluation are essential to distinguish genuine therapeutic signals from findings that may ultimately reflect noise.

The value of phenomenological observation

Detailed phenomenological observation, which was central to many historical serendipitous discoveries, continues to hold value in modern psychiatry. As Parnas and colleagues have noted, close attention to subjective experience and subtle behavioural features can uncover dimensions of mental illness that standardised assessments may overlook. ^{Reference Parnas, Sass and Zahavi34} Such observations can point to novel treatment targets or reveal unanticipated effects of existing interventions.

Personalised medicine and individual variation

The move towards personalised or precision medicine in psychiatry makes it increasingly important to attend to unexpected individual treatment responses. As the heterogeneity within psychiatric diagnoses becomes clearer, and as we better understand the complex interplay of genetic, environmental and treatment-related factors, careful observation of individual variation takes on greater significance. ^{Reference Ozomaro, Wahlestedt and Nemeroff35} An apparently anomalous response in one patient may, in fact, signal a distinct illness subtype or reveal a biological pathway that could shape future therapeutic strategies.

The expanding role of pharmacogenomics in psychiatry demonstrates how responses once regarded as idiosyncratic can have systematic explanations with direct clinical relevance. Serendipitous recognition of unusual drug effects in single patients has led to the identification of genetic polymorphisms that influence drug metabolism and treatment response. ^{Reference Müller, Kekin, Kao and Brandl36}

The individual level: cultivating prepared minds

At the level of the individual clinician, several approaches can increase the likelihood of recognising and acting on serendipitous findings.

• • Phenomenological training: Psychiatric education should place greater emphasis on detailed phenomenological observation alongside structured assessment. As Stanghellini and Broome note, teaching clinicians to attend to patients’ subjective experiences and subtle behavioural features can reveal aspects of illness not captured by standardised interviews. ^{Reference Stanghellini and Broome37} This includes grounding in descriptive psychopathology that extends beyond DSM criteria and draws on the broader tradition of psychiatric phenomenology.

• • Reflective practice: Creating space for reflection, even within busy services, enables clinicians to notice patterns and anomalies that might otherwise pass unnoticed. Regular case discussions that allow open-ended exploration of puzzling or unexpected observations can nurture curiosity. As Schön described, the ability to reflect both in action and on action is central to professional growth and discovery. ^{Reference Schön38}

• • Interdisciplinary exposure: Maintaining awareness of developments in related fields – such as neurology, immunology and endocrinology – can help psychiatrists recognise connections with potential clinical significance. Historically, many discoveries in psychiatry came from individuals applying insights from other medical domains. Regular interdisciplinary meetings and collaborations can help sustain such cross-pollination.

• • Documentation practices: Encouraging clinical records that capture more than checkbox symptoms, and include unexpected or seemingly tangential observations, creates a resource for identifying patterns over time. Although electronic health records are often criticised for their limitations, they could be adapted to support free-text entries alongside structured data. ^{Reference Cimino39}

The institutional level: creating supportive environments

Healthcare institutions can play a central role in creating environments that support serendipitous discovery.

• • Protected time for observation: Institutions should recognise the importance of detailed clinical observation by building protected time for it into clinical schedules. This could include longer initial assessments, dedicated time for complex case discussions or opportunities for clinicians to follow up on unexpected findings. As Gabbay and le May observed in their ethnographic work, the informal knowledge gained through careful observation can be as valuable as formal research evidence. ^{Reference Gabbay and le May40}

• • Flexible research support: Mechanisms that allow rapid pursuit of unexpected clinical leads can help translate serendipitous observations into structured inquiry. Examples include small grant schemes for pilot studies, streamlined ethics review processes for observational research and collaborations with basic scientists to explore potential mechanisms. ^{Reference Woolf41}

• • Culture of inquiry: Institutional leadership can promote a culture that prizes curiosity and the exploration of anomalies. This might involve celebrating serendipitous findings from the organisation’s history, shielding clinicians from productivity pressures when they pursue such leads, and establishing regular forums for sharing puzzling cases or unusual treatment responses.

• • Database infrastructure: Robust clinical data systems can make it easier to detect unusual treatment responses or other unexpected patterns. Integrating natural language processing and machine learning into clinical databases could help identify anomalous patterns in narrative notes, whereas positive-signal pharmacovigilance systems could systematically record unexpected benefits alongside adverse events. ^{Reference Jensen, Jensen and Brunak42}

The systemic level: policy and research infrastructure

At the broader systemic level, several measures could help create an environment more conducive to serendipitous discovery.

• • Funding mechanisms: Research agencies should develop dedicated programmes for investigating unexpected findings. The National Institutes of Health’s R21 exploratory grants offer one example, but additional schemes tailored specifically to serendipitous observations could add value. As Heinze et al found, funding structures that allow flexibility and tolerate risk are associated with more innovative outcomes. ^{Reference Heinze, Shapira, Rogers and Senker43} Embedding such mechanisms within learning health systems could speed the path from initial observation to formal evaluation.

• • Regulatory flexibility: In addition to maintaining necessary safety standards, regulatory bodies could create streamlined pathways for the rapid investigation of unexpected therapeutic effects from approved medicines. The US Food and Drug Administration’s expanded access programmes offer a precedent, but further targeted mechanisms for studying serendipitous findings could accelerate their translation into practice. ^{Reference Darrow, Sarpatwari, Avorn and Kesselheim44}

• • Publication venues: Establishing reputable outlets for well-documented case reports and case series describing unexpected treatment responses could improve the dissemination of serendipitous observations. Although such reports sit low in the evidence hierarchy, they have historically been central to recognising new therapeutic possibilities. Journals focusing on phenomenological observation and unexpected clinical findings, alongside structured registries for recording unexpected benefits, could help restore this role. ^{Reference Vandenbroucke45}

• • Training reform: In addition to the psychiatric training reforms already discussed, medical education should explicitly address the role of serendipity in discovery, equipping clinicians with the skills to recognise and follow up on unexpected observations. This might include teaching the history of medical breakthroughs, philosophy of science and research methods suited to investigating serendipitous effects. ^{Reference Goldacre, Heneghan, Mahtani and Godlee46}

Ketamine and rapid antidepressant action

The recognition of ketamine’s rapid antidepressant effects offers a contemporary example of serendipity reshaping psychiatric thinking. For years, anaesthesiologists had noted that some patients reported improved mood after ketamine anaesthesia, but these accounts were largely regarded as incidental side-effects. It was only when Berman and colleagues conducted a small, controlled trial based on such observations that ketamine’s striking, rapid antidepressant action was formally demonstrated. ^{Reference Berman, Cappiello, Anand, Oren, Heninger and Charney47}

This finding has transformed approaches to depression, overturning the long-standing assumption that antidepressants require weeks to take effect, and stimulating intensive investigation into glutamatergic pathways in mood regulation. The subsequent development and US Food and Drug Administration’s approval of intranasal esketamine for treatment-resistant depression exemplifies how a serendipitous clinical observation can be successfully translated into an approved therapeutic option. ^{Reference Daly, Singh, Fedgchin, Cooper, Lim and Shelton48}

Anti-inflammatory approaches to depression

Reports that some patients with autoimmune disorders experienced unexpected improvements in mood or psychotic symptoms when receiving anti-inflammatory treatments have fuelled growing interest in the role of inflammation in mental illness. Although links between inflammation and psychiatric disorders had been suggested for decades, it was often these unanticipated clinical improvements during immunological treatment that prompted systematic research. ^{Reference Miller, Haroon, Raison and Felger49}

Such observations have led to clinical trials of anti-inflammatory agents for conditions such as depression, opening potential new avenues for treatment. ^{Reference Kappelmann, Lewis, Dantzer, Jones and Khandaker50,Reference Bai, Guo, Feng, Zhang, Zhang and Liu51} That these findings arose from attentive monitoring of patients undergoing therapy for non-psychiatric illnesses highlights the enduring value of cross-disciplinary clinical observation.

Psychedelic renaissance

The resurgence of interest in psychedelic-assisted psychotherapy is partly rooted in serendipitous observations from clinicians and researchers who noted unexpected, lasting benefits in research participants and patients who had used these substances. Although studies in the 1950s and 1960s had suggested therapeutic potential, the work was largely discontinued for political and social, rather than scientific reasons. Over time, persistent anecdotal accounts of benefit led contemporary investigators to revisit these findings and test them systematically. ^{Reference Nichols52} Recent controlled trials have confirmed aspects of the early reports, indicating possible breakthrough treatments for conditions such as treatment-resistant depression and post-traumatic stress disorder. ^{Reference Carhart-Harris and Goodwin53} In parallel, 3,4-methylenedioxymethamphetamine-assisted therapy has shown efficacy for post-traumatic stress disorder in randomised trials. ^{Reference Mitchell, Bogenschutz, Lilienstein, Harrison, Kleiman and Parker-Guilbert54} This revival demonstrates how revisiting research abandoned for non-scientific reasons can open valuable therapeutic possibilities.

Integration with precision medicine

Rather than viewing attention to serendipitous observation as competing with precision medicine approaches, we should recognise their complementary nature. Unexpected treatment responses in individuals may reveal previously unrecognised biological subtypes or mechanisms. Building infrastructure to systematically capture and investigate such observations could accelerate precision medicine efforts. ^{Reference Collins and Varmus55}

Technology-enhanced observation

Digital health technologies, including smartphone applications and wearable devices, offer new ways to identify unexpected patterns in symptoms or treatment responses. Practical steps to enable this include the following.

• • Electronic health records (EHR) outlier detection: Developing anomaly-detection models using natural language processing to flag unusual response trajectories, rapid-onset effects or distinctive improvement patterns for clinical review.

• • Positive-signal pharmacovigilance: Adapting adverse event reporting systems to capture unexpected benefits, using structured fields and allowing for patient-reported input.

• • Single-patient (N-of-1) and micro-randomised trials: Incorporating lightweight, consent-based individual experiments within routine care to rapidly test emerging signals.

• • Pragmatic trial ‘sidecar’ fields: Adding short free-text and checklist options to standard outcome workflows to log unexpected findings prospectively.

• • Rapid institutional review board pathways: Creating fast-track ethical review processes to study emerging clinical signals promptly, while safeguarding safety, privacy and transparency.

Machine learning can support novelty detection, but these tools should be designed to highlight and triage unexpected positive outcomes rather than focus solely on confirming anticipated patterns. ^{Reference Torous, Onnela and Keshavan56}

Global collaboration

Establishing international networks for sharing and investigating serendipitous observations could help accelerate discovery. Variation across populations and treatment settings may reveal different unexpected effects, and coordinated investigation can aid in distinguishing genuine signals from background noise. Existing models, such as the World Health Organization’s pharmacovigilance programmes, could be adapted to capture and evaluate positive, unanticipated outcomes. ^{Reference Lindquist57}

Ethical considerations

In promoting attention to serendipitous observations, it is essential to address the accompanying ethical considerations. Patients should be made aware when treatments are being offered on the basis of serendipitous findings rather than evidence from controlled trials. Systems designed to investigate such observations must safeguard patient privacy while still enabling meaningful discovery. The principle of beneficence supports pursuing unexpected findings that may offer clinical benefit, but this pursuit must be balanced with careful evaluation of safety and efficacy. ^{Reference Emanuel, Wendler and Grady58}

Taken together, the future imperatives for the field are to train clinicians as prepared observers of anomalous responses, to equip services with technology-enabled tools that can capture and aggregate unexpected signals, and to ensure that emerging leads can flow efficiently into flexible trial platforms. Combining enhanced phenomenological training, digital phenotyping and EHR-based anomaly detection with adaptive platform and rapid-fail proof-of-concept trial designs would allow promising observations to be tested more quickly, while minimising patient burden and opportunity cost. Framing serendipity in this way as a system-level responsibility, rather than an individual virtue alone, offers a more concrete roadmap for research and practice.