Vladimir Coric

A systematic review: antipsychotic augmentation with treatment refractory obsessive-compulsive disorder

As many as half of obsessive-compulsive disorder (OCD) patients treated with an adequate trial of serotonin reuptake inhibitors (SRIs) fail to fully respond to treatment and continue to exhibit significant symptoms. Many studies have assessed the effectiveness of antipsychotic augmentation in SRI-refractory OCD. In this systematic review, we evaluate the efficacy of antipsychotic augmentation in treatment-refractory OCD. The electronic databases of PubMed, PsychINFO (1967–2005), Embase (1974–2000) and the Cochrane Central Register of Controlled Trials (CENTRAL, as of 2005, Issue 3) were searched for relevant double-blind trials using keywords ‘antipsychotic agents’ or ‘neuroleptics’ and ‘obsessive-compulsive disorder’. Search results and analysis were limited to double-blind, randomized control trials involving the adult population. The proportion of subjects designated as treatment responders was defined by a greater than 35% reduction in Yale Brown Obsessive-Compulsive Scale (Y-BOCS) rating during the course of augmentation therapy. Nine studies involving 278 participants were included in the analysis. The meta-analysis of these studies demonstrated a significant absolute risk difference (ARD) in favor of antipsychotic augmentation of 0.22 (95% confidence interval (CI): 0.13, 0.31). The subgroup of OCD patients with comorbid tics have a particularly beneficial response to this intervention, ARD=0.43 (95% CI: 0.19, 0.68). There was also evidence suggesting OCD patients should be treated with at least 3 months of maximal-tolerated therapy of an SRI before initiating antipsychotic augmentation owing to the high rate of treatment response to continued SRI monotherapy (25.6%). Antipsychotic augmentation in SRI-refractory OCD is indicated in patients who have been treated for at least 3 months of maximal-tolerated therapy of an SRI. Unfortunately, only one-third of treatment-refractory OCD patients show a meaningful treatment response to antipsychotic augmentation. There is sufficient evidence in the published literature, demonstrating the efficacy of haloperidol and risperidone, and evidence regarding the efficacy of quetiapine and olanzapine is inconclusive. Patients with comorbid tics are likely to have a differential benefit to antipsychotic augmentation.

Riluzole Augmentation in Treatment-Resistant Obsessive-Compulsive Disorder: An Open-Label Trial

BACKGROUND Most patients with obsessive-compulsive disorder (OCD) show only partial reduction of symptoms with standard therapy. Recent imaging data suggests glutamatergic dysfunction in the corticostriatal pathway in OCD. We investigated the efficacy of augmentation therapy with riluzole, a glutamate-modulating agent, in treatment-resistant OCD. METHODS Thirteen patients aged between 18 and 65 years with a primary diagnosis of OCD that had proven resistant to standard treatment were treated with the addition of riluzole to their existing pharmacotherapy. Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Hamilton Depression Inventory (HAM-D), and Hamilton Anxiety Inventory (HAM-A) scores were obtained weekly. RESULTS Thirteen treatment-resistant OCD patients received riluzole 50 mg twice a day. Y-BOCS scores improved significantly over time. Of 13 patients, 7 (54%) demonstrated a >35% reduction in Y-BOCS scores, and 5 (39%) were categorized as treatment responders. HAM-D and HAM-A scores for the group also significantly improved over time. Riluzole was well tolerated with no serious adverse effects noted. CONCLUSIONS Riluzole appears to have significant antiobsessional, antidepressant, and antianxiety properties. The addition of this agent may be of practical clinical benefit in patients with OCD.

Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder.

SummaryObsessive-compulsive disorder (OCD) is a common psychiatric disorder that produces significant morbidity. The introduction of serotonin reuptake inhibitors in the 1980s represented an important advance in the treatment of OCD. However, few patients show complete remission of their symptoms, and some patients show minimal improvement with existing treatments. We review current treatment strategies and initial data supporting the efficacy of glutamate modulating agents as a novel class of Pharmaceuticals for the treatment of OCD. Functional neuroimaging studies repeatedly reported metabolic hyperactivity in the cortico-striato-thalamo-cortical circuitry in patients with OCD. Recent magnetic resonance spectroscopy studies provide evidence of elevated glutamate levels in several brain regions in patients suffering from OCD. These findings raised the possibility that agents that reduce glutamate hyperactivity or its consequences in the CNS might be efficacious as novel therapeutic interventions. Indeed, initial evidence from our group suggests that the antiglutamatergic agent riluzole (Rilutek), which was developed for the treatment of amyotrophic lateral sclerosis, is effective in treatment-resistant OCD. Case reports suggest that other agents that modulate glutamatergic activity may likewise be effective. This new application of glutamate modulating agents holds promise for the treatment of this disabling and often inadequately treated disease.

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.

Riluzole in the Treatment of Mood and Anxiety Disorders

Recent advances implicate amino acid neurotransmission in the pathophysiology and treatment of mood and anxiety disorders. Riluzole, which is approved and marketed for the treatment of amyotrophic lateral sclerosis, is thought to be neuroprotective through its modulation of glutamatergic neurotransmission. Riluzole has multiple molecular actions in vitro; the two that have been documented to occur at physiologically realistic drug concentrations and are therefore most likely to be clinically relevant are inhibition of certain voltage-gated sodium channels, which can lead to reduced neurotransmitter release, and enhanced astrocytic uptake of extracellular glutamate.Although double-blind, placebo-controlled trials are lacking, several open-label trials have suggested that riluzole, either as monotherapy or as augmentation of standard therapy, reduces symptoms of obsessive-compulsive disorder, unipolar and bipolar depression, and generalized anxiety disorder. In studies of psychiatrically ill patients conducted to date, the drug has been quite well tolerated; common adverse effects include nausea and sedation. Elevation of liver function tests is common and necessitates periodic monitoring, but has been without clinical consequence in studies conducted to date in psychiatric populations. Case reports suggest utility in other conditions, including trichotillomania and self-injurious behaviour associated with borderline personality disorder. Riluzole may hold promise for the treatment of several psychiatric conditions, possibly through its ability to modulate pathologically dysregulated glutamate levels, and merits further investigation.

Multicenter, randomized, double‐blind, active comparator and placebo‐controlled trial of a corticotropin‐releasing factor receptor‐1 antagonist in generalized anxiety disorder

Background: Antagonism of corticotropin‐releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF‐1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD). Method: This was a multicenter, randomized, double‐blind, placebo‐controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100 mg/day (after a 1 week loading dose of 300 mg/day), placebo or escitalopram 20 mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score. Results: Pexacerfont 100 mg/day did not separate from placebo on the primary outcome measure. The half‐powered active comparator arm, escitalopram 20 mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P<.02). Response rates for pexacerfont, placebo, and escitalopram were 42, 42, and 53%, respectively. Genetic and psychometric rating scale data was obtained in 175 randomized subjects. There was a significant association between a single nucleotide polymorphism (SNP) of the gene encoding plexin A2 (PLXNA2‐2016) with the HAM‐A psychic subscale score for the entire cohort at baseline (FDR‐adjusted P=.015). Conclusions: Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment. Depression and Anxiety, 2010.

Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with obsessive-compulsive disorder and major depressive disorder

Altered glutamatergic neurotransmission has been implicated in the pathophysiology of mood and anxiety disorders (Berman et al. 2000; Rosenberg et al. 2000). Preclinical and clinical studies suggest that drugs that reduce glutamatergic activity might play a role in the treatment of both mood and obsessive-compulsive disorders (Krystal et al. 1999, 2002; Rosenberg et al. 2000). One candidate agent is the antiglutamatergic drug, riluzole (Rilutek). This drug, initially approved as a neuroprotective agent for patients with amyotrophic lateral sclerosis, has several actions in the brain that appear to contribute to its antiglutamatergic activity: an inhibitory effect on glutamate release, inactivation of voltage dependent sodium channels in cortical neurons, and blockade of GABA reuptake (Stefani et al. 1997; Jehle et al. 2000; Urbani et al. 2000). The following case describes the beneficial effects of riluzole in a patient with obsessive-compulsive disorder (OCD) and major depressive disorder. We postulated that the addition of a drug that reduces both glutamate release and its postsynaptic consequences would attenuate regional brain hyperactivity implicated in the pathophysiology of these disorders. This case is selected from an ongoing openlabel study evaluating the safety and preliminary efficacy of riluzole in the treatment of obsessive-compulsive disorder. Mr. A was a 47-year-old man whose obsessions/ compulsions dated to adolescence and preceded his depressive symptoms. His obsessions and depressive symptoms worsened in the past 2 years despite appropriate primary pharmacotherapeutic and augmentation strategies. Within the last 2 years, he had been hospitalized on two occasions for suicidal ideations. Past pharmacotherapy included adequate trials of serotonin reuptake inhibitors (clomipramine, fluvoxamine, sertraline, citalopram, venlafaxine) alone or in combination with antipsychotics (risperidone, olanzapine, quetiapine). At the time of study enrollment he was taking fluvoxamine (150 mg PO bid) and clonazepam (1 mg every 4 h). He had been recently taken off risperidone (2–4mg every 4 h) by his outpatient psychiatrist. After obtaining written informed consent, Mr A. participated in a study approved by the Yale University Human Investigations Committee, New Haven, Conn.. At the time of entry into the study, Mr. A reported recurrent, ego-dystonic, intrusive thoughts and severe depression. His obsessions were so severe that they interfered with his ability to concentrate and perform sustained tasks. He also reported symptoms of decreased concentration, insomnia, feelings of hopelessness, anhedonia, decreased appetite, low energy, lack of sex drive, and suicidal ideations. He described his mood as “severely depressed.” He demonstrated flat affect, psychomotor retardation, poor eye contact, and inattention to grooming. Additionally, he was unable to work for several months prior to his hospitalization. Mr. A had several family members diagnosed with OCD (sister, paternal grandfather) and his sister also was diagnosed with anorexia nervosa. Clinical diagnosis was confirmed with the Structured Clinical Interview for DSM-IV Disorders (SCID-I/P version 2.0) as OCD and major depressive disorder. V. Coric ()) · S. Milanovic · S. Wasylink · P. Patel · R. Malison · J. H. Krystal Clinical Neuroscience Research Unit, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT 06519, USA

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.

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.

Relationships Among Plasma Dehydroepiandrosterone and Dehydroepiandrosterone Sulfate, Cortisol, Symptoms of Dissociation, and Objective Performance in Humans Exposed to Underwater Navigation Stress

BACKGROUND A growing body of research has provided evidence that dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are involved in an organisms response to stress and that it may provide beneficial behavioral and neurotrophic effects. METHODS This study investigated plasma DHEA and DHEAS, cortisol, psychological symptoms of dissociation, and military performance in 41 healthy active duty subjects enrolled in the military Combat Diver Qualification Course (CDQC). RESULTS Baseline values of DHEA and DHEAS were significantly and positively predictive of superior performance in the underwater navigation exam; in addition, DHEA and DHEAS were significantly and negatively related to stress-induced symptoms of dissociation during performance of the task. Similarly, participants who reported fewer symptoms of dissociation exhibited superior military performance and increased levels of DHEA after the test. CONCLUSIONS These data provide prospective, empiric evidence that DHEA and DHEAS are associated with superior stress tolerance, fewer symptoms of dissociation, and superior, objectively assessed, military performance.