Antipsychotic Drugs: When and How to Withdraw Them?
Authors: Ian R.H. Falloon
Journal: Psychotherapy and Psychosomatics (2006)

One of the great conundrums in modern medicine is how to target medicines so that they exert the maximum benefits in assisting the body to recover fully and stably from illnesses without contributing to added impairment or disability. This problem is increased when the drugs under question have a potent effect on the control of distressing symptoms of major disorders. The case of antipsychotic medicine for schizophrenic disorders highlights such difficulties for the clinician. There is overwhelming evidence from double-blind controlled trials that the pharmacotherapy for acute psychotic episodes as well as the prevention of subsequent episodes is extremely beneficial, has low mortality and relatively low morbidity [1]. However, as with most treatments, it is also very clear that not every person diagnosed with these syndromes benefits equally, and that a substantial percentage show minimal if any benefit [2]. This latter group may be divided into two subgroups: (A) those cases who recover from a psychotic disorder without any pharmacotherapy, and (B) those in whom psychotic symptoms persist despite the best efforts to provide optimal pharmacotherapy. Epidemiological studies indicate that this first group varies from 5 to 60%, with an overall average of around 25% [2, 3]. Remarkably this proportion has remained fairly constant for over 100 years, with variability being attributed more to social than to medical factors [2,3,4]. The second group of medication-resistant cases would appear to have benefited from recent developments in pharmacotherapy, especially the wider use of clozapine, which has been considered to have benefits for up to one third of this group, thereby reducing the proportion from around 30 to 20%. Thus, it may be concluded that about half the cases of schizophrenic disorders benefit clinically from optimal pharmacotherapy. Such a conclusion may seem pessimistic, but it should be noted that compared with pharmacotherapy in other branches of medicine, this is an extremely high rate of benefit. It is estimated that most highly successful medical treatments have specific benefits for around one third of cases.The problem that psychiatry has faced, but not yet resolved, is how to select those cases who will benefit from pharmacological treatment, and those who will benefit from non-pharmacological treatments or combinations of both these approaches. Preliminary studies suggested that group A patients who are likely to have a benign course are those with an acute onset, often triggered by major life stress or substance abuse, with good pre-morbid social functioning and supportive relationships [5,6,7]. Recent interest has focused on early detection and intervention with pharmacotherapy, but the benefits have all too often been attributed to initiating early pharmacotherapy, rather than the confounding effects of these good prognostic factors that are clearly likely to promote early treatment [6, 8]. Unfortunately there is also substantial evidence to suggest that while it may provide rapid suppression of acute psychotic symptoms, early continuous pharmacotherapy may delay full and lasting recovery in a proportion of these cases [9,10,11,12,13,14,15].Psychosocial treatments that exert their effects through stress management strategies that help patients and their caregivers to cope with distressing and confusing symptoms as well as to deal more efficiently with current and future life stresses have proven successful in decreasing the short- to medium-term morbidity of schizophrenic disorders when combined with optimal pharmacotherapy [16, 17]. A small number of trials that have not employed the highest quality methodology have suggested that the provision of very intensive psychosocial support in homely environments may be as effective as antipsychotic medicine in the relief of the first acute psychotic episodes of young patients [16,17,18,19]. Approximately half the patients in these studies showed a good outcome without receiving antipsychotic medication. However, these groups were self-selected and the majority of non-drug responders probably represented group A with good prognostic features or were cases with psychotic symptoms that did not meet the full criteria for schizophrenia. Furthermore, other forms of sedative drugs such as benzodiazepines were used for many of these cases, and controlled trials have demonstrated that these medicines are effective antipsychotics for acute episodes [20]. Follow-ups of the 'non-neuroleptic' cohorts have shown that they generally have a somewhat better social outcome than those who received conventional neuroleptics [16, 18, 19]. Early prospective placebo-controlled studies of antipsychotics did indeed indicate that a substantial minority recovered well from their acute psychotic episodes while receiving only inactive preparations [9]. The proportions of symptom-free cases were very similar to those reported in the epidemiological studies prior to the introduction of modern neuroleptic drugs [21,22,23]. Of course all these studies included cases that would not now be diagnosed as schizophrenia.It is erroneous to conclude from the extant data, however, that treatment with neuroleptics to promote remission of acute psychotic episodes is harmful, either in the short term or in preventing full and lasting clinical and social recovery. A series of epidemiological studies in developing countries where neuroleptic drugs were used in acute episodes, but were usually withdrawn once these episodes were resolved showed long-term outcomes at least as good as those reported in the intensive psychosocial/'no neuroleptic' cohorts described above [24,25,26,27]. This paradoxical effect has not been fully elucidated, but one hypothesis is that a supportive social environment with encouragement to continue participation in all aspects of community life may assist in the recovery process. Thus, it would seem reasonable to consider that all patients experiencing their first acute psychotic episode have a trial of antipsychotic medication. However, it may be equally important to provide a highly supportive psychosocial environment, and wherever possible to withhold medications for a period to observe the benefits of the psychosocial programme on the patients' clinical state for at least 48 h [28]. This also allows any toxic drug- or stress-induced effects to begin to resolve. But it would be dangerous to assume that all cases who respond in this period have drug- or stress-induced episodes. The response to supportive nursing care and placebo pharmacological effects would account for a high proportion of such cases. Of course those cases who have had persisting psychotic symptoms for a considerable period before receiving specialised psychiatric treatment would not be likely to show dramatic improvements either with psychosocial or pharmacological interventions, and it may be months or even years before the full benefits of any pharmacotherapy will be observed [29]. For this reason such cases are often prematurely dubbed 'treatment resistant' after only several weeks of acute pharmacological interventions in the absence of any effective psychosocial strategies.The nub of the issue is not whether or not antipsychotic drugs are useful in helping to resolve acute psychotic episodes, but whether all cases of schizophrenic disorders benefit from continuation after they have recovered from all their symptoms, and at what point is it advantageous to discontinue them in a pharmacologically sound manner. The remainder of this paper will attempt to address these issues, and highlight current knowledge as well as future research questions that may clarify this important issue.Overall the evidence that antipsychotic medicines can be successfully withdrawn is highly pessimistic [30,31,32]. However, this is not surprising, because most studies have been conducted on people in the sub-acute phase of recovery from a major psychotic episode, when they have regained some stability in their conditions, but have had significant residual psychotic and non-psychotic symptoms and have been under substantial life stress in their efforts to return to life in the community. The evidence is very clear that at this point withdrawal from effective medication is extremely hazardous and common sense would predict that exacerbations are highly likely. Furthermore, because exacerbations have been defined as any sign of deterioration in the clinical state both minor and major exacerbations of both psychotic and non-psychotic symptoms, as well as withdrawal responses have been defined as treatment failure. The results are much less pessimistic when only major exacerbations, usually requiring re-admission to hospital, have been used as the criteria [32, 33]. In addition, withdrawal has usually involved double-blind immediate change from active to placebo medication; a procedure that would be considered poor practice by most clinicians to the extent that today it is extremely difficult to obtain ethical approval for such studies [34]. Baldessarini and his team have also demonstrated that when withdrawal has been conducted in a more gradual manner, following sound pharmacological principles, the rate of exacerbation has been significantly lower, approaching levels that would appear acceptable in clinical practice [35]. It is also important to acknowledge that even under optimal pharmacological treatment around 40% of patients will suffer major recurrences or exacerbations within the 1st year after an acute psychotic episode and around 60% within 2 years [36]. These rates do not appear to be substantially lower in first episode cases [37, 38]. When optimal pharmacotherapy is integrated with continued psychosocial stress management programmes this rate is reduced consistently by about 20% [36].It is evident that the period of maximum vulnerability to exacerbations is in the first 6 months after a hospital admission for an acute psychotic episode, when residual symptoms are usually present and re-entry stress is very high [10, 31,37,38,39,40,41,42]. It may be concluded that during this phase the protective benefits of antipsychotic medication are maximal, although it is crucial to ensure that dosages are optimal (i.e. minimally effective doses) so that any extra-biological and psychosocial stresses from side-effects are avoided. It could be argued that patients who have remained symptom free for 6 months after a major psychotic episode and have re-established their lifestyles may be considered for a trial of carefully managed medication withdrawal. Needless to say this opinion is often shared by the patients themselves, who feeling well again, begin to conduct their own withdrawal experiments without the expert advise of their prescribing physicians, usually stopping taking their medication abruptly, or even worse taking drugs sporadically.However, it would be wrong to assume from the extant data that patients who are asymptomatic on medications for 6 months or more will remain well when confronted with the biological stress associated with their withdrawal, even when this is conducted in a gradual way. Prognostic indicators that are more sensitive than overt symptoms may prove useful in determining whether vulnerability to exacerbations remains at a high level. Promising indicators include physiological arousal [43], environmental stress and coping factors [5, 44, 45]. The link between poor adherence to pharmacotherapy and recurrent episodes may be, at least partially, associated with impaired cognitive functioning in the early phase of a recurrence contributing to irregular compliance [46]. Hence measures of cognitive functioning may serve to detect increased vulnerability before symptomatic impairments become evident, and a fall-off in adherence to tablet taking may be a simple indicator of this. However, at present most of these measures require refinement and/or simplification before they can be useful in clinical practice. Thus, the best indicator probably remains the presence of residual psychopathology, and in particular the re-emergence of the characteristic features that precede an exacerbation for each individual [47, 48]. This careful monitoring by patients, key carers, case managers and psychiatrists is a core aspect of educational self-management interventions, that together with carer-based stress management training are now considered treatments of choice for all patients recovering from schizophrenic disorders [49, 50].To date the hypothesis outlined above has not been formally tested. Two studies involving recent onset cases both withdrew medication abruptly with substitution with placebos in a double-blind manner in symptom-free patients after 18 months of continued medication after an acute episode [32, 51]. In both studies exacerbation rates were high and almost all patients had their medicines restored after no more than a few months on placebo. However, neither study employed the educational and stress management procedures that have proven effective in the prevention of exacerbations.A third pilot study that employed continued integrated pharmacotherapy and extensive psychosocial treatments withdrew medicines gradually in patients who had been clinically stable for 24 months after an acute episode [52]. During the subsequent year that patients and caregivers monitored their early warning signs and continued regular structured problem solving, not one of the 12 cases experienced any exacerbations or deterioration in their social functioning. This small cohort represented two thirds of the entire sample and half were first episode cases. It should be noted that 24 months free of significant symptoms is a far cry from 6 months, and that the continued training in stress management (comprising structured problem solving and monitoring stress levels) throughout 2 years was possibly the key ingredient that enabled these cases to control their biological and environmental vulnerability factors. Without long-term training in the self-management of all types of environmental stress, continuation of pharmacotherapy appears necessary to prevent major symptom exacerbations. Although following similar principles but using somewhat different training methods, less structured psychosocial programmes have reported good outcomes in the absence of continued pharmacotherapy [16,17,18,19]. It is clear that we have extremely limited research on his important issue, and that no clear guidelines can be offered at present.The time appears long overdue to examine when and how to withdraw medicines from patients who may no longer benefit from them, or may never have benefited from them. Despite the good safety record of antipsychotics they do have a high risk of morbidity [53, 54] and a small risk of mortality [55, 56]. In the continuing absence of adequate studies to enable us to target pharmacotherapy in the 50% of cases who will derive specific benefits, most clinical guidelines assume that all people suffering a psychotic episode should receive these potent drugs for the rest of their lives. For those with persisting psychotic symptoms it may be argued that they function as sedative agents that reduce the distress of continued psychosis. However, newer psychosocial treatments now offer an alternative method of achieving this objective, and in a proportion of cases also contribute to clinically significant reductions in symptoms [52, 57]. As yet no study has withdrawn antipsychotic medication from patients with medication-resistant persisting psychosis. Furthermore, it is likely that lasting benefits from cognitive-behavioural interventions will only be achieved when patients learn to apply these psychosocial strategies in a competent manner, and when they receive continued monitoring and further intensive training in a long-term maintenance programme, similar to that provided for effective pharmacotherapy.In conclusion, a sequential approach to the long-term clinical management of schizophrenic disorders that integrates biomedical and psychosocial strategies is proposed. After initial intensive pharmacotherapy and stress management achieves remission of acute psychotic symptoms, doses of antipsychotics are lowered to minimally effective levels and combined with training in psychosocial stress management until a full and stable recovery from all symptoms of schizophrenia is achieved. Stable recovery is defined as 12 months free of symptoms for first episode cases and 24 months for recurrent episodes. At this stage both medication and psychosocial interventions are slowly withdrawn with close monitoring. Boosters of both types of interventions are targeted to periods when warning signs of impending exacerbations or stressful life crises threaten patients' continued mental health [48]. This latter targeted approach has not been adequately studied in stable remitted cases, where it may be a viable alternative to continued medication [58]. Such a sequential approach is straightforward, but requires a dedicated and well-trained team, that currently is seldom available in mental health services. Schizophrenia is a major public health problem that merits such dedicated and sophisticated treatment approaches that may improve the recovery rate from the 15–25% that has not changed for more than a century [2,3,4] to the 40–50% rates obtained in those preliminary studies that have integrated minimally effective doses of antipsychotics with extensive training in stress management [16,17,18,19, 52], thereby replicating the common practice of managing these disorders in developing countries where similar recovery rates have been observed [24, 25]. Well-controlled research studies are essential to further our understanding of these apparently optimal treatment strategies that are now recommended in most clinical practice guidelines [49, 50].