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Molecular Psychiatry (2012) 17, 1168–1173 & 2012 Macmillan Publishers Limited All rights reserved 1359-4184/12 www.nature.com/mp

PERSPECTIVE Another view of the history of antipsychotic discovery and development

WT Carpenter Jr1 and JM Davis2

Chlorpromazine initiated effective pharmacotherapy for 60 years ago. This discovery initiated or stimulated key developments in the field of psychiatry. Nonetheless, advances in pharmacotherapy of schizophrenia have been modest. remains the primary aspect of psychopathology addressed, and core pathologies such as cognition and negative symptom remain unmet therapeutic challenges. New clinical and basic neuroscience paradigms may guide the near future and provide a more heuristic construct for novel and innovative discovery.

Molecular Psychiatry (2012) 17, 1168–1173; doi:10.1038/mp.2012.121; published online 14 August 2012 Keywords: antipsychotic ; ; history; ; schizophrenia

Efficacious therapy for persons suffering with schizophrenia and hindered the development of practical case management and related psychotic disorders was not established before the dis- supportive therapies, and created a flawed versus covery of the antipsychotic properties of chlorpromazine reported polemic. Society was sometimes viewed as causative in 1952.1 Following the remarkable success in treating and pre- of schizophrenia leading to legal efforts to impede treatment. The venting tertiary syphilis with therapy, there was reason cumulative result was trans-institutionalization that even today is to hope for substantial therapeutic advances. Electroconvulsive represented with large schizophrenia populations in jails, prisons, therapy had been introduced and appeared effective for some homeless or in forensic psychiatric settings.7 forms of schizophrenia, especially those with catatonic features Against this historical backdrop, the chance observation that and acute psychotic episodes.2 , an antihypertensive chlorpromazine induced a calming effect initiated a remarkable compound that was later determined to reduce storage and release period of efficacious therapy. In France, chlorpromazine was being of at a presynaptic level was tried with some success to tried as an anesthesia adjunct that might prevent shock or have benefit schizophrenia.3 other beneficial properties. Chosen as the least of the Before the 1950s there were other heroic attempts, often with antihistamines available at that time, it was tested in a wide severe adverse effects and without known efficacy. These have variety of patients. When tried in patients with schizophrenia, been cataloged elsewhere.4 Prefrontal had the broadest Delay8 initially reported their results at a psychiatric meeting in application and achieved a desired ‘calming’ effect but at the Luxemburg and then very quickly in a journal article in 1952 expense of vital emotional processing and motivational qualities. describing spectacular results in acutely psychotic schizophrenic As soon as ACTH and the became available to patients. The use of chlorpromazine spread very quickly administer to patients, clinicians observed beneficial effects on throughout the world. Initially it was used in a rather low many diseases, which resulted in trails to alter cortisol level in both dose, but even so in New York state hospitals, it reduced directions: of adrenalectomy, which failed to help schizophrenia, episodes of violence and days in seclusion by 90–95%. At that and cortisone administration, which was initially reported by one time, the number of state hospital beds had been rising investigator to have a beneficial effect. This was not replicated in progressively in the United States. After the introduction of subsequent open or case-controlled studies.5,6 Absence of efficacy chlorpromazine the number of beds for schizophrenia may have implication for the current interest in immunosuppres- decreased steadily. The large state hospitals, some exceeding sion and anti-inflammatory therapeutics. The asylum movement 15 000 beds, were downsized or disappeared. Clinicians noted attempted to provide more humane care, but adverse con- that in acutely psychotic patients, chlorpromazine reduced sequences of sequestration in non-therapeutic environments were excitement and some patients appeared to be recovered. associated with the long-term confinement in large institutions. Decreased emotion was associated with sustained psychotic The social psychiatry movement, initiated in England before symptoms in more chronic patients. They also noticed that the discovery of chlorpromazine, shifted clinical care closer to chlorpromazine was not very effective in dull, apathetic, patients’ natural environment, but antipsychotic drugs were to deteriorated schizophrenic patients. This early insight was lost prove invaluable to the deinstitutionalization movement. In the and only recently have negative symptoms in schizophrenia United States chronic hospital care was drastically reduced, but been identified as a separate therapeutic indication.9 Clinicians communities were inadequately prepared for the comprehensive also began to describe acute extrapyramidal side-effects, clinical and rehabilitation care and living support required. The including dystonic and dysphoric effects as well as cause of schizophrenia was sometimes conceptualized only at the and pseudoparkinsonism. Later, the significance of tardive psychological level. The belief in psychodynamic therapeutic was appreciated. The term ‘neuroleptic’ for chlorpromazine and

1Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA and 2Department of Psychiatry, University of Illinois at Chicago, Baltimore, MD, USA. Correspondence: Dr WT Carpenter, Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, PO Box 21247, Baltimore, MD 21228, USA. E-mail: [email protected] Received 13 June 2012; accepted 5 July 2012; published online 14 August 2012 Antipsychotic drug discovery and development WT Carpenter and JM Davis 1169 subsequent drugs captured both the drug, alone, neither treatment, or both, for 6 months to 1 year tranquilization and neurological effects. after which time all patients received drug. Five-year follow-up The initial conceptualization of chlorpromazine action focused found patients not receiving drugs in the first 6 months to 1 year on its so-called ‘tranquilization effect,’ antianxiety and antiag- had double the days in hospital for the next 5 years compared gressive effects. Meprobamate was introduced in 1955 and had with those receiving initial drug treatment.20 Another study antianxiety properties, but it was recognized relatively early that showed that the patients randomized to for 1 month had meprobamate was ineffective in schizophrenia. This led to the no worse outcome than those initially receiving drug, indicating conceptualization of major tranquilizers and minor tranquilizers. that brief off-medication periods did not produce lasting In the late 1960s, the term ‘antipsychotic’ was used to better morbidity.21,22 It is clear that acute treatment is efficacious and depict the behavioral effects of chlorpromazine in schizophrenic maintenance treatment substantially reduces relapse frequency. patients.10 It is also documented that periods off medication for research The history of antipsychotic drug therapy has been described can be safely and ethically conducted.23 A recent comprehen- in detail.11,12 Here, we will briefly note highlights from 1952 to sive review of placebo drug effects on course and outcome is the present with emphasis on limitations as well as advances. available.24 Two paradigm shifts to encourage discovery related to unmet 3. Scientific methodology: Historically, many treatments based on therapeutic needs in schizophrenia treatment will be presented. open trials later proved to be ineffective in controlled investiga- Following the initiation of efficacious pharmacotherapy with tions. Medicine developed the controlled randomized chlorpromazine, four developments have had a major impact on method to provide more stringent scientific testing of efficacy schizophrenia research and treatment: hypotheses. Regarding the third major advance, the clinically observed therapeutic effect of chlorpromazine raised the question 1. Determining that efficacy was based on antipsychotic rather of standard of evidence needed to provide solid science for than tranquilizing properties; therapeutic interventions in psychiatry. This was a pressing issue 2. Identifying psychotic relapse prevention efficacy; in psychiatry, in part because of the implementation of treatments 3. Establishing scientific methodology for ascertainment of such as prefrontal lobotomy without adequate knowledge of risk/ efficacy; and benefit or patient selection. The resolution of this problem 4. Initiating the field of psychopharmacology. resulted in methodology for determining efficacy and effective- ness of treatments and assessment of adverse effects. The 1. Antipsychotic rather than tranquilizer: The major tranquilizer methodologies for the random assignment, double-blind clinical construct suggested that therapeutic success was based on trial and systematic clinical assessment tools were developed calming the patient with reduction in aggression, agitation, violence along with statistical methodology. These methods were applied and anxiety. This conception suggested use in a broad range of initially for chlorpromazine, then , iproniazid, mepro- conditions where ‘minor tranquilizers’ such as meprobamate or bamate and the , and extended to the evaluation were not adequate. Recognizing that the primary of the psychosocial therapeutics. The methods then developed in effect was reduction of psychotic symptoms not secondary to psychiatry enables the field to produce evidence-based recom- anxiety reduction resulted in a more focused application in mendations on a full range of treatments25,26,27 The random schizophrenia. assignment-controlled clinical trial became and remains the gold With this shift in concept the hope of advancing knowledge of standard for efficacy. etiopathophysiology and therapeutic mechanism was initiated 4. The field of psychopharmacology: Psychopharmacology as a (see dopamine hypothesis below). The ability of chlorpromazine to discipline emerged following the introduction of chlorpromazine. reduce psychosis and agitation reinforced the view that psychosis Chlorpromazine efficacy challenged basic scientist to determine was the core of schizophrenia. This had the unfortunate effect of mechanism of action. Carlsson and Linquist28 discovered dopamine equating schizophrenia with psychosis and neglecting core signal blocking as the mechanism. This provided the basis for elements such as cognitive impairments and avolition described discovery of all compounds approved for the treatment of schiz- by Kraepelin13 and Bleuler14 and as conceptualized by ophrenia during the past 60 years. This discovery was the foundation Rado15 and Meehl.16 Although key domains of pathology within of the dopamine hypothesis of schizophrenia, a hypothesis that the schizophrenia syndrome have also been described in more remains a basis for much schizophrenia research today. recent studies,17,18 drug discovery has focused on antipsychotic Creese and Snyder29 and Seeman30 showed the remarkable efficacy and has failed to address other key domains. This problem correlation between the ability to block dopamine receptors and has recently been addressed in the NIMH MATRICS process (http:// dose used in treating persons with schizophrenia. This correlation www.matrics.ucla.edu/matrics-recommendations.shtml). is now seen using imaging measurement of 2. Relapse prevention: A prevention of relapse paradigm had not occupancy.31 However, clinical dosing was primarily determined been considered in schizophrenia therapeutics before chlorpro- by side-effect toleration and the correlation of dose with dopamine mazine. A few years after efficacy was established in clinical trials, receptor blockade was primarily related to extrapyramidal relapse prevention was tested in placebo-controlled studies of symptoms (EPS). High dose of dopamine-releasing drugs such chlorpromazine and later antipsychotic drugs. Efficacy was as or can produce a paranoid maintained over long periods of time and relapse rates were psychosis. The intraveneous administration of dopamine-releasing reduced compared with placebo. The first meta-analysis in psy- drugs to active schizophrenic patients may worsen the psychosis. chiatry and second in medicine documented a vanishingly small Recent in vivo neuroimaging studies can measure the excessive probability of a chance finding.19 Patients with schizophrenia release of dopamine with amphetamine as an aspect of relapse at about 10% per month progressively over time, so that schizophrenia pathophysiology,32,33 and dopamine dysregulation by several years virtually every patient with schizophrenia would may be involved in schizophrenia psychopathology involving have relapsed on placebo. The relapse rate on medication was emotional processing and learning.34 cut down from 10% per month on placebo to 2 or 3% per month The dopamine hypothesis raised hopes that biological mechan- (a three- or four-fold reduction), on medication. Patients who have isms in mental disorders would be discovered, and psychiatry been stable on maintenance antipsychotics as long as 5 years or shifted emphasis to biological constructs. In the United States so, still relapse at the rate (per month) as patients who have been this shift created a gulf between psychological and biological stable a few months. The NIMH funded a double-blind study constructs that has more recently matured into an integrative comparing psychodynamic psychotherapy alone, antipsychotic science.

& 2012 Macmillan Publishers Limited Molecular Psychiatry (2012), 1168 – 1173 Antipsychotic drug discovery and development WT Carpenter and JM Davis 1170 The beneficial effects of chlorpromazine and the 1948 observa- The second advance in antipsychotic drug treatment for tion of a mood-stabilizing effect of carbonate in manic- schizophrenia came with formulation that provides long-term depressive disorder by John Cade35 stimulated the field of antipsychotic efficacy when the antipsychotic drug is adminis- psychopharmacology. tered with injection. These provide advantages for medication At the time, in an effort to make a better chlorpromazine, adherence over time and provide a long period of medication imipramine was synthesized, and was observed to help schizo- coverage in patient who stops medication or has poor adherence. phrenia patients with comorbid , leading to its trial in This approach became common in many countries, but has been depressed patients, where it was found to have an substantially underutilized in the United States.36 effect. Iproniazid (the first monoamine oxidase inhibitor) was The third significant advance was the introduction of used in and observed to benefit depression. These in the early 1970s.37 Initial use was limited because of drugs were explored in the laboratory, leading to understanding . But clinicians experienced with the drug the neurochemical mechanisms (amine transporters and metabo- believed that it was more effective than other antipsychotic lism). The discovery that selective reuptake inhibitor had agents. Controlled studies supported this observation. However, efficacy for panic attacks, obsessive compulsive disorder, social to market in the United States, the food and drug administration phobia and other disorders contributed to the delineation of these (FDA) required a very rigorous study to approve a drug with diagnostic entities, There were initial studies showing chlorpro- potential for fatal agranulocytosis. Clozapine Study #30 met this mazine to be useful in both depression and . But when requirement, documenting clozapine as superior to chlorpromazine lithium became the primary treatment for the in severely treatment-resistant cases.38 The fact that clozapine did field tended to conceptualize a disorder class for each . not increase levels or induce EPS reinforced the view of Interest in differential diagnosis increased, especially in the United uniqueness and a non-trivial advance in pharmacotherapy of States where psychodynamic formulations often took priority over schizophrenia. Clinical use broadened with evidence that diagnostic classification. Although not validated in clinical trials, agranulocytosis risk was managed and that the superior efficacy the view that drugs were specific for disorders became influential. extended to partial responders.39 Superiority for violence and Antipsychotics are for schizophrenia, lithium for bipolar, suicide have also been documented.40,41 Clozapine has a wide and monoamine oxidase inhibitors for depression, range of receptor effects including action at several serotonin specific serotonin reuptake inhibitors for depression and other receptors, and has less sustained occupancy of dopamine receptors, disorders was presumed, and pathways for regulatory approval but the basis for superior action is not yet determined. It is still the continue to follow this paradigm today. Psychotropic drugs do only antipsychotic drug approved for superiority. The hope for have some diagnostic specificity. For example, benzodiazepines efficacy on primary negative symptoms and impaired cognition do not have antipsychotic properties and lithium and the mood has not been established. stabilizers are not very effective in schizophrenia. The alternate The fourth advance is modest and complicated. Following view, that some psychopathologies cut across diagnostic bound- clozapine, a number of new drugs (second-generation agents) aries and are more valid targets for therapeutic discovery is have been approved for the treatment of schizophrenia. It was discussed below. hoped that combining serotonin and dopamine antagonism The field of psychopharmacology grew rapidly following the would provide superiority to first-generation agents. Whether this discovery of chlorpromazine for schizophrenia and was formalized has been accomplished is debated and no regulatory body has in professional societies such as the American College of approved a superiority claim. In head to head competition, that celebrated its 50th birthday in clozapine appears superior to other second-generation agents.42 2011. It is difficult to overstate the importance of discovering a drug When compared with first-generation agents, the data are mixed with efficacy for psychosis, providing clinicians with a method to and provide some support for modest advantage in efficacy for sustain symptom improvement and reduce subsequent exacer- only a few of the second-generation agents.43 Using time on drug bations and psychotic relapse, the development of scientific as a proxy for effectiveness, has an advantage over methods now broadly applied in drug discovery and evaluation, other drugs in the clinical antipsychotic trials of intervention and the initiation of a scientific field dedicated to basic, clinical effectiveness (CATIE) study and in time to relapse and duration of and translational research on the of brain disorders. good response, but did not show advantages on some other measures.42 The other second-generation antipsychotic (SGA) used in this trial were not more efficacious than the first- SOME OTHER SIGNIFICANT ADVANCES FOLLOWING generation drugs. CATIE, cost utility of the latest antipsychotic CHLORPROMAZINE drugs in schizophrenia study and the treatment of early onset In the 60 years following the introduction of antipsychotic drug schizophrenia spectrum disorders studies found the SGA not therapy, advances have been modest. Preparation of antipsychotic to be cost-effective.42,44,45,46 These efficacy differences are con- drugs for intramuscular administration enhanced emergency troversial but there is good agreement that clozapine is more treatment. A number of new compounds have been approved effective e than all the other SGA. for schizophrenia. All are antipsychotic rather than antischizo- Keeping in mind that generalizations about first- and SGA drugs phrenia and all share the dopamine D2 receptor mechanism of do not apply evenly across individual compounds, a broader view action. It is not surprising that gains in efficacy are minimal. of clinically relevant effects suggest the following: Increased potency of the D2 antagonism (for example, haloper- idol) and increased dosing increase risk for , EPS and  Second-generation agents are associated with less EPS than without improving efficacy. The increased first-generation agents and a lower liability for tardive variability in profiles emerged over time. With dyskinesia. However, this advantage is minimized when first- similar efficacy and dissimilar adverse effects, clinicians now can generation agents are used in low to moderate doses and when give emphasis to adverse side-effects in making informed drug agents are coadministered. selection for each individual. This has become particularly  The atypical profile is defined by low EPS at therapeutic levels. important in the past 20 years as some second-generation drugs The serotonin antagonistic property appears important in this are more benign for neuroleptic effects but more severe for regard, but is not required for this profile as demonstrated by metabolic effects. Also, reduced dosing improves safety for some the atypical second-generation drug ,44 and by drugs and some compounds have relatively benign adverse moderate dosing of low-potency first-generation drugs, which effects across the range. have other side-effects such as sedation or or in the

Molecular Psychiatry (2012), 1168 – 1173 & 2012 Macmillan Publishers Limited Antipsychotic drug discovery and development WT Carpenter and JM Davis 1171 case of sudden cardiac and avoiding high- standing debate concerning the most heuristic concept for potency drugs such as .42,44,46 schizophrenia. It can be regarded as a single disease entity, but  Many, but not all, second-generation drugs have important the weakness of this paradigm is seen in the few and weak adverse metabolic effects. Clozapine and olanzapine are most findings from large cohort genomewide association studies severe in this regard, but and also have and failure to replicate many candidate genes.50 An alterna- an adverse metabolic effect. Increase in weight, body mass tive is to deconstruct the syndrome17,18,51 into psycho- index and biochemical risk substances such as cholesterol pathology domains. In this framework, discovery pathways and triglycerides are often very substantial. Schizophrenia is would be developed for discrete symptom complexes. With associated with an average loss of about 25 years of life recent emphasis on the poor functional outcomes being expectancy probably based on life-style factors and risk innate associated with impaired cognition and negative symptoms, to the disorder. But adding adverse metabolic effects in this these two domains have been identified as leading unmet population raises concerns for what is already a public health therapeutic needs in schizophrenia.9,52,53 In this regard, the field crisis. is only now coming to grips with the challenge of creating  The wide range of adverse effects and extensive similarity in preclinical models useful in early testing of compounds for efficacy challenge clinicians to focus on side-effect profiles and these indications. Thus far predictive validity for efficacy in the matching individual patients to the agent most compatible with human condition has not been established for preclinical their general health and well-being. models of cognition or negative symptoms. This discourages  Although most atypical or SGAs are not more efficacious than investment in drug discovery for these domains of pathology. the classical typical antipsychotics, amisulpride, risperidone and olanzapine appear to fall somewhat between the efficacy induced by clozapine and efficacy of most other antipsychotic drugs. We do not know if this difference becomes more manifest over a patient’s lifetime, but exacerbation rates appear DRUG DEVELOPMENT IN THE NEAR FUTURE to be reduced. As these compounds cause an increase in The distant future cannot be predicted with confidence, but metabolic risk factors, a long-term view must also consider the changes presently underway will effect drug development in the risk of , and diabetes. The clinician near future. First of all is the influence of a paradigm shift that must balance risk and benefit applying imperfect group data to addresses the heterogeneous syndrome nature of current disorder the individual he or she is treating. A final paradox is that the classification. There is insufficient knowledge to dramatically most beneficial drug for partial responders, clozapine, also has change the diagnostic/categorical landscape for disorders asso- the most robust adverse metabolic effects. Doctors and patients ciated with psychosis. Hence, DSM5 will have roughly the same often have quite different values relating to pharmacotherapy disorders and similar criteria for classification as present in DSM-IV and the physician must be respectful of the patient’s view and ICD-9. However, the psychosis work group (William T and wishes. Carpenter chairs the psychosis work group) is testing a set of dimensions intended to capture the key domains of pathology associated with psychotic disorders, domains that represent the CRITIQUE OF DRUG DEVELOPMENT FOR SCHIZOPHRENIA clinical therapeutic targets for clinicians. In addition to diagnostic The introduction of chlorpromazine for the treatment of schizo- class, each patient would be assessed for depression, mania, phrenia was the most important advance in treatment of psychosis reality distortion, negative symptoms, cognition impairment, as antibiotic therapy led to the cure and prevention of syphilis. It is psychomotor abnormalities and disorganization of thought. disappointing now, 60 years later, to realize the minimal progress (http://www.dsm5.org/Pages/Default.aspx) Each domain may and relative absence of innovation and discovery. The FDA has not represent an independent target for drug discovery. The FDA approved a drug with a novel mechanism for schizophrenia since has already recognized efficacy for violence and suicide preven- chlorpromazine. Clozapine is the only drug that would be judged tion, and have indicated that cognition and negative psycho- a significant advance in efficacy. Reasons for lack of progress have pathology domains are candidates for indications within been detailed elsewhere47,48,49 and roughly parallels the modest schizophrenia. As noted above, the FDA is willing to consider advances in antidepressant treatment since the introduction of psychopathology domains as therapeutic indications. This may imipramine, and bipolar disorder since lithium was introduced. move drug development to the symptom complex level rather Briefly noted, reasons for slow progress include: than the syndrome level. It will help the clinician focus on the specific therapeutic needs of each patient without presuming that  Schizophrenia is a heterogeneous syndrome and the precise a syndrome diagnosis provides adequate guidance. molecular pathology is not established for any disease entity The second shift in this new paradigm is represented by the within the syndrome. Drug discovery in this circumstance is National Institute of Mental Health Research Domain Criteria either serendipitous, based on hypotheses, or based on models initiative. Here, deconstruction is taken a step further and overlap that work for already established drugs creating a ‘me-too’ of pathologies across diagnostic boundaries is explicit. The developmental path. program encourages conceptualizing clinical psychopathology at  The market for antipsychotic drugs grew rapidly in price and specific behavioral levels, levels that are understood at the neural number of prescriptions with the advent of SGA. Developmental circuit level. With the aim to develop knowledge of pathophysiol- methods for antipsychotic efficacy based on dopamine ogy at the neural circuit level, the behavior and neural circuit antagonism were well established. The incentive for producing replace the diagnostic syndrome as the independent variable in and marketing these compounds was strong, but the result is a research. It is presumed that developing knowledge at the series of ‘me-too’ new products. genetic, molecular, cellular, network level will be facilitated within  Developing treatment for schizophrenia has been misconcep- this framework. Anhedonia, for example, may be associated with a tualized. What has been developed is treatment for psychosis positive valence behavioral construct in a number of different and efficacy is for this aspect of schizophrenia and other core disorders. Anhedonia as a behavior with valid assessment tools features have been neglected. Antipsychotics are effective for provides a sharper target for investigation and can be related to psychosis in disorders other than schizophrenia. So these components of a neural network. Acquisition of new knowledge compounds are neither specific for schizophrenia or broad in on pathophysiology at the neural circuit level will be enhanced addressing core pathologies of the syndrome. There is a long- when molecular-, genetic-, and cellular-level investigations relate

& 2012 Macmillan Publishers Limited Molecular Psychiatry (2012), 1168 – 1173 Antipsychotic drug discovery and development WT Carpenter and JM Davis 1172 to behavioral constructs that have known relationships with 20 May Philip RA. Treatment of Schizophrenia: A comparative study of five treatment neural circuits and cut across boundaries in our present diagnostic methods. 1st edn (Science House, New York, 1968). classes.54,55 21 Carpenter WT, Schooler NR, Kane JM. The rationale and ethics of medication-free research in schizophrenia. Arch Gen Psychiatry 1997; 54: 401–407. 22 Carpenter WT. The risk of medication-free research. Schizophr Bull 1997; 23: CONCLUSION 11–18. 23 Carpenter WT, Appelbaum PS, Levine RJ. The declaration of Helsinki and clinical The introduction of chlorpromazine 60 years ago has had a trials: a focus on placebo-controlled trials in schizophrenia. Am J Psychiatry 2003; profound beneficial effect on treatment of psychosis and initiated 160: 356–362. the field of psychopharmacology. There has been important, but 24 Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G et al. Antipsychotic modest progress since. High profits associated with ‘me-too’ drugs versus placebo for relapse prevention in schizophrenia: a systematic review antipsychotics has had a negative impact on novel treatment and meta-analysis. Lancet 2012; 379: 2063–2071. discovery. Progress in the near future will be enhanced with clarity 25 Dixon LB, Dickerson F, Bellack AS, Bennett M, Dickinson D, Goldberg RW et al. on the limitations of current antipsychotic drugs and a paradigm The 2009 schizophrenia PORT psychosocial treatment recommendations and shift away from schizophrenia as a syndrome and towards summary statements. Schizophr Bull 2010; 36: 48–70. 26 Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA et al. The domains of psychopathology providing new clinical targets for 2009 schizophrenia PORT psychopharmacological treatment recommendations development. A further shift to a paradigm linking behavioral con- and summary statements. Schizophr Bull 2010; 36: 71–93. structs to neural circuits may address across disorder pathologies 27 Kreyenbuhl J, Buchanan RW, Dickerson FB, Dixon LB. The Schizophrenia Patient enhancing fundamental discovery of pathophysiology. How the Outcomes Research Team (PORT): updated treatment recommendations 2009. field will eventually identify molecular targets for the rational Schizophr Bull 2010; 36: 94–103. development of novel treatments is unknown, but the paradigm 28 Carlsson A, Lindqvist M. Effect of chlorpromazine or haloperidol on formation shifts are promising next steps and may accelerate progress. of 3methoxytramine and normetanephrine in mouse brain. Acta Pharmacol Tox- icol 1963; 20: 140–144. 29 Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical CONFLICT OF INTEREST and pharmacological potencies of antischizophrenic drugs. Science 1976; 192: 481–483. During the past 12 months, Dr Carpenter has attended an advisory board meeting 30 Seeman P, Lee T. Antipsychotic drugs: direct correlation between clinical (Shire, 2011; Genentech, 2012) or conference call (Astra Zeneca, 2011) relating to potency and presynaptic action on dopamine neurons. Science 1975; 188: psychopharmacology of schizophrenia. Dr Davis has no conflict of interest to report. 1217–1219. 31 Kapur S, Zipursky R, Jones C, Remington G, Houle S. Relationship between dopamine D2 occupancy, clinical response, and side effects: A Double-Blind PET REFERENCES Study of First-Episode Schizophrenia. Am J Psychiatry 2000; 157: 514–520. 1 Lopez-Munoz F, Alamo C, Cuenca E, Shen WW, Clervoy P, Rubio G. History of the 32 Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A et al. discovery and clinical introduction of chlorpromazine. Ann Clin Psychiatry 2005; Schizophrenia is associated with elevated amphetamine-induced synaptic 17: 113–135. dopamine concentrations: evidence from a novel positron emission tomography 2 Sabbatini RME. The History of Shock Therapy in Psychiatry. method. Proc Natl Acad Sci USA 1997; 94: 2569–2574. 3 Dawson DJC, Kernohan GA, Knox SJ. Reserpine in schizophrenia. Lancet 1958; 33 Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D’Souza CD, Erdos J et al. Single 272: 589. photon emission computerized tomography imaging of amphetamine-induced 4 Braslow JT. Mental Ills and Bodily Cures: Psychiatric Treatment in the First Half of the dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA Twentieth Century. University of California Press, 1997. 1996; 93: 9235–9240. 5 Rees L, King GM. Cortisone in the treatment of schizophrenia. Br J Psychiatry 1952; 34 Smith A, Li M, Becker S, Kapur S. Dopamine, prediction error and associative 98: 401–403. learning: a model-based account. Network 2006; 17: 61–84. 6 Rees L, King GM. Intensive cortisone therapy in schizophrenia. Br J Psychiatry 1956; 35 Cade JFJ. Lithium salts in the treatment of psychotic excitement. Med J Aust 1949; 102: 155–159. 2: 349–352. 7 Lamb HR, Weinberger LE. The shift of psychiatric inpatient care from hospitals to 36 Kane JM. The use of depot neuroleptics: clinical experience in the United States. jails and prisons. J Am Acad Psychiatry Law 2005; 33: 529–534. J Clin Psychiatry 1984; 45(5 Pt 2): 5–12. 8 Delay J, Deniker P. Le traitement des psychoses par une methode neurolytique 37 Hippius H. A historical perspective of clozapine. J Clin Psychiatry 1999; derivee de l’hibernotherapie. Congres des medecins alienistes et neurologistes; 60(Suppl 12): 22–23. Luxembourg; July 1952. 38 Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant 9 Kirkpatrick B, Fenton WS, Carpenter Jr WT, Marder SR. The NIMH-MATRICS con- schizophrenic. A double-blind comparision with chlorpromazine. Arch Gen sensus statement on negative symptoms. Schizophr Bull 2006; 32: 214–219. Psychiatry 1988; 45: 789–796. 10 Klein DF, Davis JM. Diagnosis and Drug Treatment of Psychiatric Disorders. Williams 39 Breier A, Buchanan RW, Kirkpatrick B, Davis OR, Irish D, Summerfelt A et al. Effects and Wilkins: Baltimore 1969. of clozapine on positive and negative symptoms in outpatients with schizo- 11 Healy D. The Creation of Psychopharmacology. Harvard University Press: phrenia. Am J Psychiatry 1994; 151: 20–26. Cambridge, MA, 2002. 40 Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A et al. International 12 Thuillier J. Ten Years that Changed the Face of Mental Illness. English edition Suicide Prevention Trial Study Group. Clozapine treatment for suicidality in approved by David Healy; translated by Gordon HickishMartin Dunitz: London; schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psy- Blackwell Science: Malden, MA 1999. chiatry, 2003; 60: 82–91Erratum in: Arch Gen Psychiatry.2003;60(7):735. 13 Kraepelin E. Praecox and Paraphrenia. Krieger: New York, 1971, [First 41 Spivak B, Mester R, Wittenberg N, Maman Z, Weizman A. Reduction of published, 1919]. aggressiveness and impulsiveness during clozapine treatment in chronic 14 Blueler E. Dementia Praecox or the Group of . International neuroleptic-resistant schizophrenic patients. Clin Neuropharmacol 1997; 20: Universities Press: New York, 1950, [First Published, 1911]. 442–446. 15 Rado S. Psychoanalysis of Behavior: The Collected Papers of Sandor Rado Vol 2. 42 Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO et al. Grune and Stratton: New York, 1962. Clinical antipsychotic trials of intervention effectiveness (CATIE) investigators. 16 Meehl PE. Primary and secondary hypohedonia. J Abnorm Psychol 2001; 110: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl 188–193. JMed2005; 353: 1209–1223. 17 Strauss JS, Carpenter Jr WT , Bartko JJ. The diagnosis and understanding of 43 Leucht S, Komossa K et al. A meta-analysis of head-to-head comparisons of schizophrenia. Part III. Speculations on the processes that underlie schizophrenic second-generation antipsychotics in the treatment of schizophrenia. Am J Psy- symptoms and signs. Schizophr Bull 1974; 11: 61–69. chiatry 2009; 166: 152–163. 18 Peralta V, Cuest MJ. How many and which are the psychopathological dimensions 44 Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP et al. Randomized in schizophrenia? Issues influencing their ascertainment. Schizophr Res 2001; 49: controlled trial of the effect on quality of life of second – vs first-generation 269–285. antipsychotic drugs in schizophrenia: cost utility of the latest antipsychotic 19 Davis JM. Overview: maintenance therapy in psychiatry: I. Schizophrenia. Am J drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63: Psychiatry 1975; 132: 1237–1245. 1079–1087.

Molecular Psychiatry (2012), 1168 – 1173 & 2012 Macmillan Publishers Limited Antipsychotic drug discovery and development WT Carpenter and JM Davis 1173 45 Davies LM, Lewis S, Jones PB, Barnes TR, Gaughran F, Hayhurst K et al. CUtLASS 50 Bergen SE, Petryshen TL. Genome-wide association studies of schizophrenia: does team. Cost-effectiveness of first- v. second-generation antipsychotic drugs: results bigger lead to better results? Curr Opin Psychiatry 2012; 25: 76–82. from a randomized controlled trial in schizophrenia responding poorly to pre- 51 Allardyce J, Gaebel W, Zielasek J, van Os J. Deconstructing Psychosis Conference vious therapy. Br J Psychiatry 2007; 191: 14–22. February 2006: the validity of schizophrenia and alternative approaches to the 46 Sikich L, Frazier JA, McClellan J, Findling RL, Vitiello B, Ritz L et al. Double-blind classification of psychosis. Schizophr Bull 2007; 33: 863–867. comparison of first-and second- generation antipsychotics in early-onset schizo- 52 Buchanan RW, Davis M, Goff D, Green MF, Keefe RS, Leon AC et al. A summary of phrenia and schizo-affective disorder: findings from the treatment of early-onset the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry 2008; 165: drugs for schizophrenia. Schizophr Bull 2005; 31: 5–19. 1420–1431. 53 Marder SR, Daniel DG, Alphs L, Awad AG, Keefe RS. Methodological issues in 47 Scolnick E. Program to improve cognitive functioning in patients with schizo- negative symptom trials. Schizophr Bull 2011; 37: 250–254. phrenia: reflections. Schizophr Res 2004; 72: 75–77. 54 Cuthbert BN, Insel TR. Toward new approaches to psychotic disorders: The NIMH. 48 Carpenter Jr. WT . Clinical constructs and therapeutic discovery. Schizophr Res Res Domain Criteria Project Schizophr Bull 2010; 36: 1061–1062. 2004; 72: 69–73. 55 Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K et al. Research Domain 49 Carpenter WT, Koenig JI. The evolution of drug development in schizophrenia: past Criteria (RDoC): toward a new classification framework for research on mental issues and future opportunities. Neuropsychopharmacology 2008; 33: 2061–2079. disorders. Am J Psychiatry 2010; 167: 748–751.

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