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Recovery in Remitted First-Episode Psychosis at 7 Yearsof Follow-up of an Early Dose Reduction/Discontinuationor Maintenance Treatment StrategyLong-term Follow-up of a 2-Year Randomized Clinical Trial Lex Wunderink, MD, PhD; Roeline M. Nieboer, MA; Durk Wiersma, PhD; Sjoerd Sytema, PhD;Fokko J. Nienhuis, MA Editorial page 898 IMPORTANCE Short-term outcome studies of antipsychotic dose-reduction/discontinuation
strategies in patients with remitted first-episode psychosis (FEP) showed higher relapse rates
but no other disadvantages compared with maintenance treatment; however, long-term
effects on recovery have not been studied before.
OBJECTIVE To compare rates of recovery in patients with remitted FEP after 7 years of
follow-up of a dose reduction/discontinuation (DR) vs maintenance treatment (MT) trial.
DESIGN Seven-year follow-up of a 2-year open randomized clinical trial comparing MT
and DR.
SETTING One hundred twenty-eight patients participating in the original trial were recruited
from 257 patients with FEP referred from October 2001 to December 2002 to 7 mental
health care services in a 3.2 million–population catchment area. Of these, 111 patients refused
to participate and 18 patients did not experience remission.
PARTICIPANTS After 7 years, 103 patients (80.5%) of 128 patients who were included in the
original trial were located and consented to follow-up assessment.
INTERVENTION After 6 months of remission, patients were randomly assigned to DR strategy
or MT for 18 months. After the trial, treatment was at the discretion of the clinician.
MAIN OUTCOMES AND MEASURES Primary outcome was rate of recovery, defined as meeting
the criteria of symptomatic and functional remission. Determinants of recovery were
examined using logistic regression analysis; the treatment strategy (MT or DR) was controlled
for baseline parameters.
RESULTS The DR patients experienced twice the recovery rate of the MT patients (40.4% vs
17.6%). Logistic regression showed an odds ratio of 3.49 (P = .01). Better DR recovery rates
were related to higher functional remission rates in the DR group but were not related to
symptomatic remission rates.
Author Affiliations: Department of
Research and Education, Friesland
CONCLUSIONS AND RELEVANCE Dose reduction/discontinuation of antipsychotics during the
Mental Health Services, Leeuwarden, early stages of remitted FEP shows superior long-term recovery rates compared with the the Netherlands (Wunderink, rates achieved with MT. To our knowledge, this is the first study showing long-term gains of Nieboer); Department of Psychiatry,Rob Giel Research Center, University an early-course DR strategy in patients with remitted FEP. Additional studies are necessary Medical Center Groningen, University before these results are incorporated into general practice.
of Groningen, Groningen, theNetherlands (Wunderink, Wiersma,Sytema, Nienhuis).
Corresponding Author: Lex
Wunderink, MD, PhD, Department of
Research and Education, Friesland
Mental Health Services, Sixmastraat
2, PO Box 8932 PS, Leeuwarden, the
Published online July 3, 2013.
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Research Original Investigation Recovery in Remitted First-Episode Psychosis with first-episode psychosis (FEP) will stop taking antipsy- substance; diagnostic category of nonaffective psychosis chotic drugs, resulting in increased relapse risk and lower (schizophrenia, schizophreniform disorder, schizoaffective dis- rates of recovery.1 Robinson et al2 studied self-elected discon- order, delusional disorder, brief psychotic disorder, or psy- tinuation in patients with FEP and found a 5-fold increase in chotic disorder not otherwise specified); symptom severity; relapse rates compared with patients who continued to take social functioning; quality of life; and time from start of anti- antipsychotics. In patients with multiple episodes who were psychotic treatment to first remission. A detailed description receiving intermittent treatment, higher relapse rates were of the instruments and measurement methods was reported demonstrated compared with the rates in patients receiving by Wunderink et al.14 maintenance treatment (MT).3 The first randomized clinical In the present study, the patients were followed up after trial in patients with remission of FEP comparing MT with dose 7 years, which was calculated from the start of the original trial reduction/discontinuation (DR) also showed higher relapse (the start date of the first remission). The follow-up assess- rates and no advantages of DR.4 More recent studies con- ment included symptom severity and level of social function- firmed these results.5-7 This further supported the guidelines ing during the past 6 months, relapses during the whole fol- stating that MT with antipsychotics is recommended for at least low-up period, and the type and dose of antipsychotics used 1 year when a first episode has remitted.8,9 However, all stud- during the past 2 years. Dosage data registered in patient rec- ies on treatment strategies have a short-term follow-up of 2 ords were verified during the assessment interviews.
years or less.4,10 The long-term effects of treatment strategies Symptoms were assessed with the Positive and Negative are therefore unknown. Moreover, treatment recommenda- Syndrome Scale (PANSS).15 The PANSS was used to measure tions and guidelines are undifferentiated regarding stability and observer-rated severity of symptoms during the preceding remission of the illness.11,12 The present guidelines are di- week, as well as during the past 6 months.
rected mainly toward the prevention of relapse. However, Social functioning was assessed with the Groningen So- awareness is growing that, in addition to relapse, functional cial Disability Schedule (GSDS), a semistructured investigator- status should be included in outcome evaluation. Therefore, based interview measuring disabilities in social functioning in recovery, including both symptomatic and functional remis- 8 domains (7 of which were included in this study) over the sion, would be a more adequate concept for outcome past 4 weeks, as well as during the past 6 months.16 The 7 do- mains are self-care, housekeeping, family relationships, part- The aim of the present study was to evaluate the long- ner relationships, relationships with peers, community inte- term outcome of an early-course DR strategy on recovery com- gration, and vocational functioning. The parenthood domain pared with MT. Therefore, a 7-year follow-up assessment was was omitted because of limited applicability. A disability is rated conducted in a cohort of patients with FEP who originally par- by the investigator on a 4-point scale: none (0), minimal (1), ticipated in an early-course DR trial.4 obvious (2), and serious (3).
Training for administration of PANSS and GSDS was pro- vided for all research assistants before the study. Training in-cluded ratings of videotaped and real-life interviews, fol- lowed by discussions and review of ratings.
At baseline, predictors of recovery (symptomatic and func- Patients seen for the first time in mental health care services tional remission) were recorded as part of the original trial: with a first episode of psychosis from October 1, 2001, until demographic variables, DUP, psychopathologic characteris- December 1, 2002 (N = 257), in a 3.2 million–population tics (PANSS), cannabis and any other substance abuse, social catchment area were asked to participate in the original functioning (GSDS), quality of life (World Health Organiza- 2-year trial comparing DR with MT.4 Of these, 111 patients tion Quality of Life [WHOQoL]), living situation, and voca- refused to participate or were lost to follow-up, and 18 tional situation. Details on the measurement of DUP and other patients did not show response of symptoms within 6 baseline variables have been described elsewhere.14 months of antipsychotic treatment or sustained symptomremission during 6 months. One hundred twenty-eight Definitions of Recovery, Symptomatic Remission, Relapse, patients were included in the original trial and completed it.
and Functional Remission At the end of this trial, all patients consented to follow-up.
Criteria for recovery were met when patients had sympto- Research assistants who recruited the patients in the original matic and functional remission for at least 6 months at the study contacted them 5 years later, requesting their partici- 7-year follow-up. Criteria for symptomatic remission were ad- pation in a one-time interview regarding the course and out- opted from Andreasen et al.17 All relevant PANSS item scores come of psychosis during the follow-up period.
have to be 3 (mild) or less on a scale ranging from 1 (not pre-sent) to 7 (severe) during an observational period of 6 months.
Patients were assessed retrospectively for any symptomatic re- Baseline data were sampled as part of the original trial. These lapse occurring during this period. A symptomatic relapse was included sex; duration of untreated psychosis (DUP); age at on- defined as an exacerbation of symptoms during at least 1 week set of psychosis; educational level; having a regular job for at with at least 1 relevant PANSS item score above 3 (mild). Any least 16 hours a week; living alone vs with others; diagnosis relapse in symptoms during the 6 months preceding the as- JAMA Psychiatry September 2013 Volume 70, Number 9
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Recovery in Remitted First-Episode Psychosis Original Investigation Research sessment prevented the individual from being categorized as Potential explanatory variables included demographic recovered at the time of the assessment.
measures, baseline symptoms (positive, negative, and gen- According to generally accepted views, functional remis- eral), baseline social functioning, substance abuse, and DUP.
sion implies proper social functioning in the main domains of Logistic regression analyses were used to study the contribu- everyday life. The 7 domains of the GSDS included in the pre- tions of relevant predictors to recovery and its constituents sent study adequately represent these domains. A patient with (symptomatic and functional remission) as dependent vari- functional remission should function adequately in all 7 do- ables. Relevant variables were entered in the regression model mains with none or only a minimal disability in any of them if bivariate analysis showed a significant association (P < .05) (not allowing a score of 2 or 3 on any GSDS domain).13 Patients with recovery, symptomatic remission, or functional remis- were considered to have functional remission if, during an ob- sion at the 7-year follow-up. Time to first relapse during fol- servational period of 6 months before assessment, all func- low-up from random assignment to DR or MT groups was ana- tional domain scores remained at 1 or lower.
lyzed with a Kaplan-Meier survival analysis. The mean numberof relapses with DR and MT was compared using an unpaired Conversion of Antipsychotics to Haloperidol Equivalents 2-tailed t test, and the cross tabulation of number of relapses To compare medication use, prescribed antipsychotics were and treatment arm was analyzed with a Pearson χ2 test. The converted to haloperidol equivalents. Because of different difference of the mean daily dose of antipsychotic medica- mechanisms of action, there is no generally accepted algo- tion during the last 2 years of follow-up between DR and MT, rithm to convert the novel or even the first-generation anti- calculated by determining the mean daily dosage including pe- psychotics to haloperidol equivalents. We used existing dose riods with zero intake of antipsychotics, was analyzed with an range recommendation tables to convert the applied antipsy- unpaired 2-tailed t test. The same analysis was done compar- chotic agents to haloperidol equivalents.9,18 ing the mean daily doses excluding periods with zero intake,the mean number of months with zero intake and with daily Calculation of Mean Daily Dose of Antipsychotics doses below 1 mg of haloperidol equivalents per patient, and and Timeline of Dosing the mean number of patients per month with zero intake and The calculation of the mean daily doses of antipsychotics dur- with doses below 1 mg of haloperidol equivalents. Finally, we ing the last 2 years of follow-up was based on registration of dos- performed an as-treated post hoc analysis to compare the out- age data in patient records verified during assessment inter- come of patients who successfully discontinued or achieved views. Prescription data are accurately registered in electronic substantial dose reduction (mean daily dose <1 mg of halo- patient files in all participating services in this study. First, the peridol equivalents) determined with Pearson χ2. To find pre- mean daily dose for each month was calculated, including days dictors of successful dose reduction/discontinuation of anti- of zero intake, to get an impression of the timeline of dosing.
psychotic medication during the last 2 years of follow-up, we The mean daily dose during the 2-year period was then calcu- performed another logistic regression analysis. Relevant pre- lated by adding the means for each month and dividing by 24.
dictors of dose reduction/discontinuation were selected by bi- To obtain a more accurate impression of prescribed dosages, we variate analyses (showing a significant association with dose also calculated the mean daily dose during the last 2 years of reduction/discontinuation) and entered into a stepwise logis- the 7-year follow-up, excluding days of zero intake. To get an tic regression analysis with discontinuation or dose reduc- impression of the timeline of dose reduction and discontinua- tion to a mean daily dose of less than 1 mg of equivalents of tion, we calculated the mean number of months per patient and haloperidol during the last 2 years of follow-up as a depen- the mean number of patients per month with zero intake, as well dent variable.
as with doses below 1 mg of haloperidol equivalents during thelast 2 years of the 7-year follow-up.
Statistical AnalysisAnalyses were carried out using commercial software (SPSS, Of the 128 patients who participated in the original study, 103 version 18.0; SPSS Inc). Baseline characteristics of partici- patients (80.5%) were located and consented to participate in pants and nonparticipants and of DR and MT groups were the 7-year follow-up. Of the 25 nonparticipants, 1 patient had evaluated with Pearson χ2 tests for categorical variables and committed suicide, 18 patients refused further participation, unpaired 2-tailed t tests for continuous variables. Selection of and 6 individuals were lost to follow-up. There were no sig- variables to be included in the regression models was based nificant differences in baseline characteristics and functional on bivariate analyses, Pearson χ2 tests for categorical vari- data between participants and nonparticipants in the 7-year ables, and t tests for continuous variables of baseline vari- follow-up study and also none between the 2 treatment strat- ables and recovery, as well as symptomatic and functional re- egy groups (Table 1).
mission at follow-up. The DUP was log transformed in these The variable DUP has been log transformed in Table 1 be- analyses for its skewed distribution. z Scores for skewness of cause of its skewed distribution. The actual values of DUP in the distribution were 13.95 for non–log-transformed DUP days the follow-up sample (n = 103) were mean (SD), 266.6 (529.9) vs −0.75 for log-transformed DUP days. However, the same con- days; median, 31.0 days; 25th percentile, 0 days; 50th percen- clusions were obtained by including DUP days in the analyses tile, 31 days; 75th percentile, 184 days; and maximum, 3560 instead of the log-transformed DUP days.
days (interquartile range, 0-184 days).
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Research Original Investigation Recovery in Remitted First-Episode Psychosis Table 1. Baseline Characteristics of Participants and Nonparticipants and of DR and MT Participants Strategy, No. (%) Age at onset of psychosis, Regular job for ≥16 h/wkb Dependence or abuse Schizoaffective disorder Delusional disorder Brief psychotic disorder Psychotic disorder, NOS PANSS subscale,mean (SD) Total score, mean (SD) Abbreviations: DR, dose reduction strategy; DUP, duration of untreated a DUP days were log transformed because of the skewed distribution.
psychosis; GSDS, Groningen Social Disability Schedule; MT, maintenance b Three cases missing in follow-up sample: 2 in the DR group and 1 in MT group.
treatment; NOS, not otherwise specified; PANSS, Positive and NegativeSyndrome Scale; WHOQoL, World Health Organization Quality of Life scale.
Table 2. Recovery, Symptomatic Remission, and Functional Remission After 7 Years of Follow-up Abbreviations: DR, dosereduction/discontinuation; MT, maintenance treatment.
Recovery, Symptomatic Remission, of all patients (DR, 25.0%; MT, 31.4%) achieved neither symp- and Functional Remission tomatic remission nor functional remission.
Recovery rates were significantly higher in patients who re-ceived DR than in those who received MT (Pearson χ2 = 8.2; Predictors of Recovery, Symptomatic Remission, P = .004). Symptom remission after 7 years did not differ sig- and Functional Remission nificantly across the original treatment strategies of DR and MT Table 3 reports the results of the bivariate analyses of associa- (Pearson χ2 = 0.08; P = .78), but functional remission differed tions of conceivable predictors at baseline and recovery, symp- significantly in favor of DR (Pearson χ2 = 6.45; P = .01) (Table 2).
tomatic remission, and functional remission at the 7-year fol- Symptomatic remission without functional remission was low-up. Recovery was bivariately significantly associated with achieved by 38.8% of all patients (DR, 28.8%; MT, 49.0%). Func- PANSS positive symptoms, negative symptoms, general symp- tional remission without symptomatic remission was reached toms (less severe), living with others vs living alone, social func- by 3.9% of all patients (DR, 5.8%; MT, 2.0%). In addition, 28.2% tioning (better), and trial arm (DR). When entered stepwise in JAMA Psychiatry September 2013 Volume 70, Number 9
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Recovery in Remitted First-Episode Psychosis Original Investigation Research Table 3. Bivariate Analyses of Conceivable Baseline Predictors of Recovery, Symptomatic Remission, and Functional Remission at 7-Year Follow-up Baseline Variable Pearson χ2 = 1.58 Educational level Pearson χ2 = 0.78 Pearson χ2 = 6.82 Holding a regular job for ≥16 Pearson χ2 = 3.06 DUP (log transformed) Age at onset of psychosis Pearson χ2 = 4.61 Dependence or abuse Pearson χ2 = 1.88 Pearson χ2 = 0.04 Time to remission, d Pearson χ2 = 6.45 Abbreviations: DR, dose reduction/discontinuation; DUP, duration of untreated treatment; PANSS, Positive and Negative Syndrome Scale; WHOQoL, World psychosis; GSDS, Groningen Social Disability Schedule; MT, maintenance Health Organization Quality of Life scale.
a logistic regression analysis, less severe negative symptoms Figure 1. Kaplan-Meier Survival Analysis (odds ratio [OR ], 0.84; P = .007), living together (OR , 4.44; P = .01), and trial arm (DR) (OR , 3.49; P = .01) remained as vari- ables significantly related to recovery at the 7-year follow-up.
Three baseline variables were significantly associated with symptom remission in the bivariate analyses: DUP (shorter), social functioning (better), and PANSS negative symptoms (less severe). Entered stepwise in a logistic regression analysis, only DUP (shorter) was significantly related to symptom remis- sion at follow-up (OR , 0.62; P = .02).
Functional remission was bivariately associated with the same variables as recovery. Stepwise logistic regression analy- sis showed that less severe negative symptoms (OR , 0.85; P = .02), living together (OR , 4.68; P = .01), better social func- tioning (OR , 0.86; P = .04), and treatment arm (DR) (OR , 4.62; Time to Relapse from t6, d P = .004) were significantly related to functional remission.
Time to first relapse after first remission (t6) during 7 years of follow-up inpatients assigned to 18 months (547 days) of dose reduction/discontinuation Relapse Rates During 7 Years of Follow-up (DR) or maintenance treatment (MT).
The mean (SD) number of relapses in the sample was 1.24(1.37). Categorized by group, the mean numbers were DR,1.13 (1.22) and MT, 1.35 (1.51); this difference was nonsignifi- of follow-up. From then on, the findings were not significantly = –0.81, P = .42).
different (log-rank [Mantel-Cox] χ2 = 0.003; P = .96).
Time to first relapse from entry into the experimental phase Overall, 67 of the participants (65.0%) had at least 1 re- of the trial (which was at 6 months of stable remission from base- lapse during the 7 years of follow-up. Categorized by group, line) was entered in a Kaplan-Meier survival analysis, compar- 32 relapses occurred in the DR group (61.5% of all DR pa- ing the survival curves of the patients who were in the DR and tients) and 35 in the MT group (68.6% of all MT patients).
MT strategies (Figure 1). The initial relapse rates appeared to be No relapse occurred in 36 patients (34.9%), 20 of whom were about twice as high in the DR group, but the curves then ap- in the DR group (38.5% of all DR patients) and 16 in the MT group proached each other and came on par at approximately 3 years (31.4% of all MT patients). The number of patients with a certain JAMA Psychiatry September 2013 Volume 70, Number 9
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Research Original Investigation Recovery in Remitted First-Episode Psychosis Figure 2. Mean Daily Dose in Dose Reduction/Discontinuation (DR) and Figure 3. Dose Reduction/Discontinuation in DR and MT During the Last Maintenance Treatment (MT) During the Last 2 Years of 7-Year Follow-up 2 Years of 7-Year Follow-up DR 0 < MDD < 1 mg MT 0 < MDD < 1 mg Haloperidol E 1.0 number of relapses in the DR (range, 0-5) and MT (range, 0-8) DR indicates dose reduction strategy; MDD, mean daily dose (haloperidolequivalent milligrams); and MT, maintenance treatment strategy.
groups did not differ significantly (Pearson χ2 = 4.96; P = .55).
Antipsychotic Dose During the Last 2 Years of Follow-up out substantial antipsychotic medication: 22 patients (42.3%) The mean antipsychotic dose (daily dose in haloperidol- in the DR group and 12 patients (23.5%) in the MT group (Pear- equivalent milligrams) in patients originally receiving DR (2.20 son χ2 = 4.11; P = .04).
[2.27] mg) remained significantly lower during the last 2 years The mean number of months per patient with zero intake of follow-up compared with the dose in patients who were re- in the DR (6.38 [10.28]) and MT (4.35 [8.49]) groups during the ceiving MT (mean, 3.60 [4.01] mg; t = −2.18; P = .03). The time last 2 years of follow-up did not differ significantly, nor did the course of mean daily doses during the last 2 years of follow-up mean number of months per patient with a mean daily dose of in the DR and MT groups is graphically represented in Figure 2.
less than 1 mg (DR, 2.92; MT, 1.61). The mean number of patients When the patients who discontinued antipsychotics dur- per month who had zero intake was 13.8 (26.5%) in the DR group ing the last 2 years of follow-up (DR, 11; MT, 6) were left out of and 9.3 (18.2%) in the MT group, a significant difference the analysis, the difference of mean haloperidol equivalent = 12.70; P < .001). The mean number of patients per month daily dose still bordered on significance: 2.79 (2.21) mg in the who had low doses below 1 mg also differed significantly: 6.3 pa- DR group vs 4.08 (4.03) mg in the MT group (t tients (12.1%) in the DR group and 3.4 patients (6.7%) in the MT P = .07). The mean daily dose in DR vs MT patients, excluding = 9.17; P < .001). The time course of dose reduction/ days of zero intake to give an impression of prescribed dos- discontinuation is graphically represented in Figure 3.
ages, bordered on significance: 2.89 (2.19) mg in the DR group To explore whether discontinuation was associated with vs 4.29 (4.01) mg in the MT group (t = −1.98; P = .05).
good or bad general outcome, we performed an as-treated posthoc comparison, comparing patients who successfully discon- Discontinuation and Dose Reduction of Antipsychotics tinued antipsychotics or achieved a substantial dose reduc- tion (n = 34) with those who did not (n = 69), regardless of the Of the 17 patients who successfully discontinued antipsy- original treatment strategy.
chotic treatment in the original trial, 13 were located and in- In the successfully discontinued/dose reduction patients cluded in the present follow-up; 10 of these patients were in compared with the not discontinued/tapered patients, symp- the DR group and 3 were in the MT group. Two patients (both tomatic remission was achieved by 29 of 34 patients (85.3%) DR) restarted antipsychotic therapy; thus, 11 (8 DR and 3 MT) vs 41 of 69 patients (59.4%) (χ2 = 7.00; P = .008), functional patients still were not using antipsychotic agents during the remission by 19 of 34 patients (55.9%) vs 15 of 69 patients (21.7%) last 2 years of the 7-year follow-up.
(χ2 = 12.00; P = .001), and recovery by 18 of 34 patients (52.9%) At the 7-year follow-up, an additional 3 DR and 3 MT pa- vs 12 of 69 patients (17.4%) (χ2 = 13.94; P < .001). The mean tients had stopped taking antipsychotics during the last 2 years, number of relapses in the discontinued/tapered patients dur- amounting to a total of 17 patients who had stopped antipsy- ing the 7-year follow-up was 0.71 (0.94) vs 1.51 (1.47) in the not chotic therapy at follow-up: 11 patients (21.1%) of the DR group discontinued/tapered group, a significant difference and 6 patients (11.8%) of the MT group. In addition, an equal = 2.90; P = .005).
number of patients used a mean haloperidol-equivalent daily Bivariate analysis of predictors of successful discontinua- dose of less than 1 mg during the last 2 years of follow-up: 11 tion or dose reduction to a mean daily dose of less than 1 mg of in the DR group and 6 in the MT group. These patients may be haloperidol equivalents during the last 2 years of follow-up in- considered to have achieved a major dose reduction of anti- dicated no relapse occurring during follow-up (Pearson χ2 = 7.22; psychotics. This would amount to 34 patients (33.0%) with- P = .007), treatment arm (DR or MT) (Pearson χ2 = 4.11; P = .04), JAMA Psychiatry September 2013 Volume 70, Number 9
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Recovery in Remitted First-Episode Psychosis Original Investigation Research successful discontinuation of antipsychotics during the origi- drugs than did their counterparts in the MT strategy. This was nal trial (Pearson χ2 = 23.66; P < .001), short DUP (t mainly a consequence of a higher discontinuation rate in the P = .009), better social functioning (t = 2.09; P = .04), and less DR group, but in addition, the patients in the DR group who severe PANSS general symptoms (t = 2.23; P = .03). When did not discontinue their antipsychotic medication showed a these variables were entered in a stepwise logistic regression trend to use of a lower daily dosage. This is in keeping with the analysis, only successful discontinuation of antipsychotics dur- findings of a German group.11 ing the original trial significantly and independently predicted It might well be the effect of less antipsychotic load that successful discontinuation/dose reduction to a mean daily dose results in better functional capacity in the long term. Antipsy- of less than 1 mg of haloperidol equivalents during the last 2 years chotic postsynaptic blockade of the dopamine signaling sys- of the 7-year follow-up (OR , 0.03; P = .001).
tem, particularly of the mesocortical and mesolimbic tracts, not only might prevent and redress psychotic derangementsbut also might compromise important mental functions, suchas alertness, curiosity, drive, and activity levels, and aspects of executive functional capacity to some extent.19,20 On the To our knowledge, this study is the first to identify major advan- other hand, the dopamine system might play a more periph- tages of a DR strategy over MT in patients with remission of FEP.
eral role in psychosis than previously thought, while hypoth- In patients originally assigned to a DR strategy sustained for 18 esized primary derangements, such as N-methyl-D-aspartate months, after a long-term follow-up of 7 years, recovery and receptor and/or interneuron dysfunction, remain untouched functional remission rates were more than twice those of patients by dopamine blockade.21-23 Thus, dose reduction and, where who were assigned to MT (40.4% vs 17.6% and 46.2% vs 19.6%, possible, discontinuation might relieve redundant dopamine respectively). There was no significant difference in symptom blockade, that is, not necessary to redress psychosis, and remission rate (69.2% vs 66.7%) between the groups.
thereby improve functional capacity in the long term.
One of the first things to consider is the selection of the However, the psychological impact of having been in a DR sample included in the original trial. As noted, approxi- strategy might have been effective. We were not able to evalu- mately half the eligible patients with FEP were not willing to ate this latter factor because we did not measure it. In the origi- participate. Compared with participants, these nonpartici- nal trial we did not observe any differences between the DR pants differed in showing a lower level of functioning, being and MT groups in the intensity of outpatient or community less adherent to therapy, and being more difficult to engage.
care, as well as visits to psychiatrists, community psychiatric In the present study, one could say "the best half" of the FEP nurses, or crisis intervention contacts.24 In clinical practice, patients presenting in clinical practice was evaluated.
we did experience the DR strategy fitting in with the current The major issue is, of course, whether these striking re- concept of the physician-patient relationship, positioning the sults may be attributed to the treatment strategies in the origi- patient as the key player in his or her own treatment, taking nal trial. There were no significant differences in any of the con- the perspectives seriously, and assisting the patient in well- ceivable confounding variables between the 2 groups. Therefore, founded decision making on antipsychotic treatment.
it seems likely that the original treatment strategy, be it DR or Another striking finding is the flattening of the relapse rates MT, has a profound effect on long-term outcome. The differ- in the DR arm after approximately 3 years of follow-up. Al- ence after 7 years does not appear in the domains of symptom though relapse rates in the MT arm did not seem to level off remission or relapse rates but in the domains of functional re- as much, the relapse rates in the DR arm seem to have been mission and recovery. Even though the short-term relapse rates running ahead of those in the MT group, but only for the du- showed a significant disadvantage of DR strategy,4 the long- ration of the original trial and about 1 year afterward. Maybe term relapse rates did not show any significant difference, from the MT strategy postpones the relapses compared with the DR approximately 3 years of follow-up onward. On the other hand, strategy but does not prevent them. At the 7-year end point, short-term outcome did not show any advantages of DR in the relapse rates were not significantly different.
domains of recovery or functional remission, but striking dif- The results of this study lead to the following conclu- ferences were seen at longer-term follow-up.
sions: schizophrenia treatment strategy trials should include A possible weakness of the present study could be the ab- recovery or functional remission rates as their primary out- sence of rater blindness. We cannot rule out the possibility that come and should also include long-term follow-up for more this may have influenced the results in favor of the DR strat- than 2 years, even up to 7 years or longer. In the present study, egy, although it is not very likely to account for the magni- short-term drawbacks, such as higher relapse rates, were lev- tude of the identified differences.
eled out in the long term, and benefits that were not evident Another consideration is the mechanism in the DR arm that in short-term evaluation, such as functional gains, only ap- could be responsible for the gains in functional capacity com- peared during long-term monitoring. As a matter of fact, so- pared with MT. It was shown that even 5 years after the comple- cial functioning is mostly measured in a global way, for ex- tion of the original trial the treatment strategies used in that ample, by means of Global Assessment of Functioning or Social study still had an influence on the dosage of antipsychotics.
Functioning Assessment Scale scores, instead of using an in- Successful discontinuation in the early course of FEP was sus- strument dedicated to measuring the key domains of func- tained for many years in almost all patients and, on average, tional capacity. These key domains are daily living and self- patients in the DR strategy used a lower dose of antipsychotic care, working and studying, and relationships with others.
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Research Original Investigation Recovery in Remitted First-Episode Psychosis While in the present study we used the GSDS, a dedicated in- remitted FEP and stresses the need for studying alternative strument for the evaluation of social functioning in patients treatment strategies. Apart from a guided DR strategy exam- with schizophrenia, this instrument has the disadvantage of ined in the present study, the extended-dosing plan (admin- taking about 1 hour to complete. There is a need to develop an istering antipsychotics with a 1-, 2-, or even 3-day interval), international consensus about the criteria of functional remis- proposed by Remington and colleagues,25 might offer a use- sion and appropriate instruments to measure them. This would ful perspective.
also result in an international understanding about the crite- Of course, only one study indicating advantages of a DR ria for recovery in a clinical sense.13 strategy in patients with remitted FEP is not enough evi- The present study poses some serious considerations dence in such an important matter. However, these results about the long-term benefits of antipsychotic MT following merit replication by other research groups.
ARTICLE INFORMATION 3. Kane JM. Schizophrenia. N Engl J Med.
14. Wunderink A, Nienhuis FJ, Sytema S, Wiersma
Submitted for Publication: July 11, 2012; final
D. Treatment delay and response rate in first revision received December 21, 2012; accepted 4. Wunderink L, Nienhuis FJ, Sytema S, Slooff CJ,
episode psychosis. Acta Psychiatr Scand.
December 25, 2012.
Knegtering R, Wiersma D. Guided discontinuation Published Online: July 3, 2013.
versus maintenance treatment in remitted 15. Kay SR, Fiszbein A, Opler LA. The Positive and
first-episode psychosis: relapse rates and functional Negative Syndrome Scale (PANSS) for outcome. J Clin Psychiatry. 2007;68(5):654-661.
schizophrenia. Schizophr Bull. 1987;13(2):261-276.
Author Contributions: All authors had full access
to all the data in the study and take responsibility
5. Chen EYH, Hui CLM, Lam MML, et al.
16. Wiersma D, DeJong A, Ormel J. The Groningen
for the integrity of the data and the accuracy of the Maintenance treatment with quetiapine versus Social Disabilities Schedule: development, data analysis.
discontinuation after one year of treatment in relationship with I.C.I.D.H., and psychometric Study concept and design: Wunderink, Wiersma, patients with remitted first episode psychosis: properties. Int J Rehabil Res. 1988;11(3):213-224.
Sytema, Nienhuis.
randomised controlled trial. BMJ. 2010;341:c4024.
17. Andreasen NC, Carpenter WT Jr, Kane JM,
Acquisition of data: Nieboer, Nienhuis.
Lasser RA, Marder SR, Weinberger DR. Remission in Analysis and interpretation of data: Wunderink, 6. Vazquez-Barquero J, Perez-Iglesias R,
schizophrenia: proposed criteria and rationale for Nieboer, Sytema.
Crespo-Facorro B, Mata I, van Don J. How long consensus. Am J Psychiatry. 2005;162(3):441-449.
Drafting of the manuscript: Wunderink, Sytema.
should early intervention last in the first episode 18. Woods SW. Chlorpromazine equivalent doses
Critical revision of the manuscript for important psychosis? insights from the discontinuation for the newer atypical antipsychotics. J Clin intellectual content: All authors.
protocol of the Cantabria's first episode clinical Statistical analysis: Wunderink, Sytema.
program (PAFIP). Schizophr Res. 2010;117(2-3):116.
Obtained funding: Wunderink, Wiersma, Nienhuis.
19. Artaloytia JF, Arango C, Lahti A, et al. Negative
Administrative, technical, and material support: signs and symptoms secondary to antipsychotics: a 7. Emsley R, Oosthuizen PP, Koen L, Niehaus DJH,
double-blind, randomized trial of a single dose of Martinez G. Symptom recurrence following Study supervision: Wiersma.
placebo, haloperidol, and risperidone in healthy intermittent treatment in first-episode volunteers. Am J Psychiatry. 2006;163(3):488-493.
Conflict of Interest Disclosures: None reported.
schizophrenia successfully treated for 2 years: a 20. Kim JH, Son YD, Kim HK, et al.
Funding/Support: This study was funded by
3-year open-label clinical study. J Clin Psychiatry.
Antipsychotic-associated mental side effects and unconditional grants from Janssen-Cilag their relationship to dopamine D receptor Netherlands and Friesland Mental Health Services, 8. National Collaborating Centre for Mental Health
occupancy in striatal subdivisions: a high-resolution Leeuwarden, the Netherlands.
(UK). Schizophrenia: Core Interventions in the PET study with [11C]raclopride. J Clin Role of the Sponsors: The sponsors had no further
Treatment and Management of Schizophrenia in role in any part of the study or preparation of the Adults in Primary and Secondary Care (Update). 21. Grace AA. Dopamine system dysregulation by
London, England: National Institute for Health andClinical Excellence; 2009.
the hippocampus: implications for the Additional Contributions: The following mental
pathophysiology and treatment of schizophrenia.
health care services within the Netherlands 9. American Psychiatric Association. Practice
participated in data acquisition: Dimence Guideline for the Treatment of Patients with 22. Lewis DA, Curley AA, Glausier JR, Volk DW.
(Deventer), GGNet (Warnsveld), GGZ Drenthe Schizophrenia. Vol 2. Washington, DC: American Cortical parvalbumin interneurons and cognitive (Assen), GGZ Friesland (Leeuwarden), Lentis Psychiatric Association; 2004.
dysfunction in schizophrenia. Trends Neurosci.
(Groningen), Mediant (Enschede), University 10. Gilbert PL, Harris MJ, McAdams LA, Jeste DV.
Psychiatric Center/University Medical Center Neuroleptic withdrawal in schizophrenic patients: a Groningen (Groningen), and Yulius (Dordrecht).
review of the literature. Arch Gen Psychiatry.
23. Howes OD, Kapur S. The dopamine hypothesis
of schizophrenia: version III—the final common pathway. Schizophr Bull. 2009;35(3):549-562.
11. Gaebel W, Riesbeck M, Wölwer W, et al; German
1. Perkins DO, Gu H, Weiden PJ, McEvoy JP, Hamer
Study Group on First-Episode Schizophrenia.
24. Stant AD, TenVergert EM, Wunderink L,
RM, Lieberman JA; Comparison of Atypicals in First Relapse prevention in first-episode Nienhuis FJ, Wiersma D. Economic consequences of Episode study group. Predictors of treatment schizophrenia—maintenance vs intermittent drug alternative medication strategies in first episode discontinuation and medication nonadherence in treatment with prodrome-based early intervention: non-affective psychosis. Eur Psychiatry.
patients recovering from a first episode of results of a randomized controlled trial within the schizophrenia, schizophreniform disorder, or German Research Network on Schizophrenia. J Clin 25. Remington G, Seeman P, Feingold A, Mann S,
schizoaffective disorder: a randomized, Shammi C, Kapur S. "Extended" antipsychotic double-blind, flexible-dose, multicenter study. J Clin 12. Remington G. Antipsychotic dosing: still a work
dosing in the maintenance treatment of in progress. Am J Psychiatry. 2010;167(6):623-625.
schizophrenia: a double-blind, placebo-controlled 2. Robinson D, Woerner MG, Alvir JM, et al.
trial. J Clin Psychiatry. 2011;72(8):1042-1048.
13. Wunderink L, Sytema S, Nienhuis FJ, Wiersma
Predictors of relapse following response from a first D. Clinical recovery in first-episode psychosis.
episode of schizophrenia or schizoaffective Schizophr Bull. 2009;35(2):362-369.
disorder. Arch Gen Psychiatry. 1999;56(3):241-247.
JAMA Psychiatry September 2013 Volume 70, Number 9
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