Antipsychotics in First-Episode Psychosis: Less Is More

Nancy A. Melville

July 16, 2013

Patients treated with antipsychotics after remission of a first episode of psychosis are substantially more likely to experience long-term recovery if treated with a dose-reduction or discontinuation strategy vs maintenance therapy, a long-term follow-up study shows.

Shorter-term outcome studies have consistently shown higher relapse rates with the dose-reduction/discontinuation approach, but the study is said to be among the first to provide a longer-term perspective on the issue, with a follow-up period as long as 7 years.

"To our knowledge, this is the first study showing long-term gains of an early-course dose-reduction strategy in patients with remitted first-episode psychosis," the authors write.

The study was published online July 3 in JAMA Psychiatry.

Functional Remission

Investigators led by Lex Wunderink, MD, PhD, of Friesland Mental Health Services, in Leeuwarden, the Netherlands, conducted a 7-year follow-up of 103 patients who had originally been part of a 2-year randomized clinical trial comparing maintenance therapy with dose-reduction/discontinuation treatment.

In the original study, 257 patients with first-episode psychosis presenting between October 2001 and December 2002 were asked to participate in the trial. Among them, 111 refused or were lost to follow-up, and 18 did not experience remission.

The remaining 128 were randomly assigned to receive either maintenance therapy or dose-reduction/discontinuation therapy for 18 months, starting after 6 months of remission from their first episode of psychosis.

At the conclusion of that study, relapse rates, consistent with previous research, were significantly higher in the dose-reduction/discontinuation group, compared with those on maintenance therapy, and there were no improvements with dose reduction in functional remission.

The follow-up at 7 years of 103 patients from the original study, however, showed the rate of recovery, defined according to criteria for symptomatic and functional remission for at least 6 months at the 7-year follow-up, in the dose-reduction/discontinuation group (40.4%) to be more than twice the rate in the maintenance therapy group (17.6%).

Functional remission in the dose-reduction/discontinuation group was 46.2% vs 19.6% in the maintenance group; however, there were no differences between the 2 groups in terms of symptomatic remission.

According to Dr. Wunderink, the distinction between functional and symptomatic remission is important.

"The functional domain is what matters most from a patient perspective," he told Medscape Medical News.

"These gains were not apparent after 2 years of follow-up, just after applying the strategy for 18 months, but only after longer-term follow-up, in our case, after 7 years. Gains might already have shown up after 3 or 4 years, but we don't exactly know," he noted.

At 7-year follow-up, "relapse rates came on par and functional recovery was far better in patients who were discontinued in the original trial," he said.

Although the study did not specify which antipsychotics drugs were used, owing to low numbers, Dr. Wunderink said that they included the most common antipsychotics, including risperidone, olanzapine, and clozapine, with lower percentages of aripiprazole, quetiapine, and first-generation antipsychotics.

Probable Mechanism

The authors hypothesized that the long-term improvements associated with dose reduction or discontinuation are directly associated with the role of dopaminergic blockage in psychosis treatment possibly diminishing over time.

"The underlying background [of the study] was our hypothesis that dopaminergic blockade is a good and necessary means of symptomatic treatment of positive symptoms of the acute episode but does not really touch underlying pathological mechanisms of most psychoses, including schizophrenia's, that are still unknown to a large extent," Dr. Wunderink explained.

"We felt that dopaminergic blockade might have a negative impact on functional capacity, which in the end turned out to be true — endorsed by the long-term results — unexpectedly.

Over time, the lower antipsychotic load in the dose-reduction group "took away the redundant dopamine blockage, and that allowed for better functional recovery," he said.

A key limitation of the study was that participants may be described as "the best half" of the first-episode psychosis patients who presented in the first study, according to the authors. Other weaknesses could have included the absence of rater blindness and the mechanism in the dose-reduction arm that could have played a role in improved functional capacity, compared with maintenance therapy.

Although recommending additional research on the issue, Dr. Wunderink said that the findings support an argument for a shift away from blanket recommendations for maintenance therapy.

"[The findings] mean that we do have to consider dose-reduction strategies in all first-episode patients who are free of symptoms and meet the remission criteria, in order to promote functional recovery," he said.

"These dose-reduction strategies should be further elaborated, for instance, by adding psychological interventions like cognitive-behavior therapy and individual placement and support to pharmacological treatment."

Need for Replication

In an accompanying editorial, Patrick McGorry, MD, PhD, of the University of Melbourne, in Victoria, Australia, and colleagues agreed that the therapeutic strategies should be implemented whenever possible, and they called for clinicians to more carefully consider which patients may be appropriate for antipsychotic dose reduction.

"It now seems probable for patients who achieve clinical remission from first-episode psychosis that as many as 40% can achieve a good long-term recovery with use of no or low-dose antipsychotic medication," they write.

"It is important to identify these patients at an early stage."

In further commenting on the study to Medscape Medical News, Dr. McGorry called the research "groundbreaking," but he noted that the findings will need to be replicated in order to have serious influence.

He added that although many clinicians are inclined to err on the side of caution by keeping patients on maintenance therapy, the findings suggest that even an approach of trying a lower dose, as opposed to discontinuation, may offer improved recovery in the long run.

"This will be a challenge to many clinicians; however, dose reduction is a more cautious goal than discontinuation, and all clinicians should embrace that, at least in patients with good early remissions," Dr. McGorry said.

"More intensive psychosocial care aimed at functional recovery could further enhance recovery rates if offered via specialized early-psychosis services," he said.

Valuable Insights

Dr. Philip R. Muskin, MD, a professor of psychiatry at the Columbia University Medical Center in New York City, agreed that the study has important limitations, particularly in that the patients appear to have relatively mild psychosis, but the research nevertheless offers valuable insights, he said.

"This has got to be one of the longest studies that have ever been done, and they have pretty convincing data that people do better with dose reduction," he told Medscape Medical News.

"And I like their argument that function matters more than symptoms," he said, noting reports of patients who experience psychotic symptoms but who are able to function well in society, even in positions such as CEOs.

"I think what you can take from this study is that if you treat a patient for a year — particularly someone with mild symptoms and who responds to a relatively low dose of medication — you can probably consider not maintaining them forever, and perhaps try a trial of slow dosage reduction and careful follow-up," he said.

"You may find the patient winds up doing better and no longer needs the medication."

"It doesn't necessarily have to be all or nothing," he added. "It looks like the big risk period is the first few years, but as long as they do okay, those first few years they should be okay."

The study received funding from Janssen-Cilag Netherlands and Friesland Mental Health Services. Dr. Wunderink, Dr. McGorry, and Dr. Muskin report no relevant financial relationships.

JAMA Psychiatry. Published Online July 3, 2013. Abstract, Editorial

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