‘Rapid tranquillisation’: an historical perspective on its emergence in the context of the development of antipsychotic medications

Before antipsychotics

Prior to the advent of what we now call ‘antipsychotic’ drugs, there was little interest in discussing or evaluating techniques for managing highly disturbed behaviour in mental health settings. The first edition of Henderson and Gillespie’s Textbook of Psychiatry in 1927, for example, gives little coverage to any sort of treatment. Drug treatment of emergencies is presented as being secondary to other forms of intervention; ‘episodes of violence should be treated with explanation, suggestion, analysis or, where necessary, by hydrotherapy or drugs’ (Henderson and Gillespie, 1927: 224). The only specific agent mentioned in this context is the drug hyoscine hydrobromide, used hypodermically, and again it is stressed that it should be used ‘only in case of emergency’ (p. 157). The same drug is also suggested for the emergency, last resort treatment of delirium tremens (p. 278), and it continues to be the only drug recommended for use in psychiatric emergencies until the 1950 edition of the textbook. The sedative drug paraldehyde is mentioned elsewhere, but only as a less potent treatment given orally for sleeplessness.

The first edition of Clinical Psychiatry by Meyer-Gross, Slater and Roth (1954) reflects the increasing interest and confidence in the possibility of treating mental disorders through physical methods such as ECT and insulin coma therapy. In contrast to the Textbook of Psychiatry, it contains a comprehensive section on treatments and their rationales and promotes a biomedical approach to psychiatry. Insulin coma therapy is presented as the principle form of treatment for people diagnosed with schizophrenia, and the authors suggest that ‘since the introduction of insulin and convulsion therapy, the symptomatic use of sedative drugs has diminished in importance’ (Meyer-Gross et al., 1954: 287). They still provide advice on ‘how to deal with the emergency of an acute schizophrenic attack in the patient’s home’ (p. 278, original italics), however, and also recommend hyoscine for this purpose, in this case intravenously: ‘If the patient refuses to take any drug by mouth and no skilled help is available to give an intravenous injection, hypodermically administered hyoscine is the simplest and safest method of calming excitement and overcoming resistance’ (p. 287). They also mention other options, including use of paraldehyde, chloral hydrate, barbiturates, and a combination of hyoscine with morphine and atropine. There is a statement to suggest that the purpose of using these medications was seen as allowing the transport of a patient to hospital where ECT would be used for tranquillisation: ‘after admission to hospital many acutely excited schizophrenics calm down remarkably well after one or a few electrically induced convulsions’ (p. 287).

Retrospective accounts, including a paper from the 1970s, recall ‘full restraints, maximum security chambers, frequent ECT and heavy sedation’ as the ‘traditional methods’ of control prior to the advent of antipsychotics (Fann and Linton, 1972: 478). Psychiatrist John Bradley remembered the use of strait-jackets as well as barbiturates and paraldehyde in the early 1950s when he worked as a psychiatrist in the Royal Air Force. Despite this evidence that sedative drugs of various kinds were being employed to calm agitated and disturbed patients within psychiatric institutions, advertisements in the Journal of Mental Science from the early 1950s make no reference to this practice. At this time, advertisements tended to be for ECT equipment and for private psychiatric institutions, although a few promoted the use of barbiturates. One of these suggested the use of the barbiturate, Soneryl, for ‘mild sedation during periods of stress to prolonged narcosis in states of agitation or acute anxiety’, suggesting that prolonged barbiturate-induced sleep, known as ‘deep sleep therapy’, was also being used as a method of containing disturbed behaviour (Soneryl ad., 1953).

The introduction of ‘antipsychotics’

The first advertisements for antipsychotics promoted their use in a range of psychiatric and non-psychiatric situations from neurosis to psychosis to adjuncts in anaesthesia. There is also evidence of the emergence of the marketing of antipsychotics for the control of agitation and aggression. In contrast, although barbiturates were advertised for use in anxiety, their use for emergency sedation was not mentioned and no other sedative drugs were advertised at this period for this purpose.

In 1955 the first advertisement for a drug that would now be considered as an ‘antipsychotic’ appeared in the Journal of Mental Science. The advertisement was for reserpine and stated that the drug ‘induced a state of mental quietitude and relaxation’ (Reserpine ad., 1955). The first two issues of 1956 also contained advertisements for reserpine ‘for use in psychiatry’, but specific uses were not stated. Instead, the advertisement stated that the drug ‘possesses a remarkable calming and relaxing action, and is capable of wide application in mental illness’ (Reserpine ad., 1956).

Through the late 1950s, an increasing number of agents now considered as antipsychotics, or related to antipsychotics, started to be advertised. In 1957 there were advertisements for the pheno-thiazine drugs Pacatal (mepazine) and Sparine (promazine hydrochloride). The one for Sparine makes reference to its use in ‘controlling acute agitation’, the first mention in the 1950s of a drug being marketed specifically for this situation (Sparine ad., 1957). The advertisement for Pacatal (1957) focused on its use as a ‘tranquilliser’ for a range of psychiatric indications, including for ‘the control of aggression, impulsiveness and overactivity, particularly in the over-50s’.

The first advertisement in this journal for the antipsychotic drug Stelazine (trifluoperazine) appeared in 1959. This features an illustration of a ‘Squirrel cage’; the caption explains that this was used for ‘calming mental patients (18th Century)’, suggesting that the action of Stelazine is equivalent to physical confinement. Unlike earlier antipsychotic advertisements, the text also claims that the drug is ‘specific for the hallucinated, delusional and aggressive psychotic’ (Stelazine ad., 1959a). In a later version, a preliminary report on a double-blind trial is referenced, suggesting that regular oral medication is superior to emergency medication regimes in people diagnosed with schizophrenia (Stelazine ad., 1959b). This suggests the advertisement was aimed at reducing the use of emergency drug treatment, but, given the continued use of the picture of the squirrel cage, it is likely it was still intended to suggest the use of Stelazine for emergency situations.

Dr Bradley recollects that chlorpromazine was favoured for emergency sedation while he was working in St Mary’s Hospital in Paddington, London, in 1957; he was then sent to work in France with Professor Delay in the Hôpital Sainte-Anne in Paris where chlorpromazine was used in combination with strait-jackets. In 1959, while working for William Sargant at St Thomas’ Hospital, London, ECT was the treatment of choice, but the use of chlorpromazine and other phenothiazine antipsychotics had also started.

The eighth edition of Henderson and Gillespie’s Textbook of Psychiatry (1956: 276) mentions the use of chlorpromazine for the first time for ‘cases of emergency’, in relation to the ‘control of cases of manic excitement’. In other cases, a combination of morphine and hyoscine is recommended in this edition.

The 1960s: therapeutic containment

Throughout the 1960s more and more antipsychotics came onto the market. The volume of advertising in the British Journal of Psychiatry, as it became in 1962, increased along with the size of the journal itself. By 1962 there were 100 pharmaceutical advertisements, constituting 65% of the total of 153 advertisements, compared with 17% in 1952 (11 of a total of 64).

Advertisements for antipsychotics continued to list the control of behavioural disturbance as an indication for use, but this was increasingly associated with the idea that the drugs’ principle action was to reduce the symptoms of particular disorders, namely psychosis, schizophrenia and mania. Emergency sedation was also portrayed as part of an overall therapeutic programme as a way of rendering the patient more amenable to other forms of therapy. In 1961 Majeptil (thioproperazine), marketed by May and Baker Ltd, was first advertised with the claim that it is ‘remarkably effective in controlling acute mania and other states of psychotic excitement’ (Majeptil ad., 1961). Also during this year the first advertisement appeared for Seranace (haloperidol), marketed by Searle Ltd, stating that this drug ‘controls the major manifestations of psychotic illness’ including ‘agitation’ (Serenace ad., 1961). In 1963, advertisements for Seranace began to emphasize its rapid action, a desirable property of any drug used to calm patients in an emergency (Serenace ad., 1963). By 1965 Seranace was advertised in every single one of the journal’s 12 publications with advertisements continuing to emphasize its rapid onset of action and its usefulness for treating aggressive patients, but also its therapeutic potential. Serenace ‘quickly controls the psychotic manifestations of schizophrenia’, one advertisement claimed (Serenace ad., 1965a), and another quoted a research paper in large, bold text describing how ‘A very powerful, restless man, greatly feared by all the staff for his aggressive outbreaks and unreliability … became calm and kindly after receiving the preparation [of haloperidol]. Nowadays he sits with a contented smile and carries out simple hobby tasks’ (Serenace ad., 1965b).

Stelazine marketing was now targeted explicitly at people with a diagnosis of schizophrenia, but the drug continued to be promoted for emergency use in people with ‘acute schizophrenia’, with a 1962 advertisement suggesting it could be given ‘by injection, to control violent and disturbed behaviour or severe agitation’ (Stelazine ad., 1962). By 1965 however, the practice was rendered in more therapeutic terms: ‘the first consideration in treating the violently agitated and hostile schizophrenic is to calm, restore insight, and establish rapport’ (Stelazine ad., 1965).

Some antipsychotics continued to be advertised for a variety of different indications. Thus, chlorpromazine (Largactil) was promoted for use in psychosis but also for use in the treatment of ‘psychoneuroses’, sleep therapy and the rehabilitation of drug addicts. In psychoses it was said to produce ‘rapid reduction of psychomotor over-activity without clouding of consciousness or dulling of intellect’ (Largactil ad., 1961). The drug Neulactil was advertised for indications that cut across diagnostic groups such as agitation in the elderly and in children (Neulactil ad., 1965). It is also notable that although other sedatives, including barbiturates, thalidomide and the newly emerging benzodiazepines, were widely promoted for use in neurotic and anxiety disorders, no advertisements for the use of any other sedative type drugs for emergency sedation were retrieved from the journal issues examined during the 1960s.

As in advertisements, the ninth edition of Henderson and Gillespie’s Textbook of Psychiatry (1962), which contains a section on ‘Various Drug Treatments’ for the first time, stresses that the new tranquillisers (antipsychotics) ‘in particular chlorpromazine and trifluoperazine, are useful in allaying turmoil and tension and in allowing the patient to become more accessible to other therapeutic influences’ (Henderson and Gillespie, 1962: 287). However, there is no specific reference to the drugs being used to calm or sedate patients in emergencies. The final, tenth edition (1969) has a short chapter on ‘Psychiatric Emergencies’ (Henderson and Gillespie, 1969: 439–47). After emphasizing that the doctor should try to manage the situation without recourse to drugs, it recommends either oral barbiturates or chlorpromazine by intramuscular injection. Haloperidol is not mentioned here, but the textbook does make reference to it as a treatment option in manic states, saying that chlorpromazine and haloperidol are the most useful drugs in the treatment of manic states, and that both can be given by injection (Henderson and Gillespie, 1969: 244).

In the second edition of Clinical Psychiatry (1960), chlorpromazine and ‘neuroleptic’ drugs are mentioned for the first time as having equivalent effects to insulin coma therapy in the long-term treatment of schizophrenia. The section on the ‘treatment of the emergency of an acute schizophrenic attack’ is the same as in the first edition, however, except this time the paragraph begins ‘although the neuroleptic [antipsychotic] drugs have diminished the importance of sedation in schizophrenia …’ instead of the same statement made about insulin coma therapy in the previous edition (Meyer-Gross et al., 1960: 298). In the third edition (1969) the first medication suggested for treatment in an emergency is chlorpromazine, administered intramuscularly at a dose of 100 mg, although hyoscine is still recommended ‘if a particularly quick response is required’ (Slater and Roth 1969: 330). Antipsychotic drugs are first introduced in this textbook therefore in a therapeutic capacity, before their use for behavioural control is suggested.

Despite the commercial interest and the increasing coverage in textbooks, the management of disturbed behaviour, and particularly the use of drugs in this situation, continued to receive little attention in the academic literature. In 1968 a rare review of the area entitled ‘Comprehensive management of psychiatric emergencies’ made no mention of the use of drugs or other forms of restraint specifically, except to say briefly that the majority of patients respond to ‘supportive treatment such as talking, rest, sedation and, where indicated, food and fluids’ (Frazier, 1968: 10).

The emergence of ‘rapid tranquillisation’

From the 1970s onwards, the use of drugs to control aggressive and agitated behaviour started to be discussed more frequently in psychiatric journals. Only antipsychotics were mentioned in this respect, however and, like material from the 1960s, articles adopted various strategies in order to emphasize the therapeutic aspects of emergency drug treatment and play down its coercive function. A review of the management of ‘acute behavioural disturbance’ published in 1975, for example, described the aim of emergency drug treatment as being the initiation of ‘a treatment programme aimed at returning the patient to being a useful and healthy member of society’ (Freed, 1975: 638).

The earliest PubMed-indexed article in which the term ‘rapid tranquillisation’ was used was dated November 1971 and was entitled simply ‘Rapid tranquilization’ (Polak and Laycob, 1971). It describes a method of treating acute schizophrenia by the administration of chlorpromazine at a dose of 50 mg to 200 mg orally every one or two hours, with the aim that the patient is ‘tranquilized’ within six hours. The ultimate aim of the regime is described as alleviating psychotic symptoms so that the patient can be treated with social and psychotherapeutic interventions. This is somewhat different from the way in which the term ‘rapid tranquillisation’ is used in current practice, where it refers to a strategy designed to sedate within minutes not hours, but the paper indicates the emergence of the concept in association with aspirations for a genuinely therapeutic role for drug treatment.

An article on ‘rapid digitalization’ from 1974 also advocates the administration of ‘high dosages of the more potent, less sedating antipsychotic drugs to schizophrenic patients to promote the patients’ rapid improvement’ (Donlon and Tupin, 1974). The authors distinguish between what they were trying to achieve, which was treatment of the psychosis, and what was usually understood by ‘digitalization’ (synonymous here with ‘tranquillisation’). They stress that their ‘rapid “digitalization” method is by no means a chemical straightjacket’ (p. 310). Use of the term ‘digitalization,’ however, again suggests that sedation of the acutely disturbed patient was aligned with treatment of the actual psychotic illness.

Subsequent publications of the early 1970s that use the term ‘rapid tranquillisation’ also refer exclusively to the use of antipsychotic drugs, particularly chlorpromazine and haloperidol (Man and Chen, 1973). An epitome published in 1974 suggests that ‘methods to safely and effectively tranquilize violent, agitated and psychotic patients have recently been proposed in the psychiatric literature’ (Hoell, 1975, emphasis added). Again the article recommends chlorpromazine or haloperidol, and it appears that previous methods of tranquillisation had been dissociated from contemporary practice. In this account, the author assumes that adequate tranquillisation is achieved if the patient is asleep, a suggestion that is more consistent with ‘sedation’ rather than the therapeutic calming described in previous papers.

In 1975 a special issue of the American Journal of Nervous and Mental Disease was dedicated to the management of violence in psychiatric patients. The issue presents the management of aggression as a diagnosis-driven, therapeutic activity that should be targeted not at the behaviour itself, but at the underlying mental disorder (Lion, 1975). According to this view, drug treatment is not to be construed as a ‘paralysing chemical straight jacket’ but as a specific treatment for the condition that gave rise to the disturbed behaviour in the first place (Monroe, 1975: 119). The issue is organized into articles that discuss the use of different sorts of drugs in different diagnostic groups. Antipsychotics are associated principally with the treatment of violence in people with psychosis or schizophrenia where their effects are deemed to be ‘due to the effect the drug has on the psychosis and not the aggression itself’ (Lion, 1975: 76). A paper on the use of benzodiazepines suggests their use should be restricted to aggressive behaviour in people with anxiety, where they are suggested to have a specific effect (Azcarate, 1975).

A 1972 paper on the use of the antipsychotic drug perphenazine, subtitled ‘The concept of chemical restraint’, is unusual for its explicit description of the physical mechanism by which antipsychotics can control excited and violent behaviour (Fann and Linton, 1972). The authors describe how the ‘drug-induced rigidity’, or the ‘Parkinsonoid state’, produced by antipsychotics ‘may not be deleterious’ in emergency situations and that antipsychotics ‘offer an excellent alternative to the physical measures that might otherwise be required in acute situations’ (p. 479). While still emphasizing that the purpose of tranquillisation is for the patient to be rendered able to participate in other therapeutic activities, the authors suggest that the ‘ideal agent’ for the purpose of chemical restraint ‘should permit definite control of the patient’s motor activity without reducing his mentation to the point where he cannot participate in ward activities’ (p. 479).

In 1970 some antipsychotic medications such as Neulactil were still being aimed at controlling ‘behaviour disorders’ across diagnoses, but were not marketed for the management of emergency situations specifically (Neulactil ad., 1970). By 1975 all advertisements for antipsychotics mentioned the diagnoses of schizophrenia and sometimes mania as specific indications for the drugs, but some advertisements listed a broader range of indications alongside these. Advertisements for Seranace, for example, included indications such as treatment of schizophrenia and mania, but also childhood behaviour disorders and tics. Treatment of ‘agitation in psychotic illness’ was mentioned specifically (Serenace ad., 1975). Fentazin (perphenazine) was also explicitly marketed for administration to patients by injection in acute emergencies, as well as for the symptomatic treatment of schizophrenia and ‘senile psychoses’. The advertisements referenced a controlled trial which found the drug to be equal to haloperidol in terms of its efficacy to treat ‘acutely disturbed patients’ (Fentazin ad., 1975), thereby suggesting that haloperidol was already established as a treatment of choice in psychiatric emergencies. By this time, in contrast, Stelazine was being targeted at the treatment of ‘withdrawn schizophrenics’ (Stelazine ad., 1975).

One other sedative, the anti-epileptic drug sultiame (Ospolot), was advertised for the treatment of aggression in 1975 (Opsolot ad., 1975). Testimony from Dr Bradley and Professor Bebbington, however, suggests that the benzodiazepine drug diazepam (Valium) was increasingly employed either alone or alongside antipsychotics such as chlorpromazine and haloperidol. Despite widespread advertising of Valium and other benzodiazepines for anxiety, there was no marketing of their use for the treatment of acutely disturbed behaviour in emergency situations.

Rapid tranquillisation comes of age

Professor Bebbington recalls that by the 1980s, haloperidol had gradually taken over from chlorpromazine as the antipsychotic most frequently used by psychiatrists in acutely disturbed patients. Although there were some safety concerns about the use of chlorpromazine, especially its propensity to lower blood pressure, it appears this was also related to the concerted marketing of haloperidol. The benzodiazepine lorezepam also started to be used.

The April 1980 issue of the British Journal of Psychiatry had an advertisement for ‘Droleptan’ (droperidol), marketed by Janssen pharmaceuticals, as an orally and parenterally administrable anti-psychotic that gives a ‘rapid control of acute agitation’ (Droleptan ad., 1980). The advertisement goes further, claiming that this is ‘the drug of choice’ for the treatment of acute episodes of schizophrenia, manic behaviour, the control of aggression in epileptic patients and the ‘sedation of severe emotional disturbances in autistic and brain-damaged patients’. The drug is claimed to ‘sedate’ in about 30 minutes. Thereafter this advertisement for Droleptan appeared in every single issue of the British Journal of Psychiatry in 1980. Droperidol is significant because it was introduced and marketed primarily as a treatment for the control of acutely disturbed behaviour across diagnoses. It appears that by the 1980s a viable market was perceived to exist for the pharmaceutical control of behaviour in its own right, but only for antipsychotic-type drugs. The fact that droperidol was produced by Janssen, which also produced haloperidol, and that it was chemically similar to haloperidol, suggest that the widespread use of haloperidol in emergency situations may have established this particular market niche. Again, although benzodiazepines continued to be marketed for the treatment of anxiety, there are no advertisements that mention their use for the purpose of rapid tranquillisation.

Classification and specificity

Prior to the 1950s, drug treatment in psychiatry was largely regarded with some embarrassment as merely a form of containment (Braslow, 1997). When new drugs like chlorpromazine and haloperidol were introduced, their sedating and tranquillising properties were quickly identified, but over the course of the 1950s and 1960s the belief grew that they had specific effects on the underlying pathology presumed to give rise to the symptoms of psychosis or schizophrenia (Moncrieff, 2013). The emergence of the dopamine hypothesis of schizophrenia in the 1970s finally provided a rationale for the view that the new drugs were disease-specific agents. Healy (2000) has suggested that it was this sort of theoretical framework that established the new drugs as the most important treatment for schizophrenia. The transformation in the understanding of drug action is reflected in changes in nomenclature, with the term ‘tranquilliser’, by which the drugs were originally known, increasingly replaced by the implicitly more specific term ‘antipsychotic’ (King and Voruganti, 2002).

The emerging view of drug treatments as having disease-targeting properties paralleled the development of detailed classification systems in psychiatry, modelled increasingly on medical taxonomy. The Diagnostic and Statistical Manual (DSM) was first published by the American Psychiatric Association in 1952. The first two editions contained descriptions reflecting the psychodynamic approach to psychiatry that was popular at the time but subsequent editions of the Manual became increasingly focused on demarcating a specific set of symptoms relating to a presumed specific underlying pathology (Mayes and Horwitz, 2005). The World Health Organization’s description of mental disorders in the International Classification of Diseases followed suit.

There continues to be a symbiosis between the new forms of classification and views about the specificity of drug action. As discussed elsewhere, professional interests and political considerations merged through the later part of the twentieth century to promote the view that mental disorders were properly regarded as medical diseases which responded to simple, targeted interventions like drugs (Moncrieff, 2009; Wilson, 1993). The evolution of views about emergency treatment also reflect the aspiration to emphasize the therapeutic and play down the custodial nature of psychiatric practice, and to align it as far as possible with the medical model of disease and its treatment.

Attitudes to emergency sedation

Prior to the introduction of antipsychotics, relatively little attention was paid to the common and challenging situation of managing disturbed behaviour in psychiatric settings, and particularly to what chemical agents might be suitable for this purpose. Coverage in the psychiatric literature was minimal, and there were no advertisements for drugs for this situation, despite other evidence that use of various sedative drugs and physical restraints was commonplace. It appears that it was anti-psychotic drugs, through their posited specificity of action, that made emergency sedation, later known as ‘rapid tranquillisation’, visible and respectable within the psychiatric community. Although other sedatives, including barbiturates and later benzodiazepines, were most likely also employed throughout the period examined, they remain largely invisible, perhaps because, in contrast to the antipsychotic agents, they continued to harbour the taint of non-specificity.

The control of aggressive behaviour or agitation was identified early on in marketing material as a useful property of antipsychotic drugs. Subsequently, the use of these drugs for emergency sedation was increasingly portrayed as part of a more global therapeutic endeavour to reduce specific symptoms, and effect change through other forms of therapy. Professional literature also aligned the use of antipsychotics for behavioural control with their therapeutic potential.

Subsuming the use of drugs for emergency sedation into the therapeutic process in this way, however, obscures the actual purpose for which medications are needed in these circumstances; that is to calm the patient and manage acutely disturbed and/or violent behaviour. It also eliminates consideration of the particular properties that make antipsychotics effective chemical restraints. As far back as 1957, Szasz was suggesting that the new drugs were chemical strait-jackets, in opposition to the emerging view that they were therapeutic agents (Szasz, 1957). Their prolific use as animal tranquillisers confirmed their ability to restrict physical activity, but these properties were only exceptionally glimpsed in the official literature.

Acknowledging that antipsychotics are effective physical restraints does not detract from evidence that they have therapeutic benefits in suppressing psychotic symptoms. It does suggest, however, that their use for emergency sedation needs to be evaluated for what it is, and compared explicitly and directly with the use of alternative agents. Several large randomized controlled trials have started to address this issue, and their results suggest that antipsychotics are one among many alternatives for emergency sedation, and not necessarily the best or the safest option (Powney et al., 2012).

As a result of these trials, alongside concerns about the toxicity of haloperidol (Food and Drug Administration, 2007), recent clinical guidelines are starting to recommend a wider range of pharmacological options for situations requiring the use of rapid tranquillisation, reflecting a desire to use agents with the least noxious and harmful profile, rather than attempting to elide the emergency situation with treatment of the underlying condition (Taylor et al., 2012). There is also increasing acknowledgement of the need for more research to evaluate different strategies. Perhaps this represents a move towards a more reflective attitude of re-evaluation of established treatments within psychiatry and an echoing of the sentiment of the authors of the tenth edition of Textbook of Psychiatry in 1969:

too many of [the new drugs] are being produced too quickly and are being used without guidance from properly controlled trials of their efficacy. We are in fact repeating the mistakes made with the shock therapies of the thirties, using these new therapeutic agents too enthusiastically, too indiscriminately and frequently naively. (Henderson and Gillespie, 1969: 321)