Psychiatry - Research Publications

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http://hdl.handle.net/11343/232

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Does Post-traumatic Stress Disorder Impact Treatment Outcomes within a Randomised Controlled Trial of Mitochondrial Agents for Bipolar Depression?

Russell, SE ; Wrobel, AL ; Ashton, MM ; Turner, A ; Mohebbi, M ; Berk, M ; Cotton, S ; Dodd, S ; Ng, CH ; Malhi, GS ; Dean, OM (KOREAN COLL NEUROPSYCHOPHARMACOLOGY, 2023-08)

OBJECTIVE: Bipolar disorder often co-occurs with post-traumatic stress disorder, yet few studies have investigated the impact of post-traumatic stress disorder in bipolar disorder on treatment outcomes. The aim of this sub-analysis was to explore symptoms and functioning outcomes between those with bipolar disorder alone and those with comorbid bipolar disorder and post-traumatic stress disorder. METHODS: Participants (n = 148) with bipolar depression were randomised to: (i) N-acetylcysteine alone; (ii) a combination of nutraceuticals; (iii) or placebo (in addition to treatment as usual) for 16 weeks (＋4 weeks discontinuation). Differences between bipolar disorder and comorbid bipolar disorder and post-traumatic stress disorder on symptoms and functioning at five timepoints, as well as on the rate of change from baseline to week 16 and baseline to week 20, were examined. RESULTS: There were no baseline differences between bipolar disorder alone and comorbid bipolar disorder and post-traumatic stress disorder apart from the bipolar disorder alone group being significantly more likely to be married (p = 0.01). There were also no significant differences between bipolar disorder alone and comorbid bipolar disorder and post-traumatic stress disorder on symptoms and functioning. CONCLUSION: There were no differences in clinical outcomes over time within the context of an adjunctive randomised controlled trial between those with bipolar disorder alone compared to those with comorbid bipolar disorder and post-traumatic stress disorder. However, differences in psychosocial factors may provide targets for areas of specific support for people with comorbid bipolar disorder and post-traumatic stress disorder.
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

Schwartz, OS ; Amminger, P ; Baune, BT ; Bedi, G ; Berk, M ; Cotton, SM ; Daglas-Georgiou, R ; Glozier, N ; Harrison, B ; Hermens, DF ; Jennings, E ; Lagopoulos, J ; Loo, C ; Mallawaarachchi, S ; Martin, D ; Phelan, B ; Read, N ; Rodgers, A ; Schmaal, L ; Somogyi, AA ; Thurston, L ; Weller, A ; Davey, CG (BMC, 2023-10-24)

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 .
Predictors of suicidal ideation severity among treatment-seeking young people with major depressive disorder: The role of state and trait anxiety

Moller, C ; Badcock, PB ; Hetrick, SE ; Rice, S ; Berk, M ; Witt, K ; Chanen, AM ; Dean, OM ; Gao, C ; Cotton, SM ; Davey, CG (SAGE PUBLICATIONS LTD, 2023-08)

OBJECTIVE: Depression and suicidal ideation are closely intertwined. Yet, among young people with depression, the specific factors that contribute to changes in suicidal ideation over time are uncertain. Factors other than depressive symptom severity, such as comorbid psychopathology and personality traits, might be important contributors. Our aim was to identify contributors to fluctuations in suicidal ideation severity over a 12-week period in young people with major depressive disorder receiving cognitive behavioural therapy. METHODS: Data were drawn from two 12-week randomised, placebo-controlled treatment trials. Participants (N = 283) were 15-25 years old, with moderate to severe major depressive disorder. The primary outcome measure was the Suicidal Ideation Questionnaire, administered at baseline and weeks 4, 8 and 12. A series of linear mixed models was conducted to examine the relationship between Suicidal Ideation Questionnaire score and demographic characteristics, comorbid psychopathology, personality traits and alcohol use. RESULTS: Depression and anxiety symptom severity, and trait anxiety, independently predicted higher suicidal ideation, after adjusting for the effects of time, demographics, affective instability, non-suicidal self-injury and alcohol use. CONCLUSIONS: Both state and trait anxiety are important longitudinal correlates of suicidal ideation in depressed young people receiving cognitive behavioural therapy, independent of depression severity. Reducing acute psychological distress, through reducing depression and anxiety symptom severity, is important, but interventions aimed at treating trait anxiety could also potentially be an effective intervention approach for suicidal ideation in young people with depression.
Fair funding for mental health research

Yung, AR ; Milicevic, M ; Berk, M (SAGE PUBLICATIONS LTD, 2023-08)
Metformin is Protective Against the Development of Mood Disorders

Lake, J ; Bortolasci, CC ; Stuart, AL ; Pasco, JA ; Kidnapillai, S ; Spolding, B ; Truong, TTT ; Panizzutti, B ; Liu, ZSJ ; Dean, OM ; Crowley, T ; Richardson, M ; Kim, JH ; Berk, M ; Williams, LJ ; Walder, K (GEORG THIEME VERLAG KG, 2023-01)

INTRODUCTION: Mood disorders are a major cause of disability, and current treatment options are inadequate for reducing the burden on a global scale. The aim of this project was to identify drugs suitable for repurposing to treat mood disorders. METHODS: This mixed-method study utilized gene expression signature technology and pharmacoepidemiology to investigate drugs that may be suitable for repurposing to treat mood disorders. RESULTS: The transcriptional effects of a combination of drugs commonly used to treat mood disorders included regulation of the steroid and terpenoid backbone biosynthesis pathways, suggesting a mechanism involving cholesterol biosynthesis, and effects on the thyroid hormone signaling pathway. Connectivity Map analysis highlighted metformin, an FDA-approved treatment for type 2 diabetes, as a drug having global transcriptional effects similar to the mood disorder drug combination investigated. In a retrospective cohort study, we found evidence that metformin is protective against the onset of mood disorders. DISCUSSION: These results provide proof-of-principle of combining gene expression signature technology with pharmacoepidemiology to identify potential novel drugs for treating mood disorders. Importantly, metformin may have utility in the treatment of mood disorders, warranting future randomized controlled trials to test its efficacy.
Regional, circuit and network heterogeneity of brain abnormalities in psychiatric disorders

Segal, A ; Parkes, L ; Aquino, K ; Kia, SM ; Wolfers, T ; Franke, B ; Hoogman, M ; Beckmann, CF ; Westlye, LT ; Andreassen, OA ; Zalesky, A ; Harrison, BJ ; Davey, CG ; Soriano-Mas, C ; Cardoner, N ; Tiego, J ; Yucel, M ; Braganza, L ; Suo, C ; Berk, M ; Cotton, S ; Bellgrove, MA ; Marquand, AF ; Fornito, A (NATURE PORTFOLIO, 2023-09)

The substantial individual heterogeneity that characterizes people with mental illness is often ignored by classical case-control research, which relies on group mean comparisons. Here we present a comprehensive, multiscale characterization of the heterogeneity of gray matter volume (GMV) differences in 1,294 cases diagnosed with one of six conditions (attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, depression, obsessive-compulsive disorder and schizophrenia) and 1,465 matched controls. Normative models indicated that person-specific deviations from population expectations for regional GMV were highly heterogeneous, affecting the same area in <7% of people with the same diagnosis. However, these deviations were embedded within common functional circuits and networks in up to 56% of cases. The salience-ventral attention system was implicated transdiagnostically, with other systems selectively involved in depression, bipolar disorder, schizophrenia and attention-deficit/hyperactivity disorder. Phenotypic differences between cases assigned the same diagnosis may thus arise from the heterogeneous localization of specific regional deviations, whereas phenotypic similarities may be attributable to the dysfunction of common functional circuits and networks.
Effects of risperidone/paliperidone versus placebo on cognitive functioning over the first 6 months of treatment for psychotic disorder: secondary analysis of a triple-blind randomised clinical trial

Allott, K ; Yuen, HP ; Baldwin, L ; O'Donoghue, B ; Fornito, A ; Chopra, S ; Nelson, B ; Graham, J ; Kerr, MJJ ; Proffitt, T-M ; Ratheesh, A ; Alvarez-Jimenez, M ; Harrigan, S ; Brown, E ; Thompson, ADD ; Pantelis, C ; Berk, M ; McGorry, PDD ; Francey, SMM ; Wood, SJJ (SPRINGERNATURE, 2023-06-10)

The drivers of cognitive change following first-episode psychosis remain poorly understood. Evidence regarding the role of antipsychotic medication is primarily based on naturalistic studies or clinical trials without a placebo arm, making it difficult to disentangle illness from medication effects. A secondary analysis of a randomised, triple-blind, placebo-controlled trial, where antipsychotic-naive patients with first-episode psychotic disorder were allocated to receive risperidone/paliperidone or matched placebo plus intensive psychosocial therapy for 6 months was conducted. A healthy control group was also recruited. A cognitive battery was administered at baseline and 6 months. Intention-to-treat analysis involved 76 patients (antipsychotic medication group: 37; 18.6Mage [2.9] years; 21 women; placebo group: 39; 18.3Mage [2.7]; 22 women); and 42 healthy controls (19.2Mage [3.0] years; 28 women). Cognitive performance predominantly remained stable (working memory, verbal fluency) or improved (attention, processing speed, cognitive control), with no group-by-time interaction evident. However, a significant group-by-time interaction was observed for immediate recall (p = 0.023), verbal learning (p = 0.024) and delayed recall (p = 0.005). The medication group declined whereas the placebo group improved on each measure (immediate recall: p = 0.024; ηp2 = 0.062; verbal learning: p = 0.015; ηp2 = 0.072 both medium effects; delayed recall: p = 0.001; ηp2 = 0.123 large effect). The rate of change for the placebo and healthy control groups was similar. Per protocol analysis (placebo n = 16, medication n = 11) produced similar findings. Risperidone/paliperidone may worsen verbal learning and memory in the early months of psychosis treatment. Replication of this finding and examination of various antipsychotic agents are needed in confirmatory trials. Antipsychotic effects should be considered in longitudinal studies of cognition in psychosis.Trial registration: Australian New Zealand Clinical Trials Registry ( http://www.anzctr.org.au/ ; ACTRN12607000608460).
Distress, burden, and wellbeing in siblings of people with mental illness: a mixed studies systematic review and meta-analysis.

Jayasinghe, A ; Wrobel, A ; Filia, K ; Byrne, LK ; Melvin, G ; Murrihy, S ; Moller, C ; Berk, L ; Berk, M ; Cotton, S (Cambridge University Press (CUP), 2023-07-25)

BACKGROUND: Family members of people with mental illness (MI) may experience a host of psychological adversities such as increased stress, burden, and reduced wellbeing. However, relatively little is known about siblings. This study aimed to characterise the experience of distress (viz. depressive and anxiety symptoms), burden, and wellbeing in siblings of people with MI. METHODS: Studies reporting on quantitative measures of depression, anxiety, burden, or wellbeing in siblings; and/or qualitative findings on siblings' experience were eligible. The literature search was conducted up until 20th October 2022. RESULTS: Sixty-two studies comprising data from 3744 siblings were included. The pooled mean percentage of depressive symptoms fell in the mild range at 15.71 (k = 28, N = 2187, 95% CI 12.99-18.43) and anxiety symptoms fell in the minimal range at 22.45 (k = 16, N = 1122, 95% CI 17.09-27.80). Moderator analyses indicate that siblings of people with a schizophrenia spectrum disorder experience greater depressive symptoms than siblings of people with other types of MI (β = -16.38, p < 0.001). Qualitative findings suggest that individuals may be particularly vulnerable during their siblings' illness onset and times of relapse. Limited communication, confusion about MI, and the need to compensate may contribute to siblings' distress and/or burden. Siblings' experience of wellbeing and caregiving were closely related. CONCLUSION: This review highlights the complex psychological experience of siblings and the need for greater research and clinical support for this important yet often overlooked cohort.
The Addition of Fish Oil to Cognitive Behavioral Case Management for Youth Depression: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial.

Amminger, GP ; Rice, S ; Davey, CG ; Quinn, AL ; Hermens, DF ; Zmicerevska, N ; Nichles, A ; Hickie, I ; Incerti, L ; Weller, A ; Joseph, S ; Hilton, Z ; Pugh, C ; Rayner, M ; Reid, N ; Ratheesh, A ; Yung, AR ; Yuen, HP ; Mackinnon, A ; Hetrick, S ; Parker, A ; Street, R ; Berger, M ; Berk, M ; McGorry, PD ; Lin, A (Elsevier BV, 2023-06-22)

BACKGROUND: Clinical trials suggest that long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) (fish oil) may reduce depressive symptoms in adults with major depressive disorder. Therefore, n-3 PUFAs may be a potential treatment for depression in youth. METHODS: Participants were 15- to-25 year-old individuals with major depressive disorder who sought care in one of three government-funded mental health services for young people in metropolitan Melbourne, Perth, or Sydney, Australia. Participants were randomly assigned in a double-blind, parallel-arm design to receive either fish oil (840 mg of eicosapentaenoic acid and 560 mg of docosahexaenoic acid) or placebo capsules as adjunct to cognitive behavioral case management. All participants were offered 50-minute cognitive behavioral case management sessions every 2 weeks delivered by qualified therapists (treatment as usual) at the study sites during the intervention period. The primary outcome was change in the interviewer-rated Quick Inventory of Depressive Symptomatology, Adolescent Version, score at 12 weeks. Erythrocyte n-3 PUFA levels were assessed pre-post intervention. RESULTS: A total of 233 young people were randomized to the treatment arms: 115 participants to the n-3 PUFA group and 118 to the placebo group. Mean change from baseline in the Quick Inventory of Depressive Symptomatology score was -5.8 in the n-3 PUFA group and -5.6 in the placebo group (mean difference, 0.2; 95% CI, -1.1 to 1.5; p = .75). Erythrocyte PUFA levels were not associated with depression severity at any time point. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: This placebo-controlled trial and biomarker analysis found no evidence to support the use of fish oil for treatment in young people with major depressive disorder.
Comorbidity between major depressive disorder and physical diseases: a comprehensive review of epidemiology, mechanisms and management.

Berk, M ; Köhler-Forsberg, O ; Turner, M ; Penninx, BWJH ; Wrobel, A ; Firth, J ; Loughman, A ; Reavley, NJ ; McGrath, JJ ; Momen, NC ; Plana-Ripoll, O ; O'Neil, A ; Siskind, D ; Williams, LJ ; Carvalho, AF ; Schmaal, L ; Walker, AJ ; Dean, O ; Walder, K ; Berk, L ; Dodd, S ; Yung, AR ; Marx, W (Wiley, 2023-10)

Populations with common physical diseases - such as cardiovascular diseases, cancer and neurodegenerative disorders - experience substantially higher rates of major depressive disorder (MDD) than the general population. On the other hand, people living with MDD have a greater risk for many physical diseases. This high level of comorbidity is associated with worse outcomes, reduced adherence to treatment, increased mortality, and greater health care utilization and costs. Comorbidity can also result in a range of clinical challenges, such as a more complicated therapeutic alliance, issues pertaining to adaptive health behaviors, drug-drug interactions and adverse events induced by medications used for physical and mental disorders. Potential explanations for the high prevalence of the above comorbidity involve shared genetic and biological pathways. These latter include inflammation, the gut microbiome, mitochondrial function and energy metabolism, hypothalamic-pituitary-adrenal axis dysregulation, and brain structure and function. Furthermore, MDD and physical diseases have in common several antecedents related to social factors (e.g., socioeconomic status), lifestyle variables (e.g., physical activity, diet, sleep), and stressful live events (e.g., childhood trauma). Pharmacotherapies and psychotherapies are effective treatments for comorbid MDD, and the introduction of lifestyle interventions as well as collaborative care models and digital technologies provide promising strategies for improving management. This paper aims to provide a detailed overview of the epidemiology of the comorbidity of MDD and specific physical diseases, including prevalence and bidirectional risk; of shared biological pathways potentially implicated in the pathogenesis of MDD and common physical diseases; of socio-environmental factors that serve as both shared risk and protective factors; and of management of MDD and physical diseases, including prevention and treatment. We conclude with future directions and emerging research related to optimal care of people with comorbid MDD and physical diseases.

Psychiatry - Research Publications

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