Treatment resistance in first‐episode psychosis

Psychosis usually emerges in early adulthood, a period in which a life’s trajectory is being set. The impact of events at this juncture can be disproportionately large, altering interpersonal relationships, education, employment, and physical health. As a result, this is a time when providing the most effective treatment possible is particularly important. The pharmacological treatment of first-episode psychosis usually begins with the prescription of a dopamine D2 receptor antagonist, and in most people this leads to clinically meaningful reduction in the presenting positive symptoms. However, the observed clinical response to antipsychotic treatment is variable, and reflects more than just differences in the direct effects of the drug1. The evolution of symptoms is also influenced by a host of broader interacting biological, psychological and social factors. A substantial minority of patients do not experience sufficient symptomatic relief. In some, this may reflect inadequate treatment adherence. However, in a proportion of patients, symptoms persist despite good adherence to therapeutic doses of at least two different antipsychotic medications, a phenomenon known as treatment resistance. For the majority of individuals who develop treatment-resistant schizophrenia, this resistance is evident from the onset of psychosis2. Understanding what underlies treatment resistance remains a central question in psychosis research. Psychiatric symptoms can be conceptualized as emergent properties of a dynamic network comprising neurobiological vulnerability, life experiences, cognitive schemas, and social context. Within this framework, treatment resistance could represent a system that is stuck in a maladaptive attractor state. The longer an individual remains with symptoms, the more self-reinforced these may become. Offering effective treatment as early as possible maximizes the chance of shifting a dysfunctional system into a more adaptive state while patterns are still malleable. Early intervention (EI) services were first developed around 30 years ago to provide clinical care at this stage of both vulnerability and opportunity. The rationale was that delivering optimal treatment early would reduce the likelihood of the chronicity and self-reinforcing functional decline that often accompany psychotic disorders. Although this logic applies equally to the recognition and management of treatment resistance, the original EI model places relatively little emphasis on how to help the substantial minority of individuals who do not benefit from standard treatment. As a result, many EI teams may lack the capacity to identify or manage people with treatment resistance and may not see this as part of their clinical remit. Clozapine is the only licensed medication for treatment-resistant schizophrenia. Its use in treatment resistance is supported by both clinical trials and a host of real-world evidence showing benefits in terms of suicidality, substance use, and cost-effectiveness3. There do remain, however, some doubts as to whether clozapine is clearly superior to its closer pharmacological relatives, such as olanzapine, with a recent individual participant data meta-analysis not finding evidence of clozapine’s superiority4. It should also be recognized that while “treatment resistance” refers to refractory positive symptoms, many individuals may have a relative resolution of positive symptoms, yet still be affected by cognitive and negative symptoms that severely impair functioning, and there is no evidence that clozapine is better than standard treatment for these domains. Nevertheless, switching to clozapine in people with first-episode psychosis appears to have a greater benefit than switching to a different standard antipsychotic, and the earlier clozapine is started the better the outcome5. When clozapine is initiated earlier, there may be potential to engender symptomatic improvement through interruption of pathological symptomatic feedback loops. This improvement in core psychopathology may, in turn, facilitate engagement in psychosocial interventions, improve functioning, and restore a sense of agency – a virtuous cycle that promotes further improvement and catalyzes broader recovery. In addition to pharmacological optimization, addressing modifiable psychosocial contributors such as unhelpful family dynamics, housing insecurity, and substance use is critical to supporting recovery. At present, clozapine is rarely used in EI services6. Indeed, the time to clozapine initiation is still over five years in many services7. In theory, the gold standard definition of treatment resistance – a lack of response to two antipsychotic trials of adequate dose and duration – can be determined within 2-3 months. However, in real-world practice, it can be difficult to precisely and promptly assess the response to treatment and the level of adherence. Moreover, once treatment resistance has been recognized, EI clinicians may be deterred from prescribing clozapine, and patients may be unwilling to accept it, because of the logistical burdens of initiation and monitoring, concerns about side effects, and a perception that being treated with clozapine is a marker of severe and enduring illness. A further complexity is that, after their first experience of illness, young people are understandably hoping for recovery without a need for long-term mental health care, an ambition central to the traditional ethos of EI services. Treatment with clozapine, and indeed the stigma attached to the labels of “schizophrenia” and “treatment resistance”, may seem incompatible with this goal. Communicating the rationale for early clozapine use in a way that aligns with a young person’s hopes – emphasizing function, quality of life, and personal goals – is, therefore, critical. Improving the care of individuals with treatment resistance in early psychosis requires change at multiple levels. Recent research has focused on predicting treatment resistance using clinical, cognitive or biological markers. While predictive tools might allow us to avoid the need for lengthy evaluations of treatment response, they cannot address the fact that, even when resistance has been recognized, clozapine is often not used. As such, changes should be designed to lead to better treatment implementation as well as earlier detection of resistance. Reducing barriers to clozapine use is essential. Targeted community-based services can markedly increase clozapine initiation rates8. Point-of-care testing technologies that make blood monitoring more convenient and less invasive are now widely available. There is increasing evidence that the current stringency of longer-term blood monitoring is overzealous, and regulatory bodies in some countries are beginning to reconsider the frequency of blood tests and the absolute neutrophil count thresholds required for continuation3, 9. The risk of weight gain, a major reason for discontinuation among young people, can be reduced through structured physical activity programmes, lifestyle counselling, and adjunctive treatments such as metformin. Updating the EI model, such that the detection and management of treatment resistance are included as a core part of the clinical offer, would ensure that patients who do not benefit from standard care have access to the right treatment at the right time. While clozapine remains central to the management of treatment resistance, the advent of novel medications with non-dopaminergic mechanisms of action, such as xanomeline-trospium, evenamide and cannabidiol, offers hope for expanding the range of options available for those not responding to treatment in the first episode. While their precise role in the treatment pathway is not yet established, these compounds may eventually offer effective alternatives or adjuncts to clozapine, with potentially more tolerable side effect profiles. In the long term, a more nuanced and flexible model of treatment resistance may be needed – one that recognizes the heterogeneity of underlying mechanisms and the need for personalized intervention strategies. In the short term, however, the goal should be to detect treatment resistance early and remove the systemic barriers that delay access to effective management. This means better education for clinicians, better communication with patients, and better clinical systems that enable rather than obstruct treatment. Treatment resistance in the first episode of psychosis is not rare; it is a predictable clinical reality for around 25% of patients2. Clinical pathways should be designed to not only identify it early, but also manage it with clarity, compassion, and evidence-based care. By doing so, we can prevent the entrenchment of disability and offer individuals the best possible chance of recovery when everything is still to play for.