Duration of antipsychotic treatment and risk of relapse after discontinuation

A key clinical question is what the risk of relapse is after a single episode of psychosis, and whether the risk is reduced with a longer treatment period. Despite the fact that several studies have assessed the risk of relapse after discontinuation of antipsychotic medication, there is no consensus on the recommended duration of treatment. A recent systematic review of guidelines for maintenance treatment of schizophrenia found that, of 14 such guidelines, discontinuation of antipsychotic medication after a first-episode of schizophrenia was partially recommended after 1 to 2 years in six, not recommended in two, and not mentioned in six [28].

It can be seen from Table ​Table11 that the duration of treatment periods before withdrawal varied. There was no indication of reduced risk with longer treatment periods - in fact, the study with the longest prior treatment period (2 years) [10] had the highest risk of symptom recurrence. This has implications for clinical practice, and suggests that lengthening the recommended treatment period after a first psychotic episode does not reduce the risk of recurrence. It could even be speculated that a longer treatment duration might increase risk of relapse, although the study with the shortest reported treatment period (3 months in remission) had an equally high symptom recurrence rate [21].

Time to relapse after treatment discontinuation

The interval between treatment discontinuation and symptom recurrence is highly variable. Three of the eight studies investigating relapse rates after treatment discontinuation (Table ​(Table1)1) reported mean times to relapse of 235 days [21], 323 days [27] and 207 days [10]. This could create the impression that patients remain well for a considerable period – perhaps months – before relapse. While this may be so for some, in many cases relapse occurs within days or weeks of discontinuation. In our own study all patients were treated with long-acting risperidone injection which is associated with the persistence of steady state blood levels for several weeks after the last injection [29]. Despite this several symptom recurrences occurred within a few weeks of the last injection, suggesting that relapse occurs with treatment reduction even in the presence of substantial antipsychotic occupancy of D2 receptors. Symptom recurrence shortly after treatment discontinuation is well recognized and has raised the question whether relapse may be a feature of drug withdrawal rather than the re-emergence of an underlying illness, at least in some patients [30]. The term “neuroleptic-induced supersensitivity psychosis” was originally proposed, and was linked to a hypothesised underlying mechanism of increased sensitivity of mesolimbic dopamine D2 receptors as a consequence of chronic D2 blockade with antipsychotic medication [31]. Moncrieff [30] suggested an alternative term of “rapid onset psychosis”, which does not imply underlying mechanisms. In a review article he pointed out that if the process of antipsychotic drug withdrawal is in itself psychotogenic, then the psychosis would be expected to have its own distinct symptom profile, different to that of the underlying illness. He underlined the need for further urgent research in this area. We were able to investigate this possibility by comparing the factor analysis derived symptom domains observed in the first psychotic episode with that of a recurrence episode. We found that symptom expression profiles were similar for the two episodes and, except for the positive domain, of similar severity [10]. While this counts against a role for a distinct antipsychotic withdrawal syndrome, we did not specifically examine the symptom profiles of those patients with rapid onset of relapse.

Onset of relapse may be abrupt

Reliable early warning signs of relapse would be of great value in clinical settings. They would offer the opportunity of early intervention and prevention of florid relapse. Indeed, success has been reported in identifying early signs of relapse [32]. However, whereas the onset of a first episode of psychosis may be gradual and is typically heralded by a prodromal period lasting months to even years [33], this does not appear to be the case in relapse episodes. For these reasons it has been recommended that the term “prodromal symptoms” be restricted to precursors of a first psychotic episode and "early warning signs" be used to describe antecedents of psychotic relapse [34]. Studies suggest that it may be difficult to identify many patients who are at risk of imminent relapse in clinical practice, and that early warning signs are relatively unreliable predictors of relapse [35-37]. Using a structured interview for early signs of relapse, Herz and Mellville [38] assessed 145 patients with chronic schizophrenia and 80 family members. Approximately half of the patients and 68% of the family members indicated that the interval between the onset of noticeable symptoms and relapse was at least 1 week. Between 8 and 15% of patients and families gave this interval as 1 to 3 days and 7 to 8% patients and 11% families indicated that it was less than 1 day. Birchwood et al. [32] reported that 75% of relatives of patients noticed changes from 2 to 4 weeks before relapse. Henmi [39] retrospectively investigated 61 schizophrenic outpatients in remission, of whom 33 had relapses in the past 20 months. Non-specific (non-psychotic) prodromal symptoms were identified 4 weeks prior to relapse in 64%, although no changes were detected in global assessment of function. Tarrier et al. [40] compared symptoms of 16 patients who relapsed within 9 months after discharge with 16 patients who had not, and found a significant increase in depressive symptoms and hallucinations in the preceding month in those who had relapsed. In a review of the pertinent literature Norman and Malla [35] concluded that prodromal symptoms have only modest power as predictors of relapse. In a study investigating the predictive validity of self-reported early warning signs of relapse in a cohort of 60 remitted first-episode patients, the Early Signs Scale (ESS) achieved adequate sensitivity but poor specificity and positive predictive validity in predicting relapse or symptom exacerbations [41].

One difficulty in interpreting results of longitudinal studies assessing precursors of relapse is that the relapse events occur at different timepoints in different individuals. Therefore, group mean symptom scores at assessment visits do not give an accurate picture of symptom changes prior to relapse. To circumvent this problem we analysed precursors of relapse in a different way in two studies [10,11]. With the relapse visit as starting point we grouped patients with the preceding visits arranged before that (i.e. visit −1, -2, -3). We did not find a gradual worsening of symptoms prior to relapse, but rather that patients remained in remission right up until and including the visit prior to relapse. Retrospective estimates of caregivers indicated a mean duration 16.3±10.9 days between the onset of the first recognisable symptoms and psychotic symptom recurrence, with several patients relapsing within a matter of days [10]. Our analyses were conducted retrospectively and it is possible that with more frequent assessments and with the use of more sensitive instruments designed specifically to detect prodromal symptoms more subtle symptoms could have been detected. Nevertheless, the results suggest that in everyday clinical practice relying on early warning signs to prevent full-blown relapse would not be feasible. Frequent and careful follow-up together with the use of instruments specifically designed to detect early warning signs would be necessary [42].

Once illness recurrence occurs symptom severity rapidly returns to levels similar to the initial psychotic episode

We observed a rapid return of symptoms in the relapse episode to severity levels similar to those in the acute phase of the first psychotic episode. This rapid return of symptoms occurred despite marked differences in estimated duration of untreated psychosis for the first-episode (129 ± 199 days) [43] and the second episode (16.3 ± 10.9 days) [12]. This finding is consistent with that of Chen et al. who found no significant correlation between symptom severity and time to receiving treatment [22].

Is relapse associated with disease progression?

In addition to its associated psychosocial risks, active psychosis may affect the brain in a more fundamental way. It has been suggested that psychosis may be neurotoxic and that acute psychotic exacerbations represent active periods of a morbid process that leads to disease progression and to impairment of treatment response [4,44,45]. Supportive evidence was initially provided by the well replicated finding that a longer duration of untreated psychosis is associated with a poorer long-term outcome [46]. Similarly, relapses also represent episodes of active psychosis and may also be associated with illness progression. However, to date there is limited empirical evidence to support the neurotoxic psychosis hypothesis, and specifically for illness progression after relapse. A search of the literature revealed the following: 1) Treatment response has been observed to be better in first-episode schizophrenia than in chronic multi-episode schizophrenia [45]. 2) A study utilizing the neuroleptic threshold principle found that first-episode patients required lower doses of haloperidol to achieve optimal clinical response than multi-episode patients [47], raising the possibility that tolerance to the effects of antipsychotics may develop. 3) Eighty % of patients with schizophrenia were judged to have deteriorated over time in a 7-yr follow-up study, and the degree of deterioration was significantly correlated with the number of relapses that patients experienced [48]. 4) In another long-term follow-up study of the natural course of schizophrenia, Wiersma et al. examined the course of patients over the first four psychotic episodes. They reported a remarkable observation, namely that, on average 1 in 6 patients failed to remit after each episode, irrespective of which episode it was. 5) More direct evidence was obtained in a preliminary study comparing treatment response times of first and subsequent episodes, where median (SE) times to remission were significantly longer for the second episode and third episode [4]. On the other hand, there is evidence to suggest that disease progression does not occur as a consequence of relapse: 1) It has been reported that patients’ symptoms rapidly return to baseline with resumption of antipsychotic medication shortly after recurrence of psychotic symptoms [49]; 2) In patients with relatively refractory schizophrenia who were exposed to placebo treatment for at least 6 weeks and experienced symptom worsening, it was found that, given a sufficiently lengthy recovery period, symptom levels returned to those of baseline [50]; 3) Response trajectory analyses in early psychosis suggest that, while some patients respond poorly initially, response is generally characterised by amelioration [51]; 4) The clinical and neurobiological evidence for neurotoxicity of psychosis has been reviewed and found wanting [52]; 5. Finally, a recent paper challenges the concept of schizophrenia as a progressive brain disease, arguing the following: a) While longitudinal studies report a poor outcome in approximately 25% of patients, few of them describe incremental deterioration that would characterize neurodegenerative disorders; b) while some neuro-imaging studies report brain tissue volumes decreasing over time, this could be attributed to the effects of antipsychotic medication, substance abuse, effects of lifestyle or elevated glucocorticoid levels associated with chronic stress; c) cognitive functioning does not appear to deteriorate over time; and d) the deterioration that occurs in some patients could reflect poor access, or adherence, to treatment, the effects of concomitant conditions, and social and financial impoverishment [53].

We were able to compare treatment response before and after relapse in both a first-episode [12] and a multi-episode [11] sample. We found that in both groups treatment response was highly variable, with some patients rapidly returning to pre-relapse symptom severity levels, and others having a more protracted recovery. Most notably, we found evidence of emergent treatment failure in a subset of 16% of the first episode and 14% of the multi-episode samples respectively. These results are consistent with the findings of Wiersma et al. [54] who reported that on average 1 in 6 patients failed to recover from each of their first four relapses, irrespective of which relapse it was.