Ben Kelmendi

N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder

RationaleDysfunction of glutamatergic neurotransmission has been implicated in the pathophysiology of obsessive-compulsive disorder (OCD) and recent clinical reports suggest that some glutamate modulating agents are efficacious in the treatment of this disorder. N-acetylcysteine (NAC) is a readily available amino acid compound that is thought to attenuate glutamatergic neurotransmission. NAC may be useful in treating psychiatric disorders involving glutamatergic dysfunction such as OCD.ObjectivesTo examine the efficacy of augmentation with NAC in a patient with serotonin reuptake inhibitor (SRI)-refractory OCD.MethodsA patient with SRI-refractory OCD was treated with an off-label use of NAC augmentation of fluvoxamine over several weeks.ResultsNAC augmentation of fluvoxamine resulted in a marked decrease in Yale-Brown Obsessive Compulsive Scale (Y-BBOCS) score and a clinically significant improvement in OCD symptoms.ConclusionsNAC augmentation was effective in treating SRI-refractory OCD in this single case. Further research is warranted to investigate the use of NAC and other glutamate modulating agents in the treatment of OCD.

Association of the Serotonin Transporter Polymorphism and Obsessive-Compulsive Disorder: Systematic Review

We investigated the association between the long (l) and short (s) alleles of the serotonin transporter polymorphism (5‐HTTLPR) in the promoter region of the SLC6A4 gene and obsessive‐compulsive disorder (OCD) using meta‐analysis to combine all published data from case–control and family based association studies (2,283 cases). In stratified meta‐analysis we investigated whether age of sample (child and adult), ethnicity (Caucasian and Asian) and study design (case–control and family‐based association studies) moderated any association. In the overall meta‐analysis we found no evidence of association between genetic variation at the 5‐HTTLPR locus and OCD. We did find significant heterogeneity between studies. In the stratified meta‐analyses, we demonstrated a significant association between the l‐allele and OCD in family‐based association studies and in studies involving children and Caucasians. Our meta‐analysis suggests the possibility that the l‐allele may be associated with OCD in specific OCD subgroups such as childhood‐onset OCD and in Caucasians. Further meta‐analyses based on individual patient data would be helpful in determining whether age of OCD onset, gender and the presence of comorbid illness (e.g., tics) moderates the relationship between 5‐HTTLPR and OCD.

Rapid antidepressant effect of ketamine in the electroconvulsive therapy setting.

Objectives Studies now provide strong evidence that the N-methyl-D-aspartate receptor antagonist ketamine possesses rapidly acting antidepressant properties. This study aimed to determine if a low dose of ketamine could be used to expedite and augment the antidepressant effects of electroconvulsive therapy (ECT) treatments in patients experiencing a severe depressive episode. Materials and Methods Subjects with major depressive disorder or bipolar disorder referred for ECT treatment of a major depressive episode were randomized to receive thiopental alone or thiopental plus ketamine (0.5 mg/kg) for anesthesia before each ECT session. The Hamilton Depression Rating Scale (HDRS) was administered at baseline and at 24 to 72 hours after the first and sixth ECT sessions. Results Electroconvulsive therapy exerted a significant antidepressant effect in both groups (F2,24 = 14.35, P < 0.001). However, there was no significant group effect or group-by-time interaction on HDRS scores. In addition, post hoc analyses of the time effect on HDRS showed no significant HDRS reduction after the first ECT session for either group. Conclusions The results of this pilot study suggest that ketamine, at a dose of 0.5 mg/kg, given just before ECT, did not enhance the antidepressant effect of ECT. Interestingly, the results further suggest that the coadministration of ketamine with a barbiturate anesthetic and ECT may attenuate the immediate antidepressant effects of the N-methyl-D-aspartate antagonist.

Dimensional predictors of response to SRI pharmacotherapy in obsessive-compulsive disorder.

BACKGROUND Obsessive-compulsive disorder (OCD) is clinically heterogeneous. Previous studies have reported different patterns of treatment response to serotonin reuptake inhibitors (SRI) based on symptom dimension. Our objective was to replicate these results in OCD patients who participated in one of four randomized, placebo-controlled, clinical trials (RCT). METHODS A total of 165 adult OCD subjects participated in one or more eight-week RCT with clomipramine, fluvoxamine, or fluoxetine. All subjects were classified as having major or minor symptoms in four specific OC symptom dimensions that were derived in a previous factor analytic study involving many of these same patients. Ordinal logistic regression was used to test the association between OC symptom dimensions and SRI response. RESULTS We found a significant association between the symptom dimension involving sexual, religious and harm-related obsessions as well as checking compulsions (AGG/SR) and improved SRI response. This increased rate of SRI response was experienced primarily by individuals with harm-related obsessions. Over 60% of patients with AGG/SR OCD symptoms were rated as very much improved after SRI treatment. LIMITATIONS As some of the RCTs included were conducted prior to the development of the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), improvement in OCD severity was assessed using the Clinical Global Improvement (CGI) Scale. Data from the double-blind and open-label continuation phases of these trials was collapsed together to increase statistical power. CONCLUSIONS Patients with OCD vary in their response to SRIs. The presence of AGG/SR symptoms is associated with an initial positive response to SRIs. These data add to the growing body of work linking central serotonin systems with aggressive behavior.

Riluzole augmentation in treatment-refractory obsessive-compulsive disorder: a series of 13 cases, with long-term follow-up.

To the Editors:First-line treatments for obsessive-compulsive disorder (OCD)-cognitive-behavioral therapy and pharmacotherapy with selective serotonin reuptake inhibitors-producesignificant improvement in only about 60% of patients with OCD.1 Further symptomatic improvement can be achieved in approx

Riluzole Augmentation in Treatment-Refractory Obsessive-Compulsive Disorder: A Pilot Randomized Placebo-Controlled Trial

OBJECTIVE Obsessive-compulsive disorder (OCD) affects approximately 2.5% of the population and is associated with significant morbidity. Many patients receive little benefit from the best available treatments, and even those who do respond often suffer from significant residual symptoms. Convergent evidence suggests that abnormalities in glutamate homeostasis and neurotransmission may contribute to OCD and that glutamate-modulating medications may be of benefit in patients whose symptoms are refractory to standard interventions. Small open-label trials of augmentation of serotonin reuptake inhibitor (SRI) pharmacotherapy with the glutamate modulator riluzole have suggested benefit in adults with refractory symptoms. We report a pilot randomized placebo-controlled trial of riluzole augmentation of ongoing SRI treatment in SRI-refractory patients. METHOD Outpatients (n = 27) and inpatients (n = 11) with DSM-IV OCD on stable SRI pharmacotherapy were randomized between November 2006 and December 2012 to receive riluzole 50 mg or placebo twice a day and followed for 12 weeks after a 2-week placebo lead-in phase. RESULTS Riluzole was well tolerated; 1 patient experienced moderate nausea, but none discontinued treatment due to side effects. While there was nominally greater Y-BOCS improvement in the riluzole group (our primary outcome) compared to placebo, it did not reach statistical significance. In the outpatient subsample, a trend suggesting benefit from riluzole augmentation for obsessions (P = .056, 2-tailed, uncorrected) was found in a secondary analysis. Among outpatients, more achieved at least a partial response (> 25% improvement) with riluzole than with placebo (P = .02 in a secondary analysis). CONCLUSIONS Riluzole may be of benefit to a subset of patients. Larger samples would be required to detect effects of the order suggested by the nominal improvement in our outpatient subsample. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00523718.