The Study of Ketamine for Youth Depression (SKY-D): study protocol for a randomised controlled trial of low-dose ketamine for young people with major depressive disorder.

BACKGROUND: Existing treatments for young people with severe depression have limited effectiveness. The aim of the Study of Ketamine for Youth Depression (SKY-D) trial is to determine whether a 4-week course of low-dose subcutaneous ketamine is an effective adjunct to treatment-as-usual in young people with major depressive disorder (MDD). METHODS: SKY-D is a double-masked, randomised controlled trial funded by the Australian Government's National Health and Medical Research Council (NHMRC). Participants aged between 16 and 25 years (inclusive) with moderate-to-severe MDD will be randomised to receive either low-dose ketamine (intervention) or midazolam (active control) via subcutaneous injection once per week for 4 weeks. The primary outcome is change in depressive symptoms on the Montgomery-Åsberg Depression Rating Scale (MADRS) after 4 weeks of treatment. Further follow-up assessment will occur at 8 and 26 weeks from treatment commencement to determine whether treatment effects are sustained and to investigate safety outcomes. DISCUSSION: Results from this trial will be important in determining whether low-dose subcutaneous ketamine is an effective treatment for young people with moderate-to-severe MDD. This will be the largest randomised trial to investigate the effects of ketamine to treat depression in young people. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ID: ACTRN12619000683134. Registered on May 7, 2019. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377513 .

Isolating the impact of antipsychotic medication on metabolic health: Secondary analysis of a randomized controlled trial of antipsychotic medication versus placebo in antipsychotic medication naïve first-episode psychosis (the STAGES study).

BACKGROUND: Cardiovascular and metabolic diseases are the leading contributors to the early mortality associated with psychotic disorders. To date, it has not been possible to disentangle the effect of medication and non-medication factors on the physical health of people with a first episode of psychosis (FEP). This study aimed to isolate the effects of antipsychotic medication on anthropometric measurements, fasting glucose and lipids. METHODS: This study utilized data from a triple-blind randomized placebo-controlled trial comparing two groups of antipsychotic-naïve young people with a FEP who were randomized to receive a second-generation antipsychotic medication (FEP-medication group) or placebo (FEP-placebo group) for 6 months. Twenty-seven control participants were also recruited. RESULTS: Eighty-one participants commenced the trial; 69.1% completed at least 3 months of the intervention and 33.3% completed the full 6 months. The FEP-placebo group gained a mean of 2.4 kg (±4.9) compared to 1.1 kg (±4.9) in the control participants (t = 0.76, p = .45). After controlling for multiple analyses, there was no difference in blood pressure, waist circumference or heart rate between the FEP-placebo group and controls. After 6 months, the FEP medication group had gained 4.1 kg (±4.5), higher than those receiving placebo but not statistically significant (t = 0.8, p = .44). There were no differences in fasting glucose or lipids between the FEP groups after 3 months. CONCLUSIONS: While limited by small numbers and high attrition, these findings indicate that some of the metabolic complications observed in psychotic disorders could be attributable to factors other than medication. This emphasizes the need to deliver physical health interventions early in the course of FEP.

"You're damned if you do, you're damned if you don't": a qualitative exploration of parent motives for provision of mobile screen devices in early childhood.

BACKGROUND: Exploring parental motives for providing smartphones and tablets to young children is important to better understand ways to optimise healthy use of mobile screens in early childhood. To date, no study has qualitatively examined the factors underpinning parental motives of providing mobile screens to young children, using a theoretically driven approach. METHODS: We conducted 45 in-depth, semi structured online interviews with primary caregivers of toddlers and pre-schoolers from diverse family backgrounds who participated in a large online survey in Australia. Themes were generated from the transcribed interviews using template thematic analysis. The coding was completed deductively using the Theory of Planned Behaviour (TPB) and data-driven induction. RESULTS: Participants consistently reported a spectrum of attitudes, subjective norms and perceived behavioural control aspects which drove their decision to provide or not provide a mobile screen device to their child. Five main descriptive themes were generated, guided by the TPB: (1) Convenience, connection, and non-traditional learning experience; (2) Negative behavioural consequences and potential activity displacement through mobile screens; (3) Influences of society and resources; (4) Managing and achieving a balance; (5) External challenges. CONCLUSIONS: Overall, the findings demonstrated that parents experienced cognitive dissonance between their attitudes and behaviour, primarily from perceived behavioural control and subjective norms negating the influence of attitudes on their motives to provide a device. These insights offer important avenues for public health messaging and resources to better involve and support parents in decision-making relating to mobile screens in everyday lives of young children.

A comparison of experiences of care and expressed emotion among caregivers of young people with first-episode psychosis or borderline personality disorder features.

OBJECTIVE: Caregivers of individuals with severe mental illness often experience significant negative experiences of care, which can be associated with higher levels of expressed emotion. Expressed emotion is potentially a modifiable target early in the course of illness, which might improve outcomes for caregivers and patients. However, expressed emotion and caregiver experiences in the early stages of disorders might be moderated by the type of severe mental illness. The aim was to determine whether experiences of the caregiver role and expressed emotion differ in caregivers of young people with first-episode psychosis versus young people with 'first-presentation' borderline personality disorder features. METHOD: Secondary analysis of baseline (pre-treatment) data from three clinical trials focused on improving caregiver outcomes for young people with first-episode psychosis and young people with borderline personality disorder features was conducted (ACTRN12616000968471, ACTRN12616000304437, ACTRN12618000616279). Caregivers completed self-report measures of experiences of the caregiver role and expressed emotion. Multivariate generalised linear models and moderation analyses were used to determine group differences. RESULTS: Data were available for 265 caregivers. Higher levels of negative experiences and expressed emotion, and stronger correlations between negative experiences and expressed emotion domains, were found in caregivers of young people with borderline personality disorder than first-episode psychosis. Caregiver group (borderline personality disorder, first-episode psychosis) moderated the relationship between expressed emotion and caregiver experiences in the domains of need to provide backup and positive personal experiences. CONCLUSION: Caregivers of young people with borderline personality disorder experience higher levels of negative experiences related to their role and expressed emotion compared with caregivers of young people with first-episode psychosis. The mechanisms underpinning associations between caregiver experiences and expressed emotion differ between these two caregiver groups, indicating that different supports are needed. For borderline personality disorder caregivers, emotional over-involvement is associated with both negative and positive experiences, so a more detailed understanding of the nature of emotional over-involvement for each relationship is required to guide action.

A pilot trial of moderated online social therapy for family and friends of young people with borderline personality disorder features.

AIM: We evaluated the acceptability, usability and safety of Kindred, a novel online intervention for carers of young people with borderline personality disorder (BPD) using a pre-post pilot trial design. The secondary aim explored whether Kindred use was associated with clinical improvements for caregivers on measures of burden of caregiving, stress, expressed emotion, family communication, disability, coping and knowledge of BPD and for patients on measures of severity of BPD symptoms and level of functional impairment. METHODS: The trial site was the Helping Young People Early program for young people with BPD at Orygen in Melbourne, Australia. Informed consent was obtained from 20 adult carers (i.e., relatives or friends) and 10 young people aged 15-25 with BPD. Kindred, which was available for 3 months, incorporated online psychoeducation, carer-to-carer social networking and guidance from expert and peer moderators. Assessments were completed at baseline and 3 months follow-up. Multiple indicators of acceptability, usability and safety were utilized. RESULTS: Seventeen carers were enrolled in Kindred and eight young people completed baseline measures. A priori acceptability, usability and safety criteria were met. Carer burden, stress, expressed emotion, family communication, quality of life, functioning, coping and perceived knowledge of BPD improved at follow-up. Sixty-six percent of the young people (4/6) reported that they believed Kindred had improved their carers' understanding of BPD. CONCLUSION: Kindred was shown to be acceptable, usable and safe, with encouraging improvements in both carer and young person outcomes. Kindred warrants evaluation of its efficacy via an randomized controlled trial.

Cognitive functioning in ultra-high risk for psychosis individuals with and without depression: Secondary analysis of findings from the NEURAPRO randomized clinical trial.

Neurocognitive impairments are well established in both ultra-high risk (UHR) for psychosis and major depressive disorder (MDD). Despite this understanding, investigation of neurocognitive deficits in UHR individuals with MDD and its association with MDD within this population, has been scarce. Hence, this study aimed to examine any differences in neurocognition at baseline between those with MDD at baseline and those with no history of MDD, as well as determine whether neurocognitive variables are significantly associated with meeting criteria for MDD at follow-up, while controlling for relevant clinical variables, within a UHR cohort. Data analysis was conducted on 207 participants whose baseline neurocognition was assessed using Brief Assessment of Cognition for Schizophrenia, as part of a trial of omega-3 fatty acids (NEURAPRO) for UHR individuals. While baseline MDD was the strongest predictor, poorer verbal memory and higher verbal fluency were significantly associated with MDD at 12 months (p = .04 and 0.026, respectively). Further, higher processing speed was significantly associated with MDD at medium-term follow-up (p = .047). These findings outline that neurocognitive skills were independently associated with meeting criteria for MDD at follow-up within UHR individuals, with novel findings of better verbal fluency and processing speed being linked to MDD outcomes. Hence, neurocognitive performance should be considered as a marker of risk for MDD outcomes and a target for management of MDD in UHR.

Depressive psychopathology in first-episode schizophrenia spectrum disorders: a systematic review, meta-analysis and meta-regression.

BACKGROUND: Despite knowing for many decades that depressive psychopathology is common in first-episode schizophrenia spectrum disorders (FES), there is limited knowledge regarding the extent and nature of such psychopathology (degree of comorbidity, caseness, severity) and its demographic, clinical, functional and treatment correlates. This study aimed to determine the pooled prevalence of depressive disorder and caseness, and the pooled mean severity of depressive symptoms, as well as the demographic, illness, functional and treatment correlates of depressive psychopathology in FES. METHODS: This systematic review, meta-analysis and meta-regression was prospectively registered (CRD42018084856) and conducted in accordance with PRISMA and MOOSE guidelines. RESULTS: Forty studies comprising 4041 participants were included. The pooled prevalence of depressive disorder and caseness was 26.0% (seven samples, N = 855, 95% CI 22.1-30.3) and 43.9% (11 samples, N = 1312, 95% CI 30.3-58.4), respectively. The pooled mean percentage of maximum depressive symptom severity was 25.1 (38 samples, N = 3180, 95% CI 21.49-28.68). Correlates of depressive psychopathology were also found. CONCLUSIONS: At least one-quarter of individuals with FES will experience, and therefore require treatment for, a full-threshold depressive disorder. Nearly half will experience levels of depressive symptoms that are severe enough to warrant diagnostic investigation and therefore clinical intervention - regardless of whether they actually fulfil diagnostic criteria for a depressive disorder. Depressive psychopathology is prominent in FES, manifesting not only as superimposed comorbidity, but also as an inextricable symptom domain.

Exploring the use of the Hinting Task in first-episode psychosis.

INTRODUCTION: The aim of the study was to elucidate the association between performance-related neurocognitive abilities and Theory of Mind (ToM) as measured by the Hinting Task (HT) performance and investigate the psychometric properties of the HT for use in First-Episode Psychosis (FEP). METHODS: Cross-sectional data of 132 participants with FEP, aged 15-25 years, enrolled in a randomised controlled trial of vocational intervention, were analysed. A comprehensive cognitive battery including social cognitive and neurocognitive measures, a social and occupational functioning measure and psychopathological measures, were used. Psychometric properties were measured through bivariate correlations and associations with neurocognitive domains were assessed through hierarchical regression. RESULTS: Low convergent validity of the HT with other ToM measures, moderate discriminant validity with an emotion recognition task, low predictive validity with social and occupational functioning, and high internal consistency were revealed. HT performance was significantly associated with verbal reasoning and verbal memory. CONCLUSION: Results provide preliminary evidence of low convergent validity and moderate discriminant validity of the HT in FEP, and the influence of verbal reasoning and verbal memory on HT performance, indicating that caution is warranted when employing the HT as a screening tool in isolation for detection of ToM deficits in FEP.

Longitudinal Cognitive Performance in Individuals at Ultrahigh Risk for Psychosis: A 10-year Follow-up.

It remains unclear whether the onset of psychosis is associated with deterioration in cognitive performance. The aim of this study was to examine the course of cognitive performance in an ultrahigh risk (UHR) cohort, and whether change in cognition is associated with transition to psychosis and change in functioning. Consecutive admissions to Personal Assessment and Crisis Evaluation (PACE) Clinic between May 1994 and July 2000 who had completed a comprehensive cognitive assessment at baseline and follow-up were eligible (N = 80). Follow-up ranged from 7.3 to 13.4 years (M = 10.4 years; SD = 1.5). In the whole sample, significant improvements were observed on the Similarities (P = .03), Information (P < .01), Digit Symbol Coding (P < .01), and Trail Making Test-B (P = .01) tasks, whereas performance on the Rey Auditory Verbal Learning Test (Trials 1-3) declined significantly (P < .01) over the follow-up period. Change in performance on cognitive measures was not significantly associated with transition status. Taking time to transition into account, those who transitioned after 1 year showed significant decline on Digit Symbol Coding, whereas those who did not transition improved on this measure (P = .01; effect size [ES] = 0.85). Small positive correlations were observed between improvements in functioning and improvements in performance on Digit Symbol Coding and Arithmetic (0.24, P = .03 and 0.28, P = .01, respectively). In summary, the onset of psychosis was not associated with deterioration in cognitive ability. However, specific findings suggest that immediate verbal learning and memory, and processing speed may be relevant domains for future risk models and early intervention research in UHR individuals.