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Adjunctive Risperidone Effective for Treatment-Resistant Major Depressive Disorder: Presented at ECNP

By Chris Berrie

PARIS, FRANCE -- September 22, 2006 -- Combination of risperidone with standard antidepressant therapies -- known as risperidone augmentation -- results in greater resolution of depressive symptoms compared with placebo augmentation in patients with major depressive disorder (MDD), according to a multicentre, prospective, randomised, double-blind, placebo-controlled trial presented here.

MDD is associated with high incidence of morbidity and mortality, significant functional impairment and substantial healthcare costs, with some 50% of patients responding at best only partially to antidepressant monotherapy, researchers said in a presentation on September 19^th at the 19^th Congress of the European College of Neuropsychopharmacology (ECNP).

While the selective serotonin reuptake inhibitors are the treatment of choice for MDD, when insufficient response is obtained, the options include switching, combination and augmentation treatment.

"Treatment resistance, and especially patients with residual symptoms of depression, is one of the greatest areas of unmet need in psychiatry, so this is a very important issue that affects a lot of patients," presenter Mary Kujawa, MD, PhD, data coordinator and risperidone team leader for US Medical Affairs, Janssen Pharmaceutica Inc., Titusville, New Jersey.

In Dr. Kujawa's study, patient underwent a 4-week open-label period on their standard antidepressant therapy, for dose-optimisation, followed by randomisation of 133 patients to augmentation with placebo (mean age, 46.4 years; male, 23.7%) and 141 patients to augmentation with risperidone (mean age, 45.9 years; male, 29.2%) while they continued on their antidepressant therapy.

The study enrolled patients who were 18 to 65 years of age and diagnosed with Diagnostic and Statistical Manual of Mental Disorders, Revision IV (DSM-IV) MDD. They had also demonstrated suboptimal response to at least 4 weeks with standard antidepressant therapy immediately prior to enrolment.

Before randomisation, patients had to continue to meet the DSM-IV criteria for MDD, and to have a Carroll Depression Scale (CDS) >20 and a Clinical Global Impression of Severity (CGI-S) of 4 or more (moderately ill).

The main exclusion criteria were for women of child-bearing potential, and patients with serious medical/neurological illness or history of suicide attempts, or with alcohol or substance abuse. For their current treatment, those on a tricyclic antidepressant, a monoamine oxidase inhibitor, a mood stabiliser and/or antiepileptic, or a centrally acting agent for the treatment of attention deficit disorder or attention deficit hyperactivity disorder or neurolepsy were excluded.

At the double-blind baseline (randomisation), the demographic and clinical characteristics showed no significant differences between the groups. Their primary antidepressant treatments at baseline were (placebo vs risperidone): bupropion (12.2% vs 14.6%); the antidepressants mirtazapine (1.5% vs 0.7%), trazodone (0.8% vs 1.5%), venlafaxine (18.3% vs 21.9%), and other (6.9% vs 1.5%); and the SSRIs citalopram (6.1% vs 2.9%), escitalopram (19.1% vs 16.1%), fluoxetine (15.3% vs 13.1%), paroxetine (6.1% vs 10.2%), and sertraline (13.0% vs 16.8%).

Risperidone dosing during the first 4 weeks of the double-blind stage was 1 mg/day, with an increase allowed to 2 mg/day to study end (used in 18% of the risperidone group). As Dr. Kujawa stressed, "This is a dose that is typically much lower than is used in treatment of schizophrenia."

For the investigator-led efficacy assessments at week 6 (study end) there was a significant benefit for risperidone over placebo seen as greater least square means total scores of 17-item Hamilton Rating Scale for Depression (HRSD 17) as last observation carried forward (placebo, -8.06 vs risperidone, -10.5, P = .004). This difference reached significance in the first week of double-blind treatment (-3.70 vs -5.12, respectively; P = .042).

Also of interest are HRSD-17 decreases in the risperidone group of patients who were (n = 81) or were not (n = 51) using SSRIs as their primary antidepressant therapy, with significant risperidone benefit at week 4 only in those who were on SSRIs.

Further significant benefits at week 6 for placebo versus risperidone were: remission (10% vs 20%; P = .016); treatment responders (29% vs 41%; P = .017); CGI-S (3.5 vs 3.1; P = .002); Quality of Live Enjoyment and Satisfaction Questionnaire total (54.3 vs 59.6; P = .002); very much/much improved (25.6% vs 41.0%; P = .016); and Sheehan Disability Scale total (16.3 vs 12.8; P < .001).

For the safety analysis, no unexpected adverse events were reported during the 6-week, double-blind phase, and no clinically meaningful differences in safety were noted between placebo and risperidone.

"While over the 6-week double-blind period there was improvement in both arms, suggesting that yes, [the patients] do need more time with their optimal dose of antidepressant, there was also a statistically and clinically meaningful improvement even above and beyond that when using risperidone augmentation," Dr. Kujawa. "And even at the end of the trial, there is no plateau reached in the improvement."

This study was supported by funding from Janssen,LP.


[Presentation title: A Double-Blind, Placebo-Controlled Study of Adjunctive Risperidone for Treatment-Resistant Major Depressive Disorder. Abstract P.8.a.053]

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