Effects of a dissociative drug on fronto-limbic resting-state functional connectivity in individuals with posttraumatic stress disorder: a randomized controlled pilot study.

RATIONALE: A subanesthetic dose of ketamine, a non-competitive N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist, elicits dissociation in individuals with posttraumatic stress disorder (PTSD), who also often suffer from chronic dissociative symptoms in daily life. These debilitating symptoms have not only been linked to worse PTSD trajectories, but also to increased resting-state functional connectivity (RSFC) between medial prefrontal cortex (mPFC) and amygdala, supporting the conceptualization of dissociation as emotion overmodulation. Yet, as studies were observational, causal evidence is lacking. OBJECTIVES: The present randomized controlled pilot study examines the effect of ketamine, a dissociative drug, on RSFC between mPFC subregions and amygdala in individuals with PTSD. METHODS: Twenty-six individuals with PTSD received either ketamine (0.5mg/kg; n = 12) or the control drug midazolam (0.045mg/kg; n = 14) during functional magnetic resonance imaging (fMRI). RSFC between amygdala and mPFC subregions, i.e., ventromedial PFC (vmPFC), dorsomedial PFC (dmPFC) and anterior-medial PFC (amPFC), was assessed at baseline and during intravenous drug infusion. RESULTS: Contrary to pre-registered predictions, ketamine did not promote a greater increase in RSFC between amygdala and mPFC subregions from baseline to infusion compared to midazolam. Instead, ketamine elicited a stronger transient decrease in vmPFC-amygdala RSFC compared to midazolam. CONCLUSIONS: A dissociative drug did not increase fronto-limbic RSFC in individuals with PTSD. These preliminary experimental findings contrast with prior correlative findings and call for further exploration and, potentially, a more differentiated view on the neurobiological underpinning of dissociative phenomena in PTSD.

An answered call for aid? Cannabinoid clinical framework for the opioid epidemic.

BACKGROUND: The opioid crisis continues in full force, as physicians and caregivers are desperate for resources to help patients with opioid use and chronic pain disorders find safer and more accessible non-opioid tools. MAIN BODY: The purpose of this article is to review the current state of the opioid epidemic; the shifting picture of cannabinoids; and the research, policy, and current events that make opioid risk reduction an urgent public health challenge. The provided table contains an evidence-based clinical framework for the utilization of cannabinoids to treat patients with chronic pain who are dependent on opioids, seeking alternatives to opioids, and tapering opioids. CONCLUSION: Based on a comprehensive review of the literature and epidemiological evidence to date, cannabinoids stand to be one of the most interesting, safe, and accessible tools available to attenuate the devastation resulting from the misuse and abuse of opioid narcotics. Considering the urgency of the opioid epidemic and broadening of cannabinoid accessibility amidst absent prescribing guidelines, the authors recommend use of this clinical framework in the contexts of both clinical research continuity and patient care.

Long term structural and functional neural changes following a single infusion of Ketamine in PTSD.

NMDA receptor antagonists have a vital role in extinction, learning, and reconsolidation processes. During the reconsolidation window, memories are activated into a labile state and can be reconsolidated in an altered form. This concept might have significant clinical implications in treating PTSD. In this pilot study we tested the potential of a single infusion of ketamine, followed by brief exposure therapy, to enhance post-retrieval extinction of PTSD trauma memories. 27 individuals diagnosed with PTSD were randomly assigned to receive either ketamine (0.5 mg/kg 40 min; N = 14) or midazolam (0.045 mg/kg; N = 13) after retrieval of the traumatic memory. 24 h following infusion, participants received a four-day trauma-focused psychotherapy. Symptoms and brain activity were assessed before treatment, at the end of treatment, and at 30-day follow-up. Amygdala activation to trauma scripts (a major biomarker of fear response) served as the main study outcome. Although PTSD symptoms improved equally in both groups, post-treatment, ketamine recipients showed a lower amygdala (-0.33, sd = 0.13, 95%HDI [-0.56,-0.04]) and hippocampus (-0.3 (sd = 0.19), 95%HDI [-0.65, 0.04]; marginal effect) reactivation to trauma memories, compared to midazolam recipients. Post-retrieval ketamine administration was also associated with decreased connectivity between the amygdala and hippocampus (-0.28, sd = 0.11, 95%HDI [-0.46, -0.11]), with no change in amygdala-vmPFC connectivity. Moreover, reduction in fractional anisotropy in bi-lateral uncinate fasciculus was seen in the Ketamine recipients compared with the midazolam recipients (right: post-treatment: -0.01108, 95% HDI [-0.0184,-0.003]; follow-up: -0.0183, 95% HDI [-0.02719,-0.0107]; left: post-treatment: -0.019, 95% HDI [-0.028,-0.011]; follow-up: -0.017, 95% HDI [-0.026,-0.007]). Taken together it is possible that ketamine may enhance post-retrieval extinction of the original trauma memories in humans. These preliminary findings show promising direction toward the capacity to rewrite human traumatic memories and modulate the fear response for at least 30 days post-extinction. When combined with psychotherapy for PTSD, further investigation of ketamine dose, timing of administration, and frequency of administration, is warranted.

Palliative care provider attitudes toward existential distress and treatment with psychedelic-assisted therapies.

BACKGROUND: Existential distress is a significant source of suffering for patients facing life-threatening illness. Psychedelic-Assisted Therapies (PAT) are novel treatments that have shown promise in treating existential distress, but openness to providing PAT may be limited by stigma surrounding psychedelics and the paucity of education regarding their medical use. How PAT might be integrated into existing treatments for existential distress within palliative care remains underexplored. METHODS: The present study aimed to elucidate the attitudes of palliative care clinicians regarding treatments for existential distress, including PAT. We recruited palliative care physicians, advanced practice nurses, and spiritual and psychological care providers from multiple US sites using purposive and snowball sampling methods. Attitudes toward PAT were unknown prior to study involvement. Semi-structured interviews targeted at current approaches to existential distress and attitudes toward PAT were analyzed for thematic content. RESULTS: Nineteen respondents (seven physicians, four advanced practice nurses, four chaplains, three social workers, and one psychologist) were interviewed. Identified themes were 1) Existential distress is a common experience that is frequently insufficiently treated within the current treatment framework; 2) Palliative care providers ultimately see existential distress as a psychosocial-spiritual problem that evades medicalized approaches; 3) Palliative care providers believe PAT hold promise for treating existential distress but that a stronger evidence base is needed; 4) Because PAT do not currently fit existing models of existential distress treatment, barriers remain. CONCLUSIONS: PAT is seen as a potentially powerful tool to treat refractory existential distress. Larger clinical trials and educational outreach are needed to clarify treatment targets and address safety concerns. Further work to adapt PAT to palliative care settings should emphasize collaboration with spiritual care as well as mental health providers and seek to address unresolved concerns about equitable access.

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.

Rapid antidepressant effect of ketamine in the electroconvulsive therapy setting.

OBJECTIVES: Studies now provide strong evidence that the N-methyl-D-aspartate receptor antagonist ketamine possesses rapidly acting antidepressant properties. This study aimed to determine if a low dose of ketamine could be used to expedite and augment the antidepressant effects of electroconvulsive therapy (ECT) treatments in patients experiencing a severe depressive episode. MATERIALS AND METHODS: Subjects with major depressive disorder or bipolar disorder referred for ECT treatment of a major depressive episode were randomized to receive thiopental alone or thiopental plus ketamine (0.5 mg/kg) for anesthesia before each ECT session. The Hamilton Depression Rating Scale (HDRS) was administered at baseline and at 24 to 72 hours after the first and sixth ECT sessions. RESULTS: Electroconvulsive therapy exerted a significant antidepressant effect in both groups (F2,24 = 14.35, P < 0.001). However, there was no significant group effect or group-by-time interaction on HDRS scores. In addition, post hoc analyses of the time effect on HDRS showed no significant HDRS reduction after the first ECT session for either group. CONCLUSIONS: The results of this pilot study suggest that ketamine, at a dose of 0.5 mg/kg, given just before ECT, did not enhance the antidepressant effect of ECT. Interestingly, the results further suggest that the coadministration of ketamine with a barbiturate anesthetic and ECT may attenuate the immediate antidepressant effects of the N-methyl-D-aspartate antagonist.

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.

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.

Systematic review: pharmacological and behavioral treatment for trichotillomania.

Trichotillomania is a psychiatric condition characterized by compulsive hair pulling. Three interventions have been studied in the treatment of trichotillomania: habit-reversal therapy (HRT) and pharmacotherapy with either selective-serotonin reuptake inhibitors (SSRI) or clomipramine. This systematic review compared the efficacy of these interventions in blinded, randomized clinical trials. The electronic databases of Medline, Premedline, PsychINFO, Embase, and the Cochrane Central Register of Controlled Trials were searched for relevant trials using the search terms "trichotillomania" or "hair pulling." Trials were eligible for inclusion if they compared habit-reversal therapy, SSRI pharmacotherapy, or clomipramine pharmacotherapy to each other or placebo and employed randomization and blinded assessment of outcome. Our primary outcome measure was mean change in trichotillomania severity. The summary statistic was standardized mean difference. Seven studies were eligible for inclusion in this review. Overall, meta-analysis demonstrated that habit-reversal therapy (effect size [ES] = -1.14, 95% confidence interval [CI] = -1.89, -.38) was superior to pharmacotherapy with clomipramine (ES = -.68, 95% CI = -1.28, -.07) or SSRI (ES = .02, 95% CI = -.32, .35). Clomipramine was more efficacious than placebo, while there was no evidence to demonstrate that SSRI are more efficacious than placebo in the treatment of trichotillomania. Future studies on trichotillomania should seek to determine if HRT can demonstrate efficacy against more rigorous control conditions that account for non-specific effects of therapy and determine if HRT can be an effective intervention for trichotillomania beyond the few sites where it is currently practiced in research studies. Future therapy and pharmacotherapy studies in trichotillomania should employ larger sample sizes and intention-to-treat analysis and seek to validate clinical rating scales of trichotillomania severity.

N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder.

RATIONALE: Dysfunction 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. OBJECTIVES: To examine the efficacy of augmentation with NAC in a patient with serotonin reuptake inhibitor (SRI)-refractory OCD. METHODS: A patient with SRI-refractory OCD was treated with an off-label use of NAC augmentation of fluvoxamine over several weeks. RESULTS: NAC 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. CONCLUSIONS: NAC 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.

Clinical treatment of obsessive compulsive disorder.

Obsessive compulsive disorder (OCD) was once thought to be extremely rare, but recent epidemiological studies have shown it to be the fourth most common psychiatric disorder (after substance abuse, specific phobias, and major depression). OCD is often a chronic disorder that produces significant morbidity when not properly diagnosed and treated. The mainstay of treatment includes cognitive behavioral therapy and medication management. The use of clomipramine in the 1960s and then the introduction of serotonin reuptake inhibitors in the 1980s represented important advances in the pharmacologic treatment of OCD. Despite effective treatment modalities, many patients demonstrate only a partial response or are resistant to available medications. SRI-resistant OCD is one of the few diagnoses in modern psychiatry for which invasive neurosurgical procedures remain part of the established treatment armamentarium. We review current treatment strategies used in the management of OCD symptoms.