Predictors of clinical worsening during a discontinuation trial of serotonin reuptake inhibitors for obsessive compulsive disorder.

OBJECTIVE: To explore predictors and moderators of clinical worsening during a double-blind trial in which patients with obsessive-compulsive disorder (OCD) were randomized to either continue or discontinue their Serotonin Reuptake Inhibitor (SRI) medication after achieving wellness from the addition of exposure and response prevention (EX/RP) therapy. METHOD: The data came from a double-blind discontinuation trial that included N = 101 participants, 35 of whom were removed from the study due to clinical worsening. We first used LASSO logistic regression to identify which of the 34 potential baseline variables of interest (including demographics, diagnoses, other relevant clinical constructs, and specific genotypes), might moderate or predict this clinical worsening. Then logistic regression was used to examine which of these identified variables were significantly related to later clinical worsening. We verified the validity of our final prediction model using k-fold cross-validation. RESULTS: There was one significant predictor of clinical worsening: In both groups, those with more past diagnoses had a greater likelihood of clinical worsening (p = .015). There were several moderators. Rates of clinical worsening were higher in the Discontinuation group compared to the Continuation group for participants who were taking a shorter half-life SRI (p = .044), were female (p = .022), had higher baseline levels of maladaptive metacognitions (p < .001), had fewer sleep problems at baseline (p = .001), and/or had more years of education (p < .001). CONCLUSIONS: Our results identified several factors that may predict the development of clinical worsening in OCD patients discontinuing SRI medication following successful EX/RP treatment.

Maximizing remission from cognitive-behavioral therapy in medicated adults with obsessive-compulsive disorder.

Practice guidelines for adults with obsessive-compulsive disorder (OCD) recommend augmenting serotonin reuptake inhibitors (SRIs) with exposure and ritual prevention (EX/RP). However, fewer than half of patients remit after a standard 17-session EX/RP course. We studied whether extending the course increased overall remission rates and which patient factors predicted remission. Participants were 137 adults with clinically significant OCD (Yale-Brown Obsessive Compulsive Scale [Y-BOCS] score ≥18) despite an adequate SRI trial (≥12 weeks). Continuing their SRI, patients received 17 sessions of twice-weekly EX/RP (standard course). Patients who did not remit (Y-BOCS ≤12) received up to 8 additional sessions (extended course). Of 137 entrants, 123 completed treatment: 49 (35.8%) remitted with the standard course and another 46 (33.6%) with the extended course. Poorer patient homework adherence, more Obsessive-Compulsive Personality Disorder (OCPD) traits, and the Brain-Derived Neurotrophic Factor (BDNF) Val66MET genotype were associated with lower odds of standard course remission. Only homework adherence differentiated non-remitters from extended course remitters. Extending the EX/RP course from 17 to 25 sessions enabled many (69.3%) OCD patients on SRIs to achieve remission. Although behavioral (patient homework adherence), psychological (OCPD traits), and biological (BDNF genotype) factors influenced odds of EX/RP remission, homework adherence was the most potent patient factor overall.

Role of Human Ventromedial Prefrontal Cortex in Learning and Recall of Enhanced Extinction.

Standard fear extinction relies on the ventromedial prefrontal cortex (vmPFC) to form a new memory given the omission of threat. Using fMRI in humans, we investigated whether replacing threat with novel neutral outcomes (instead of just omitting threat) facilitates extinction by engaging the vmPFC more effectively than standard extinction. Computational modeling of associability (indexing surprise strength and dynamically modulating learning rates) characterized skin conductance responses and vmPFC activity during novelty-facilitated but not standard extinction. Subjects who showed faster within-session updating of associability during novelty-facilitated extinction also expressed better extinction retention the next day, as expressed through skin conductance responses. Finally, separable patterns of connectivity between the amygdala and ventral versus dorsal mPFC characterized retrieval of novelty-facilitated versus standard extinction memories, respectively. These results indicate that replacing threat with novel outcomes stimulates vmPFC involvement on extinction trials, leading to a more durable long-term extinction memory.SIGNIFICANCE STATEMENT Psychiatric disorders characterized be excessive fear are a major public health concern. Popular clinical treatments, such as exposure therapy, are informed by principles of Pavlovian extinction. Thus, there is motivation to optimize extinction strategies in the laboratory so as to ultimately develop more effective clinical treatments. Here, we used functional neuroimaging in humans and found that replacing (rather than just omitting) expected aversive events with novel and neutral outcomes engages the ventromedial prefrontal cortex during extinction learning. Enhanced extinction also diminished activity in threat-related networks (e.g., the insula, thalamus) during immediate extinction and a 24 h extinction retention test. This is new evidence for how behavioral protocols designed to enhance extinction affects neurocircuitry underlying the learning and retention of extinction memories.

Abnormal reward circuitry in anorexia nervosa: A longitudinal, multimodal MRI study.

Anorexia nervosa (AN) is a debilitating illness and existing interventions are only modestly effective. This study aimed to determine whether AN pathophysiology is associated with altered connections within fronto-accumbal circuitry subserving reward processing. Diffusion and resting-state functional MRI scans were collected in female inpatients with AN (n = 22) and healthy controls (HC; n = 18) between the ages of 16 and 25 years. Individuals with AN were scanned during the acute, underweight phase of the illness and again following inpatient weight restoration. HC were scanned twice over the same timeframe. Based on univariate and multivariate analyses of fronto-accumbal circuitry, underweight individuals with AN were found to have increased structural connectivity (diffusion probabilistic tractography), increased white matter anisotropy (tract-based spatial statistics), increased functional connectivity (seed-based correlation in resting-state fMRI), and altered effective connectivity (spectral dynamic causal modeling). Following weight restoration, fronto-accumbal structural connectivity continued to be abnormally increased bilaterally with large (partial η2 = 0.387; right NAcc-OFC) and moderate (partial η2 = 0.197; left NAcc-OFC) effect sizes. Increased structural connectivity within fronto-accumbal circuitry in the underweight state correlated with severity of eating disorder symptoms. Taken together, the findings from this longitudinal, multimodal neuroimaging study offer converging evidence of atypical fronto-accumbal circuitry in AN. Hum Brain Mapp 37:3835-3846, 2016. © 2016 Wiley Periodicals, Inc.

In vivo effects of ketamine on glutamate-glutamine and gamma-aminobutyric acid in obsessive-compulsive disorder: Proof of concept.

We previously reported the rapid and robust clinical effects of ketamine versus saline infusions in a proof-of-concept crossover trial in unmedicated adults with obsessive-compulsive disorder (OCD). This study examined the concurrent neurochemical effects of ketamine versus saline infusions using proton magnetic resonance spectroscopy ((1)H MRS) during the clinical proof-of-concept crossover trial. Levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the excitatory neurochemicals glutamate+glutamine (Glx) were acquired in the medial prefrontal cortex (MPFC), a region implicated in OCD pathology. Seventeen unmedicated OCD adults received two intravenous infusions at least 1 week apart, one of saline and one of ketamine, while lying supine in a 3.0 T GE MR scanner. The order of each infusion pair was randomized. Levels of GABA and Glx were measured in the MPFC before, during, and after each infusion and normalized to water (W). A mixed effects model found that MPFC GABA/W significantly increased over time in the ketamine compared with the saline infusion. In contrast, there were no significant differences in Glx/W between the ketamine and saline infusions. Together with earlier evidence of low cortical GABA in OCD, our findings suggest that models of OCD pathology should consider the role of GABAergic abnormalities in OCD symptomatology.

Obsessive-compulsive disorder (OCD): Practical strategies for pharmacological and somatic treatment in adults.

This narrative review gathers together a range of international experts to critically appraise the existing trial-based evidence relating to the efficacy and tolerability of pharmacotherapy for obsessive compulsive disorder in adults. We discuss the diagnostic evaluation and clinical characteristics followed by treatment options suitable for the clinician working from primary through to specialist psychiatric care. Robust data supports the effectiveness of treatment with selective serotonin reuptake inhibitors (SSRIs) and clomipramine in the short-term and the longer-term treatment and for relapse prevention. Owing to better tolerability, SSRIs are acknowledged as the first-line pharmacological treatment of choice. For those patients for whom first line treatments have been ineffective, evidence supports the use of adjunctive antipsychotic medication, and some evidence supports the use of high-dose SSRIs. Novel compounds are also the subject of active investigation. Neurosurgical treatments, including ablative lesion neurosurgery and deep brain stimulation, are reserved for severely symptomatic individuals who have not experienced sustained response to both pharmacological and cognitive behavior therapies.

Modulation of motor cortex excitability in obsessive-compulsive disorder: an exploratory study on the relations of neurophysiology measures with clinical outcome.

Low-frequency repetitive transcranial magnetic stimulation (rTMS) to supplementary motor area (SMA) showed clinical benefit in obsessive-compulsive disorder (OCD). Here we tested whether clinical improvement was associated with enhanced cortical inhibition as measured by single and paired-pulse TMS variables. In 18 OCD patients receiving 4 weeks of either active or sham rTMS in a double-blind randomized trial, we assessed bilateral resting and active motor thresholds (RMT and AMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). We tested correlations between changes in Yale-Brown Obsessive Compulsive Scale-Self-report (Y-BOCS-SR), Clinical Global Impression-Severity subscale (CGI-S) and cortical excitability measures. Active rTMS increased right hemisphere RMT whose change correlated with Y-BOCS-SR improvement. Baseline RMT hemispheric asymmetry, defined as the difference between left and right hemispheres RMT, and its normalization after active rTMS correlated with Y-BOCS-SR and CGI-S improvements. Active rTMS also increased right hemisphere SICI whose change correlated with Y-BOCS-SR and CGI-S at week 4, and with normalization of baseline RMT hemispheric asymmetry. Treatment-induced changes in cortical excitability measures are consistent with an inhibitory action of SMA rTMS on dysfunctional motor circuits in OCD. Correlations of neurophysiology measures with therapeutic outcome are supportive of the role of SMA in the modulation of OCD symptoms.

Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept.

Serotonin reuptake inhibitors (SRIs), the first-line pharmacological treatment for obsessive-compulsive disorder (OCD), have two limitations: incomplete symptom relief and 2-3 months lag time before clinically meaningful improvement. New medications with faster onset are needed. As converging evidence suggests a role for the glutamate system in the pathophysiology of OCD, we tested whether a single dose of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, could achieve rapid anti-obsessional effects. In a randomized, double-blind, placebo-controlled, crossover design, drug-free OCD adults (n=15) with near-constant obsessions received two 40-min intravenous infusions, one of saline and one of ketamine (0.5 mg/kg), spaced at least 1-week apart. The OCD visual analog scale (OCD-VAS) and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) were used to assess OCD symptoms. Unexpectedly, ketamine's effects within the crossover design showed significant (p<0.005) carryover effects (ie, lasting longer than 1 week). As a result, only the first-phase data were used in additional analyses. Specifically, those receiving ketamine (n=8) reported significant improvement in obsessions (measured by OCD-VAS) during the infusion compared with subjects receiving placebo (n=7). One-week post-infusion, 50% of those receiving ketamine (n=8) met criteria for treatment response (≥35% Y-BOCS reduction) vs 0% of those receiving placebo (n=7). Rapid anti-OCD effects from a single intravenous dose of ketamine can persist for at least 1 week in some OCD patients with constant intrusive thoughts. This is the first randomized, controlled trial to demonstrate that a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an SRI and is consistent with a glutamatergic hypothesis of OCD.

Public-academic partnerships: a rapid small-grant program for policy-relevant research: motivating public-academic partnerships.

To help grow a cadre of researchers with the knowledge and skills to pursue topics of great utility to public mental health systems, the director of the Division of Mental Health Services and Policy Research at Columbia University used funding from the New York State Office of Mental Health (OMH) to create a rapid small-grant program called the OMH Policy Scholars Program. This column uses two case examples to describe how this public-academic partnership exposes early-career researchers to the needs and complexities of large public mental health systems while providing them with senior research and policy mentors to help ensure the success of the scholars' projects and oversee their introduction to and work within the public mental health system. This type of collaboration is one model of encouraging early-career psychiatric researchers to pursue policy-relevant research.

Investigation of cortical glutamate-glutamine and γ-aminobutyric acid in obsessive-compulsive disorder by proton magnetic resonance spectroscopy.

Glutamatergic abnormalities in corticostriatal brain circuits are thought to underlie obsessive-compulsive disorder (OCD). Whether these abnormalities exist in adults with OCD is not clear. We used proton magnetic resonance spectroscopy (¹H MRS) to test our hypothesis that unmedicated adults with OCD have reduced glutamate plus glutamine (Glx) levels in the medial prefrontal cortex (MPFC) compared with healthy controls. Levels of γ-aminobutyric acid (GABA) were also explored. Twenty-four unmedicated adults with OCD and 22 matched healthy control subjects underwent ¹H MRS scans at 3.0 T. Resonances of both Glx and GABA were obtained using the standard J-editing technique and assessed as ratios relative to voxel tissue water (W) in the MPFC (the region of interest) and the dorsolateral prefrontal cortex (DLPFC) to explore the regional specificity of any finding. In the MPFC, Glx/W did not differ by diagnostic group (p=0.98) or sex (p=0.57). However, GABA/W was decreased in OCD (2.16±0.46 × 10⁻³) compared with healthy controls (2.43±0.45 × 10⁻³, p=0.045); moreover, age of OCD onset was inversely correlated with MPFC GABA/W (r=-0.50, p=0.015). MPFC GABA/W was higher in females than in males. In the DLPFC, there were no main effects of diagnosis or gender on Glx/W or GABA/W. These data indicate that unmedicated adults with OCD do not have Glx abnormalities in a MPFC voxel that includes the pregenual anterior cingulate cortex. However, they may have decreased MPFC GABA levels. How GABA abnormalities might contribute to corticostriatal dysfunction in OCD deserves further study.

Randomized sham-controlled trial of repetitive transcranial magnetic stimulation in treatment-resistant obsessive-compulsive disorder.

In open trials, 1-Hz repetitive transcranial magnetic stimulation (rTMS) to the supplementary motor area (SMA) improved symptoms and normalized cortical hyper-excitability of patients with obsessive-compulsive disorder (OCD). Here we present the results of a randomized sham-controlled double-blind study. Medication-resistant OCD patients (n=21) were assigned 4 wk either active or sham rTMS to the SMA bilaterally. rTMS parameters consisted of 1200 pulses/d, at 1 Hz and 100% of motor threshold (MT). Eighteen patients completed the study. Response to treatment was defined as a > or = 25% decrease on the Yale-Brown Obsessive Compulsive Scale (YBOCS). Non-responders to sham and responders to active or sham rTMS were offered four additional weeks of open active rTMS. After 4 wk, the response rate in the completer sample was 67% (6/9) with active and 22% (2/9) with sham rTMS. At 4 wk, patients receiving active rTMS showed on average a 25% reduction in the YBOCS compared to a 12% reduction in those receiving sham. In those who received 8-wk active rTMS, OCD symptoms improved from 28.2+/-5.8 to 14.5+/-3.6. In patients randomized to active rTMS, MT measures on the right hemisphere increased significantly over time. At the end of 4-wk rTMS the abnormal hemispheric laterality found in the group randomized to active rTMS normalized. The results of the first randomized sham-controlled trial of SMA stimulation in the treatment of resistant OCD support further investigation into the potential therapeutic applications of rTMS in this disabling condition.

Assessing the validity of current mouse genetic models of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a disorder characterized by unwanted and intrusive thoughts, images, or impulses and/or repetitive behavior. OCD is a major cause of disability; however, the genetic factors and pathophysiological mechanisms underlying this complex, heterogeneous disorder remain largely unknown. During the past decade, a number of putative mouse genetic models of OCD have been developed for the purpose of studying the neural mechanisms underlying this disorder and developing novel treatments. This review presents and evaluates these experimental preparations to date. Models using knockout or transgenic approaches, as well as those examining variation in genetically diverse populations, are evaluated and discussed.