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Depression is the leading cause of disability worldwide, and half of patients with depression have treatment-resistant depression. Intermittent theta-burst stimulation (iTBS) is approved by the U.S. Food and Drug Administration for the treatment of treatment-resistant depression but is limited by suboptimal efficacy and a 6-week duration. The authors addressed these limitations by developing a neuroscience-informed accelerated iTBS protocol, Stanford neuromodulation therapy (SNT; previously referred to as Stanford accelerated intelligent neuromodulation therapy, or SAINT). This protocol was associated with a remission rate of ∼90% after 5 days of open-label treatment. Here, the authors report the results of a sham-controlled double-blind trial of SNT for treatment-resistant depression.Participants with treatment-resistant depression currently experiencing moderate to severe depressive episodes were randomly assigned to receive active or sham SNT. Resting-state functional MRI was used to individually target the region of the left dorsolateral prefrontal cortex most functionally anticorrelated with the subgenual anterior cingulate cortex. The primary outcome was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 4 weeks after treatment.At the planned interim analysis, 32 participants with treatment-resistant depression had been enrolled, and 29 participants who continued to meet inclusion criteria received either active (N=14) or sham (N=15) SNT. The mean percent reduction from baseline in MADRS score 4 weeks after treatment was 52.5% in the active treatment group and 11.1% in the sham treatment group.SNT, a high-dose iTBS protocol with functional-connectivity-guided targeting, was more effective than sham stimulation for treatment-resistant depression. Further trials are needed to determine SNT's durability and to compare it with other treatments.

New antidepressant treatments are needed that are effective, rapid acting, safe, and tolerable. Intermittent theta-burst stimulation (iTBS) is a noninvasive brain stimulation treatment that has been approved by the U.S. Food and Drug Administration for treatment-resistant depression. Recent methodological advances suggest that the current iTBS protocol might be improved through 1) treating patients with multiple sessions per day at optimally spaced intervals, 2) applying a higher overall pulse dose of stimulation, and 3) precision targeting of the left dorsolateral prefrontal cortex (DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. The authors examined the feasibility, tolerability, and preliminary efficacy of Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), an accelerated, high-dose resting-state functional connectivity MRI (fcMRI)-guided iTBS protocol for treatment-resistant depression.Twenty-two participants with treatment-resistant depression received open-label SAINT. fcMRI was used to individually target the region of the left DLPFC most anticorrelated with sgACC in each participant. Fifty iTBS sessions (1,800 pulses per session, 50-minute intersession interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT.One participant withdrew, leaving a sample size of 21. Nineteen of 21 participants (90.5%) met remission criteria (defined as a score11 on the Montgomery-Åsberg Depression Rating Scale). In the intent-to-treat analysis, 19 of 22 participants (86.4%) met remission criteria. Neuropsychological testing demonstrated no negative cognitive side effects.SAINT, an accelerated, high-dose, iTBS protocol with fcMRI-guided targeting, was well tolerated and safe. Double-blinded sham-controlled trials are needed to confirm the remission rate observed in this initial study.

Introduction Ibogaine is an indole alkaloid traditionally used in spiritual and healing rites in some African cultures. Ibogaine is primarily studied in the context of substance dependence, but indications suggest it may enhance recovery from trauma. Here, we investigated the effects of ibogaine treatment for multisystem effects of exposure to repeated blasts and combat on self-reported sleep disturbance, insomnia severity, and trauma-related symptoms. Methods Participants were Special Operations Veterans who independently and voluntarily underwent ibogaine treatment at a specialized clinic outside the USA. After meeting rigorous screening requirements, 30 participants were enrolled, all endorsing histories of repeated combat and blast exposure and traumatic brain injury. Participants were seen in person for baseline, immediate post-treatment, and 1-month post-treatment assessments, including the Clinician-Administered Posttraumatic Stress Disorder (PTSD) Scale for DSM-5 (CAPS-5), the Pittsburgh Sleep Quality Index (PSQI), and the Pittsburgh Insomnia Rating Scale (PIRS). Twenty-six participants completed sleep measures at baseline and 1-month post-treatment. Results Two-tailed paired samples t-tests revealed significant effects of time, with post-treatment improvements in CAPS (ΔM = -26.8±11.1, t(25) = 12.283, p < .001), PSQI (ΔM = -6.5±5.6, t(25) = 5.920, p < .001), and PIRS (ΔM = -23.8±15.5, t(24) = 7.690, p < .001). However, pre-post changes in PTSD symptom severity were not a significant predictor of improvements in PSQI (R² = .229, b = .354, p = .074) or PIRS (R² = .232, b = .339, p = .090) after controlling for age (p = .206 and p = .165, respectively). Conclusion To our knowledge, this is the first study examining the effects of ibogaine use on sleep in humans. Results indicated that while sleep and PTSD symptom severity improve 1-month post-treatment, they might be impacted by different mechanisms targeted by ibogaine. Even though a small sample size may have hindered the ability to reach desired probability values, the variance explained by the improvement in PTSD symptoms was still relatively modest (up to 23%). These promising findings demonstrate ibogaine’s therapeutic potential for disturbed sleep in the context of traumatic brain injury and trauma. Potential explanations are discussed. Support (if any) This study was supported by a private fund.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the safety and efficacy of repetitive transcranial magnetic stimulation (rTMS) for the treatment of post‐traumatic stress disorder (PTSD) in adults.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) and the Dementia Rating Scale‐2 (DRS‐2) are recommended screeners for Parkinson's disease mild cognitive impairment (PD‐MCI). Cross‐cultural studies examining their diagnostic precision have not addressed cultural bias in a multicultural setting. OBJECTIVES: To compare DRS‐2 and MoCA performance between patients born in Canada, the USA, and the UK (Anglosphere group) and immigrant patients born elsewhere (International group). To identify sources of cultural bias by comparing group characteristics, and by assessing the relationships between performance and immigration and socio‐development variables. To examine the diagnostic precision of both tools in detecting PD‐MCI in each group. METHODS: We conducted a clinical chart review of advanced PD patients who completed cognitive screeners (MoCA: n = 288, 30% International group; DRS‐2: n = 426, 31% International group). All completed a comprehensive neuropsychological assessment to apply Level II PD‐MCI diagnostic criteria. RESULTS: The International group performed worse than the Anglosphere group on the MoCA and DRS‐2, and the only variable that accounted for some of the group difference was the Historical Index of Human Development, a societal variable, which fully mediated the group effect on the DRS‐2. Diagnostic precision of the MoCA was at chance level in the International group, and was poorer than that of the DRS‐II in this group and that of the MoCA in the Anglosphere group, although these were considered poor. CONCLUSIONS: Our results support the recommendation to exert caution in using cognitive screeners to capture PD‐MCI in all patients and particularly with first generation immigrants.

BackgroundCurrent treatments for depression are limited by suboptimal efficacy, delayed response, and frequent side effects. Intermittent theta-burst stimulation (iTBS) is a non-invasive brain stimulation treatment that is FDA-approved for treatment-resistant depression (TRD). Recent methodological advancements suggest iTBS could be improved through 1) treating with multiple sessions per day at optimally-spaced intervals, 2) applying a higher overall pulse-dose of stimulation and 3) precision targeting of the left dorsolateral prefrontal cortex (L-DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. We examined the feasibility, tolerability, and preliminary efficacy of an accelerated, high-dose, resting-state functional connectivity MRI (fcMRI)-guided iTBS protocol for TRD termed ‘Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT)’.MethodsTwenty-one participants with TRD received open-label SAINT. FcMRI was used to individually target the region of L-DLPFC most anticorrelated with sgACC. Fifty iTBS sessions (1800 pulses per session, 50-minute inter-session interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT.ResultsNineteen of 21 participants (90.48%) met criteria for remission (≤10 on the Montgomery-Åsberg Depression Rating Scale) immediately after SAINT. Neuropsychological testing demonstrated no negative cognitive side-effects. There were no seizures or other severe adverse events.DiscussionOur accelerated, high-dose, iTBS protocol with fcMRI-guided targeting (SAINT) was well tolerated and safe. Efficacy was strikingly high, especially for this treatment-resistant population. Double-blinded sham-controlled trials are required to confirm the high remission rate found in this initial study.Trial registrationClinicalTrials.govNCT03240692

The Hypothalamic Pituitary Adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity in major depression, a relationship of HPA axis activity to cognitive performance, and a potential role of HPA axis genetic variation in cognition. In schizophrenia differential HPA activity has been found, including higher rates of non-suppression to dexamethasone challenge and higher salivary cortisol levels, which have been a premonitory risk factor for conversion to psychosis in adolescents at risk for developing schizophrenia. The present study investigated the simultaneous roles HPA axis activity and clinical symptomatology play in poor cognitive performance. Patients with major depression with psychosis (PMD) or schizophrenia spectrum disorder (SCZ) and healthy controls (HC) were studied. All participants underwent a diagnostic interview and psychiatric ratings, a comprehensive neuropsychological battery, and overnight hourly blood sampling for cortisol. Cognitive performance did not differ between the clinical groups, though they both performed more poorly than the HC's across a variety of cognitive domains. Across all subjects, cognitive performance was negatively correlated with higher cortisol, and PMD patients had higher evening cortisol levels than did SCZ and HCs. Cortisol and clinical symptoms, as well as age, sex, and antipsychotic use predicted cognitive performance. Diathesis stress models and their links to symptomatology, cognition, and HPA function are discussed.