Refractory Major Depressive Disorder Research Articles

Factor structure of posttraumatic stress disorder (PTSD) in persons with serious mental illness

Background Trauma and posttraumatic stress disorder (PTSD) are common among individuals with serious mental illness (SMI; e.g., schizophrenia, schizoaffective disorder, bipolar disorder, treatment refractory major depressive disorder), with resultant functional impairment. Previous studies have not evaluated the factor structure of the PTSD Checklist (PCL) among persons with SMI. Aims This study evaluated the factor structure of the PCL in two large SMI samples from public mental health treatment sectors screened for PTSD using the PCL. Methods Four different models of PTSD were tested using confirmatory factor analyses. Results Results indicated that the DSM-5 4-factor model (intrusion, avoidance, numbing, and hyperarousal) had the best fit. Further, the DSM-5 4-factor model demonstrated measurement invariance. Conclusions Results supported the suitability of the DSM-5 4-factor model of PTSD among people with SMI.

Accelerated Theta Burst Transcranial Magnetic Stimulation for Refractory Depression in Autism Spectrum Disorder.

Major depressive disorder (MDD) disproportionately affects those living with autism spectrum disorder (ASD) and is associated with significant impairment and treatment recidivism. We studied the use of accelerated theta burst stimulation (ATBS) for the treatment of refractory MDD in ASD (3 treatments daily x 10 days). This prospective open-label 12-week trial included 10 subjects with a mean age of 21.5 years, randomized to receive unilateral or bilateral stimulation of the dorsolateral prefrontal cortex. One participant dropped out of the study due to intolerability. In both treatment arms, depressive symptoms, scored on the Hamilton Depression Rating Scale scores, diminished substantially. At 12 weeks post-treatment, full remission was sustained in 5 subjects and partial remission in 3 subjects. Treatment with ATBS, regardless of the site of stimulation, was associated with a significant, substantial, and sustained improvement in depressive symptomatology via the primary outcome measure, the Hamilton Depression Rating Scale. Additional secondary measures, including self-report depression scales, fluid cognition, and sleep quality, also showed significant improvement. No serious adverse events occurred during the study. Mild transient headaches were infrequently reported, which are expected side effects of ATBS. Overall, ATBS treatment was highly effective and well-tolerated in individuals with ASD and co-occurring MDD. The findings support the need for a larger, sham-controlled randomized controlled trial to further evaluate efficacy of ATBS in this population.

Deep brain stimulation for refractory major depressive disorder: a comprehensive review.

Deep brain stimulation (DBS) has emerged as a promising treatment for select patients with refractory major depressive disorder (MDD). The clinical effectiveness of DBS for MDD has been demonstrated in meta-analyses, open-label studies, and a few controlled studies. However, randomized controlled trials have yielded mixed outcomes, highlighting challenges that must be addressed prior to widespread adoption of DBS for MDD. These challenges include tracking MDD symptoms objectively to evaluate the clinical effectiveness of DBS with sensitivity and specificity, identifying the patient population that is most likely to benefit from DBS, selecting the optimal patient-specific surgical target and stimulation parameters, and understanding the mechanisms underpinning the therapeutic benefits of DBS in the context of MDD pathophysiology. In this review, we provide an overview of the latest clinical evidence of MDD DBS effectiveness and the recent technological advancements that could transform our understanding of MDD pathophysiology, improve the clinical outcomes for MDD DBS, and establish a path forward to develop more effective neuromodulation therapies to alleviate depressive symptoms.

Efficacy of Ketamine Therapy in the Treatment of Refractory Major Depressive Disorder

Efficacy of Ketamine Therapy in the Treatment of Refractory Major Depressive Disorder

Deep Brain Stimulation Surgery Programs in Canada


 Deep brain stimulation involves the surgical insertion of electrodes to stimulate targeted areas of the brain. It is recommended to help control movement-related symptoms of Parkinson disease with certain indications and contraindications to consider.
 This rapid Environmental Scan describes the landscape of deep brain stimulation surgery across Canada and identifies conditions other than Parkinson disease that can benefit from the therapy. It also provides an overview of cost-effectiveness studies on deep brain stimulation for Parkinson disease.
 Emerging indications for deep brain stimulation include refractory obsessive-compulsive disorder, refractory epilepsy, treatment-resistant Tourette syndrome, certain types of pain, refractory major depressive disorder, tardive dyskinesia, and essential tremor.
 In Canada, there are deep brain stimulation surgery programs in Alberta, British Columbia, Manitoba, Nova Scotia, Ontario, Quebec, and Saskatchewan. The number of qualified neurosurgeons for deep brain stimulation surgery ranges from 1 to 5 (at least) across jurisdictions.
 Overall, deep brain stimulation is considered cost-effective for people living with advanced Parkinson disease. The risk of developing Parkinson disease increases with age, with onset typically occurring in late adulthood. The number of people eligible for deep brain stimulation in Canada is expected to increase with the aging population and emerging indications. Information related to existing surgery programs can help support capacity planning for deep brain stimulation surgery in Canada.

Management for A Depressive Patient with Femoral Neck Fracture by Electroconvulsive Therapy during COVID-19 Pandemic: A Case Report and Literature Review

Electroconvulsive therapy (ECT) is an effective treatment for refractory major depressive disorder with suicidal ideation. The most common adverse medical events are transient retrograde amnesia, falls and pneumonia. Hip fractures, associated with high-energy trauma by convulsions, were occasionally reported in western countries, in the period before the COVID-19 pandemic. Strict COVID-19 regulations influenced the course and further investigation of the treatment of post-ECT complications. A 33-year-old man, previously diagnosed with major depressive disorder, had a history of nine successful sessions of ECT treatment for depression five years ago. He was hospitalized again for 12 sessions of ECT for recurrent depression. Unfortunately, an ECT-induced right hip-neck fracture was noted after the ninth session of ECT, in March 2021. After receiving close reduction and internal fixation of the right femoral neck fracture, with three screws, his original daily function was restored. His treatment was regularly followed up at the outpatient clinic for 20 months; he achieved partial remission with three combined antidepressants. This case of ECT-induced right hip-neck fracture informed psychiatric staff to be aware of this rare adverse complication and ensure its appropriate management, especially during the COVID-19 pandemic.

Stereotactic Radiofrequency Ablation for Treatment-Refractory Depression: A Systematic Review and Meta-Analysis.

(1) Background: Major depressive disorder (MDD) generates a large proportion of global disease burden. Stereotactic radiofrequency ablation (SRA) may be beneficial for selected patients with its most debilitating and refractory forms, but effect size is uncertain. (2) Methods: A systematic literature review and meta-analysis on SRA for MDD was carried out. Patient-level data were extracted from articles reporting validated depression measures (Beck Depression Inventory (BDI), Montgomery–Åsberg Depression Rating Scale (MADRS)), pre- and at least six months post surgery. To accommodate different outcome measures, the standardised mean difference (SMD) between both scores was used as the principal effect size. Data were synthesised using a random-effects model. (3) Results: Five distinct studies were identified, comprising 116 patients (64 included in meta-analysis). Effect size comparing post- vs. pre-operative scores was 1.66 (CI 1.25–2.07). Anterior cingulotomy (two studies, n = 22) and anterior capsulotomy (three studies, n = 42) showed similar effect sizes: 1.51 (CI 0.82–2.20) vs. 1.74 (CI 1.23–2.26). Multiple procedures were performed in 30 of 116 (25.9%) patients. Based on patient-level data, 53% (n = 47) were responders (≥50% improvement), of which 34% reached remission (MADRS ≤ 10 or BDI ≤ 11). BDI mean improvement was 16.7 (44.0%) after a second procedure (n = 19). (4) Conclusions: The results are supportive of the benefit of SRA in selected patients with refractory MDD.

Lateralized subgenual ACC metabolic connectivity patterns in refractory melancholic depression: does it matter?

Although treatment resistance to antidepressant pharmacotherapy is quite common, the phenomenon of refractory major depressive disorder (rMDD) is not well understood. Nevertheless, the metabolic activity of the subgenual anterior cingulate cortex (sgACC) has been put forward as a possible metabolic biomarker of clinical prediction and response, albeit sgACC lateralization differences in functional connectivity have not yet been extensively examined. Also not in the refractory depressed state. To examine sgACC lateralization differences in metabolic connectivity, we recruited 43 right-handed antidepressant-free unipolar melancholic rMDD patients and 32 right-handed healthy controls to participate in this 18FDG PET study and developed a searchlight-based interregional covariance connectivity approach. Compared to non-depressed individuals, sgACC covariance analysis showed stronger metabolic connections with frontolimbic brain regions known to be affected in the depressed state. Furthermore, whereas the left sgACC showed stronger metabolic connections with ventromedial prefrontal cortical regions, implicated in anhedonia, suicidal ideation, and self-referential processes, the right sgACC showed significantly stronger metabolic connections with posterior hippocampal and cerebellar regions, respectively specialized in memory and social processing. Overall, our results substantiate earlier research that the sgACC is a metabolic key player when clinically depressed and that distinct lateralized sgACC metabolic connectivity patterns are present.

Noninvasive Capsulotomy for Refractory Depression by Frameless Stereotactic Radiosurgery

Effective treatment options for refractory depression are needed. Recent advancements permit both precise ablative radiation and functional neurologic connectome analysis using standard magnetic resonance imaging. We combined these innovations to perform stereotactic radiosurgical capsulotomy for the treatment of medically refractory major depressive disorder and study connectome response using a novel tractography-based approach. Patients with medically refractory depression were enrolled on a prospective pilot single-arm observational trial from 2020 to 2021 at a single academic tertiary referral center. Bilateral ablation of the anterior limb of the internal capsule was accomplished by mask-based linear accelerator stereotactic radiosurgery. Beck's Depression Inventory measured efficacy. Montreal Cognitive Assessment evaluated cognition. Three patients were enrolled. Depression burden was improved by 88% at 12-month follow-up and by 55% at 18-month follow-up for patient 1 and 2, respectively. Patient 1 discontinued ketamine therapy, and patient 2 discontinued electroconvulsive therapy. Patient 3 reported global improvement in symptoms and function at 3 months. All 3 patients had reduction or resolution of suicidal ideation. No patient experienced cognitive decline or neurologic toxicity, and Montreal Cognitive Assessment score, as well as subjective patient-reported evaluations of concentration and attention, were superior after treatment. Tractography confirmed intended disruption of the cortico-striatal-thalamo-cortical loop with structural reorganization in the connectome. Connectome change was consistent between patients. Observed increases in caudate and putamen connectivity and decreases in thalamic connectivity may explain improved concentration, attention, and depression. The diversity and magnitude of connectome change may correlate with degree of clinical response. In 3 patients with refractory depression, radiosurgical capsulotomy significantly reduced the burden of depression. Functional connectome reorganization offers neurobiological evidence to support further investigations of the role of radiosurgery in depression.

Adjunctive D-Cycloserine with Intermittent Theta-Burst Stimulation: A Randomized Placebo-Controlled Trial in Major Depressive Disorder

Intermittent theta-bust stimulation (iTBS) is emerging as a first-choice transcranial magnetic stimulation (TMS) protocol in the treatment of refractory Major Depressive Disorder (MDD). While the mechanisms for antidepressant efficacy remain unclear, physiological studies suggest that N-Methyl-D-Aspartate (NMDA) receptor activation is required for iTBS related synaptic plasticity. No study to date has directly targeted the NMDA receptor as a means of enhancing clinical efficacy in MDD.

Treatment of Persistent Postconcussion Syndrome With Repetitive Transcranial Magnetic Stimulation Using Functional Near-Infrared Spectroscopy as a Biomarker of Response: Protocol for a Randomized Controlled Clinical Trial.

BackgroundApproximately one-third of all concussions lead to persistent postconcussion syndrome (PPCS). Repetitive transcranial magnetic stimulation (rTMS) is a form of noninvasive brain stimulation that has been extensively used to treat refractory major depressive disorder and has a strong potential to be used as a treatment for patients with PPCS. Functional near-infrared spectroscopy (fNIRS) has already been used as a tool to assess patients with PPCS and may provide insight into the pathophysiology of rTMS treatment in patients with PPCS.ObjectiveThe primary objective of this research is to determine whether rTMS treatment improves symptom burden in patients with PPCS compared to sham treatment using the Rivermead postconcussion symptom questionnaire. The secondary objective is to explore the neuropathophysiological changes that occur following rTMS in participants with PPCS using fNIRS. Exploratory objectives include determining whether rTMS treatment in participants with PPCS will also improve quality of life, anxiety, depressive symptoms, cognition, posttraumatic stress, and function secondary to headaches.MethodsA total of 44 adults (18-65 years old) with PPCS (>3 months to 5 years) will participate in a double-blind, sham-controlled, concealed allocation, randomized clinical trial. The participants will engage in either a 4-week rTMS treatment protocol or sham rTMS protocol (20 treatments). The left dorsolateral prefrontal cortex will be located through Montreal Neurologic Institute coordinates. The intensity of the rTMS treatment over the left dorsolateral prefrontal cortex will be 120% of resting motor threshold, with a frequency of 10 Hz, 10 trains of 60 pulses per train (total of 600 pulses), and intertrain interval of 45 seconds. Prior to starting the rTMS treatment, participant and injury characteristics, questionnaires (symptom burden, quality of life, depression, anxiety, cognition, and headache), and fNIRS assessment will be collected. Repeat questionnaires and fNIRS will occur immediately after rTMS treatment and at 1 month and 3 months post rTMS. Outcome parameters will be analyzed by a 2-way (treatment × time) mixed analysis of variance.ResultsAs of May 6, 2021, 5 participants have been recruited for the study, and 3 have completed the rTMS protocol. The estimated completion date of the trial is May 2022.ConclusionsThis trial will expand our knowledge of how rTMS can be used as a treatment option of PPCS and will explore the neuropathophysiological response of rTMS through fNIRS analysis.Trial RegistrationClinicalTrials.gov NCT04568369; https://clinicaltrials.gov/ct2/show/NCT04568369International Registered Report Identifier (IRRID)DERR1-10.2196/31308

C.2 The use of magnetic resonance guided focused ultrasound for refractory psychiatric illness

Background: Obsessive compulsive disorder (OCD) and major depressive disorder (MDD) are common, often refractory, neuropsychiatric conditions for which new treatment approaches are urgently needed. Magnetic resonance guided focused ultrasound (MRgFUS) is a novel surgical technique permitting incisionless ablative neurosurgery. Methods: We examined the safety profile, clinical response, and imaging correlates of MRgFUS anterior capsulotomy (MRgFUS-AC) in patients with refractory OCD (n=7) and MDD (n = 10). Results: There were no serious adverse clinical or radiographic events. 5/7 OCD patients and 3/10 MDD patients met pre-established clinical response criteria. Neurocognitive performance improved on several measures of executive function (p<0.05). By 6 months, there were significant reductions in cerebral glucose metabolism, and reductions in the bilateral tracts connecting the thalamus with the orbitofrontal cortices, anterior cingulate cortex (p<0.05). Preoperative functional connectivity between the right ventral striatum and hippocampus was predictive of eventual clinical response (p-FDR<0.05). Conclusions: MRgFUS-AC is safe and demonstrates important evidence of efficacy in treatment resistant psychiatric disease, particularly OCD. The procedure was associated with structural and metabolic changes in brain networks implicated in affective regulation, Resting-state fMRI offers the ability to predict response, and potentially select patients most likely to improve.

Long-term Efficacy and Tolerability of Adjunctive Aripiprazole for Major Depressive Disorder: Systematic Review and Meta-analysis.

Objective: To assess the long-term efficacy and safety of aripiprazole as an augmentation strategy for major depressive disorder (MDD).Data Sources: Ovid MEDLINE, PsycInfo, and Embase databases were systematically searched for clinical studies of adult patients with MDD on long-term aripiprazole augmentation.Study Selection and Data Extraction: Long-term follow-up was defined as ≥ 6 months. Primary outcome was remission from depression. Secondary outcome was incidence of adverse effects.Results: Four open-label studies were included in this review. Random effects meta-analysis of 3 studies (n = 2,117) revealed a weighted average remission proportion of 0.33 (0.16-0.51), showing trend of improved response with duration of treatment. Three studies (n = 2,231) provided adverse effects data. Medically significant weight gain (25%-28% participants) was higher in studies with patients receiving doses ≥ 5 mg and lower (3.5%) in a study using doses < 5 mg. Akathisia (15%-16%), insomnia (12%-17%), somnolence (14%), and fatigue (18%) were common adverse effects. Tardive dyskinesia risk was low (< 1%) at 1-year follow-up. All included studies were open-label, noncontrolled studies, with longest follow-up of 52 weeks, limiting efficacy and safety conclusions.Conclusions: Aripiprazole augmentation may be an effective long-term strategy for treatment of refractory MDD. Lower maintenance doses (2-5 mg) of aripiprazole may be effective and have fewer side effects compared to larger doses (> 5 mg-10 mg).

Functional connectivity patterns of the subgenual anterior cingulate cortex in first-episode refractory major depressive disorder.

Although accumulating evidence has been elucidating the neuronal basis of refractory/nonrefractory major depressive disorder (rMDD/nrMDD), the results are inconsistent, and little is known about the distinct neural mechanisms underlying rMDD. Here, we explored the convergent/divergent brain networks between first-episode MDD subtypes using the resting-state functional connectivity (RSFC) approach. In total, 33 healthy controls (HCs), 31 first-episode rMDD patients and 33 first-episode nrMDD patients were enrolled and underwent MRI scanning. The left subgenual anterior cingulate cortex (sgACC) was selected as the seed region, and RSFC was employed to evaluate associations between the seed and other regions in the whole brain. Both MDD subtypes exhibited convergent left sgACC-based neural networks, including increased RSFC with the dorsal prefrontal cortex (DPFC) and decreased RSFC with the bilateral orbitofrontal cortex (OFC) and right parahippocampus. rMDD patients exhibited increased left sgACC-OFC RSFC relative to nrMDD patients, and RSFC with the bilateral OFC in rMDD patients was negatively correlated with HAMD scores. These findings confirmed our speculation that convergent and divergent neural networks exist between rMDD and nrMDD. Cortical-limbic circuits, especially the prefrontal-limbic circuit, may serve as the convergent dysfunctional neural circuitry in MDD subtypes. As an important biomarker, a unique OFC-sgACC circuit abnormality was identified in rMDD patients, which might help elucidate the underlying mechanism regarding treatment responses in rMDD patients.

Examining cognitive change in magnetic resonance-guided focused ultrasound capsulotomy for psychiatric illness

Magnetic resonance-guided focused ultrasound (MRgFUS) anterior capsulotomy is a novel treatment option for patients with refractory obsessive compulsive disorder (OCD) or major depressive disorder (MDD). However, there is concern that lesional psychiatric surgery procedures may have adverse effects on cognition. In this study, we examined whether MRgFUS capsulotomy causes cognitive decline in patients with psychiatric illness. Ten patients with refractory OCD (n = 5) or MDD (n = 5) underwent MRgFUS capsulotomy. Cognitive functioning was measured at baseline as well as 6 months and 12 months postoperatively, with a battery of neuropsychological tests assessing domains of executive function, memory, and processing speed. Scores were analyzed at the individual-level, and changes ≥2 standard deviations were considered clinically significant. We also examined whether changes in clinical symptoms were associated with changes in cognitive performance. At baseline intellectual functioning was in the average to high-average range for the group. Following MRgFUS capsulotomy, there were no deteriorations in cognition that reached ≥2 standard deviations at 6 or 12 months. Eight out of ten patients demonstrated a ≥2 standard deviation improvement in at least one cognitive score at 6 or 12 months postoperatively. Improvements in clinical symptoms correlated significantly with self-reported improvements in frontal lobe function (p < 0.05), but not with objective measures of cognitive functioning. To summarize, MRgFUS capsulotomy did not result in cognitive decline in this cohort of patients with refractory OCD or MDD, suggesting that this procedure can be offered to patients with a very low risk of cognitive side effects.

Gender Differences in Transcranial Magnetic Stimulation Treatment Outcomes for Major Depressive Disorder: A Single Institution Experience

Background: Transcranial Magnetic Stimulation is an FDA-approved treatment option for patients with treatment refractory major depressive disorder and obsessive compulsive disorder. Previous studies have suggested that there are significant differences in treatment outcomes for MDD based on gender1. The objective of this study was to determine if this difference was reproduced in the patient population of a new TMS clinic. Methods: A retrospective analysis of recent cases of patients ages 28 to 72 who underwent treatment with TMS for refractory major depressive disorder in 2019. The Beck's Depression Inventory-II (BDI-II) was used to gauge symptom severity at the initiation and completion of treatment, and the differences between the BDI-II for each patient was used to calculate the change in BDI-II as the primary outcome measure. The BDI-II changes divided by patient sex, and the averages of each group were analyzed using the two-sample T-test. A secondary analysis was performed after separating the female cohort into premenopausal up to age 50 and postmenopausal groups. Results: Of the 22 individuals in the study, 16 were female and 6 were male. The statistical analysis of treatment outcomes revealed no significant differences in BDI-II changes between females versus male patients, even when separating the female cohort into premenopausal (n=3) and postmenopausal groups (n=13); p > 0.05, two-tailed test. Conclusions: Conclusions are limited due to sample size.

Vitamin D and N-Acetyl Cysteine Supplementation in Treatment-Resistant Depressive Disorder Patients: A General Review.

Major Depressive Disorder (MDD) is often a lifetime disabling mental illness as individuals with MDD might not benefit from standard-therapy, including both pharmacological and psychosocial interventions. Novel therapies are, therefore, required. It was shown by recent preclinical and clinical studies that the dysfunction of glutamatergic neurotransmission might be involved in the pathophysiology of MDD. Furthermore, neuroimmune alterations could have a significant role in the pathogenesis of MDD. Vitamin D is a neurosteroid hormone essential for several metabolic processes, immune responses, and for regulating neurotrophic-neuroprotective processes, neurotransmission and synaptic plasticity. Recent studies have also shown Vitamin D deficiency in patients with severe psychiatric disorders, including MDD. Lately, clinical studies have shown the neuroprotective action of N-acetyl cysteine (NAC) through the modulation of inflammatory pathways and via the modulation of synaptic release of glutamate in cortico-subcortical brain regions; the cysteine-glutamate antiporter. This paper reviews the therapeutic use of Vitamin D and NAC and among individuals with refractory MDD to the first- line pharmacological interventions, reviewing the clinical studies published in the last decade. A detailed summary of the current evidence in this area aims to better inform psychiatrists and general practitioners on the potential benefits of Vitamin D and NAC supplementation for this disorder. Nutraceutical supplementation with Vitamin D and NAC in treatment-resistant MDD patients may be important not only for improving depressive clinical manifestations but also for their safety and tolerability profile. This is of great interest, especially considering the need for treating special populations affected by MDD, such as youngsters and elders. Finally, the nutraceutical approach represents a good choice, considering its better compliance by the patients compared to traditional psychopharmacological treatment.

DNA Methylation of the t-PA Gene Differs Between Various Immune Cell Subtypes Isolated From Depressed Patients Receiving Electroconvulsive Therapy.

BackgroundMajor depressive disorder (MDD) represents a tremendous health threat to the world’s population. Electroconvulsive therapy (ECT) is the most effective treatment option for refractory MDD patients. Ample evidence suggests brain-derived neurotrophic factor (BDNF) to play a crucial role in ECT’s mode of action. Tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) are involved in BDNF production.HypothesisThe DNA methylation of gene regions encoding for t-PA and PAI-1 might be a suitable biomarker for ECT response prediction.MethodsWe withdrew blood from two cohorts of treatment-resistant MDD patients receiving ECT. In the first cohort (n = 59), blood was collected at baseline only. To evaluate DNA methylation changes throughout the treatment course, we acquired a second group (n = 28) and took blood samples at multiple time points. DNA isolated from whole blood and defined immune cell subtypes (B cells, monocytes, natural killer cells, and T cells) served for epigenetic analyses.ResultsMixed linear models (corrected for multiple testing by Sidak’s post-hoc test) revealed (1) no detectable baseline blood DNA methylation differences between ECT remitters (n = 33) and non-remitters (n = 53) in the regions analyzed, but (2) a significant difference in t-PA’s DNA methylation between the investigated immune cell subtypes instead (p < 0.00001). This difference remained stable throughout the treatment course, showed no acute changes after ECT, and was independent of clinical remission.ConclusionDNA methylation of both proteins seems to play a minor role in ECT’s mechanisms. Generally, we recommend using defined immune cell subtypes (instead of whole blood only) for DNA methylation analyses.

Magnetic resonance-guided focused ultrasound capsulotomy for refractory obsessive compulsive disorder and major depressive disorder: clinical and imaging results from two phase I trials.

Obsessive compulsive disorder (OCD) and major depressive disorder (MDD) are common, often refractory, neuropsychiatric conditions for which new treatment approaches are urgently needed. Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel surgical technique permitting incisionless ablative neurosurgery. We examined the safety profile, clinical response, and imaging correlates of MRgFUS bilateral anterior capsulotomy in patients with refractory obsessive compulsive disorder (OCD, N = 6) and major depressive disorder (MDD, n = 6). There were no serious adverse events. Nonserious adverse events included headaches and pin-site swelling in 7/12 patients. The response rate was 4/6 and 2/6 in the OCD and MDD cohorts respectively. To delineate the white-matter tracts impacted by capsulotomy, a normative diffusion MRI-based structural connectome was used, revealing tracts terminating primarily in the frontal pole, medial thalamus, striatum, and medial-temporal lobe. Positron emission tomography (PET) analysis (nine subjects) revealed widespread decreases in metabolism bilaterally in the cerebral hemispheres at 6 months post treatment, as well as in the right hippocampus, amygdala, and putamen. A pretreatment seed-to-voxel resting-state functional magnetic resonance imaging (rs-fMRI) analysis (12 subjects) revealed three voxel clusters significantly associated with eventual clinical response. MRgFUS capsulotomy appears to be safe, well tolerated, and according to these initial results, may be an important treatment option for patients with refractory OCD and MDD. MRgFUS capsulotomy results in both targeted and widespread changes in neural activity, and neuroimaging may hold potential for the prediction of outcome.

Chromosome 15q13.3 microduplications are associated with treatment refractory major depressive disorder.

Major depressive disorder (MDD) affects approximately 15 million Americans. Approximately 2 million of these are classified as being refractory to treatment (TR-MDD). Because of the lack of available therapies for TR-MDD, and the high risk of suicide, there is interest in identifying new treatment modalities and diagnostic methods. Understanding of the impact of genomic copy number variation in the etiology of a variety of neuropsychiatric phenotypes is increasing. Low copy repeat elements at 15q13.3 facilitate non-allelic homologous recombination, resulting in recurrent copy number variants (CNVs). Numerous reports have described association between microdeletions in this region and a variety of neuropsychiatric phenotypes, with CHRNA7 implicated as a candidate gene. However, the pathogenicity of 15q13.3 duplications is less clear. As part of an ongoing study, in which we have identified a number of metabolomic anomalies in spinal fluid from TR-MDD patients, we also evaluated genomic copy number variation in patients (n = 125) and controls (n = 26) via array-based copy number genomic hybridization (CGH); the case frequency was compared with frequencies reported in a prior study as well as a larger population-sized cohort. We identified five TR-MDD patients with microduplications involving CHRNA7. CHRNA7 duplications are the most common CNVs identified by clinical CGH in this cohort. Therefore, this study provides insight into the potential involvement of CHRNA7 duplications in the etiology of TR-MDD and informs those involved with care of affected individuals.