Long-term safety and efficacy of focused ultrasound capsulotomy for obsessive-compulsive disorder and major depressive disorder.

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) trials targeting the anterior limb of the internal capsule have shown promising results. We evaluate the long-term safety and efficacy of MRgFUS capsulotomy in patients with obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). METHODS: This phase I single center open label study recruited treatment-resistant OCD and MDD. Outcomes were measured 6mo, 12mo, and 18-24months (long-term) after MRgFUS capsulotomy. Neuropsychological testing and neuroimaging were conducted at baseline and 12mo postoperatively. The primary outcome was safety. The secondary outcome was clinical response, defined for OCD as ≥35% improvement in Yale-Brown obsessive-compulsive scale (YBOCS) scores, and for MDD as a ≥50% reduction in the Hamilton Depression Rating Scale (HAMD-17) scores, compared to baseline. RESULTS: No serious adverse effects were registered. In patients with OCD (n=15), baseline YBOCS scores (31.9±1.2) were significantly reduced by 23% (p=0.01) at 6mo and 35% (p<0.0001) at 12mo. In patients with MDD (n=12), a 26% and 25% non-significant reduction in HAMD-17 scores (baseline 24.3±1.2) was observed at 6mo and 12mo, respectively. Neuropsychological testing revealed no negative effects of capsulotomy. In the OCD and MDD cohorts we found a correlation between clinical outcome and lesion laterality, with more medial left (OCD, p=0.08) and more lateral right (MDD, p<0.05) placed lesions being respectively associated with a stronger response. In the MDD cohort, more ventral tracts appeared to be associated with a poorer response. CONCLUSIONS: MRgFUS capsulotomy is safe in patients with OCD and MDD and particularly effective in the former population.

Antidepressant class and concurrent rTMS outcomes in major depressive disorder: a systematic review and meta-analysis.

Background: Repetitive transcranial magnetic stimulation (rTMS) is frequently used as an adjunctive treatment with antidepressants for depression. We aimed to evaluate the clinical efficacy and safety of antidepressant classes when administered concurrently with rTMS for the management of major depressive disorder (MDD). Methods: In this systematic review and meta-analysis, MEDLINE, Embase, PsycINFO, and the Cochrane Library were searched from inception to April 12th 2024 for terms relating to medication, depression, and rTMS and appraised by 2 independent screeners. All randomized clinical trials that prospectively evaluated a specific antidepressant adjunctively with sham rTMS as a control in MDD were included. The study was registered with PROSPERO (CRD42023418435). The primary outcome measure assessed symptomatic improvement measured by formal depression scales. We used a random-effects model with pooled Standardized Mean Differences (SMDs) and log odds ratios (OR). All studies were assessed for their methodological quality and bias using the Cochrane Collaboration Risk of Bias tool version 2 (RoB2). Findings: 14 articles from 5376 identified studies were included in the systematic review and meta-analysis. There was only sufficient trial data to evaluate the effects of rTMS and combination therapy with selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs). Across studies, 848 participants (mean [SD] age:41.1 [18.7] years for SSRIs, 51.8 [3.8] years for SNRIs) prospectively examined the efficacy of antidepressant medication with rTMS. Combining rTMS with SSRIs led to significantly lower depression scores, (SMD [CI] of -0.65 [-0.98, -0.31], p = 0.0002, I2 = 66.1%), higher response (OR = 0.97 [0.50, 1.44], p < 0.0001, I2 = 25.33%) and remission rates (OR = 1.04 [0.55, 1.52], p < 0.0001, I2 = 0.00%) than medication with sham rTMS. No additive benefit was found for SNRIs with rTMS (SMD of 0.10 [-0.14, 0.34], p = 0.42, I2 = 0.00%; OR = 0.12 [-0.39, 0.62], p = 0.64, I2 = 0.00%; OR = -0.31 [-0.90, 0.28], p = 0.86, I2 = 39.9%). The overall risk of bias for the included studies ranged from low to high, with 1 study having a high risk of bias. Interpretation: The combination of rTMS with SSRIs, but not SNRIs, significantly reduced depression severity, increasing response and remission rates. Some analyses demonstrated high heterogeneity, which was influenced by an SSRI trial with a high effect size. Overall, these results suggest that not all antidepressant combination therapies are alike, and SSRIs should be considered when initiating rTMS. Funding: Donald T. Stuss Young Investigator Research Innovation Award from the Sandra Black Centre for Brain Resilience & Recovery and the Harquail Centre for Neuromodulation through the Sunnybrook Foundation.

IN Esketamine and IV Ketamine: Results of a multi-site observational study assessing the effectiveness and tolerability of two novel therapies for treatment-resistant depression.

Intravenous (IV) ketamine and intranasal (IN) esketamine are novel therapies to manage treatment resistant depression within major depressive disorder (MDD-TRD). This is a multi-site observational study aiming to assess the real-world effectiveness and tolerability of these novel therapies in the management of MDD-TRD. 53 patients were referred to receive IV ketamine (n = 26, 69.23 % female, 52.81 ± 14.33 years old) or IN esketamine (n = 27, 51.85 % female, 43.93 ± 13.57 years old). Treatment effectiveness was assessed using the Montgomery and Åsberg Depression Rating Scale (MADRS) for depression severity and item 10 of the MADRS for suicidal ideation (SI). Tolerability was assessed by systematically tracking side effects and depersonalization using the 6-item Clinician administered dissociative symptom scale (CADSS-6). The data was analyzed using descriptive statistics, risk ratio and effect size. Both IV ketamine and IN esketamine significantly reduced depressive symptoms and suicidal ideation by treatment endpoint. Patients receiving IN esketamine, and patients receiving IV ketamine had a similar risk of developing side effects. All side effects reported were mild and transient. These results suggested that both IV ketamine and IN esketamine are effective in the management of depressive symptoms and were well tolerated. Therefore, the results of this study could serve to inform clinical practice.

Engaging Mood Brain Circuits with Psilocybin (EMBRACE): a study protocol for a randomized, placebo-controlled and delayed-start, neuroimaging trial in depression.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide across domains of health and cognition, affecting overall quality of life. Approximately one third of individuals with depression do not fully respond to treatments (e.g., conventional antidepressants, psychotherapy) and alternative strategies are needed. Recent early phase trials suggest psilocybin may be a safe and efficacious intervention with rapid-acting antidepressant properties. Psilocybin is thought to exert therapeutic benefits by altering brain network connectivity and inducing neuroplastic changes that endure for weeks post-treatment. Although early clinical results are encouraging, psilocybin's acute neurobiological effects on neuroplasticity have not been fully investigated. We aim to examine for the first time how psilocybin acutely (intraday) and subacutely (weeks) alters functional brain networks implicated in depression. METHODS: Fifty participants diagnosed with MDD or persistent depressive disorder (PDD) will be recruited from a tertiary mood disorders clinic and undergo 1:1 randomization into either an experimental or control arm. Participants will be given either 25 mg psilocybin or 25 mg microcrystalline cellulose (MCC) placebo for the first treatment. Three weeks later, those in the control arm will transition to receiving 25 mg psilocybin. We will investigate whether treatments are associated with changes in arterial spin labelling and blood oxygenation level-dependent contrast neuroimaging assessments at acute and subacute timepoints. Primary outcomes include testing whether psilocybin demonstrates acute changes in (1) cerebral blood flow and (2) functional brain activity in networks associated with mood regulation and depression when compared to placebo, along with changes in MADRS score over time compared to placebo. Secondary outcomes include changes across complementary clinical psychiatric, cognitive, and functional scales from baseline to final follow-up. Serum peripheral neurotrophic and inflammatory biomarkers will be collected at baseline and follow-up to examine relationships with clinical response, and neuroimaging measures. DISCUSSION: This study will investigate the acute and additive subacute neuroplastic effects of psilocybin on brain networks affected by depression using advanced serial neuroimaging methods. Results will improve our understanding of psilocybin's antidepressant mechanisms versus placebo response and whether biological measures of brain function can provide early predictors of treatment response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06072898. Registered on 6 October 2023.

Cytochrome P450-soluble epoxide hydrolase oxylipins, depression and cognition in type 2 diabetes.

AIMS: This study examined serum cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) oxylipins and depressive symptoms together in relation to cognitive performance in individuals with type 2 diabetes mellitus (T2DM). METHODS: Clinically cognitively normal T2DM individuals were recruited (NCT04455867). Depressive symptom severity was assessed using the Beck Depression Inventory-II (BDI-II; total scores ≤13 indicated minimal depressive symptoms and ≥ 14 indicated significant depressive symptoms). Executive function and verbal memory were assessed. Fasting serum oxylipins were quantified by ultra-high-performance liquid chromatography tandem mass-spectrometry. RESULTS: The study included 85 participants with minimal depressive symptoms and 27 with significant symptoms (mean age: 63.3 ± 9.8 years, 49 % women). In all participants, higher concentrations of linoleic acid derived sEH (12,13-dihydroxyoctadecamonoenoic acid; DiHOME) and CYP450 (12(13)-epoxyoctadecamonoenoic acid; EpOME) metabolites were associated with poorer executive function (F1,101 = 6.094, p = 0.015 and F1,101 = 5.598, p = 0.020, respectively). Concentrations of multiple sEH substrates interacted with depressive symptoms to predict 1) poorer executive function, including 9(10)-EpOME (F1,100 = 12.137, p < 0.001), 5(6)-epoxyeicosatrienoic acid (5(6)-EpETrE; F1,100 = 6.481, p = 0.012) and 11(12)-EpETrE (F1,100 = 4.409, p = 0.038), and 2) verbal memory, including 9(10)-EpOME (F1,100 = 4.286, p = 0.041), 5(6)-EpETrE (F1,100 = 6.845, p = 0.010), 11(12)-EpETrE (F1,100 = 3.981, p = 0.049) and 14(15)-EpETrE (F1,100 = 5.019, p = 0.027). CONCLUSIONS: Associations of CYP450-sEH metabolites and depressive symptoms with cognition highlight the biomarker and therapeutic potential of the CYP450-sEH pathway in T2DM.

Cognitive Profiles in Treatment-Resistant Late-Life Depression and Their Impact on Treatment Outcomes.

BACKGROUND: Late-life depression (LLD) is associated with cognitive impairment, but substantial heterogeneity exists among patients. Data on the extent of cognitive impairments are inconclusive, particularly in patients with treatment-resistant depression (TRD). We investigated the cognitive profiles of patients with treatment-resistant versus nonresistant LLD and aimed to identify distinct cognitive subgroups. We also examined whether cognitive subgroups responded differentially to treatment with bilateral repetitive transcranial magnetic stimulation (rTMS). METHODS: A total of 165 patients with LLD were divided into treatment-resistant and nonresistant groups and compared with healthy control participants on measures of executive function, information processing speed, verbal learning, and memory. Cluster analysis identified subgroups based on cognitive scores. Demographic and clinical variables, as well as outcomes with bilateral rTMS, were compared between cognitive subgroups. RESULTS: Patients with LLD, particularly TRD, exhibited significantly worse cognitive performance than healthy controls. A 3-cluster solution was found, including cognitively intact (n = 89), cognitively diminished (n = 29), and impaired memory (n = 47) subgroups. Both the cognitively diminished and impaired memory subgroups had more anxiety symptoms and a higher proportion of patients with TRD than the cognitively intact group, although the latter difference did not survive multiple comparison correction. No significant differences were observed in outcomes to rTMS treatment. CONCLUSIONS: Patients with LLD exhibited impairments across cognitive domains, which were more pronounced in TRD. Three cognitive subgroups responded similarly to rTMS treatment, indicating its effectiveness across cognitive profiles, especially when medications are not tolerated. Future research should examine the relationships among cognitive subgroups, cognitive decline, and neurodegeneration.

Treatment expectations and clinical outcomes following repetitive transcranial magnetic stimulation for treatment-resistant depression.

BACKGROUND: Patient expectations, including both positive (placebo) and negative (nocebo) effects, influence treatment outcomes, yet their impact on acute repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) is unclear. METHODS: In this single-center retrospective chart review, 208 TRD patients completed the Stanford Expectation of Treatment Scale (SETS) before starting open-label rTMS treatment. Patients were offered two excitatory rTMS protocols (deep TMS or intermittent theta-burst stimulation), which stimulated the left dorsolateral prefrontal cortex. A minimum of 20 once daily treatments were provided, delivered over 4-6 weeks. Primary outcomes were 1) remission, measured by a post-treatment score of <8 on the Hamilton Depression Rating Scale (HAMD-17), and 2) premature discontinuation. The change in HAMD-17 scores over time was used as a secondary outcome. Physicians were blinded to SETS scores. Logistic and linear regression, adjusting for covariates, assessed SETS and HAMD-17 relationships. RESULTS: Of 208 patients, 177 had baseline and covariate data available. The mean positivity bias score (positive expectancy minus negative expectancy subscale averages) was 0.48 ± 2.21, indicating the cohort was neutral regarding the expectations of their treatment on average. Higher positive expectancy scores were significantly associated with greater odds of remission (OR = 1.90, p = 0.003) and greater reduction in HAMD-17 scores (ß = 1.30, p = 0.005) at the end of acute treatment, after adjusting for covariates. Negative expectancy was not associated with decreased odds of remission (p = 0.2) or treatment discontinuation (p = 0.8). CONCLUSIONS: Higher pre-treatment positive expectations were associated with greater remission rates with open-label rTMS in a naturalistic cohort of patients with TRD.

Insertional effect following electrode implantation: an underreported but important phenomenon.

Deep brain stimulation has revolutionized the treatment of movement disorders and is gaining momentum in the treatment of several other neuropsychiatric disorders. In almost all applications of this therapy, the insertion of electrodes into the target has been shown to induce some degree of clinical improvement prior to stimulation onset. Disregarding this phenomenon, commonly referred to as 'insertional effect', can lead to biased results in clinical trials, as patients receiving sham stimulation may still experience some degree of symptom amelioration. Similar to the clinical scenario, an improvement in behavioural performance following electrode implantation has also been reported in preclinical models. From a neurohistopathologic perspective, the insertion of electrodes into the brain causes an initial trauma and inflammatory response, the activation of astrocytes, a focal release of gliotransmitters, the hyperexcitability of neurons in the vicinity of the implants, as well as neuroplastic and circuitry changes at a distance from the target. Taken together, it would appear that electrode insertion is not an inert process, but rather triggers a cascade of biological processes, and, as such, should be considered alongside the active delivery of stimulation as an active part of the deep brain stimulation therapy.

Effects of repetitive transcranial magnetic stimulation on individual variability of resting-state functional connectivity in major depressive disorder.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depressive disorder (MDD), but substantial heterogeneity in outcomes remains. We examined a potential mechanism of action of rTMS to normalize individual variability in resting-state functional connectivity (rs-fc) before and after a course of treatment. METHODS: Variability in rs-fc was examined in healthy controls (baseline) and individuals with MDD (baseline and after 4-6 weeks of rTMS). Seed-based connectivity was calculated to 4 regions associated with MDD: left dorsolateral prefrontal cortex (DLPFC), right subgenual anterior cingulate cortex (sgACC), bilateral insula, and bilateral precuneus. Individual variability was quantified for each region by calculating the mean correlational distance of connectivity maps relative to the healthy controls; a higher variability score indicated a more atypical/idiosyncratic connectivity pattern. RESULTS: We included data from 66 healthy controls and 252 individuals with MDD in our analyses. Patients with MDD did not show significant differences in baseline variability of rs-fc compared with controls. Treatment with rTMS increased rs-fc variability from the right sgACC and precuneus, but the increased variability was not associated with clinical outcomes. Interestingly, higher baseline variability of the right sgACC was significantly associated with less clinical improvement (p = 0.037, uncorrected; did not survive false discovery rate correction).Limitations: The linear model was constructed separately for each region of interest. CONCLUSION: This was, to our knowledge, the first study to examine individual variability of rs-fc related to rTMS in individuals with MDD. In contrast to our hypotheses, we found that rTMS increased the individual variability of rs-fc. Our results suggest that individual variability of the right sgACC and bilateral precuneus connectivity may be a potential mechanism of rTMS.

Predictors of remission after repetitive transcranial magnetic stimulation for the treatment of late-life depression.

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment in patients with depression, yet treatment response remains variable. While previous work has identified predictors of remission in younger adults, relatively little data exists in late-life depression (LLD). To address this gap, data from 164 participants with LLD from a randomized non-inferiority treatment trial comparing standard bilateral rTMS to bilateral theta burst stimulation (TBS) (ClinicalTrials.gov identifier: NCT02998580) were analyzed using binary logistic regression and conditional inference tree (CIT) modeling. Lower baseline depression symptom severity, fewer prior antidepressant treatment failures, and higher global cognition predicted remission following rTMS treatment. The CIT predicted a higher likelihood of achieving remission for patients with a total score of 19 or lower on the Montgomery-Åsberg Depression Rating Scale, 1 or fewer prior antidepressant treatment failures, and a total score of 23 or higher on the Montreal Cognitive Assessment. Our results indicate that older adults with lower severity of depression, fewer antidepressant treatment failures, and higher global cognition benefit more from current forms of rTMS. The results suggest that there is potentially higher value in using rTMS earlier in the treatment pathway for depression in older adults.

Adverse Effects of Deep Brain Stimulation for Treatment-Resistant Depression: A Scoping Review.

Deep brain stimulation (DBS) is an emerging therapy for treatment-resistant depression (TRD). Although adverse effects have been reported in early-phase and a few randomized clinical trials, little is known about its overall safety profile, which has been assumed to be similar to that of DBS for movement disorders. The objective of this study was to pool existing safety data on DBS for TRD. Following PRISMA guidelines, PubMed was searched for English articles describing adverse outcomes after DBS for TRD. Studies were included if they reported at least 5 patients with a minimal follow-up of 6 months. After abstract (n = 607) and full-article review (n = 127), 28 articles reporting on 353 patients met criteria for final inclusion. Follow-up of the studies retrieved ranged from 12 to 96 months. Hemorrhages occurred in 0.8% of patients and infections in 10.2%. The rate of completed suicide was 2.5%. Development or worsening of depressive symptoms, anxiety, and mania occurred in 18.4%, 9.1%, and 5.1%, respectively. There were some differences between targets, but between-study heterogeneity precluded statistical comparisons. In conclusion, DBS for TRD is associated with surgical and psychiatric adverse events. Hemorrhage and infection occur at rates within an accepted range for other DBS applications. The risk of suicide after DBS for TRD is 2.5% but may not represent a significant deviation from the natural history of TRD. Finally, risks of worsening depression, anxiety, and the incidence of mania should be acknowledged when considering DBS for TRD.

Seasonal pattern and depression outcomes from repetitive transcranial magnetic stimulation.

Individuals with major depressive disorder (MDD) may exhibit a seasonal pattern. The impact of a seasonal pattern in depressive symptoms on rTMS outcomes is unexplored. A retrospective analysis was performed on patients with MDD receiving open-label high frequency rTMS to the left dorsolateral prefrontal cortex. Having a seasonal pattern was defined as scoring ≥ 12 on the Personal Inventory for Depression and Seasonal Affective Disorder (PIDS). Primary outcomes included improvement in the Hamilton Depression Rating Scale (HAMD) and remission. Secondary analyses included the use of the self-rated Quick Inventory of Depressive Symptomatology (QIDS) to assess for changes in atypical neurovegetative symptoms. Multiple linear regression, multiple logistic regression, and linear mixed effects analyses were performed. 46 % (58/127) of the sample had a seasonal pattern. Seasonal pattern did not significantly influence improvement in HAMD (PIDS < 12, 7.8, SD 5.9; PIDS ≥ 12, 10.4, SD 4.9 or remission (PIDS < 12, 30 %; PIDS ≥ 12, 34 %). There were equivalent degrees of improvement in atypical neurovegetative symptoms over time as assessed using the QIDS. Depression with seasonal pattern was found to respond to rTMS treatment similarly to depression without seasonal pattern, suggesting that this may be a viable treatment for this group.

Effect of prior pharmacotherapy on remission with sequential bilateral theta-burst versus standard bilateral repetitive transcranial magnetic stimulation in treatment-resistant late-life depression.

Repetitive transcranial magnetic stimulation (rTMS) is used for treatment of late-life depression. In the FOUR-D study, sequential bilateral theta-burst stimulation (TBS) had comparable remission rates to standard bilateral rTMS. Data were analysed from the FOUR-D trial to compare remission rates between two types of rTMS based on the number and class of prior medication trials. The remission rate was higher in participants with ≤1 previous trial (43.9%) than in participants with 2 previous trials (26.5%) or ≥3 previous trials (24.6%; χ² = 6.36, d.f. = 2, P = 0.04). Utilising rTMS earlier in late-life depression may lead to better outcomes.

Adverse childhood experiences and repetitive transcranial magnetic stimulation outcomes for depression.

BACKGROUND: History of adverse childhood experiences (ACEs) is associated with poorer treatment outcomes in depression. How ACEs affect outcomes from repetitive transcranial magnetic stimulation (rTMS) is not well-defined. The primary aim was to investigate whether ACEs affect depression outcomes in patients receiving high frequency rTMS, either deep TMS (dTMS) or intermittent theta burst stimulation (iTBS), to the left dorsolateral prefrontal cortex. METHODS: The Hamilton Depression Rating Scale (HAMD-17) was collected at baseline and every 2 weeks for 4-6 weeks. Outcomes included improvement in HAMD-17 and remission. The ACE-10 questionnaire was used to quantify categories of ACEs. Data from 99 patients with MDD receiving an acute rTMS course were analyzed. RESULTS: Patients had a mean of 2.4 ACEs (SD 2.5). No significant differences in outcomes were found between dTMS or iTBS so these data were pooled. Using a continuous ACE variable showed no significant impact on outcomes. Using a categorical ACE variable (0, 1, 2, 3, 4 or more) did not reveal significant effects of ACEs on outcomes. Higher ACE was associated with steeper decrease in HAMD-17 only from baseline to week 2 but not at other times. LIMITATIONS: This was an open-label study. The well-validated ACE questionnaire does not measure severity or frequency of adversities. CONCLUSIONS: Patients with depression receiving rTMS reported on average 2.4 ACEs. ACE scores may lead to a steeper early decline in HAMD-17 but did not otherwise impact depression outcomes. Presence of high levels of ACEs should not preclude consideration of rTMS for depression.

Mapping the future of interventional psychiatry for the obsessive-compulsive related disorders: A scoping review.

Body dysmorphic disorder (BDD), hoarding disorder (HD), skin-picking disorder (SPD), and hair-pulling disorder (HPD) are characterized by compulsive behaviours leading to distress and impairment. Current treatments attain only partial or non-response. Interventional psychiatric approaches may target specific regions of the brain for treatment. This scoping review maps the current literature and synthesizes key findings. Databases were searched up to June 27, 2022 for studies examining interventional psychiatric treatments for BDD, HD, SPD, and HPD, producing 910 results. Twenty were included; 16 were case reports, two were case series, and two were randomized controlled trials. Studies reported on electroconvulsive therapy (ECT) (n=7), deep brain stimulation (DBS) (n=1), and intermittent theta-burst stimulation repetitive transcranial magnetic stimulation (rTMS) (n=1) for BDD; rTMS (n=1) and transcranial direct current stimulation (n=1) for HD; gamma knife capsulotomy (n=1) and rTMS (n=1) for SPD; and rTMS (n=2) and ECT (n=1) for HPD. Four studies reported on DBS for other indications complicated by SPD or HPD. The current literature consists mainly of case reports. Future studies should be randomized, controlled, adequately powered and blinded, examining rTMS localized to the anatomical targets for each disorder. Presently, the mainstay of treatment remains disorder-specific psychotherapy with limited evidence for medications.