SLC25A48 influences plasma levels of choline and localizes to the inner mitochondrial membrane.

Choline contributes to the biogenesis of methyl groups, neurotransmitters, and cell membranes. Our genome-wide association study (GWAS) of circulating choline in 2228 college students found that alleles in SLC25A48 (rs6596270) influence choline concentrations in men (p = 9.6 × 10-8), but not women. Previously, the subcellular location and function of SLC25A48 were unknown. Using super-resolution immunofluorescence microscopy, we localized SLC25A48 to the inner mitochondrial membrane. Our results suggest that SLC25A48 transports choline across the inner mitochondrial membrane.

GluK2 Is a Target for Gene Therapy in Drug-Resistant Temporal Lobe Epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) is characterized by recurrent seizures generated in the limbic system, particularly in the hippocampus. In TLE, recurrent mossy fiber sprouting from dentate gyrus granule cells (DGCs) crea an aberrant epileptogenic network between DGCs which operates via ectopically expressed GluK2/GluK5-containing kainate receptors (KARs). TLE patients are often resistant to anti-seizure medications and suffer significant comorbidities; hence, there is an urgent need for novel therapies. Previously, we have shown that GluK2 knockout mice are protected from seizures. This study aims at providing evidence that downregulating KARs in the hippocampus using gene therapy reduces chronic epileptic discharges in TLE. METHODS: We combined molecular biology and electrophysiology in rodent models of TLE and in hippocampal slices surgically resected from patients with drug-resistant TLE. RESULTS: Here, we confirmed the translational potential of KAR suppression using a non-selective KAR antagonist that markedly attenuated interictal-like epileptiform discharges (IEDs) in TLE patient-derived hippocampal slices. An adeno-associated virus (AAV) serotype-9 vector expressing anti-grik2 miRNA was engineered to specifically downregulate GluK2 expression. Direct delivery of AAV9-anti grik2 miRNA into the hippocampus of TLE mice led to a marked reduction in seizure activity. Transduction of TLE patient hippocampal slices reduced levels of GluK2 protein and, most importantly, significantly reduced IEDs. INTERPRETATION: Our gene silencing strategy to knock down aberrant GluK2 expression demonstrates inhibition of chronic seizure in a mouse TLE model and IEDs in cultured slices derived from TLE patients. These results provide proof-of-concept for a gene therapy approach targeting GluK2 KARs for drug-resistant TLE patients. ANN NEUROL 2023;94:745-761.

Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force.

BACKGROUND: Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of established and off-label ADHD therapies in BD. METHODS: We included studies of ADHD medications in BD patients, which involved cognitive and/or safety measures. We followed the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed, Embase and PsycINFO from inception until June 2023. Two authors reviewed the studies independently using the Revised Cochrane Collaboration's Risk of Bias tool for Randomized trials. RESULTS: Seventeen studies were identified (N = 2136), investigating armodafinil (k = 4, N = 1581), methylphenidate (k = 4, N = 84), bupropion (k = 4, n = 249), clonidine (k = 1, n = 70), lisdexamphetamine (k = 1, n = 25), mixed amphetamine salts (k = 1, n = 30), or modafinil (k = 2, n = 97). Three studies investigated cognition, four ADHD symptoms, and 10 the safety. Three studies found treatment-related ADHD symptom reduction: two involved methylphenidate and one amphetamine salts. One study found a trend towards pro-cognitive effects of modafinil on some cognitive domains. No increased risk of (hypo)mania was observed. Five studies had low risk of bias, eleven a moderate risk, and one a serious risk of bias. CONCLUSIONS: Methylphenidate or mixed amphetamine salts may improve ADHD symptoms in BD. However, there is limited evidence regarding the effectiveness on cognition. The medications produced no increased mania risk when used alongside mood stabilizers. Further robust studies are needed to assess cognition in BD patients receiving psychostimulant treatment alongside mood stabilizers.

The management of depression: the evidence speaks for itself.

Comparing the recommendations of two recently published national clinical practice guidelines for depression, this editorial highlights the concordance of advice concerning the selection and sequencing of therapies. Lifestyle and psychological interventions feature prominently and there is broad agreement regarding medication choice and optimisation strategies. The guidelines are therefore a useful resource.

Childhood trauma and cognitive functioning in mood disorders: A systematic review.

BACKGROUND: Cognitive impairment is a core feature of mood disorders and has been identified as an important treatment target. A better understanding of the factors contributing to cognitive impairment in mood disorders would be beneficial in developing interventions to address cognitive impairment. One key factor is childhood trauma. The aim of this review was to systematically synthesise and review research examining associations between reported childhood trauma and cognitive functioning in mood disorders. METHODS: Studies in adult samples examining the relationship between objective cognitive function and reported childhood trauma in major depressive disorder and/or bipolar disorder (in-episode or euthymia) were identified. Searches were conducted on PubMed, Embase and PsycINFO until January 2022. A narrative review technique was used due to the heterogeneity of group comparisons, cognitive tests and data analysis across studies. RESULTS: Seventeen studies met the criteria for inclusion (mood disorders N = 1723, healthy controls N = 797). Evidence for childhood trauma being related to poorer cognitive functioning was consistent across global cognitive functioning and executive function domains for euthymic patients and psychomotor speed for in-episode patients. There was mixed evidence for verbal learning and memory and executive function for in-episode patients. Identification of patterns within other domains was difficult due to limited number of studies. CONCLUSION: Findings from this review suggest childhood trauma is associated with poorer cognitive functioning in people with mood disorders. Targeted interventions to improve cognition may be warranted for this group.

Difficult decision-making in major depressive disorder: Practical guidance based on clinical research and experience.

OBJECTIVES: To extend current published guidance regarding the management of major depression in clinical practice, by examining complex cases that reflect real-world patients, and to integrate evidence and experience into recommendations. METHODS: The authors who contributed to recently published clinical practice guidelines were invited to identify important gaps in extant guidance. Drawing on clinical experience and shared knowledge, they then generated four fictional case studies to illustrate the real-world complexities of managing mood disorders. The cases focussed specifically on issues that are not usually addressed in clinical practice guidelines. RESULTS: The four cases are discussed in detail and each case is summarised using a life chart and accompanying information. The four cases reflect important real-world challenges that clinicians face when managing mood disorders in day-to-day clinical practice. To partly standardise the presentation of each case and for ease of reference we provide a Time Line, History Box and Management Chart, along with a synopsis where relevant. Discussion and formulation of the cases illustrate how to manage the complexities of each case and provide one possible pathway to achieving functional recovery. CONCLUSION: These cases draw on the combined clinical experience of the authors and illustrate how to approach diagnostic decision-making when treating major depressive disorder and having to contend with complex presentations. The cases are designed to stimulate discussion and provide a real-world context for the formulation of mood disorders.

Non-Indigenous privilege in health, justice and social services preceding first episode psychosis: A population-based cohort study.

BACKGROUND: There is evidence of disparities between non-Indigenous and Indigenous incidence of psychotic disorders. Despite these disparities being a clear signpost of the impact of structural racism, there remains a lack of evidence to target institutional factors. We aimed to investigate non-Indigenous and Indigenous differences in government service use prior to first episode diagnosis as a means of identifying points of intervention to improve institutional responses. METHODS: We used a previously established national New Zealand cohort of 2385 13 to 25-year-old youth diagnosed with psychosis between 2009 and 2012 and a linked database of individual-level multiple government agency administration data, to investigate the differences in health, education, employment, child protection and criminal-justice service use between non-Indigenous (60%) and Indigenous youth (40%) in the year preceding first episode diagnosis. Further comparisons were made with the general population. RESULTS: A high rate of health service contact did not differ between non-Indigenous and Indigenous youth (adjusted rate ratio 1.0, 95% confidence interval [0.9, 1.1]). Non-Indigenous youth had higher rates of educational enrolment (adjusted rate ratio 1.2, 95% confidence interval [1.1, 1.3]) and employment (adjusted rate ratio 1.2, 95% confidence interval [1.1, 1.3]) and were 40% less likely to have contact with child protection services (adjusted rate ratio 0.6, 95% confidence interval [0.5, 0.8]) and the criminal-justice system (adjusted rate ratio 0.6, 95% confidence interval [0.5, 0.7]). Both first episode cohorts had a higher risk of criminal justice contact compared to the general population, but the difference was greater for non-Indigenous youth (risk ratio 3.0, 95% confidence interval [2.7, 3.4] vs risk ratio 2.0, 95% confidence interval [1.8, 2.2]), explained by the lower background risk. INTERPRETATION: The results indicate non-Indigenous privilege in multiple sectors prior to first episode diagnosis. Indigenous-based social disparities prior to first episode psychosis are likely to cause further inequities in recovery and will require a response of health, education, employment, justice and political systems.

Racism, early psychosis and institutional contact: a qualitative study of Indigenous experiences.

There is evidence of Indigenous and ethnic minority inequities in the incidence and outcomes of early psychosis. racism has an important role. This study aimed to use Indigenous experiences to develop a more detailed understanding of how racism operates to impact early psychosis. Critical Race Theory informed the methods used. Twenty-three Indigenous participants participated in 4 family focus group interviews and 13 individual interviews, comprising of 9 youth, 10 family members and 4 mental health professionals. An analysis of the data was undertaken using deductive structural coding to identify descriptions of racism, followed by inductive descriptive and pattern coding. Participant experiences revealed how racism operates as a socio-cultural phenomenon that interacts with institutional policy and culture across systems. This is described across three themes: (1) selective responses based on racial stereotypes, (2) race related risk assessment bias and (3) institutional racism in the mental health workforce. The impacts of racism were reported as inaction in the face of social need, increased coercion and an under resourced Indigenous workforce. These findings indicate that organizational cultures may differentially impact Indigenous and minority people and that social responsiveness, risk discourse and the distribution of workforce expenditure are important targets for anti-racism efforts.

A novel exploration of irritability in adolescent males: A preliminary study.

OBJECTIVE: Irritability is a key symptom of mood disorders and is common in adolescence; nevertheless, it is poorly understood and assessed. Research examining irritability and its relationship to mood and anxiety disorders risk factors in adolescent males is lacking. Therefore, the current study aimed to address this gap. METHOD: An online survey designed to interrogate the relationship between irritability and other risk factor variables was administered to 627 adolescent males (ages 12-17). Findings were analysed statistically using MANOVAs. RESULTS: When divided into high and low irritability groups, higher irritability scores were significantly correlated with higher scores on all risk factor variables. Further, higher irritability scores were associated with higher scores on all variables that indicate an increased risk for development of psychological disorders, such as depression and anxiety. CONCLUSION: This study is the first to focus on subjective irritability. In adolescent males, it identifies a potentially novel model of irritability's involvement in maladaptive processes relating to emotional dysregulation, behavioural difficulties and anxiety.

Positioning of psychodynamic psychotherapy in the treatment of depression: A comparison of the RANZCP 2020 and NICE 2022 guidelines.

OBJECTIVE: To compare the 2022 NICE guidelines (NG222) and 2020 RANZCP clinical practice guidelines (MDcpg2020) recommendations for the treatment of depression using psychodynamic psychotherapy. CONCLUSIONS: Both guidelines recommend psychological interventions first-line. However, only short-term psychodynamic psychotherapy (STPP) is recommended, and in the NG222 it is ranked last for less severe depression and 7th for more severe depression. In contrast, cognitive behavioural therapy and behavioural activation are deemed the more clinically effective and cost-effective psychological therapies. And antidepressants play a significant role - largely in more severe depression.

Neurobiological and behavioral mechanisms of circadian rhythm disruption in bipolar disorder: A critical multi-disciplinary literature review and agenda for future research from the ISBD task force on chronobiology.

AIM: Symptoms of bipolar disorder (BD) include changes in mood, activity, energy, sleep, and appetite. Since many of these processes are regulated by circadian function, circadian rhythm disturbance has been examined as a biological feature underlying BD. The International Society for Bipolar Disorders Chronobiology Task Force (CTF) was commissioned to review evidence for neurobiological and behavioral mechanisms pertinent to BD. METHOD: Drawing upon expertise in animal models, biomarkers, physiology, and behavior, CTF analyzed the relevant cross-disciplinary literature to precisely frame the discussion around circadian rhythm disruption in BD, highlight key findings, and for the first time integrate findings across levels of analysis to develop an internally consistent, coherent theoretical framework. RESULTS: Evidence from multiple sources implicates the circadian system in mood regulation, with corresponding associations with BD diagnoses and mood-related traits reported across genetic, cellular, physiological, and behavioral domains. However, circadian disruption does not appear to be specific to BD and is present across a variety of high-risk, prodromal, and syndromic psychiatric disorders. Substantial variability and ambiguity among the definitions, concepts and assumptions underlying the research have limited replication and the emergence of consensus findings. CONCLUSIONS: Future research in circadian rhythms and its role in BD is warranted. Well-powered studies that carefully define associations between BD-related and chronobiologically-related constructs, and integrate across levels of analysis will be most illuminating.

Randomised controlled cognition trials in remitted patients with mood disorders published between 2015 and 2021: A systematic review by the International Society for Bipolar Disorders Targeting Cognition Task Force.

BACKGROUND: Cognitive impairments are an emerging treatment target in mood disorders, but currently there are no evidence-based pro-cognitive treatments indicated for patients in remission. With this systematic review of randomised controlled trials (RCTs), the International Society for Bipolar Disorders (ISBD) Targeting Cognition Task force provides an update of the most promising treatments and methodological recommendations. METHODS: The review included RCTs of candidate pro-cognitive interventions in fully or partially remitted patients with major depressive disorder or bipolar disorder. We followed the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE and Cochrane Library from January 2015, when two prior systematic reviews were conducted, until February 2021. Two independent authors reviewed the studies with the Revised Cochrane Collaboration's Risk of Bias tool for Randomised trials. RESULTS: We identified 16 RCTs (N = 859) investigating cognitive remediation (CR; k = 6; N = 311), direct current or repetitive magnetic stimulation (k = 3; N = 127), or pharmacological interventions (k = 7; N = 421). CR showed most consistent cognitive benefits, with two trials showing improvements on primary outcomes. Neuromodulatory interventions revealed no clear efficacy. Among pharmacological interventions, modafinil and lurasidone showed early positive results. Sources of bias included small samples, lack of pre-screening for objective cognitive impairment, no primary outcome and no information on allocation sequence masking. CONCLUSIONS: Evidence for pro-cognitive treatments in mood disorders is emerging. Recommendations are to increase sample sizes, pre-screen for impairment in targeted domain(s), select one primary outcome, aid transfer to real-world functioning, investigate multimodal interventions and include neuroimaging.

Can magnetic resonance imaging enhance the assessment of potential new treatments for cognitive impairment in mood disorders? A systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force.

BACKGROUND: Developing treatments for cognitive impairment is key to improving the functioning of people with mood disorders. Neuroimaging may assist in identifying brain-based efficacy markers. This systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force examines the evidence from neuroimaging studies of pro-cognitive interventions. METHODS: We included magnetic resonance imaging (MRI) studies of candidate interventions in people with mood disorders or healthy individuals, following the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE, Cochrane Library, and Clinicaltrials.gov from inception to 30th April 2021. Two independent authors reviewed the studies using the National Heart, Lung, Blood Institutes of Health Quality Assessment Tool for Controlled Intervention Studies and the quality of neuroimaging methodology assessment checklist. RESULTS: We identified 26 studies (N = 702). Six investigated cognitive remediation or pharmacological treatments in mood disorders (N = 190). In healthy individuals, 14 studies investigated pharmacological interventions (N = 319), 2 cognitive training (N = 73) and 4 neuromodulatory treatments (N = 120). Methodologies were mostly rated as 'fair'. 77% of studies investigated effects with task-based fMRI. Findings varied but most consistently involved treatment-associated cognitive control network (CCN) activity increases with cognitive improvements, or CCN activity decreases with no cognitive change, and increased functional connectivity. In mood disorders, treatment-related default mode network suppression occurred. CONCLUSIONS: Modulation of CCN and DMN activity is a putative efficacy biomarker. Methodological recommendations are to pre-declare intended analyses and use task-based fMRI, paradigms probing the CCN, longitudinal assessments, mock scanning, and out-of-scanner tests.

A randomised controlled trial of psychotherapy and cognitive remediation to target cognition in mood disorders.

OBJECTIVE: To examine the impact of a treatment package combining Interpersonal and Social Rhythm Therapy (IPSRT) and cognitive remediation (CR), vs IPSRT alone, on cognition, functioning, and mood disturbance outcomes in mood disorders. METHODS: A pragmatic randomised controlled trial in adults with bipolar disorder (BD) or major depressive disorder (MDD), recently discharged from mental health services in Christchurch, New Zealand, with subjective cognitive difficulties. Individuals were randomised to a 12-month course of IPSRT with CR (IPSRT-CR), or without CR (IPSRT). In IPSRT-CR, CR was incorporated into therapy sessions from approximately session 5 and continued for 12 sessions. The primary outcome was change in Global Cognition (baseline to 12 months). RESULTS: Sixty-eight individuals (BD n = 26, MDD n = 42; full/partial remission n = 39) were randomised to receive IPSRT-CR or IPSRT (both n = 34). Across treatment arms, individuals received an average of 23 IPSRT sessions. Change in Global Cognition did not differ between arms from baseline to treatment-end (12 months). Psychosocial functioning and longitudinal depression symptoms improved significantly more in the IPSRT compared with IPSRT-CR arm over 12 months, and all measures of functioning and mood symptoms showed moderate effect size differences favouring IPSRT (0.41-0.60). At 18 months, small to moderate, non-significant benefits (0.26-0.47) of IPSRT vs IPSRT-CR were found on functioning and mood outcomes. CONCLUSIONS: Combining two psychological therapies to target symptomatic and cognitive/functional recovery may reduce the effect of IPSRT, which has implications for treatment planning in clinical practice and for CR trials in mood disorders.

Randomised controlled trial of Interpersonal and Social Rhythm Therapy and group-based Cognitive Remediation versus Interpersonal and Social Rhythm Therapy alone for mood disorders: study protocol.

BACKGROUND: Individuals with mood disorders frequently experience cognitive impairment, which impacts on the long-term trajectory of the disorders, including being associated with persisting difficulties in occupational and psychosocial functioning, residual mood symptoms, and relapse. Current first-line treatments for mood disorders do little to improve cognitive function. Targeting cognition in clinical research is thus considered a priority. This protocol outlines a prospectively-registered randomised controlled trial (RCT) which examines the impact of adding group-based Cognitive Remediation (CR) to Interpersonal and Social Rhythm Therapy (IPSRT-CR) for individuals with mood disorders. METHODS: This is a pragmatic, two-arm, single-blinded RCT comparing IPSRT-CR with IPSRT alone for adults (n = 100) with mood disorders (Major Depressive Disorder or Bipolar Disorder) with subjective cognitive difficulties, on discharge from Specialist Mental Health Services in Christchurch, New Zealand. Both treatment arms will receive a 12-month course of individual IPSRT (full dose = 24 sessions). At 6 months, randomisation to receive, or not, an 8-week group-based CR programme (Action-based Cognitive Remediation - New Zealand) will occur. The primary outcome will be change in Global Cognition between 6 and 12 months (treatment-end) in IPSRT-CR versus IPSRT alone. Secondary outcomes will be change in cognitive, functional, and mood outcomes at 6, 12, 18, and 24 months from baseline and exploratory outcomes include change in quality of life, medication adherence, rumination, and inflammatory markers between treatment arms. Outcome analyses will use an intention-to-treat approach. Sub-group analyses will assess the impact of baseline features on CR treatment response. Participants' experiences of their mood disorder, including treatment, will be examined using qualitative analysis. DISCUSSION: This will be the first RCT to combine group-based CR with an evidence-based psychotherapy for adults with mood disorders. The trial may provide valuable information regarding how we can help promote long-term recovery from mood disorders. Many issues have been considered in developing this protocol, including: recruitment of the spectrum of mood disorders, screening for cognitive impairment, dose and timing of the CR intervention, choice of comparator treatment, and choice of outcome measures. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry, ACTRN12619001080112 . Registered on 6 August 2019.

Social Rhythm Disruption is Associated with Greater Depressive Symptoms in People with Mood Disorders: Findings from a Multinational Online Survey During COVID-19.

OBJECTIVES: Societal restrictions imposed to prevent transmission of COVID-19 may challenge circadian-driven lifestyle behaviours, particularly amongst those vulnerable to mood disorders. The overarching aim of the present study was to investigate the hypothesis that, in the routine-disrupted environment of the COVID-19, amongst a sample of people living with mood disorders, greater social rhythm disruption would be associated with more severe mood symptoms. METHODS: We conducted a two-wave, multinational survey of 997 participants (MAge=39.75±13.39,Female=81.6%) who self-reported a mood disorder diagnosis (i.e., major depressive disorder or bipolar disorder). Respondents completed questionnaires assessing demographics, social rhythmicity (The Brief Social Rhythm Scale), depression symptoms (Patient Health Questionnaire-9), sleep quality and diurnal preference (The Sleep, Circadian Rhythms and Mood questionnaire) and stressful life events during the COVID-19 pandemic (The Social Readjustment Rating Scale). RESULTS: The majority of participants indicated COVID-19-related social disruption had affected the regularity of their daily routines to at least some extent (n = 788, 79.1%). As hypothesised, lower social rhythmicity was associated with greater depressive symptoms when tested cross-sectionally (standardised ß = -.25, t = -7.94, P = 0.000) and when tested using a 2-level hierarchical linear model across two time points (b = -0.14, t = -3.46, df = 264, P ≤ 0.001). CONCLUSIONS: These results are consistent with the social zeitgeber hypothesis proposing that mood disorders are sensitive to life events that disrupt social rhythms.

Rate of polycystic ovary syndrome in mental health disorders: a systematic review.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with increased risk of many mental health conditions, including mood and anxiety disorders. Whether PCOS is more common in mental health conditions than in the general population is less clear. A systematic review investigating this question may provide clarity regarding whether increased prevalence of PCOS is seen in particular mental health disorders, and thus, whether screening female mental health patients for PCOS is warranted. AIMS: To systematically synthesise and review research examining rates of PCOS in mental health disorders. METHODS: Peer-reviewed articles assessing the prevalence of PCOS within a sample of reproductive-aged females with a diagnosis of Axis I or II mental health disorder were included. Key studies were identified through a comprehensive search of PubMed and Web of Science. RESULTS: Eleven studies met inclusion criteria, assessing rate of diagnosed PCOS in samples with bipolar disorder (n = 7), autism spectrum disorders (ASD; n = 2), bulimia nervosa (n = 1), and post-traumatic stress disorder (PTSD; n = 1). Overall, there was limited evidence of elevated rates of PCOS in bipolar disorder, compared with population estimates or healthy control group rates. In ASD, bulimia nervosa, and PTSD samples, significantly increased rates of PCOS were reported compared with healthy control samples, although studies were relatively small. CONCLUSIONS: This review highlights complexities and methodological considerations in this area of research. There are a limited number of studies assessing PCOS in mental health samples, and thus, important areas of future research have been identified. TRIAL REGISTRATION: This systematic review was registered on PROSPERO (ID: CRD42020151420; https://www.crd.york.ac.uk/prospero/ ) on 28 April 2020.

Free testosterone is related to aspects of cognitive function in women with and without polycystic ovary syndrome.

Evidence suggests impairment in aspects of cognitive function in women with polycystic ovary syndrome (PCOS). Direct effects of raised testosterone levels associated with PCOS are a potential mechanism. We aimed to explore the relationship between testosterone levels and cognitive functioning in women. Women with a range of testosterone levels, including women with PCOS, were recruited. Depressive and anxiety symptoms were measured by self-report. Participants underwent a comprehensive battery of cognitive tests assessing psychomotor speed, visuospatial learning and memory, verbal learning and memory, and executive function. Free testosterone serum levels were assessed. All measures were completed at the same time point. Correlation analysis (Spearman's Rho) was used to explore associations between free testosterone and cognitive test variables. Eighty-one women were recruited, with 40 meeting diagnostic criteria for PCOS. Free testosterone was normally distributed, with significant overlap between women with PCOS and controls. Mean depressive and anxiety symptoms were in the mild range. Higher free testosterone levels were significantly correlated with poorer performance on measures assessing psychomotor speed and visuospatial learning. These significant correlations remained after adjusting for confounders (premorbid verbal IQ, depressive, and anxiety symptoms). Higher free testosterone levels in women were associated with poorer cognitive function, specifically psychomotor speed and visuospatial learning. Women with PCOS and raised free testosterone levels may experience impairment in these aspects of cognitive function which are not accounted for by mood or anxiety symptoms.

Long-term efficacy of metacognitive therapy and cognitive behaviour therapy for depression.

OBJECTIVE: To examine the two-year outcomes for depression, anxiety, cognitive and global social functioning after cognitive behavioural therapy (CBT) and metacognitive therapy (MCT) for depression. METHOD: Participants were 31 adults with a diagnosis of major depressive disorder in a randomised pilot study comparing MCT and CBT. Therapy modality differences in change in depression and anxiety symptoms, dysfunctional attitudes, metacognitions, rumination, worry and global social functioning were examined at the two-year follow-up for those who completed therapy. RESULTS: Significant improvements, with large effect sizes, were evident for all outcome variables. There were no significant differences in outcome between CBT and MCT. The greatest change over time occurred for depression and anxiety. Large changes were evident for metacognitions, rumination, dysfunctional attitudes, worry and global social functioning. Sixty-seven percent had not experienced a major depression and had been well during all of the past year, prior to the follow-up assessment. CONCLUSION: The finding at end treatment, of no modality specific differences, was also evident at two-year follow-up. Although CBT and MCT targeted depression, improvements were much wider, and although CBT and MCT take different approaches, both therapies produced positive change over time across all cognitive variables. CBT and MCT provide treatment options, that not only improve the longer-term outcome of depression, but also result in improvements in anxiety, global social functioning and cognitive status.

An Evidence-Based Perspective on The 2020 Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines.

OBJECTIVE: To rebut the claims made in an opinion piece by Anaf and colleagues regarding the recommendations for psychotherapy within the 2020 RANZCP Mood Disorders Clinical Practice Guidelines (CPG). CONCLUSIONS: The CPG attaches importance to psychological interventions and recommends their administration as first-line in the treatment of depression. The concerns raised by Anaf and colleagues have no basis and are readily dismissed by referring to the guidelines. Therefore, we strongly encourage clinicians to formulate their own views by reading the guidelines for themselves.