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Stress is prevalent in people experiencing suicidality and is a major contributor to the development of mental disorders. Evidence suggests ketamine shows capacity to reverse stress-induced brain changes. Though stress and ketamine have been explored individually for suicidality, this study is the first to examine ketamine treatment for self-reported stress in adults with chronic suicidality, building on pre-clinical evidence of ketamine's capacity to normalize stress-induced responses and contributing to our understanding of oral ketamine in clinical populations.Thirty two adult participants (22-72 years; 17 female) with chronic suicidality completed 6 weeks of active treatment, receiving low (0.5 mg/kg - 3.0 mg/kg) doses of oral ketamine once per week, with a 4-week follow-up phase, to assess the effect of ketamine on their perceived stress. Stress was measured via self-report utilizing the Depression Anxiety Stress Scale-21(DASS-21), and analysed at pre-treatment (week 0), post-treatment (week 6) and at follow-up (week 10).Repeated measures ANOVA showed a significant reduction in stress (p.001) post-treatment and Reliable Change Index calculations confirmed this to be clinically significant. Furthermore, those classified as 'prolonged responders' demonstrated a sustained reduction in stress at follow-up (i.e. after 4 weeks of nil ketamine).Small sample size, open label design, expectancy, secondary analysis CONCLUSIONS: Ketamine showed the capacity to produce a robust and sustained improvement in stress symptoms, in people with chronic suicidality. Future larger, controlled studies examining treatment suitability in a range of stress related disorders are warranted.

Background Neurocognitive impairment is recognised as a risk factor for suicidal behaviour in adults. The current study aims to determine whether neurocognitive deficits also predict ongoing or emergent suicidal behaviour in young people with affective disorders. Methods Participants were aged 12-30 years and presented to early intervention youth mental health clinics between 2008 and 2018. In addition to clinical assessment a standardised neurocognitive assessment was conducted at baseline. Clinical data was extracted from subsequent visits using a standardised proforma. Results Of the 635 participants who met inclusion criteria (mean age 19.6 years, 59% female, average follow up 476 days) 104 (16%) reported suicidal behaviour during care. In 5 of the 10 neurocognitive domains tested (cognitive flexibility, processing speed, working memory, verbal memory and visuospatial memory) those with suicidal behaviour during care were superior to clinical controls. Better general neurocognitive function remained a significant predictor (OR=1.94, 95% CI 1.29- 2.94) of suicidal behaviour in care after controlling for other risk factors. Limitations The neurocognitive battery used was designed for use with affective and psychotic disorders and may not have detected some deficits more specific to suicidal behaviour. Conclusion Contrary to expectations, better neurocognitive functioning predicts suicidal behaviour during care in young people with affective disorders. While other populations with suicidal behaviour, such as adults with affective disorders or young people with psychotic disorders, tend to experience neurocognitive deficits which may limit their capacity to engage in some interventions, this does not appear to be the case for young people with affective disorders.

Background Evidence from family and twin studies suggests that mood and anxiety disorders, and related temperamental factors may share common etiologic factors. We examine the familial aggregation and coaggregation of anxiety disorder subtypes and anxiety-related temperamental traits, and their association with mood disorders. Methods A total of 477 probands and 549 first-degree adult relatives from a large community based family study of affective spectrum disorders completed semi-structured diagnostic interviews and self-reported assessments of temperamental traits including: negative affectivity on the ‘Positive and Negative Affect Schedule’ (PANAS), neuroticism anxiety on the ‘Zuckerman-Kuhlman Personality Questionnaire’ (ZKPQ), and anxiety sensitivity on the ‘Anxiety Sensitivity Index’ (ASI). Results The anxiety-related temperamental traits of negative affectivity, neuroticism anxiety and anxiety sensitivity had significant familial specificity, even after controlling for comorbid mood and anxiety disorders in probands and relatives. Yet, these traits in probands did not predict anxiety disorders in relatives. Although some anxiety subtypes were familial, there were no longer familial links between anxiety disorder subtypes (generalized anxiety disorder, social anxiety or panic disorder) after controlling for mood disorder subtypes in probands and relatives. Limitations Cross-sectional interviews were used to estimate disorders, and self-report measures were used for temperamental traits. Conclusions These results confirm previous research regarding familial overlap between anxiety subtypes and mood disorders, however their shared liability cannot be fully explained by anxiety-related temperamental traits. These findings suggest that anxiety-related temperamental traits may indicate a vulnerability for mood and anxiety disorders or a potential consequence of these conditions.

Background: There is growing evidence to support the need for personalised intervention in the early stages of a major psychiatric illness, as well as the clear delineation of subgroups in psychiatric disorders based on cognitive impairment. Affective disorders are often accompanied by neurocognitive deficits; however a lack of research among young adult inpatients highlights the need to assess the utility of cognitive testing in this population. Methods: A computerised cognitive battery was administered to 50 current inpatient young adults (16–30 years; 75% female) with an affective disorder. Patients also completed a computerised self-report questionnaire (to measure demographics and clinical features) that included items evaluating subjective impressions of their cognition. Results: Hierarchical cluster analysis determined two neurocognitive subgroups: cluster 1 (n = 16) showed more severe impairments in sustained attention and memory as well as higher anxiety levels, compared to their peers in cluster 2 (n = 30) who showed the most impaired attentional switching. Across the sample, poor sustained attention was significantly correlated with higher levels of current anxiety and depressive symptoms, whereas poor verbal memory was significantly associated with increased psychological distress. Limitations: This study has a relatively small sample size (due to it being a pilot/feasibility study). Furthermore, future studies should aim to assess inpatient samples compared to community care samples, as well as healthy controls, on a larger scale. Conclusions: The findings suggest neurocognitive profiles are important in understanding phenotypes within young people with severe affective disorders. With clear subgroups based on cognitive impairment being demonstrated, the clinical utility and use of new and emerging technologies is warranted in such inpatients facilities. This pilot/feasibility study has strengthened the utility of cognitive screening as standard clinical care in an inpatient unit.

Background Sex differences in rates of depression emerge during adolescence. However, it is unclear whether symptom patterns and trajectories differ significantly according to gender in youth. Barriers to research include the fact that most self-report tools are weighted towards psychological rather than somatic symptoms. Methods Data were collected on symptoms of depression in about 1800 individuals at ages 12, 14 and 16 years. Odds ratios and 95% confidence intervals were used to examine the trajectory of psychological and somatic phenotypes and self-reported depression caseness over time. Results At age 12, 24% of participants met criteria for self-reported depression caseness. Although there was only a small incremental increase in the prevalence over time (about 5%), 57% of participants met criteria for self-reported depression caseness at least once. Generic symptoms at age 12 were associated with depression longitudinally, although early transition to caseness was reported in females only. Categorization as a psychological phenotype at age 12 predicted depression at age 14 and/or 16 years, especially in females. The somatic phenotype was more common in males, but showed a weaker association with self-reported depression caseness over time. Limitations Depression was assessed by self-report; only 30% of participants had ratings for age 12, 14 and 16. Conclusions Although sub-threshold psychological and somatic syndromes often co-occur in cases of self-reported depression in adolescence, longitudinally they may represent independent symptom trajectories. However, it is important to remember that self-reported depression is indicative of, but not confirmation of a depressive episode that meets diagnostic criteria.

BACKGROUND: Risky drinking in young people is harmful, highly prevalent and often complicated by comorbid mental health problems that compound alcohol-induced impairment. The hippocampus and the glutamate system have been implicated in the pathophysiology of alcoholism and depression. This study aimed to determine whether risky drinking is associated with glutamate levels recorded within the hippocampus of young adults with major depression. METHODS: Sixty-three young persons with major depression (22.1±3.1 years; 65% female) and 38 healthy controls were recruited. Participants completed the alcohol use disorder identification test and underwent proton magnetic resonance spectroscopy to measure in vivo glutamate levels within the hippocampus following a period of at least 48h of abstinence. RESULTS: Young adults with depression had significantly increased hippocampal glutamate levels and a positive association between the level of alcohol use and glutamate. Regression analysis revealed that higher levels of hippocampal glutamate were predicted by having increased levels of risky drinking and depression. LIMITATIONS: Small sample sizes for testing diagnosis by risky drinking interaction and use of creatine ratios rather than the absolute concentrations of glutamate. DISCUSSION: The hippocampus is a critical region; given its role in learning and memory as well as mood regulation, and the neurochemical changes observed in this study may precede structural changes, which are commonly observed in both depression and alcohol misuse. These findings suggest that young adults with major depression who engage in risky drinking may be at increased risk of glutamate excitotoxicity. Language: en

Major depression is common in older adults and associated with greater health care utilisation and increased risk of poor health outcomes. Oxidative stress may be implicated in the pathophysiology of depression and can be measured via the neurometabolite glutathione using proton magnetic resonance spectroscopy ((1)H-MRS). This study aimed to examine the relationship between glutathione concentration and depressive symptom severity in older adults 'at-risk' of depression. In total, fifty-eight older adults considered 'at-risk' of depression (DEP) and 12 controls underwent (1)H-MRS, medical and neuropsychological assessments. Glutathione was measured in the anterior cingulate cortex (ACC), and calculated as a ratio to creatine. Depressive and anxiety symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS). Compared to controls, DEP patients had increased glutathione/creatine ratios in the ACC (t=2.7, p=0.012). In turn, these increased ratios were associated with greater depressive symptoms (r=0.28, p=0.038), and poorer performance on a verbal learning task (r=-0.28, p=0.040). In conclusion, depressive symptoms in older people are associated with increased glutathione in the ACC. Oxidative stress may be pathophysiologically linked to illness development and may represent an early compensatory response. Further research examining the utility of glutathione as a marker for depressive symptoms and cognitive decline is now required.

Background Recurrent-episode Major Depressive Disorder (MDD) is associated with a number of neuropsychological deficits. To date, less is known about whether these are present in the first-episode. The current aim was to systematically evaluate the literature on first-episode MDD to determine whether cognition may be a feasible target for early identification and intervention. Methods Electronic database searches were conducted to examine neuropsychological studies in adults (mean age greater than 18 years old) with a first-episode of MDD. Effect sizes were pooled by cognitive domain. Using meta-regression techniques, demographic and clinical factors potentially influencing heterogeneity of neuropsychological outcome were also investigated. Results The 15 independent samples reviewed yielded data for 644 patients with a mean age of 39.36 years (SD = 10.21). Significant cognitive deficits were identified (small to medium effect sizes) for psychomotor speed, attention, visual learning and memory, and all aspects of executive functioning. Symptom remission, inpatient status, antidepressant use, age and educational attainment, each significantly contributed to heterogeneity in effect sizes in at least one cognitive domain. Limitations Reviewed studies were limited by small sample sizes and often did not report important demographic and clinical characteristics of patients. Conclusions The current meta-analysis was the first to systematically demonstrate reduced neuropsychological functioning in first-episode MDD. Psychomotor speed and memory functioning were associated with clinical state, whereas attention and executive functioning were more likely trait-markers. Demographic factors were also associated with heterogeneity across studies. Overall, cognitive deficits appear to be feasible early markers and targets for early intervention in MDD.

Background Alcohol misuse is highly prevalent in bipolar disorder (BD) and has been associated with increased formation of reactive oxygen species in the CNS. Proton magnetic resonance spectroscopy ( 1 H-MRS) is an in vivo tissue-based imaging modality that allows the investigation of changes in the brains primary antioxidant, glutathione (GSH), as a result of alcohol use in this population. Methods Thirty-three patients with BD and 17 controls aged 18–30 years were recruited. Participants completed the Alcohol Use Disorders Identification Test (AUDIT) and underwent 1 H-MRS. Levels of GSH in the anterior cingulate cortex (ACC) were determined. ANOVA was conducted to determine differences between high and low risk drinking bipolar participants and controls. Results ANOVA with all groups revealed a significant difference in GSH between bipolar high and low risk drinkers, with those in the high-risk group displaying reduced GSH levels. A significant negative correlation was found between total AUDIT score and GSH in bipolar ( R =−0.478, p =0.005) which remained significant when controlling for age and medication status. Limitations Our participant sample consisted of a heterogeneous group of patients, most of whom were medicated at time of testing. Conclusions Young people with emerging BD who drink at risky levels display reduced levels of ACC-GSH. Increased oxidative stress and its resulting neurotoxic effects may be especially detrimental in an emerging bipolar sample where the illness trajectory is unclear and the brain is still undergoing significant development.

Circadian disturbances may play a key role in the pathogenesis of some forms of mood disorders. Despite marked changes in circadian rhythms during the normal course of adolescence and young adulthood, less is known about changes in the 24-h sleep-wake cycle in young persons with mood disorders.Seventy-five young participants with mood disorders (unipolar: n=46, 20.1 ± 4.7 years old; bipolar I or II: n=29, 23.2 ± 4.3) and 20 healthy participants (24.8 ± 2.5 years old) underwent actigraphy monitoring during a depressive phase over seven consecutive days and nights. Sleep phase delay was defined as mean sleep onset ≥ 1:30 am and/or sleep offset ≥ 1 0:00 am.A delayed sleep phase was found in 62% of participants with bipolar disorders when depressed, compared with 30% of those with unipolar depression (χ(2)=6.0, p=0.014) and 10% of control participants (χ(2)=11.2, p0.001). Sleep offset times were significantly later in subjects with mood disorders compared to the control group, and later in those with bipolar as compared with unipolar disorders (all p ≤ 0.043).This study was cross-sectional and the depressed groups were somewhat younger compared to the healthy controls. Longitudinal studies are required to determine the predictive significance of these findings.Young patients with mood disorders, especially those with bipolar disorders, are particularly likely to have a delayed sleep phase. Therapies focused on advancing sleep phase may be of specific benefit to these young persons.

To facilitate early intervention, there is a need to distinguish unipolar versus bipolar illness trajectories in adolescents and young adults with adult-type mood disorders.Detailed clinical and neuropsychological evaluation of 308 young persons (aged 12 to 30 years) with moderately severe unipolar and bipolar affective disorders.Almost 30% (90/308) of young people (mean age=19.4±4.4yr) presenting for care with affective disorders met criteria for a bipolar-type syndrome (26% with bipolar I). Subjects with bipolar- and unipolar-type syndromes were of similar age (19.8 vs. 19.2yr) and reported comparable ages of onset (14.5 vs. 14.3yr). Clinically, those subjects with unipolar and bipolar-type disorders reported similar levels of psychological distress, depressive symptoms, current role impairment, neuropsychological dysfunction and alcohol or other substance misuse. Subjects with unipolar disorders reported more social anxiety (p0.01). Subjects with bipolar disorders were more likely to report a family history of bipolar (21% vs. 11%; [χ(2)=4.0, p.05]) or psychotic (19% vs. 9%; [χ(2)=5.5, p.05]), or substance misuse (35% vs. 23%; [χ(2)=3.9, p.05]), but not depressive (48% vs. 53%; χ(2)=0.3, p=.582]) disorders.Young subjects with bipolar disorders were best discriminated by a family history of bipolar, psychotic or substance use disorders. Early in the course of illness, clinical features of depression, or neuropsychological function, do not readily differentiate the two illness trajectories.

Depression in older people has been consistently linked with a variety of neurobiological brain changes. One measure of preattentive auditory processing, the mismatch negativity (MMN), has not been previously examined in late-life depression. This study examined MMN elicited by duration deviant stimuli in older people with lifetime depression, and explored its relationship with neuropsychological functioning and disability.Twenty-two older health-seeking patients (mean age=65.2 years) with lifetime major depressive disorder and twelve age and sex-matched control participants (mean age=64.6 years) completed detailed clinical and neuropsychological assessments and the WHO-DAS as a measure of disability. MMN amplitudes were elicited using a two-tone passive auditory oddball paradigm and measured at frontal (Fz), central (Cz) and temporal (left and right mastoid: M1 and M2, respectively) sites.Patients with depression demonstrated reduced mean MMN amplitude at temporal (M1, t=3.1, p0.01; M2, t=3.8, p0.01), but not fronto-central sites. Reduced temporal MMN amplitudes did not relate to depressive symptom severity, but were associated with reduced semantic fluency and greater self-rated functional disability.The contribution of depressive symptom 'state' and medications on MMN need to be considered.Reduced mean amplitudes of mastoid MMN in older patients with lifetime depression may reflect underlying brain changes. This preattentive marker relates to neuropsychological probes of frontotemporal circuits, and importantly, is associated with disability. Longitudinal analysis of MMN in this group will determine its predictive utility as a biomarker for ongoing cognitive decline and illness chronicity.