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Less Is More: Antipsychotic Dose After First-Episode Psychosis

July 10, 2013. Better long-term recovery is achieved with a dose reduction or discontinuation of antipsychotics during remission after first-episode psychosis, according to a new study published online July 3, 2013, in JAMA Psychiatry. Lead study author Lex Wunderink of Friesland Mental Health Services in Leeuwarden, the Netherlands, and colleagues randomized patients in recovery from first-episode psychosis to a dose reduction/discontinuation or maintenance treatment for 18 months. After seven years, patients in the reduction group experienced more than double the functional recovery rate of those in the maintenance group.

In an accompanying editorial, Patrick McGorry and colleagues of the University of Melbourne, Australia, discuss the implications of these data for the relationship between relapse and recovery. The new data “appear to put relapse into perspective,” they say. “Although certainly not desirable, a contained relapse is rarely the end of the world. Modest exacerbations of symptoms …may be a price worth paying for better longer-term functional recovery.”

The short view and the long view
Many patients with first-episode psychosis stop taking antipsychotic medications, resulting in an elevated risk of relapse and poorer recovery (Chen et al., 2010). In 2007, Wunderink’s group published similar findings from a clinical trial that compared dose reduction (DR) to maintenance treatment (MT) after first-episode psychosis (see SRF related news story). After six months of positive symptom remission, 128 patients were randomly and openly assigned to either a gradual tapering of their medication dose (and discontinuation where feasible) or a continuation of their regimen for 18 months. Follow-up at the end of the 18 months revealed that relapse rates in the DR group were double (43 percent) those of the MT group (21 percent).

In the current study, Wunderink and colleagues followed 103 patients from the 2007 trial for an additional five years—the longest follow-up period reported to date—allowing them to examine longer-term effects of antipsychotic DR. Patients were interviewed once, a total of seven years after the start of their first remission, and asked about symptom severity and social functioning during the preceding six months, relapses during the entire follow-up period, and antipsychotic dose during the past two years.

While the earlier, short-term study favored maintenance treatment, the situation was reversed after seven years. Although the relapse rate in the DR group was twice as high as in the MT group initially, by three years later the two had equalized. More importantly, in the DR group, the recovery rate after seven years was more than double that of the MT group (40 percent vs. 18 percent). Recovery was defined as having experienced both symptomatic and functional remission in the six months preceding follow-up. The rate of symptomatic remission, defined as a score of 3 or lower on the Positive and Negative Syndrome Scale (PANSS), did not differ between the groups. In contrast, the rate of functional remission, defined as a score of 1 or lower on all domains of the Groningen Social Disability Schedule (GSDS), was more than twice as high in the DR group than in the MT group (46 percent vs. 20 percent).

Using a logistic regression analysis, Wunderink and colleagues found that three variables (less severe negative symptoms, living with other people, and the DR trial arm) were associated with recovery after seven years. Functional remission was also associated with these variables, plus better social functioning, while symptomatic remission was only associated with the duration of untreated psychosis.

Not surprisingly, patients in the DR group had a significantly lower mean antipsychotic daily dose (measured in haloperidol-equivalent milligrams) than those in the MT group during the last two years of follow-up, and this difference trended toward significance when the patients who completely discontinued the drugs were excluded from the analysis. Some patients in both the DR and MT groups had either stopped or reduced their antipsychotic dose during the last two years of follow-up, so the authors performed a post-hoc comparison of those who successfully discontinued or reduced their dosage (n = 34) versus those who did not (n = 69) without taking the original trial arm into account. They found that those who successfully tapered the drugs had better outcomes in general, as indexed by higher rates of recovery, symptomatic remission, and functional remission, as well as a lower mean number of relapses.

Findings from a recent pilot study published July 1, 2013, in Schizophrenia Bulletin suggest that, in addition to improving recovery, antipsychotic dose reduction may also be beneficial to cognitive function. Hiroyoshi Takeuchi and colleagues of Keio University in Tokyo, Japan, randomly and openly assigned 54 patients with schizophrenia to either a 50 percent reduction in their dose of risperidone or olanzapine, or maintenance treatment. Similar to the findings of Wunderink's group, after 28 weeks there was no difference in the PANSS total score. However, the dose reduction group showed significant improvements in cognitive measures on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

Of course, more evidence is needed to confirm the findings that early dose reduction/discontinuation of antipsychotics improves recovery after first-episode psychosis. Potential next steps are outlined in McGorry and colleagues’ editorial, where they call for a more complex trial of DR supplemented with relapse prevention and early functional/vocational recovery interventions.—Allison A. Curley.

References:
McGorry P, Alvarez-Jimenez M, Killackey E. Antipsychotic Medication During the Critical Period Following Remission From First-Episode Psychosis: Less Is More. JAMA Psychiatry. 2013 Jul 3. Abstract

Takeuchi H, Suzuki T, Remington G, Bies RR, Abe T, Graff-Guerrero A, Watanabe K, Mimura M, Uchida H. Effects of Risperidone and Olanzapine Dose Reduction on Cognitive Function in Stable Patients With Schizophrenia: An Open-Label, Randomized, Controlled, Pilot Study. Schizophr Bull . 2013 Jul 1. Abstract

Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. 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 Jul 3. Abstract

 
Comments on News and Primary Papers
Comment by:  Robin Emsley (Disclosure)
Submitted 2 August 2013 Posted 7 August 2013
  I recommend the Primary Papers

The article by Wunderink et al., like the original paper, is thoughtful and informative. However, the results are a bit surprising and will hopefully not encourage clinicians to discontinue maintenance antipsychotic treatment. My own view is that we should be taking relapse very seriously, as it may play a critical role in disease progression, in addition to the obvious associated psychosocial risks. An earlier Dutch cohort study with a 15-year follow-up found accruing morbidity and identified relapse as a critical factor. After each relapse, a subset of patients experienced persistence of positive and negative symptoms (Wiersma et al., 1998).

Given the very strong association between treatment discontinuation and relapse (Robinson et al., 1999), our inability to accurately identify early warning signs of relapse, and the failure of rescue medication to abort relapse, together with additional evidence for emergent treatment refractoriness in a subset of patients after relapse (  Read more


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Comment by:  Martin HarrowThomas JobeRobert Faull
Submitted 14 August 2013 Posted 14 August 2013

While the empirical data on short-term studies of antipsychotics has produced considerable positive results, there is very little evidence on the long-term (four years or longer) efficacy of antipsychotics. Leucht and colleagues have noted “nothing is known about the effects of antipsychotic drugs compared to placebo after three years….” (Leucht et al., 2012).

Since multiyear (four years or longer) double-blind, drug-placebo studies of schizophrenia cannot be done, the relative lack of firm, long-term evidence on antipsychotic medications makes it more important that evidence from other types of studies be considered more carefully. This includes the long-term outcome of lower-dose and non-medicated schizophrenia patients from the seven-year Wunderink study and our 15- to 20-year naturalistic research finding more favorable long-term outcomes for unmedicated schizophrenia patients than those continuously prescribed antipsychotics (Harrow and Jobe, 2007;   Read more


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Comment by:  Stephen Marder
Submitted 16 August 2013 Posted 16 August 2013

This is an important contribution that has a number of important implications:

First, outcomes such as relapse and remission seem very crude to me, and they tell very little about what is of interest to many people with schizophrenia. An advantage of this study is that the authors used a sophisticated functional measure. I agree with Cenk Tek that patients who have a recurrence when the dose of antipsychotic is too low or medications have been stopped can become better managers of their illnesses (see Cenk Tek's full comment). I also believe that one of the goals of early treatment should be to educate patients to self-manage symptoms when they occur so that a minor exacerbation can be successfully managed.

Second, this study reminds us of an older literature from the 1980s, including my work (Marder et al., 1984), which documented that living with excessive dopamine blockade can be a personal burden that is...  Read more


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Comment by:  Clive AdamsStephanie Sampson
Submitted 14 August 2013 Posted 20 August 2013

One swallow does not necessarily indicate summer has arrived.

Shortly after publishing a Cochrane review on intermittent drug techniques for schizophrenia (Sampson et al., 2013), we were pleased to see Lex Wunderink and colleagues publish these new findings from their five-year follow-up. This current review includes the initial data of Wunderink et al. from the two-year study demonstrating double the relapse rates in their dose-reduction strategy relative to the maintenance treatment group. These data must be considered within the totality of all similar evidence, or there is risk of overextrapolating results from small trials. However, along with five other important and pioneering trials, the two-year findings by Wunderink et al. are entirely consistent (I2 = 0 percent) with other results (RR Relapse 2.46 95 percent CI 1.7-3.5), with Wunderink and colleagues' data contributing 42 percent of the weight to the finding. At around two years, maintenance treatment does seem to avoid more relapses than a variety of intermittent...  Read more


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