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Recently, low-dose ketamine has been proposed as a rapid-acting treatment option for suicidality. The majority of studies to date have utilised intravenous (IV) ketamine, however, this route of administration has limitations. On the other hand, oral ketamine can be administered in a range of settings, which is important in treating suicidality, although studies as to safety and feasibility are lacking. n = 32 adults (aged 22–72 years; 53% female) with chronic suicidal thoughts participated in the Oral Ketamine Trial on Suicidality (OKTOS), an open-label trial of sub-anaesthetic doses of oral ketamine over 6 weeks. Participants commenced with 0.5 mg/kg of ketamine, which was titrated to a maximum 3.0 mg/kg. Follow-up assessments occurred at 4 weeks after the final dose. The primary outcome measure was the Beck Scale for Suicide Ideation (BSS) and secondary measures included scales for suicidality and depressive symptoms, and measures of functioning and well-being. Mean BSS scores significantly reduced from a high level of suicidal ideation at the pre-ketamine (week 0) timepoint to below the clinical threshold at the post-ketamine (week 6) timepoint. The proportion of participants that achieved clinical improvement within the first 6 weeks was 69%, whereas 50% achieved a significant improvement by the follow-up (week 10) timepoint. Six weeks of oral ketamine treatment in participants with chronic suicidality led to significant reduction in suicidal ideation. The response observed in this study is consistent with IV ketamine trials, suggesting that oral administration is a feasible and tolerable alternative treatment for chronic suicidality.

Neurocognitive impairment is commonly associated with functional disability in established depressive, bipolar and psychotic disorders. However, little is known about the longer-term functional implications of these impairments in early phase transdiagnostic cohorts. We aimed to examine associations between neurocognition and functioning at baseline and over time. We used mixed effects models to investigate associations between neurocognitive test scores and longitudinal social and occupational functioning (“Social and Occupational Functioning Assessment Scale”) at 1–7 timepoints over five-years in 767 individuals accessing youth mental health services. Analyses were adjusted for age, sex, premorbid IQ, and symptom severity. Lower baseline functioning was associated with male sex (coefficient −3.78, 95% CI −5.22 to −2.34 p

Improving our understanding of the causes of functional impairment in young people is a major global challenge. Here, we investigated the relationships between self-reported days out of role and the total quantity and different patterns of self-reported somatic, anxious-depressive, psychotic-like, and hypomanic symptoms in a community-based cohort of young adults. We examined self-ratings of 23 symptoms ranging across the four dimensions and days out of role in >1900 young adult twins and non-twin siblings participating in the “19Up” wave of the Brisbane Longitudinal Twin Study. Adjusted prevalence ratios (APR) and 95% confidence intervals (95% CI) quantified associations between impairment and different symptom patterns. Three individual symptoms showed significant associations with days out of role, with the largest association for impaired concentration. When impairment was assessed according to each symptom dimension, there was a clear stepwise relationship between the total number of somatic symptoms and the likelihood of impairment, while individuals reporting ≥4 anxious-depressive symptoms or five hypomanic symptoms had greater likelihood of reporting days out of role. Furthermore, there was a stepwise relationship between the total number of undifferentiated symptoms and the likelihood of reporting days out of role. There was some suggestion of differences in the magnitude and significance of associations when the cohort was stratified according to sex, but not for age or twin status. Our findings reinforce the development of early intervention mental health frameworks and, if confirmed, support the need to consider interventions for subthreshold and/or undifferentiated syndromes for reducing disability among young people.

Abnormalities in circadian rhythms have been reported in people with mood disorders, but these abnormalities are marked by considerable inter-individual variability. This study aimed to identify pathophysiological subgroups on the basis of circadian markers and evaluate how these subgroups relate to psychiatric profiles. Thirty-five young adults (18–31 years old) receiving clinical care for unipolar depressive disorders and 15 healthy controls took part to this study. The Hamilton Rating Scale for Depression and the Young Mania rating scale were used to evaluate the severity of mood symptoms in participants with depressive disorders. All participant underwent ambulatory sleep monitoring with actigraphy for about 12 days before attending a laboratory-based chronobiological assessment which included repeated salivary samples to determine dim light melatonin onset (DLMO) and continuous core body temperature (CBT) monitoring using an ingestible temperature sensor. Cluster analyses were conducted across all participants to identify subgroups with consistent circadian timing profiles based on DLMO and the nocturnal minima of CBT. Two clusters were identified: ‘delayed’ and ‘conventional timing’ circadian phase. Descriptive analyses showed that the delayed cluster was characterised by abnormal time relationships between circadian phase markers and the sleep–wake cycle. Importantly, individuals from the delayed cluster had worse depression severity (t(28) = −2.7, p = 0.011) and hypomanic symptoms (Z = −2.2, p = 0.041) than their peers with conventional circadian timing. These findings suggest that delayed and disorganised circadian rhythms may be linked to worse psychiatric profiles in young people with depressive disorders.

Cognitive impairment is a functionally disabling feature of depression contributing to maladaptive decision-making, a loss of behavioral control and an increased disease burden. The ability to calculate the causal efficacy of ones actions in achieving specific goals is critical to normal decision-making and, in this study, we combined voxel-based morphometry (VBM), shape analysis and diffusion tensor tractography to investigate the relationship between cortical–basal ganglia structural integrity and such causal awareness in 43 young subjects with depression and 21 demographically similar healthy controls. Volumetric analysis determined a relationship between right pallidal size and sensitivity to the causal status of specific actions. More specifically, shape analysis identified dorsolateral surface vertices where an inward location was correlated with reduced levels of causal awareness. Probabilistic tractography revealed that affected parts of the pallidum were primarily connected with the striatum, dorsal thalamus and hippocampus. VBM did not reveal any whole-brain gray matter regions that correlated with causal awareness. We conclude that volumetric reduction within the indirect pathway involving the right dorsolateral pallidum is associated with reduced awareness of the causal efficacy of goal-directed actions in young depressed individuals. This causal awareness task allows for the identification of a functionally and biologically relevant subgroup to which more targeted cognitive interventions could be applied, potentially enhancing the long-term outcomes for these individuals.

Functional disability is the lead contributor to burden of mental illness. Cognitive deficits frequently limit functional recovery, although whether changes in cognition and disability are longitudinally associated in recent-onset individuals remains unclear. Using a prospective, cohort design, 311 patients were recruited and assessed at baseline. One hundred and sixty-seven patients met eligibility criteria (M=21.5 years old, s.d.=4.8) and returned for follow-up (M=20.6 months later, s.d.=7.8). Two-hundred and thirty participants were included in the final analysis, comprising clinically stable patients with major depression (n=71), bipolar disorder (BD; n=61), schizophrenia-spectrum disorders (n=35) and 63 healthy controls. Neuropsychological functioning and self-rated functional disability were examined using mixed-design, repeated-measures analysis, across diagnoses and cognitive clusters, covarying for relevant confounds. Clinical, neuropsychological and functional changes did not differ between diagnoses (all P>0.05). Three reliable neuropsychological subgroups emerged through cluster analysis, characterized by psychomotor slowing, improved sustained attention, and improved verbal memory. Controlling for diagnosis and changes in residual symptoms, clusters with improved neuropsychological functioning observed greater reductions in functional disability than the psychomotor slowing cluster, which instead demonstrated a worsening in disability (PP

Currently, there are no validated neurobiological methods for distinguishing different pathophysiological pathways in young patients presenting in the early phases of major psychiatric disorders. Hence, treatments are delivered simply on the basis of their possible effects on nonspecific symptom constructs such as depression, cognitive change or psychotic symptoms. In this study, the ratios (relative to creatine) of key metabolites (N-acetyl aspartate, myoinositol, glutamate and glutathione) were measured with proton magnetic resonance spectroscopy ((1)H-MRS) within the anterior cingulate cortex of 88 young persons presenting with major mood or psychotic symptoms. We derived empirically (using a cluster analytical technique) three subgroups of subjects on the basis of their patterns of in vivo brain biochemistry. The three subgroups were distinguished (from each other) by all the four metabolites, in particular, glutathione and glutamate. By contrast, the groups could not be distinguished by differences in terms of other demographic, functional or clinical measures. We propose that this (1)H-MRS-based subclassification system could be used as the basis for much more specific tests of novel intervention strategies (notably, antioxidant and glutamatergic therapies) early in the course of major psychiatric disorders.