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Objective: Conventional antidepressant treatments result in symptom remission in 30% of those treated for major depressive disorder, raising the need for effective adjunctive therapies. Inflammation has an established role in the pathophysiology of major depressive disorder, and minocycline has been shown to modify the immune-inflammatory processes and also reduce oxidative stress and promote neuronal growth. This double-blind, randomised, placebo-controlled trial examined adjunctive minocycline (200 mg/day, in addition to treatment as usual) for major depressive disorder. This double-blind, randomised, placebo-controlled trial investigated 200 mg/day adjunctive minocycline (in addition to treatment as usual) for major depressive disorder. Methods: A total of 71 adults with major depressive disorder ( Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition) were randomised to this 12-week trial. Outcome measures included the Montgomery–Asberg Depression Rating Scale (primary outcome), Clinical Global Impression–Improvement and Clinical Global Impression–Severity, Hamilton Anxiety Rating Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, Social and Occupational Functioning Scale and the Range of Impaired Functioning Tool. The study was registered on the Australian and New Zealand Clinical Trials Register: www.anzctr.org.au , #ACTRN12612000283875. Results: Based on mixed-methods repeated measures analysis of variance at week 12, there was no significant difference in Montgomery–Asberg Depression Rating Scale scores between groups. However, there were significant differences, favouring the minocycline group at week 12 for Clinical Global Impression–Improvement score – effect size (95% confidence interval) = −0.62 [−1.8, −0.3], p = 0.02; Quality of Life Enjoyment and Satisfaction Questionnaire score – effect size (confidence interval) = −0.12 [0.0, 0.2], p < 0.001; and Social and Occupational Functioning Scale and the Range of Impaired Functioning Tool score – 0.79 [−4.5, −1.4], p < 0.001. These effects remained at follow-up (week 16), and Patient Global Impression also became significant, effect size (confidence interval) = 0.57 [−1.7, −0.4], p = 0.017. Conclusion: While the primary outcome was not significant, the improvements in other comprehensive clinical measures suggest that minocycline may be a useful adjunct to improve global experience, functioning and quality of life in people with major depressive disorder. Further studies are warranted to confirm the potential of this accessible agent to optimise treatment outcomes.

BackgroundProlonged separation from parental support is a risk factor for psychopathology. This study assessed the impact of brief separation from parents during childhood trauma on adult attachment tendencies and post-traumatic stress.MethodChildren (n = 806) exposed to a major Australian bushfire disaster in 1983 and matched controls (n = 725) were assessed in the aftermath of the fires (mean age 7–8 years) via parent reports of trauma exposure and separation from parents during the fires. Participants (n = 500) were subsequently assessed 28 years after initial assessment on the Experiences in Close Relationships scale to assess attachment security, and post-traumatic stress disorder (PTSD) was assessed using the PTSD checklist.ResultsBeing separated from parents was significantly related to having an avoidant attachment style as an adult (B = −3.69, s.e. = 1.48, β = −0.23, p = 0.013). Avoidant attachment was associated with re-experiencing (B = 0.03, s.e. = 0.01, β = 0.31, p = 0.045), avoidance (B = 0.03, s.e. = 0.01, β = 0.30, p = 0.001) and numbing (B = 0.03, s.e. = 0.01, β = 0.30, p < 0.001) symptoms. Anxious attachment was associated with re-experiencing (B = 0.03, s.e. = 0.01, β = 0.18, p = 0.001), numbing (B = 0.03, β = 0.30, s.e. = 0.01, p < 0.001) and arousal (B = 0.04, s.e. = 0.01, β = 0.43, p < 0.001) symptoms.ConclusionsThese findings demonstrate that brief separation from attachments during childhood trauma can have long-lasting effects on one's attachment security, and that this can be associated with adult post-traumatic psychopathology.

ObjectiveThis study aimed to explore effects of adjunctive N-acetylcysteine (NAC) treatment on inflammatory and neurogenesis markers in unipolar depression.MethodsWe embarked on a 12-week clinical trial of NAC (2000 mg/day compared with placebo) as an adjunctive treatment for unipolar depression. A follow-up visit was conducted 4 weeks following the completion of treatment. We collected serum samples at baseline and the end of the treatment phase (week 12) to determine changes in interleukin-6 (IL6), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) following NAC treatment.ResultsNAC treatment significantly improved depressive symptoms on the Montgomery–Asberg Depression Rating Scale (MADRS) over 16 weeks of the trial. Serum levels of IL6 were associated with reductions of MADRS scores independent of treatment response. However, we found no significant changes in IL6, CRP and BDNF levels following NAC treatment.ConclusionOverall, this suggests that our results failed to support the hypothesis that IL6, CRP and BDNF are directly involved in the therapeutic mechanism of NAC in depression. IL6 may be a useful marker for future exploration of treatment response.

Background Irritability and emotion regulation are both important transdiagnostic factors that contribute to the development of internalizing symptoms during adolescence. The current study examined whether emotion regulation mediates the relationship between irritability and internalizing symptoms. Methods To examine this relationship we analysed the indirect effect of irritability (measured using a single item from the Goldberg Mania Questionnaire) on internalizing symptoms (anxiety and depression) via the mediator, emotion regulation (Difficulties in Emotion Regulation Scale) in 112 adolescent females. Results Mediation analysis, using bootstrapping, showed a significant indirect effect and suggests that the relationship between irritability and internalizing symptoms is mediated by emotion dysregulation. Limitations These include measuring irritability using a single item and employing a cross sectional design. Conclusions These novel findings add to our understanding of the processes and mechanisms by which irritability contributes to the development of internalizing symptoms.

A significant minority of people presenting with a major depressive episode (MDE) experience co-occurring subsyndromal hypo/manic symptoms. As this presentation may have important prognostic and treatment implications, the DSM–5 codified a new nosological entity, the “mixed features specifier,” referring to individuals meeting threshold criteria for an MDE and subthreshold symptoms of (hypo)mania or to individuals with syndromal mania and subthreshold depressive symptoms. The mixed features specifier adds to a growing list of monikers that have been put forward to describe phenotypes characterized by the admixture of depressive and hypomanic symptoms (e.g., mixed depression, depression with mixed features, or depressive mixed states [DMX]). Current treatment guidelines, regulatory approvals, as well the current evidentiary base provide insufficient decision support to practitioners who provide care to individuals presenting with an MDE with mixed features. In addition, all existing psychotropic agents evaluated in mixed patients have largely been confined to patient populations meeting the DSM–IV definition of “mixed states” wherein the co-occurrence of threshold-level mania and threshold-level MDE was required. Toward the aim of assisting clinicians providing care to adults with MDE and mixed features, we have assembled a panel of experts on mood disorders to develop these guidelines on the recognition and treatment of mixed depression, based on the few studies that have focused specifically on DMX as well as decades of cumulated clinical experience.

Supplemental Material, MITO-NAC_Physical_activity_Supplementary_Material for Physical Activity as a Predictor of Clinical Trial Outcomes in Bipolar Depression: A Subanalysis of a Mitochondrial-Enhancing Nutraceutical Randomized Controlled Trial by Melanie M. Ashton, Mohammadreza Mohebbi, Alyna Turner, Wolfgang Marx, Michael Berk, Gin S. Malhi, Chee H. Ng, Sue M. Cotton, Seetal Dodd, Jerome Sarris, Malcolm Hopwood, Brendon Stubbs and Olivia M. Dean in The Canadian Journal of Psychiatry

Supplemental material, sj-docx-1-anp-10.1177_0004867420979353 for The 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders by Gin S Malhi, Erica Bell, Darryl Bassett, Philip Boyce, Richard Bryant, Philip Hazell, Malcolm Hopwood, Bill Lyndon, Roger Mulder, Richard Porter, Ajeet B Singh and Greg Murray in Australian & New Zealand Journal of Psychiatry

Supplemental material, Table_S2 for Minocycline as adjunctive treatment for major depressive disorder: Pooled data from two randomized controlled trials by Robson Zazula, Muhammad Ishrat Husain, Mohammadreza Mohebbi, Adam J Walker, Imran B Chaudhry, Ameer B Khoso, Melanie M Ashton, Bruno Agustini, Nusrat Husain, JFW Deakin, Allan H Young, Michael Berk, Buranee Kanchanatawan, Chee H Ng, Michael Maes, Lesley Berk, Ajeet B Singh, Gin S Malhi and Olivia M Dean in Australian & New Zealand Journal of Psychiatry

Abnormal melatonin secretion has been demonstrated in patients with affective disorders such as major depressive disorder (MDD) and bipolar disorder (BD). However, magnetic resonance imaging (MRI) studies that previously investigated the volume of the pineal gland, which regulates circadian rhythms by secreting melatonin, in these patients reported inconsistent findings. The present study employed MRI to examine pineal gland volumes and pineal cyst prevalence in 56 MDD patients (29 currently depressed and 27 remitted patients), 26 BD patients, and matched controls (33 for MDD and 24 for BD). Pineal volumes and cyst prevalence in the current MDD, remitted MDD, and BD groups did not significantly differ from those of the healthy controls. However, pineal gland volumes were significantly smaller in the current MDD subgroup of non-melancholic depression than in the melancholic MDD subgroup. Interestingly, pineal volumes correlated negatively with the severity of loss of interest in the current MDD group. Medication and the number of affective episodes were not associated with pineal volumes in the MDD or BD group. While these results do not suggest that pineal volumes reflect abnormal melatonin secretion in affective disorders, they do point to the possibility that pineal abnormalities are associated with clinical subtypes of MDD and its symptomatology.

SummaryTreatment-resistant depression is widely defined as non-response to two ‘adequate’ courses of treatment. However, the definitions of treatment and depression are inconsistent reflecting gaps in our understanding. We argue that a failure to respond is often the result of administering inappropriate treatment, which occurs principally because of paradigm failure.Declaration of interestNone.

Oxytocin (OXT) is a neuropeptide involved in social behaviour and is sensitive to environmental influences to alter individual vulnerability or resilience to stress resulting in both negative and positive outcomes. The effects of the OXT receptor (OXTR) single nucleotide polymorphism (SNP) rs53576 on hippocampal and amygdala structure and functions in adults are differentially associated with susceptibility to adversity and social behaviours, but this evidence is lacking in healthy adolescents. Adolescence is a developmental period characterised by neurobiological and psychosocial changes resulting in higher susceptibility to mood disorders, particularly among girls. As the brain is highly plastic at this stage, to understand psychosocial and emotional development, clarity of the interactions between rs53576 and adversity on hippocampal and amygdala volumes and social behaviours is needed. In this study, we investigated the interactions between rs53576 and emotional trauma (ET) exposure on hippocampal and amygdala volumes of adolescent girls, and associations with parenting style, perceived social support and bullying behaviour. Based on an unbiased and corrected analytical approach, we found smaller left hippocampal volumes in higher (hET) compared to minimally (mET) exposed AA homozygotes, but no differences in G allele carriers nor in the amygdala. Within the mET AA group, larger volumes were associated with peer perceived social support, but in their hET counterparts, smaller volumes were associated with familial perceived social support. This evidence supports an important role for the hippocampus in social behaviours but extends current knowledge to suggest that hippocampal social behavioural features are contextually dependent on rs53576.

The current study aimed to identify alterations in brain activation and connectivity related to memory suppression in posttraumatic stress disorder (PTSD) using the Think/No-Think paradigm during functional magnetic resonance imaging (fMRI). Reduced activation in the parahippocampal cortex during No-Think vs. Baseline trials was found in participants with PTSD compared to controls with no history of trauma (pFWE

Objectives Individuals with bipolar disorder (BD) generally engage in low levels of physical activity (PA), and yet few studies have investigated the relationship between PA and change in BD symptom severity. The aim of this subanalysis of an adjunctive nutraceutical randomized controlled trial for the treatment of bipolar depression was to explore the relationship between PA, the active adjunctive treatments (a nutraceutical “mitochondrial cocktail”), and clinical outcomes. Methods Participants with bipolar depression were randomized to receive N-acetylcysteine alone, N-acetylcysteine with a combination of nutraceuticals (chosen for the potential to increase mitochondrial activity), or placebo for 16 weeks. Participants ( n = 145) who completed the International Physical Activity Questionnaire–Short Form (IPAQ-SF; measured at Week 4) were included in this exploratory subanalysis. Assessments of BD symptoms, functioning, and quality of life were completed at monthly visits up until Week 20. Generalised Estimating Equations were used to explore whether IPAQ-SF scores were a moderator of treatment received on outcomes of the study. Results Week-4 PA was not related to changes in Montgomery Åsberg Depression Rating Scale scores across the study until Week 20. However, participants who engaged in more PA and who received the combination treatment were more likely to have a reduction in scores on the Bipolar Depression Rating Scale ( P = 0.03). However, this was not consistent in all domains explored using the IPAQ-SF. Participants who engaged in higher levels of PA also experienced greater improvement in social and occupational functioning and less impairment in functioning due to their psychopathology and improvement in quality of life at Week 20, irrespective of treatment. Conclusions This study provides novel evidence of the association between PA and reduction in BD symptoms in a nutraceutical clinical trial. However, further research assessing the potential synergistic effects of PA in BD is required.

We aimed to explore the relationships between diet quality, dietary inflammatory potential or body mass index and outcomes of a clinical trial of nutraceutical treatment for bipolar depression.This is a sub-study of a randomised controlled trial of participants with bipolar depression who provided dietary intake data (In participants taking combination treatment compared to placebo, change in depression scores was not predicted by Australian Recommended Food Score, dietary inflammatory index or body mass index scores. However, participants with better diet quality (Australian Recommended Food Score) reported reduced general depression and bipolar depression symptoms (These data support a possible association between diet (quality and inflammatory potential), body mass index and response to treatment for bipolar depression in the context of a nutraceutical trial. The results should be interpreted cautiously because of limitations, including numerous null findings, modest sample size and being secondary analyses.

Objectives Dysfunction of cognitive control is a feature of both bipolar disorder (BP) and major depression (MDD) and persists through to remission. However, it is unknown whether these disorders are characterized by common or distinct disruptions of cognitive control function and its neural basis. We investigated this gap in knowledge in asymptomatic BP and MDD participants, interpreted within a framework of normative function. Methods Participants underwent fMRI scans engaging cognitive control through a working memory task and completed a cognitive battery evaluating performance across multiple subdomains of cognitive control, including attention, impulsivity, processing speed, executive function, and memory. Analysis was performed in two stages: (i) cognitive control-related brain activation and deactivation were correlated with cognitive control performance in 115 healthy controls (HCs), then, (ii) significantly correlated regions from (i) were compared between 25 asymptomatic BP, 25 remitted MDD, and with 25 different HCs, matched for age and gender. Results Impulsivity and executive function performance were significantly worse in BP compared to both MDD and HCs. Both BP and MDD had significantly poorer memory performance compared to HCs. Greater deactivation of the medial prefrontal cortex (MPFC) during the fMRI task was associated with better executive function in healthy controls. Significantly less deactivation in this region was present in both BP and MDD compared to HCs. Conclusions Failure to deactivate the MPFC, a key region of the default mode network, during working memory processing is a shared neural feature present in both bipolar and major depression and could be a source of common cognitive dysfunction.

Borecky and colleagues (Borecky, Thomsen, and Dubov 2019) argue that involuntary hospitalization causes more harm than good, and that limiting its use would afford greater autonomy and lead to disc...

Background Anxiety and depression may hamper a smooth transition from military to civilian life and may be important predictors of longer-term health and functioning. However, it is as yet unclear to what extent they are determined by childhood factors in a recently transitioned population. Methods We utilised logistic regression and Generalised Structural Equation Modelling to analyse associations of ICD-10 past-year anxiety and depression with childhood trauma and disorder in a recently transitioned population using detailed interview data from the ADF (Australian Defence Force) Transition and Wellbeing Research Programme. Results Past-year anxiety (including PTSD) was prevalent (36.4%, 95% CI, 31.9-41.1) and associated with childhood anxiety (but not other types of childhood disorder), childhood interpersonal trauma (but not other childhood trauma) and adult-onset trauma. Childhood anxiety had a direct and significant association with past-year anxiety. The pathway between childhood interpersonal trauma and past-year anxiety was fully mediated by childhood anxiety. Past-year depression was less prevalent (11.3%, 95% CI, 8.7-14.5) and had no association with childhood disorder or trauma variables. Limitations The main predictor variables utilized in this analysis were childhood experiences recalled from adulthood, thus rendering the responses vulnerable to autobiographical bias. Conclusions Past-year anxiety was highly prevalent in the period of transition and had strong associations with childhood and military factors, suggesting predictability and potentially preventability.

Background Although trauma-focused cognitive behavioral therapy (TF-CBT) is the frontline treatment for posttraumatic stress disorder (PTSD), at least one-third of patients are treatment nonresponders. This study aimed to identify neural markers of treatment response, specifically the prediction of remission of specific PTSD symptoms. Methods This study assessed PTSD treatment-seeking patients (n = 40) before TF-CBT during functional magnetic brain resonance imaging (fMRI) when they processed fearful, sad, happy, and neutral faces. Patients underwent nine sessions of TF-CBT and were independently assessed on the Clinician-Administered PTSD Scale (CAPS) following treatment. Treatment responders and nonresponders were compared with healthy controls (n = 40). The severity of PTSD was assessed with the CAPS. fMRI responses were calculated for each emotion face compared to neutral contrast, which were correlated with reduction in PTSD severity from pretreatment to posttreatment. Treatment response was categorized by at least 50% reduction in the severity of PTSD. Results The activation of left insula during the processing of both sad and fearful faces was associated with a greater reduction of fear but not with dysphoric symptoms after treatment. Connectivity of the left insula to the pregenual anterior cingulate cortex was associated with poorer response to treatment. Responders and controllers had similar levels of activation and connectivity and were different from nonresponders. Conclusions Positive response to TF-CBT is predicted during emotion processing by normal levels of recruitment of neural networks implicated in emotional information. These findings suggest that distinct neural networks are predictive of PTSD fear and dysphoric symptom reduction following TF-CBT.

Summary We present the reasoning behind a retraction noting that even small, honest errors can result in significant changes in findings. Declaration of interest K.R.K. is the Editor-in-Chief, G.S.M., the Deputy Editor and K.S.B. an editorial board member of BJPsych Open.

There is an urgent need to integrate the findings converging from different perspectives examining hippocampal volume changes both overall but in particular within its subfields in relation to childhood trauma and illness. We comment on a recent paper's findings and link these to our own research in an effort to provide impetus to this endeavor.

The concept of early intervention for bipolar disorder (BD) is both attractive and logical as there is often a considerable delay between the onset of BD symptoms and diagnosis. This chapter addresses key definitional and conceptual considerations for early intervention in BD and exposes the expansive gaps in our knowledge of the phenomenology of BD, prognostication, and disease progression and trajectory. These gaps highlight that early intervention for BD—in terms of treatment specificity and timing—is far from being realised. There are though significant risks associated with implementing early intervention strategies at this stage, which may range from unnecessarily prescribing potentially harmful medication to perhaps inadvertently accelerating the progression of the illness. Until there are major scientific and clinical advancements, this chapter provides a conservative yet involved approach for early intervention in BD.

BackgroundSubsyndromal emotional symptoms in adolescence may represent precursors for full-blown emotional disorders in early adulthood. Understanding the neurobiological mechanisms that drive this development is essential for prevention.AimsSelf-referential processing and emotion regulation are remodelled substantively during adolescence, therefore this study examined integration of key neural networks involved in these processes.MethodAt baseline, clinical and resting-state functional magnetic resonance imaging data were collected for 88 adolescent girls (mean age 15 years), and 71 of these girls underwent repeat clinical assessment after 2 years. These 71 girls were then partitioned into two groups depending on the presence (ES+) or absence (ES−) of emotional symptoms, and differences in dynamic functional network connectivity were determined and correlated with clinical variables.ResultsThe two groups displayed a differential pattern of functional connectivity involving the left lateral prefrontal network (LPFN). Specifically, in the ES+ group this network displayed positive coupling with the right LPFN but negative coupling with the default mode network, and the inverse of this pattern was found in the ES− group. Furthermore, the coupling strengths between left and right LPFN at the irst time point predicted follow-up depression and state anxiety scores.ConclusionsOur findings suggest that in adolescent girls, emotional symptoms may emerge as a result of impaired integration between networks involved in self-referential information processing and approach-avoidance behaviours. These impairments can compromise the pursuit of important goals and have an impact on emotion processing and finally may lead to the development of emotional disorders, such as anxiety and depression in adulthood.Declaration of interestNone.

Objective Mood disorders are strongly associated with suicide, the prevention of which is predicated on timely detection of suicidal activity (ideation, behaviour). Building on our previous work, we sought to determine the nature of neural responses to an emotional-cognitive task in patients with varying degrees of suicidal activity. Method Seventy-nine patients with mood disorders were assessed clinically and scanned using fMRI. Neural responses to an Emotional Face-Word Stroop task were compared with 66 healthy controls. We identified regions of interest from seven key networks and examined responses to incongruent stimuli (Happy face-'Sad' word; Sad face-'Happy' word). Results In comparison with healthy controls, patients had differential activity during both incongruent conditions. When examining for associations with suicidal activity within the patient group, those with higher scores had decreased default mode network activity for Happy face-'Sad' word manipulation, and increased basal ganglia network activity for Sad face-'Happy' word manipulation, after controlling for patient characteristics. Conclusion The fMRI findings suggest that suicidal activity in patients with mood disorders may be underpinned by cognitive-emotional deficits. These findings have implications for future suicide research and for achieving a deeper understanding of suicidal activity that may ultimately inform clinical detection and management.

Objective: Adolescence is a time of increased susceptibility to environmental stress and mood disorders, and girls are particularly at risk. Genes interacting with the environment (G × E) are implicated in hypothalamic-pituitary-adrenal axis dysregulation, hippocampal volume changes and risk or resilience to mood disorders. In this study, we assessed the effects of stress system G × E interactions on hippocampal volumes and cortisol secretion in adolescent girls. Methods: We recruited 229 girls aged 12–18 years, and scans were obtained from 202 girls. Of these, 76 had been exposed to higher emotional trauma (abuse or neglect). Hippocampal volumes were measured using Freesurfer and high-resolution structural magnetic resonance imaging scans. Saliva samples were collected for measurement of cortisol levels and genotyping of stress system genes: FKBP5, NR3C1 (both N = 194) and NR3C2 ( N = 193). Results: Among girls with the ‘G’ allelic variant of the NR3C1 gene, those who had been exposed to higher emotional trauma had significantly smaller left hippocampal volumes ( N = 44; mean = 4069.58 mm3, standard deviation = 376.99) than girls who had been exposed to minimal emotional trauma with the same allelic variant ( N = 69; mean = 4222.34 mm3, standard deviation = 366.74). Conclusion: In healthy adolescents, interactions between emotional trauma and the ‘protective’ NR3C1 ‘GG’ variant seem to induce reductions in left hippocampal volumes. These G × E interactions suggest that vulnerability to mood disorders is perhaps driven by reduced ‘protection’ that may be specific to emotional trauma. This novel but preliminary evidence has implications for targeted prevention of mood disorders and prospective multimodal neuroimaging and longitudinal studies are now needed to investigate this possibility.

Darryl Bassett, Gordon Parker, Amber Hamilton, Grace Morris, Bernhard T Baune, Philip Boyce, Malcolm Hopwood, Roger Mulder, Richard Porter, Ajeet Singh, Tim Outhred, Zola Mannie, Pritha Das and Gin S Malhi