Significant age by childhood trauma interactions on grey matter volumes: A whole brain VBM analysis.

BACKGROUND: Childhood trauma is deleterious to long term brain development. The changes are variable, and depend on gender, age and the nature of the trauma. In this exploratory analysis, we investigated the effects of exposure to emotional trauma on grey matter (GM) volumes in adolescent females. METHODS: We explored GM volumes in non-clinical females aged 12-17 years who had been exposed to either higher (HET; N = 75) or minimal (MET; N = 127) emotional trauma. High-resolution T1-weighted structural images were analysed with an optimised FSL-VBM protocol. The General Linear Model was run on HET versus MET with continuous age as an interaction. Mean GM volumes were extracted from significant corrected age interaction statistical maps and scrutinised with SPSS®. RESULTS: We observed greater HET*age than MET*age interactions (corrected p-value = 0.0002), in 4 separate bilateral cortical regions associated with mood disorders. Scrutiny of these regions showed significant GM volume enlargements in the early adolescent HET group (p = 0.017) and reductions in the late adolescent HET group (p < 0.0001). Notably, there were no differences in middle adolescence (p > 0.05). LIMITATIONS: Causality cannot be inferred from this cross-sectional study and the onset of trauma cannot be determined using retrospective measures. CONCLUSIONS: Whilst GM volumes diminish from early adolescence onwards, our results show that HET impacts this brain development, perhaps first via unstable adaptative mechanisms, followed by maladaptive processes in late adolescence. This suggests that compromises of emotional and cognitive self-regulation in mood disorders may underpin the structural abnormalities observed across multiple brain regions in these teenage girls.

Lithium replacement dose recommendations using Monte Carlo simulations.

OBJECTIVES: Missed medication doses are a common clinical problem, and cause consternation when prescribing lithium because its plasma levels must be kept within a narrow therapeutic window. Therefore, this study set out to determine the potential impact of missed lithium doses on its pharmacokinetics, and to explore the optimal compensatory dosing scheme. This is difficult to determine clinically and in research because of ethical constraints and therefore we modelled the effects using simulations. METHODS: Monte Carlo simulations were used to simulate lithium concentrations under different missed dose scenarios. For patients with normal renal function, the optimal replacement dosing scheme was selected based on the lowest percentage of deviation from the full adherence scenario. However, for patients with renal impairment the appropriate dosing schedule was selected based on the lowest number of simulated concentrations above the upper range of 1.2 mEq/L. RESULTS: The impact of a missed lithium dose depended on its daily dose. The higher the daily dose, the higher the deviation from full adherence. In patients with normal renal function, replacement with a regular dose was most appropriate. But in patients with renal impairment, replacement with a partial dose appeared to be most suitable. CONCLUSIONS: This study has enabled insights into the optimal suitable lithium replacement dosing schemes for patients with normal renal function and renal impairment. These proposed schemes can be used cautiously in clinical practice in conjunction with clinician judgment and can also be used as a basis for future clinical research.

Profiling rTMS: A critical response.

This article is a detailed response to the criticisms levelled by the authors of an accompanying viewpoint, which claims that the positioning of repetitive transcranial magnetic stimulation (rTMS) in the 2020 Royal Australian and New Zealand College of Psychiatrists (RANZCP) clinical practice guidelines for the management mood disorders (MDcpg2020) is incorrect. We, the authors of the MDcpg2020, strongly refute these assertions and argue that first we have determined the positioning of rTMS using the same criteria as those applied to other treatments for depression. Second, in accordance with National Health and Medical Research Council (NHMRC) guidelines, the processes by which we have developed the MDcpg2020 have been guided by best practice and have been overseen throughout by the RANZCP. Third, our objective and detailed examination of the relevant research has shown that the evidence needed to support the positioning of rTMS alongside standard therapies for depression is severely deficient. And therefore, as a consequence, we set out clearly both our logic and reasoning with respect to interpreting rTMS data and outline our evidence-informed position in which rTMS remains a potential alternative therapy that can be considered in certain clinical circumstances once both suitable psychological and pharmacological treatments have been trialled. We also discuss why, until further research is conducted, rTMS is perhaps best regarded as an experimental therapy and an investigational tool, and to assist in this regard, we propose a framework for consideration by those conducting rTMS studies in the future. Thus, based on current knowledge, we conclude that rTMS does not have a sufficient evidence base to warrant recognition as a standard therapy for depression alongside established treatments such as psychological interventions, pharmacotherapy, and electroconvulsive therapy. Furthermore, there is no clinical profile for depressed patients that might benefit from rTMS and therefore tolerability alone is not good enough reason to promote rTMS in the management of major depression.

Treatment-resistant depression: problematic illness or a problem in our approach?

Treatment-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.

The effects of childhood trauma on adolescent hippocampal subfields.

OBJECTIVE: Mood disorders are more common among girls and typically emerge during adolescence. The precise reasons for this are unknown, but among the many mechanisms implicated are stress-induced hippocampal structural changes during this developmental stage. The hippocampus is a complex structure comprised of subfields that develop differentially and respond variably to stress and childhood adversity, both of which are risk factors for mood disorders. To better understand vulnerability to mood disorders, we investigated a cohort of adolescent girls and determined volumetric changes in their hippocampal subfields to elucidate the potential effects of childhood trauma. METHODS: Of the 229 participants, 201 girls (aged 12-17 years) fulfilled our analysis inclusion criteria. Of these, 76 had been exposed to higher emotional trauma (emotional abuse or neglect). The girls underwent high-resolution structural magnetic resonance imaging scans, and hippocampal subfield volumes were measured using FreeSurfer. We compared hippocampal subfield volumes in those exposed to higher emotional trauma and those exposed to minimal emotional trauma, at three time-points of adolescent development: early (12-13 years), mid (14-15 years) and late (16-17 years). RESULTS: Mid-adolescent girls exposed to higher emotional trauma had significantly smaller left CA3 volumes than minimal emotional trauma girls ( p = 0.028). Within the minimal emotional trauma group, mid-adolescents had significantly larger left CA3 volumes than early ( p = 0.034) and late ( p = 0.036) adolescents. Within the higher emotional trauma group, early adolescents had significantly larger left CA3 volumes than late adolescents ( p = 0.036). CONCLUSION: In our exploratory study, we observed higher emotional trauma-induced volume changes in the left CA3 hippocampal subfield, which varied depending on age, and may ultimately produce deficits in behavioural, cognitive and emotional processes. We propose that these changes (1) may provide a mechanism through which vulnerability to mood disorders may be increased in adolescent girls, and (2) may signal the best times to implement targeted prevention interventions.

Effect of stress gene-by-environment interactions on hippocampal volumes and cortisol secretion in adolescent girls.

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.

Modeling suicide in bipolar disorders.

INTRODUCTION: Suicide is a multicausal human behavior, with devastating and immensely distressing consequences. Its prevalence is estimated to be 20-30 times greater in patients with bipolar disorders than in the general population. The burden of suicide and its high prevalence in bipolar disorders make it imperative that our current understanding be improved to facilitate prediction of suicide and its prevention. In this review, we provide a new perspective on the process of suicide in bipolar disorder, in the form of a novel integrated model that is derived from extant knowledge and recent evidence. METHODS: A literature search of articles on suicide in bipolar disorder was conducted in recognized databases such as Scopus, PubMed, and PsycINFO using the keywords "suicide", "suicide in bipolar disorders", "suicide process", "suicide risk", "neurobiology of suicide" and "suicide models". Bibliographies of identified articles were further scrutinized for papers and book chapters of relevance. RESULTS: Risk factors for suicide in bipolar disorders are well described, and provide a basis for a framework of epigenetic mechanisms, moderated by neurobiological substrates, neurocognitive functioning, and social inferences within the environment. Relevant models and theories include the diathesis-stress model, the bipolar model of suicide and the ideation-to-action models, the interpersonal theory of suicide, the integrated motivational-volitional model, and the three-step theory. Together, these models provide a basis for the generation of an integrated model that illuminates the suicidal process, from ideation to action. CONCLUSION: Suicide is complex, and it is evident that a multidimensional and integrated approach is required to reduce its prevalence. The proposed model exposes and provides access to components of the suicide process that are potentially measurable and may serve as novel and specific therapeutic targets for interventions in the context of bipolar disorder. Thus, this model is useful not only for research purposes, but also for future real-world clinical practice.

Is "early intervention" in bipolar disorder what it claims to be?

BACKGROUND: The notion of early intervention is understandably appealing for conditions such as bipolar disorder (BD), a chronic life-long illness that increases risk of suicide and diminishes quality of life. It is purported that intervening early in the course of the illness with suitable interventions could substantially alter the trajectory of BD and improve outcomes. However, while there are obvious benefits to the prompt commencement of treatment, it is important to consider the gaps in our understanding regarding the aetiopathogenesis of bipolar disorder-upon which the paradigm of early intervention is predicated. METHODS: A literature search was undertaken using recognized search engines: PubMed, PsycINFO Medline, and Scopus, along with auxiliary manual searches. RESULTS: This review first examines how the unpredictable nature of BD creates substantial difficulties when determining an optimal therapeutic target for early intervention. Second, the challenges with identifying appropriate populations and apposite times for early intervention strategies is discussed. Finally, the risks associated with intervening early are examined, highlighting the potential harmful effects of initiating medication. CONCLUSION: Early intervention for BD is a potentially useful strategy that warrants investigation, but until the emergence and trajectory of the illness are definitive, and a clear view of key targets is achieved, a more conservative approach to treating nascent BD and its antecedent symptoms is needed.

Cardiovascular and metabolic risk profile in young people at familial risk of depression.

BACKGROUND: Depression is associated with increased risk of several general medical conditions, including diabetes and cardiovascular disease. The nature of the association is complex and may involve bidirectional causation or a common pathophysiology. AIMS: To determine whether young people without depression but at increased familial risk have altered metabolic and blood pressure markers relative to matched controls. METHOD: We studied young people (n = 85), who had a parent with depression but no personal history of depressive illness (FH+) and healthy controls (n = 69). Cardiovascular risk profile was assessed by a fasting blood sample to measure insulin, glucose, lipids and high-sensitivity C-reactive protein (CRP) and blood pressure was measured centrally and peripherally. Arterial stiffness and waking cortisol concentration were also measured. RESULTS: Compared with controls, the FH+ group demonstrated increased peripheral and central systolic blood pressure, increased arterial stiffness and diminished insulin sensitivity but they did not differ from controls in measures of lipids, CRP or waking cortisol. CONCLUSIONS: Our data suggest that young people at increased familial risk of depression show evidence of altered cardiovascular risk profile in young adulthood even in the absence of depressive symptoms. It is possible therefore that vulnerability to conditions such as hypertension and diabetes may precede the onset of major depression and may share common risk factors.

Elevated cortical glutamate in young people at increased familial risk of depression.

Using proton magnetic resonance spectroscopy (MRS), we have demonstrated regional abnormalities in cortical γ-aminobutyric acid (GABA) and glutamate in medication-free recovered depressed patients. It is unclear whether these changes represent an underlying trait vulnerability to depression, or an after-effect of episodes of illness or its treatment. We sought to examine this question by examining a group of high-risk, never-depressed, individuals. We used MRS to measure GABA and glutamate in parieto-occipital cortex in young people (ages 16-21 yr) with a family history of parental depression (n=24) but no personal history of illness and a control group without a history of depression in any first-degree relative (n=28). Participants with a parental history of depression had significantly higher levels of glutamate than controls in parieto-occipital cortex (F1,47=5.5, p=0.02). These findings suggest that abnormalities in glutamate neurotransmission may reflect a trait marker of vulnerability to depression.

Irritability and mood symptoms in adolescent girls: Trait anxiety and emotion dysregulation as mediators.

BACKGROUND: Irritability is a common symptom in youth that is thought to be predictive of mood disorders. Its effects on mood are likely to be age-dependent, with direct and indirect mediators. We assessed age-related effects and mediators of irritability in adolescent girls with subthreshold depressive and manic symptoms. METHODS: We analysed the irritability item from the Mood Disorder Questionnaire in 3 cohorts of girls aged 12-18years (N=229); 12-13years (N=82); 14-15years (N=68); and 16-18years (N=79). They also completed mood, anxiety and emotion regulation questionnaires. MANOVA, correlations and bootstrapped mediation analyses were performed with SPSS®v25 and Hayes Processv3.5®. RESULTS: Overall, irritable girls had higher depressive and manic symptoms, trait anxiety and emotion dysregulation than those who were not irritable. Significantly higher rates of irritability were observed in mid-adolescents (aged 14-15years; p = 0.001). Notably, irritability exerted effects on depressive symptoms via trait anxiety, non-acceptance of emotions and dysregulation in emotion clarity throughout adolescence. However, irritability directly exerted effects on manic symptoms in mid-adolescence but in older adolescents, their relationship was indirect via impulse control dysregulation. LIMITATIONS: The cross-sectional design and non-clinical sample limit generalisability of our findings. CONCLUSIONS: Irritability is involved in subthreshold depressive symptoms, via trait anxiety and perceptual emotion dysregulation. On the other hand, irritability is directly and indirectly associated with subthreshold manic symptoms via dysregulated impulse control depending on age. Therefore, screening for irritability, trait anxiety and emotion dysregulation throughout adolescence may facilitate the early detection of subthreshold depressive and manic symptoms, and the implementation of preventive strategies.

Novel insights into irritability: the relationship between subjective experience, age and mood.

BACKGROUND: The relationship between irritability as a subjective experience and the behavioural indicators typically used to measure the construct are not known. Its links to mood, and contextual relationships, vary with age and are yet to be thoroughly examined. AIMS: First, to interrogate the relationship between the subjective experience of irritability and mood, and that with its behavioural indicators. Second, to determine how these relationships vary with age and over time. METHOD: This study examined data from a previous clinical trial of adolescents and young adults (N = 82) with bipolar disorder, who received a psychological intervention over 18 months. Participants completed a battery of questionnaires, which included assessments of irritability. Analyses of covariance were conducted to examine the interaction between mood symptoms, subjective measures of irritability, behavioural measures of irritability and age over time. RESULTS: Subjective irritability scores differed significantly over time when controlling for manic, but not depressive, symptom scores. Further, subjective irritability significantly differed when controlling for behavioural measures of irritability (temper outbursts and argumentativeness). There were significant interactions between scores of depressive symptoms, temper outbursts and subjective irritability with age, wherein younger participants showed no correlation between depressive symptoms and temper outbursts. In addition, younger participants showed lower correlations between subjective irritability and both depressive and temper outburst scores, than older participants. CONCLUSIONS: Subjective irritability is linked to mood morbidity and behavioural outbursts, and these relationships are contingent on age. Our novel findings suggest that subjective irritability should be assessed in greater detail in patients with mood disorders.