Clinical Outcome Following Neuroleptic Discontinuation in Patients With Remitted Recent-Onset Schizophrenia. Michael Gitlin, M.D.. Keith Nuechterlein, Ph.D.
Article
Clinical Outcome Following Neuroleptic Discontinuation in Patients With Remitted Recent-Onset Schizophrenia Michael Gitlin, M.D. Keith Nuechterlein, Ph.D. Kenneth L. Subotnik, Ph.D. Joseph Ventura, Ph.D. Jim Mintz, Ph.D. David L. Fogelson, M.D. George Bartzokis, M.D. Manickam Aravagiri, Ph.D.
Objective: The goal of this report was to examine the clinical course following neuroleptic discontinuation of patients with recent-onset schizophrenia who had been receiving maintenance antipsychotic treatment for at least 1 year. Method: Fifty-three volunteer patients with recent-onset schizophrenia who had been clinically stabilized on a maintenance regimen of fluphenazine decanoate for a mean of 16.7 months had their antipsychotic medications withdrawn under clinical supervision. Participants initially entered a 24-week, double-blind crossover trial in which fluphenazine and placebo were administered for 12 weeks each. For those who did not experience symptom exacerbation or relapse during this period, fluphenazine was openly withdrawn; participants were then followed for up to 18 additional months.
Results: When a low threshold for defining symptom reemergence was used, 78% (N=39 of 50) of the patients experienced an exacerbation or relapse within 1 year; 96% (N=48 of 50) did so within 2 years. Mean time to exacerbation or relapse was 235 days. When hospitalization was used as a relapse criterion, only six of 45 of individuals (13%) experiencing an exacerbation or relapse who continued in treatment in the clinic were hospitalized, demonstrating the sensitivity of the psychotic exacerbation criterion. Conclusions: The vast majority of clinically stable individuals with recent-onset schizophrenia will experience an exacerbation or relapse after antipsychotic discontinuation, even after more than a year of maintenance medication. However, clinical monitoring and a low threshold for reinstating medications can prevent hospitalization for the majority of these patients. (Am J Psychiatry 2001; 158:1835–1842)
C
onsistent evidence shows that neuroleptics, administered as a maintenance treatment, reduce relapse rates in schizophrenic patients. A comprehensive review that analyzed 66 studies found a mean cumulative relapse rate of 53% in patients withdrawn from neuroleptic therapy compared to 16% for those maintained on a regimen of neuroleptic therapy over a mean follow-up period of 9.7 months (1). Despite this conclusion, many questions remain regarding the optimal use of antipsychotics as a maintenance treatment. A central question is how long to continue maintenance antipsychotic treatment for patients after their first episode of schizophrenia. Patients in the early course of schizophrenia frequently request a decrease or discontinuance of their antipsychotic medications, and many have poor adherence to treatment (2). After successful antipsychotic treatment, many patients believe that they will no longer need medication. Given that the early course of the disorder is highly variable across patients and is generally not well characterized in the literature, clinicians are hard put to insist on indefinite neuroleptic treatment. Among the 66 studies reviewed in the article by Gilbert et al. (1), only two examined relapse rates in first-break or recent-onset patients (3, 4). In the first of the two studies,
Am J Psychiatry 158:11, November 2001
seven of 17 patients (41%) with remitted first-episode psychosis who received placebo experienced a relapse, whereas none of the 11 patients who continued taking fluphenazine over a 1-year period relapsed (3). In contrast, Crow et al. (4) randomly assigned 120 first-break schizophrenia patients to continued treatment with antipsychotic medication (five different agents were used) or placebo following acute treatment. Relapse rates over a 2year period were 62% for those given placebo versus 46% for those receiving active medication. In these two initial studies, random assignment to possible placebo treatment occurred shortly after resolution of psychotic symptoms. Since the Gilbert et al. review (1) was published, we know of one other study that has addressed the risk of relapse after medication discontinuation in first-break schizophrenia patients. Robinson et al. (5) found that patients who discontinued antipsychotic medications (not randomly assigned but self-selected) following at least 1 year of treatment relapsed at a rate almost five times that of those who continued taking medications over a 5-year period. Specific data on relapse rates for patients who discontinued medications were not provided. In addition to the scarcity of studies involving firstbreak schizophrenia patients and the discrepant results
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OUTCOME FOLLOWING NEUROLEPTIC WITHDRAWAL
in these three studies (clear benefit of continued treatment [3, 5] versus a less robust effect [4]), many questions remain. For example, the Kane et al. study (3), with a total of 28 subjects, included patients with diagnoses of mania with schizotypal features (N=1), depression with schizotypal features (N=1), unspecified functional psychosis (N=3), and other psychiatric disorders (N=4), leaving only 19 schizophrenic patients within the study group. Furthermore, as has been described in detail elsewhere (1, 6, 7), definitions of “relapse” differ markedly across studies. Relapse rates are likely to differ across studies when the definition of the term ranges from return of active medication to a specified change in symptom rating scales or hospitalization. Consistent with this definitional disarray, the rate of relapse during neuroleptic withdrawal across all studies included in the review (1) ranged from 0% to 100%! Studies with more sensitive, symptom-based definitions of relapse will likely show higher rates of relapse but lower rates of hospitalization, since reinstitution of treatment will occur more quickly. The Kane et al. study (3) used the criteria of “substantial clinical deterioration with a potential for marked social impairment,” whereas Crow et al. (4) defined relapse as a point at which the responsible clinician considered rehospitalization to be necessary or resumption of active antipsychotic medication essential. In the Robinson et al. study (5), relapse was defined as at least “moderately ill” on the CGI severity scale (8), “much worse” or “very much worse” on the CGI improvement scale, and a rating of “moderate” for at least 1 week on one or more psychotic symptom items from the Schedule for Affective Disorders and Schizophrenia—Change Version With Psychosis and Disorganization Items (9). Current consensus suggests approximately 1 year of antipsychotic treatment for a first episode of schizophrenia followed by consideration of medication discontinuation for stable patients. In 1991, Johnson (10) recommended continuing medication for 12–24 months depending on the patient’s stability, followed by a gradual discontinuation of medication. Similar recommendations have been made elsewhere in 1997 and 1998 (11, 12). The APA Practice Guideline for the Treatment of Patients With Schizophrenia (13), published in 1997, states that “a patient who has had only one episode of positive symptoms and has had no symptoms during the following year of maintenance therapy may be considered for a trial period without medication.” Despite these consistent recommendations, the natural history of clinically stable patients with recent-onset (i.e., nonchronic) schizophrenia who discontinue antipsychotic medication remains relatively unexplored by systematic clinical study, leading to a lack of empirical basis for decisions about continuing maintenance antipsychotic medication after an initial year. Therefore, to help clarify this issue, as one phase of a longitudinal study, we examined the clinical course of a cohort of patients with
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recent-onset schizophrenia who gave permission to have their antipsychotic medication withdrawn while continuing to receive ongoing psychosocial treatment and prospective clinical management. The design of this study (conducted between 1982 and 1993) parallels fairly closely the schizophrenia treatment recommendations published before, during, and after the current study. In essence, this study may be viewed as an attempt to apply a targeted medication approach to a recent-onset schizophrenia cohort (14–16), in that patients were followed regularly when not receiving medication, and treatment was again recommended as soon as symptom exacerbation occurred. As has been noted elsewhere (16), targeted medication approaches might be most applicable for clinically stable patients in the early phases of schizophrenia. At this point, patients are frequently unwilling to commit to long-term maintenance medication and voice concerns about avoiding adverse side effects.
Method The 53 participants in this study were drawn from a larger cohort of patients (N=104) followed as part of a three-phase longitudinal study evaluating the roles of vulnerability factors and stressors in recent-onset schizophrenia patients—the Developmental Processes in Schizophrenic Disorders Project (17, 18). Entry criteria required all subjects to have had their first onset of a psychotic episode no more than 2 years before study entry. Seventy-nine percent (N=42 of 53) of participants were in their first psychotic episode at the time of study entry. All subjects met Research Diagnostic Criteria (19) for schizophrenia or schizoaffective disorder, mainly schizophrenic subtype. Full inclusion and exclusion criteria are presented elsewhere (17, 18). Briefly, subjects were 18–45 years of age (mean=25.0 years, SD=4.3) and had no evidence of a neurological disorder (e.g., epilepsy, encephalitis). Additionally, patients with a history of significant and habitual drug use in the 6 months before study entry and those for whom there was substantive evidence that drug use triggered the psychotic episode were excluded from the study. All subjects were treated every 2 weeks with fluphenazine decanoate administered intramuscularly with an initial target dose of 12.5 mg. Doses were increased to a higher maintenance level during the course of the first outpatient year if the subject’s symptoms were not adequately controlled. Doses were decreased if intolerable side effects could not be adequately controlled by antiparkinsonian medications. To be considered for inclusion in the neuroleptic discontinuation protocol that is the subject of this report, individuals were required to have their antipsychotic regimen stabilized and to be clinically stable. Specific inclusion criteria were 1) fluphenazine decanoate treatment for at least 1 year with clinical evaluations every 2 weeks, and 2) no notable psychotic symptoms for at least the last 3 months. The mean length of fluphenazine treatment before entry into this protocol was 16.7 months (SD= 5.5). An exclusion criterion was the treating psychiatrist’s clinical judgment that the patient was too unstable to be considered for medication withdrawal (even if rating scale criteria for clinical stability were met). With these criteria, 54 of the original cohort of 104 patients were eligible for the study. The 54 subjects did not differ in age, gender, ethnicity, educational background, socioeconomic status, length of illness before study entry, or age at onset from the other 50 individuals who were ineligible for the protocol. Of the 51 subjects who did not enter this study, 28 had Am J Psychiatry 158:11, November 2001
GITLIN, NUECHTERLEIN, SUBOTNICK, ET AL. TABLE 1. Demographic and Clinical Characteristics of 53 Clinically Stable Patients With Recent-Onset Schizophreniaa Who Voluntarily Entered an Antipsychotic Withdrawal Protocol Characteristic Male gender Diagnosis Research Diagnostic Criteria (19) Schizophrenia Schizoaffective disorder, mainly schizophrenic subtype DSM-III-R schizophrenia, schizoaffective disorder, or schizophreniform disorder Ethnicity Caucasian Latino Asian American Mixed a
N 46
% 87
47
89
6
11
44
83
44 5 2 2
83 9 4 4
Patients had experienced their first psychotic episode no more than 2 years earlier, had received fluphenazine treatment for at least 1 year with clinical evaluations every 2 weeks, and had been free of notable psychotic symptoms for at least 3 months.
dropped out of the clinic, 21 were excluded because of insufficient clinical stability, one subject was excluded per the psychiatrist’s clinical judgment, and one eligible subject declined to enter the study because of fear of a potential return of symptoms. Table 1 presents the demographic data for the 53 individuals included in the study.
Treatment Protocol During the first 24 weeks of the study, patients were randomly assigned to treatment in a double-blind fashion to 12 weeks of their usual fluphenazine decanoate regimen or 12 weeks of placebo treatment, administered by a research nurse or physician. As shown in Figure 1, those assigned to condition A were given placebo followed by active drug, while those in condition B were given their usual dose of fluphenazine decanoate followed by placebo. For patients who did not experience symptom exacerbation or psychotic relapse during these 24 weeks, intramuscular medication shots were openly discontinued, and the patient was followed for up to 18 months. Thus, the entire time of observation in this study was 102 weeks, or just under 2 years. During the first 24 weeks of the study (the double-blind crossover phase), patients were seen every 2 weeks and were evaluated with the expanded Brief Psychiatric Rating Scale (BPRS) (20) by their case managers. Each rater achieved a median intraclass correlation coefficient of 0.80 or higher across all BPRS items compared with the criterion ratings (21). During the open withdrawal phase, patients were evaluated with the BPRS every 2 weeks for the first 6 months and then every 4 weeks thereafter. If dictated by clinical need, the frequency of clinical evaluations was increased. Aside from the scheduled BPRS evaluation, if a patient called with a possible change in symptoms, a BPRS rating was done at that point. Patients were removed from the medication discontinuation trial if any of the following three conditions were met: 1) An increase in psychotic symptoms assessed with the BPRS met the a priori definition for exacerbation or relapse. The definition of exacerbation was any 2-point change on any of the three BPRS psychotic items (hallucinations, unusual thought content, and conceptual disorganization), excluding changes in which the ratings remained at nonpsychotic levels (i.e., ≤3). Psychotic relapse was defined as a rating of 6 or 7 on any of the three BPRS psychotic symptom items. One patient had a nonpsychotic relapse (depression), which was not included in the current analysis. 2) A worsening of clinical condition occurred that warranted a change in treatment according to the treating psychiatrist, even if the BPRS Am J Psychiatry 158:11, November 2001
FIGURE 1. Antipsychotic Withdrawal Protocol for 53 Clinically Stable Patients With Recent-Onset Schizophreniaa Stabilization Phase
Double-Blind Crossover Phase
Open Withdrawal Phase
Condition A FluphenPlacebo azine Fluphenazine (12 weeks) Decanoate (12 weeks) Decanoate (at least Condition B 1 year) FluphenPlacebo azine Decanoate (12 weeks) (12 weeks)
No Medication
No Medication
12 13 14 15 16 17 18 19 20 21 22 23 ... 36 Months Since Stabilization With Fluphenazine Decanoate a
Patients had experienced their first psychotic episode no more than 2 years earlier, had received fluphenazine treatment for at least 1 year with clinical evaluations every 2 weeks, and had been free of notable psychotic symptoms for at least 3 months.
ratings did not meet criteria for exacerbation or relapse. 3) The patient decided to withdraw from protocol participation. The criteria for removal from the medication discontinuation trial were purposely sensitive to relatively small symptomatic changes. Our goal was to intervene as soon as it became clear that the patient had a clinically significant return of symptoms in order to avoid, as much as possible, a full psychotic episode. Information on the nature of the double-blind crossover and the open medication withdrawal components of this protocol was described verbally and with a written informed consent form. After complete description of the study to the potential participants, written informed consent (approved by the institutional review board of the University of California, Los Angeles, and the National Institute of Mental Health) was obtained before study entry. These informed consent procedures were separate from the procedures that occurred at entry into the preceding protocol, which involved repeated assessment batteries during an initial year of maintenance treatment with fluphenazine decanoate. Blood samples for fluphenazine levels were scheduled to be drawn every 2 weeks during the crossover portion of the study and every 4 weeks during the first 6 months of open withdrawal. To accommodate patients’ personal schedules, occasionally patients were seen and had their blood drawn 3 weeks after the prior fluphenazine injection. During the crossover phase of the protocol, blood samples were taken before the administration of the next intramuscular shot. Plasma levels of fluphenazine were measured by using a specific radioimmunoassay that was validated for specificity by using gas chromatography mass spectroscopy (22, 23). The sensitivity of the assay was 0.1 ng/ml for most of the samples analyzed. The coefficient of variation was 3%. Some of the initial samples were analyzed by an earlier method with a sensitivity of 0.3 ng/ml.
Data Analysis In calculating time to return of psychotic symptoms, we used 2 weeks after the last active fluphenazine injection as day 0 of drug withdrawal; for example, a return of psychotic symptoms declared at 14 days occurred 28 days after the last injection. Drug withdrawal was considered to start during the placebo condition for subjects whose psychotic symptoms returned during initial assignment to placebo in the crossover phase (condition A in Figure 1). Condition A subjects who did not experience a return of psychotic symptoms during the placebo condition and had their
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OUTCOME FOLLOWING NEUROLEPTIC WITHDRAWAL TABLE 2. Fluphenazine Levels of 53 Clinically Stable Patients With Recent-Onset Schizophreniaa During the Double-Blind Crossover Phase of an Antipsychotic Withdrawal Protocol Patients Receiving Placebo First (Condition A)
Patients Receiving Fluphenazine First (Condition B)
Fluphenazine Level (ng/ml) Week Baseline 2 4 6 8 10 12 14b 16 18 20 22 24
N 24 21 23 22 22 18 22 20 20 20 20 21 16
Mean 0.42 0.38 0.40 0.31 0.25 0.18 0.26 0.30 0.30 0.38 0.46 0.39 0.47
SD 0.25 0.37 0.51 0.49 0.20 0.51 0.42 0.24 0.25 0.30 0.51 0.38 0.31
Analysis
Fluphenazine Level (ng/ml) N 25 25 26 25 24 25 22 25 23 20 21 18 17
Mean 0.44 0.48 0.61 0.35 0.50 0.42 0.45 0.39 0.30 0.21 0.24 0.18 0.12
SD 0.28 0.32 0.56 0.24 0.40 0.28 0.37 0.23 0.17 0.22 0.22 0.24 0.16
t 0.25 0.93 1.37 0.33 2.67 3.15 1.61 1.20 0.10 –2.00 –1.81 –2.06 –4.05
df 47 44 47 45 44 41 42 43 41 38 39 37 31
p 0.81 0.36 0.17 0.74 0.01
