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From an economic perspective, drugs for psychiatric disorders have historically been among the largest sources of revenue (Table 1) for the pharmaceutical industry. Given the high prevalence of psychiatric disorders (1), their massive ef ect on global disease burden (2), and limitations in the ef cacy of cur-rent therapies, large markets for new and better therapies already exist, and current demographic and socioeconomic trends predict the development of expanded markets. Such projections are based on gains in global life expectancy, increas-ing attention to mental health and cognitive performance in the devel-oped world, rapid unplanned ur-banization in the developing world, and large numbers of individuals af ected by conf ict and postconf ict situations worldwide.

Advances continue to be made in modes of cognitive psychother-apy (3) and in device-based psy-chiatric treatments (4); but despite the growing market opportunities, major pharmaceutical companies recently announced substantial cutbacks or complete discontinu-ation of ef orts to discover new drugs for psychiatric disorders (5, 6). T is exodus creates a danger-ous gap in the public health eco-system, because safe and ef ective drugs can be readily deployed in both primary care and specialist settings and, when generic, can be highly cost-ef ective. Although large com-panies may continue to in-license new drug candidates, their complete or near com-plete exits from psychiatric research deplete

expertise and f nancial resources from ther-apeutics discovery. Here, I describe how we arrived at this crossroads and how we might get back on a productive path of discovery.

BRILLIANT PROMISE UNFULFILLEDJohn Cade discovered the sedating ef ects of lithium in 1949, f rst in guineas pigs and soon thereaf er in manic patients. In the re-markably short period that followed—less than a decade—prototypes of the other major classes of psychiatric drugs were

identif ed: the antipsychotic drugs (begin-ning with chlorpromazine), antidepres-sants [the tricyclic drug imipramine and the monoamine oxidase inhibitor (MAOI) iproniazid], and benzodiazepines (chlordi-azepoxide). Each of these discoveries had an important component of serendipity but also motivated path-breaking research on neurotransmitter release, receptors, and transporters (7).

What has happened—or rather not hap-pened—in the intervening half-century was as unexpected as the initial spate of discov-eries. Many antidepressant drugs have been developed since the 1950s, but none has improved on the ef cacy of imipramine or the f rst MAOIs, leaving many patients with modest benef ts or none at all (8, 9). Anti-

psychotic drugs achieved a peak in ef cacy—never equaled (10) and still not understood—with the discovery of clozapine in the mid-1960s. Although valproic acid and other drugs developed as anticonvulsants were shown in the early 1980s to be mood stabi-lizers, lithium remains a mainstay of treatment for bipolar disorder, despite its serious toxicities. T ere are still no broadly useful pharma-cological treatments for the core symptoms of autism—social def -cits, language delay, narrowed in-terests, and repetitive behaviors—or for the disabling negative (def -cit) and cognitive symptoms of schizophrenia (11, 12). T e mo-lecular targets of all of today’s ap-proved psychiatric drugs are the same as the targets of their pre-1960 prototypes (Table 2), and their mechanisms of action are not understood beyond a few ini-tial molecular events (13). Indeed, the critical molecular target (or targets) for lithium have not been established with certainty (13).

T ere has been some progress, of course. Important advances have been made in the safety and tolerability of antidepressants. More recently, clinical observation

and small clinical trials with ketamine have suggested that the N-methyl-d-aspartate (NMDA) glutamate receptor channel rep-resents a possible new target for antidepres-sants associated with more rapid onset of therapeutic ef ects (14). A second generation of antipsychotic drugs was developed on the

P S Y C H I AT R I C D R U G D I S C O V E R Y

Revolution StalledSteven E. Hyman

E-mail: seh@harvard.edu

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Drug discovery is at a near standstill for treating psychiatric disorders such as schizo-phrenia, bipolar disorder, depression, and common forms of autism. Despite high prevalence and unmet medical need, major pharmaceutical companies are deemphasiz-ing or exiting psychiatry, thus removing signif cant capacity from ef orts to discover new medicines. In this Commentary, I develop a view of what has gone wrong scientif cally and ask what can be done to address this parlous situation.

Fig. 1. Terrible thing to waste. Pharma has removed psychiatric diseases from its body of drug discovery projects. Geneticists might help reverse the trend. [The Pilgrim by René Magritte. 1966]

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basis of a subset of the receptor-binding prop-erties of clozapine. As a result, the second-generation drugs cause fewer motor side ef ects than do the f rst-generation drugs but exhibit their own serious side ef ects—typically, signif cant weight gain and meta-bolic derangements such as elevated serum levels of glucose and lipids. In the main, the second-generation drugs are not more ef ca-cious than the f rst-generation ones (15), and none is as ef cacious as clozapine.

HOSTAGE IMAGINATIONT e astonishing series of discoveries be-tween 1949 and 1957 was a great blessing for psychiatric patients, who had previously lacked ef ective treatments, and helped move psychiatry from its focus on a disem-bodied psyche to biological models of dis-ease and pharmacological interventions. By capturing the imagination of researchers to excess, however, and in the absence of other robust biological tools to probe brain func-tion, these drugs may have proved some-thing of a scientif c curse. Although it was recognized that disease mechanisms could not simply be inferred from drug action, the newly discovered drugs of the 1950s and 1960s exerted a powerful inf uence over the development of animal models, biochemi-

cal and genetic hypotheses, and approaches to psychiatric diagnosis that continues to this day.

T e newly discovered antidepressants, antipsychotic drugs, and benzodiazepines were used to develop animal-based screens, with the goal of identifying new drug can-didates. It was recognized that screens based on existing drugs might fail to identify new therapeutic mechanisms, and unfortunately this risk has been fully borne out (16). More troubling, these screens occasionally became imposters for disease models in the academ-ic literature as well as in industry, despite scant corroborative evidence. In the widely used forced-swim and tail-suspension tests, for example, a compound is considered to be an antidepressant when, compared with a control, it causes a rat or mouse to con-tinue swimming or actively struggling lon-ger. Forced-swim and tail-suspension tests do not even model the therapeutic action of antidepressants, because in these rodent screens, a single dose of antidepressant is active, whereas in depressed patients, anti-depressant drugs require weeks of admin-istration to exert a therapeutic ef ect. T ese screens may have taken on plausibility as de-pression models because of their theoretical relationship to learned helplessness, a phe-

nomenon considered by some as a possible cause of depression. In learned helplessness paradigms, an organism subjected to loss of control over circumstances subsequently tolerates aversive conditions that could have been avoided (17). For example, forced-swim and tail-suspension tests have become commonly used methods for classifying la-boriously developed transgenic mice and other animals as having “depression-like” or “antidepressant-like” phenotypes. T ere is, in fact, only a tenuous connection between human depression and these rodent assays, which perhaps predictably have not yielded durable mechanistic insights or novel thera-peutic agents.

Pharmacological therapeutics inf u-enced much other translational research, as exemplif ed by the selection of biologi-cal candidates for genetic association stud-ies. A PubMed search using the terms “serotonin transporter polymorphism de-pression” yielded 715 papers (18), and a less-constrained search on the “serotonin trans-porter polymorphism” yielded 1943 papers (18). T is is an extraordinary deployment of human capital and scarce research funds on a very large number of studies, many under-powered and all focused on the known tar-get of moderately ef ective drugs. Despite the resource investment, this research has not substantially clarif ed the pathogenesis or pathophysiology of depression or other phe-notypes characterized by negative af ectivity, or the complex and interesting actions of se-rotonin in the human brain. A recent mega-analysis of genome-wide association studies in human subjects suf ering from depression failed to conf rm an association with sero-tonin transporter polymorphisms (19).

Although these examples do not do jus-tice to the breadth of translational research in psychiatry, which includes much cognitive neuroscience and brain imaging unrelated to monoamine pharmacology, they do dem-onstrate the power and pitfalls of what Kuhn (20) described as scientif c paradigms that sustain the practice of “ordinary science” and that resist fundamental questioning.

MIND, THE GAPIn the period from 1993 to 2004, only 8% of central nervous system (CNS) drug can-didates that reached the stage of initial hu-man testing (phase 1) eventually achieved regulatory approval (21). Failures occurred occasionally because a signi% cant toxic-ity emerged in late-stage clinical trials but more commonly because of an inability to

Table 1. Sale of psychiatric drugs (2010). In addition, a large fraction of prescriptions for anticon-vulsants are written for patients with bipolar disorder and impulse-control disorders.

Drug class/indication Global sales

Antipsychotic drugs $22 billion

Antidepressant drugs $20 billion

Antianxiety drugs $11 billion

Stimulants $5.5 billion

Dementia $5.5 billion

Sleep disorders $4.5 billion

Substance use and addictive disorders

$3 billion

*Although much research favors GSK3β (glycogen synthase kinase β) as the relevant target of Li+, the drug’s mechanism of action remains uncertain.

Table 2. Major classes of drugs developed to treat psychiatric disorders. NE, norepineph-rine; 5-HT, 5-hydroxytryptamine (serotonin); GABA, γ-aminobutyric acid.

Drug class Prototype compound Molecular target(s)

Mood stabilizer Lithium (Li+) GSK3β, inositol 1-phosphatase*

Antipsychotic drugs Chlorpromazine Dopamine D2 receptor

Antidepressants Iproniazid, Imipramine Monoamine oxidase, NE, and 5-HT transporters

Benzodiazepine receptor agonists Chlordiazepoxide GABAA receptor, benzodiaz-epine site

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C O M M E N TA R Y “ ”demonstrate ef cacy. More recently, Euro-pean regulators have begun to demand ei-ther improvement in ef cacy over existing drugs or biomarkers that identify patient subgroups for whom a new drug would be advantageous. Perhaps understandably, many pharmaceutical companies have de-cided that the science to achieve these goals is lacking and that, for the time being, re-sources could be more productively spent on other disease areas.

T e central problem is clear: Neither vast unmet medical need, nor large and grow-ing markets, nor concerted sales campaigns that attempt to recast “me-too drugs” as in-novative (22) can illuminate a path across very dif cult scienti% c terrain. Compared with other areas of translational medicine, psychiatry % nds itself with few, if any, vali-dated molecular targets. Indeed, short of a proof-of-concept clinical trial, it is not easy to de% ne criteria for molecular target vali-dation for polygenic human brain disorders. As noted above, current animal-based as-says have failed to identify ef cacious drugs with new molecular mechanisms, and given scant understanding of the pathophysiology of common psychiatric disorders, it is dif -cult to develop better models. Furthermore, objective diagnostic tests and treatment-responsive biomarkers are lacking. Without the latter, clinical trials of psychiatric treat-ments are dependent on disease de% nitions grounded in the descriptive psychiatry of the 1960s and 1970s (23) as well as on sub-jective rating scales that are unsatisfactory for conditions in which symptoms wax and wane over time and change with context.

T e best-recognized obstacles to ef ec-tive clinical translation in psychiatry in-clude the complexity of the brain and the associated challenge of connecting levels of analysis from molecules to cells, synapses, circuits, and thence to higher cognition, emotion regulation, and executive function. T e relative uniqueness of the human brain creates high hurdles for development of ani-mal models. Anatomically, much of the neu-ral circuitry involved in psychiatric symp-toms—for example, that of the prefrontal cerebral cortex—is new or vastly expanded in humans, and gene expression patterns in the human cerebral cortex also appear to be newly evolved, even compared with nonhu-man primates (24). T at said, for neural cir-cuits that are conserved in evolution—those involved in basic emotions such as fear and reward as well as some basic cognitive func-tions—rodents and other organisms can po-

tentially provide useful preclinical models (16, 25). Transgenic mice constructed with highly penetrant genetic variants that cause rare monogenic disorders have also proven informative (26), and in the case of fragile X syndrome they have predicted drug ef cacy against a subset of symptoms (27). How-ever, most psychiatric disorders are highly heterogeneous and polygenic (28), casting doubt about the utility of existing genetic mouse models. Overall, industry has come to the justi% able view that with few excep-tions, valid disease models do not exist for psychiatric disorders.

Unfortunately, the need for models is greater in psychiatry than in other areas of medicine because the human brain is gen-erally inaccessible to direct study. In other % elds, diseased tissue is of en removed by biopsy or resection and made available for study (for example, analysis of somatic mu-tations or transcriptomes) or for generation of cell lines. In contrast, removal of brain tis-sue is generally reserved for brain tumor and epilepsy surgeries and would not necessarily reveal mechanisms of psychiatric diseases that, far from being cell autonomous, ref ect abnormal functioning of widely distributed circuits. T us, most human brain studies are perforce limited to indirect methods such as electroencephalography and nonin-vasive neuroimaging. T ese are substantial challenges, but it is still important to ask whether useful lessons can be learned from recent research history and whether new tools, ideas, and forms of organization that are emerging in neuroscience, and in the life sciences more broadly, can help revitalize translational psychiatry.

REFOCUSING TRANSLATIONAL PSYCHIATRYT e exit of the pharmaceutical industry from psychiatry, even in the face of substan-tial markets, underscores the dif culty of brain research but, more importantly, draws attention to the limitations of translational paradigms of the past several decades. It is time to eschew models and tools that have progressively shown themselves to be un-successful. It is time to look beyond patho-physiological hypotheses derived from small, disconnected islands of data that we had the good fortune to acquire. Given the radical incompleteness of our knowl-edge of the molecular and cellular bases of psychiatric illness, large-scale, unbiased (hypothesis-free) approaches to data collec-tion and analysis should prove to be criti-

cal platforms for new, ef ective hypothesis generation. For such approaches to achieve the scale and scope that will be necessary to understand heterogeneous, polygenic disor-ders of the human brain, they will require broad collaboration and sharing of tools, specimens, and data. Given the uniqueness of the human brain, such approaches must be complemented by tool building that will advance human experimental neurobiology.

Fortunately, this is a time in the life sci-ences—and in neuroscience more particu-larly—when new tools, new ideas, and new kinds of scienti% c organization (based on collaboration) can help revitalize transla-tional psychiatry. For example, the cost of DNA sequencing has declined by ~1 mil-lion–fold over the past decade, making it feasible to study the large number of sub-jects necessary to discover the genetic ar-chitecture of heterogeneous, polygenic dis-orders (28). Human neurons can be derived from readily obtainable skin % broblasts or blood cells, and these systems are begin-ning to show promise as disease models that should prove amenable to high-throughput biological and chemical interrogation. At the level of basic neurobiology, optogenet-ics has given neuroscientists the ability to activate or inhibit single cell types and, thus, selected circuits with remarkable speci% city and temporal control (29). T is technol-ogy complements and will likely inform advances in human neurobiology, including various modalities of neuroimaging, and may also help explicate clinical responses to interventions such as deep brain stimula-tion (4). Studies of structural and functional connectivity may also complement genet-ics in facilitating diagnostic reform and the identi% cation of biomarkers.

To date, the most advanced large-scale, unbiased investigations of psychiatric dis-orders lie in genetics. Given the heteroge-neity of psychiatric illnesses and the very large number of genetic variants that confer risk—common and rare, single-nucleotide variants (SNVs) and larger copy number variants (CNVs), inherited variation, and de novo mutation—success depends on di-verse (and still evolving) study designs that compare very large numbers of af ected and unaf ected human subjects. T ere is no shortage of skepticism about the ability of genetics to inform the biology of poly-genic disorders, but that bias is of en based on mistaken expectations. T e value of genome-scale genetic analyses for psychia-try, as for much of medicine, lies in the iden-

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C O M M E N TA R Y “ ”ti% cation of biochemical pathways involved in disease pathogenesis because these path-ways of er clues about what functions to tar-get for therapeutics discovery. T is research is still in its early stages and thus has not yet de% ned clear disease-related biochemi-cal pathways. Nonetheless, emerging re-sults from genome-scale genetics studies of schizophrenia and of both monogenic and complex forms of autism appear not to pin-point random loci in the genome but, rather, to suggest certain areas of neural function—for example, synaptic transmission—as pos-sible sources of disease risk (30, 31). In ad-dition to genetics, large-scale studies of gene function, epigenetics, transcriptomics, and proteomics should all contribute to a new understanding of pathogenesis as they have in other % elds of medicine. However, given the inaccessibility of the living human brain and the limitations of postmortem tissue for functional analyses, all of these follow-on studies to genetics will require the iden-ti% cation of appropriate living systems in which to conduct experiments.

Without biologically appropriate living systems (cells or organisms) that permit ro-bust and high-throughput interrogation of the functions of disease-risk alleles compared with neutral or protective alleles, recent ge-netic % ndings will yield only a fraction of their informational potential. Without ap-propriate living systems it will not be pos-sible to study epigenetic modi% cations of risk versus protective genes, changing transcrip-tional pro% les, or biochemical mechanisms relevant to psychiatric disease. I would argue that in developing or selecting relevant test systems, it is more important to be able to accurately model molecular mechanisms of disease than behavioral outputs.

As described, animal behavior can, in the right circumstances, be both informative and useful in treatment development (13, 25–27); however, excessive reliance on what is called face validity—behavior that plau-sibly models human symptoms—has of en led into blind alleys (11). Reliance on symp-tomlike behavior rather than on molecular mechanism is akin to classifying all winged animals together rather than classifying by evolutionary relationships. Although a stretch, the issue may be akin to cancer, in which the mutations within cancer cells (that is, molecular mechanisms) are proving to be more important to therapy than cell of origin. Although rodent models will remain useful for some translational investigations and, of course, for basic studies in neuro-

science, they lack many molecular (24) and circuit-based characteristics needed for mo-lecular studies of psychiatric disease. In ad-dition, the construction of transgenic mice is simply too slow and too costly to inter-rogate all of the allelic variants of interest or even functions of the genes in which they reside. Nonhuman primates may prove to be useful models in some cases but are likely to be used only rarely because of cost, less well developed technology (such as production of transgenic lines), and ethical hurdles. For initial high-throughput molecular investi-gations of the functions of the hundreds of risk alleles emerging from genetic studies, perhaps invertebrate models or zebra% sh will prove useful, albeit at the price of evolu-tionary distance.

An important set of tools for the study of molecular mechanisms comes from the abil-ity to generate neurons in vitro from human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs) derived from human skin % broblasts or the ability to derive neurons directly from human % broblasts in vitro. Although still in the early stages, this technology is being used to compare neurons from patients with neurons derived from control subjects (32). Given the cell-type speci% city of such important properties as gene expression, synaptic connectivity, and neurotransmitter and receptor utilization, the next stage of progress will require the en-gineering of neurons that approximate real, mature neural cell types relevant to patho-genesis. Although cultured neurons will nev-er be identical to those embedded in circuits in a brain, they are likely to prove informa-tive and permit high-throughput approaches. For example, genetic engineering of cultured human neurons using elements that encode functional protein domains—such as tran-scription activator–like ef ector nucleases (TALENs) (33), zinc % nger nucleases, or zinc % nger transcription factors—should facilitate mechanism-based biological analyses and high-throughput chemical biology screens aimed at the development of compounds to be used as research tools and therapeutics. T ese cultured designer neurons might also be used to engineer small, reproducible cir-cuits in vitro to study synaptic protein net-works already implicated by genetic results in autism, schizophrenia, and bipolar disorder; such circuits can then be used in chemical biology screens.

Should it be possible to reproduce dis-ease mechanisms in culture and to rescue disease phenotypes with candidate drugs,

companies and regulators would then need to muster the courage to proceed from cell-based models with compelling molecular mechanisms into early human trials without requiring the intermediate step of possibly misleading animal behavioral models.

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Acknowledgments: I thank the members and staff of the Institute of Medicine Forum on Neuroscience and Nervous System Disorders for multiple probing discussions touching on many of the topics discussed here. Funding: This work was supported by the Stanley Foundation. Competing interests: I serve on the Novartis Science Board.

Citation: S. E. Hyman, Revolution stalled. Sci. Transl. Med. 4, 155cm11 (2012).

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REFERENCES

http://stm.sciencemag.org/content/4/155/155cm11#BIBLThis article cites 28 articles, 3 of which you can access for free

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