The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study1 is the single largest treatment study of patients with chronic schizophrenia. The primary outcome measure in this seminal study was the incidence of "all-causes discontinuation of medication" in the first 18 months of the trial. The term all-causes discontinuation is defined as discontinuation of treatment for any reason, including lack of efficacy, intolerable side effects or other adverse effects, and patient and/or clinician decision to stop medication altogether or switch to a different medication. Thus, medication adherence is an important component of this measure. The 74% all-causes discontinuation rate reported in the CATIE study was an important finding that has focused the field on exploring the question of why patients discontinue medications. Nevertheless, many clinicians were not surprised by this finding, given that medication switches and nonadherence to treatment are common in the course of chronic schizophrenia and represent important treatment issues.
Although it was conducted in patients with chronic illness, the CATIE study provides background for considering medication discontinuation in first-episode psychosis (FEP). Recently, there has been tremendous growth in research on FEP. Initial treatment of FEP represents a critical juncture that influences patient and family attitudes about subsequent treatment, as well as the longitudinal course and outcome of illness. Two landmark studies have brought the issue of all-causes medication discontinuation in patients with FEP to the forefront of clinical attention. In the Comparison of Atypicals in First Episode (CAFE) study of 400 patients with FEP, McEvoy et al.2 reported a 70% all-causes discontinuation rate. Of note, over half of all the discontinuations in this study occurred against the recommendations of the treating clinicians. That the incidence of all-causes discontinuation was essentially the same in patients with FEP as in those with chronic schizophrenia was a surprising finding, especially given that both studies employed largely the same methodology, with the exception that switching medications was not an option in the CAFE study. In the recently published European First Episode Schizophrenia Trial (EUFEST), Kahn et al.3 reported a 42% all-causes discontinuation rate among the 498 patients in this study. Although this rate was not as high as the discontinuation rate in the CAFE study, it was still substantial.
These two studies suggest that medication discontinuation is a major issue in FEP from the onset of treatment. Thus, further exploration of the overall incidence, clinical outcomes, reasons, and potential interventions for medication discontinuation in FEP is warranted. Yet this is a challenging undertaking, particularly because much of the existing literature on the treatment of FEP has focused on efficacy or relapse prevention. All-causes discontinuation is reported in only a subset of these studies, and information on specific causes of discontinuation was included in even fewer studies. This review, which is largely restricted to a consideration of second-generation antipsychotics (SGAs), first provides a brief overview of data on the efficacy of medications in FEP. The clinical implications of medication discontinuation in FEP are then considered, and an analysis of all-causes discontinuation of SGAs in treatment trials of FEP is presented. Next, reasons for medication discontinuation and strategies for improving adherence in FEP are reviewed. Finally, the issue of how to decide whether to discontinue medication or to provide continued maintenance treatment following remission of FEP is explored, since there is little evidence to guide this decision. The goals of this review are to estimate the incidence of SGA discontinuation in FEP, to begin to develop a profile of the typical patient who discontinues treatment, and to identify potential interventions to decrease discontinuation rates.
Evidence for the Efficacy of Second-Generation Antipsychotics in First-Episode Psychosis
A systematic review of the literature was performed to identify studies published between 1997 and 2008 that investigated the efficacy of SGAs in first-episode psychosis. A total of 28 studies, 21 that investigated single agents,4-24 and 7 that compared multiple SGAs2,3,25-29 were identified on PubMed by searching using the following terms, "first-episode psychosis" and "risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, or paliperidone" and by a thorough review of references from studies that were identified. These studies generally either compared two fixed doses of the same medication or compared one or more SGAs with a first-generation antipsychotic agent (FGA). The general characteristics of these studies are outlined in Table 1.
Risperidone has been the most widely studied single SGA to date in FEP, with 17 published studies. At present there is no information on the use of paliperidone in FEP. However, the adverse-effect profile of this SGA30 might make it a more advantageous choice over risperidone (from which it is derived) in this patient group. Published data on the use of olanzapine in FEP come from 13 studies. Five studies concerning the use of quetiapine in the treatment of FEP have been published. Aripiprazole and ziprasidone have each been investigated in only one study. One example of an evidence-based guideline for treating patients with psychotic disorders is the Texas Medication Algorithm Project (TMAP).31 Based on the available data, the most recent iteration of the TMAP does not preferentially endorse any particular antipsychotic as a "lead-off" agent in FEP.
While 21 of the 28 studies identified involved single SGA agents, 7 studies compared the relative efficacy of several SGAs in FEP.2,3,25-29 Apiquian et al.25 compared the efficacy of low-dose haloperidol with risperidone and olanzapine in a 6-month, open-label trial in 42 patients with FEP. All three treatment groups showed improvement in symptoms, but a likely source of bias was that patients incurred direct cost for treatment with risperidone, whereas olanzapine was provided at no cost. Crespo-Facorro et al.26 completed a 6-week, randomized trial of risperidone, olanzapine, and haloperidol in 172 patients with a first-episode of nonaffective psychosis. Symptom improvement and the proportion of responders were similar in all three treatment groups, with no statistical differences found between the groups. Robinson et al.28 compared 4-month treatment outcomes in 112 patients with schizophrenia spectrum disorders treated with olanzapine and risperidone. They found that the clinical response rate did not significantly differ between olanzapine (43.7%) and risperidone (54.3%). The all-causes discontinuation rate in this study was 20.5%. Montes et al.27 evaluated 182 patients with FEP who were part of a larger, naturalistic study of patients treated with olanzapine, risperidone, or an FGA. They found similar improvements on efficacy measures, including the Clinical Global Impressions-Severity scale and the Global Assessment of Functioning scale. In the CAFE study,2 McEvoy et al. completed a 52-week randomized, double-blind, flexible-dose, multicenter study of the efficacy (measured by rates of treatment discontinuation) of olanzapine, quetiapine, and risperidone in 400 patients with first-episode psychosis. They reported no differences in all-causes treatment discontinuation rates for olanzapine (68.4%), quetiapine (70.9%), and risperidone (71.4%). In the EUFEST study,3 Kahn et al. presented findings from a 1-year, open, randomized, double-blind, multicenter study comparing amisulpride, quetiapine, olanzapine, and ziprasidone to a low dose of haloperidol in an unselected sample of 498 patients with first-episode schizophrenia and minimal prior exposure to antipsychotics. The all-causes discontinuation rate, which was the primary outcome measure in this study, was 41.6%.
Clinical Implications of Medication Discontinuation in First-Episode Psychosis
The efficacy of SGAs in the treatment of FEP is well documented. However, as noted in the recent CAFE and EUFEST studies, there is an alarmingly high incidence of medication discontinuation in FEP. Keshevan et al.32 argued that nonadherence to medication is the most robust predictor of 5-year outcome in FEP. What, then, are the clinical implications of medication discontinuation? A limited number of studies are available to address this question. Medication discontinuation has an impact on the likelihood of remission during the initial treatment of FEP. In a sample of 107 patients with FEP, Malla et al.33 found that 82% of patients achieved remission over a period of 2 years. In this study, greater medication adherence was a significant predictor of remission status. As reviewed by Wyatt et al.,34 early interventions with antipsychotic medication in FEP are also associated with decreased long-term morbidity. Beyond the initial acute response to treatment of FEP, the consequences of medication discontinuation also include an increased risk of relapse as well as a greater likelihood of the emergence of treatment-resistant symptoms.35-38 There is almost a five-fold increase in relapse rates after medication discontinuation in FEP.38,39 Medication discontinuation also influences functional outcomes. In 66 patients with FEP, Malla et al.40 found that adherence to medication at 1 year was a significant predictor of social relations, working memory for social relations, ability to perform activities of daily living, and level of psychomotor poverty. Bachmann et al.41 followed 40 patients with FEP for 14 months after hospital discharge and found that adherence to medication was the most important predictor of outcome-as measured by the Positive and Negative Syndrome Scale, the Strauss-Carpenter Scale, and the Global Assessment of Functioning scale-during the follow-up period.
Incidence of Discontinuation of Second-Generation Antipsychotics in First-Episode Psychosis
While individual studies have presented data on all-causes discontinuation, either as a primary or secondary outcome measure, to date the overall incidence of medication discontinuation in FEP has not been reviewed. As described above, a total of 28 studies of SGAs in FEP were identified. From these studies, data on medication discontinuation were identified in 18 treatment trials that involved a total of 2,905 patients. Data were stratified based on individual SGAs. These trials included data from 12 studies of risperidone, 10 studies of olanzapine, 4 studies of quetiapine, and 1 study of ziprasidone. No studies of aripiprazole in FEP were identified that included data on medication discontinuation. The available data on all-causes discontinuation are summarized in Table 2.
The mean duration of these studies was 34.8 weeks, and the overall all-causes discontinuation rate was 40.8%. All-causes discontinuation rates and mean duration of studies were 39.7% and 28 weeks for risperidone; 37.9% and 32.9 weeks for olanzapine; 56.4% and 55 weeks for quetiapine; and 37.8% and 52 weeks for ziprasidone. There are several obvious limitations to this methodology. Several studies presented data on discontinuation at multiple time points for the same patient population (e.g., Gutierrez et al.8 for risperidone, and Green et al.7 and Lieberman et al.14 for olanzapine). Thus, the studies for individual SGAs are not independent. It might be expected that discontinuation rates would increase in proportion to the duration of the trial (that is, higher all-causes discontinuation rates would be expected in longer trials). However, the small number of studies, particularly for quetiapine and ziprasidone, limited the ability to analyze for such a trend. It was also not possible to control for factors such as patient demographics, medication dosage, and assessments of medication adherence. Furthermore, because several trials compared multiple SGA agents "head-to-head" and these data were stratified by individual SGA, it was also not possible to compare all-causes discontinuation rates between the various agents. However, this estimate of the incidence of all-causes discontinuation is consistent with findings from the EUFEST study. Furthermore, there are no previous reviews of the incidence of medication discontinuation in FEP; thus, even this "crude" estimate provides useful information and further validation of findings from the CAFE and EUFEST studies.
A more detailed analysis of specific causes of discontinuation was not feasible, owing to the heterogeneity mentioned above as well as the lack of this information in many studies. However, within individual studies, the incidence of several specific reasons for discontinuation is notable. In the EUFEST study, Kahn et al.3 found that 34.6% of patients (36/104) randomized to quetiapine and 20.7% of patients (17/82) randomized to ziprasidone discontinued medication due to a lack of efficacy. It is difficult to interpret these findings, given the limited number and sample sizes of studies of these two SGAs. In two other studies,2,7 the patient's decision to discontinue medication against the preferences of the treating clinician was a common reason for discontinuation, occurring in 41.5% of all patients (166/400) in the CAFE study2 and 22.9% of patients (30/131) on olanzapine in the study by Green et al.7 This finding suggests a potential area for further exploration to improve medication adherence.
Reasons for Medication Discontinuation in First-Episode Psychosis
A number of risk factors for medication discontinuation in psychosis have been consistently identified in literature reviews, including severity of psychopathology, impaired insight, comorbid substance abuse, medication side effects or adverse effects, poor social support, and other barriers such as inability to afford medications.42,43 Several studies have specifically explored predictors of medication discontinuation in FEP.44-56Table 3 summarizes the significant findings from this literature. Further details of several studies are given below.
Verdoux et al.44 followed 65 patients with FEP at 6-month intervals for 2 years. They found that 53% of patients interrupted their medication against medical advice at least once during the follow-up period. Predictors of poor medication adherence included lower baseline occupational status, alcohol abuse, and the intensity of suspiciousness and delusions.
Coldham et al.45 followed 200 patients admitted to an early psychosis program. They found that, in the first year of the program, 39% of patients were nonadherent to medications, 20% were partially adherent, and 41% were adherent. Greater positive symptoms, more relapses, more alcohol and cannabis use, decreased insight, and poorer quality of life were found among nonadherent patients.
In an epidemiological sample of 189 patients admitted for treatment of FEP from the Suffolk County (New York) Mental Health Project, Mojtabai et al.54 found that, in the first year after initiation of treatment, 63% of these patients had one or more gaps (i.e., periods of nonadherence) in antipsychotic treatment, and 51% had gaps of at least 30 days. They found that most gaps occurred soon after discharge, and that 73% of gaps were initiated by patients. Another study from this patient population55 found that SGAs (versus FGAs) were associated with a lower risk of medication gaps. In a study of 59 patients with FEP followed for the first 3 months of treatment, Kampman et al.46 found that determinants of medication nonadherence were side effects, male gender, lack of social activities, low scores on PANSS positive symptoms but high total PANSS scores, and younger age. The authors also noted "during the acute phase of psychosis, insight and attitudes toward treatment are the sole determinants of the patients' prediction of compliance."
Novak-Rubik and Tavcar47 studied predictors of medication nonadherence in 56 males with FEP in a 1-year, naturalistic, follow-up study and found that 54% of these (30/56) patients dropped out of treatment, 70% of whom (21/30) relapsed. Significant predictors of nonadherence included a diagnosis of schizophrenia (versus schizophreniform or schizoaffective disorder), positive symptoms at admission, and impaired insight at discharge. Of note, only 25% of these patients were treated with SGAs.
Robinson et al.52 studied medication discontinuation during the first year of treatment and following recovery from the first relapse in 112 patients with FEP. Of these 112 patients, 29 (26%) stopped medication during this study. They found that discontinuation during the first year of treatment was more likely among patients with poorer premorbid cognitive functioning.
In the West London first-episode schizophrenia study, Mutsatsa et al.49 assessed medication adherence in 101 patients with FEP. Negative attitudes toward medications and lack of insight were significant predictors of poor adherence. This study did not find an association between medication adherence and side effects, negative symptoms, disorganization, subjective well-being, or substance abuse.
Kamali et al.48 assessed 60 patients with FEP for medication adherence at 6 month follow-up. Of these 60 patients, one-third (n = 20) were nonadherent as measured using the Compliance Interview.57 Significant predictors of nonadherence included high baseline positive symptoms, lack of insight at baseline, alcohol abuse, and previous drug abuse. The authors also found that impaired insight was the best predictor of nonadherence in patients without comorbid substance abuse. They argued that the constellation of these factors constitutes "an identifiable subgroup of patients with first episode schizophrenia [that] is at high risk of early non-adherence to medication."
In a 5-year prospective study of 119 patients admitted for FEP, de Haan et al.51 found that hostility and uncooperativeness, as well as involuntary admission, were significant predictors of medication nonadherence
Perkins et al.50 examined the relationship between medication nonadherence and patient beliefs using prospective data from 254 patients recovering from FEP. They found a greater likelihood of nonadherence for at least 1 week among the patients who had a lower degree of belief in the need for treatment or who believed that medications were of little benefit. Using data from this same patient population, McEvoy et al.56 found that increased insight throughout the study was associated with a longer time to medication nonadherence; however, baseline insight was not significantly related to the probability of discontinuing medication.
In a subinvestigation based on data from the CAFE study, Perkins et al.53 compared the 115 patients who discontinued treatment against medical advice with the 119 patients who completed the study. Poor treatment response and low medication adherence were independent predictors of discontinuation against medical advice. Comorbid substance abuse, depression, failure of efficacy, higher cognitive performance at baseline (in contrast to premorbid cognitive deficits found by Robinson et al.52), and African-American race all predicted poor medication adherence. The authors also found a trend towards an association between impaired insight and poor medication adherence.
In summary, predictors of discontinuation in FEP that have been replicated (i.e., identified in more than one study) include severity of psychopathology, lack of insight into illness, negative patient attitudes, comorbid substance use, and medication side effects. These findings suggest that vigilant monitoring for and adequate treatment of positive symptoms and medication side effects may decrease discontinuation rates. In addition, patients with a combination of impaired insight into illness, negative attitudes towards medications, and comorbid substance use may be among those at highest risk for medication discontinuation, and it is therefore crucial to assess for these risk factors. Further investigations of predictive factors for medication discontinuation are warranted.
Interventions for Improving Medication Discontinuation Rates in First-Episode Psychosis
Although the studies reviewed above suggest potential areas for intervention to decrease discontinuation rates, no strategy studied to date has demonstrated efficacy in the prevention of nonadherence in FEP.50,56,58 In patients with chronic psychosis, however, there is varying evidence for improved adherence with several interventions, including use of particular drug formulations such as long-acting injections and orally disintegrating tablets, psychotherapy, and family support/interventions. Given the scope and implications of medication discontinuation in FEP, there is clearly a need to investigate these interventions in FEP. Potential interventions are outlined in Table 4, and discussed in more detail below.
One potential approach to improving discontinuation rates in FEP is the use of long-acting injectable agents. While these drugs are classically reserved for patients with chronic schizophrenia at high-risk for noncompliance, Chue and Emsley59 argued that the stage in treatment at which these agents should be introduced should be reconsidered. Emsley et al.60 presented an analysis of 51 patients with FEP treated with long-acting risperidone for 2 years. In this study, 72% of the intent-to-treat population (N = 50) completed the trial. The authors concluded that this formulation was efficacious and well-tolerated. Further investigations of long-acting injectable drugs, in conjunction with other psychosocial interventions, in FEP are warranted.
The use of orally disintegrating antipsychotics may improve medication compliance,61 because these rapidly dissolving agents can prevent cheeking or spitting. An open, 6-week study of orally disintegrating olanzapine in 85 hospitalized patients with schizophrenia or schizoaffective disorder who met criteria for medication nonadherence found significant improvement in measures of medication adherence and patient attitudes.62 However, to date, no studies of the use of orally disintegrating antipsychotics in FEP have been published.
Turkington et al.63 recently reviewed the evidence for the efficacy of cognitive-behavioral therapy (CBT) in the treatment of schizophrenia. The authors noted that most studies of CBT in schizophrenia excluded patients who were nonadherent with medications. However, studies that used medication adherence as a primary outcome measure have had inconsistent results.64
Kemp et al.65,66 conducted two randomized controlled trials of compliance therapy, a brief intervention based on principles of motivational interviewing and CBT, in comparison with nonspecific counseling in 74 patients followed for 18 months. The authors found significant post-treatment advantages for the compliance therapy group on measures of insight, attitudes to treatment, and observer-rated adherence, although other researchers have failed to replicate these findings.67 Thus, CBT/compliance therapy is another potential area of investigation for improving discontinuation rates in FEP.
Family-based therapies represent another potential intervention for reducing discontinuation rates in FEP. Chue68 reported that a lack of involvement of family members in the care plan was one of the most important reasons for dissatisfaction with treatment in schizophrenia. Family-based therapies, when used together with antipsychotics, have been shown to dramatically reduce relapse rates in patients with chronic schizophrenia.69 Another recent review found that family intervention may encourage medication adherence in schizophrenia.70 One study of family intervention in FEP has been published; however, this study did not assess the impact of the intervention on medication adherence.71
A movement that is currently transforming the delivery of mental health services is the adoption of the recovery model concept and recovery-oriented care. An integral component of the recovery model is the use of certified peer specialists (CPS). A CPS is a licensed professional who has progressed in his or her own recovery from mental illness and works to assist other consumers in regaining control over their own lives and over their own recovery process. A CPS provides peer support services, serves as consumer advocate, is a resource for psychoeducation, and offers the unique perspective of his or her individual experiences. Additional information about CPS services can be accessed at the websites from the Georgia Certified Peer Specialist Project (www.gacps.org), the National Alliance on Mental Illness (www.nami.org), and the Depression and Bipolar Support Alliance (www.dbsalliance.org). The Medical College of Georgia (MCG) is the first academic institution in the country with a CPS on staff, and the recovery model is a growing part of resident education at MCG.72 Thus, the use of peer support services represents another potential intervention for addressing medication discontinuation in FEP that has not been previously explored.
Medication Discontinuation Following Remission from First-Episode Psychosis
In addition to the issue of medication discontinuation in the acute treatment of FEP, another equally important question is how long patients with FEP should be treated with antipsychotics. The optimal duration of maintenance antipsychotic treatment in patients who are in remission from FEP is not known. This decision requires consideration of multiple factors, including response to treatment, patient preferences, risk of relapse, and risk of movement disorders and/or metabolic disturbances.
According to the TMAP for schizophrenia,31 "A trial period off antipsychotics may be reasonable for some patients early in the course of illness. This, an individualized decision, depends on a number of factors that do not lend themselves to an algorithmic approach. Thus, the schizophrenia algorithm contains no guidelines for antipsychotic medication discontinuation, which is anticipated to be a rare event in the typical mental health clinic patient population." Although treatment guidelines generally recommend at least 1 year of antipsychotic treatment, some consider indefinite maintenance treatment reasonable. The American Psychiatric Association (APA) Practice Guideline for the Treatment of Patients with Schizophrenia, Second Edition concludes that "Unfortunately there is no reliable indicator to differentiate the minority who will not from the majority who will relapse with drug discontinuation. Indefinite maintenance antipsychotic medication is recommended for patients who have had multiple prior episodes or two episodes within five years."73
There are currently no consensus guidelines for how medication can be optimally discontinued in patients in remission from FEP. In a Japanese maintenance treatment algorithm, Saito and Saijo74 suggested that clinicians consider a slow taper to half of the maintenance dose, with close monitoring for symptom exacerbation or relapse, after 1 year of maintenance treatment following remission from a first episode. However, these authors did not provide additional details on the duration of the medication taper or evidence concerning the efficacy of this strategy.
Two randomized trials of medication discontinuation in patients in remission from FEP have been published. In a Scottish first-episode study, McCreadie et al.75 conducted a small, 12-month double-blind discontinuation trial of maintenance antipsychotic medication in 15 patients with schizophrenia who had already completed the first year of the study. None of the 8 patients who continued to receive active medication was rehospitalized during the second year, while 4 of the 7 patients (57%) who were switched from active medication to placebo were, although the difference failed to reach statistical significance. In a prospective, randomized, controlled trial, Wunderink et al.76 compared a guided discontinuation strategy with maintenance therapy. In this study, 131 patients who had been in remission from FEP for 6 months were randomized to receive maintenance treatment carried out according to the APA guidelines, preferably using low-dose SGAs, or a discontinuation strategy that involved gradual symptom-guided tapering of dosage and discontinuation, if feasible. The investigators followed patients for 18 months after randomization to one of these two groups and found significantly increased relapses in the group receiving the discontinuation strategy (43% versus 21%). Among patients assigned to the discontinuation strategy group, 20% were successfully discontinued, 30% restarted antipsychotic treatment due to symptom recurrence, and discontinuation was not feasible at all in the remaining 50%. Furthermore, there were no functional outcome advantages observed for the discontinuation strategy. The authors concluded "Only a limited number of patients can be successfully discontinued. High relapse rates do not allow a discontinuation strategy to be universal practice. However, if relapse risk can be carefully managed by close monitoring, in some remitted first-episode patients a guided discontinuation strategy may offer a feasible alternative to maintenance treatment." Another study in this same patient population77 found that there were no differences between patients assigned to the discontinuation strategy and those in the maintenance treatment group in either the mean cost of treatment or in measurement of quality-adjusted life years.
Medication nonadherence has long been recognized as an important treatment issue in the management of chronic schizophrenia. This review highlights the fact that medication discontinuation is also a major treatment issue in FEP right from the onset of treatment. More than 40% of patients with FEP discontinue medication in the first 9 months of treatment, a finding that has important implications for long-term outcomes. Specifically, early intervention with antipsychotic medication in FEP is associated with decreased long-term morbidity.3 In addition, medication adherence is a robust predictor of both reduced relapse38,39 and improved functional outcomes.40,41 Predictors of medication discontinuation in this patient population that have been replicated (i.e., identified in more than one study) include severity of psychopathology (particularly positive symptoms), lack of insight into illness, negative attitudes in patients towards medications, comorbid substance use, and medication side effects. Further investigation of these factors is needed to identify those patients at highest risk for medication discontinuation. In addition to vigilant monitoring for and adequate treatment of psychopathology and medication side effects, interventions that appear to have the potential to decrease discontinuation rates-based on evidence of their efficacy in patients with chronic illness-include orally disintegrating tablets, long-acting injectable antipsychotics, CBT, compliance therapy, and family support/intervention. However, these strategies have largely been unexplored in FEP. The growth of the recovery model suggests that peer support services are another intervention with potential to improve medication adherence in FEP.
Another important issue related to medication use in FEP is that there is currently no consensus concerning how long a patient should remain on antipsychotic medication following remission of FEP. Studies are needed to identify predictors of which patients in remission from FEP are less likely to relapse when medication is discontinued.
Taken together, the findings presented here underscore the importance of addressing medication discontinuation both as a means of preventing long-term morbidity and of enhancing remission and functional recovery in FEP.
Acknowledgements: The author would like to thank Dr. Peter Buckley and Dr. Brian Kirkpatrick for feedback.
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