Neuroanatomical distribution of fluorophores within adult RXFP3 Cre-tdTomato/YFP mouse brain.

Relaxin-family peptide 3 receptor (RXFP3) is activated by relaxin-3 in the brain to influence arousal and related functions, such as feeding and stress responses. Two transgenic mouse lines have recently been developed that co-express different fluorophores within RXFP3-expressing neurons: either yellow fluorescent protein (YFP; RXFP3-Cre/YFP mice) or tdTomato (RXFP3-Cre/tdTomato mice). To date, the characteristics of neurons that express RXFP3-associated fluorophores in these mice have only been investigated in the bed nucleus of the stria terminalis and the hypothalamic arcuate nucleus. To better determine the utility of these fluorophore-expressing mice for further research, we characterised the neuroanatomical distribution of fluorophores throughout the brain of these mice and compared this to the published distribution of Rxfp3 mRNA (detected by in situ hybridisation) in wildtype mice. Coronal sections of RXFP3-Cre/YFP (n = 8) and RXFP3-Cre/tdTomato (n = 8) mouse brains were imaged, and the density of fluorophore-expressing cells within various brain regions/nuclei was qualitatively assessed. Comparisons with our previously reported RXFP3 mRNA distribution revealed that of 212 brain regions that contained either fluorophore or RXFP3 mRNA, approximately half recorded densities that were within two qualitative measurements of each other (on a 9-point scale), including hippocampal dentate gyrus and amygdala subregions. However, many brain areas with likely non-authentic, false-positive, or false-negative fluorophore expression were also detected, including the cerebellum. Therefore, this study provides a guide to which brain regions should be prioritized for future study of RXFP3 in these mice, to better understand the neuroanatomy and function of this intriguing, neuronal peptide receptor.

The potential of baicalin to enhance neuroprotection and mitochondrial function in a human neuronal cell model.

Baicalin is a flavone glycoside derived from flowering plants belonging to the Scutellaria genus. Previous studies have reported baicalin's anti-inflammatory and neuroprotective properties in rodent models, indicating the potential of baicalin in neuropsychiatric disorders where alterations in numerous processes are observed. However, the extent of baicalin's therapeutic effects remains undetermined in a human cell model, more specifically, neuronal cells to mimic the brain environment in vitro. As a proof of concept, we treated C8-B4 cells (murine cell model) with three different doses of baicalin (0.1, 1 and 5 µM) and vehicle control (DMSO) for 24 h after liposaccharide-induced inflammation and measured the levels of TNF-α in the medium by ELISA. NT2-N cells (human neuronal-like cell model) underwent identical baicalin treatment, followed by RNA extraction, genome-wide mRNA expression profiles and gene set enrichment analysis (GSEA). We also performed neurite outgrowth assays and mitochondrial flux bioanalysis (Seahorse) in NT2-N cells. We found that in C8-B4 cells, baicalin at ≥ 1 µM exhibited anti-inflammatory effects, lowering TNF-α levels in the cell culture media. In NT2-N cells, baicalin positively affected neurite outgrowth and transcriptionally up-regulated genes in the tricarboxylic acid cycle and the glycolysis pathway. Similarly, Seahorse analysis showed increased oxygen consumption rate in baicalin-treated NT2-N cells, an indicator of enhanced mitochondrial function. Together, our findings have confirmed the neuroprotective and mitochondria enhancing effects of baicalin in human-neuronal like cells. Given the increased prominence of mitochondrial mechanisms in diverse neuropsychiatric disorders and the paucity of mitochondrial therapeutics, this suggests the potential therapeutic application of baicalin in human neuropsychiatric disorders where these processes are altered.

Network-based drug repurposing for schizophrenia.

Despite recent progress, the challenges in drug discovery for schizophrenia persist. However, computational drug repurposing has gained popularity as it leverages the wealth of expanding biomedical databases. Network analyses provide a comprehensive understanding of transcription factor (TF) regulatory effects through gene regulatory networks, which capture the interactions between TFs and target genes by integrating various lines of evidence. Using the PANDA algorithm, we examined the topological variances in TF-gene regulatory networks between individuals with schizophrenia and healthy controls. This algorithm incorporates binding motifs, protein interactions, and gene co-expression data. To identify these differences, we subtracted the edge weights of the healthy control network from those of the schizophrenia network. The resulting differential network was then analysed using the CLUEreg tool in the GRAND database. This tool employs differential network signatures to identify drugs that potentially target the gene signature associated with the disease. Our analysis utilised a large RNA-seq dataset comprising 532 post-mortem brain samples from the CommonMind project. We constructed co-expression gene regulatory networks for both schizophrenia cases and healthy control subjects, incorporating 15,831 genes and 413 overlapping TFs. Through drug repurposing, we identified 18 promising candidates for repurposing as potential treatments for schizophrenia. The analysis of TF-gene regulatory networks revealed that the TFs in schizophrenia predominantly regulate pathways associated with energy metabolism, immune response, cell adhesion, and thyroid hormone signalling. These pathways represent significant targets for therapeutic intervention. The identified drug repurposing candidates likely act through TF-targeted pathways. These promising candidates, particularly those with preclinical evidence such as rimonabant and kaempferol, warrant further investigation into their potential mechanisms of action and efficacy in alleviating the symptoms of schizophrenia.

Exploring Clinical Subgroups of Participants with Major Depressive Disorder that may Benefit from Adjunctive Minocycline Treatment.

Objective: : To explore illness-related factors in patients with major depressive disorder (MDD) recipients of adjunctive minocycline (200 mg/day) treatment. The analysis included participants experiencing MDD from a 12-week, double blind, placebo-controlled, randomized clinical trial (RCT). Methods: : This is a sub-analysis of a RCT of all 71 participants who took part in the trial. The impact of illness chronicity (illness duration and number of depressive episodes), systemic illness (endocrine, cardiovascular and obesity), adverse effects and minocycline were evaluated as change from baseline to endpoint (12-week) using ANCOVA. Results: : There was a consistent but statistically non-significant trend on all outcomes in favour of the use of adjunctive minocycline for participants without systemic illness, less illness chronicity, and fewer adverse effects. Conclusion: : Understanding the relationship between MDD and illness chronicity, comorbid systemic illness, and adverse effects, can potentially better characterise those individuals who are more likely to respond to adjunctive anti-inflammatory medications.

Use of gene regulatory network analysis to repurpose drugs to treat bipolar disorder.

BACKGROUND: Bipolar disorder (BD) presents significant challenges in drug discovery, necessitating alternative approaches. Drug repurposing, leveraging computational techniques and expanding biomedical data, holds promise for identifying novel treatment strategies. METHODS: This study utilized gene regulatory networks (GRNs) to identify significant regulatory changes in BD, using network-based signatures for drug repurposing. Employing the PANDA algorithm, we investigated the variations in transcription factor-GRNs between individuals with BD and unaffected individuals, incorporating binding motifs, protein interactions, and gene co-expression data. The differences in edge weights between BD and controls were then used as differential network signatures to identify drugs potentially targeting the disease-associated gene signature, employing the CLUEreg tool in the GRAND database. RESULTS: Using a large RNA-seq dataset of 216 post-mortem brain samples from the CommonMind consortium, we constructed GRNs based on co-expression for individuals with BD and unaffected controls, involving 15,271 genes and 405 TFs. Our analysis highlighted significant influences of these TFs on immune response, energy metabolism, cell signalling, and cell adhesion pathways in the disorder. By employing drug repurposing, we identified 10 promising candidates potentially repurposed as BD treatments. LIMITATIONS: Non-drug-naïve transcriptomics data, bulk analysis of BD samples, potential bias of GRNs towards well-studied genes. CONCLUSIONS: Further investigation into repurposing candidates, especially those with preclinical evidence supporting their efficacy, like kaempferol and pramocaine, is warranted to understand their mechanisms of action and effectiveness in treating BD. Additionally, novel targets such as PARP1 and A2b offer opportunities for future research on their relevance to the disorder.

The Influence of Personality Disorder Symptoms on Treatment Outcomes in Bipolar Disorder: A Secondary Analysis of a Randomised Controlled Trial: L'influence des symptômes du trouble de la personnalité sur les résultats du traitement dans le trouble bipolaire : Une analyse secondaire d'un essai randomisé contrôlé.

OBJECTIVES: Many people who are diagnosed with bipolar disorder also have comorbid personality disorder. Few studies have explored how personality disorder may influence pharmacological treatment outcomes. The aim of this study was to conduct a secondary analysis of data from a clinical trial of adjunctive nutraceutical treatments for bipolar depression, to determine whether maladaptive personality traits influence treatment outcomes. METHODS: Scores on the Standardised Assessment of Personality - Abbreviated Scale screener were used to classify participants as having bipolar disorder with (n = 119) and without (n = 29) above threshold personality disorder symptoms (personality disorder). Outcome measures included: The Montgomery Åsberg Depression Rating Scale, Clinical Global Impressions and Improvement Severity Scales, Patient Global Impressions-Improvement scale, Bipolar Depression Rating Scale, Range of Impaired Functioning Tool, Social and Occupational Functioning Assessment Scale and Quality of Life and Enjoyment Scale (Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form). Generalised estimated equations examined the two-way interactions of personality disorder by time or treatment and investigated personality disorder as a non-specified predictor of outcomes. RESULTS: Over time, the Patient Global Impressions-Improvement scores were significantly higher in those in the personality disorder group. No other significant differences in the two-way interactions of personality disorder by treatment group or personality disorder by time were found. Personality disorder was a significant but non-specific predictor of poorer outcomes on the Bipolar Depression Rating Scale, Range of Impaired Functioning Tool, and Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form, regardless of time or treatment group. CONCLUSIONS: This study highlights the potential impact of maladaptive personality traits on treatment outcomes and suggests that the presence of comorbid personality disorder may confer additional burden and compromise treatment outcomes. This warrants further investigation as does the corroboration of these exploratory findings. This is important because understanding the impact of comorbid personality disorder on bipolar disorder may enable the development of effective psychological and pharmacotherapeutic options for personalised treatments.

Metergoline Shares Properties with Atypical Antipsychotic Drugs Identified by Gene Expression Signature Screen.

Novel approaches are required to find new treatments for schizophrenia and other neuropsychiatric disorders. This study utilised a combination of in vitro transcriptomics and in silico analysis with the BROAD Institute's Connectivity Map to identify drugs that can be repurposed to treat psychiatric disorders. Human neuronal (NT2-N) cells were treated with a combination of atypical antipsychotic drugs commonly used to treat psychiatric disorders (such as schizophrenia, bipolar disorder, and major depressive disorder), and differential gene expression was analysed. Biological pathways with an increased gene expression included circadian rhythm and vascular endothelial growth factor signalling, while the adherens junction and cell cycle pathways were transcriptionally downregulated. The Connectivity Map (CMap) analysis screen highlighted drugs that affect global gene expression in a similar manner to these psychiatric disorder treatments, including several other antipsychotic drugs, confirming the utility of this approach. The CMap screen specifically identified metergoline, an ergot alkaloid currently used to treat seasonal affective disorder, as a drug of interest. In mice, metergoline dose-dependently reduced MK-801- or methamphetamine-induced locomotor hyperactivity confirming the potential of metergoline to treat positive symptoms of schizophrenia in an animal model. Metergoline had no effects on prepulse inhibition deficits induced by MK-801 or methamphetamine. Taken together, metergoline appears a promising drug for further studies to be repurposed as a treatment for schizophrenia and possibly other psychiatric disorders.

Barriers to and facilitators of success for early and Mid-Career professionals focused on bipolar disorder: A global needs survey by the International Society for Bipolar Disorders.

INTRODUCTION: The International Society for Bipolar Disorders created the Early Mid-Career Committee (EMCC) to support career development of the next generation of researchers and clinicians specializing in bipolar disorder (BD). To develop new infrastructure and initiatives, the EMCC completed a Needs Survey of the current limitations and gaps that restrict recruitment and retention of researchers and clinicians focused on BD. METHODS: The EMCC Needs Survey was developed through an iterative process, relying on literature and content expertise of workgroup members. The survey included 8 domains: navigating transitional career stages, creating and fostering mentorship, research activities, raising academic profile, clinical-research balance, networking and collaboration, community engagement, work-life balance. The final survey was deployed from May to August 2022 and was available in English, Spanish, Portuguese, Italian, and Chinese. RESULTS: Three hundred participants across six continents completed the Needs Survey. Half of the participants self-identified as belonging to an underrepresented group in health-related sciences (i.e., from certain gender, racial, ethnic, cultural, or disadvantaged backgrounds including individuals with disabilities). Quantitative results and qualitative content analysis revealed key barriers to pursuing a research career focused on BD with unique challenges specific to scientific writing and grant funding. Participants highlighted mentorship as a key facilitator of success in research and clinical work. CONCLUSION: The results of the Needs Survey are a call to action to support early- and midcareer professionals pursuing a career in BD. Interventions required to address the identified barriers will take coordination, creativity, and resources to develop, implement, and encourage uptake but will have long-lasting benefits for research, clinical practice, and ultimately those affected by BD.

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

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.

Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine.

Bipolar disorder's core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology implies that a range of inherited and environmental factors are involved. This heterogeneity and poorly understood neurobiology pose significant challenges to existing drug development paradigms, resulting in scarce treatment options, especially for bipolar depression. Therefore, novel approaches are needed to discover new treatment options. In this review, we first highlight the main molecular mechanisms known to be associated with bipolar depression-mitochondrial dysfunction, inflammation and oxidative stress. We then examine the available literature for the effects of trimetazidine in said alterations. Trimetazidine was identified without a priori hypothesis using a gene-expression signature for the effects of a combination of drugs used to treat bipolar disorder and screening a library of off-patent drugs in cultured human neuronal-like cells. Trimetazidine is used to treat angina pectoris for its cytoprotective and metabolic effects (improved glucose utilization for energy production). The preclinical and clinical literature strongly support trimetazidine's potential to treat bipolar depression, having anti-inflammatory and antioxidant properties while normalizing mitochondrial function only when it is compromised. Further, trimetazidine's demonstrated safety and tolerability provide a strong rationale for clinical trials to test its efficacy to treat bipolar depression that could fast-track its repurposing to address such an unmet need as bipolar depression.

Interpersonal Trauma and Depression Severity Among Individuals With Bipolar Disorder: Findings From the Prechter Longitudinal Study of Bipolar Disorder.

Background: Experiences of interpersonal trauma, both in childhood and in adulthood, can affect the trajectory of bipolar disorder (BD). However, the degree to which childhood and/or adult trauma impacts the longitudinal trajectory of depression severity among individuals with BD actively receiving treatment remains unclear.Methods: The effects of childhood trauma (Childhood Trauma Questionnaire) and adult trauma (Life Events Checklist) on depression severity (Hamilton Depression Rating Scale) were investigated in a treatment-receiving subsample with BD (DSM-IV) of the Prechter Longitudinal Study of Bipolar Disorder (2005-present). A mixed-effects linear regression model was used to assess the trajectory of depression severity over 4 years.Results: Depression severity was evaluated in 360 participants, of whom 267 (74.8%) reported a history of interpersonal trauma. A history of childhood trauma alone (n = 110) and childhood and adult trauma combined (n = 108)-but not adult trauma alone (n = 49) -were associated with greater depression severity at the 2-year and 6-year follow-up assessments. However, the trajectory of depression severity (ie, change over time) was similar between participants with a history of childhood trauma, those with a history of adult trauma, and those with no history of interpersonal trauma. Interestingly, participants with a history of both types of trauma showed more improvement in depression severity (ie, from year 2 to year 4: ß = 1.67, P = .019).Conclusions: Despite actively receiving treatment for BD, participants with a history of interpersonal trauma-particularly childhood trauma-presented with more severe depressive symptoms at several follow-up assessments. Hence, interpersonal trauma may represent an essential treatment target.

The Impact of N-acetylcysteine on Major Depression: Qualitative Observation and Mixed Methods Analysis of Participant Change during a 12-week Randomised Controlled Trial.

Objective: N-acetylcysteine (NAC) is a novel therapeutic agent with multiple mechanisms of action in the central nervous system and a favourable side effect profile. Clinical evidence indicates that adjunctive NAC may reduce the severity of depressive symptoms in individuals with major depressive disorder (MDD). Methods: A 12-week randomised controlled trial of 2,000 mg/day adjunctive NAC for MDD found no significant improvement at the primary endpoint (week 12) but did see improvements at the post-discontinuation interview (week 16). Within the context of patient-centered treatment, mixed-methods qualitative analysis was also included to explore factors that may determine individual responses to adjunctive NAC treatment. These data were drawn, under blinded conditions, from clinician notes recorded in the case report form. Using the DSM-5 symptom profile for MDD as the initial framework, themes were developed and explored. Frequencies were compared between placebo and NAC groups. Results: Per protocol analysis of individual themes across the six interviews revealed group differences in favour of NAC for overall depressive affect, optimism, relationships and reduced functional impairment. Conclusion: This study provides further evidence for the utility of the mixed methods approach complimenting the primary findings using traditional quantitative analyses, as well as being able to capture additional, often more subtle, evidence of individual symptom-level change that reflects improvement in functional abilities in response to NAC supplementation. The use of mixed methods to explore outcomes from psychiatric studies should be considered in future to work towards improved patient-centred care and both confirm quantitative findings and generate novel hypotheses.

Childhood trauma relates to worse memory functioning in bipolar disorder.

BACKGROUND: Childhood trauma is commonly experienced by individuals diagnosed with bipolar disorder (BP). In BP, childhood trauma is related to a more severe clinical course, but its association with cognition remains unclear. METHODS: This study evaluated 405 adult participants diagnosed with BP and 136 controls. Participants completed the Childhood Trauma Questionnaire and a comprehensive neuropsychological battery. High versus low childhood trauma was defined with one standard deviation above the control participant's mean Childhood Trauma Questionnaire score. Neuropsychological data was transformed into eight cognitive factors, including four executive functioning, auditory and visual memory, fine motor, and emotion processing. Multivariate analysis of covariance evaluated group differences in cognition, while adjusting for covariates. RESULTS: There were significant differences among the three groups, F(16, 968) = 4.05, p < .001, Wilks' Λ = 0.88, partial η2 = 0.06. Comparing the high and low trauma BP groups, high trauma was related to lower auditory and visual memory factor scores (p < .05). As compared to controls, the BP high trauma group had lower scores on six of eight factors (all p < .01), while the BP low trauma group had lower scores on four of eight factors (all p < .01). LIMITATIONS: Analyses of factor score do not address which aspect of the memory process is affected and biomarkers may help guide interventions addressing underlying biological process. CONCLUSIONS: Adults diagnosed with BP with higher childhood trauma have worse memory functioning, beyond the lower childhood trauma BP group, highlighting the importance of understanding the long-term cognitive outcomes of childhood trauma.

Use of a gene expression signature to identify trimetazidine for repurposing to treat bipolar depression.

OBJECTIVES: The aim of this study was to repurpose a drug for the treatment of bipolar depression. METHODS: A gene expression signature representing the overall transcriptomic effects of a cocktail of drugs widely prescribed to treat bipolar disorder was generated using human neuronal-like (NT2-N) cells. A compound library of 960 approved, off-patent drugs were then screened to identify those drugs that affect transcription most similar to the effects of the bipolar depression drug cocktail. For mechanistic studies, peripheral blood mononuclear cells were obtained from a healthy subject and reprogrammed into induced pluripotent stem cells, which were then differentiated into co-cultured neurons and astrocytes. Efficacy studies were conducted in two animal models of depressive-like behaviours (Flinders Sensitive Line rats and social isolation with chronic restraint stress rats). RESULTS: The screen identified trimetazidine as a potential drug for repurposing. Trimetazidine alters metabolic processes to increase ATP production, which is thought to be deficient in bipolar depression. We showed that trimetazidine increased mitochondrial respiration in cultured human neuronal-like cells. Transcriptomic analysis in induced pluripotent stem cell-derived neuron/astrocyte co-cultures suggested additional mechanisms of action via the focal adhesion and MAPK signalling pathways. In two different rodent models of depressive-like behaviours, trimetazidine exhibited antidepressant-like activity with reduced anhedonia and reduced immobility in the forced swim test. CONCLUSION: Collectively our data support the repurposing of trimetazidine for the treatment of bipolar depression.

Minocycline as Treatment for Psychiatric and Neurological Conditions: A Systematic Review and Meta-Analysis.

Minocycline has anti-inflammatory, antioxidant, and anti-apoptotic properties that explain the renewed interest in its use as an adjunctive treatment for psychiatric and neurological conditions. Following the completion of several new clinical trials using minocycline, we proposed an up-to-date systematic review and meta-analysis of the data available. The PICO (patient/population, intervention, comparison and outcomes) framework was used to search 5 databases aiming to identify randomized controlled trials that used minocycline as an adjunctive treatment for psychiatric and neurological conditions. Search results, data extraction, and risk of bias were performed by two independent authors for each publication. Quantitative meta-analysis was performed using RevMan software. Literature search and review resulted in 32 studies being included in this review: 10 in schizophrenia, 3 studies in depression, and 7 in stroke, with the benefit of minocycline being used in some of the core symptoms evaluated; 2 in bipolar disorder and 2 in substance use, without demonstrating a benefit for using minocycline; 1 in obsessive-compulsive disorder, 2 in brain and spinal injuries, 2 in amyotrophic lateral sclerosis, 1 in Alzheimer's disease, 1 in multiple systems atrophy, and 1 in pain, with mixes results. For most of the conditions included in this review the data is still limited and difficult to interpret, warranting more well-designed and powered studies. On the other hand, the studies available for schizophrenia seem to suggest an overall benefit favoring the use of minocycline as an adjunctive treatment.

Childhood trauma and depressive symptoms in bipolar disorder: A network analysis.

BACKGROUND: Childhood trauma is related to an increased number of depressive episodes and more severe depressive symptoms in bipolar disorder. The evaluation of the networks of depressive symptoms-or the patterns of relationships between individual symptoms-among people with bipolar disorder with and without a history of childhood trauma may assist in further clarifying this complex relationship. METHODS: Data from over 500 participants from the Heinz C. Prechter Longitudinal Study of Bipolar Disorder were used to construct a series of regularised Gaussian Graphical Models. The networks of individual depressive symptoms-self-reported (Patient Health Questionnaire-9; n = 543) and clinician-rated (Hamilton Depression Rating Scale-17; n = 529)-among participants with bipolar disorder with and without a history of childhood trauma (Childhood Trauma Questionnaire) were characterised and compared. RESULTS: Across the sets of networks, depressed mood consistently emerged as a central symptom (as indicated by strength centrality and expected influence); regardless of participants' history of childhood trauma. Additionally, feelings of worthlessness emerged as a key symptom in the network of self-reported depressive symptoms among participants with-but not without-a history of childhood trauma. CONCLUSION: The present analyses-although exploratory-provide nuanced insights into the impact of childhood trauma on the presentation of depressive symptoms in bipolar disorder, which have the potential to aid detection and inform targeted intervention development.

Adjunctive minocycline for major depressive disorder: A sub-study exploring peripheral immune-inflammatory markers and associated treatment response.

Background: Adjunctive minocycline shows promise in treating affective and psychotic disorders; however, the therapeutic mechanism remains unclear. Identifying relevant biomarkers may enhance the efficacy of novel adjunctive treatment candidates. We thus investigated the peripheral immune-inflammatory profile in a randomized controlled trial (RCT) of minocycline in major depressive disorder (MDD). Methods: This sub-study investigated serum samples from a RCT evaluating minocycline (200 mg/day, 12 weeks) in addition to treatment as usual for MDD (ACTRN12612000283875). Of the original sample (N = 71), serum assays were conducted in 47 participants (placebo n = 24; minocycline n = 23) targeting an array of 46 immune-inflammatory analytes including cytokines, chemokines, and acute-phase reactants. General estimating equations (GEE) were used to assess whether analyte concentration at baseline (effect modification) and change in analytes (change association) influenced change in Montgomery-Åsberg Depression Rating Scale (MADRS) score over time. The Benjamini-Hochberg approach was applied when adjusting for false discovery rates (FDR). Results: GEE models revealed several interaction effects. After adjusting for FDR several change association-models survived correction. However, no such models remained significant for effect modification. Three-way group × time × marker interactions were significant for complement C3 (B = -10.46, 95%CI [-16.832, -4.095], q = 0.019) and IL-1Ra (B = -9.008, 95%CI [-15.26, -2.751], q = 0.036). Two-way group × biomarker interactions were significant for ICAM-1/CD54 (B = -0.387, 95%CI [-0.513, -0.26], q < 0.001) and IL-8/CXCL8 (B = -4.586, 95%CI [-7.698, -1.475], q = 0.036) indicating that increases in the serum concentration of these analytes were associated with an improvement in MADRS scores in the minocycline group (compared with placebo). Conclusions: Change in complement C3, IL-1Ra, IL-8/CXCL8, and ICAM-1 may be associated with greater change in depressive scores following adjunctive minocycline treatment in MDD. Further investigations are needed to assess the utility of these biomarkers.

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

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.