Perinatal factors as risk factors of bipolar disorder onset in young adulthood: a 22-year birth cohort.

BACKGROUND: Bipolar disorder (BD) is a leading cause of disability-adjusted life years in young adults. Complications during prenatal periods have been associated with BD previously. The study aims to examine the association between perinatal factors and BD in order to prevent the risk of developing BD. METHODS: 3,794 subjects from the 1993 Pelotas population-based birth cohort study were included. We assessed 27 initial variables at birth and modelled BD onset at 18 and 22 years. We performed bivariate analysis, using binomial logistic regression models. The variables with p-value smaller than 0.05 were included into a multiple regression with confounding variables. RESULTS: Maternal smoking was associated with a 1.42-fold increased risk of BD at 18 or 22 years old (95% CI: 1.091-1.841), and maternal passive exposure to tobacco with a 1.43-fold increased risk (95% CI: 1.086-1.875). No association was found between other perinatal factors and BD after controlling for confounding factors. CONCLUSION: The results of this cohort corroborate with previous findings in the literature that already indicate the negative outcomes of maternal smoking during pregnancy. They may now be linked to other studies to target these factors for preventing the development of BD.

Early growth response 1 (EGR1) is downregulated in peripheral blood from patients with major psychiatric disorders.

OBJECTIVES: To evaluate relative expression of genes with the potential to translate environmental stimuli into long-term alterations in the brain - namely Early Growth Response (EGR)1, EGR3, and Cryptochrome Circadian Regulator 2 (CRY2) - in peripheral blood from patients with Bipolar Disorder (BD), Schizophrenia (SZ), Major Depressive Disorder (MDD) and healthy controls (HC). METHODS: Thirty individuals ranging from 18 to 60 years were recruited for each group (BD, SZ, MDD or HC) from a Brazilian public hospital. Therefore, individuals' peripheral blood was collected and EGR1, EGR3 and CRY2 gene expression analyzed by PCR Real Time. RESULTS: EGR1 mRNA levels are significantly lower in psychiatric patients when compared to HC, but there is no difference for EGR3 and CRY2. Exploring the findings for each diagnosis, there is a significant difference between each diagnosis group only for EGR1, which was lower in BD, MDD and SZ as compared to HC. No significant correlations were found between gene expression and clinical features. CONCLUSIONS: EGR1 is downregulated in psychiatric patients, regardless of the diagnosis and may be a potential common target in major psychiatric disorders. EGR1, as a transcription factor, modulates many other genes and participates in crucial neuronal and synaptic processes, such as plasticity, neurotransmitters metabolism, vesicular transport and signaling pathways. The study of EGR1 and its upstream regulators in psychiatry might lead to potential new therapeutic targets.

Cannabidiol as an Adjunctive Treatment for Acute Bipolar Depression: A Pilot Study: Le cannabidiol comme traitement d'appoint de la dépression bipolaire aiguë : une étude pilote.

OBJECTIVE: The treatment of bipolar depression remains challenging due to the limited effective and safe therapeutic options available; thus, developing newer treatments that are effective and well tolerable is an urgent unmet need. The objective of the present trial was to test 150 to 300 mg/day of cannabidiol as an adjunctive treatment for bipolar depression. METHOD: A randomized, double-blind, placebo-controlled pilot study to assess the efficacy of adjunctive cannabidiol in bipolar depression was used. Efficacy parameters were changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 8. Secondary outcomes included response and remission rates, changes in anxiety and psychotic symptoms, and changes in functioning. Patients continued double-blind treatment until week 12 to monitor for adverse effects, laboratory analysis, and manic symptoms. Study registry: NCT03310593. RESULTS: A total of 35 participants were included. MADRS scores significantly decreased from baseline to the endpoint (placebo, -14.56; cannabidiol, -15.38), but there was no significant difference between the groups. Similarly, there were no other significant effects on the secondary outcomes. However, an exploratory analysis showed a significant effect of cannabidiol 300 mg/day in reducing MADRS scores from week 2 to week 8 (placebo, -6.64; cannabidiol, -13.72). There were no significant differences in the development of manic symptoms or any other adverse effects. CONCLUSION: Cannabidiol did not show significantly higher adverse effects than placebo. Despite the negative finding on the primary outcome, an exploratory analysis suggested that cannabidiol should be further studied in bipolar depression in higher doses of at least 300 mg/day and under research designs that could better control for high placebo response.

Ketamine study: Protocol for naturalistic prospective multicenter study on subcutaneous ketamine infusion in depressed patients with active suicidal ideation.

Background: Psychiatric disorders are associated with more than 90% of reported suicide attempts worldwide, but few treatments have demonstrated a direct effect in reducing suicide risk. Ketamine, originally an anesthetic, has been shown anti-suicide effects in clinical trials designed to treat depression. However, changes at the biochemical level were assessed only in protocols of ketamine with very limited sample sizes, particularly when the subcutaneous route was considered. In addition, the inflammatory changes associated with ketamine effects and their correlation with response to treatment, dose-effect, and suicide risk warrant further investigation. Therefore, we aimed to assess whether ketamine results in better control of suicidal ideation and/or behavior in patients with depressive episodes and whether ketamine affects psychopathology and inflammatory biomarkers. Materials and methods: We report here the design of a naturalistic prospective multicenter study protocol of ketamine in depressive episodes carried out at Hospital de Clínicas de Porto Alegre (HCPA) and Hospital Moinhos de Vento (HMV). The study was planned to recruit adult patients with Major depressive disorder (MDD) or Bipolar disorder (BD) types 1 or 2, who are currently in a depressive episode and show symptoms of suicidal ideation and/or behavior according to the Columbia-Suicide Severity Rating Scale (C-SSRS) and have been prescribed ketamine by their assistant psychiatrist. Patients receive ketamine subcutaneously (SC) twice a week for 1 month, but the frequency can be changed or the dose decreased according to the assistant physician's decision. After the last ketamine session, patients are followed-up via telephone once a month for up to 6 months. The data will be analyzed using repeated measures statistics to evaluate the reduction in suicide risk as a primary outcome, as per C-SSRS. Discussion: We discuss the need for studies with longer follow-ups designed to measure a direct impact on suicide risk and that additional information about the safety and tolerability of ketamine in particular subset of patients such as those with depression and ideation suicide. In line, the mechanism behind the immunomodulatory effects of ketamine is still poorly understood. Trial registration: https://clinicaltrials.gov/, identifier NCT05249309.

The relationship between objective and subjective cognitive performance to clinical features in bipolar disorder: A 6 years follow-up study

There is a consensus in the literature indicating that patients with Bipolar Disorder (BD) show cognitive impairments, especially in executive function, during both acute episodes and euthymia.1 An emerging body of knowledge indicates the importance of promoting functional recovery and improving cognitive deficits to achieve an adequate treatment of BD. However, the trajectories of cognitive deficits are still unclear. The neuroprogression hypothesis suggests that BD may present a progressive course with cognitive and functioning decline, which may be associated with mood episodes, length of the illness, early trauma,2 and biological rhythms disturbance, which may be a feature of BD.3 However, most of the evidence in this field came from cross-sectional studies, and the few existing longitudinal studies bring contrary results.4 A small number of studies assess the patient's perception of their cognitive function, which might be highly relevant to their everyday life.5 Therefore, the ideal study to assess the progression of cognition in BD might include objective as well as subjective measures from a longitudinal perspective.Thus, the purpose of the present study was to evaluate longitudinal cognitive performance in a sample of individuals with BD at baseline and after six years. All patients were in a depressive episode at baseline and euthymic at follow-up. We assessed subjective and objective cognitive difficulties in both points. We also investigated the relationship between psychosocial functioning, biological rhythms, and childhood trauma to cognition and the course of the illness. As far as we know, this is the first report using specific instruments to measure the relationship between these aspects to objective and subjective cognitive difficulties in a longitudinal BD sample. (AU)

Inflammation and damage-associated molecular patterns in major psychiatric disorders.

BACKGROUND: Emerging evidence indicates that inflammation plays an important role as a mechanism underlying mental disorders. However, most of the research on inflammatory mechanisms focuses on serum levels of interleukins and very few studies have investigated molecules that initiate and expand innate immune pathways such as damage-associated molecular patterns (DAMPs). OBJECTIVES: This study investigated the levels of DAMPs among patients diagnosed with major depressive disorder (MDD), bipolar disorder (BD) I and II, schizophrenia (SCZ), and generalized anxiety disorder (GAD). We quantified serum levels of heat shock proteins (HSPs) 70 and 60 and of S100 calcium-binding protein B (S100B). METHODS: Serum levels of HSP70, HSP60, and S100B were assessed in a sample of participants with psychiatric disorders (n = 191) and a control group (CT) (n = 59) using enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum HSP70 concentrations were significantly higher in the MDD group compared to the CT, SCZ, and BD groups. The GAD group had higher concentrations of HSP70 than the SCZ group. Exploring associations with medications, lithium (p = 0.003) and clozapine (p = 0.028) were associated with lower HSP70 levels. Approximately 64% of the sample had DAMPs levels below the limits of detection indicated by the respective ELISA kit. CONCLUSION: This was the first study to assess DAMPs levels in a transdiagnostic sample. Our preliminary findings suggest that HSP70 may be associated with MDD pathophysiology. Medications such as lithium and clozapine were associated with lower HSP70 levels in BD and SCZ groups, respectively. Therefore, it is worth mentioning that all participants were medicated and many psychotropic drugs exert an anti-inflammatory effect, possibly reducing the signs of inflammation.

Trauma history in veterans with bipolar disorder and its impact on suicidality.

OBJECTIVES: Veterans are at increased risk for exposure to trauma, developing serious mental illnesses, and death by suicide. History of trauma correlates with worsening outcomes in patients with bipolar disorder. This study investigated associations between trauma exposure (type and timing) and suicide attempt in Veterans with bipolar disorder. METHODS: One hundred six Veterans with a diagnosis of bipolar disorder and 815 Veterans with no psychiatric history (age rage = 20-72 years old) completed a clinical questionnaire, the Beck Scale for Suicide Ideation, and the Traumatic Live Events Questionnaire. Multinomial logistic regressions investigated correlations between diagnosis, time of trauma (before, during, or after the military), trauma type (attack, illness, accident, child violence, child sexual abuse, and adult sexual abuse), and suicide attempt. RESULTS: Seventy-five Veterans with bipolar disorder had comorbid PTSD. Controlling for PTSD, Veterans with bipolar disorder had a higher prevalence of trauma including physical assault [odds ratio (OR) = 2.85; 95% confidence interval (CI) = 1.39-5.86] and child sexual trauma (OR = 2.89; CI = 1.38-6.05). Veterans with bipolar disorder who endorsed previous suicide attempts (n = 42) had significantly higher levels of exposure to childhood trauma (OR = 5.69; CI = 1.84-17.62). CONCLUSIONS: Results support incorporating history of previous trauma exposure when assessing Veterans at risk for bipolar disorder. Especially, trauma characterized as attack and childhood sexual abuse. Particular attention should be given to Veterans with bipolar disorder and exposure to trauma during childhood, which may be associated with increased risk of suicidality.

Prenatal and perinatal risk factors for bipolar disorder: A systematic review and meta-analysis.

BACKGROUND: Perinatal and prenatal risk factors may be implicated in the development of bipolar disorder, but literature lacks a comprehensive account of possible associations. METHODS: We performed a systematic review and meta-analyses of observational studies detailing the association between prenatal and perinatal risk factors and bipolar disorder in adulthood by searching PubMed, Embase, Web of Science and Psycinfo for articles published in any language between January 1st, 1960 and September 20th, 2021. Meta-analyses were performed when risk factors were available in at least two studies. FINDINGS: Twenty seven studies were included with 18 prenatal or perinatal factors reported across the literature. Peripartum asphyxia (k = 5, OR = 1.46 [1.02; 2.11]), maternal stress during pregnancy (k = 2, OR = 12.00 [3.30; 43.59]), obstetric complications (k = 6, OR = 1.41 [1.18; 1.69]), and birth weight less than 2500 g (k = 5, OR = 1.28 [1.04; 1.56]) were associated with an increased risk for bipolar disorder. INTERPRETATION: Perinatal and prenatal risk factors are implicated in the pathogenesis of bipolar disorder, supporting a role of prenatal care in preventing the condition.

Earlier age of onset is associated with a pro-inflammatory state in major depressive disorder.

Major depressive disorder (MDD) is a common condition that affects the general population over a wide range of ages, regardless of gender and social background. Early-onset of MDD in adulthood, between ages of 18 and 30 years, is associated with worse outcomes and increased years of disability. Stress load and physical health have been associated with age of onset in MDD. We aim to investigate whether early onset MDD might be associated with changes in systemic inflammatory markers. We examined levels of following cytokines: IL-1ß, IL-6, IL-10 and TNFα in 234 patients with MDD. Higher serum levels of TNFα and IL-1ß are associated with the early onset of the disorder in patients with MDD. IL-6 levels were also higher in the early onset group and IL-10 levels were higher in the late onset group, but with no significant difference. Changes in the anti-inflammatory/pro-inflammatory balance have been described in mood disorders and may be implicated in its severity and pattern of progression. Our findings reinforce that higher serum levels of IL-1ß and TNFα may be associated with the earlier onset subgroup of MDD patients. Future research that target inflammatory markers of immune modulation may be, key in the search for novel preventative therapeutics.

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) recommendations for the management of patients with bipolar disorder with mixed presentations.

OBJECTIVES: The 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines provided clinicians with pragmatic treatment recommendations for bipolar disorder (BD). While these guidelines included commentary on how mixed features may direct treatment selection, specific recommendations were not provided-a critical gap which the current update aims to address. METHOD: Overview of research regarding mixed presentations in BD, with treatment recommendations developed using a modified CANMAT/ISBD rating methodology. Limitations are discussed, including the dearth of high-quality data and reliance on expert opinion. RESULTS: No agents met threshold for first-line treatment of DSM-5 manic or depressive episodes with mixed features. For mania + mixed features second-line treatment options include asenapine, cariprazine, divalproex, and aripiprazole. In depression + mixed features, cariprazine and lurasidone are recommended as second-line options. For DSM-IV defined mixed episodes, with a longer history of research, asenapine and aripiprazole are first-line, and olanzapine (monotherapy or combination), carbamazepine, and divalproex are second-line. Research on maintenance treatments following a DSM-5 mixed presentation is extremely limited, with third-line recommendations based on expert opinion. For maintenance treatment following a DSM-IV mixed episode, quetiapine (monotherapy or combination) is first-line, and lithium and olanzapine identified as second-line options. CONCLUSION: The CANMAT and ISBD groups hope these guidelines provide valuable support for clinicians providing care to patients experiencing mixed presentations, as well as further influence investment in research to improve diagnosis and treatment of this common and complex clinical state.

Consensus on nomenclature for clinical staging models in bipolar disorder: A narrative review from the International Society for Bipolar Disorders (ISBD) Staging Task Force.

OBJECTIVES: Clinical staging is widely used in medicine to map disease progression, inform prognosis, and guide treatment decisions; in psychiatry, however, staging remains a hypothetical construct. To facilitate future research in bipolar disorders (BD), a well-defined nomenclature is needed, especially since diagnosis is often imprecise with blurred boundaries, and a full understanding of pathophysiology is lacking. METHODS: Under the auspices of the International Society of Bipolar Disorders, a Task Force of international experts was convened to review, discuss, and integrate findings from the scientific literature relevant to the development of a consensus staging model and standardize a terminology that could be used to advance future research including staging of BD and related disorders. RESULTS: Consensus opinion and areas of uncertainty or difference were identified in regard to terms referring to staging as it may apply to BD, to at-risk status and subthreshold stages, and to various clinical stages of BD as it is currently diagnosed. CONCLUSION: The use of a standardized nomenclature about the clinical stages of BD will facilitate communication about research on clinical and pathological components of this heterogeneous group of disorders. The concepts presented are based on current evidence, but the template provided allows for further refinements as etiological advances come to light.

Remission and recurrence in bipolar disorder: The data from health outcomes and patient evaluations in bipolar disorder (HOPE-BD) study.

BACKGROUND: The HOPE-BD was a naturalistic study established to follow individuals in Canada seeking treatment for bipolar disorder (BD). The study aimed to examine the course of BD and describe how clinical and sociodemographic factors are associated with outcomes. METHODS: Individuals with BD had their clinical data recorded at enrolment and were naturalistically treated. Participant were followed for up to four years, and visits occurred at least once every three months. We investigated the longitudinal outcomes with logistic, Cox, and quantile regressions. RESULTS: Among the 354 participants, 57.3% had BD type I. Depression as first episode, younger ages at onset and older ages of the first professional help predicted longer delays in correct diagnosis. Among the symptomatic patients at baseline, the median time to remission was 10.9 months. Comorbid alcohol use disorder and the severity of baseline depressive symptoms predicted longer times to remission. Among the euthymic participants, the median time to recurrence was 14.5 months. History of anxiety disorder and younger ages at onset predicted shorter times to recurrence. Baseline depression scores predicted recurrence in euthymic patients. LIMITATIONS: We did not investigate the predictors of each polarity. Our findings may not apply to individuals followed in non-specialised outpatient services. CONCLUSION: Our study reinforces the necessity of early diagnosis and interventions, as well as the importance of treating depressive symptoms and comorbidities.

Emotional memory in bipolar disorder: Impact of multiple episodes and childhood trauma.

BACKGROUND: Emotional memory is a critical amygdala-dependent cognitive function characterized by enhanced memory for emotional events coupled with retrograde amnesia. Our study aims to assess the influence of bipolar disorder (BD), trauma, and the number of mood episodes on emotional memory. METHODS: 53 subjects (33 euthymic patients with BD and 20 healthy controls) answered a clinical assessment, childhood trauma questionnaire (CTQ), and an emotional memory test composed of lists of nouns, including neutral words, one emotional (E), one preceding (E-1) and one following word (E + 1). We assessed for the influence of type, position, diagnosis, trauma, and number of mood episodes in word recall using generalized estimating equations. RESULTS: Controlling for neutral words, BD had a higher recall for E-1 (p = 0.038) and a trend for a higher recall of E (p = 0.055). There was no difference between patients with and without trauma. Patients with BD who suffered multiple mood episodes had a higher recall of E compared to patients with fewer episodes (p = 0.016). LIMITATIONS: Cross-sectional design and small sample size. CONCLUSION: Our results indicate dysfunction in emotional memory in patients with BD, particularly after multiple mood episodes. While we expected an impaired emotional memory, patients with BD showed an increased recall for emotional stimuli and events preceding them. Childhood trauma does not seem to interfere with emotional memory changes in patients with BD. Emotional memory enhancement seems to be a promising marker of progression in BD.

Cannabidiol as a Treatment for Mood Disorders: A Systematic Review.

OBJECTIVE: To review the current evidence for efficacy of cannabidiol in the treatment of mood disorders. METHODS: We systematically searched PubMed, Embase, Web of Science, PsychInfo, Scielo, ClinicalTrials.gov , and The Cochrane Central Register of Controlled Trials for studies published up to July 31, 2019. The inclusion criteria were clinical trials, observational studies, or case reports evaluating the effect of pure cannabidiol or cannabidiol mixed with other cannabinoids on mood symptoms related to either mood disorders or other health conditions. The review was reported in accordance with guidelines from Preferred Reporting Items for Systematic reviews and Meta-Analyses protocol. RESULTS: Of the 924 records initially yielded by the search, 16 were included in the final sample. Among them, six were clinical studies that used cannabidiol to treat other health conditions but assessed mood symptoms as an additional outcome. Similarly, four tested cannabidiol blended with Δ-9-tetrahydrocannabinol in the treatment of general health conditions and assessed affective symptoms as secondary outcomes. Two were case reports testing cannabidiol. Four studies were observational studies that evaluated the cannabidiol use and its clinical correlates. However, there were no clinical trials investigating the efficacy of cannabidiol, specifically in mood disorders or assessing affective symptoms as the primary outcome. Although some articles point in the direction of benefits of cannabidiol to treat depressive symptoms, the methodology varied in several aspects and the level of evidence is not enough to support its indication as a treatment for mood disorders. CONCLUSIONS: There is a lack of evidence to recommend cannabidiol as a treatment for mood disorders. However, considering the preclinical and clinical evidence related to other diseases, cannabidiol might have a role as a treatment for mood disorders. Therefore, there is an urgent need for well-designed clinical trials investigating the efficacy of cannabidiol in mood disorders.

Decoding rumination: A machine learning approach to a transdiagnostic sample of outpatients with anxiety, mood and psychotic disorders.

OBJECTIVE: To employ machine learning algorithms to examine patterns of rumination from RDoC perspective and to determine which variables predict high levels of maladaptive rumination across a transdiagnostic sample. METHOD: Sample of 200 consecutive, consenting outpatient referrals with clinical diagnoses of schizophrenia, schizoaffective, bipolar, depression, anxiety disorders, obsessive compulsive and post-traumatic stress. Machine learning algorithms used a range of variables including sociodemographics, serum levels of immune markers (IL-6, IL-1ß, IL-10, TNF-α and CCL11) and BDNF, psychiatric symptoms and disorders, history of suicide and hospitalizations, functionality, medication use and comorbidities. RESULTS: The best model (with recursive feature elimination) included the following variables: socioeconomic status, illness severity, worry, generalized anxiety and depressive symptoms, and current diagnosis of panic disorder. Linear support vector machine learning differentiated individuals with high levels of rumination from those ones with low (AUC = 0.83, sensitivity = 75, specificity = 71). CONCLUSIONS: Rumination is known to be associated with poor prognosis in mental health. This study suggests that rumination is a maladaptive coping style associated not only with worry, distress and illness severity, but also with socioeconomic status. Also, rumination demonstrated a specific association with panic disorder.

Differential biomarker signatures in unipolar and bipolar depression: A machine learning approach.

OBJECTIVE: This study used machine learning techniques combined with peripheral biomarker measurements to build signatures to help differentiating (1) patients with bipolar depression from patients with unipolar depression, and (2) patients with bipolar depression or unipolar depression from healthy controls. METHODS: We assessed serum levels of interleukin-2, interleukin-4, interleukin-6, interleukin-10, tumor necrosis factor-α, interferon-γ, interleukin-17A, brain-derived neurotrophic factor, lipid peroxidation and oxidative protein damage in 54 outpatients with bipolar depression, 54 outpatients with unipolar depression and 54 healthy controls, matched by sex and age. Depressive symptoms were assessed using the Hamilton Depression Rating Scale. Variable selection was performed with recursive feature elimination with a linear support vector machine kernel, and the leave-one-out cross-validation method was used to test and validate our model. RESULTS: Bipolar vs unipolar depression classification achieved an area under the receiver operating characteristics (ROC) curve (AUC) of 0.69, with 0.62 sensitivity and 0.66 specificity using three selected biomarkers (interleukin-4, thiobarbituric acid reactive substances and interleukin-10). For the comparison of bipolar depression vs healthy controls, the model retained five variables (interleukin-6, interleukin-4, thiobarbituric acid reactive substances, carbonyl and interleukin-17A), with an AUC of 0.70, 0.62 sensitivity and 0.7 specificity. Finally, unipolar depression vs healthy controls comparison retained seven variables (interleukin-6, Carbonyl, brain-derived neurotrophic factor, interleukin-10, interleukin-17A, interleukin-4 and tumor necrosis factor-α), with an AUC of 0.74, a sensitivity of 0.68 and 0.70 specificity. CONCLUSION: Our findings show the potential of machine learning models to aid in clinical practice, leading to more objective assessment. Future studies will examine the possibility of combining peripheral blood biomarker data with other biological data to develop more accurate signatures.

Gene Regulatory Network of Dorsolateral Prefrontal Cortex: a Master Regulator Analysis of Major Psychiatric Disorders.

Despite the strong genetic component of psychiatric disorders, traditional genetic studies have failed to find individual genes of large effect size. Thus, alternative methods, using bioinformatics, have been proposed to solve these biological puzzles. Of these, here we employ systems biology-based approaches to identify potential master regulators (MRs) of bipolar disorder (BD), schizophrenia (SZ), and major depressive disorder (MDD), their association with biological processes and their capacity to differentiate disorders' phenotypes. High-throughput gene expression data was used to reconstruct standard human dorsolateral prefrontal cortex regulatory transcriptional network, which was then queried for regulatory units and MRs associated with the psychiatric disorders of interest. Furthermore, the activity status (active or repressed) of MR candidates was obtained and used in cluster analysis to characterize disease phenotypes. Finally, we explored the biological processes modulated by the MRs using functional enrichment analysis. Thirty-one, thirty-four, and fifteen MR candidates were identified in BD, SZ, and MDD, respectively. The activity state of these MRs grouped the illnesses in three clusters: MDD only, mostly BD, and a third one with BD and SZ. While BD and SZ share several biological processes related to ion transport and homeostasis, synapse, and immune function, SZ showed peculiar enrichment of processes related to cytoskeleton and neuronal structure. Meanwhile, MDD presented mostly processes related to glial development and fatty acid metabolism. Our findings suggest notable differences in functional enrichment between MDD and BD/SZ. Furthermore, similarities between BD and SZ may impose particular challenges in attempts to discriminate these pathologies based solely on their transcriptional profiles. Nevertheless, we believe that systems-oriented approaches are promising strategies to unravel the pathophysiology peculiarities underlying mental illnesses and reveal therapeutic targets.