OCD is associated with an altered association between sensorimotor gating and cortical and subcortical 5-HT1b receptor binding.

Obsessive-compulsive disorder (OCD) is characterized by impaired sensorimotor gating, as measured using prepulse inhibition (PPI). This effect may be related to abnormalities in the serotonin (5-HT) system. 5-HT1B agonists can impair PPI, produce OCD-like behaviors in animals, and exacerbate OCD symptoms in humans. We measured 5-HT1B receptor availability using (11)C-P943 positron emission tomography (PET) in unmedicated, non-depressed OCD patients (n=12) and matched healthy controls (HC; n=12). Usable PPI data were obtained from 20 of these subjects (10 from each group). There were no significant main effects of OCD diagnosis on 5-HT1B receptor availability ((11)C-P943 BPND); however, the relationship between PPI and (11)C-P943 BPND differed dramatically and significantly between groups. 5-HT1B receptor availability in the basal ganglia and thalamus correlated positively with PPI in controls; these correlations were lost or even reversed in the OCD group. In cortical regions there were no significant correlations with PPI in controls, but widespread positive correlations in OCD patients. Positive correlations between 5-HT1B receptor availability and PPI were consistent across diagnostic groups only in two structures, the orbitofrontal cortex and the amygdala. Differential associations of 5-HT1B receptor availability with PPI in patients suggest functionally important alterations in the serotonergic regulation of cortical/subcortical balance in OCD.

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.

Histidine decarboxylase deficiency causes tourette syndrome: parallel findings in humans and mice.

Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.

Global resting-state functional magnetic resonance imaging analysis identifies frontal cortex, striatal, and cerebellar dysconnectivity in obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is associated with regional hyperactivity in cortico-striatal circuits. However, the large-scale patterns of abnormal neural connectivity remain uncharacterized. Resting-state functional connectivity studies have shown altered connectivity within the implicated circuitry, but they have used seed-driven approaches wherein a circuit of interest is defined a priori. This limits their ability to identify network abnormalities beyond the prevailing framework. This limitation is particularly problematic within the prefrontal cortex (PFC), which is large and heterogeneous and where a priori specification of seeds is therefore difficult. A hypothesis-neutral, data-driven approach to the analysis of connectivity is vital. METHODS: We analyzed resting-state functional connectivity data collected at 3T in 27 OCD patients and 66 matched control subjects with a recently developed data-driven global brain connectivity (GBC) method, both within the PFC and across the whole brain. RESULTS: We found clusters of decreased connectivity in the left lateral PFC in both whole-brain and PFC-restricted analyses. Increased GBC was found in the right putamen and left cerebellar cortex. Within regions of interest in the basal ganglia and thalamus, we identified increased GBC in dorsal striatum and anterior thalamus, which was reduced in patients on medication. The ventral striatum/nucleus accumbens exhibited decreased global connectivity but increased connectivity specifically with the ventral anterior cingulate cortex in subjects with OCD. CONCLUSIONS: These findings identify previously uncharacterized PFC and basal ganglia dysconnectivity in OCD and reveal differentially altered GBC in dorsal and ventral striatum. Results highlight complex disturbances in PFC networks, which could contribute to disrupted cortical-striatal-cerebellar circuits in OCD.

Long-term outcome in adults with obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic condition that often produces lifelong morbidity, but few studies have examined long-term outcome (greater than 5 years) in adult patients. Available studies suggest that 32-74% of adult OCD patients will experience clinical improvement over the long term. However, these studies were conducted before validated OCD rating scales were established and the development of evidence-based treatments for OCD. METHODS: We investigated the 10-20 year outcome of 83 of 165 eligible subjects previously enrolled after participation in placebo-controlled trials of serotonin reuptake inhibitor (SRI) medications for OCD. We examined the association between clinical characteristics at initial assessment and OCD symptom severity at follow-up. We hypothesized that primary OCD symptom dimension and initial response to pharmacotherapy with serotonin reuptake inhibitors would be associated with later symptom severity. RESULTS: Only 20% (17 of 83) of subjects had experienced a remission of their OCD symptoms at follow-up (Y-BOCS ≤ 8). Forty-nine percent (41 of 83) of subjects were still experiencing clinically significant OCD symptoms. Response to initial SRI pharmacotherapy was significantly associated with long-term outcome: 31% (13 of 42) of subjects who responded (CGI < 3) to initial SRI pharmacotherapy were remitted at follow-up, compared to 12% (3 of 25) of partial responders and none of the 16 subjects who had no response to initial SRI pharmacotherapy. We did not find a significant association between long-term clinical outcome and any of the OCD symptom dimensions. CONCLUSION: Despite the introduction and dissemination of several evidence-based treatments for OCD, most adult OCD patients do not achieve remission. Initial response to pharmacotherapy was strongly associated with long-term outcome.

Effects of ketamine in treatment-refractory obsessive-compulsive disorder.

BACKGROUND: Treatments for obsessive-compulsive disorder (OCD) usually lead to incomplete symptom relief and take a long-time to reach full effect. Convergent evidence suggests that glutamate abnormalities contribute to the pathogenesis of OCD. Ketamine is a potent noncompetitive antagonist of the N-methyl-D-aspartate glutamate receptor. Trials have reported rapid antidepressant effects after low-dose ketamine infusion. METHODS: We conducted an open-label trial of ketamine (.5 mg/kg IV over 40 min) in 10 subjects with treatment-refractory OCD. Response was defined as >35% improvement in OCD symptoms and >50% improvement in depression symptoms from baseline at any time between 1 and 3 days after infusion. RESULTS: None of 10 subjects experienced a response in OCD symptoms in the first 3 days after ketamine. Four of seven patients with comorbid depression experienced an antidepressant response to ketamine in the first 3 days after infusion. Both OCD and depression symptoms demonstrated a statistically significant improvement in the first 3 days after infusion compared with baseline, but the OCD response was <12%. The percentage reduction in depressive symptoms in the first 3 days after ketamine infusion was significantly greater than the reduction in OCD symptoms. CONCLUSIONS: Ketamine effects on OCD symptoms, in contrast to depressive symptoms, did not seem to persist or progress after the acute effects of ketamine had dissipated.

Baseline and modulated acoustic startle responses in adolescent girls with posttraumatic stress disorder.

OBJECTIVE: To assess baseline and modulated acoustic startle responses in adolescent girls with posttraumatic stress disorder (PTSD). METHOD: Twenty-eight adolescent girls with PTSD and 23 healthy control girls were recruited for participation in the study. Acoustic stimuli were bursts of white noise of 104 dB presented biaurally through headphones. Baseline startle responses as well as prepulse inhibition, a 1,000-Hz prestimulation tone presented 120 milliseconds before the startle stimulus for 30 milliseconds, and prepulse facilitation, a 1000-Hz prestimulation tone presented continuously for 2, 000 milliseconds before the startle stimulus, were compared in these two groups of girls. RESULTS: At baseline and under neutral testing conditions, the magnitude of the startle response (eye blink) did not differ significantly between girls with PTSD and healthy control girls. There were no significant differences in the degree of prepulse inhibition or facilitation between the two groups of girls. CONCLUSIONS: Unlike combat veterans with PTSD, adolescent girls with PTSD who report exaggerated startle may not have exaggerated baseline acoustic startle responses in the laboratory. Further research should explore whether girls with PTSD demonstrate altered startle responses under stress and/or evidence of other types of psychophysiological abnormalities.

Posttraumatic stress disorder and substance use in inner-city adolescent girls.

The purpose of this study is to examine rates of nicotine, marijuana, and alcohol use as well as patterns of problematic substance use and posttraumatic stress disorder (PTSD) symptoms in inner-city adolescent girls. One hundred four adolescents who obtained medical care at a hospital-based adolescent clinic were systematically surveyed for trauma exposure, posttraumatic stress symptoms, and substance use. A subset (N = 54, 52%) of girls completed a semistructured psychiatric diagnostic interview (K-SADS-PL) to ascertain timing of PTSD symptoms relative to substance use. Compared with traumatized girls without PTSD, girls with full and partial PTSD were significantly more likely to use nicotine, marijuana, and/or alcohol on a regular basis. Fifteen girls met criteria for both PTSD and a substance-use disorder. For 80% of these girls, the age of onset of PTSD was either before or concurrent with the onset of their substance-use disorder. Inner-city adolescent girls with PTSD exhibit problematic substance use and may be at high risk of developing a comorbid substance-use disorder.