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.

Condition Monitoring of Railway Bridges Using Vehicle Pitch to Detect Scour.

This study proposes the new condition monitoring concept of using features in the measured rotation, or 'pitch' signal, of a crossing vehicle as an indicator of the presence of foundation scour in a bridge. The concept is explored through two-dimensional vehicle-bridge interaction modelling, with a reduction in stiffness under a pier used to represent the effects of scour. A train consisting of three 10-degree-of-freedom carriages cross the model on a profiled train track, each train varying slightly in terms of mass and velocity. An analysis of the pitch of the train carriages can clearly identify when scour is present. The concept is further tested in a scaled laboratory experiment consisting of a tractor-trailer crossing a four-span simply supported bridge on piers. The foundation support is represented by four springs under each pier, which can be replaced with springs of a reduced stiffness to mimic the effect of scour. The laboratory model also consistently shows a divergence in vehicle pitch between healthy and scoured bridge states.

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.

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.

Obsessive-compulsive disorder (OCD) is associated with increased engagement of frontal brain regions across multiple event-related potentials.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a psychiatric condition leading to significant distress and poor quality of life. Successful treatment of OCD is restricted by the limited knowledge about its pathophysiology. This study aimed to investigate the pathophysiology of OCD using electroencephalographic (EEG) event-related potentials (ERPs), elicited from multiple tasks to characterise disorder-related differences in underlying brain activity across multiple neural processes. METHODS: ERP data were obtained from 25 OCD patients and 27 age- and sex-matched healthy controls (HCs) by recording EEG during flanker and go/nogo tasks. Error-related negativity (ERN) was elicited by the flanker task, while N200 and P300 were generated using the go/nogo task. Primary comparisons of the neural response amplitudes and the topographical distribution of neural activity were conducted using scalp field differences across all time points and electrodes. RESULTS: Compared to HCs, the OCD group showed altered ERP distributions. Contrasting with the previous literature on ERN and N200 topographies in OCD where fronto-central negative voltages were reported, we detected positive voltages. Additionally, the P300 was found to be less negative in the frontal regions. None of these ERP findings were associated with OCD symptom severity. CONCLUSIONS: These results indicate that individuals with OCD show altered frontal neural activity across multiple executive function-related processes, supporting the frontal dysfunction theory of OCD. Furthermore, due to the lack of association between altered ERPs and OCD symptom severity, they may be considered potential candidate endophenotypes for OCD.

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.

The prescription of psychedelic therapies in Australia and New Zealand: A brief survey of psychiatrists.

OBJECTIVE: To explore the knowledge and attitudes of psychiatrists about psychedelics therapies. METHOD: Access to a cross-sectional survey was distributed to psychiatrists through social media channels. Attitudes and knowledge about psychedelic therapies were recorded using Likert scales and ranking questions. RESULTS: Fifty-eight complete responses were collected (44 fully trained +14 trainee RANZCP members). Greater than 85% of respondents agreed there is a shortfall in effective psychiatric treatments, and greater than 65% agreed that psychedelic therapies might address this shortfall. The psychiatrists did not consider themselves knowledgeable about psychedelic therapies, with 60% showing interest in further training on this topic. About 70% of the sample hold various concerns about psychedelic therapies, and more believe that the prescription of psychedelics should be limited to psychiatrists in the future. CONCLUSION: Considering these results in the context of a rapidly changing landscape relating to psychedelic research and regulations, we suggest there is scope to develop up-to-date education about psychedelics for psychiatrists.

Effects of aspirin on the long-term management of depression in older people: a double-blind randomised placebo-controlled trial.

Late-life depression is common and often inadequately managed using existing therapies. Depression is also associated with increased markers of inflammation, suggesting a potential role for anti-inflammatory agents. ASPREE-D is a sub-study of ASPREE, a large multi-centre, population-based, double-blind, placebo-controlled trial of aspirin vs placebo in older Australian and American adults (median follow-up: 4.7 years) of whom 1879 were depressed at baseline. Participants were given 100 mg daily dose of aspirin or placebo. Depressive symptoms were assessed annually using the validated, self-rated short version of the Center for Epidemiological Studies Depression scale. There was a significant increase in depressive scores (0.6; 95% CI 0.2 to 0.9; χ2 (1) = 10.37; p = 0.001) and a decreased score in the mental health component of a quality of life scale (-0.7; 95% CI -1.4 to -0.1; χ2 (1) = 4.74; p = 0.029) in the aspirin group compared to the placebo group. These effects were greater in the first year of follow-up and persisted throughout the study, albeit with small to very small effect sizes. This study failed to demonstrate any benefit of aspirin in the long-term course of depression in this community-dwelling sample of older adults over a 5-year period, and identified an adverse effect of aspirin in the course of depression in those with pre-existing depressive symptoms.

Anomalies in global network connectivity associated with early recovery from alcohol dependence: A network transcranial magnetic stimulation and electroencephalography study.

Although previous research in alcohol dependent populations identified alterations within local structures of the addiction 'reward' circuitry, there is limited research into global features of this network, especially in early recovery. Transcranial magnetic stimulation (TMS) is capable of non-invasively perturbing the brain network while electroencephalography (EEG) measures the network response. The current study is the first to apply a TMS inhibitory paradigm while utilising network science (graph theory) to quantify network anomalies associated with alcohol dependence. Eleven individuals with alcohol-dependence (ALD) in early recovery and 16 healthy controls (HC) were administered 75 single pulses and 75 paired-pulses (inhibitory paradigm) to both the left and right prefrontal cortex (PFC). For each participant, Pearson cross-correlation was applied to the EEG data and correlation matrices constructed. Global network measures (mean degree, clustering coefficient, local efficiency and global efficiency) were extracted for comparison between groups. Following administration of the inhibitory paired-pulse TMS to the left PFC, the ALD group exhibited altered mean degree, clustering coefficient, local efficiency and global efficiency compared to HC. Decreases in local efficiency increased the prediction of being in the ALD group, while all network metrics (following paired-pulse left TMS) were able to adequately discriminate between the groups. In the ALD group, reduced mean degree and global clustering was associated with increased severity of past alcohol use. Our study provides preliminary evidence of altered network topology in patients with alcohol dependence in early recovery. Network anomalies were predictive of high alcohol use and correlated with clinical features of alcohol dependence. Further research using this novel brain mapping technique may identify useful network biomarkers of alcohol dependence and recovery.

The evidence is in: Repetitive transcranial magnetic stimulation is an effective, safe and well-tolerated treatment for patients with major depressive disorder.

Despite more than 25 years of research establishing the antidepressant efficacy of repetitive transcranial magnetic stimulation, there remains uncertainty about the depth and breadth of this evidence base, resulting in confusion as to where repetitive transcranial magnetic stimulation fits in the therapeutic armamentarium in the management of patients with mood disorders. The purpose of this article is to provide a concise description of the evidence base supporting the use of repetitive transcranial magnetic stimulation in the context of the stages of research that typically accompanies the development of evidence for a new therapy. The antidepressant efficacy for the use of repetitive transcranial magnetic stimulation in the treatment of depression has been established through a relatively traditional pathway beginning with small case series, progressing to single-site clinical trials and then to larger multisite randomised double-blind controlled trials. Antidepressant effects have been confirmed in numerous meta-analyses followed more recently by large network meta-analysis and umbrella reviews, with evidence that repetitive transcranial magnetic stimulation may have greater efficacy than alternatives for patients with treatment-resistant depression. Finally, repetitive transcranial magnetic stimulation has been shown to produce meaningful response and remission rates in real-world samples of greater than 5000 patients. The evidence for the antidepressant efficacy of repetitive transcranial magnetic stimulation therapy is overwhelming, and it should be considered a routine part of clinical care wherever available.

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.

Locus coeruleus toggles reciprocal prefrontal firing to reinstate fear.

The medial prefrontal cortex (mPFC) plays an essential role in regulating emotion, including inhibiting fear when danger has passed. The extinction of fear, however, is labile and a number of factors, including stress, cause extinguished fear to relapse. Here we show that fear relapse in rats limits single-unit activity among infralimbic (IL) neurons, which are critical for inhibiting fear responses, and facilitates activity in prelimbic (PL) neurons involved in fear expression. Pharmacogenetic activation of noradrenergic neurons in the locus coeruleus mimics this shift in reciprocal IL-PL spike firing, increases the expression of conditioned freezing behavior, and causes relapse of extinguished fear. Noradrenergic modulation of mPFC firing represents a mechanism for relapse and a potential target for therapeutic interventions to reduce pathological fear.

Is There a Novel Biosynthetic Pathway in Mice That Converts Alcohol to Dopamine, Norepinephrine and Epinephrine?

Previous studies in animals and humans have shown multiple types of interaction between alcohol (ethanol) intake and the catecholamine signaling molecules: dopamine, norepinephrine and epinephrine. This literature suggests that the administration of alcohol to rodents affects the central and peripheral (blood plasma) levels of these catecholamines. Two prior publications (Fitzgerald 2012, 2020) put forth the hypothesis that there may be a currently unidentified biosynthetic pathway, in a range of organisms, that actually converts alcohol to dopamine, norepinephrine and epinephrine. This publication describes the details for how to test this hypothesis in mice. Mice can be systemically injected with an intoxicating dose of commercially available stable isotope-labeled ethanol (ethanol-1-13C), and blood plasma samples and brains can be collected approximately two to 24 h post-injection. Liquid chromatography-mass spectrometry analysis can then be used to test whether some of the labeled ethanol molecules have been incorporated into new dopamine, norepinephrine, and epinephrine molecules, in plasma and brain samples. If confirmed, this hypothesis may have broadly reaching implications both for basic neuroscience and our understanding of alcohol abuse and alcoholism.

Personalized connectivity-guided DLPFC-TMS for depression: Advancing computational feasibility, precision and reproducibility.

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) is an established treatment for refractory depression, however, therapeutic outcomes vary. Mounting evidence suggests that clinical response relates to functional connectivity with the subgenual cingulate cortex (SGC) at the precise DLPFC stimulation site. Critically, SGC-related network architecture shows considerable interindividual variation across the spatial extent of the DLPFC, indicating that connectivity-based target personalization could potentially be necessary to improve treatment outcomes. However, to date accurate personalization has not appeared feasible, with recent work indicating that the intraindividual reproducibility of optimal targets is limited to 3.5 cm. Here we developed reliable and accurate methodologies to compute individualized connectivity-guided stimulation targets. In resting-state functional MRI scans acquired across 1,000 healthy adults, we demonstrate that, using this approach, personalized targets can be reliably and robustly pinpointed, with a median accuracy of ~2 mm between scans repeated across separate days. These targets remained highly stable, even after 1 year, with a median intraindividual distance between coordinates of only 2.7 mm. Interindividual spatial variation in personalized targets exceeded intraindividual variation by a factor of up to 6.85, suggesting that personalized targets did not trivially converge to a group-average site. Moreover, personalized targets were heritable, suggesting that connectivity-guided rTMS personalization is stable over time and under genetic control. This computational framework provides capacity for personalized connectivity-guided TMS targets to be robustly computed with high precision and has the flexibly to advance research in other basic research and clinical applications.

Deletion of beaded filament proteins or the C-terminal end of Aquaporin 0 causes analogous abnormal distortion aberrations in mouse lens.

Lens-specific beaded filament (BF) proteins CP49 and filensin interact with the C-terminus of the water channel protein Aquaporin 0 (AQP0). Previously we have reported that a C-terminally end-deleted AQP0-expressing transgenic mouse model AQP0ΔC/ΔC developed abnormal optical aberrations in the lens. This investigation was undertaken to find out whether the total loss of the BF structural proteins alter the optical properties of the lens and cause optical aberrations similar to those in AQP0ΔC/ΔC lenses; also, to map the changes in the optical quality as a function of age in the single or double BF protein knockouts as well as to assess whether there is any significant change in the water channel function of AQP0 in these knockouts. A double knockout mouse (2xKO) model for CP49 and filensin was developed by crossing CP49-KO and filensin-KO mice. Wild type, CP49-KO, filensin-KO, and 2xKO lenses at different ages, and AQP0ΔC/ΔC lenses at postnatal day-17 were imaged through the optical axis and compared for optical quality and focusing property. All three knockout models showed loss of transparency, and development of abnormal optical distortion aberration similar to that in AQP0ΔC/ΔC. Copper grid focusing by the lenses at 6, 9 and 12 months of age showed an increase in aberrations as age advanced. With progression in age, the grid images produced by the lenses of all KO models showed a transition from a positive barrel distortion aberration to a pincushion distortion aberration with the formation of three distinct aberration zones similar to those produced by AQP0ΔC/ΔC lenses. Water permeability of fiber cell membrane vesicles prepared from CP49-KO, filensin-KO and 2xKO models, measured using the osmotic shrinking method, remained similar to that of the wild type without any statistically significant alteration (P > 0.05). Western blotting and quantification revealed the expression of comparable quantities of AQP0 in all three BF protein KOs. Our study reveals that loss of single or both beaded filament proteins significantly affect lens refractive index gradient, transparency and focusing ability in an age-dependent manner and the interaction of BF proteins with AQP0 is critical for the proper functioning of the lens. The presence of BF proteins is necessary to prevent abnormal optical aberrations and maintain homeostasis in the aging lens.

Sex- and stress-dependent effects of a single injection of ketamine on open field and forced swim behavior.

Ketamine has emerged as a novel treatment for common psychiatric conditions such as Major Depressive Disorder (MDD) and anxiety disorders, many of which can be initiated and exacerbated by psychological stress. Sex differences in the frequency of both anxiety and depressive disorders are well known and could be due to sex differences in neuroendocrine responses to stress. Ketamine is known to modulate the hormonal response to stress, specifically corticosterone. It is not clear if the acute effect of ketamine on corticosterone differs by sex, or what role this could play in subsequent behavior. Here we test whether a single injection of (R,S)-ketamine (30 mg/kg, i.p.), administered either with or without unpredictable chronic stress (UCS), has different sustained effects on open field test (OFT), elevated zero maze (EZM) or forced swim test (FST) behavior in female versus male C57BL/6J mice. In the OFT (24 h post-injection), ketamine increased center square exploration in males but not females. In contrast, in the FST (72 h post-injection), females showed a trend toward a decrease in immobility after ketamine whereas males were not strongly modulated. These behavioral effects of ketamine were stronger in the presence of UCS than in unstressed animals. UCS animals also showed lower corticosterone after injection than unstressed animals, and in the presence of UCS ketamine increased corticosterone; these effects were similar in both sexes. Corticosterone post-injection did not predict subsequent behavior. These findings complement a growing preclinical literature suggesting both stress-dependency and sex differences in OFT and FST behavioral responses to ketamine.LAY SUMMARYIn humans, it is known that major depression and anxiety disorders, which can be caused or made worse by exposure to psychological stress, occur roughly twice as frequently in women than in men, but the underpinnings of these effects are not well characterized. In the current study, we explored how sex interacts with stress and ketamine (a rapidly acting antidepressant) by assessing both open field and forced swim behavior in mice after chronic mild stress. We report the novel finding that male mice exhibit greater exploration of the aversive center square in the open field after ketamine, whereas females trended toward lower immobility (often interpreted as an antidepressant-like effect) in the forced swim test after this drug, and these effects were amplified by prior stress exposure.

A pilot study of magnetic seizure therapy for treatment-resistant obsessive-compulsive disorder.

BACKGROUND: There is growing interest in the potential of neuromodulation options in treatment-resistant obsessive-compulsive disorder (OCD). Magnetic seizure therapy (MST), is a new treatment intervention in which generalized seizures are induced with transcranial magnetic stimulation. We conducted a pilot study to assess the efficacy and cognitive effects of MST in patients with treatment-resistant OCD. METHODS: In an open-label pilot study, participants with treatment-resistant OCD and a baseline Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores of ≥16 were treated with up to 24 acute treatments. The primary clinical outcomes were clinical response (Y-BOCS score reduction ≥30%) and remission (final Y-BOCS score ≤8). A neurocognitive battery, the Quick Inventory for Depressive Symptoms-Self Report (QIDS-SR), the Beck Scale for Suicidal Ideation (SSI), and the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) were also completed as secondary measures. RESULTS: Ten participants with OCD who had not responded to medications or psychotherapy enrolled in the study and seven completed an adequate trial (defined as ≥8 treatments). MST was associated with minimal cognitive effects except for some decrease in autobiographical memory and no serious adverse effects. Only one participant met the predefined criteria for response, and none for remission. The baseline and endpoint Y-BOCS scores were not statistically different. CONCLUSION: Overall, MST was not beneficial in a small group of patients with treatment-resistant OCD. At this time, other studies of MST for OCD are not warranted until different coil placements targeting other brain circuits can be proposed.

Stiffness-Dependent Intracellular Location of Cylindrical Polymer Brushes.

Cylindrical polymer brushes (CPBs) are macromolecules with nanoparticle proportions. Their modular synthesis enables tailoring of their chemical composition as well as the dialing-up of overall dimensions and physicochemical properties. In this study, two rod-like poly[(ethylene glycol) methyl ether methacrylate] (PEGMA)-based CPBs with varying stiffness but otherwise comparable features and functionality, are synthesized. Differences in particle stiffness are assessed using small angle neutron scattering (SANS). It is observed that the fate of the two CPBs within cells is distinctly different. Stiffer CPBs seem to gravitate toward the mitochondria, whereas CPBs with reduced stiffness are present in different intracellular vesicles.

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.

Many Drugs of Abuse May Be Acutely Transformed to Dopamine, Norepinephrine and Epinephrine In Vivo.

It is well established that a wide range of drugs of abuse acutely boost the signaling of the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis, where norepinephrine and epinephrine are major output molecules. This stimulatory effect is accompanied by such symptoms as elevated heart rate and blood pressure, more rapid breathing, increased body temperature and sweating, and pupillary dilation, as well as the intoxicating or euphoric subjective properties of the drug. While many drugs of abuse are thought to achieve their intoxicating effects by modulating the monoaminergic neurotransmitter systems (i.e., serotonin, norepinephrine, dopamine) by binding to these receptors or otherwise affecting their synaptic signaling, this paper puts forth the hypothesis that many of these drugs are actually acutely converted to catecholamines (dopamine, norepinephrine, epinephrine) in vivo, in addition to transformation to their known metabolites. In this manner, a range of stimulants, opioids, and psychedelics (as well as alcohol) may partially achieve their intoxicating properties, as well as side effects, due to this putative transformation to catecholamines. If this hypothesis is correct, it would alter our understanding of the basic biosynthetic pathways for generating these important signaling molecules, while also modifying our view of the neural substrates underlying substance abuse and dependence, including psychological stress-induced relapse. Importantly, there is a direct way to test the overarching hypothesis: administer (either centrally or peripherally) stable isotope versions of these drugs to model organisms such as rodents (or even to humans) and then use liquid chromatography-mass spectrometry to determine if the labeled drug is converted to labeled catecholamines in brain, blood plasma, or urine samples.