Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023 : Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes.

BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) last published clinical guidelines for the management of major depressive disorder (MDD) in 2016. Owing to advances in the field, an update was needed to incorporate new evidence and provide new and revised recommendations for the assessment and management of MDD in adults. METHODS: CANMAT convened a guidelines editorial group comprised of academic clinicians and patient partners. A systematic literature review was conducted, focusing on systematic reviews and meta-analyses published since the 2016 guidelines. Recommendations were organized by lines of treatment, which were informed by CANMAT-defined levels of evidence and supplemented by clinical support (consisting of expert consensus on safety, tolerability, and feasibility). Drafts were revised based on review by patient partners, expert peer review, and a defined expert consensus process. RESULTS: The updated guidelines comprise eight primary topics, in a question-and-answer format, that map a patient care journey from assessment to selection of evidence-based treatments, prevention of recurrence, and strategies for inadequate response. The guidelines adopt a personalized care approach that emphasizes shared decision-making that reflects the values, preferences, and treatment history of the patient with MDD. Tables provide new and updated recommendations for psychological, pharmacological, lifestyle, complementary and alternative medicine, digital health, and neuromodulation treatments. Caveats and limitations of the evidence are highlighted. CONCLUSIONS: The CANMAT 2023 updated guidelines provide evidence-informed recommendations for the management of MDD, in a clinician-friendly format. These updated guidelines emphasize a collaborative, personalized, and systematic management approach that will help optimize outcomes for adults with MDD.

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.

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.

Local neuroanatomical and tract-based proxies of optimal subcallosal cingulate deep brain stimulation.

BACKGROUND: Deep brain stimulation of the subcallosal cingulate area (SCC-DBS) is a promising neuromodulatory therapy for treatment-resistant depression (TRD). Biomarkers of optimal target engagement are needed to guide surgical targeting and stimulation parameter selection and to reduce variance in clinical outcome. OBJECTIVE/HYPOTHESIS: We aimed to characterize the relationship between stimulation location, white matter tract engagement, and clinical outcome in a large (n = 60) TRD cohort treated with SCC-DBS. A smaller cohort (n = 22) of SCC-DBS patients with differing primary indications (bipolar disorder/anorexia nervosa) was utilized as an out-of-sample validation cohort. METHODS: Volumes of tissue activated (VTAs) were constructed in standard space using high-resolution structural MRI and individual stimulation parameters. VTA-based probabilistic stimulation maps (PSMs) were generated to elucidate voxelwise spatial patterns of efficacious stimulation. A whole-brain tractogram derived from Human Connectome Project diffusion-weighted MRI data was seeded with VTA pairs, and white matter streamlines whose overlap with VTAs related to outcome ('discriminative' streamlines; Puncorrected < 0.05) were identified using t-tests. Linear modelling was used to interrogate the potential clinical relevance of VTA overlap with specific structures. RESULTS: PSMs varied by hemisphere: high-value left-sided voxels were located more anterosuperiorly and squarely in the lateral white matter, while the equivalent right-sided voxels fell more posteroinferiorly and involved a greater proportion of grey matter. Positive discriminative streamlines localized to the bilateral (but primarily left) cingulum bundle, forceps minor/rostrum of corpus callosum, and bilateral uncinate fasciculus. Conversely, negative discriminative streamlines mostly belonged to the right cingulum bundle and bilateral uncinate fasciculus. The best performing linear model, which utilized information about VTA volume overlap with each of the positive discriminative streamline bundles as well as the negative discriminative elements of the right cingulum bundle, explained significant variance in clinical improvement in the primary TRD cohort (R = 0.46, P < 0.001) and survived repeated 10-fold cross-validation (R = 0.50, P = 0.040). This model was also able to predict outcome in the out-of-sample validation cohort (R = 0.43, P = 0.047). CONCLUSION(S): These findings reinforce prior indications of the importance of white matter engagement to SCC-DBS treatment success while providing new insights that could inform surgical targeting and stimulation parameter selection decisions.

Reduction of aggressive behaviour following hypothalamic deep brain stimulation: Involvement of 5-HT1A and testosterone.

BACKGROUND: Aggressive behaviour (AB) may occur in patients with different neuropsychiatric disorders. Although most patients respond to conventional treatments, a small percentage continue to experience AB despite optimized pharmacological management and are considered to be treatment-refractory. For these patients, hypothalamic deep brain stimulation (pHyp-DBS) has been investigated. The hypothalamus is a key structure in the neurocircuitry of AB. An imbalance between serotonin (5-HT) and steroid hormones seems to exacerbate AB. OBJECTIVES: To test whether pHyp-DBS reduces aggressive behaviour in mice through mechanisms involving testosterone and 5-HT. METHODS: Male mice were housed with females for two weeks. These resident animals become territorial and aggressive towards intruder mice placed in their cages. Residents had electrodes implanted in the pHyp. DBS was administered for 5 h/day for 8 consecutive encounters prior to the interaction with the intruder. After testing, blood and brains were recovered for measuring testosterone and 5-HT receptor density, respectively. In a second experiment, residents received WAY-100635 (5-HT1A antagonist) or saline injections prior to pHyp-DBS. After the first 4 encounters, the injection allocation was crossed, and animals received the alternative treatment during the next 4 encounters. RESULTS: DBS-treated mice showed reduced AB that was correlated with testosterone levels and an increase in 5-HT1A receptor density in the orbitofrontal cortex and amygdala. Pre-treatment with WAY-100635 blocked the anti-aggressive effect of pHyp-DBS. CONCLUSIONS: This study shows that pHyp-DBS reduces AB in mice via changes in testosterone and 5-HT1A mechanisms.

Interventional Psychiatry and Neurotechnologies: Education and Ethics Training.

The last two decades have seen dramatic growth in the application of procedurally based interventions for treating refractory psychiatric conditions, leading to interest in developing the foundations for the subspecialty of "Interventional Psychiatry." However, there is cause for concern that the rate of expansion of clinical advances in this field may be outpacing the ability of postgraduate curricula to provide sufficient exposure to and teaching and supervision of these treatments. The paucity of adequately trained practitioners in Interventional Psychiatry further exacerbates inequities in the ability of eligible patients to access and benefit from these approaches. This paper explores the rates of utilization of Interventional Psychiatry treatments, the current state of education in these treatments, and the role that training can play in translating scientific advances in this area to ensure equitable access and maximum impact at a population level. The majority of the discussion is centered on electroconvulsive therapy (ECT), the most established and available of these treatments, highlighting how enhancing education and training in ECT can reduce barriers to its utilization. It is argued that innovations in pedagogical approaches for disseminating the learning of these procedures are needed to increase the current low rates of competency in these treatments and can facilitate the more rapid dissemination of other Interventional Psychiatry approaches and neurotechnologies, such as repetitive transcranial magnetic stimulation, ketamine, deep brain stimulation, and focused ultrasound.

Multi-centre analysis of networks and genes modulated by hypothalamic stimulation in patients with aggressive behaviours.

Deep brain stimulation targeting the posterior hypothalamus (pHyp-DBS) is being investigated as a treatment for refractory aggressive behavior, but its mechanisms of action remain elusive. We conducted an integrated imaging analysis of a large multi-centre dataset, incorporating volume of activated tissue modeling, probabilistic mapping, normative connectomics, and atlas-derived transcriptomics. Ninety-one percent of the patients responded positively to treatment, with a more striking improvement recorded in the pediatric population. Probabilistic mapping revealed an optimized surgical target within the posterior-inferior-lateral region of the posterior hypothalamic area. Normative connectomic analyses identified fiber tracts and functionally connected with brain areas associated with sensorimotor function, emotional regulation, and monoamine production. Functional connectivity between the target, periaqueductal gray and key limbic areas - together with patient age - were highly predictive of treatment outcome. Transcriptomic analysis showed that genes involved in mechanisms of aggressive behavior, neuronal communication, plasticity and neuroinflammation might underlie this functional network.

Competencies for Repetitive Transcranial Magnetic Stimulation in Postgraduate Medical Education: Expert Consensus Using a Modified Delphi Process.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is recommended in Canadian guidelines as a first-line treatment for major depressive disorder. With the shift towards competency-based medical education, it remains unclear how to determine when a resident is considered competent in applying knowledge of rTMS to patient care. Given inconsistencies between postgraduate training programmes with regards to training requirements, defining competencies will improve the standard of care in rTMS delivery. OBJECTIVE: The goal of this study was to develop competencies for rTMS that can be implemented into a competency-based training curriculum in postgraduate training programmes. METHODS: A working group drafted competencies for postgraduate psychiatry trainees. Fourteen rTMS experts from across Canada were invited to participate in the modified Delphi process. RESULTS: Ten experts participated in all three rounds of the modified Delphi process. A total of 20 items reached a consensus. There was improvement in the Cronbach's alpha over the rounds of modified Delphi process (Cronbach's alpha increased from 0.554 to 0.824) suggesting improvement in internal consistency. The intraclass correlation coefficient (ICC) increased from 0.543 to 0.805 suggesting improved interrater agreement. CONCLUSIONS: This modified Delphi process resulted in expert consensus on competencies to be acquired during postgraduate medical education programmes where a learner is training to become competent as a consultant and/or practitioner in rTMS treatment. This is a field that still requires development, and it is expected that as more evidence emerges the competencies will be further refined. These results will help the development of other curricula in interventional psychiatry.

Neurochemical mechanisms of deep brain stimulation for depression in animal models.

Deep brain stimulation (DBS) has emerged as a neuromodulation therapy for treatment-resistant depression, but its actual efficacy and mechanisms of action are still unclear. Changes in neurochemical transmission are important mechanisms of antidepressant therapies. Here, we review the preclinical DBS literature reporting behavioural and neurochemical data associated with its antidepressant-like effects. The most commonly studied target in preclinical models was the ventromedial prefrontal cortex (vmPFC). In rodents, DBS delivered to this target induced serotonin (5-HT) release and increased 5-HT1B receptor expression. The antidepressant-like effects of vmPFC DBS seemed to be independent of the serotonin transporter and potentially mediated by the direct modulation of prefrontal projections to the raphe. Adenosinergic and glutamatergic transmission might have also play a role. Medial forebrain bundle (MFB) DBS increased dopamine levels and reduced D2 receptor expression, whereas nucleus accumbens (NAcc), and lateral habenula (LHb) stimulation increased catecholamine levels in different brain regions. In rodents, subthalamic nucleus (STN) DBS induced robust depression-like responses associated with a reduction in serotonergic transmission, as revealed by a decrease in serotonin release. Some of these effects seemed to be mediated by 5HT1A receptors. In conclusion, the antidepressant-like effects of DBS in preclinical models have been well documented in multiple targets. Though variable mechanisms have been proposed, DBS-induced acute and long-term changes in neurochemical substrates seem to play an important role in the antidepressant-like effects of this therapy.

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.

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.

Suicide Assessment and Prevention in Bipolar Disorder: How Current Evidence Can Inform Clinical Practice.

Bipolar disorder is associated with a considerable risk of suicide, and this fact must be incorporated into management of all patients with the condition. This article highlights the importance of a more nuanced understanding of the factors associated with the increased risk of suicidal behavior in people diagnosed as having bipolar disorder and interventions that could mitigate it. Several sociodemographic, clinical, environmental, and other variables have been associated with suicide attempts or deaths in bipolar disorder. Youths with bipolar disorder are a particularly vulnerable group, and their trajectory of illness could be modified by early interventions. Several medications have been studied regarding their relationship to suicide risk in bipolar disorder, and interventional psychiatry is a newer area of research focus. Finally, community-based approaches can be incorporated into a comprehensive approach to suicide prevention. This article summarizes the current understanding of key variables that can help inform a clinical risk assessment of individuals and interventions that can be employed in suicide prevention in bipolar disorder.

Association of intranasal esketamine, a novel 'standard of care' treatment and outcomes in the management of patients with treatment-resistant depression: protocol of a prospective cohort observational study of naturalistic clinical practice.

INTRODUCTION: Esketamine is the S-enantiomer of racemic ketamine and has been approved by the Food and Drug Administration for the management of treatment resistant depression, demonstrating effective and long-lasting benefits. The objective of this observational study is to elucidate the association of intranasal (IN) esketamine with beneficial and negative outcomes in the management of treatment resistant major depressive disorder. METHODS AND ANALYSIS: This is a multicentre prospective cohort observational study of naturalistic clinical practice. We expect to recruit 10 patients per research centre (6 centres, total 60 subjects). After approval to receive IN esketamine as part of their standard of care management of moderate to severe treatment resistant depression, patients will be invited to participate in this study. Association of esketamine treatment with outcomes in the management of depression will be assessed by measuring the severity of depression symptoms using the Montgomery-Åsberg Depression Rating Scale (MADRS), and tolerability by systematically tracking common side effects of ketamine treatment, dissociation using the simplified 6-Item Clinician Administered Dissociative Symptom Scale and potential for abuse using the Likeability and Craving Questionnaire (LCQ). Change in depressive symptoms (MADRS total scores) over time will be evaluated by within-subject repeated measures analysis of variance. We will calculate the relative risk associated with the beneficial (reduction in total scores for depression) outcomes, and the side effect and dropout rates (tolerability) of adding IN esketamine to patients' current pharmacological treatments. Covariate analysis will assess the impact of site and demographic variables on treatment outcomes. ETHICS AND DISSEMINATION: Approval to perform this study was obtained through the Health Sciences Research Ethics Board at Queen's University. Findings will be shared among collaborators, through departmental meetings, presented on different academic venues and publishing our manuscript.

Deep brain stimulation of the subgenual cingulum and uncinate fasciculus for the treatment of posttraumatic stress disorder.

Deep brain stimulation (DBS) has been investigated for neuropsychiatric disorders. In this phase 1 trial, we treated four posttraumatic stress disorder (PTSD) patients with DBS delivered to the subgenual cingulum and the uncinate fasciculus. In addition to validated clinical scales, patients underwent neuroimaging studies and psychophysiological assessments of fear conditioning, extinction, and recall. We show that the procedure is safe and potentially effective (55% reduction in Clinical Administered PTSD Scale scores). Posttreatment imaging data revealed metabolic activity changes in PTSD neurocircuits. During psychophysiological assessments, patients with PTSD had higher skin conductance responses when tested for recall compared to healthy controls. After DBS, this objectively measured variable was significantly reduced. Last, we found that a ratio between recall of extinguished and nonextinguished conditioned responses had a strong correlation with clinical outcome. As this variable was recorded at baseline, it may comprise a potential biomarker of treatment response.

Cognitive effects of unilateral thalamotomy for tremor: a meta-analysis.

Tremor is a debilitating symptom that can lead to functional impairment. Pharmacotherapy is often successful, but up to 50% of patients are resistant to medications or cannot tolerate side effects. Thalamotomy to the ventral intermediate nucleus of the thalamus is a surgical intervention for refractory tremor. Thalamotomy surgeries include radiofrequency and incisionless procedures, such as Gamma Knife radiosurgery and magnetic resonance-guided focused ultrasound. Cognitive changes following thalamotomy have been inconsistently reported across studies. We performed a meta-analysis to summarize the impact of unilateral thalamotomy to the ventral intermediate nucleus of the thalamus across multiple cognitive domains. We searched MEDLINE, Embase Classic, Embase and EBM Reviews for relevant studies. Neuropsychological tests were categorized into seven cognitive domains: global cognition, verbal memory, non-verbal memory, executive function, phonemic fluency, semantic fluency and visuospatial processing. We calculated standardized mean differences as Hedges' g and 95% confidence intervals of the change between pre- and postoperative cognitive scores. Pooling of standardized mean differences across studies was performed using random-effects models. Risk of bias across studies and quality of evidence for each cognitive domain were assessed with the National Institute of Health quality assessment tool and the GRADEpro Guideline Development Tool, respectively. Of the 1251 records reviewed, eight studies met inclusion criteria. We included 193 patients with essential tremor, Parkinson's disease, or multiple sclerosis in the meta-analysis. There was a small significant decline in phonemic fluency [standardized mean difference = -0.29, 95% confidence interval: (-0.52, -0.05), P = 0.017] and a trend towards a decline in semantic fluency [standardized mean difference = -0.19, 95% confidence interval: (-0.40, 0.01), P = 0.056]. No postoperative changes were observed in the other cognitive domains (P values >0.14). In secondary analyses, we restricted the analyses to studies using magnetic resonance-guided focused ultrasound given its growing popularity and more precise targeting. In those analyses, there was no evidence of cognitive decline across any domain (P values >0.37). In terms of risk of bias, five studies were rated as 'good' and three studies were rated as 'fair'. According to GRADEpro guidelines, the certainty of the effect for all cognitive domains was low. This study provides evidence that unilateral thalamotomy to the ventral intermediate nucleus of the thalamus is relatively safe from a cognitive standpoint, however, there may be a small decline in verbal fluency. Magnetic resonance-guided focused ultrasound might have a more favourable postoperative cognitive profile compared with other thalamotomy techniques.