Setting the scene

Cooper & Shepherd suggest that modern notions of psychiatry may be said to date from the publication of Pinel's Traite Medico-philosophique in 1801, ^{Reference Cooper, Shepherd and Price27,Reference Pinel and Davis28} which included a range of potential social, emotional and physical causes for mental disorder. They also highlight Pinel's statistical approach to classification. A unitary psychosis with multifactorial causation enunciated by Griesinger in 1867 and the influential Kraepelinian system of classification in 1896 were both considered as further advances for psychiatry. ^{Reference Cooper, Shepherd and Price27} Bleuler in 1911 introduced the term ‘schizophrenia’ for the concept of dementia praecox, with emphasis upon flattening of affect and loosening of associations.

In the 1970s there was a dramatic resurgence of interest in classification, particularly in the USA. ^{Reference Kendal, Pighot and von Cranach29,Reference Kendal, Kerr and Snaith30} This new outlook was heralded by the publication of strict operational criteria for the diagnosis of 15 major syndromes, ^{Reference Feigher, Robins, Guze, Woodruff, Winokur and Munoz31} and then proclaimed 8 years later by the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM–III). ³² Before this there were serious international differences in diagnostic concepts, particularly between North America and Europe. ^{Reference Leff and Wing33} The previous broader diagnosis of schizophrenia in the USA was well illustrated by the World Health Organization's International Pilot Study of Schizophrenia. ³⁴ It is only since the 1970s that it has been possible to have truly international research or full understanding of research from other countries. This development of an international standardisation of diagnostic methodology subsequently enabled more consistent identification of schizophrenia to which a specific treatment regimen could then also be more consistently applied.

Evolution in the management of schizophrenia

Mandelbrote divides the management of schizophrenia into various time-related era. ^{Reference Mandelbrote and Price35} The moral era (1825–75) described the importance of the social setting in which ‘treatment’ took place and led to changes in the social setting of mental hospitals. Greenblatt et al summarised it ‘as therapy that emphasized close and friendly association with the patient, intimate discussions of his difficulties and the daily pursuit of purposeful activity’. ^{Reference Greenblatt, York and Brown36} The benefit of social change within the hospital environment is illustrated by a follow-up study over 20 years of first admissions in the USA, ^{Reference Bockhoven37} which suggested a high rate of discharge from hospital; 70% were discharged as recovered or improved. Even among patients with chronic disorder, 45% were discharged as recovered or improved. The custodial era refers to a later period between the end of the 19th century and the early part of the 20th century. The emphasis was on institutional care, supervision and regimentation. It resulted in a significant fall in discharges and a rapid increase in the patient population. The prime consideration was the protection of the community. Nevertheless, a review of surveys in the USA by Standt & Zubin showed that approximately 30–40% of individuals with acute schizophrenia recovered or improved over a 5-year period. ^{Reference Standt and Zubin38}

Between the two World Wars a number of treatments were introduced. These included insulin coma, electroconvulsive therapy (ECT) and intensive occupational therapy. The first two have long since been abandoned, apart from ECT in catatonic states or depressive phases resistant to other treatments. Moniz introduced prefrontal leucotomy as a treatment for schizophrenia, ^{Reference Moniz39} but this was discontinued because of the resultant personality changes and other unwanted effects. Formal psychotherapy was tried in schizophrenia but the outcome over 5 years was no different from the spontaneous remission rate. ^{Reference Appel, Lhamon, Myers and Harvey40}

After the 1950s the new formally trained psychiatrists began to evaluate critically the symptoms of schizophrenia and the treatments offered, thus recognising that not all the associated disabilities were an essential part of the illness, but that some resulted from prolonged residence in a restrictive and socially sterile institution. The mental hospitals began to change and adopt features of the ‘therapeutic community’. Wing & Brown in their study of female patients with schizophrenia concluded that there was good preliminary evidence that the social conditions in a mental hospital do influence the patients' mental state. ^{Reference Wing and Brown41} An increasing number of patients were admitted and discharged. It was against this changing social background in the pattern of management of schizophrenia that new pharmacological preparations were introduced into clinical practice in the 1950s (phenothiazines, tricyclic antidepressants, monoamine oxidase inhibitors and the benzodiazepines), leading to the antipsychotic LAIs in 1966.

Birley & Brown found, first, that both life events and reducing or stopping phenothiazines acted as precipitants of schizophrenia (i.e. non-adherence leading to possible relapse), and second, that the symptoms of acute schizophrenia were largely unrelated to its precipitants. ^{Reference Birley and Brown42} The increasing reliance on medication was in part because social change was more expensive to achieve, took place more slowly and was dependent on a change of attitudes not only within the psychiatric profession but also among the general public. However, the research evaluating the social influences upon schizophrenia has not been without its critics, and a balanced view is presented by Bebbington & Kuipers. ^{Reference Bebbington, Kuipers, Bebbington and McGuffin43} No single treatment should be regarded as exclusive. ^{Reference Greenblatt44,Reference Bebbington and McGuffin45}

Continuous maintenance medication

It became increasingly clear that not only did phenothiazines control the symptoms and distressed behaviour of the acute psychotic illness, but continuous medication for a prolonged period thereafter prevented, delayed or modified a further relapse. ^{Reference Prien, Cole and Belkin3,Reference Davis11,Reference Schooler, Levine, Severe, Brauzer, DiMascio and Klerman14,Reference Wistedt16,Reference Kane, Rifkin, Quitkin, Nayak and Ramos-Lorenzi17,Reference Crow, McMillan, Johnson and Johnstone20,Reference Kissling23,Reference Leff and Wing33,Reference Davis, Schaffer, Kinard and Chan49–Reference Barnes, Hirsch and Kissling51} It was also demonstrated that continuous, or maintenance, medication could protect individuals with schizophrenia against the stress of their environment which often arose from within their own families, ^{Reference Brown, Birley and Wing52,Reference Vaughn and Leff53} and facilitate the delivery of social interventions and rehabilitation which formed part of their treatment package. ^{Reference Hogarty, Ulrich, Goldberg, Spitzer and Klein9,Reference Hogarty, Goldberg, Schooler and Greenblatt54} However, approximately 20–25% of all patients with schizophrenia have a good prognosis, independent of active maintenance medication. ^{Reference Leff and Wing33,Reference Cutting, Kerr and Snaith55} Unfortunately no satisfactory method of identifying this good prognosis group has emerged.

Need for medication adherence

By the 1960s there was a widely held view that communication between medical professionals and their patients needed improvement. Ley & Spelman investigated this problem in both psychiatric and non-psychiatric patients. ^{Reference Ley and Spelman56} They found that a quarter to a half of patients failed to recall instructions, even when their importance was emphasised. In their review of the literature, they found that the same percentage of individuals failed to follow instructions concerning medication even when a serious illness such as tuberculosis was involved, or they were mothers who were responsible for their baby's care. ^{Reference Ley and Spelman56} Wilcox et al showed that 48% of psychiatric out-patients failed to take their medication, ^{Reference Wilcox, Gillan and Hare57} and Neve found that 11% of in-patients on chlorpromazine failed to take medication as prescribed. ^{Reference Neve58} Prospective studies in the setting of general practice showed similar results. ^{Reference Johnson18,Reference Johnson59,Reference Johnson60} With the increasing weight of evidence that maintenance medication was essential, the need for improved medication adherence was self-evident. The LAI offered great potential in this respect. In particular, it identified the actual drug and dose taken, to allow informed decisions to be made about future treatment. Unfortunately, prospective monitoring showed that drug defaulting on an LAI without a specific system of organisation was also considerable. The infrastructure to develop specialised clinics within the community and arrange for psychiatric-trained nurses to follow up defaulters simply did not exist at that time. Attempts to involve non-psychiatric-trained district nurses (who were not part of the hospital or the psychiatric service) or general practitioners largely proved a failure. ^{Reference Johnson and Freeman61} The need for special delivery services such as LAI or depot clinics or outreach facilities, whether hospital- or community-based, was apparent. Happily, over time the development of the mental health service has been transformed. The service is now more integrated, with psychiatrists, general practitioners, community psychiatric nurses, social workers and psychologists all working in the community, often in well-defined roles as assertive outreach teams, early intervention teams, home treatment teams or dual diagnosis teams. The adoption of these community team strategies has probably reduced drug defaulting from oral medication.

Injection frequency

A number of mistakes associated with the initial use of the LAI compounded the very real problems of side-effects, principally extrapyramidal symptoms, and the need for an efficient drug delivery system. These mistakes continue to haunt the correct use of LAIs and the often related problem of polypharmacy. The original LAI of fluphenazine enanthate was recommended to be given every 2 weeks. Two years later, fluphenazine decanoate was introduced as a 3-weekly injection. The next available preparation, flupenthixol decanoate, was also recommended as a 3-weekly injection. The concept of an individual flexible dose regimen was initially completely overlooked, possibly because it did not fit the marketing strategy of the time. This was a major error because flexibility is the key to maximising the therapeutic benefits and minimising the adverse effects of drug therapy. This was increasingly recognised from the mid-1970s onwards. ^{Reference Baldessarini, Cohen and Teicher62–Reference Marder, van Putten, Mintz, Lebell, McKenzie and May65} In addition, regular consideration needs to be given to the dose prescribed, with an aim of achieving the minimum effective dose for long-term care. ^{Reference Kissling, Kane, Barnes, Dencker, Fleischhacker, Goldstein and Kissling66}

Extrapyramidal symptoms and tardive dyskinesia

Extrapyramidal symptoms when they occurred as a side-effect were usually treated with an anticholinergic drug, and some clinicians even prescribed such drugs on a routine basis as a prophylactic measure. The strategy of increasing the interval between injections and/or adjusting the injection dose was seldom explored. One study demonstrated that by varying the dose regimen, such as by giving smaller doses more frequently, the incidence of extrapyramidal symptoms could be reduced to 34%. ^{Reference Johnson67} By delaying the next injection for 2–3 weeks, and sometimes even longer, before introducing the new dose regimen the symptoms often settle without recourse to additional treatments. The very real risks associated with the prescription of anticholinergic drugs, ^{Reference Johnson68,69} which include physical and psychological side-effects and an exacerbation of existing tardive dyskinesia, may possibly be avoided. Another consideration is to note that the prescription of a tricyclic antidepressant in combination with an antipsychotic may have an adverse effect on existing tardive dyskinesia. ^{Reference Johnson68} The wide-ranging disadvantages of polypharmacy to the patient, particularly with the overuse of anticholinergic drugs, were never fully appreciated or addressed by psychiatrists and continued over many years despite repeated warnings. This is not to deny the very real benefit to individual patients of additional drugs, particularly the selective prescription of anticholinergic drugs to patients with Parkinsonism unresponsive to other strategies and ‘akinetic’ depression. ^{Reference Johnson67}

Antidepressant co-prescribing

Antidepressants were often added without due consideration of the cause of any apparent depressive signs or symptoms. The causes of depression in the course of treated schizophrenia are many and varied. ^{Reference Johnson68,Reference Johnson70–Reference Brockington, Kendell and Leff82} They include premorbid personality, post-psychotic depression, drug-related akinetic depression, depression as a symptom of schizophrenia and schizoaffective psychoses. In the early days of antipsychotic treatment, surveys of drug prescriptions to patients with schizophrenia revealed that at least 20% were prescribed antidepressants, yet no study showed that the broad spectrum of patients gained any benefit. Only Siris et al, studying a group of patients with post-psychotic depression, reported any overall advantage. ^{Reference Siris, Williams and Dalby83} Again we had the problem of polypharmacy – with the risk of a spectrum of unwanted side-effects, including worsening of tardive dyskinesia – for no justifiable reason.

The problems of polypharmacy were not fully appreciated by all psychiatrists, and repeat surveys showed that it remained a problem for many years. ^{Reference Johnson and Wright84}

Administration of LAIs

Other important early difficulties included the problem that drug administration often was not centralised nor carried out by team members with appropriate training in mental health. The occasion for an injection administration was not seen as an opportunity to support and evaluate the patient, both for changes in mental state and the early development of side-effects. Health staff who were not sympathetic to psychiatric problems may have played a part in significant defaulting among patients receiving LAIs and less than optimum care in many respects. ^{Reference Johnson and Freeman61} The use of LAI or depot clinics then fell somewhat from favour with some psychiatrists, and has been considered as leading to stigmatisation of patients. ^{Reference Johnson72,Reference McGlashen and Carpenter73} As a consequence, it was suggested that such clinics should be renamed ‘maintenance medication clinics’, although it also is essential to recognise that research and experience has demonstrated that the success of LAIs rests with the quality of the follow-up service, ^{Reference Johnson and Freeman61} which now includes several forms of service delivery within the community.

Duration of maintenance treatment

Over time the treatment of people with schizophrenia has been increasingly based in the community, involving a widening range of professionals offering supervision and advice to patients and their families. A survey in 1997 by teleconference was carried out to explore the professional attitudes of psychiatrists, general practitioners, pharmacists and community psychiatric nurses, throughout all parts of the UK, towards the duration of maintenance therapy for both first-episode and multi-episode illnesses. ^{Reference Johnson and Rasmussen85} The results caused grave concern in that the professions varied widely in the advice they offered to patients and their families, and this was often substantially different to the multinational Consensus Group recommendations which were widely accepted worldwide. ^{Reference Kissling23} For first episodes, over half of psychiatrists recommended 1–2 years of maintenance therapy, but only 45% of general practitioners, 33% of community psychiatric nurses and 30% of pharmacists recommended similar periods. For multi-episode disorder, the variation was even greater: 90% of psychiatrists recommended 3–5 years or more of maintenance therapy, but only 79% of community psychiatric nurses, 69% of general practitioners and 55% of pharmacists recommended similar periods.

It is recognised by the author that no individual or authority can give absolute guidelines with regard to duration of maintenance therapy with antipsychotic drugs, but the issue is the conflict in information received by patients and their families, and the likelihood that this will influence adherence.