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Original Investigation |

Recovery in Remitted First-Episode Psychosis at 7 Years of Follow-up of an Early Dose Reduction/Discontinuation or Maintenance Treatment Strategy:  Long-term Follow-up of a 2-Year Randomized Clinical Trial

Lex Wunderink, MD, PhD1,2; Roeline M. Nieboer, MA1; Durk Wiersma, PhD2; Sjoerd Sytema, PhD2; Fokko J. Nienhuis, MA2
[+] Author Affiliations
1Department of Research and Education, Friesland Mental Health Services, Leeuwarden, the Netherlands
2Department of Psychiatry, Rob Giel Research Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
JAMA Psychiatry. 2013;70(9):913-920. doi:10.1001/jamapsychiatry.2013.19.
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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.

Conclusions and Relevance  Dose reduction/discontinuation of antipsychotics during the early stages of remitted FEP shows superior long-term recovery rates compared with the rates achieved with MT. To our knowledge, this is the first study showing long-term gains of an early-course DR strategy in patients with remitted FEP. Additional studies are necessary before these results are incorporated into general practice.

Trial Registration  isrctn.org Identifier: ISRCTN16228411

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Figure 1.
Kaplan-Meier Survival Analysis

Time to first relapse after first remission (t6) during 7 years of follow-up in patients assigned to 18 months (547 days) of dose reduction/discontinuation (DR) or maintenance treatment (MT).

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Figure 2.
Mean Daily Dose in Dose Reduction/Discontinuation (DR) and Maintenance Treatment (MT) During the Last 2 Years of 7-Year Follow-up
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Figure 3.
Dose Reduction/Discontinuation in DR and MT During the Last 2 Years of 7-Year Follow-up

DR indicates dose reduction strategy; MDD, mean daily dose (haloperidol equivalent milligrams); and MT, maintenance treatment strategy.

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Submit a Comment
Convergence of relapse rates is misleading
Posted on February 11, 2014
Nick Kerrison
The Open University
Conflict of Interest: No conflicts of interest
I believe that cumulative percent relapse is a flawed statistic for measuring positive symptoms over the study based on the fact that I would expect a convergence in cumulative percent relapse even if the two treatments were equally effective at preventing relapse from the end of the first year or so.I have three reasons for this opinion:Firstly, consider the relapse rates after the 18 month follow up. At the end of 18 months, more patients relapsed in the discontinuation group. 21% of the medicated group and 43% of the discontinuation group had relapsed by the end of 18 months. Therefore, between months 19 and 84 inclusive, 79% of the original medicated group have the potential to relapse versus only 57% of the discontinuation group. So we might expect greater numbers of relapses in the medicated group due to this, from month 19 onward (until relapse rates actually converge).Secondly, this effect is compounded by the consistent finding in studies that approximately 20% of patients don’t relapse even when taken off medication long term. In this study, the authors have used the “best half” (their words) of patients, which may explain why the figure appears to be 40%, or double the normal finding. If we assume that these 40% will not relapse in either group, we can edit our earlier 79% and 57% figures by subtracting 40% from each to reveal that, from month 19 onward, 57-40 = 17% of the discontinuation group have the potential to relapse versus 79-40 = 39% of the medicated group.Thirdly, if we consider that, in the 18 months, 43-21 = 22% of patients are prevented from relapsing due to medication, it is reasonable to conclude that the 22% prevented from relapsing are likely to be from a higher risk group, were we able to assess predictors for relapse with good accuracy. Therefore, 22% of patients in the medicated group are more at risk of relapse than the 17% in the discontinuation group, if we ignore medicated status. Since these 22% make up more than half of the 39% “at risk” of relapse, in the medicated group, the average risk of relapse should be higher in the medicated group.So, from month 19 onward, we can expect more patients to have the potential to still relapse in the medicated group and the average risk rating of the patients in the medicated group to be higher. Therefore, in future studies, I think it would be a good idea to separate the initial group into good and bad prognostic status before randomisation, so that in addition to cumulative percent relapse, it would be possible to compare percent and total number of relapses per year and overall relapse count by prognostic group and medicated status.If the measures I recommend were undertaken in future studies, I believe that it would shed further light on the situation concerning long term efficacy of antipsychotics in preventing relapse.
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