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The evidence for illness progression after relapse in schizophrenia
Schizophrenia Research, 1-3, 148, pages 117 - 121
It has long been suspected that relapse in schizophrenia is associated with disease progression in so far as time to response is longer, negative and other symptoms persist, some patients become treatment refractory and neuroprogression in terms of structural brain changes may occur. This article examines the evidence for illness progression after relapse in patients with schizophrenia. It reports on indirect evidence obtained from retrospective, naturalistic and brain-imaging studies, as well as a few prospective studies examining pre- and post-relapse treatment response. Findings suggest that the treatment response after relapse is variable, with many patients responding rapidly, others exhibiting protracted impairment of response and a subgroup displaying emergent refractoriness. This subgroup comprises about 1 in 6 patients, irrespective of whether it is the first or a subsequent relapse, and even when the delay between onset of first symptoms of relapse and initiation of treatment is brief. While there is a lack of well-designed studies investigating the post-relapse treatment outcome, available evidence gives sufficient cause for concern that, in addition to the considerable psychosocial risks, an additional risk of biological harm may be associated with relapse.
Keywords: Relapse, Schizophrenia, Progression, Psychosis.
While patients have high rates of response to treatment after a first-episode of schizophrenia ( Robinson et al., 1999a ) the subsequent outcome is generally poor, and the long-term course of illness is typically characterized by multiple relapses, persistence of symptoms and enduring cognitive and functional deficits ( Andreasen et al., 2005 ). Despite the prioritization of relapse prevention as a treatment goal ( Kane, 2006 ), about four out of five patients experience multiple relapses within the first five years of treatment ( Robinson et al., 1999b ). Relapses, characterized by acute psychotic exacerbation, may have serious psychosocial implications — in addition to the risk of self-harm and harm to others, relapses may cause patients and families distress, jeopardize friendships and relationships, disrupt education or employment, diminish personal autonomy, contribute to stigma ( Kane, 2007 ) and add to the economic burden of treating schizophrenia ( Ascher-Svanum et al., 2010 ). In addition, relapse may carry a risk of biological harm. It has been proposed that active psychosis reflects a period of disease progression insofar as patients may not return to their previous level of function and treatment refractoriness may emerge (Lieberman et al, 1996 and Wyatt, 1997). This review critically examines the evidence for illness progression after relapse. While other factors are likely to contribute to poor treatment response and persistence of symptoms, this review is restricted to the role of relapse in outcome. We conducted Medline searches using the search terms “relapse”, “recurrence” and “exacerbation” linked with “schizophrenia”, “psychosis” and “antipsychotic”. References of the identified studies were cross-checked for additional relevant studies.
2. Course of the illness
While the neurodevelopmental model for schizophrenia is widely accepted ( Rapoport et al., 2012 ), it is also recognized that the course of the illness is not static. Almost a century ago Kraepelin described the deteriorating course of schizophrenia as a core feature of the illness ( Kraepelin, 1971 ). However, the trajectory of that deterioration has been difficult to characterize, although it has been suggested that there are two phases — a time limited active phase of deterioration starting in the prodrome and persisting through the early years after a first psychotic episode, followed by a chronic plateau phase with relative stability of illness ( McGlashan, 2006 ). Indeed, it has been proposed that the first years of illness represent a “critical period” where the illness is at its most aggressive, risk of relapse is high, and deterioration is most likely to occur ( Birchwood et al., 1998 ).
3. The “neurotoxic psychosis” hypothesis
In a formative paper assessing the role of antipsychotics in treating schizophrenia, Wyatt (1991) reviewed the course of illness in studies reporting the long-term outcome in patients who received antipsychotic treatment and in those who did not. He reported a robust beneficial effect of antipsychotics and proposed that, in addition to treating the active psychotic symptoms these drugs prevented deterioration (i.e. they had a neuroprotective effect). He commented that, if a psychosis is allowed to proceed unmitigated, some patients are left with a damaging residual. He speculated that something associated with being psychotic may be responsible for the disease progression and posed the question whether there is something about being psychotic that is biologically toxic.
3.1. Duration of untreated psychosis
Supportive evidence for the toxic psychosis hypothesis has been forthcoming from studies investigating the relationship between the duration of untreated psychosis (DUP) and illness outcome. The first report of a relationship was in 1992 ( Loebel et al., 1992 ), and subsequently a multitude of studies with various outcome measures have mostly replicated these findings, indicating that longer DUP is an independent risk factor for poor illness outcome (Marshall et al, 2005 and Boonstra et al, 2012). However, McGlashan (2006) has cautioned that an association between DUP and outcome does not necessarily imply causality.
In addition to untreated first-episode psychosis, relapse episodes represent another period of active psychosis and it stands to reason that these periods may also be associated with disease progression and diminished treatment responsiveness, although far fewer studies have explored this possibility.
3.2.1. The evidence for illness progression after relapse
Considerable indirect evidence suggests deterioration after relapse. It has been observed that treatment response is better in first-episode schizophrenia than in chronic multi-episode schizophrenia ( Lieberman et al., 1993 ). Also, a study assessing the lowest possible antipsychotic dose by establishing the so-called neuroleptic threshold found that first-episode patients required lower doses of haloperidol to achieve optimal clinical response compared to multi-episode patients, raising the possibility that tolerance to the effects of antipsychotics may develop ( McEvoy et al., 1991 ). Lieberman et al., in their Hillside Hospital prospective first-episode cohort study reported that, in the course of their illness and in the context of subsequent psychotic episodes, patients may experience some decrease in their treatment response due to illness progression. (Lieberman et al, 1993 and Lieberman et al, 1996). Other naturalistic long-term outcome studies have suggested a link between relapse and deterioration. For example, the 1972 study by Manfred Bleuler ( Bleuler, 1978 ) on the long-term course of schizophrenic illness reported step-wise deterioration in patients with multiple psychotic episodes, and Johnson et al. (1983) observed lengthy periods of social and occupational recovery after relapse in a prospective follow-up study of patients with chronic schizophrenia who discontinued antipsychotic therapy. In a 7-year follow-up study Curson et al. (1985) found that 80% of patients with chronic schizophrenia had deteriorated and the degree of deterioration was significantly correlated with the number of relapses.
In a 15-year follow-up study of the natural course of schizophrenia and other non-affective functional psychoses in a Dutch incidence cohort of 82 first-contact cases, Wiersma et al. (1998) examined the course of illness after each of the first four psychotic episodes. They reported two findings that they described as striking. First, on average 17% (ranging from 8 to 27%) of the patients – i.e. one in six - did not remit after each psychotic episode, irrespective of which episode it was. Second, about 21% (ranging from 15 to 25%) – i.e. one out of every five – remitted only partially, with persistence of negative symptoms. In other words, poor treatment response in terms of persistence of positive and/or negative symptoms increased from 27% after the first psychotic episode to 47% after the psychotic fourth episode. There was also a gradual increase in the mean duration of each subsequent psychotic episode from 9 months for the second, 15 months for the third, and 27 months for the fourth episode.
A preliminary study ( Lieberman et al., 1996 ) has provided some direct evidence of changed treatment response after relapse. A sample of 70 patients with first-episode schizophrenia was treated according to a specific protocol and followed up over 5 years. If patients relapsed they were placed back onto their original treatment. Of those whose first episode remitted, 22 subsequently relapsed, and 6 patients had a second relapse. The time to remission for each episode was examined for the 22 patients who had two episodes and the 6 patients who had three episodes. Increased times to treatment response in succeeding episodes were recorded — median (SE) times to remission were 8.4 (1.3) weeks for the first episode and 11.9 (2.3) weeks for the second episode (p = 0.06) for 22 patients who had two episodes; and 4 (2.5) weeks, 7 (1.6) weeks and 24.1 (2.5) weeks for the first, second and third episodes respectively, for 6 patients who had three episodes (p = 0.001).
A recent study prospectively investigated whether illness progression and treatment refractoriness emerge following relapse in schizophrenia by comparing the treatment responses for the first and second episodes of schizophrenia in a cohort of patients followed up over 7 years and treated according to an identical protocol for two years after each episode. This was an open-label non-comparative outcome study comprising three phases. In the first phase 50 patients with a first-episode of schizophrenia, schizophreniform or schizo-affective disorder were treated with flexible doses of risperidone long acting injection (RLAI) for two years. For the second phase, 33 patients who had responded well and had achieved remission were entered into a 3-year intermittent treatment extension phase in which antipsychotic medication was reduced and discontinued. For the third phase 31 patients who relapsed in phase two entered a further 2-year treatment phase with RLAI for therecurrence episode. When the first- and second-episode treatment responses were compared it was found that, for the patients who remained in the study throughout (n = 14, 45%), response rates, remission rates, time to response, time to remission, functional outcome scores and modal RLAI doses were similar for the two treatment periods. However, treatment failure emerged in 5 (16%) participants who had previously responded well to treatment ( Emsley et al., 2013b ). These results concur with the observations of Wiersma et al. (1998) that some patients do not remit after relapse and suggest that relapse may be biologically harmful in perhaps 1 in 6 patients. The Emsley et al. (2013b) study failed to replicate the finding of delayed time to response after relapse originally reported by Lieberman et al. (1996) . One possible explanation for this could be that in the former study the patients were closely monitored in the intermittent treatment phase and medication was re-introduced at the first sign of re-emergence of symptoms (mean time from onset of first recognizable symptoms and re-initiation of treatment was 16 days ( Emsley et al., 2012a )). Therefore, the findings of this study may not be generalizable to clinical settings where there is likely to be a greater delay between the onset of relapse and initiation of treatment. It is possible that, with longer delays in re-introduction of treatment, a larger number of patients may fail to respond to treatment and more residual symptoms may persist.
3.2.2. Follow-up of participants in placebo-controlled studies
We identified three studies that have examined the effects of exposure to placebo on the subsequent treatment outcome. The first study traced 64 of 81 patients with chronic schizophrenia who had participated in a nine-month placebo-controlled trial and re-evaluated them seven years later. Relapse rates in the trial were 66% for those receiving placebo and 8% for those receiving active treatment. The authors reported that no long-term untoward effects of a single relapse during the trial were found insofar as there were no eventual group differences in any clinical or social outcome measures. However, they reported that 80% of the entire sample had deteriorated over the seven years, and there was a highly significant correlation between the number of relapses and the degree of social deterioration. The authors noted that it was perhaps therefore not surprising that none of the long-term deterioration could be attributed to placebo treatment during the trial ( Curson et al., 1986 ).
The second study was conducted retrospectively on data from 127 patients with relatively refractory chronic schizophrenia who had participated in a double-blind placebo study in the National Institute of Mental Health Neuropsychiatric Research Hospital in the United States of America. Participants were hospitalized and received placebo treatment for at least 6 weeks. The subsequent treatment response when antipsychotics were re-introduced differed markedly among patients. Many responded rapidly, returning to previous levels of symptom improvement by day 3 while others failed to do so by day 42. At discharge, which was about 340 days after the placebo treatment period, symptom improvement had returned to baseline levels although there was again much individual variability, with some patients exhibiting worsening. However, a similar degree of worsening was also observed in the comparator group who had received antipsychotic treatment throughout, suggesting that illness deterioration does not only occur during periods when patients are off medication. The authors concluded that, given a sufficiently lengthy recovery period, no detrimental long-term effects of exposure to placebo are likely ( Wyatt et al., 1999 ).
The third study comprised a recent post-hoc analysis of data from a multinational relapse-prevention clinical trial comparing paliperidone palmitate with placebo in patients with chronic schizophrenia. The design of this study provided a unique opportunity to compare the response to antipsychotic treatment before and after relapse. The participants underwent an initial open-label treatment phase of 33 weeks, a double-blind phase during which stabilized patients were randomized 1:1 to either continue paliperidone palmitate or receive placebo, and a further 52-week open-label extension phase. The analysis was conducted on 97 patients with schizophrenia who relapsed while receiving placebo. On average, these patients had slightly reduced response to treatment after relapse, with higher mean PANSS total endpoint scores for the post-relapse treatment phase (56.7[12.68]) as compared with the endpoint scores prior to relapse (54.5[11.74]) (p = 0.026). This difference, although statistically significant, is of doubtful clinical significance. More notably, 14 of the 97 patients (14.4%) who had initially responded favourably to treatment met a priori nonresponse criteria in the post-relapse treatment phase, providing further evidence that treatment refractoriness may evolve in a subset of patients after relapse, even in the chronic stages of illness (Emsley et al, 2012b and Emsley et al, 2013b). This is contrary to the proposal that illness progression occurs largely in the early years of illness (Birchwood et al, 1998 and McGlashan, 2006). It needs to be noted however that in the same study relapses occurred in 18% of the patients who were randomized to ongoing treatment in the double-blind phase. These relapses do not necessarily represent emergent refractoriness as there are other factors that may precipitate relapse ( Alvarez-Jimenez et al., 2012 ). However, it does raise the possibility that in some cases refractoriness may evolve in patients receiving ongoing antipsychotic treatment.
The pattern of treatment–refractoriness developing abruptly in a subset of patients suggests a threshold phenomenon, and is consistent with a sensitization, or “kindling” model perhaps involving neostriatal dopaminergic receptor supersensitivity ( Emsley et al., 2013a ).The association between frequent relapse and poorer outcome does not necessarily imply causality. It could be that both are manifestations of a more severe or intrinsically treatment-refractory illness which is characterized by poorer treatment response, greater propensity to relapse, and poorer outcome. Additionally, the association of relapse and poor outcome could be linked to some other factor such as substance or poor medication adherence.
3.2.3. Brain imaging and relapse
Brain-imaging studies have demonstrated that structural brain alterations occur extensively in schizophrenia. A recent meta-analysis in over 18 000 subjects on cross-sectional volumetric brain alterations in both medicated and antipsychotic-naive patients reported that intracranial and total brain volume was significantly decreased. The most prominent changes were observed for gray matter structures and this was associated with longer duration of illness and higher dose of antipsychotic medication ( Haijma et al., 2012 ). While structural alterations are present at illness onset, there is now accumulating evidence from longitudinal studies that brain volume changes are progressive during the course of the illness, although many of the studies have been limited by small samples and short or infrequent follow-up intervals. In a large longitudinal study it was shown that different age-related trajectories of brain tissue loss are present in patients compared with healthy subjects, suggesting that brain maturation that occurs in the third and fourth decade of life is abnormal in schizophrenia ( van Haren et al., 2008 ). The Iowa, USA Longitudinal Study prospectively studied 542 first-episode patients for up to 18 years. Adequate structural magnetic resonance imaging data were available for 202 patients and 125 control subjects. A significant decrease in multiple gray matter regions and white matter regions and a corresponding increase in cerebrospinal fluid were reported. The changes were most severe during the early years after onset of illness and were observed only in a subset of patients ( Andreasen et al., 2011 ). However, an investigation by the same group of the relationship between duration of untreated psychosis and brain volume measures in 156 first-episode patients failed to find a significant relationship and the authors concluded that the absence of significant correlations suggests that untreated initial psychosis has no direct toxic neural effects. They further argued that large-scale initiatives designed to prevent neurodegeneration may be based on incorrect assumptions that neurotoxicity or cognitive deterioration may be avoided ( Ho et al., 2003a ). In another study the same group reported on 211 patients who underwent a series of neuroimaging studies soon after illness onset. Longer follow-up correlated with smaller brain tissue volumes and larger cerebrospinal fluid volumes. Greater intensity of antipsychotic treatment was associated with indicators of generalized and specific brain tissue reduction. More antipsychotic treatment was associated with smaller gray matter volumes and progressive decrement in white matter volume. Illness severity was only modestly correlated with volume reductions. The authors concluded that antipsychotic treatment has a subtle but measurable influence on brain tissue loss over time ( Ho et al., 2003b ). Therefore, although progressive brain changes appear to occur in schizophrenia, it is not clear whether these changes are related to periods of not receiving treatment or to the antipsychotic medication itself. We are aware of two neuroimaging studies addressing the relationship of neuroprogression to relapse. In the first study van Haren et al. (2007) reported the findings of a 5-year longitudinal study of MRI whole brain scans from 96 patients with schizophrenia and 113 matched healthy controls. They found that excessive decreases in gray matter density occurred in the left superior frontal area, left superior temporal gyrus, right caudate nucleus, and right thalamus as compared to healthy individuals. Notably, excessive gray matter density decrease in the superior frontal gray matter was related to increased number of hospitalizations, suggesting an association between number of relapses and degree of morphological brain change. In the second study, Andreasen et al. (2013) analyzed longitudinal data from 202 first-episode schizophrenia patients drawn from the Iowa Longitudinal Study who were regularly scanned over an average of 7 years. They computed measures of the number and duration of relapses and related them to structural MRI measures. They found that relapse duration, but not relapse frequency, was related to significant decreases in general and regional (particularly frontal) brain measures. They concluded by suggesting that extended periods of relapse may have a negative effect on brain integrity in schizophrenia.
4. The evidence against disease progression
It needs to be cautioned that not all evidence points to illness progression after relapse. It has been reported that patients' symptoms return rapidly to baseline levels when antipsychotic medication is re-introduced shortly after relapse ( Glovinsky et al., 1992 ). Also, a response trajectory analysis in early psychosis patients suggested that, while some patients do poorly initially, response is generally characterized by amelioration ( Levine and Leucht, 2010 ). Additionally, the clinical and neurobiological evidence for neurotoxicity of psychosis has been reviewed and found wanting ( McGlashan, 2006 ). Finally, while neuro-imaging studies indicate progressive structural brain changes over time, the same has not been found for cognitive impairment. Cognitive impairment has been reported to be present at illness onset, but remains stable at least over the early course of schizophrenia ( Albus et al., 2006 ).
A recent publication has challenged the concept of schizophrenia as a progressive brain disease, citing the following as evidence against neurodegenration: 1) While longitudinal studies indicate that approximately 25% of individuals with schizophrenia have a poor outcome, few of them show incremental loss of function that is characteristic of neurodegenerative disorders; 2) decreases in brain tissue volumes reported in neuro-imaging studies could be explained by the effects of antipsychotic medication, substance abuse, effects of lifestyle or elevated glucocorticoid levels associated with chronic stress; 3) cognitive functioning does not appear to deteriorate over time; and 4) 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 ( Zipursky et al., 2012 ).
In addition to the potentially serious psychosocial consequences of relapse, there appears to be a risk of biological harm insofar as treatment refractoriness may emerge and brain morphological changes may occur. The results of studies suggest that the treatment response after relapse is variable, with many patients responding rapidly, others exhibiting protracted impairment of response ( Wyatt et al., 1999 ) and a subgroup developing emergent treatment refractoriness. This subgroup appears to comprise about 1 in 6 patients, irrespective of whether it is the first or a subsequent relapse episode (Wiersma et al, 1998 and Emsley et al, 2012b), and even when the duration between onset of relapse and initiation of treatment is brief ( Emsley et al., 2012a ). That this phenomenon is not limited to the early stages of illness is not consistent with the “critical period” hypothesis ( Birchwood et al., 1998 ), and suggests that disease progression may continue in the chronic stage of illness. This has important clinical implications insofar as our focus on relapse prevention should not only be directed towards the early years of illness.
There is a lack of well-designed studies investigating the post-relapse treatment outcome. More prospective studies are indicated to further elucidate the role of relapse in the progression of the illness. These studies should compare pre- and post-relapse outcome in terms of clinical, cognitive and imaging changes, and should include patients in an early phase of illness as well as multi-episode samples. They should investigate the relationship between post-relapse emergent refractoriness and structural brain changes. They should also investigate whether treatment refractoriness emerges in patients who are receiving ongoing treatment. In the meantime, there is sufficient cause for concern that, in addition to the psychosocial risks, there may be an additional risk of biological harm associated with relapse. Given our limited success in relapse prevention ( Robinson et al., 1999a ), novel approaches to this major clinical challenge are indicated ( Gleeson, 2005 ).
Role of funding source
All of the authors met International Council of Medical Journal Editors criteria and all those who fulfilled those criteria are listed as authors. All authors provided direction and comments on the manuscript. They provided intellectual contributions and approved the final draft submission to the journal.
Conflicts of interest
Drs. Emsley, Chiliza and Asmal are employed as faculty members by University of Stellenbosch, South Africa. Dr Emsley has participated in speakers/advisory boards and received honoraria from AstraZeneca, Janssen, Lilly, Lundbeck, Pfizer, Servier, Otsuka and Wyeth. He has received research funding from Janssen, Lundbeck and AstraZeneca.
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Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, 7505, Cape Town, South Africa
Corresponding author at: University of Stellenbosch, Room 2027, 2nd Floor Clinical Building, Francie van Zijl Drive, Tygerberg 7500, Cape Town, South Africa. Tel.: + 27 21 9389766; fax: + 27 21 9389738.
☆ This submission is for the special section on relapse in schizophrenia guest edited by Emsley and Zipursky.
© 2013 Elsevier B.V., All rights reserved.