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.

Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.

To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.

Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.

Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.

AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

To outline features of the neurologic examination that can be performed virtually through telemedicine platforms (the virtual neurological examination [VNE]), and provide guidance for rapidly pivoting in-person clinical assessments to virtual visits during the COVID-19 pandemic and beyond.

The full neurologic examination is described with attention to components that can be performed virtually.

A screening VNE is outlined that can be performed on a wide variety of patients, along with detailed descriptions of virtual examination maneuvers for specific scenarios (cognitive testing, neuromuscular and movement disorder examinations).

During the COVID-19 pandemic, rapid adoption of virtual medicine will be critical to provide ongoing and timely neurological care. Familiarity and mastery of a VNE will be critical for neurologists, and this article outlines a practical approach to implementation.