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.
Abstract 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.
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.
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.
Abstract 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.
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 ⩾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.
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.
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.
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).
Our results identified several factors that may predict the development of clinical worsening in OCD patients discontinuing SRI medication following successful EX/RP treatment.
Genetic alterations that potentiate PI3K signaling are frequent in prostate cancer, yet how different genetic drivers of the PI3K cascade contribute to prostate cancer is unclear. Here, we report
...mutation/amplification correlates with poor survival of patients with prostate cancer. To interrogate the requirement of different PI3K genetic drivers in prostate cancer, we employed a genetic approach to mutate
in mouse prostate epithelium. We show
mutation causes p110α-dependent invasive prostate carcinoma
Furthermore, we report that
mutation and
loss coexist in patients with prostate cancer and can cooperate
to accelerate disease progression via AKT-mTORC1/2 hyperactivation. Contrasting single mutants that slowly acquire castration-resistant prostate cancer (CRPC), concomitant
mutation and
loss caused
CRPC. Thus,
mutation and
deletion are not functionally redundant. Our findings indicate that
mutation is an attractive prognostic indicator for prostate cancer that may cooperate with
loss to facilitate CRPC in patients.
We show
mutation correlates with poor prostate cancer prognosis and causes prostate cancer in mice. Moreover,
mutation and
loss coexist in prostate cancer and can cooperate
to accelerate tumorigenesis and facilitate CRPC. Delineating this synergistic relationship may present new therapeutic/prognostic approaches to overcome castration/PI3K-AKT-mTORC1/2 inhibitor resistance.
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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.
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