Does Aggressive Treatment of Psychosis Mean Sustained Use of Antipsychotics?

Treating first-episode psychosis aggressively is vital to halt or impede what may otherwise be a rapid downward trajectory. But, does treating these patients require the aggressive use of antipsychotic medications?

The results of a 2013 follow-up study caught the attention of clinicians and researchers: first-episode patients enrolled in an antipsychotic dose reduction/discontinuation strategy had better functional outcomes at seven years than patients receiving maintenance antipsychotic therapy.

Four experts who spoke with Psychiatric News said that the study, while not definitive, was an important contribution to the field and continues to remind clinicians of the value of an integrated approach to treatment that does not rely on antipsychotic medication alone.

The study, led by Lex Wunderink, M.D., Ph.D., and colleagues at the University of Groningen, Netherlands, appeared in JAMA Psychiatry (September, 2013). In it, the authors described the long-term outcomes of patients who participated in an initial study comparing a dose reduction/discontinuation strategy with maintenance medication for first-episode psychosis patients.

In the initial study, which appeared in the Journal of Clinical Psychiatry in 2007, a sample of 131 first-episode patients, aged 18 to 45 years, whose positive symptoms were remitted for at least six months were randomly assigned to a discontinuation strategy or maintenance treatment. Maintenance treatment was carried out according to APA guidelines, preferably using low-dose atypical antipsychotics. The discontinuation strategy was carried out by gradual symptom-guided tapering of dosage and discontinuation if feasible.

The results of the original study, based on a follow-up with patients at 18 months, were not encouraging. Twice as many relapses occurred in the discontinuation strategy group. In patients who received the discontinuation strategy, only 20 percent were successfully discontinued. Recurrent symptoms caused approximately 30 percent in the discontinuation group to restart antipsychotic treatment. After determining no advantages of the discontinuation strategy on functional outcome, the authors concluded, “Only a limited number of patients can be successfully discontinued. High relapse rates do not allow a discontinuation strategy to be universal practice.”

Of the original cohort, 103 patients were located and consented to participate in a follow-up study seven years later. The follow-up assessment asked participants to document symptom severity and level of social functioning during the past six months, relapses during the follow-up period, and the type and dose of antipsychotics used during the past two years.

What Wunderink and colleagues found was eye-opening: recovery rates were significantly higher in patients who received dose reduction than in those who received maintenance therapy. Importantly, symptom remission after seven years did not differ, but functional remission differed significantly in favor of dose reduction.

“It might well be the effect of less antipsychotic load that results in better functional capacity in the long term,” Wunderink and colleagues wrote. “Antipsychotic postsynaptic blockade of the dopamine signaling system, particularly of the mesocortical and mesolimbic tracts, not only might prevent and redress psychotic derangements but also might compromise important mental functions, such as alertness, curiosity, drive, activity levels, and aspects of executive functional capacity to some extent.… Thus, dose reduction and, where possible, discontinuation might relieve redundant dopamine blockade that is not necessary to redress psychosis and thereby improve functional capacity in the long term.”

UCLA

Stephen Marder, M.D., director of the section on psychosis at the Semel Institute for Neuroscience at UCLA, said the follow-up study raises important questions for clinicians. “A few of the patients were actually being treated without antipsychotic medication and did well, which raises the question whether they did well because they were off the medication,” he said. “My view of it is that the literature has always identified a small group of people with schizophrenia who do well after a first episode without medication. It’s a small, limited group—but clinicians need to bear in mind that it’s plausible.”

Some first-episode psychosis patients could benefit from lower doses of medication that might eventually be tapered off, Marder added. “A first episode of psychosis should be treated aggressively, but aggressive does not necessarily mean antipsychotics only. It means tending to psychosocial variables—work, family, relationships—and helping patients achieve recovery in the true sense of getting back a normal life.”

Jeffrey Lieberman, M.D., a past president of APA and chair of psychiatry at Columbia University and New York Presbyterian Hospital, was more circumspect, noting several methodological factors that could have influenced its conclusions, including the fact that the patients in the follow-up portion of the study were likely the healthiest among those who participated in the original study.

“The issue of the long-term effects of antipsychotic drugs is complicated and controversial, and this study challenges the notion of their effectiveness in patients with schizophrenia,” Lieberman said.

He said it has always been the case that antipsychotic drugs should be dosed and used judiciously. “However, I still believe that sustained use of antipsychotics at minimally effective doses are preferable to psychotic relapses in affecting the long-term outcome of patients. There is nothing mutually exclusive about using medication in the most effective way possible, and having a patient-centered, recovery-oriented approach.”

John Davis, M.D., a professor of psychiatry at the University of Illinois at Chicago, agreed it was not possible to recommend discontinuation of medication on the basis of the single study alone. “It’s well-established that some patients will never have a relapse after a first episode, and some may not need to be treated with antipsychotics—but there is no way to tell which patients fall into that category,” Davis said. “On the other hand, it’s clear that most patients will relapse if they are not on maintenance therapy.”

William Carpenter, M.D., of the Maryland Psychiatric Research Center and chair of the DSM-5 work group on psychosis, summed up the lessons of the Wunderink follow-up:

• Patients are variable; so are their treatment needs.

• Integrated therapeutics is superior to fragmented therapy or over-reliance on antipsychotic drugs.

• Optimal pharmacotherapy has not been established at the individual level, but it is known that excessive dosing has adverse effects and leads to poor compliance.

• The ability to maintain a therapeutic relationship in the context of dose reduction or targeted, noncontinuous dosing is crucial. ■