Clinical Outcomes of Electroconvulsive Therapy (ECT) for Depression in Older Old People Relative to Other Age Groups Across the Adult Life Span: A CARE Network Study.

INTERVENTION: Electroconvulsive therapy (ECT) is a commonly used treatment for severe psychiatric illness in older adults, including in the 'older old' population aged 80 years and above. However, there can sometimes be a reluctance to treat the 80+ year old age group with ECT due to medical comorbidities, frailty, and concerns about cognition. OBJECTIVE, DESIGN, SETTING, AND PARTICIPANTS: This multi-site, longitudinal Australian study aimed to investigate the effectiveness and safety of ECT in older old people compared with younger age groups. Data from 310 people receiving ECT for depression at three participating hospitals was collected in a naturalistic setting, between 2015 and 2022. MEASUREMENTS: Clinical ratings were conducted pre-ECT and end-acute ECT using the Montgomery-Åsberg Depression Rating Scale (MADRS). Cognitive outcomes were assessed using the Montreal Cognitive Assessment (MoCA). RESULTS: Older old adults demonstrated a significant reduction MADRS scores at post-treatment. They were more likely to meet remission criteria compared with the younger age groups. Older old adults were also less likely to show clinically significant cognitive decline post-ECT, and were more likely to show clinically significant cognitive improvement post-ECT compared with younger age groups. CONCLUSIONS: ECT is highly effective in treating severe psychiatric illness in older old adults. Relative to the younger age groups, the older old group were more likely to remit with ECT and a greater proportion showed cognitive improvement post-ECT. These findings suggest that ECT should be considered as a valuable and safe treatment option for older old individuals with depression.

Electroconvulsive Therapy With Brain Cyst: A Simulation Study.

INTRODUCTION: Electroconvulsive therapy (ECT) is effective in treating severe depression and other neuropsychiatric disorders, but how the presence of an anatomical anomaly affects the electrical pathways between the electrodes remains unclear. We investigate the difference in electric field (E-field) distribution during ECT in the brain of a patient with an arachnoid cyst relative to hypothetical condition where the cyst was not present. METHODS: Magnetic resonance imaging scans of the head of a patient with a large left frontal cyst were segmented to construct a finite element model to study the E-field distribution during ECT. Five electrode configurations were investigated: right unilateral, left unilateral, bifrontal, and bitemporal and left anterior right temporal. The E-field distributions for all montages were compared with a hypothetical condition where brain tissue and electrical conductivity from the right frontal region was mirrored across the longitudinal fissure into the cyst. RESULTS: Differences in mean E-field and 90th percentile E-fields were mainly observed in brain regions closest to the cyst including the left inferior frontal gyrus and left middle frontal gyrus. This trend was most pronounced in montages where the electrodes were closest to the cyst such as left unilateral and bitemporal. CONCLUSION: The presence of a highly conductive cyst close to the ECT electrode tended to attract current into the cyst region, altering current pathways, with potential implications for therapeutic efficacy and safety. Placing electrodes farther away from the cyst is likely to minimize any effects on the E-field distribution and potentially clinical outcomes.

Factors associated with electroconvulsive therapy treatment for adults with serious psychiatric conditions in Australia.

OBJECTIVE: To identify factors associated with receiving electroconvulsive therapy (ECT) for serious psychiatric conditions. METHODS: Retrospective observational study using hospital administrative data linked with death registrations and outpatient mental health data in New South Wales (NSW), Australia. The cohort included patients admitted with a primary psychiatric diagnosis between 2013 and 2022. The outcome measure was receipt of ECT. RESULTS: Of 94,950 patients, 3465 (3.6%) received ECT. The likelihood of receiving ECT was higher in older (hazard ratio [HR] = 1.03), female (HR = 1.24) patients. Compared to depression, patients with schizophrenia/schizoaffective disorder (HR = 0.79), schizophrenia-related disorders (HR = 0.37), mania (HR = 0.64) and other mood disorders (HR = 0.45) had lower odds of receiving ECT. Patients with depression and one other serious psychiatric condition had higher odds of receiving ECT than depression alone. Bipolar disorder likelihood of ECT did not differ from depression. A higher number of mental health outpatient visits in the prior year and an involuntary index admission with depression were also associated with receiving ECT. Likelihood of receiving ECT increased with year of admission (HR = 1.32), private patient status (HR = 2.06), higher socioeconomic status (HR = 1.09) and being married (HR = 1.25). CONCLUSIONS: ECT use for depression and bipolar disorder in NSW aligns with clinical national guidelines. Patients with schizophrenia/schizoaffective, schizophrenia-related disorders, mania and other mood disorders had lower likelihood of ECT than depression, despite ECT being recommended by clinical guidelines for these diagnoses. Variations in ECT were strongly associated with healthcare access, with private patients twice as likely to receive ECT than their public counterparts, suggesting a need to explore ECT accessibility.

Machine Learning in Electroconvulsive Therapy: A Systematic Review.

ABSTRACT: Despite years of research, we are still not able to reliably predict who might benefit from electroconvulsive therapy (ECT) treatment. As we exhaust what is possible using traditional statistical analysis, ECT remains a good candidate for machine learning approaches due to the large data sets with data captured through electroencephalography (EEG) and other objective measures. A systematic review of 6 databases led to the full-text examination of 26 articles using machine learning approaches in examining data predicting response to ECT treatment. The identified articles used a wide variety of data types covering structural and functional imaging data (n = 15), clinical data (n = 5), a combination of clinical and imaging data (n = 2), EEG (n = 3), and social media posts (n = 1). The clinical indications in which response prediction was assessed were depression (n = 21) and psychosis (n = 4). Changes in multiple anatomical regions in the brain were identified as holding a predictive value for response to ECT. These primarily centered on the limbic system and associated networks. Clinical features predicting good response to ECT in depression included shorter duration, lower severity, higher medication dose, psychotic features, low cortisol levels, and positive family history. It has also been possible to predict the likelihood of relapse of readmission with psychosis after ECT treatment, including a better response if higher transfer entropy was calculated from EEG signals. A transdisciplinary approach with an international consortium collecting a wide range of retrospective and prospective data may help to refine and extend these outcomes and translate them into clinical practice.

Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial.

Ketamine has rapid-onset antidepressant activity in patients with treatment-resistant major depression (TRD). The safety and tolerability of racemic ketamine may be improved if given orally, as an extended-release tablet (R-107), compared with other routes of administration. In this phase 2 multicenter clinical trial, male and female adult patients with TRD and Montgomery-Asberg Depression Rating Scale (MADRS) scores ≥20 received open-label R-107 tablets 120 mg per day for 5 days and were assessed on day 8 (enrichment phase). On day 8, responders (MADRS scores ≤12 and reduction ≥50%) were randomized on a 1:1:1:1:1 basis to receive double-blind R-107 doses of 30, 60, 120 or 180 mg, or placebo, twice weekly for a further 12 weeks. Nonresponders on day 8 exited the study. The primary endpoint was least square mean change in MADRS for each active treatment compared with placebo at 13 weeks, starting with the 180 mg dose, using a fixed sequence step-down closed test procedure. Between May 2019 and August 2021, 329 individuals were screened for eligibility, 231 entered the open-label enrichment phase (days 1-8) and 168 responders were randomized to double-blind treatment. The primary objective was met; the least square mean difference of MADRS score for the 180 mg tablet group and placebo was -6.1 (95% confidence interval 1.0 to 11.16, P = 0.019) at 13 weeks. Relapse rates during double-blind treatment showed a dose response from 70.6% for placebo to 42.9% for 180 mg. Tolerability was excellent, with no changes in blood pressure, minimal reports of sedation and minimal dissociation. The most common adverse events were headache, dizziness and anxiety. During the randomized phase of the study, most patient dosing occurred at home. R-107 tablets were effective, safe and well tolerated in a patient population with TRD, enriched for initial response to R-107 tablets. ClinicalTrials.gov registration: ACTRN12618001042235 .

Prolonged intermittent theta burst stimulation targeting the left prefrontal cortex and cerebellum does not affect executive functions in healthy individuals.

Repetitive transcranial magnetic stimulation (rTMS) for alleviating negative symptoms and cognitive dysfunction in schizophrenia commonly targets the left dorsolateral prefrontal cortex (LDLPFC). However, the therapeutic effectiveness of rTMS at this site remains inconclusive and increasingly, studies are focusing on cerebellar rTMS. Recently, prolonged intermittent theta-burst stimulation (iTBS) has emerged as a rapid-acting form of rTMS with promising clinical benefits. This study explored the cognitive and neurophysiological effects of prolonged iTBS administered to the LDLPFC and cerebellum in a healthy cohort. 50 healthy participants took part in a cross-over study and received prolonged (1800 pulses) iTBS targeting the LDLPFC, cerebellar vermis, and sham iTBS. Mixed effects repeated measures models examined cognitive and event-related potentials (ERPs) from 2-back (P300, N200) and Stroop (N200, N450) tasks after stimulation. Exploratory non-parametric cluster-based permutation tests compared ERPs between conditions. There were no significant differences between conditions for behavioural and ERP outcomes on the 2-back and Stroop tasks. Exploratory cluster-based permutation tests of ERPs did not identify any significant differences between conditions. We did not find evidence that a single session of prolonged iTBS administered to either the LDLPFC or cerebellum could cause any cognitive or ERP changes compared to sham in a healthy sample.

Royal Australian and New Zealand College of Psychiatrists professional practice guidelines for the administration of repetitive transcranial magnetic stimulation.

OBJECTIVES: To provide guidance for the optimal administration of repetitive transcranial magnetic stimulation, based on scientific evidence and supplemented by expert clinical consensus. METHODS: Articles and information were sourced from existing guidelines and published literature. The findings were then formulated into consensus-based recommendations and guidance by the authors. The guidelines were subjected to rigorous successive consultation within the RANZCP, involving the Section of ECT and Neurostimulation (SEN) Committee, its broader membership and expert committees. RESULTS: The RANZCP professional practice guidelines (PPG) for the administration of rTMS provide up-to-date advice regarding the use of rTMS in clinical practice. The guidelines are intended for use by psychiatrists and non-psychiatrists engaged in the administration of rTMS to facilitate best practice to optimise outcomes for patients. The guidelines strive to find the appropriate balance between promoting best evidence-based practice and acknowledging that evidence for rTMS use is a continually evolving. CONCLUSION: The guidelines provide up-to-date advice for psychiatrists and non-psychiatrists to promote optimal standards of rTMS practice.

Drug dependence and prescribing ketamine for treatment-resistant depression in Australia and New Zealand.

Ketamine is a restricted and regulated medication in Australia and New Zealand, which has implications when considering treatment for patients with treatment-resistant depression and a history of illicit drug use, abuse or dependence. Regulations governing prescription of ketamine for treatment-resistant depression vary between jurisdictions in Australia and New Zealand, though most restrict use in those with drug dependence. There is substantial variation in definitions of drug dependence used in each jurisdiction, and between the legal and clinical definitions, with the latter specified in the current International Classification of Diseases, Eleventh Revision and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. This paper reviews the literature assessing the risk of ketamine misuse and dependence in patients with a history of illicit drug use, abuse or dependence and presents recommendations for psychiatrists who prescribe ketamine in such patients with treatment-resistant depression.

Individualised Transcranial Magnetic Stimulation Targeting of the Left Dorsolateral Prefrontal Cortex for Enhancing Cognition: A Randomised Controlled Trial.

Repetitive transcranial magnetic stimulation (rTMS) has been demonstrated to produce cognitive enhancing effects across different neuropsychiatric disorders; however, so far, these effects have been limited. This trial investigated the efficacy of using a novel individualised approach to target the left dorsolateral prefrontal cortex (L-DLPFC) for enhancing cognitive flexibility based on performance on a cognitive task. First, forty healthy participants had their single target site at the L-DLPFC determined based on each individual's performance on a random letter generation task. Participants then received, in a cross-over single-blinded experimental design, a single session of intermittent theta burst stimulation (iTBS) to their individualised DLPFC target site, an active control site and sham iTBS. Following each treatment condition, participants completed the Task Switching task and Colour-Word Stroop test. There was no significant main effect of treatment condition on the primary outcome measure of switch reaction times from the Task Switching task [F = 1.16 (2, 21.6), p = 0.33] or for any of the secondary cognitive outcome measures. The current results do not support the use of our novel individualised targeting methodology for enhancing cognitive flexibility in healthy participants. Research into alternative methodological targeting approaches is required to further improve rTMS's cognitive enhancing effects.

Cognitive outcomes from the randomised, active-controlled Ketamine for Adult Depression Study (KADS).

BACKGROUND: Due to its rapid antidepressant effect, ketamine has recently been clinically translated for people with treatment-resistant depression. However, its cognitive profile remains unclear, particularly with repeated and higher doses. In the present study, we report the cognitive results from a recent large multicentre randomised controlled trial, the Ketamine for Adult Depression Study (KADS). METHODS: In this randomised, double-blind, active-controlled, parallel group, multicentre phase 3 trial study we investigated potential cognitive changes following repeated treatment of subcutaneous racemic ketamine compared to an active comparator, midazolam, over 4 weeks, which involved two cohorts; Cohort 1 involved a fixed dose treatment protocol (0.5 mg/kg ketamine), Cohort 2 involved a dose escalation protocol (0.5-0.9 mg/kg) based on mood outcomes. Participants with treatment-resistant Major Depressive Disorder (MDD) were recruited from 7 mood disorder centres and were randomly assigned to receive ketamine (Cohort 1 n = 33; Cohort 2 n = 53) or midazolam (Cohort 1 n = 35; Cohort 2 n = 53) in a 1:1 ratio. Cognitive measurements were assessed at baseline and at the end of randomised treatment. RESULTS: Results showed that in Cohort 1, there were no differences between ketamine and midazolam in cognitive outcomes. For Cohort 2, there was similarly no difference between conditions for cognitive outcomes. LIMITATIONS: The study included two Cohorts with different dosing regimes. CONCLUSIONS: The findings support the cognitive safety of repeated fixed and escalating doses at least in the short-term in people with treatment resistant MDD.

Who are you after psychedelics? A systematic review and a meta-analysis of the magnitude of long-term effects of serotonergic psychedelics on cognition/creativity, emotional processing and personality.

This systematic review and a meta-analysis synthesised the results from contemporary, randomized and non-randomized controlled studies to assess lasting (one week minimum) changes on cognition/creativity, emotional processing and personality from serotonergic psychedelics. PubMed, Embase and PsycInfo were searched in July 2022. Risk of bias was assessed using Rob 2.0 and ROBINS-I. Ten studies met the eligibility criteria which involved 304 participants. No statistically significant effects were found for the majority outcome measures across the three constructs. A meta-analysis of emotional recognition outcomes found an overall significant effect for faster reaction times in the active treatment groups for disgust (SMD=-0.63, 95% CI=[-1.01 to -0.25], I2 = 65%) and sadness (SMD=-0.45, 95% CI=[-0.85 to -0.06], I2 = 60%). Future research should include larger samples, better control conditions, standardized doses and longer follow-up periods to confirm these preliminary findings.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

BACKGROUND: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed. AIMS: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au. METHOD: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4. RESULTS: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. CONCLUSIONS: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.

Efficacy of Repetitive Transcranial Magnetic Stimulation (rTMS) Combined with Psychological Interventions: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

(1) Background: Psychological interventions are effective in alleviating neuropsychiatric symptoms, though results can vary between patients. Repetitive transcranial magnetic stimulation (rTMS) has been proven to improve clinical symptoms and cognition. It remains unclear whether rTMS can augment the efficacy of psychological interventions. (2) Methods: We examined the effects of rTMS combined with psychological interventions on clinical, functional, and cognitive outcomes from randomized controlled trials conducted in healthy and clinical populations. We searched PubMed, EMBASE, Cochrane Library, and PsycINFO databases up to April 2023. (3) Results: Twenty-seven studies were ultimately included. Compared to sham rTMS combined with psychological interventions, active rTMS combined with psychological interventions significantly improved overall clinical symptoms (k = 16, SMD = 0.31, CIs 0.08 to 0.54, p < 0.01). We found that 10 or more sessions of rTMS combined with cognitive behavioural therapy significantly improved clinical outcomes overall (k = 3, SMD = 0.21, CIs 0.05 to 0.36, Z = 2.49, p < 0.01). RTMS combined with cognitive training (CT) significantly improved cognition overall compared to sham rTMS combined with CT (k = 13, SMD = 0.28, CIs 0.15 to 0.42, p < 0.01), with a significant effect on global cognition (k = 11, SMD = 0.45, CIs 0.21 to 0.68, p < 0.01), but not on the other cognitive domains. (4) Conclusion: The current results provide preliminary support for the augmentation effects of active rTMS on clinical and cognitive outcomes across diverse populations. Future clinical trials are required to confirm these augmentation effects for specific psychological interventions in specific clinical populations.

Precision non-implantable neuromodulation therapies: a perspective for the depressed brain

Current first-line treatments for major depressive disorder (MDD) include pharmacotherapy and cognitive-behavioral therapy. However, one-third of depressed patients do not achieve remission after multiple medication trials, and psychotherapy can be costly and time-consuming. Although non-implantable neuromodulation (NIN) techniques such as transcranial magnetic stimulation, transcranial direct current stimulation, electroconvulsive therapy, and magnetic seizure therapy are gaining momentum for treating MDD, the efficacy of non-convulsive techniques is still modest, whereas use of convulsive modalities is limited by their cognitive side effects. In this context, we propose that NIN techniques could benefit from a precision-oriented approach. In this review, we discuss the challenges and opportunities in implementing such a framework, focusing on enhancing NIN effects via a combination of individualized cognitive interventions, using closed-loop approaches, identifying multimodal biomarkers, using computer electric field modeling to guide targeting and quantify dosage, and using machine learning algorithms to integrate data collected at multiple biological levels and identify clinical responders. Though promising, this framework is currently limited, as previous studies have employed small samples and did not sufficiently explore pathophysiological mechanisms associated with NIN response and side effects. Moreover, cost-effectiveness analyses have not been performed. Nevertheless, further advancements in clinical trials of NIN could shift the field toward a more "precision-oriented" practice.

Noninvasive brain stimulation in psychiatric disorders: a primer

Objective: Noninvasive brain stimulation (NIBS) techniques, such as transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), are increasingly being used to treat mental disorders, particularly major depression. The aim of this comprehensive review is to summarize the main advances, limitations, and perspectives of the field. Methods: We searched PubMed and other databases from inception to July 2017 for articles, particularly systematic reviews and meta-analyses, evaluating the use of NIBS in psychiatric disorders. Results: We reviewed the mechanisms of action, safety, tolerability, efficacy, and relevant clinical parameters of NIBS. Repetitive TMS is already an established technique for the treatment of depression, and there is theoretically room for further methodological development towards a high-end therapeutic intervention. In contrast, tDCS is a technically easier method and therefore potentially suitable for wider clinical use. However the evidence of its antidepressant efficacy is less sound, and a recent study found tDCS to be inferior to antidepressant pharmacotherapy. Clinical trials using rTMS for other mental disorders produced mixed findings, whereas tDCS use has not been sufficiently appraised. Conclusion: The most promising results of NIBS have been obtained for depression. These techniques excel in safety and tolerability, although their efficacy still warrants improvement.