Antipsychotic drugs revolutionised psychiatric practice and provided a range of tools for exploring brain function in health and disease. Their development and introduction were largely empirical but based on long and honourable scientific credentials and remarkable powers of clinical observation. The class shares a common core action of attenuating central dopamine transmission, which underlies the major limitation to their use – high liability to disrupt extrapyramidal function – and also the most durable hypothesis of the basis of psychotic disorders, especially schizophrenia. However, the Dopamine Hypothesis, which has driven drug development for almost half a century, has become a straight-jacket, stifling innovation, resulting in a class of compounds that are largely derivative. Recent efforts only cemented this tendency as no clinical evidence supports the notion that newer compounds, modelled on clozapine, share that drug’s unique neurological tolerability and can be considered ‘atypical’. Patients and doctors alike must await a more profound understanding of central dopamine homeostasis and novel methods of maintaining it before they can again experience the intoxicating promise antipsychotics once held.

Antipsychotics have been a major driver of psychiatric practice and neuroscience research for over 60 years. They have altered perceptions of psychiatric disorder and provided the foundation for a social revolution in health care provision. They have become tools not only for exploring mechanisms of disease but also for unlocking the nature of brain function itself. But recent years have witnessed how optimism can be manipulated to produce false hope and how theories that once seemed productive can come to define the limitations of knowledge. The pipeline of new antipsychotics has dried to a trickle and international pharma has moved on. The story of antipsychotics is a sobering rollercoaster.

Unlikely origins In 1856, 18-year-old William Perkin produced a blue ‘sticky splurge’ trying to create quinine from coal tar, but, despite his youth, immediately saw a commercial application (Swazey, 1974). The colour mauve (‘Perkin’s purple’) soon became the height of fashion. Perkin’s discovery gave birth to the commercial dye industry and the discipline of organic chemistry to feed demand. The structure of one of the most successful dyes, methylene blue, was uncovered by August Bernthsen in 1883 and named ‘thiodiphenylamine’ or phenothiazine (Swazey, 1974). Many medical applications were sought for methylene blue and phenothiazine, but tolerability issues inhibited their development. However, after many years of neglect, a growing European focus on neurotransmission turned attention back to phenothiazines. In 1937, Daniel Bovet hypothesised that if there were compounds that could block acetylcholine, it might also be possible to produce agents that blocked histamine (Swazey, 1974). French company Rhone-Poulenc began to explore this using the readily synthesisable substituted phenothiazines, the outcome being promethazine, the first synthetic antihistamine. During the Second World War, substituted phenothiazines were investigated unsuccessfully as antimalarials in both America and France, but French interest in their antihistamine actions led to diphenhydramine. However, the war had a further crucial impact. Major advances in surgical technique were not matched by improvements in outcomes and a new indication arose in the late 1940s when surgeon Henri Laborit postulated (wrongly, as it happened) that surgical hazards, mainly from haemodynamic shock, could be obviated by preoperative administration of a drug cocktail that dampened, or ‘lysed’, the autonomic nervous system. The phenothiazine development programme, instigated at Rhone-Poulenc in October 1950, was first and foremost about preoperative technique and only as an afterthought about psychiatry (Swazey, 1974). In 1951, psychiatrists who tried the newly synthesised chlorpromazine in their patients thought it merely a sedative, but Laborit noticed something different: not any loss of consciousness, not any change in the patient’s mentality but a slight tendency to sleep and above all ‘disinterest’ for all that goes on around him. (Laborit et al., 1952) His patients, although aware of the life-threatening procedures they were facing, seemed curiously unconcerned. What he had noticed was an affective numbing similar, as was later suggested, to a ‘chemical lobotomy’. Laborit thought this would be of interest to psychiatrists, but psychiatry, heavily influenced by psychoanalysis at that time, paid little heed to a surgeon’s exhortations to try this miracle drug. However, psychiatrist Pierre Deniker, alerted by a relative who was a colleague of Laborit’s, and Jean Delay, the pre-eminent French psychiatrist of his generation, were interested and presented their striking results in 38 patients at the prestigious centennial meeting of the Société Médico-Psychologique in May 1952. Within a year, chlorpromazine had spread around the world and the era of ‘anti-psychosis’ had arrived. An array of substituted phenothiazines followed before, in 1958, Paul Janssen applied heat to pethidine (meperidine), producing norpethidine, which when heated further produced the basis of the first butyrophenone, haloperidol, for many years the class ‘market leader’, while the first thioxanthene, a slight chemical and pharmacological modification of the phenothiazines, emerged in Denmark. Also in the late 1950s, French researchers, seeking to increase the antiarrhythmic properties of procainamide, produced metoclopramide, whose subsequent refinement led to sulpiride, the first substituted benzamide (Owens, 2014). With the exception of cognitive enhancers, every class of medication that now comprises the heart of psychopharmacology had its birth in this ‘golden age’ of the 1950s. The associated optimism spread beyond clinicians and their patients as, for the first time, science was presented with a broad range of safe, clinically usable compounds with which to explore not only disease mechanisms but also the workings of the central nervous system. Neuroscience was coming of age. By definition, ‘golden ages’ are limited and while the years that followed have produced an exponential increase in knowledge of brain mechanisms, the story of antipsychotics illustrates how elusive understanding remains.

50 years and beyond So, what is the future for antipsychotics? Looking at the current commercial landscape, it is hard to be optimistic. And the commercial landscape matters for, with available psychotropics, we can look to academia for primary development of only one – lithium. All the major companies that so dominated antipsychotic development in the second ‘golden age’ have either withdrawn or down-graded neuroscience investment substantially. The torch has passed from large multinationals with deep pockets to small-/medium-sized organisations on one-off gambles. Such a major shift is not because of perceived lack of need – quite the contrary. It is commercial – economic – reality. The Dopamine Hypothesis did not create antipsychotic development but has been its driver for almost half a century. To those willing to invest, it is looking old and stale. More compounds to directly attenuate central D2 transmission, be it by post-synaptic antagonism or partial or inverse agonism, seem uninspiring. There may be room to exploit current evidence of disrupted pre-synaptic mechanisms but there are clinicians who still recall drugs of the past which did just that (e.g. tetrabenazine) but were abandoned on ‘weak’ and ineffective reputations and poor tolerability profiles. Almost 30 years ago, the amphetamine-based model that supported pursuit of direct dopaminergic antagonism acquired a rival. Clinically, psychoses associated with the dissociative anaesthetics, ketamine and phencyclidine are more convincingly ‘schizophrenic’ than the circumscribed, predominantly delusional states associated with amphetamine (Javitt and Zukin, 1991; Krystal et al., 1994), face-validity that has supported intense interest in modulation of excitatory glutamatergic mechanisms as the ‘next-generation’ approach to antipsychotic development. But the secrets of these complex systems remain hidden. Looking at pipeline developments for the foreseeable future, it is ironic that despite the research emphasis of past decades, it seems that drugs modifying glutamatergic mechanisms will make their impact on the antidepressant, rather than the antipsychotic, market. Ways forward might come from widening our repertoire of non-dopaminergic targets beyond glutamate to nicotinic, peptidogenic, hormonal, histaminergic and pro-inflammatory mechanisms among others, but the evidence so far is not encouraging that new avenues in this direction have hitherto gone undetected (Girgis et al., 2018). Alternatively, clearer understanding of the structure and binding mechanics of the D2 receptor itself (Wang et al., 2018), particularly with use of different antipsychotic ligands, may allow for better pharmacological targeting on efficacy, though this work is still in its infancy. The immediate future does not look rosy and the shift of investment remains a concern. As the British Neuroscience Association moves into its second half-century, it is to be hoped that a younger generation of researchers will break out of the confines of traditional theorising that started a process but left the path to its conclusion obscure.

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