Antipsychotic Tapering in FEP Beneficial in the Long-term

MILAN, Italy — Tapering antipsychotic medication for patients in remission after first episode psychosis (FEP) may be challenging in the short term but beneficial over the long term, early results of a new study suggest.

Clinicians face challenges in determining how long to continue antipsychotic treatment in this patient population,” lead investigator Iris Sommer, MD, PhD, professor of psychiatry at the University Medical Center Groningen in Groningen, the Netherlands, told Medscape Medical News.

Most guidelines recommend 1-2 years of antipsychotic treatment after FEP symptom remission. However, many clinicians deviate from this timeline, often due to patient preferences, as many find the duration too lengthy due to negative side effects including weight gain, anhedonia, sedation, sexual dysfunction and parkinsonism.

In patients where there have been dangerous situations during FEP “tapering is not such a good idea, but for those where this hasn’t been a case, 1 or 2 years of maintenance treatment can be a long period,” she said.

The findings were presented September 21 at the 37th European College of Neuropsychopharmacology (ECNP) Congress.

Conflicting Findings

Few trials have compared dose reduction or medication discontinuation with maintenance therapy. While short-term studies suggest that treatment continuation is linked to lower relapse rates and symptom reduction, there are conflicting data on long-term outcomes, said Sommer.

The Handling Antipsychotic Medication: Long-term Evaluation of Targeted Treatment (HAMLETT) study included 347 patients with FEP who were in remission and who had no dangerous episodes during psychosis.

Participants had a mean age of 27.9 years, 69.5% were male, and all had been in remission for 3-6 months. Patients taking any type of approved antipsychotic were allowed to participate. Roughly one third of participants were taking olanzapine, one-third aripiprazole, and the remainder were classified as miscellaneous.

Participants were randomly assigned to receive either medication tapering (n = 168) or maintenance (n = 179) and were followed up for 4 years.

“We provided clinicians and patients with a tapering schedule, which, depending on how high the original dose was, could be implemented over 3-6 months,” said Sommer.

Patients randomly assigned to the maintenance group were permitted to have a maximum dose reduction of 25%.

The primary outcome of the study was patient-reported World Health Organization Disability Assessment Scale 2.0 (WHODAS2) for physical, social, and psychological disability and communication skills.

Long-Term Benefits

More than 65% of patients in the tapering group were able to completely discontinue antipsychotic medication, with a mean dose reduction of −7.2 mg olanzapine equivalents. This is substantial, as “baseline olanzapine equivalents were a little bit higher than 10 mg,” said Sommer.

Preliminary results showed a curious lack of correlation WHODAS2 vs the physician-rated Global Assessment of Functioning (GAF), said Sommer.

WHODAS scores also did not correlate to symptom severity as measured by the mean Positive and Negative Syndrome Scale (PANSS), she added.

What to make of this remains unclear, Sommer said. Several patients, especially those with negative symptoms, overestimated their social interaction and functioning and underestimated their symptom severity, she noted.

“If I were to design this study again, I would not take the WHODAS as the main outcome as this does not seem that helpful to assess patients with schizophrenia spectrum disorder,” she added.

However, several secondary outcomes provided greater insight.

“The 12-month relapse rate was clearly higher in the discontinuation group, which is to be expected,” but results for GAF were more granular, said Sommer.

There were no significant differences in the short-term, up to 12 months, but after that, the discontinuation group started to do better, she explained. The differences first reached significance at 24 months and remained significant in year 3 and year 4.

Similarly, looking at symptom severity on the PANSS, there were also no early differences between groups, but starting at month 36 onwards the discontinuation group had lower symptom severity. 

Side-effects were not significantly different, and very low in both groups. In fact, weight gain seemed greater in the discontinuation group probably because a significant number of participants had discontinued aripiprazole, which is known to help reduce weight, Sommer noted.

The advantages of early tapering were clear, but they only started at 24-months, she concluded.

Sommer noted the long-term benefits of early discontinuation may not be directly because the tapering group was on less medication than the maintenance group. “If this were the case, you would expect these benefits at month 12,” she said. In addition, there was no significant difference in side effects.

Sommer said believes it is actually the empowerment and engagement of tapering and, in some cases, restarting that is associated with these long-term benefits.

Even if patients do relapse, and symptoms return, patients learn that the medication is beneficial, and they restart. It can increase also increase insight into the disease and increase build trust with clinicians, she added.

Clinical Implications Unclear

Commenting on the findings, session chair John Cryan, PhD from University College Cork, Cork, Ireland, and chair of the ECNP Scientific Committee, told Medscape Medical News that the study results are good news in many ways.

“These are important questions for the field. They are unknowns that need to be challenged in a large-scale way,” Cryan said.

The HAMLETT study is doing this, and there will be another 6-year follow up in the subsequent OPHELIA study, he added.

“I think it’s a really exciting study,” said Cryan. It considers some of the metabolic effects, as well as other issues often seen with tapering, he added.

However, he pointed out that it’s unclear how the results might affect clinical practice since they apply to a small subset of psychosis patients. These are first-episode patients that were fully in remission, he said. Therefore, there’s a concern about these findings being misinterpreted in a wider patient population.

The study was funded by ZonMW. Sommer and Cryan reported no conflicts.