Cognitive Effects Following Offline High-Frequency Repetitive Transcranial Magnetic Stimulation (HF-rTMS) in Healthy Populations: A Systematic Review and Meta-Analysis.

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) is a commonly used form of rTMS to treat neuropsychiatric disorders. Emerging evidence suggests that 'offline' HF-rTMS may have cognitive enhancing effects, although the magnitude and moderators of these effects remain unclear. We conducted a systematic review and meta-analysis to clarify the cognitive effects of offline HF-rTMS in healthy individuals. A literature search for randomised controlled trials with cognitive outcomes for pre and post offline HF-rTMS was performed across five databases up until March 2022. This study was registered on the PROSPERO international prospective protocol for systematic reviews (PROSPERO 2020 CRD 42,020,191,269). The Risk of Bias 2 tool was used to assess the risk of bias in randomised trials. Separate analyses examined the cognitive effects of excitatory and inhibitory forms of offline HF-rTMS on accuracy and reaction times across six cognitive domains. Fifty-three studies (N = 1507) met inclusion criteria. Excitatory offline HF-rTMS showed significant small sized effects for improving accuracy (k = 46, g = 0.12) and reaction time (k = 44, g = -0.13) across all cognitive domains collapsed. Excitatory offline HF-rTMS demonstrated a relatively greater effect for executive functioning in accuracy (k = 24, g = 0.14). Reaction times were also improved for the executive function (k = 21, g = -0.11) and motor (k = 3, g = -0.22) domains following excitatory offline HF-rTMS. The current review was restricted to healthy individuals and future research is required to examine cognitive enhancement from offline HF-rTMS in clinical cohorts.

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.

Ensuring the affordable becomes accessible-lessons from ketamine, a new treatment for severe depression.

In this paper, the case study of ketamine as a new treatment for severe depression is used to outline the challenges of repurposing established medicines and we suggest potential solutions. The antidepressant effects of generic racemic ketamine were identified over 20 years ago, but there were insufficient incentives for commercial entities to pursue its registration, or support for non-commercial entities to fill this gap. As a result, the evaluation of generic ketamine was delayed, piecemeal, uncoordinated, and insufficient to gain approval. Meanwhile, substantial commercial investment enabled the widespread registration of a patented, intranasal s-enantiomeric ketamine formulation (Spravato®) for depression. However, Spravato is priced at $600-$900/dose compared to ~$5/dose for generic ketamine, and the ~AUD$100 million annual government investment requested in Australia (to cover drug costs alone) has been rejected twice, leaving this treatment largely inaccessible for Australian patients 2 years after Therapeutic Goods Administration approval. Moreover, emerging evidence indicates that generic racemic ketamine is at least as effective as Spravato, but no comparative trials were required for regulatory approval and have not been conducted. Without action, this story will repeat regularly in the next decade with a new wave of psychedelic-assisted psychotherapy treatments, for which the original off-patent molecules could be available at low-cost and reduce the overall cost of treatment. Several systemic reforms are required to ensure that affordable, effective options become accessible; these include commercial incentives, public and public-private funding schemes, reduced regulatory barriers and more coordinated international public funding schemes to support translational research.

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.

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.

Electroconvulsive Therapy Credentialing for Psychiatrists-Review of Required Standards Across States and Territories in Australia.

ABSTRACT: Electroconvulsive therapy (ECT) is a complex medical procedure, the delivery of which requires specialist knowledge and skills. We reviewed the standards required for ECT credentialing in different jurisdictions in Australia. We reviewed the Chief Psychiatrist guidelines and statewide policy standards on ECT and focused on standards required for initial credentialing and ongoing privileging in ECT. We compared the credentialing requirements within these documents with the standards specified in the Royal Australian and New Zealand College of Psychiatrists professional practice guideline for ECT. Most of the jurisdictions had specific standards for initial credentialing and maintenance of this credentialing; however, there was significant variance in the credentialing process and standards required. It would be useful to have a minimum standard for credentialing for ECT psychiatrists and prescribers. This standard would be relevant for practice of ECT internationally. States and territories would have the responsibility for implementation of these standards. Appropriate training and establishing good clinical governance processes are essential to the provision of high quality ECT.

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.

Transcranial Direct Current Stimulation Modulates Working Memory Maintenance Processes in Healthy Individuals.

The effects of transcranial direct current stimulation (tDCS) at the pFC are often investigated using cognitive paradigms, particularly working memory tasks. However, the neural basis for the neuromodulatory cognitive effects of tDCS, including which subprocesses are affected by stimulation, is not completely understood. We investigated the effects of tDCS on working memory task-related spectral activity during and after tDCS to gain better insights into the neurophysiological changes associated with stimulation. We reanalyzed data from 100 healthy participants grouped by allocation to receive either sham (0 mA, 0.016 mA, and 0.034 mA) or active (1 mA or 2 mA) stimulation during a 3-back task. EEG data were used to analyze event-related spectral power in frequency bands associated with working memory performance. Frontal theta event-related synchronization (ERS) was significantly reduced post-tDCS in the active group. Participants receiving active tDCS had slower RTs following tDCS compared with sham, suggesting interference with practice effects associated with task repetition. Theta ERS was not significantly correlated with RTs or accuracy. tDCS reduced frontal theta ERS poststimulation, suggesting a selective disruption to working memory cognitive control and maintenance processes. These findings suggest that tDCS selectively affects specific subprocesses during working memory, which may explain heterogenous behavioral effects.

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.

Prescribing electroconvulsive therapy for depression: Not as simple as it used to be.

In the last century, prescribing electroconvulsive therapy usually involved considering the relative merits of unilateral versus bilateral electroconvulsive therapy, with most other parameters fixed. However, research over the last 30 years has discovered that several parameters of the electroconvulsive therapy stimulus can have a significant impact on efficacy and cognitive side effects. The stimulus dose relative to seizure threshold was shown to significantly affect efficacy, especially for right unilateral electroconvulsive therapy, where suprathreshold doses in the vicinity of 5-6 times seizure threshold were far more efficacious than doses closer to threshold. However, this did not hold for bitemporal electroconvulsive therapy, where near-threshold stimuli were equally effective as suprathreshold stimuli. Then, changes in stimulus pulse width were found to also have a significant impact on both efficacy and side effects, with ultrabrief pulse widths of 0.3 ms having significantly fewer cognitive side effects in unilateral electroconvulsive therapy than standard brief pulse widths of 1.0 ms, with only slightly reduced efficacy. Therefore, choosing the optimum electroconvulsive therapy prescription for an individual patient now requires consideration of placement, pulse width and stimulus dose relative to seizure threshold, and how these three interact with each other. This viewpoint aims to raise awareness of these issues for psychiatrists involved in electroconvulsive therapy practice.

Impact on Electroconvulsive Therapy Services, Including Patient Relapse and Death, During the COVID-19 Pandemic: Quantitative Results From a Multinational Survey.

OBJECTIVES: Electroconvulsive therapy (ECT) is important in the management of major, life-threatening, and treatment-resistant psychiatric illness. The COVID-19 pandemic has significantly disrupted ECT services. The need for new infection control measures, staff redeployment and shortages, and the perception that ECT is as an "elective" procedure have caused changes to, and reductions in, ECT delivery. The aim of this study was to explore the impact of COVID-19 on ECT services, staff, and patients globally. METHODS: Data were collected using an electronic, mixed-methods, cross-sectional survey. The survey was open from March to November 2021. Clinical directors in ECT services, their delegates, and anesthetists were asked to participate. Quantitative findings are reported. RESULTS: One hundred and twelve participants worldwide completed the survey. The study identified significant impacts on services, staff, and patients. Importantly, most participants (57.8%; n = 63) reported their services made at least 1 change to ECT delivery. More than three-quarters (81.0%; n = 73) reported that their service had identified at least 1 patient who could not access ECT. More than two-thirds (71.4%; n = 67) reported that their service identified patients who experienced a relapse in their psychiatric illness due to lack of ECT access. Six participants (7.6%) reported that their service had identified at least 1 patient who died, by suicide or other means, due to lack of ECT access. CONCLUSIONS: All ECT practices surveyed were impacted by COVID-19 with decreases in capacity, staffing, changes in workflow, and personal protective equipment requirements with relatively little change to ECT technique. Lack of access to ECT resulted in significant morbidity and mortality, including suicide, internationally. This is the first multisite, international survey to explore the impacts of COVID-19 on ECT services, staff, and patients.

A novel approach for targeting the left dorsolateral prefrontal cortex for transcranial magnetic stimulation using a cognitive task.

Repetitive transcranial magnetic stimulation (rTMS) has the potential to be developed as a novel treatment for cognitive dysfunction. However, current methods of targeting rTMS for cognition fail to consider inter-individual functional variability. This study explored the use of a cognitive task to individualise the target site for rTMS administered to the left dorsolateral prefrontal cortex (L-DLPFC). Twenty-five healthy participants were enrolled in a sham-controlled, crossover study. Participants performed a random letter generation task under the following conditions: no stimulation, sham and active 'online' rTMS applied to F3 (International 10-20 System) and four standardised surrounding sites. Across all sites combined, active 'online' rTMS was associated with significantly reduced performance compared to sham rTMS for unique trigrams (p = 0.012), but not for unique digrams (p > 0.05). Using a novel localisation methodology based on performance outcomes from both measures, a single optimal individualised site was identified for 92% [n = 23] of participants. At the individualised site, performance was significantly poorer compared to a common standard site (F3) and both control conditions (ps < 0.01). The current results suggest that this localisation methodology using a cognitive task could be used to individualise the rTMS target site at the L-DLPFC for modulating and potentially enhancing cognitive functioning.

Revisiting the effectiveness of repetitive transcranial magnetic stimulation treatment in depression, again.

Following on from the publication of the Royal Australian and New Zealand Journal of Psychiatry Mood Disorder Clinical Practice Guidelines (2020) and criticisms of how these aberrantly addressed repetitive transcranial magnetic stimulation treatment of depression, questions have continued to be raised in the journal about this treatment by a small group of authors, whose views we contend do not reflect the broad acceptance of this treatment nationally and internationally. In fact, the evidence supporting the use of repetitive transcranial magnetic stimulation treatment in depression is unambiguous and substantial, consisting of an extensive series of clinical trials supported by multiple meta-analyses, network meta-analysis and umbrella reviews. Importantly, the use of repetitive transcranial magnetic stimulation treatment in depression has also been subject to a series of health economic analyses. These indicate that repetitive transcranial magnetic stimulation is a cost-effective therapy and have been used in some jurisdictions, including Australia, in support of public funding. An argument has been made that offering repetitive transcranial magnetic stimulation treatment may delay potentially effective pharmacotherapy. In fact, there is considerably greater danger of the opposite happening. Repetitive transcranial magnetic stimulation is as, if not more effective, than antidepressant medication after two unsuccessful medication trials and should be a consideration for all patients under these circumstances where available. There is no meaningful ongoing debate about the use of repetitive transcranial magnetic stimulation treatment in depression - it is a safe, effective and cost-effective treatment.

A Clinical Case Series of Acute and Maintenance Home Administered Transcranial Direct Current Stimulation in Treatment-Resistant Depression.

OBJECTIVES: Transcranial direct current stimulation (tDCS) is a noninvasive neurostimulation technique being translated clinically for the treatment of depression. There is limited research documenting the longer-term effectiveness and safety of tDCS treatment. This case series is the first report of remotely supervised, home-administered tDCS (HA-tDCS) for depression in a clinical setting. METHODS: We report clinical, cognitive, and safety outcomes from 16 depressed patients who received acute and/or maintenance HA-tDCS. We retrospectively examined clinical data from up to 2.5 years of treatment. Descriptive statistics are reported to document patient outcomes. RESULTS: Twelve patients received acute treatment for a current depressive episode and 4 commenced tDCS maintenance therapy after responding to ECT or repetitive transcranial magnetic stimulation (rTMS). The cohort was highly treatment-resistant wherein 15 of 16 patients failed 3 trials or more of antidepressant medication in the current episode, and 6 patients failed to gain significant benefit from prior ECT or rTMS. Five of 12 patients responded to acute tDCS within 6 weeks, and 9 patients who received tDCS for more than 12 weeks maintained improvements over several months. Cognitive tests showed no evidence of impairments in cognitive outcomes after up to 2 years of treatment. Two patients were withdrawn from treatment because of blurred vision or exacerbation of tinnitus. Transcranial direct current stimulation was otherwise safe and well tolerated. CONCLUSIONS: Transcranial direct current stimulation given for at least 6 weeks may be of clinical benefit even in treatment-resistant depression. Results provide support for long-term effectiveness, safety, and feasibility of remotely supervised HA-tDCS and suggest a role for maintenance tDCS after acute treatment with tDCS, rTMS, or ECT.

The Impact of COVID-19 on Electroconvulsive Therapy: A Multisite, Retrospective Study From the Clinical Alliance and Research in Electroconvulsive Therapy and Related Treatments Network.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has led to reported change in electroconvulsive therapy (ECT) services worldwide. However, minimal data have been published demonstrating tangible changes across multiple ECT centers. This article aimed to examine changes in ECT patients and ECT service delivery during the pandemic. METHODS: We retrospectively assessed data collected on ECT patients within the Clinical Alliance and Research in Electroconvulsive Therapy and Related Treatments (CARE) Network during a 3-month period starting at the first COVID-19 restrictions in 2020 and compared data with predicted values based on the corresponding 3-month period in 2019. Mixed-effects repeated-measures analyses examined differences in the predicted and actual number of acute ECT courses started and the total number of acute ECT treatments given in 2020. Sociodemographic, clinical, treatment factors, and ECT service delivery factors were compared for 2020 and 2019. RESULTS: Four Australian and 1 Singaporean site participated in the study. There were no significant differences between the predicted and actual number of acute ECT courses and total number of acute ECT treatments administered in 2020. During 2020, there were statistically significant increases in the proportion of patients requiring ECT under substitute consent and receiving ECT for urgent reasons compared with 2019. CONCLUSIONS: This multisite empirical study is among the first that supports anecdotal reports of changes in the triaging and delivery of ECT during COVID-19. Results suggest that ECT was prioritized for the most severely ill patients. Further data assessing the impacts of COVID-19 on ECT are needed.

Cognitive function after electroconvulsive therapy for depression: relationship to clinical response.

BACKGROUND: As uncertainty remains about whether clinical response influences cognitive function after electroconvulsive therapy (ECT) for depression, we examined the effect of remission status on cognitive function in depressed patients 4 months after a course of ECT. METHOD: A secondary analysis was undertaken on participants completing a randomised controlled trial of ketamine augmentation of ECT for depression who were categorised by remission status (MADRS ⩽10 v. >10) 4 months after ECT. Cognition was assessed with self-rated memory and neuropsychological tests of anterograde verbal and visual memory, autobiographical memory, verbal fluency and working memory. Patients were assessed through the study, healthy controls on a single occasion, and compared using analysis of variance. RESULTS: At 4-month follow-up, remitted patients (N = 18) had a mean MADRS depression score of 3.8 (95% CI 2.2-5.4) compared with 27.2 (23.0-31.5) in non-remitted patients (N = 19), with no significant baseline differences between the two groups. Patients were impaired on all cognitive measures at baseline. There was no deterioration, with some measures improving, 4-months after ECT, at which time remitted patients had significantly improved self-rated memory, anterograde verbal memory and category verbal fluency compared with those remaining depressed. Self-rated memory correlated with category fluency and autobiographical memory at follow-up. CONCLUSIONS: We found no evidence of persistent impairment of cognition after ECT. Achieving remission improved subjective memory and verbal memory recall, but other aspects of cognitive function were not influenced by remission status. Self-rated memory may be useful to monitor the effects of ECT on longer-term memory.

Intravenous arketamine for treatment-resistant depression: open-label pilot study.

We aimed to analyze the efficacy and safety of arketamine, the R(-)-enantiomer of ketamine, for treatment-resistant depression (TRD) in humans. Open-label pilot trial, seven subjects with TRD received a single intravenous infusion of arketamine (0.5 mg/kg); primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) 24 h after. Mean MADRS dropped from 30.7 before infusion to 10.4 after one day, a mean difference of 20.3 points [CI 95% 13.6-27.0; p < 0.001]; dissociation was nearly absent. Arketamine might produce fast-onset and sustained antidepressant effects in humans with favorable safety profile, like previously reported with animals; further controlled-trials are needed.

Ketamine treatment for depression: A model of care.

OBJECTIVE: Ketamine and related compounds are emerging as rapidly acting therapies for treatment-resistant depression. Ketamine differs from standard antidepressants in its speed of action, specific acute and cumulative side effects, risk of dependence and regulatory requirements. However, there is currently little guidance offering translation from research studies into clinical practice. We therefore detail a comprehensive model of care for ketamine treatment of depression. METHOD: We formulated a set of policies and procedures for a 'compassionate use' ketamine programme that developed out of our clinical research in ketamine. These policies and procedures were formulated into a detailed model of care. RESULTS: The current Australian and New Zealand regulatory frameworks and professional bodies' recommendations regarding ketamine are detailed along with clinical governance and infrastructure considerations. We next describe a four-step model comprising initial assessment, pre-treatment, treatment and post-treatment phases. The model comprises thorough psychiatric and medical assessments examining patient suitability, a rigorous consenting process and structured safety monitoring across an acute treatment course or maintenance therapy. Our ketamine dose-titration method is detailed allowing flexible dosing of patients across a treatment course enabling individualised treatment. CONCLUSION: The model of care aims to bridge the gap between efficacy studies and clinical care outside of research settings as ketamine and related compounds become increasingly important therapies for treatment-resistant depression.

The place of non-invasive brain stimulation in the RANZCP clinical practice guidelines for mood disorders.

Clinical practice guidelines are important documents as they have the capacity to significantly influence and shape clinical practice in important areas of therapeutics. As such, they need to be developed informed by comprehensive and quality-based systematic reviews, involve consensus deliberations representative of the appropriate experts in the field and be subject to thorough critical review. A revised clinical practice guideline for the management of patients with mood disorders was recently published under the auspices of the Royal Australian and New Zealand College of Psychiatrists. However, this clinical practice guideline was not developed in a manner that reflects the appropriate standards that should apply to clinical practice guideline development and it has critical flaws, especially as it pertains to the use of repetitive transcranial magnetic stimulation treatment for patients with depression. The revision of the college clinical practice guideline has explicitly removed clear and unequivocal evidence-based recommendations that were found in a previous version of the clinical practice guideline and replaced these with consensus-based recommendations. However, the consensus-based recommendations were developed without consultation of the appropriate expert body within the college and contradict the scientific literature. There is substantive and unequivocal evidence supporting the antidepressant use of repetitive transcranial magnetic stimulation in the treatment of patients with depression and its use after a patient with depression has failed a limited number (typically around two) of antidepressant medication trials. Readers should refer to the college Professional Practice Guidelines for repetitive transcranial magnetic stimulation published in 2018 for thorough information about the use of this important new treatment.

Medicinal psychedelics for mental health and addiction: Advancing research of an emerging paradigm.

The medical use of psychedelic substances (e.g. psilocybin, ayahuasca, lysergic acid diethylamide and 3,4-methylenedioxymethamphetamine) is attracting renewed interest, driven by a pressing need for research and development of novel therapies for psychiatric disorders, as well as promising results of contemporary studies. In this Viewpoint, we reflect upon the 'Clinical Memorandum on Psychedelics' recently released by the Royal Australian and New Zealand College of Psychiatrists and note subsequent developments including the application for down-scheduling of psilocybin and 3,4-methylenedioxymethamphetamine presently being considered by the Therapeutic Goods Administration and approvals for access via the Special Access Scheme. We suggest that this field is worthy of rigorous research to assess potential benefits, address safety parameters and clarify therapeutic mechanisms. To this end, we outline recent research findings, provide an overview of current knowledge relating to mechanisms of action and discuss salient aspects of the psychedelic-assisted psychotherapy treatment model. The sum of this research points towards medicinal psychedelics as a potential new class of psychiatric treatments when used within a medically supervised framework with integrated psychotherapeutic support. However, before widespread translation into clinical use can occur, appropriately designed and sufficiently powered trials are required to detect both potential positive and negative outcomes. Unique safety and regulatory challenges also need to be addressed. As for any new medical therapy, psychedelic research needs to be conducted in a rigorous manner, through the dispassionate lens of scientific enquiry. Carte blanche availability to practitioners, without specific protocols and appropriate training, would be potentially harmful to individuals and detrimental to the field.