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July 8, 2013 by Sandra Steingard, MD

A Paradox Revealed – Again

Last week, an important study was published in JAMA Psychiatry. Wunderink and colleagues published results of a follow up study to one he had completed several years ago. In the initial study of first episode psychosis, subjects were randomized to one of two treatment strategies: maintenance treatment (MT) in which they were maintained on drugs for the two year study or drug discontinuation (DR) in which the drugs were stopped and then restarted if symptoms recurred.

In their initial report, they found that the DR group had a higher rate of relapse. They found no advantages to DR. This study supported the standard practice of recommending that individuals remain on these drugs continuously for at least two years.In this new study, they tracked these individuals 7 years after they had first entered the study. They defined three categories of recovery: symptomatic remission were those who had few or no psychotic symptoms, functional remission were those with good function (self-care, relationships, work), and full recovery were those who met criteria for both symptomatic remission and functional recovery.

At 7 years, there was a clear difference between the MT and DR groups: while both had similar rates of symptomatic remission (~67%), the DR group had a much higher rate of functional remission (46%) and full recovery (40%) than the MT group (19.6% and 17.6%, respectively). Thirty-four (33%) subjects were on no or very low doses of drug. Of those ~ 53% were in recovery.

Also of note, at seven years the MT group had the same number of relapses, they just occurred a bit later than in the DR group.

Martin Harrow’s study showed a correlation between neuroleptics and worse functional outcome but since this is a naturalistic study, one could not know if the drug dose caused the worse outcomes. Wunderink and colleagues randomized their subjects to each treatment approach yet they also found that maintenance treatment was correlated with worse functional outcome.

Wunderink also found that total dose had an impact on outcome. Lower average dose of neuroleptic – regardless of whether one was in the MT or DR group – was associated with better functional outcome without diminishing symptomatic improvement.

At 7 years, there was a clear difference between the MT and DR groups: while both had similar rates of symptomatic remission (~67%), the DR group had a much higher rate of functional remission (46%) and full recovery (40%) than the MT group (19.6% and 17.6%, respectively). Thirty-four (33%) subjects were on no or very low doses of drug. Of those ~ 53% were in recovery.

Timothy Crow, a prominent British psychiatrist and researcher, conducted a somewhat similar study in the 1980′s. In his study, he randomly assigned 120 subjects who had recovered from a first episode of psychosis with neuroleptics to maintenance treatment with drug or placebo. In an initial paper published in 1986, his group reported a higher rate of relapse in the placebo group. However, in a later paper on 30 month outcomes, they reported a higher rate of employment in those randomized to placebo. As they wrote in that paper, “It suggests the disquieting conclusion that the benefits of active neuroleptics in reducing relapse may exact a price in occupational terms.”

More recently, Gleeson and colleagues reported on the effects of a intensive experimental intervention that was designed to improve adherence to neuroleptic treatment in a group of individuals with first episode psychosis. Their intervention was effective – more individuals remained on drug – and at 12 months the relapse rate in experimental group was lower. But similar to Wunderink, they report that at 30 months, there was no advantage with regard to relapse rate for the experimental group and their vocational outcomes were worse.

I do not know who reads my blogs. I know that some of you do not need me to convince you that these drugs have serious problems. I want to, for a moment, intentionally address those of you who do not know what to make of the disparate messages you may read or hear, those who think that Whitaker and others make some compelling points but have not been able to walk away from the prevailing clinical narrative, and those who are wondering how to translate these studies into practice. I am still a practicing psychiatrist. I will go to work tomorrow and have these difficult conversations with the people who come to see me. This is how I am currently making sense of this.

First of all, there is a wide variability in outcome and response. I continue to believe that there are those who benefit from these drugs in both the short and long term. I am not able to accept the notion that neuroleptics are no different from other tranquilizers since they seem to yield a specificity of response – a decrease in voices, an increase in coherence – in someone who is appearing fully alert. But this is only for some and there are others for whom the response is not so great and there are those who recover without taking them. Unfortunately, we have no way of knowing who these people are.

In a situation where outcome is so variable and hard to predict, it seems imperative to avoid algorithms and directives and maintain an attitude of active shared decision making with the individual and her support system. “Relapse” is a construct that varies from individual to individual. The risk, therefore, needs to be considered on an individual basis.

Secondly, dose matters. We have known for at least twenty years, that low doses are as effective as higher ones. Many of the most troubling side effects are dose related. Wunderink found that those in the discontinuation group had overall less exposure to these drugs. It may have been this lower exposure, rather than the targeted dosing strategy, that had the greatest impact. If someone chooses to take one of these drugs, start low and go slow. Consider dose reductions.

This is important. Right now, there are an increasing number of articles in the professional literature focusing on the use of long acting injectable (LAI) drugs. This is in no doubt related to the fact that (in the US) with one exception, the current neuroleptics still on patent are LAIs. This will be the next big push – to prescribe LAI’s since they reduce relapse.

This does not need to be a polarized discussion for or against the use of these drugs. I doubt there is one correct answer. However, it is important that everyone involved remain knowledgeable about the available evidence.

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