Chlorpromazine initiated effective pharmacotherapy for schizophrenia 60 years ago. This discovery initiated or stimulated key developments in the field of psychiatry. Nonetheless, advances in pharmacotherapy of schizophrenia have been modest. Psychosis 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.
Efficacious therapy for persons suffering with schizophrenia and related psychotic disorders was not established before the discovery of the antipsychotic properties of chlorpromazine reported in 1952.1 Following the remarkable success in treating and preventing tertiary syphilis with antibiotic therapy, there was reason to hope for substantial therapeutic advances. Electroconvulsive therapy had been introduced and appeared effective for some forms of schizophrenia, especially those with catatonic features and acute psychotic episodes.2 Reserpine, an antihypertensive compound that was later determined to reduce storage and release of dopamine at a presynaptic level was tried with some success to benefit schizophrenia.3
Before the 1950s there were other heroic attempts, often with severe adverse effects and without known efficacy. These have been cataloged elsewhere.4 Prefrontal lobotomy had the broadest application and achieved a desired ‘calming’ effect but at the expense of vital emotional processing and motivational qualities. As soon as ACTH and the corticosteroids became available to administer to patients, clinicians observed beneficial effects on many diseases, which resulted in trails to alter cortisol level in both directions: of adrenalectomy, which failed to help schizophrenia, and cortisone administration, which was initially reported by one investigator to have a beneficial effect. This was not replicated in subsequent open or case-controlled studies.5, 6 Absence of efficacy may have implication for the current interest in immunosuppression and anti-inflammatory therapeutics. The asylum movement attempted to provide more humane care, but adverse consequences of sequestration in non-therapeutic environments were associated with the long-term confinement in large institutions. The social psychiatry movement, initiated in England before the discovery of chlorpromazine, shifted clinical care closer to patients’ natural environment, but antipsychotic drugs were to prove invaluable to the deinstitutionalization movement. In the United States chronic hospital care was drastically reduced, but communities were inadequately prepared for the comprehensive clinical and rehabilitation care and living support required. The cause of schizophrenia was sometimes conceptualized only at the psychological level. The belief in psychodynamic therapeutic hindered the development of practical case management and supportive therapies, and created a flawed psychotherapy versus medication polemic. Society was sometimes viewed as causative of schizophrenia leading to legal efforts to impede treatment. The cumulative result was trans-institutionalization that even today is represented with large schizophrenia populations in jails, prisons, homeless or in forensic psychiatric settings.7
Against this historical backdrop, the chance observation that chlorpromazine induced a calming effect initiated a remarkable period of efficacious therapy. In France, chlorpromazine was being tried as an anesthesia adjunct that might prevent shock or have other beneficial properties. Chosen as the least sedative of the antihistamines available at that time, it was tested in a wide variety of patients. When tried in patients with schizophrenia, Delay8 initially reported their results at a psychiatric meeting in Luxemburg and then very quickly in a journal article in 1952 describing spectacular results in acutely psychotic schizophrenic patients. The use of chlorpromazine spread very quickly throughout the world. Initially it was used in a rather low dose, but even so in New York state hospitals, it reduced episodes of violence and days in seclusion by 90–95%. At that time, the number of state hospital beds had been rising progressively in the United States. After the introduction of chlorpromazine the number of beds for schizophrenia decreased steadily. The large state hospitals, some exceeding 15 000 beds, were downsized or disappeared. Clinicians noted that in acutely psychotic patients, chlorpromazine reduced excitement and some patients appeared to be recovered. Decreased emotion was associated with sustained psychotic symptoms in more chronic patients. They also noticed that chlorpromazine was not very effective in dull, apathetic, deteriorated schizophrenic patients. This early insight was lost and only recently have negative symptoms in schizophrenia been identified as a separate therapeutic indication.9 Clinicians also began to describe acute extrapyramidal side-effects, including dystonic and dysphoric effects as well as akathisia and pseudoparkinsonism. Later, the significance of tardive dyskinesia was appreciated. The term ‘neuroleptic’ for chlorpromazine and subsequent dopamine antagonist drugs captured both the tranquilization and neurological effects.
The initial conceptualization of chlorpromazine action focused on its so-called ‘tranquilization effect,’ antianxiety and antiaggressive effects. Meprobamate was introduced in 1955 and had antianxiety properties, but it was recognized relatively early that meprobamate was ineffective in schizophrenia. This led to the conceptualization of major tranquilizers and minor tranquilizers. In the late 1960s, the term ‘antipsychotic’ was used to better depict the behavioral effects of chlorpromazine in schizophrenic patients.10
The history of antipsychotic drug therapy has been described in detail.11, 12 Here, we will briefly note highlights from 1952 to the present with emphasis on limitations as well as advances. Two paradigm shifts to encourage discovery related to unmet therapeutic needs in schizophrenia treatment will be presented.
Following the initiation of efficacious pharmacotherapy with chlorpromazine, four developments have had a major impact on schizophrenia research and treatment:
Determining that efficacy was based on antipsychotic rather than tranquilizing properties;
Identifying psychotic relapse prevention efficacy;
Establishing scientific methodology for ascertainment of efficacy; and
Initiating the field of psychopharmacology.
1. Antipsychotic rather than tranquilizer: The major tranquilizer construct suggested that therapeutic success was based on calming the patient with reduction in aggression, agitation, violence and anxiety. This conception suggested use in a broad range of conditions where ‘minor tranquilizers’ such as meprobamate or barbiturates were not adequate. Recognizing that the primary effect was reduction of psychotic symptoms not secondary to anxiety reduction resulted in a more focused application in schizophrenia.
With this shift in concept the hope of advancing knowledge of etiopathophysiology and therapeutic mechanism was initiated (see dopamine hypothesis below). The ability of chlorpromazine to reduce psychosis and agitation reinforced the view that psychosis was the core of schizophrenia. This had the unfortunate effect of equating schizophrenia with psychosis and neglecting core elements such as cognitive impairments and avolition described by Kraepelin13 and Bleuler14 and anhedonia as conceptualized by Rado15 and Meehl.16 Although key domains of pathology within the schizophrenia syndrome have also been described in more recent studies,17, 18 drug discovery has focused on antipsychotic efficacy and has failed to address other key domains. This problem has recently been addressed in the NIMH MATRICS process (http://www.matrics.ucla.edu/matrics-recommendations.shtml).
2. Relapse prevention: A prevention of relapse paradigm had not been considered in schizophrenia therapeutics before chlorpromazine. A few years after efficacy was established in clinical trials, relapse prevention was tested in placebo-controlled studies of chlorpromazine and later antipsychotic drugs. Efficacy was maintained over long periods of time and relapse rates were reduced compared with placebo. The first meta-analysis in psychiatry and second in medicine documented a vanishingly small probability of a chance finding.19 Patients with schizophrenia relapse at about 10% per month progressively over time, so that by several years virtually every patient with schizophrenia would have relapsed on placebo. The relapse rate on medication was cut down from 10% per month on placebo to 2 or 3% per month (a three- or four-fold reduction), on medication. Patients who have been stable on maintenance antipsychotics as long as 5 years or so, still relapse at the rate (per month) as patients who have been stable a few months. The NIMH funded a double-blind study comparing psychodynamic psychotherapy alone, antipsychotic drug, alone, neither treatment, or both, for 6 months to 1 year after which time all patients received drug. Five-year follow-up found patients not receiving drugs in the first 6 months to 1 year had double the days in hospital for the next 5 years compared with those receiving initial drug treatment.20 Another study showed that the patients randomized to placebo for 1 month had no worse outcome than those initially receiving drug, indicating that brief off-medication periods did not produce lasting morbidity.21, 22 It is clear that acute treatment is efficacious and maintenance treatment substantially reduces relapse frequency. It is also documented that periods off medication for research can be safely and ethically conducted.23 A recent comprehensive review of placebo drug effects on course and outcome is available.24
3. Scientific methodology: Historically, many treatments based on open trials later proved to be ineffective in controlled investigations. Medicine developed the controlled randomized clinical trial method to provide more stringent scientific testing of efficacy hypotheses. Regarding the third major advance, the clinically observed therapeutic effect of chlorpromazine raised the question of standard of evidence needed to provide solid science for therapeutic interventions in psychiatry. This was a pressing issue in psychiatry, in part because of the implementation of treatments such as prefrontal lobotomy without adequate knowledge of risk/benefit or patient selection. The resolution of this problem resulted in methodology for determining efficacy and effectiveness of treatments and assessment of adverse effects. The methodologies for the random assignment, double-blind clinical trial and systematic clinical assessment tools were developed along with statistical methodology. These methods were applied initially for chlorpromazine, then imipramine, iproniazid, meprobamate and the benzodiazepines, and extended to the evaluation of the psychosocial therapeutics. The methods then developed in psychiatry enables the field to produce evidence-based recommendations on a full range of treatments25, 26, 27 The random assignment-controlled clinical trial became and remains the gold standard for efficacy.
4. The field of psychopharmacology: Psychopharmacology as a discipline emerged following the introduction of chlorpromazine. Chlorpromazine efficacy challenged basic scientist to determine mechanism of action. Carlsson and Linquist28 discovered dopamine signal blocking as the mechanism. This provided the basis for discovery of all compounds approved for the treatment of schizophrenia during the past 60 years. This discovery was the foundation of the dopamine hypothesis of schizophrenia, a hypothesis that remains a basis for much schizophrenia research today.
Creese and Snyder29 and Seeman30 showed the remarkable correlation between the ability to block dopamine receptors and dose used in treating persons with schizophrenia. This correlation is now seen using imaging measurement of dopamine receptor occupancy.31 However, clinical dosing was primarily determined by side-effect toleration and the correlation of dose with dopamine receptor blockade was primarily related to extrapyramidal symptoms (EPS). High dose of dopamine-releasing drugs such as amphetamine or methylphenidate can produce a paranoid psychosis. The intraveneous administration of dopamine-releasing drugs to active schizophrenic patients may worsen the psychosis. Recent in vivo neuroimaging studies can measure the excessive release of dopamine with amphetamine as an aspect of schizophrenia pathophysiology,32, 33 and dopamine dysregulation may be involved in schizophrenia psychopathology involving emotional processing and learning.34
The dopamine hypothesis raised hopes that biological mechanisms in mental disorders would be discovered, and psychiatry shifted emphasis to biological constructs. In the United States this shift created a gulf between psychological and biological constructs that has more recently matured into an integrative science.
The beneficial effects of chlorpromazine and the 1948 observation of a mood-stabilizing effect of lithium carbonate in manic-depressive disorder by John Cade35 stimulated the field of psychopharmacology.
At the time, in an effort to make a better chlorpromazine, imipramine was synthesized, and was observed to help schizophrenia patients with comorbid depression, leading to its trial in depressed patients, where it was found to have an antidepressant effect. Iproniazid (the first monoamine oxidase inhibitor) was used in tuberculosis and observed to benefit depression. These drugs were explored in the laboratory, leading to understanding the neurochemical mechanisms (amine transporters and metabolism). The discovery that selective serotonin reuptake inhibitor had efficacy for panic attacks, obsessive compulsive disorder, social phobia and other disorders contributed to the delineation of these diagnostic entities, There were initial studies showing chlorpromazine to be useful in both depression and mania. But when lithium became the primary treatment for bipolar disorder the field tended to conceptualize a disorder class for each drug class. Interest in differential diagnosis increased, especially in the United States where psychodynamic formulations often took priority over diagnostic classification. Although not validated in clinical trials, the view that drugs were specific for disorders became influential. Antipsychotics are for schizophrenia, lithium for bipolar, tricyclic antidepressants and monoamine oxidase inhibitors for depression, specific serotonin reuptake inhibitors for depression and other disorders was presumed, and pathways for regulatory approval continue to follow this paradigm today. Psychotropic drugs do have some diagnostic specificity. For example, benzodiazepines do not have antipsychotic properties and lithium and the mood stabilizers are not very effective in schizophrenia. The alternate view, that some psychopathologies cut across diagnostic boundaries and are more valid targets for therapeutic discovery is discussed below.
The field of psychopharmacology grew rapidly following the discovery of chlorpromazine for schizophrenia and was formalized in professional societies such as the American College of Neuropsychopharmacology that celebrated its 50th birthday in 2011. It is difficult to overstate the importance of discovering a drug with efficacy for psychosis, providing clinicians with a method to sustain symptom improvement and reduce subsequent exacerbations and psychotic relapse, the development of scientific methods now broadly applied in drug discovery and evaluation, and the initiation of a scientific field dedicated to basic, clinical and translational research on the pharmacology of brain disorders.
Some other significant advances following chlorpromazine
In the 60 years following the introduction of antipsychotic drug therapy, advances have been modest. Preparation of antipsychotic drugs for intramuscular administration enhanced emergency treatment. A number of new compounds have been approved for schizophrenia. All are antipsychotic rather than antischizophrenia and all share the dopamine D2 receptor mechanism of action. It is not surprising that gains in efficacy are minimal. Increased potency of the D2 antagonism (for example, haloperidol) and increased dosing increase risk for dysphoria, EPS and tardive dyskinesia without improving efficacy. The increased variability in adverse effect profiles emerged over time. With similar efficacy and dissimilar adverse effects, clinicians now can give emphasis to adverse side-effects in making informed drug selection for each individual. This has become particularly important in the past 20 years as some second-generation drugs are more benign for neuroleptic effects but more severe for metabolic effects. Also, reduced dosing improves safety for some drugs and some compounds have relatively benign adverse effects across the range.
The second advance in antipsychotic drug treatment for schizophrenia came with formulation that provides long-term antipsychotic efficacy when the antipsychotic drug is administered with injection. These provide advantages for medication adherence over time and provide a long period of medication coverage in patient who stops medication or has poor adherence. This approach became common in many countries, but has been substantially underutilized in the United States.36
The third significant advance was the introduction of clozapine in the early 1970s.37 Initial use was limited because of agranulocytosis. But clinicians experienced with the drug believed that it was more effective than other antipsychotic agents. Controlled studies supported this observation. However, to market in the United States, the food and drug administration (FDA) required a very rigorous study to approve a drug with potential for fatal agranulocytosis. Clozapine Study #30 met this requirement, documenting clozapine as superior to chlorpromazine in severely treatment-resistant cases.38 The fact that clozapine did not increase prolactin levels or induce EPS reinforced the view of uniqueness and a non-trivial advance in pharmacotherapy of schizophrenia. Clinical use broadened with evidence that agranulocytosis risk was managed and that the superior efficacy extended to partial responders.39 Superiority for violence and suicide have also been documented.40, 41 Clozapine has a wide range of receptor effects including action at several serotonin receptors, and has less sustained occupancy of dopamine receptors, but the basis for superior action is not yet determined. It is still the only antipsychotic drug approved for superiority. The hope for efficacy on primary negative symptoms and impaired cognition has not been established.
The fourth advance is modest and complicated. Following clozapine, a number of new drugs (second-generation agents) have been approved for the treatment of schizophrenia. It was hoped that combining serotonin and dopamine antagonism would provide superiority to first-generation agents. Whether this has been accomplished is debated and no regulatory body has approved a superiority claim. In head to head competition, clozapine appears superior to other second-generation agents.42 When compared with first-generation agents, the data are mixed and provide some support for modest advantage in efficacy for only a few of the second-generation agents.43 Using time on drug as a proxy for effectiveness, olanzapine has an advantage over other drugs in the clinical antipsychotic trials of intervention effectiveness (CATIE) study and in time to relapse and duration of 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-generation drugs. CATIE, cost utility of the latest antipsychotic drugs in schizophrenia study and the treatment of early onset schizophrenia spectrum disorders studies found the SGA not to be cost-effective.42, 44, 45, 46 These efficacy differences are controversial but there is good agreement that clozapine is more effective e than all the other SGA.
Keeping in mind that generalizations about first- and SGA drugs do not apply evenly across individual compounds, a broader view of clinically relevant effects suggest the following:
Second-generation agents are associated with less EPS than first-generation agents and a lower liability for tardive dyskinesia. However, this advantage is minimized when first-generation agents are used in low to moderate doses and when anticholinergic agents are coadministered.
The atypical profile is defined by low EPS at therapeutic levels. The serotonin antagonistic property appears important in this regard, but is not required for this profile as demonstrated by the atypical second-generation drug amisulpride,44 and by moderate dosing of low-potency first-generation drugs, which have other side-effects such as sedation or weight gain or in the case of thioridazine sudden cardiac death and avoiding high-potency drugs such as haloperidol.42, 44, 46
Many, but not all, second-generation drugs have important adverse metabolic effects. Clozapine and olanzapine are most severe in this regard, but risperidone and quetiapine also have an adverse metabolic effect. Increase in weight, body mass index and biochemical risk substances such as cholesterol and triglycerides are often very substantial. Schizophrenia is associated with an average loss of about 25 years of life expectancy probably based on life-style factors and risk innate to the disorder. But adding adverse metabolic effects in this population raises concerns for what is already a public health crisis.
The wide range of adverse effects and extensive similarity in efficacy challenge clinicians to focus on side-effect profiles and matching individual patients to the agent most compatible with their general health and well-being.
Although most atypical or SGAs are not more efficacious than 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 to be reduced. As these compounds cause an increase in metabolic risk factors, a long-term view must also consider the risk of cardiovascular disease, stroke and diabetes. The clinician must balance risk and benefit applying imperfect group data to the individual he or she is treating. A final paradox is that the most beneficial drug for partial responders, clozapine, also has the most robust adverse metabolic effects. Doctors and patients often have quite different values relating to pharmacotherapy and the physician must be respectful of the patient’s view and wishes.
Critique of drug development for schizophrenia
The introduction of chlorpromazine for the treatment of schizophrenia was the most important advance in treatment of psychosis as antibiotic therapy led to the cure and prevention of syphilis. It is disappointing now, 60 years later, to realize the minimal progress and relative absence of innovation and discovery. The FDA has not approved a drug with a novel mechanism for schizophrenia since chlorpromazine. Clozapine is the only drug that would be judged a significant advance in efficacy. Reasons for lack of progress have been detailed elsewhere47, 48, 49 and roughly parallels the modest advances in antidepressant treatment since the introduction of imipramine, and bipolar disorder since lithium was introduced. Briefly noted, reasons for slow progress include:
Schizophrenia is a heterogeneous syndrome and the precise molecular pathology is not established for any disease entity within the syndrome. Drug discovery in this circumstance is either serendipitous, based on hypotheses, or based on models that work for already established drugs creating a ‘me-too’ developmental path.
The market for antipsychotic drugs grew rapidly in price and number of prescriptions with the advent of SGA. Developmental methods for antipsychotic efficacy based on dopamine antagonism were well established. The incentive for producing and marketing these compounds was strong, but the result is a series of ‘me-too’ new products.
Developing treatment for schizophrenia has been misconceptualized. What has been developed is treatment for psychosis and efficacy is for this aspect of schizophrenia and other core features have been neglected. Antipsychotics are effective for psychosis in disorders other than schizophrenia. So these compounds are neither specific for schizophrenia or broad in addressing core pathologies of the syndrome. There is a long-standing debate concerning the most heuristic concept for schizophrenia. It can be regarded as a single disease entity, but the weakness of this paradigm is seen in the few and weak findings from large cohort genomewide association studies and failure to replicate many candidate genes.50 An alternative is to deconstruct the syndrome17, 18, 51 into psychopathology domains. In this framework, discovery pathways would be developed for discrete symptom complexes. With recent emphasis on the poor functional outcomes being associated with impaired cognition and negative symptoms, these two domains have been identified as leading unmet therapeutic needs in schizophrenia.9, 52, 53 In this regard, the field is only now coming to grips with the challenge of creating preclinical models useful in early testing of compounds for these indications. Thus far predictive validity for efficacy in the human condition has not been established for preclinical models of cognition or negative symptoms. This discourages investment in drug discovery for these domains of pathology.
Drug development in the near future
The distant future cannot be predicted with confidence, but changes presently underway will effect drug development in the near future. First of all is the influence of a paradigm shift that addresses the heterogeneous syndrome nature of current disorder classification. There is insufficient knowledge to dramatically change the diagnostic/categorical landscape for disorders associated with psychosis. Hence, DSM5 will have roughly the same disorders and similar criteria for classification as present in DSM-IV and ICD-9. However, the psychosis work group (William T 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 clinical therapeutic targets for clinicians. In addition to diagnostic class, each patient would be assessed for depression, mania, reality distortion, negative symptoms, cognition impairment, psychomotor abnormalities and disorganization of thought. (http://www.dsm5.org/Pages/Default.aspx) Each domain may represent an independent target for drug discovery. The FDA has already recognized efficacy for violence and suicide prevention, and have indicated that cognition and negative psychopathology domains are candidates for indications within schizophrenia. As noted above, the FDA is willing to consider psychopathology domains as therapeutic indications. This may move drug development to the symptom complex level rather than the syndrome level. It will help the clinician focus on the specific therapeutic needs of each patient without presuming that a syndrome diagnosis provides adequate guidance.
The second shift in this new paradigm is represented by the National Institute of Mental Health Research Domain Criteria initiative. Here, deconstruction is taken a step further and overlap of pathologies across diagnostic boundaries is explicit. The program encourages conceptualizing clinical psychopathology at specific behavioral levels, levels that are understood at the neural circuit level. With the aim to develop knowledge of pathophysiology at the neural circuit level, the behavior and neural circuit replace the diagnostic syndrome as the independent variable in research. It is presumed that developing knowledge at the genetic, molecular, cellular, network level will be facilitated within this framework. Anhedonia, for example, may be associated with a positive valence behavioral construct in a number of different disorders. Anhedonia as a behavior with valid assessment tools provides a sharper target for investigation and can be related to components of a neural network. Acquisition of new knowledge on pathophysiology at the neural circuit level will be enhanced when molecular-, genetic-, and cellular-level investigations relate to behavioral constructs that have known relationships with neural circuits and cut across boundaries in our present diagnostic classes.54, 55
The introduction of chlorpromazine 60 years ago has had a profound beneficial effect on treatment of psychosis and initiated the field of psychopharmacology. There has been important, but modest progress since. High profits associated with ‘me-too’ antipsychotics has had a negative impact on novel treatment discovery. Progress in the near future will be enhanced with clarity on the limitations of current antipsychotic drugs and a paradigm shift away from schizophrenia as a syndrome and towards domains of psychopathology providing new clinical targets for development. A further shift to a paradigm linking behavioral constructs to neural circuits may address across disorder pathologies enhancing fundamental discovery of pathophysiology. How the field will eventually identify molecular targets for the rational development of novel treatments is unknown, but the paradigm shifts are promising next steps and may accelerate progress.
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During the past 12 months, Dr Carpenter has attended an advisory board meeting (Shire, 2011; Genentech, 2012) or conference call (Astra Zeneca, 2011) relating to psychopharmacology of schizophrenia. Dr Davis has no conflict of interest to report.
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Carpenter, W., Davis, J. Another view of the history of antipsychotic drug discovery and development. Mol Psychiatry 17, 1168–1173 (2012). https://doi.org/10.1038/mp.2012.121
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