Chlorpromazine, the first antipsychotic medication: history, controversy and legacy

Introduction

Chemical structure of chlorpromazine
Chemical structure of chlorpromazine

The 1950s saw several new classes of medication enter psychiatric practice including the antipsychotics.   The term ‘antipsychotic’ refers to medicines or drugs that are primarily used to treat schizophrenia and bipolar disorder, though some antipsychotics can also be helpful in treating other mental health problems including severe depression. Chlorpromazine was the first antipsychotic and was followed by a large number of other antipsychotics, many with diverse chemical structures.  However, so far, no antipsychotic has been shown to be significantly more effective than chlorpromazine in treating schizophrenia with the notable exception of clozapine.   Clozapine is more effective in treating schizophrenia in people who have not adequately responded to at least two previous antipsychotics.  Chlorpromazine is still used today, although in the UK more modern antipsychotics are prescribed far more frequently. Nevertheless, it remains on the World Health Organization list of essential medicines.  In this article, which has been written primarily for the public, we review the introduction of chlorpromazine and its legacy and consider some of the controversies that surround the use of antipsychotics.

Synthesis and early history

Jean Delay (left) and Pierre Deniker (right)
Jean Delay (left) and Pierre Deniker (right)

Chlorpromazine was synthesized in 1950 by the French pharmaceutical company Rhône-Poulenc, but was not originally planned to be a psychiatric drug.  The company was developing antihistaminergic drugs for use in a range of conditions including nausea and allergies.  A French surgeon and researcher, Henri Laborit, encouraged Rhône-Poulenc to develop an antihistamine with effects on the central nervous system as he believed this would be useful as a pre-anaesthetic agent given prior to surgery. Chlorpromazine was one of several compounds developed and was selected for assessment in humans after laboratory tests in rats confirmed its effect on the central nervous system.  Laborit observed that chlorpromazine induced calmness without sedation when given to patients prior to surgery and this led him to suggest it may be of use in psychiatry.  As a result, two psychiatrists, Jean Delay and Pierre Deniker, working at St Anne’s Hospital in Paris used chlorpromazine to treat inpatients, including people suffering with mania and schizophrenia.  They concluded that chlorpromazine was highly effective and published a series of reports, the first appearing in 1952.  They drew particular attention to the ability of chlorpromazine to control agitation and excitement.  This partly explains why these medicines were initially referred to as ‘major tranquillizers’ in the United States with the term ‘antipsychotic’ only being introduced in the 1960s.   Over the following years use of chlorpromazine in psychiatry spread and further publications appeared in the medical press.   Psychiatrists were impressed by its benefits and felt that a new era of treatment was starting.  By 1956 chlorpromazine was being widely prescribed by psychiatrists in both Europe and North America. Its rapid uptake in the United States partly reflected an extensive marketing campaign by the pharmaceutical company Smith Kline & French who owned the license.  In 1957 three key figures involved in this story (Henri Laborit, Pierre Deniker and the Canadian psychiatrist Heinz Lehmann) were jointly awarded a Lasker Award by the American Public Health Association in recognition of their work in introducing chlorpromazine as a treatment for schizophrenia.

Two advertisements for chlorpromazine (marketed as ‘Thorazine’ in the United States) that appeared in psychiatric journals in the 1950s and early 1960s
Two advertisements for chlorpromazine (marketed as ‘Thorazine’ in the United States) that appeared in psychiatric journals in the 1950s and early 1960s

The discovery of chlorpromazine’s psychiatric effects is often described as ‘serendipitous’ i.e. due to chance or good luck. However it can be seen that this is somewhat simplistic.  The discovery resulted from a series of deliberate decisions made by scientists working at Rhône-Poulenc plus accurate clinical observations made by clinicians who used the drug early on. Many drugs developed during the 1950s, in different areas of medicine, followed a similar path of discovery and introduction.  This was because knowledge of pharmacology and the mechanisms underlying many illnesses were too rudimentary to allow drugs to be designed to work on specific biological targets which is the way that most drugs are developed today.

Chlorpromazine entered clinical practice without any supporting clinical trials being conducted.  This reflected the systems for the development and regulation of medicines in the 1950s which were very different to current practice.  Today, a new drug cannot enter use and be prescribed without passing a rigorous and independent licensing process that will consider all the evidence.  To be approved a drug will need clinical trial data that show that it is safe, effective and compares favourably to existing treatments.  

Effectiveness in schizophrenia

The first large scale clinical trials of chlorpromazine, and other antipsychotic drugs, were conducted in the United States in the early 1960s.  These showed that antipsychotics were effective in treating a wide range of symptoms in schizophrenia.  Since then over two hundred clinical trials of antipsychotics in schizophrenia have been published.  Taken together they show that antipsychotics lead to a greater improvement in the symptoms of schizophrenia than treatment with a placebo i.e. a dummy tablet.   Longer trials, some lasting a year or more, have shown that continuing antipsychotic treatment after a person with schizophrenia has responded to the medication, as opposed to stopping treatment at that point, more than halves the risk of relapse and re-admission to hospital.  This is important, as approximately 80% of people who experience an initial episode of schizophrenia, or a related psychotic disorder, and recover will go on to experience one or more further episode of psychosis over the next 5 years.  It is important to also consider sources of evidence other than clinical trials.   These include studies that are more representative of ‘real world’ practice, so called observational studies.  Most observational studies also support the benefit of continuing antipsychotic treatment in reducing the risk of relapse of schizophrenia and its consequences including attendance at Accident and Emergency departments and hospital admission.

Controversy over antipsychotics

Most experts, and clinical guidelines including those from the National Institute for Health and Care Excellence (NICE) in the UK, regard antipsychotic medication as having an important role in the treatment of schizophrenia and related psychotic disorders.   However, some critics have called for a more selective use of antipsychotics based on their side effects and also on the possibility that their long-term use may impair social functioning and increase the likelihood of relapse when treatment is eventually stopped.  The side effects of antipsychotics are well known and include weight gain, sexual dysfunction, sedation, muscle stiffness and movement disorders.  The risk of these problems occurring varies greatly between different antipsychotics and is one factor that patients and clinicians will usually consider when choosing the most appropriate medication.  Most side effects go away after medication is stopped though it can take a long time, and require a lot of effort, to lose excess weight that has been gained on medication. The suggestion that antipsychotics could worsen the outcome of schizophrenia is highly controversial and the reality is that there are insufficient long-term and high quality studies to definitively prove or disprove this view. Further research is required to answer this and related questions.  Uncertainty about the pros and cons of long-term drug treatment is not unique to psychiatry, as shown by recent controversy about whether statins, drugs that reduce blood cholesterol levels, are over prescribed.

The decision on how long to continue an antipsychotic medication, after a person has responded to it, is best made jointly, on an individual basis, by that person and their clinician.  The decision should follow a full discussion about the risks and benefits of continuing medication and the impact of any future relapse.   Various factors can help inform this decision including how unwell the person was and whether they have had more than one episode of psychosis.  Antipsychotics should only be stopped after discussion with the supervising doctor, usually a psychiatrist.   Guidance from the National Institute of Health and Care Excellence (NICE) recommends that if a decision is made to withdraw antipsychotic medication in a person who has schizophrenia or psychosis, then the medication should be withdrawn gradually and the person monitored for signs and symptoms of relapse for at least 2 years after stopping medication.   It is very important that the patient and family know how to access help quickly if they have any concerns that the illness is reappearing.

Psychopharmacology has been criticized as leading to the importance of psychological and social factors being neglected when considering the causation of psychiatric illness and an overemphasis on medication to the detriment of psychosocial treatments. This will only happen if a narrow blinkered view of psychopharmacology and neuroscience research is adopted.  Social and psychological factors are of great importance in the causation and treatment of schizophrenia.  Neither is undermined by evidence of biological changes in people with psychosis, for example altered neurotransmitter levels in the brain.    Neuroscience and psychosocial research complement each other.  People with schizophrenia and related psychotic disorders should always be offered psychological and social interventions in addition to antipsychotic medication.  In particular, family interventions are effective in reducing the risk of relapse in schizophrenia and a talking treatment termed cognitive behavioral treatment (CBT) can improve the symptoms of psychosis when combined with antipsychotic treatment.  In addition, both CBT and family therapy, when added to standard treatment, have been shown to reduce the risk of hospitalisation compared to standard treatment alone. There is also preliminary evidence that CBT on its own (that is, without accompanying antipsychotic medication) can be effective in treating psychosis.  If this work is confirmed it will be important as it would support CBT as an alternative treatment option to antipsychotic medication, for at least some people with psychosis, and so increase treatment choice.

Legacy

Most authorities regard the introduction of the antipsychotics as a significant event in the history of psychiatry.  For the first time an effective treatment was available for schizophrenia.  Antipsychotics could treat distressing symptoms when people were ill, and also decrease their risk of relapse.   As such, antipsychotics have reduced suffering and led to better outcomes for countless people with schizophrenia. However, antipsychotics have their problems; they can cause a wide range of side effects, some people’s symptoms only respond partially to medication and a minority of people show no improvement with medication.  Among the most serious side effects of antipsychotics is their ability to increase weight and levels of glucose and lipids (‘fats’) in the blood.  These are all risk factors for cardiovascular disease, including stroke and heart attack.   Even when a person’s psychiatric symptoms respond well to medication, this is only one part of their treatment.  Other important elements include talking treatments for the person who is affected and their family, practical help in getting back to work or returning to education, a trusting and supporting relationship with health care professionals and a psychiatric service that provides continuity of care, can respond promptly to crises and which is community based but can provide inpatient care if this is needed.

It is worth reflecting on the management of psychosis in the first half of the 20th century prior to the introduction of antipsychotics.  This largely consisted of lengthy admissions to an asylum and the use of sedative drugs, and in some countries (not the UK) the use of mechanical restraints, to control severely disturbed behaviour.  During the 1940s and 1950s insulin coma treatment, leucotomy and convulsive therapy were all used to treat schizophrenia in the UK and many other countries. Today insulin coma and leucotomy are not used at all in psychiatry.   One form of convulsive treatment, called electroconvulsive treatment (ECT), is used today, but not to treat schizophrenia.  Today ECT is largely restricted to treating very severe cases of depression in which other treatments have been tried and been ineffective.  One reason why these treatments were used in schizophrenia in the past is because there was no system of rigorous research, as there is today, to assess their effectiveness.  Instead, at that time, new treatments throughout medicine were often adopted if an influential figure promoted them.  In addition, in the 1940s and 1950s the situation in psychiatry was desperate, as asylums were overcrowded, understaffed, underfunded and there were no effective treatments for psychosis.   With time it became apparent that both insulin coma and leucotomy were ineffective and could cause serious side effects and even prove fatal, and that electroconvulsive therapy (ECT) was effective in severe depression but not in schizophrenia.  Although the use of insulin coma and leucotomy was on the decrease in the early 1950s, the introduction of the antipsychotics contributed to these ineffective treatments being abandoned.

High Royds psychiatric hospital, West Yorkshire, England. This was a typical Victorian asylum. It opened in 1888 and at the end of the 19th century accommodated 1600 patients. The hospital finally closed in 2003.
High Royds psychiatric hospital, West Yorkshire, England. This was a typical Victorian asylum. It opened in 1888 and at the end of the 19th century accommodated 1600 patients. The hospital finally closed in 2003.

In the decades following the introduction of the antipsychotics, most but not all countries saw a huge fall in their psychiatric inpatient populations and the closure of asylums and a shift to community care, a process termed de-institutionalisation.  Many factors were responsible.  These changes were certainly not due to the antipsychotics alone.    Nevertheless, the antipsychotics played an important role as they provided an effective treatment for schizophrenia and gave clinicians and managers the confidence to discharge patients and set up alternative community services.   Other important factors that led to the closure of the asylums were increasing public awareness of scandals and poor care in the institutions, a realisation that institutional care could worsen some symptoms of schizophrenia and make people more dependent on hospital care, a desire to save costs by closing down large hospitals that were expensive to run, changes to mental health legislation so that voluntary hospital admission rather than compulsory admission became the norm and increasing interest in psychological and social treatments. The complexity of factors accounting for de-institutionalisation is partly shown by the different time periods over which it occurred in different countries.

The introduction of antipsychotics and other psychiatric drugs during the 1950s had a major impact on the way that psychiatric illness was viewed by clinicians and scientists.  It stimulated research into the biological nature of psychiatric illness and led to the birth of ‘psychopharmacology’ as a discipline.    The biological processes underlying psychosis and other psychiatric illnesses are still not fully understood but researchers know far more today than in the 1950s putting them in a stronger position to develop new and better treatments.  The introduction of chlorpromazine and other new drugs required a scientific way to assess their effectiveness.   This led to the methodology of randomized clinical trials in psychiatry being developed. At the same time various rating scales were developed to assess changes in symptoms and side effects during studies.  Randomised clinical trials are now regarded as the gold standard method to test the effectiveness of medications and also talking treatments.

The introduction of chlorpromazine and other psychiatric drugs in the 1950s helped change the public’s perception of psychiatry.  The fact that serious psychiatric illnesses could be treated with medicines made these disorders more equivalent to medical conditions such as diabetes and so helped to reduce the stigma of mental illness.   The availability of medications to treat schizophrenia also provided patients and families with hope and led to increased optimism among researchers and mental health professionals.

Conclusions

Chlorpromazine entered psychiatric practice in 1952 and ushered in a new era of treatment for psychiatric illness.  For the first time an effective treatment for schizophrenia and related disorders was available.  At an academic level the introduction of the antipsychotics stimulated neuroscience research, helped create psychopharmacology as a distinct discipline and contributed to the development of the methodology of clinical trials in psychiatry.  Current antipsychotics are far from perfect as they can cause a wide range of side effects and some people do not respond or show only a limited improvement.  The existence of a range of antipsychotics reduces these problems to a degree, as people who find that one drug doesn’t suit them have the option of switching to another.  Nevertheless, it is clear that new and better treatments for schizophrenia and psychosis are needed so that more people with these disorders can recover and lead active lives, and also so that there is a greater choice of treatment.  There is a need for more effective medicines with fewer side effects and more research into talking treatments and the long-term outcome of schizophrenia with different treatment approaches.  We also need a better understanding of the causes of psychosis to help with its prevention.  These developments will rely on future research involving experts from many fields and the support of people with psychosis and their families.

 

Further information

Information for the public based on the NICE (2014) guideline ‘Psychosis and schizophrenia in adults: Treatment and management [CG178]’ is available at: www.nice.org.uk/guidance/cg178/ifp/chapter/About-this-information

User friendly information leaflets on schizophrenia, psychosis and a wide range of other mental health problems are available from the Royal College of Psychiatrists at: www.rcpsych.ac.uk/healthadvice/problemsdisorders.aspx

Leaflets on antipsychotics and other treatments for mental health problems, produced by the Royal College of Psychiatrists, are available at: www.rcpsych.ac.uk/healthadvice/treatmentswellbeing.aspx

 

Acknowledgement: This article is partly based on research supported by a grant from The Wellcome Trust [grant number WT103294].

7 thoughts on “Chlorpromazine, the first antipsychotic medication: history, controversy and legacy

  1. Dear Paul
    Thank you for your comment and for letting me know about the ‘Mental Health and Best Practice’ training event you are organising with Time to Change. I’d be happy to support this. Please can you email me some further details.
    Kind regards
    Dr Peter Haddad

  2. I was prescribed chlorpromazine some 40 years ago. I found the experience rather unpleasant. I was an inpatient at the time, the nurses were great, the doctor who treated me was brilliant and even the hospital food was good. The illness was horrible and I hated the sedation. Eventually I had ECT and I made a full recovery. Happy to email you with more details of how it felt, although I regard the unpleasant experience as an unfortunate side effect and I have no complaints, I would have been worse off without it. The diagnosis was endogenous depression, and looking back on it I was psychotic.

    1. Dear Liam

      Thank you for sharing your memories of inpatient treatment for depression. I’m pleased to hear that the staff were helpful, that ECT was effective and that you made a full recovery. It wouldn’t be appropriate for me to comment on any individual case but I would like to make a few general points about depression and antipsychotics.

      As you highlight depression can be a very distressing and serious illness. Most people with depression are treated effectively by their GP often with additional help being provided by a counsellor or psychologist. Those with severe or complex depression will usually be referred by their GP for extra help from specialist mental health services including seeing a psychiatrist. Psychosocial treatments including guided self-help, cognitive behavioural treatment (CBT) and a group exercise programme are options for treating mild to moderate depression. Antidepressants tend to be reserved for people with moderate to severe depression or milder depression that is persistent or hasn’t responded to psychosocial interventions. An antipsychotic will usually be combined with an antidepressant if a person has depression with psychotic symptoms. This is a very serious form of depression that requires urgent specialist care. The combination of an antidepressant and an antipsychotic may also be recommended in the absence of psychotic symptoms if a person’s depression has not responded fully to antidepressant treatment alone (but only certain antipsychotics have been shown to be effective when used in this way). ECT is an effective treatment for severe depression and is used when other treatments haven’t worked and/or when the depression is potentially life-threatening. When medication or ECT are used to treat depression, they still need to be combined with psychosocial interventions to achieve the best outcome.

      You mentioned the unpleasant sedation you experienced with chlorpromazine. Chlorpromazine is one of the most sedating antipsychotics. In the past, there was a tendency to use higher doses of chlorpromazine, and other older antipsychotics, than is the case today. This would exacerbate sedation and many other side effects; most but not all drug side effects are dose related. It is now appreciated that higher doses of the older antipsychotics (including haloperidol and chlorpromazine) are no more effective than moderate doses.

      There are a far more antipsychotics available today than 40 years ago and they largely differ in their side effects. In current practice, people should be offered a choice of treatment including whether to take medication and if so what medication. If an antipsychotic, or any other psychiatric medication, isn’t effective or is causing unpleasant side effects, there should be a discussion about other treatment options including switching to a different medication. As such, it is usually possible to select a medication and devise a treatment plan that suits each individual.

      Kind regards

      Dr Peter Haddad

  3. I was prescribed chlorpromazine some 35 years ago. I found the experience rather unpleasant. I was an inpatient at the time, the nurses were great, the doctor who treated me was brilliant and even the hospital food was good. The illness was horrible and I hated the sedation. Eventually, I had ECT and I made a full recovery.
    Thanks For Your Information

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