Anxiety disorders and treatment-resistant major depressive disorder (TRD) are often comorbid. Studies suggest ketamine has anxiolytic and antidepressant properties.

To investigate if subcutaneous racemic ketamine, delivered twice weekly for 4 weeks, reduces anxiety in people with TRD.

The Ketamine for Adult Depression Study was a multisite 4-week randomised, double-blind, active (midazolam)-controlled trial. The study initially used fixed low dose ketamine (0.5 mg/kg, cohort 1), before protocol revision to flexible, response-guided dosing (0.5–0.9 mg/kg, cohort 2). This secondary analysis assessed anxiety using the Hamilton Anxiety (HAM-A) scale (primary measure) and ‘inner tension’ item 3 of the Montgomery–Åsberg Depression Rating Scale (MADRS), at baseline, 4 weeks (end treatment) and 4 weeks after treatment end. Analyses of change in anxiety between ketamine and midazolam groups included all participants who received at least one treatment (n = 174), with a mixed effects repeated measures model used to assess the primary anxiety measure. The trial was registered at www.anzctr.org.au (ACTRN12616001096448).

In cohort 1 (n = 68) the reduction in HAM-A score was not statistically significant: −1.4 (95% CI [−8.6, 3.2], P = 0.37), whereas a significant reduction was seen for cohort 2 (n = 106) of −4.0 (95% CI [−10.6, −1.9], P = 0.0058), favouring ketamine over midazolam. These effects were mediated by total MADRS and were not maintained at 4 weeks after treatment end. MADRS item 3 was also significantly reduced in cohort 2 (P = 0.026) but not cohort 1 (P = 0.96).

Ketamine reduces anxiety in people with TRD when administered subcutaneously in adequate doses.

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.

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.

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.

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.

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.

Public and patient expectations of treatment influence health behaviours and decision-making.

We aimed to understand how the media has portrayed the therapeutic use of ketamine in psychiatry.

We systematically searched electronic databases for print and online news articles about ketamine for psychiatric disorders. The top ten UK, USA, Canadian and Australian newspapers by circulation and any trade and consumer magazines indexed in the databases were searched from 2015 to 2020. Article content was quantitatively coded with a framework encompassing treatment indication, descriptions of prior use, references to research, benefits and harms, treatment access and process, patient and professional testimony, tone and factual basis.

We found 119 articles, peaking in March 2019 when the United States Food and Drug Administration approved esketamine. Ketamine treatment was portrayed in an extremely positive light (n = 82, 68.9%), with significant contributions of positive testimony from key opinion leaders (e.g. clinicians). Positive research results and ketamine's rapid antidepressant effect (n = 87, 73.1%) were frequently emphasised, with little reference to longer-term safety and efficacy. Side-effects were frequently reported (n = 96, 80.7%), predominantly ketamine's acute psychotomimetic effects and the potential for addiction and misuse, and rarely cardiovascular and bladder effects. Not infrequently, key opinion leaders were quoted as being overly optimistic compared with the existing evidence base.

Information pertinent to patient help-seeking and treatment expectations is being communicated through the media and supported by key opinion leaders, although some quotes go well beyond the evidence base. Clinicians should be aware of this and may need to address their patients’ beliefs directly.

This research evaluates the cost-effectiveness of repetitive transcranial magnetic stimulation (rTMS) as add-on therapy to standard care for adults with schizophrenia from an Australian health system perspective.

A Markov model estimated costs in 2021 Australian dollars and Disability-Adjusted Life-Years (DALYs) averted with rTMS added to standard care compared to standard care alone over 12-months for adults aged 25–65 years with hallucinations in schizophrenia refractory to other therapies. rTMS effect size was sourced from a meta-analysis and converted to a relative risk using the Cochrane conversion method. Probabilistic sensitivity analysis evaluated uncertainty in effect size and disability weights. One-way sensitivity analyses varied rTMS session cost and effectiveness, time horizon and inpatient costs.

The base-case average incremental cost-effectiveness ratio (ICER) was $87,310/DALY averted (95% UI: $10,157–$97,877). Reducing rTMS session cost to $100 lowered the ICER to $9,127/DALY (95% UI: Dominant–$50,699). A 4-year time horizon resulted in rTMS being less costly and more effective (Dominant) than standard care. Decreasing the 3-month probability of relapse with rTMS to 4.6% resulted in a 71% probability of rTMS being cost-effective.

Using a threshold of $50,000/ DALY averted, rTMS as add-on therapy to standard care for the treatment of refractory hallucinations in schizophrenia would not be considered a cost-effective treatment option compared to standard care alone. However, given the refractory nature of this condition and the relatively small size of this population, it may be reasonable for decision-makers to adopt a higher ICER threshold.

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.

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.

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.

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.

Electroconvulsive therapy (ECT) is a highly effective treatment for severe psychiatric disorders. Despite its high efficacy, the use of ECT would be greater if the risk of cognitive side effects were reduced. Over the last 20 years, developments in ECT technique, including improvements in the dosing methodology and modification of the stimulus waveform, have allowed for improved treatment methods with reduced adverse cognitive effects. There is increasing evidence that the electrode placement is important for orienting the electrical stimulus and therefore modifying treatment outcomes, with potential for further improvement of the placements currently used in ECT.

We used computational modelling to perform an in-depth examination into regional differences in brain excitation by the ECT stimulus for several lesser known and novel electrode placements, in order to investigate the potential for an electrode placement that may optimise clinical outcomes.

High resolution finite element human head models were generated from MRI scans of three subjects. The models were used to compare regional differences in average electric field (EF) magnitude among a total of thirteen bipolar ECT electrode placements, i.e. three conventional placements as well as ten lesser known and novel placements.

In this exploratory study on a systemic comparison of thirteen ECT electrode placements, the EF magnitude at regions of interest (ROIs) was highly dependent upon the position of both electrodes, especially the ROIs close to the cortical surface. Compared to conventional right-unilateral (RUL) ECT using a temporo-parietal placement, fronto-parietal and supraorbito-parietal RUL also robustly stimulated brain regions considered important for efficacy, while sparing regions related to cognitive functions, and may be a preferrable approach to the currently used placement for RUL ECT. The simulations also found that regional average EF magnitude varied between individual subjects, due to factors such as head size, and results also depended on the size of the defined ROI.

Reduction of the pulse width has been reported to improve ECT outcomes with unilateral ECT (similar efficacy, fewer cognitive side effects), but has been minimally studied for bitemporal ECT. The only study comparing brief and ultrabrief pulse bitemporal ECT found reduced efficacy for bitemporal ultrabrief compared to bitemporal brief pulse stimulation. This randomised controlled trial (RCT) aimed to test if ultrabrief pulse bitemporal ECT results in fewer cognitive side effects than brief pulse bitemporal ECT, when given at doses adjusted with the aim of achieving comparable efficacy.

Thirty-six participants were randomly assigned to receive ultrabrief (at 3 times seizure threshold) or brief (at 1.5 times seizure threshold) pulse bitemporal ECT given 3 times a week in a double-blind, controlled proof-of-concept trial. Blinded raters assessed mood and cognitive functioning over the ECT course.

Efficacy and cognitive outcomes did not differ significantly between the two treatment groups over the ECT course. The ultrabrief pulse group performed better on a test of visual memory assessed acutely after an ECT treatment.

This study suggests there may be a small cognitive advantage in giving bitemporal ECT with an ultrabrief pulse when dosage is increased to match the efficacy of brief pulse bitemporal ECT, but the study was underpowered to fully examine this issue.

Clinical Trials Registration: www.clinicaltrials.gov, NCT00870805.

Transcranial direct current stimulation (tDCS) is a non-pharmacological intervention for depression. It has mixed results, possibly caused by study heterogeneity.

To assess tDCS efficacy and to explore individual response predictors.

Systematic review and individual patient data meta-analysis.

Data were gathered from six randomised sham-controlled trials, enrolling 289 patients. Active tDCS was significantly superior to sham for response (34% v. 19% respectively, odds ratio (OR) = 2.44, 95% CI 1.38–4.32, number needed to treat (NNT) = 7), remission (23.1% v. 12.7% respectively, OR = 2.38, 95% CI 1.22–4.64, NNT = 9) and depression improvement (B coefficient 0.35, 95% CI 0.12–0.57). Mixed-effects models showed that, after adjustment for other predictors and confounders, treatment-resistant depression and higher tDCS ‘doses' were, respectively, negatively and positively associated with tDCS efficacy.

The effect size of tDCS treatment was comparable with those reported for repetitive transcranial magnetic stimulation and antidepressant drug treatment in primary care. The most important parameters for optimisation in future trials are depression refractoriness and tDCS dose.

Preliminary evidence suggests transcranial direct current stimulation (tDCS) has antidepressant efficacy.

To further investigate the efficacy of tDCS in a double-blind, sham-controlled trial (registered at www.clinicaltrials.gov: NCT00763230).

Sixty-four participants with current depression received active or sham anodal tDCS to the left prefrontal cortex (2 mA, 15 sessions over 3 weeks), followed by a 3-week open-label active treatment phase. Mood and neuropsychological effects were assessed.

There was significantly greater improvement in mood after active than after sham treatment (P<0.05), although no difference in responder rates (13% in both groups). Attention and working memory improved after a single session of active but not sham tDCS (P<0.05). There was no decline in neuropsychological functioning after 3–6 weeks of active stimulation. One participant with bipolar disorder became hypomanic after active tDCS.

Findings confirm earlier reports of the antidepressant efficacy and safety of tDCS. Vigilance for mood switching is advised when administering tDCS to individuals with bipolar disorder.

Although genetic epidemiological studies have confirmed increased rates of major depressive disorder among the relatives of people with bipolar affective disorder, no report has compared the clinical characteristics of depression between these two groups.

To compare clinical features of depressive episodes across participants with major depressive disorder and bipolar disorder from within bipolar disorder pedigrees, and assess the utility of a recently proposed probabilistic approach to distinguishing bipolar from unipolar depression. A secondary aim was to identify subgroups within the relatives with major depression potentially indicative of ‘genetic’ and ‘sporadic’ subgroups.

Patients with bipolar disorder types 1 and 2 (n = 246) and patients with major depressive disorder from bipolar pedigrees (n = 120) were assessed using the Diagnostic Interview for Genetic Studies. Logistic regression was used to identify distinguishing clinical features and assess the utility of the probabilistic approach. Hierarchical cluster analysis was used to identify subgroups within the major depressive disorder sample.

Bipolar depression was characterised by significantly higher rates of psychomotor retardation, difficulty thinking, early morning awakening, morning worsening and psychotic features. Depending on the threshold employed, the probabilistic approach yielded a positive predictive value ranging from 74% to 82%. Two clusters within the major depressive disorder sample were found, one of which demonstrated features characteristic of bipolar depression, suggesting a possible ‘genetic’ subgroup.

A number of previously identified clinical differences between unipolar and bipolar depression were confirmed among participants from within bipolar disorder pedigrees. Preliminary validation of the probabilistic approach in differentiating between unipolar and bipolar depression is consistent with dimensional distinctions between the two disorders and offers clinical utility in identifying patients who may warrant further assessment for bipolarity. The major depressive disorder clusters potentially reflect genetic and sporadic subgroups which, if replicated independently, might enable an improved phenotypic definition of underlying bipolarity in genetic analyses.

To determine the efficacy and tolerability of repetitive transcranial magnetic stimulation (rTMS) as a treatment for obsessive compulsive disorder (OCD) in a double-blind placebo-controlled study.

Subjects with treatment-resistant OCD were randomized to rTMS (n=10) or sham rTMS (n=8) for 10 sessions of daily stimulation over the left dorsolateral prefrontal cortex (DLPFC), with subjects and raters being blind to the treatment. Subjects were offered an open extension of up to 20 sessions of rTMS.

The two groups did not differ on change in Yale–Brown Obsessive Compulsive Scale (YBOCS) or Maudsley Obsessive-Compulsive Inventory scores over 10 sessions, with or without correction for depression ratings. Over 20 sessions, there was a significant reduction in total YBOCS scores, but not after controlling for depression. rTMS over 20 sessions was well tolerated.

Two weeks of rTMS over the left DLPFC is ineffective for treatment-resistant OCD.