Tough times never last too long: the future of psychopharmacology

The progress of psychopharmacology has witnessed very different scenarios over the past seven decades. Obviously, the greatest impact occurred with the introduction of the first effective medications, such as chlor­prom­azine, imipramine, lithium and benzo­diaz­epines1. Further refinements based on a bet­ter understanding of the pharmacological mechanisms behind those serendipitous findings led to drugs that were friendlier in terms of tolerability. Now, hopefully, we may be entering a new era with more innovative and personalized therapies. After three decades of “me-too” drugs, the business profits from that drug development model are now exhausted, and practically all those drugs have become generic. This has given an unprecedented push to the search of alternative targets and mechanisms of action. The paradox is that this is happening in the context of recent cuts in the investment of big pharma companies in neuroscience. However, smaller companies and bio-techs have taken over, and there is a bunch of promising novel drugs for the management of schizophrenia, depression, and stress-related disorders, as very well discussed by Correll et al2. The situation is somewhat less optimistic for bipolar disorder and addiction, where repurposing is the rule rather than the exception. Some of the promising agents for these indications will only get approved if they are successful for their primary indication, for example schizophrenia3. However, it has to be considered that, in many countries, there are no incentives for secondary indications (they require further investment in clinical trials and sometimes they imply price or reimbursement cuts that companies prefer to avoid). No one knows at present time how many of the new drugs that are at late stages of de­velopment will reach the market, but there are good reasons to be optimistic that at least a few will make it and may be available to patients with mental disorders soon. In schizophrenia, the new mechanisms not involving dopamine antagonism or modulation may provide opportunities to non-responders to the traditional treatments, and to tackle orphan dimensions such as negative symptoms. In depression, practically all novel therapies have in common a fast onset of action, which may save lives by reducing suicide risk and improve the quality of life of patients since treatment start, especially for those in whom the conventional treatments failed. New drugs, combined with some particular forms of adjunctive psychotherapy, may make a difference for those suffering from post-traumatic stress disorder. Further aspects that may foster optimism are the progress associated with the classification of psychopharmacologic agents4, and the focus on transdiagnostic targets5, such as emotional dysregulation and cognitive impairment. Finally, advances in the implementation of precision psychiatry6 may provide further opportunities to explore biomarker-based targets rather than traditional clinical endpoints. Nevertheless, some hurdles are still there. An obvious one is the increasing difficulties in signal detection with placebo-controlled trials7 and the limited alternatives to placebo-controlled designs8, as well as problems related to the representativeness of the patients enrolled in those trials and the generalizability of the findings9. Regulatory agencies are not consistent across the world in their requirements for marketing approval of medications, and this carries increased costs and inequalities. The stigma associated with psychiatric conditions is still a major cause of shortage of investments in research as compared to other areas of medicine, despite the huge prevalence of these disorders. Precision psychiatry will hopefully evolve over the present decade, but will likely pose novel challenges. Health care access is still an issue in many parts of the world, and this is particularly true for mental illness. The benefits of precision psychiatry and novel treatments, with their associated increased costs, may not be available for all, and cause further inequities. Given the high prevalence of psychiatric disorders, governments will likely face huge budget and reimbursement challenges as diagnostic and therapeutic progress makes the care of the mentally ill increasingly expensive. I am not particularly confident that there will be a perfect correlation between biomarkers and deep clinical phenotyping in psychiatry, although there is plenty of room for improvement in performing thorough psychopathological assessments in large samples of patients and including that information in the current clinically poor datasets of big consortia of genetics (e.g., Psychiatric Genetics Consortium) and neuroimaging (e.g., ENIGMA). But even if so-called “molecular psychopathology” ends up being too unspecific, there is hope that future biomarkers may be better correlated with functioning, making their use fruitful as relevant treatment targets. The rise of digital tools may be instrumental in this regard, yielding objective behavioral data for the assessment and monitoring of personalized outcomes. This would be relevant not only for clinical trial design, but also for clinical practice. The future of psychopharmacology depends on this, but also on establishing synergies with other treatment modalities, such as neuromodulation and advanced psychotherapies. Hence investments, either from public or charity budgets, and ideally from both, are urgently needed in psychiatry and related disciplines. Large population datasets, covering the whole life span, need to be deeply studied with all the available relevant tools and technology, as defined by consensus of worldwide experts. This is the time to make a real step further, filling the gaps described by Correll et al2, and pursuing better health and justice for the mentally ill. Efforts in searching better diagnosis and treatment of psychiatric disorders should go hand in hand with better health care access, early intervention initiatives, prevention, and promotion of mental health in the general population. The future of psycho­pharmacology is unequivocally linked to the future of psychiatry as a discipline. The stigma associated to mental disorders and to pharmacological tools for the disorders of the brain is perhaps the greatest barrier to overcoming these tough times, which should not last too long.