Ewgeni Jakubovski

Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder

OBJECTIVE Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder follows a flat response curve within the therapeutic dose range. The present study was designed to clarify the relationship between dosage and treatment response in major depressive disorder. METHOD The authors searched PubMed for randomized placebo-controlled trials examining the efficacy of SSRIs for treating adults with major depressive disorder. Trials were also required to assess improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses. The longitudinal data were analyzed with a mixed-regression model. Endpoint and tolerability analyses were analyzed using meta-regression and stratified subgroup analysis by predefined SSRI dose categories in order to assess the effect of SSRI dosing on the efficacy and tolerability of SSRIs for major depressive disorder. RESULTS Forty studies involving 10,039 participants were included. Longitudinal modeling (dose-by-time interaction=0.0007, 95% CI=0.0001-0.0013) and endpoint analysis (meta-regression: β=0.00053, 95% CI=0.00018-0.00088, z=2.98) demonstrated a small but statistically significant positive association between SSRI dose and efficacy. Higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects (meta-regression: β=0.00207, 95% CI=0.00071-0.00342, z=2.98) and decreased likelihood of all-cause dropout (meta-regression: β=-0.00093, 95% CI=-0.00165 to -0.00021, z=-2.54). CONCLUSIONS Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents (50 mg of fluoxetine). The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.

Dimensional correlates of poor insight in obsessive-compulsive disorder

BACKGROUND Cross-sectional studies have associated poor insight in patients with obsessive-compulsive disorder (OCD) with increased OCD symptom severity, earlier age of onset, comorbid depression, and treatment response. The goal of this current study was to examine the relationship between dimensions of OCD symptomatology and insight in a large clinical cohort of Brazilian patients with OCD. We hypothesized that poor insight would be associated with total symptom severity as well as with hoarding symptoms severity, specifically. METHODS 824 outpatients underwent a detailed clinical assessment for OCD, including the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS), the Brown Assessment of Beliefs Scale (BABS), a socio-demographic questionnaire, and the Structured Clinical Interview for axis I DSM-IV disorders (SCID-P). Tobit regression models were used to examine the association between level of insight and clinical variables of interest. RESULTS Increased severity of current and worst-ever hoarding symptoms and higher rate of unemployment were associated with poor insight in OCD after controlling for current OCD severity, age and gender. Poor insight was also correlated with increased severity of current OCD symptoms. CONCLUSION Hoarding and overall OCD severity were significantly but weakly associated with level of insight in OCD patients. Further studies should examine insight as a moderator and mediator of treatment response in OCD in both behavioral therapy and pharmacological trials. Behavioral techniques aimed at enhancing insight may be potentially beneficial in OCD, especially among patients with hoarding.

Prognostic Subgroups for Citalopram Response in the STAR*D Trial

OBJECTIVE Few data exist to help clinicians predict likelihood of treatment response in individual patients with major depressive disorder (MDD). Our aim was to identify subgroups of MDD patients with differential treatment outcomes based on presenting clinical characteristics. We also sought to quantify the likelihood of treatment success based on the degree of improvement and side effects after 2 and 4 weeks of selective serotonin reuptake inhibitor (SSRI) pharmacotherapy. METHOD We analyzed data from the first treatment phase of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, in which subjects with a DSM-IV diagnosis of MDD were treated for 8-14 weeks with open-label citalopram. A receiver operating characteristic (ROC) analysis was conducted to determine homogenous subgroups with different rates of response and remission in depressive symptoms. Included predictor variables were initial clinical characteristics, initial improvement, and side effects after 2 and 4 weeks of SSRI treatment. The primary outcome measures were treatment response (defined as a greater than 50% reduction in 17-item Hamilton Depression Rating Scale [HDRS-17] score from baseline) and remission (defined as an HDRS-17 score ≤ 17). RESULTS Baseline clinical characteristics were able to identify subgroups from a low likelihood of response of 18% (income <

CLINICAL PREDICTORS OF LONG‐TERM OUTCOME IN OBSESSIVE‐COMPULSIVE DISORDER

10,000, comorbid generalized anxiety disorder, < 16 years of education; P < .01) to a high likelihood of response of 68% (income ≥

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

40,000, no comorbid posttraumatic stress disorder; P < .01). Among baseline clinical characteristics, employment status (N = 2,477; χ²₁ = 78.1; P < .001) and income level (N = 2,512; χ²₁ = 77.7; P < .001) were the most informative in predicting treatment outcome. For the models at weeks 2 and 4, treatment success was best predicted by early symptom improvement. CONCLUSIONS Socioeconomic data such as low income, education, and unemployment were most discriminative in predicting a poor response to citalopram, even with disparities in access to care accounted for. This finding implies that socioeconomic factors may be more useful predictors of medication response than traditional psychiatric diagnoses or past treatment history. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00021528.

Prognostic Subgroups for Remission and Response in the Coordinated Anxiety Learning and Management (CALM) Trial

The purpose of this study was to investigate demographic and clinical factors associated with the long‐term outcome of obsessive‐compulsive disorder (OCD).

Systematic Review and Meta-Analysis: Early Treatment Responses of Selective Serotonin Reuptake Inhibitors and Clomipramine in Pediatric Obsessive-Compulsive Disorder

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.

N-Acetylcysteine in the Treatment of Pediatric Tourette Syndrome: Randomized, Double-Blind, Placebo-Controlled Add-On Trial

OBJECTIVE Most patients with anxiety disorders receive treatment in primary care settings. Limited moderator data are available to inform clinicians of likely prognostic outcomes for individual patients. We identify baseline characteristics associated with outcome in adults seeking treatment for anxiety disorders. METHOD We conducted an exploratory moderator analysis from the Coordinated Anxiety Learning and Management (CALM) trial. In the CALM trial, 1,004 adults who met DSM-IV criteria for generalized anxiety disorder (GAD), panic disorder, social anxiety disorder, and/or posttraumatic stress disorder (PTSD) were randomized to usual care (UC) or a collaborative care intervention (ITV) of cognitive-behavioral therapy and/or pharmacotherapy between June 2006 and April 2008. Logistic regression was used to examine baseline characteristics associated with remission and response overall and by treatment condition. Receiver operating curve (ROC) analyses identified subgroups associated with similar likelihood of response and remission of global anxiety symptoms. Remission was defined as score < 6 on the 12-item Brief Symptom Inventory (BSI-12) anxiety and somatization subscales. Response was defined as at least 50% reduction on BSI-12, or meeting remission criteria. RESULTS Randomization to ITV over UC was often the strongest predictor of outcome. Several baseline patient characteristics were associated with poor treatment outcome including comorbid depression, increased severity of underlying anxiety disorder(s) (P < .001), low socioeconomic status (perceived [P < .001] and actual [P < .05]), and limited social support (P < .001). Patient characteristics associated with particular benefit from ITV were being female (P < .05), increased depression (P < .01)/GAD severity (P < .05), and low socioeconomic status (P < .05). ROC analysis demonstrated prognostic subgroups with large differences in response likelihood. CONCLUSIONS Further research should focus on the effectiveness of implementing the ITV intervention of CALM in community treatment centers where patients typically are of low socioeconomic status and may particularly benefit from ITV. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00347269.

Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial

OBJECTIVE We conducted a meta-analysis to examine the following: the time course of response to selective serotonin reuptake inhibitors (SSRIs) and clomipramine in pediatric obsessive-compulsive disorder (OCD); whether higher doses of SSRIs are associated with an improved response in pediatric OCD; differences in efficacy among SSRI agents; differences in efficacy between SSRIs and clomipramine; and whether the time course and magnitude of response to SSRIs are different in pediatric and adult patients with OCD. METHOD We searched PubMed and CENTRAL for randomized controlled trials comparing SSRIs (or clomipramine) to placebo for the treatment of pediatric OCD and using the Childrens Yale-Brown Obsessive-Compulsive Scale as an outcome. We extracted weekly symptom data from trials to characterize the trajectory of pharmacological response to SSRIs. Pooled estimates of treatment effect were calculated based on weighted mean differences between the treatment and placebo groups. RESULTS Nine trials involving 801 children with OCD were included in this meta-analysis. A logarithmic model indicating that the greatest benefits occurred early in treatment best fit the longitudinal data for both clomipramine and SSRIs. Clomipramine was associated with a greater measured benefit compared to placebo than SSRIs. There was no evidence for a relationship between SSRI dosing and treatment effect, although data were limited. Adults and children with OCD demonstrated a similar degree and time course of response to SSRIs in OCD. CONCLUSION These results suggest that the greatest incremental treatment gains in pediatric OCD occur early in SSRI treatment (similar to adults with OCD and children and adults with major depression).

Anxiety Disorder-Specific Predictors of Treatment Outcome in the Coordinated Anxiety Learning and Management (CALM) Trial

BACKGROUND Current pharmacological treatments for Tourette Syndrome (TS), such as antipsychotic agents and α-2 agonists, are moderately effective in the treatment of tics, but have substantial side effects that limit their use. N-acetylcysteine (NAC) modulates glutamatergic systems, and has been used safely as an antioxidant agent with minimal side effects for decades. NAC has been increasingly studied for the treatment of other obsessive-compulsive spectrum disorders. We aim to examine the efficacy of NAC for the treatment of pediatric TS in a double-blind, placebo-controlled, add-on study. METHODS Thirty-one children and adolescents 8-17 years of age with TS were randomly assigned to receive NAC or matching placebo for 12 weeks. Our primary outcome was change in severity of tics as measured by the Yale Global Tic Severity Scale (YGTSS), Total tic score. Secondary measures assessed comorbid obsessive-compulsive disorder (OCD), depression, anxiety, and attention-deficit/hyperactivity disorder (ADHD). Linear mixed models in SAS were used to examine differences between NAC and placebo. RESULTS Of 31 randomized subjects, 14 were assigned to placebo (two females; 11.5 + 2.8 years) and 17 to active NAC (five females; 12.4 + 1.4 years) treatment. No significant difference between NAC and placebo was found in reducing tic severity or any secondary outcomes. CONCLUSIONS We found no evidence for efficacy of NAC in treating tic symptoms. Our findings stand in contrast to studies suggesting benefits of NAC in the treatment of other obsessive-compulsive spectrum disorders in adults, including OCD and trichotillomania, but are similar to a recent placebo-controlled trial of pediatric trichotillomania that found no benefit of NAC.