Off‐label use of medications in psychiatry: the need and the caveats

Psychiatric diagnosis is important to guide the formulation of a reasonable therapeutic plan and prognosis. In other areas of medicine, the need for a diagnosis is not a matter of debate, but in psychiatry, due to the variety of theoretical orientations and to social stigma, diagnosis is often seen as an expression of reductionism or as a potentially detrimental label. However, diagnosis provides the foundation for treatment indications, which are strictly regulated for the sake of our patients’ safety, especially as far as pharmacotherapy is concerned. Regulators play a central role in the advancement of science and health care, and indications are important because they ensure that an approved drug has a solid scientific evidence for its use in clinical practice. Drug approval is a long and often bumpy process aimed at ensuring that any new medication is safe and efficacious enough to be placed in the market. Reimbursement policies vary from country to country. Devices are regulated through a different process, while psychotherapies – which are presumed to be free of side effects (wrong assumption1) – are often not regulated at all, but are expected to be based on scientific evidence. Once a new medication has been granted marketing authorization, there is a period of time in which the patent owner has the privilege of exclusivity. After that period, generic versions are allowed and the investments on seeking further indications for the medication rapidly decrease. Unless public funding is placed for this purpose, the lack of financial incentives is likely to discourage the identification of other conditions for which that drug may be indicated. In psychiatry, the borders between diagnostic categories are often blurred, and there may be overlaps between different categories; this is a major source of so-called “comorbidity”. The limited clinical utility of biomarkers in our field leads to the use of “soft” outcomes such as symptom severity scales, and this makes our treatments a bit unspecific. We learnt more from the mechanism of action of drugs discovered by “serendipity” and repurposing than from direct attempts to ascertain the pathophysiology of mental disorders. Moreover, placebo is not easy to beat in the context of a clinical trial2. Given this background, there is obviously plenty of room for off-label use of drugs in psychiatry. Off-label prescription consists of implementing a treatment out of the strict guidance of the approval by the regulatory agencies. Deviations can regard indications (diagnosis), but also doses, treatment duration, adjunctive vs. monotherapy use, age range, and several other aspects. In psychiatry, off-label prescription is extremely common. It is obvious that clinical trials have limited generalizability (for example, a recent report calculated that only 20% of patients with schizophrenia would qualify to be enrolled in a registration trial3), and clinicians have to deal with complex patients that are quite different from those who provided the evidence base for drug approval. It would probably be impossible to practice psychiatry with good results if all prescriptions were in-label. However, drug indications and rules are important, and there is no excuse to ignore them as if they did not exist. The science and art of practicing medicine consists of making the best use of knowledge, tradition, experience and innovation. This often means slightly drifting from the strict statements contained in the summary of product characteristics and the medication package insert. Off-label prescription is, hence, not ideal but often necessary. Given that psychiatric drugs treat symptoms, not disorders, it is fair to use them in situations where there is no approved alternative, always looking at the specific patient’s needs and taking ethical aspects into account. Conditions such as anorexia nervosa, autism, personality disorders, and many more could not be treated pharmacologically otherwise. These and other conditions may benefit from psychosocial approaches, but some symptomatic relief is often necessary, and drugs may help in this regard. Even within approved indications, outliers such as poor or rapid metabolizers may need doses out of the approved range. The whole field of child psychiatry is full of off-label prescriptions4, due to the limited available research evidence and the substantial unmet needs. The problem of being “too permissive” about off-label drug use mainly concerns the overutilization of drugs such as antipsychotics in vulnerable populations such as children or the elderly, given their safety profile5. An open question is to what extent drug regulations and current market access barriers might contribute to the expansion of off-label prescription. For example, in many countries, if a drug is granted a second indication, its price is lowered, resulting in a disincentive to seeking secondary indications for patent owners. So, the same prescription can be, for example, in-label in the US and off-label in the UK. Treatment guidelines are important to cover the treatment gaps, but some of them rely so heavily on evidence from clinical trials that they fail to provide sensible advice on what to do beyond the approved indications for the available drug armamentarium. Anyway, safety is the priority concern, especially in children and the elderly, and it is necessary to look carefully into the tolerability profile of drugs and to exercise caution6. I recommend, before implementing off-label prescription, to look first for suitable in-label options. If these are not available, my advice is to consider guidelines, observational studies, case reports, and ultimately expert opinion supporting a reasonable choice. Make sure that you discuss the pros and cons of your prescription with the patient and, when appropriate, with his/her significant others. Write down in the clinical record the rationale of your decision and the fact that the prescription was based on an agreement with the patient. Finally, follow up the patient and monitor the safety, tolerability and effectiveness of your prescription. In the future, we may be able to predict treatment response based on genetic, imaging or other biomarkers, which may be the best guidance for safe and efficient prescription. This will be the era of precision psychiatry, which in my view has already started7, 8. Meanwhile, off-label prescription is still necessary in some cases, and the art of practicing medicine includes assessing the benefit-risk balance for each individual, and deciding when, how and for whom this prescription is appropriate.