The future of psychopharmacology: challenges beyond efficacy and tolerability.

The paper by Correll et al1 provides a comprehensive and timely overview of recent developments in psychopharmacology and offers hope for much needed breakthroughs after a period of stagnation in the field. It also considers some of the major challenges slowing further progress, including our limited understanding of the neurobiological underpinnings of psychiatric disorders and the difficulties encountered in designing and conducting trials that are able to adequately assess treatment effects on thoughts, emotions and behaviour. From the first serendipitous discoveries of compounds with psychotropic effects to modern-day targeted drug development, advances over the years have been considerable, to the extent that we now have agents with at least some beneficial effect for most psychiatric disorders. In particular, the introduction of fluoxetine more than three decades ago heralded an era of drug design aimed at specific neurotransmitter pathways, with an upsurge of interest in psychopharmacology by the pharmaceutical industry, clinicians and the general pub­lic. Numerous new agents were introduced, and their therapeutic indications broaden­ed. These new treatments have not only strengthened the armamentarium of clinicians, but also fundamentally transformed our conceptualization of psychiatric disorders2. Consequently, the role of the psychiatrist has changed, and medication management has become a central function of clinical care. As such, an extensive knowledge of psychopharmacology is now a prerequisite for practicing psychiatrists. The danger here, of course, is that the other essential components of clinical care are neglected, and we become regarded as little more than “pill pushers”. The challenge, particularly in busy clinical settings, is to balance medication management with a patient-centred ap­proach to care, in order to establish the best possible therapeutic alliance, which in turn enhances treatment engagement and medication adherence3. After the initial euphoria accompanying the Prozac era came the realization that our expectations had been unrealistic. The newer generation of psychotropic drugs displayed at best only subtle efficacy advantages over their predecessors, and, while the novel phar­macological profiles effectively addressed adverse effects of the older agents, a new set of tolerability and safety concerns emerged. Over the past two decades, there has been a steady decline in the number of new psychotropic drugs introduced, mainly due to market saturation, escalating costs and the influx of generics4. We have witnessed a substantial waning of enthusiasm, and many of the pharmaceutical companies have withdrawn from psychotropic drug development. However, this has also forced those of us in the field to re-think our approach – to target novel mechanisms and to design clinical trials in a way that they are more likely to demonstrate efficacy advantages. Consequently, sev­eral promising new agents have progressed to the stage of clinical development, as highlighted in Correll et al's paper. Hopefully, some of these agents will be introduced to clinical practice in the near future, with the potential of not only providing us with more and better options for treating our patients, but also to advance our understanding of the pathophysiology of these disorders. There are important considerations in the pharmacological treatment of psychiatric disorders that go beyond the efficacy and tolerability of the compounds. In order to be effective, most pharmacological interventions for psychiatric disorders require continuous treatment over a protracted per­iod. As is the case with all chronic treatments, non-adherence is a major consider­ation5. However, with many psychiatric disorders, the problem is further compounded by impairment of insight. This is the case particularly with psychotic disorders and cognitive disorders. In psychosis, insight im­pairment is characterized by illness unawareness and failure to recognize the need for treatment. These features have enormous implications when considering treatment options and in shared decision-making processes. In such cases, the burden of responsibility for ensuring adherence to treatment should not be left with the patient. This aspect has been recognized by some pharmaceutical companies, which have invested much effort into the development of ways of providing treatment that are more likely than oral medications to provide assured, uninterrupted delivery. In this regard, long-acting injectable formulations have received the most attention. There are also ethical and philosophical considerations in relation to the ongoing development of new psychopharmacological agents. It could be argued that the costs of developing new and better agents are not justified if they are inaccessible to the majority of individuals who would benefit from their use. This is increasingly the case, and not just in low- and middle-income countries. Even in more developed settings, the exorbitant costs of some newer psychotropic drugs have placed them beyond the reach of many. On the other hand, the alternative ethical argument is that the best available treatments should be made accessible to all. In­deed, as stipulated in the constitution of the World Health Organization, access to the highest attainable standard of health care is one of the fundamental rights of every human being6. Unfortunately, in the real world, this is not the case, particularly for mental health7. Across vast populations, mental health literacy is rudimentary and health care services inaccessible. The enormous treatment gap in these settings is surely an indictment of modern global health care. So, rather than questioning the need for psychotropic drug development, we should be encouraging those who continue to search for new and better agents – but at the same time we should be championing for their greater availability to those in need.