Recovery in Remitted First-Episode Psychosis at 7 Years of Follow-up of an Early Dose Reduction/Discontinuation or Maintenance Treatment Strategy

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Wunderink L, et al. "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". JAMA Psychiatry. 2013. 70(9):913-920.
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Clinical Question

In patients with remitted first-episode psychosis (FEP), what are the rates of recovery of an early-course dose reduction/discontinuation (DR) strategy compared with maintenance treatment (MT)?

Bottom Line

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.

Major Points

Short-term outcome studies of antipsychotic dose-reduction/discontinuation strategies in patients with remitted FEP showed higher relapse rates but no other disadvantages compared with maintenance treatment; however, in the long-term, DR during the early stages of remitted FEP shows superior long-term recovery rates compared with the rates achieved with MT.

Design

  • Open randomized, controlled trial
  • N=103
    • DR (n=52)
    • MT (n=51)
  • Setting: 7 mental health care organizations and the Department of Psychiatry of the University Medical Center Groningen in The Netherlands, covering a catchment area of 3.1 million inhabitants
  • Enrollment: October 1, 2001, until December 1, 2002 (N = 257) for the original 2-year trial
  • Mean follow-up: 7 years, which was calculated from the start of the original trial (the start date of the first remission)
  • Analysis: Determinants of recovery were examined using logistic regression analysis; the treatment strategy (MT or DR) was controlled for baseline parameters.
  • Primary outcome: Rate of recovery, defined as meeting the criteria of symptomatic and functional remission.

Population

Inclusion Criteria

  • Patients who participated in the original study
    • First-episode schizophrenia or psychotic disorder
    • Age 18-45
    • Lived in the catchment area
    • Received no prior antipsychotic for more than 3 months
    • Mastered the Dutch language
    • Estimated IQ > 70
    • Response of positive symptoms within 6 months of starting antipsychotics and sustained remission during 6 months

Exclusion Criteria

  • None listed

Baseline Characteristics

  • Mean duration of untreated psychosis (DUP): 1.51
  • Mean age of onset of psychosis: 25.83
  • Regular job >16h/week: 45
  • Alcohol dependence or abuse: 22
  • Cannabis dependence or abuse: 26
  • Any substance dependence or abuse: 37
  • Schizophrenia: 45
  • Schizophreniform disorder: 26
  • Schizoaffective: 6
  • Delusional disorder: 12
  • Brief psychotic episode: 3
  • Psychotic disorder, NOS: 11
  • Positive and Negative Syndrome Scale (PANSS) subscale
    • Positive: 10.28
    • Negative: 13.50
    • General: 25.85
  • Total mean Groningen Social Disability Schedule (GSDS) score: 8.46
  • Total mean World Health Organization Quality of LIfe score: 91.48

Interventions

  • 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.
    • MT was carried out according to American Psychiatric Association guidelines, with preference for low-dose second-generation antipsychotics (mostly risperidone, olanzapine, quetiapine, and clozapine).
    • In the DR strategy, the dosage was gradually discontinued and tapered if feasible. Tapering was guided by symptom severity and patient preference. If early warning signs of relapse occurred, or positive symptoms recurred, clinicians were to restart or increase the dosage of antipsychotics.

Outcomes

Comparisons are DR vs. MT

Primary Outcomes

Rate of recovery after 7 years (defined as meeting the criteria of symptomatic and functional remission)
40.4% vs. 17.6% (Pearson χ21 = 8.2; P = 0.004).
Symptomatic remission
69.2% vs 66.7% (Pearson χ21 = 0.08; P = 0.78)
Functional remission
46.2% vs. 19.6% (Pearson χ21 = 6.45; P = 0.01)

Secondary Outcomes

Mean (SD) relapse rates
1.13 (1.22) vs. 1.35 (1.51) (t101 = –0.81, P = .42).
Mean antipsychotic dose (daily dose in haloperidol-equivalent milligrams) during the last 2 years of follow-up
2.20 [2.27] mg vs. 3.60 [4.01] mg (t101 = −2.18; P = .03)

Subgroup Analysis

Variables significantly associated with recovery at 7-years follow-up
  • Bivariate analyses: PANSS positive symptoms, negative symptoms, general symptoms (less severe), living with others vs. living alone, social functioning (better), and trial arm (DR)
  • Logistic regression analysis: less severe negative symptoms (odds ratio [OR1], 0.84; P = .007), living together (OR1, 4.44; P = .01), and trial arm (DR) (OR1, 3.49; P = .01)
Variables significantly associated with symptom remission at 7-years follow-up
  • Bivariate analyses: DUP (shorter), social functioning (better), and PANSS negative symptoms (less severe).
  • Logistic regression analysis: DUP (shorter) (OR1, 0.62; P = .02)
Variables significantly associated with functional remission at 7-years follow-up
  • Bivariate analyses: PANSS positive symptoms, negative symptoms, general symptoms (less severe), living with others vs/ living alone, social functioning (better), and trial arm (DR).
  • Logistic regression analysis: less severe negative symptoms (OR1, 0.85; P = .02), living together (OR1, 4.68; P = .01), better social functioning (OR1, 0.86; P = .04), and treatment arm (DR) (OR1, 4.62; P = .004)

Criticisms

  • More patients in the MT group were diagnosed with schizophrenia (51%) and fewer with delusional disorder (7.8%) than their DR counterparts (36.5% and 15.4%, respectively).
  • DR group had a more stable pattern of medication dose than the MT group in the last 2 years. This suggests that patients in the MT group may have a more fluctuating course of illness.
  • Data from their initial 18-month follow-up trial show that 51 of 65 patients (78.5%) in the DR group could not discontinue drug treatment (only 14 patients [21.5%] accomplished discontinuation successfully) vs 58 of 63 (92.1%) in the maintenance treatment (MT) group. In the long term, only 8 patients in the DR group and 3 patients in the MT group sustained treatment discontinuation during follow-up.
  • No blinding of the primary outcome, which could bias the results concerning the functional assessment.

Funding

  • Funders: Janssen-Cilag Netherlands and Friesland Mental Health Services, Leeuwarden, the Netherlands
  • Additional Contributions: The following mental health care services within the Netherlands participated in data acquisition: Dimence (Deventer), GGNet (Warnsveld), GGZ Drenthe (Assen), GGZ Friesland (Leeuwarden), Lentis (Groningen), Mediant (Enschede), University Psychiatric Center/University Medical Center Groningen (Groningen), and Yulius (Dordrecht).

Further Reading

[1]

[2]
  1. Hui CL & Chen EY Early medication discontinuation on long-term recovery outcome in first-episode psychosis. JAMA Psychiatry 2014. 71:207-8.
  2. Undurraga J et al. Early medication discontinuation on long-term recovery outcome in first-episode psychosis. JAMA Psychiatry 2014. 71:206-7.