Aerobic capacity and mitochondrial function in bipolar disorder: a longitudinal study during acute phases and after clinical remission.

Background: Aerobic capacity has shown to predict physical and mental health-related quality of life in bipolar disorder (BD). However, the correlation between exercise respiratory capacity and mitochondrial function remains understudied. We aimed to assess longitudinally intra-individual differences in these factors during mood episodes and remission in BD. Methods: This study included eight BD patients admitted to an acute psychiatric unit. Incremental cardiopulmonary exercise test (CPET) was conducted during acute episodes (T0), followed by constant work rate cycle ergometry (CWRCE) to evaluate endurance time, oxygen uptake at peak exercise (VO2peak) and at the anaerobic threshold. The second test was repeated during remission (T1). Mitochondrial respiration rates were assessed at T0 and T1 in peripheral blood mononuclear cells. Results: Endurance time, VO2peak, and anaerobic threshold oxygen consumption showed no significant variations between T0 and T1. Basal oxygen consumption at T1 tended to inversely correlate with maximal mitochondrial respiratory capacity (r=-0.690, p=0.058), and VO2peak during exercise at T1 inversely correlated with basal and minimum mitochondrial respiration (r=-0.810, p=0.015; r=-0.786, p=0.021, respectively). Conclusions: Our preliminary data showed that lower basal oxygen consumption may be linked to greater mitochondrial respiratory capacity, and maximum oxygen uptake during the exercise task was associated with lower basal mitochondrial respiration, suggesting that lower oxygen requirements could be associated with greater mitochondrial capacity. These findings should be replicated in larger samples stratified for manic and depressive states.

Lithium response in bipolar disorder: Epigenome-wide DNA methylation signatures and epigenetic aging.

Lithium (Li) is the first-line treatment for bipolar disorder (BD) even though only 30 % of BD patients are considered excellent responders. The mechanisms by which Li exerts its action are not clearly understood, but it has been suggested that specific epigenetic mechanisms, such as methylation processes, may play a role. In this regard, DNA methylation patterns can be used to estimate epigenetic age (EpiAge), which is accelerated in BD patients and reversed by Li treatment. Our first aim was to compare the DNA methylation profile in peripheral blood between BD patients categorized as excellent responders to Li (Ex-Rp) and non-responders (N-Rp). Secondly, EpiAge was estimated to detect differential age acceleration between the two groups. A total of 130 differentially methylated positions (DMPs) and 16 differentially methylated regions (DMRs) between Ex-Rp (n = 26) and N-Rp (n = 37) were identified (FDR adjusted p-value < 0.05). We found 122 genes mapping the DMPs and DMRs, nine of which (HOXB6, HOXB3, HOXB-AS3, TENM2, CACNA1B, ANK3, EEF2K, CYP1A1, and SORCS2) had previously been linked to Li response. We found genes related to the GSK3ß pathway to be highly represented. Using FUMA, we found enrichment in Gene Ontology Cell Component for the synapse. Gene network analysis highlighted functions related to the cell cycle, nervous system development and function, and gene expression. No significant differences in age acceleration were found between Ex-Rp and N-Rp for any of the epigenetic clocks analysed. Our findings indicate that a specific methylation pattern could determine the response to Li in BD patients. We also found that a significant portion of the differentially methylated genes are closely associated with the GSK3ß pathway, reinforcing the role of this system in Li response. Future longitudinal studies with larger samples will help to elucidate the epigenetic mechanisms underlying Li response.

Maintenance Electroconvulsive Therapy in Catatonia: Clinical Profiles From a Case Series.

OBJECTIVES: This study aims to conduct a descriptive analysis of the clinical features and treatment responses in 6 patients with catatonia who received maintenance electroconvulsive therapy (ECT). METHODS: Our study included all patients who underwent maintenance ECT (mECT) at the Hospital Clínic de Barcelona between September 2020 and September 2022 following a catatonic episode. RESULTS: The study cohort comprised 5 patients with schizophrenia and 1 patient with major depressive disorder. Among patients with schizophrenia, the first catatonic episode occurred several years after their initial paranoid psychotic episode, whereas the patient with depression experienced a rapid progression from the first depressive episode to catatonia. After acute ECT, 4 patients achieved complete symptomatic remission, 1 patient exhibited a partial response, and another maintained a severe catatonic state. Maintenance ECT was indicated because of the high risk of severe relapses. The mean frequency of mECT sessions was 9.83 (SD, 5.60) days. Notably, 66.67% of the patients were concurrently receiving clozapine as part of their pharmacological treatment. Among patients with schizophrenia, mECT sessions could not be extended beyond 7 to 10 days, whereas the depressed patient could space ECT sessions up to 21 days without experiencing a relapse. CONCLUSIONS: Maintenance ECT proves to be a safe and well-tolerated strategy for preventing relapses in severe catatonic patients who have previously stabilized with acute ECT. Further research is needed to develop clinical guidelines that define optimal application strategies for mECT in catatonia.

Catatonic postpartum paternal depression as a first debut of a bipolar disorder: a case report.

Paternal postpartum depression (PD) is considered an affective disorder that affects fathers during the months following childbirth. Interestingly, it has been observed that during these months the chances of a male parent suffering from depression are double that for a non-parent male counterpart. We present the case of a 34-year-old man with no relevant medical history in who, overlapping her daughter's birth, several depressive symptoms emerged, such as fatigue, lack of concentration, sleeping disturbances and abandonment of care of the newborn. Prior to consultation, patient refused to eat and open his eyes, and his speech became progressively more parsimonious until reaching mutism. The patient was diagnosed with a severe depressive disorder with catatonia. Given the lack of improvement with pharmacological treatment and due to the evidence of electroconvulsive therapy (ECT)'s effectiveness on patients with catatonia, acute ECT treatment was indicated and started. It should be noted that PD is an important entity to consider in our differential diagnosis of young parents who present a depressive episode. Few cases of relatively young patients presenting with such clinical presentation have been described and, although this case presents some of the characteristics described in the epidemiology of PD, other clinical aspects are not typical of this entity. Informed consent was obtained from the patient for the purpose of publication.

Reduced mitochondrial respiratory capacity in patients with acute episodes of bipolar disorder: Could bipolar disorder be a state-dependent mitochondrial disease?

BACKGROUND: Bipolar disorder (BD) is a chronic and recurrent disease characterized by acute mood episodes and periods of euthymia. The available literature postulates that a biphasic dysregulation of mitochondrial bioenergetics might underpin the neurobiology of BD. However, most studies focused on inter-subject differences rather than intra-subject variations between different mood states. To test this hypothesis, in this preliminary proof-of-concept study, we measured in vivo mitochondrial respiration in patients with BD during a mood episode and investigated differences compared to healthy controls (HC) and to the same patients upon clinical remission. METHODS: This longitudinal study recruited 20 patients with BD admitted to our acute psychiatric ward with a manic (n = 15) or depressive (n = 5) episode, and 10 matched HC. We assessed manic and depressive symptoms using standardized psychometric scales. Different mitochondrial oxygen consumption rates (OCRs: Routine, Leak, electron transport chain [ETC], Rox) were assessed during the acute episode (T0) and after clinical remission (T1) using high-resolution respirometry at 37°C by polarographic oxygen sensors in a two-chamber Oxygraph-2k system in one million of peripheral blood mononuclear cells (PMBC). Specific OCRs were expressed as mean ± SD in picomoles of oxygen per million cells. Significant results were adjusted for age, sex, and body mass index. RESULTS: The longitudinal analysis showed a significant increase in the maximal oxygen consumption capacity (ETC) in clinical remission (25.7 ± 16.7) compared to the acute episodes (19.1 ± 11.8, p = 0.025), and was observed separately for patients admitted with a manic episode (29.2 ± 18.9 in T1, 22.3 ± 11.9 in T0, p = 0.076), and at a trend-level for patients admitted with a depressive episode (15.4 ± 3.9 in T1 compared to 9.4 ± 3.2 in T0, p = 0.107). Compared to HC, significant differences were observed in ETC in patients with a bipolar mood episode (H = 11.7; p = 0.003). Individuals with bipolar depression showed lower ETC than those with a manic episode (t = -3.7, p = 0.001). Also, significant differences were observed in ETC rates between HC and bipolar depression (Z = 1.000, p = 0.005). CONCLUSIONS: Bioenergetic and mitochondrial dysregulation could be present in both manic and depressive phases in BD and, importantly, they may restore after clinical remission. These preliminary results suggest that mitochondrial respiratory capacity could be a biomarker of illness activity and clinical response in BD. Further studies with larger samples and similar approaches are needed to confirm these results and identify potential biomarkers in different phases of the disease.

The Mixed Tendency in Bipolar Disorder: An Operational Proposal for the Integration of Mixed Episodes in Predominant Polarity.

Predominant Polarity (PP) is an established specifier of Bipolar Disorder (BD), holding significant clinical implications. Nevertheless, there exists no consensus on how to incorporate mixed states into PP, leaving patients prone to mixed recurrences that are unclassified. In a comprehensive study involving 701 euthymic BD patients, we sought to redefine PP by introducing a novel metric, the "mixed tendency", and establish a practical threshold to identify patients with a "mixed phenotype". Furthermore, we investigated potential associations between the mixed phenotype and specific PP categories. Our findings revealed that the mixed tendency correlated significantly with early BD type I, lifetime suicide attempts, self-aggressive behaviour, and lifetime number of affective episodes (>5). Using a ROC curve analysis, we determined an optimal cut-off point for the mixed tendency at 0.228, suggesting that patients with ~25% of lifetime mixed episodes relative to total affective episodes should be identified as having a mixed phenotype. Notably, the mixed phenotype was positively associated with undetermined PP and negatively with manic and depressive PP. This study introduces a promising approach to incorporating mixed episodes into the PP definition, potentially enabling tailored interventions for patients with a substantial history of mixed episodes. However, further research in large, longitudinal cohorts is essential to validate these findings.

Neuropsychiatric symptoms in a patient under cystic fibrosis transmembrane conductance regulator modulators treatment: a case report.

In recent times, some research has focused on the study of potential treatments for cystic fibrosis (CF), such as cystic fibrosis transmembrane conductance regulator (CFTR) modulators. These treatments have been reported to produce neuropsychiatric symptoms in a few patients, even though there is still no clear correlation nor underlying mechanism proposed. We present the case of a 23-year-old woman with CF and no previous psychiatric history who was admitted to our inpatient psychiatric unit presenting a wide range of neuropsychiatric symptoms, such as disorganized speech, bizarre poses or persecutory delusional ideation, after going under CFTR modulators treatment. After several diagnostic tests, other possible organic causes were ruled out. Multiple antipsychotic treatments were tested during her admission, with poor tolerance and scarce response. Finally, symptomatic remission was only observed after electroconvulsive therapy was initiated. The final diagnostic hypothesis was unspecified psychosis. This case highlights the relevance of considering the possibility of neuropsychiatric symptoms appearing in patients under CFTR modulators treatment.

Manic episode in a patient with pancreatic adenocarcinoma: a case report.

Psychiatric comorbidity is common in cancer patients, emphasizing the need for comprehensive care. While depressive symptoms in pancreatic cancer have been studied, there is limited attention given to manic symptoms. This case report aims to contribute to the knowledge of pancreatic cancer psychiatric comorbidities by describing a case of a patient with stage IV pancreatic cancer who presented a sudden onset manic episode. The patient, a 61-year-old male with stage IV pancreatic cancer, presented at the Emergency Room with abrupt behavioural changes suggestive of a manic episode of 2 weeks of evolution. The patient had been undergoing chemotherapy and short 3-day cycles of corticosteroids for the past 9 months but had been off this treatment for 20 days when the episode began. Acute organic causes were ruled out. The patient was admitted to the psychiatric unit, where organic screening was expanded and treatment with antipsychotics and a mood stabiliser was initiated with subsequent remission of symptoms after 2 weeks. This case shows a manic episode as a rare psychiatric complication in pancreatic cancer. In the literature reviewed, four other similar cases have been observed. Further research is needed to elucidate the underlying pathophysiology and explore possible treatment strategies.

Effects of malnutrition on length of stay in patients hospitalized in an acute psychiatric ward.

INTRODUCTION: Psychiatric patients are considered at risk for malnutrition due to pharmacological treatments, lifestyle habits and the mental illness by itself. Even though metabolic risk factors have been related to worse outcomes in certain conditions, the evidence regarding the nutritional status and its impact on the length of stay in psychiatric inpatients is scarce. This study aims to characterize the nutritional status in acute psychiatric patients, to correlate it with the length of stay, and to find specific potential indicators of malnutrition. METHODS: Adult patients admitted to the Hospital Clínic of Barcelona acute psychiatric ward throughout a 1-year period were included in this cross-sectional study. Sociodemographic and clinical variables were registered, including length of stay and the nutritional status measured with the CONUT score. RESULTS: Malnutrition was observed in 42.5% of patients. Plasmatic transferrin saturation, protein and iron levels were inversely correlated with length of stay, having low iron levels an association with longer hospitalizations. The length of stay was not influenced by diagnosis or treatment. Negative correlations with the nutritional status were found in: BMI, cholesterol, triglycerides, albumin, total proteins, prealbumin, iron, lymphocytes and zinc levels, and transferrin saturation. The multivariate analysis showed a significant association for cholesterol and zinc levels, lymphocyte count, and BMI. CONCLUSIONS: Our results suggest that nutritional status might influence the course of psychiatric admissions. Cholesterol and zinc levels, lymphocyte count, and BMI might be factors strongly associated with malnutrition. This consideration might allow the identification of profiles in which lifestyle interventions could be implemented.

Anxiety and depression played a central role in the COVID-19 mental distress: A network analysis.

INTRODUCTION: Psychological, socio-demographics, and clinical factors play an important role in patients with COVID-19, but their relationship is complex. The network approach might be used to disentangle complex interactions in different systems. Using data from a multicentre, cross-sectional, survey among patients with COVID-19 in Spain (July-November 2020), we investigated the network structure of mental disorders symptoms, social support, and psychological resilience, and changes in network structures according to the presence of a pre-existing mental disorder or hospitalization for COVID-19. METHODS: Subjects completed a survey to evaluate sociodemographic characteristics, COVID-19 infection status, resilience, social support, and symptoms of depression, anxiety disorders, post-traumatic stress disorder, panic attacks, and substance use disorder. 2084 patients with COVID-19 were included in the analysis. Network analysis was conducted to evaluate network and bridge centrality, and the network properties were compared between COVID-19 patients with and without a history of lifetime mental disorder, and between hospitalized and non-hospitalized patients. LIMITATIONS: Generalization of our findings may be difficult since differences in network connectivity may exist in different populations or samples. RESULTS: Anxiety and depression showed high centrality in patients with COVID-19 and anxiety showed the highest bridge influence in the network. Resilience and social support showed a low influence on mental disorder symptoms. Global network estimations show no statistically significant changes between patients with and without pre-existing mental disorders or between hospitalized and non-hospitalized patients. CONCLUSIONS: Anxiety might be a key treatment target in patients with COVID-19 since its treatment might prevent other mental health adverse outcomes.

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.

Exploring Digital Biomarkers of Illness Activity in Mood Episodes: Hypotheses Generating and Model Development Study.

BACKGROUND: Depressive and manic episodes within bipolar disorder (BD) and major depressive disorder (MDD) involve altered mood, sleep, and activity, alongside physiological alterations wearables can capture. OBJECTIVE: Firstly, we explored whether physiological wearable data could predict (aim 1) the severity of an acute affective episode at the intra-individual level and (aim 2) the polarity of an acute affective episode and euthymia among different individuals. Secondarily, we explored which physiological data were related to prior predictions, generalization across patients, and associations between affective symptoms and physiological data. METHODS: We conducted a prospective exploratory observational study including patients with BD and MDD on acute affective episodes (manic, depressed, and mixed) whose physiological data were recorded using a research-grade wearable (Empatica E4) across 3 consecutive time points (acute, response, and remission of episode). Euthymic patients and healthy controls were recorded during a single session (approximately 48 h). Manic and depressive symptoms were assessed using standardized psychometric scales. Physiological wearable data included the following channels: acceleration (ACC), skin temperature, blood volume pulse, heart rate (HR), and electrodermal activity (EDA). Invalid physiological data were removed using a rule-based filter, and channels were time aligned at 1-second time units and segmented at window lengths of 32 seconds, as best-performing parameters. We developed deep learning predictive models, assessed the channels' individual contribution using permutation feature importance analysis, and computed physiological data to psychometric scales' items normalized mutual information (NMI). We present a novel, fully automated method for the preprocessing and analysis of physiological data from a research-grade wearable device, including a viable supervised learning pipeline for time-series analyses. RESULTS: Overall, 35 sessions (1512 hours) from 12 patients (manic, depressed, mixed, and euthymic) and 7 healthy controls (mean age 39.7, SD 12.6 years; 6/19, 32% female) were analyzed. The severity of mood episodes was predicted with moderate (62%-85%) accuracies (aim 1), and their polarity with moderate (70%) accuracy (aim 2). The most relevant features for the former tasks were ACC, EDA, and HR. There was a fair agreement in feature importance across classification tasks (Kendall W=0.383). Generalization of the former models on unseen patients was of overall low accuracy, except for the intra-individual models. ACC was associated with "increased motor activity" (NMI>0.55), "insomnia" (NMI=0.6), and "motor inhibition" (NMI=0.75). EDA was associated with "aggressive behavior" (NMI=1.0) and "psychic anxiety" (NMI=0.52). CONCLUSIONS: Physiological data from wearables show potential to identify mood episodes and specific symptoms of mania and depression quantitatively, both in BD and MDD. Motor activity and stress-related physiological data (EDA and HR) stand out as potential digital biomarkers for predicting mania and depression, respectively. These findings represent a promising pathway toward personalized psychiatry, in which physiological wearable data could allow the early identification and intervention of mood episodes.

Affective temperaments mediate aggressive dimensions in bipolar disorders: A cluster analysis from a large, cross-sectional, international study.

BACKGROUND: Affective temperaments show potential for aggressive behavior (AB) preventive strategies in bipolar disorder (BD). We aim to define intra-diagnostic subgroups of patients with BD based on homogeneous behaviors related to AB. Subsequently, to assess whether affective temperament dimensions may contribute to the presence and severity of AB. METHODS: Patients with BD were recruited. AB was evaluated through the modified overt aggression scale (MOAS); affective temperaments were assessed with the TEMPS-A. A cluster analysis was conducted based on TEMPS-A and MOAS scores. Stepwise backward logistic regression models were used to identify the predictive factors of cluster membership. RESULTS: 799 patients with BD were enrolled. Three clusters were determined: non-aggressive (55.5 %), self-aggressive (18 %), and hetero-aggressive (26.5 %). Depressive, irritable, and anxious temperament scores significantly increased from the non-aggressive (lower) to the self-aggressive (intermediate) and the hetero-aggressive group (highest). A positive history of a suicide attempt (B = 5.131; OR = 169.2, 95 % CI 75.9; 377) and rapid cycling (B = -0.97; OR = 0.40, 95 % CI 0.17; 0.95) predicted self-aggressive cluster membership. Atypical antipsychotics (B = 1.19; OR = 3.28, 95 % CI 2.13; 5.06) or SNRI treatment (B = 1.09; OR = 3, 95 % CI 1.57; 5.71), psychotic symptoms (B = 0.73; OR = 2.09, 95 % CI 1.34; 3.26), and history of a suicide attempt (B = -1.56; OR = 0.20, 95 % CI 0.11; 0.38) predicted hetero-aggressive cluster membership. LIMITATIONS: Recall bias might have affected the recollection of AB. CONCLUSIONS: Clinical factors orientate the prevention of different ABs in BD. Affective temperaments might play a role in preventing AB since patients with more pronounced affective temperaments might have an increased risk of showing AB, in particular hetero-AB.

Upward trends in eating disorders, self-harm, and suicide attempt emergency admissions in female adolescents after COVID-19 lockdown.

INTRODUCTION: Increased mental health problems have been reported in children and adolescents related to the COVID-19 lockdown and its immediate aftermath, especially among adolescent females. However, the longer-term impact of persistent quarantine measures and social restrictions on this population is yet to be further explored. MATERIALS AND METHODS: We compared the number of children/adolescents admissions to the psychiatric emergency department (ED) of Hospital Clínic de Barcelona during the COVID-19 lockdown and the following year with the numbers of admissions the year before lockdown, adjusting for variations in the population. We also conducted separate analyses by gender, age group, and diagnostic categories. Finally, we also repeated the analyses considering the cumulated deficit/excess since the start of the lockdown. Statistical significance was estimated using binomial tests with Bonferroni correction. RESULTS: A total of 2425 admissions were recorded. Globally, admission rates decreased during the lockdown (46%) and progressively increased during the one-year aftermath (43% by spring 2021). This increase was particularly high in adolescent females (85%) while unclear in children and/or males. The main diagnostic categories involved were anxiety, depressive, and eating disorders, as well as self-harm behavior, suicidal ideation, and suicide attempts. The increase in eating disorders, self-harm behavior, and suicide attempts admissions in female adolescents remained statistically significant when considering the cumulated deficit/excess. CONCLUSIONS: We found increased ED admissions during the aftermath of the COVID-19 lockdown among adolescent females. We recommend strengthening the attention to this population to provide adequate specialized care and prevention strategies.

Uso de cariprazina en el trastorno bipolar: una revisión sistemática y aspectos prácticos / Use of cariprazine in bipolar disorder: A systematic review and practical considerations

Cariprazina es un antipsicótico de nueva generación que actúa como agonista parcial de los receptores de la dopamina D2 y D3, y de los receptores de serotonina 5HT1A. Actualmente, la cariprazina está aprobada por la Asociación Española del Medicamento para el tratamiento de la esquizofrenia, y por la Food and Drug Administration para el tratamiento de las fases maníacas, depresivas y mixtas asociadas al trastorno bipolar. La evidencia científica disponible, así como varias guías clínicas internacionales, acreditan la eficacia, seguridad y tolerabilidad de este fármaco y avalan su uso en cualquier tipo de episodio agudo del TB, con o sin síntomas mixtos. Los efectos adversos más frecuentes son los síntomas extrapiramidales, especialmente la acatisia. En dichos estudios se propone individualizar la dosis de cariprazina en función del tipo y la gravedad del episodio, así como de la tolerabilidad del paciente. Los estudios más recientes parecen indicar también un potencial beneficio para la prevención de recaídas en la fase de eutimia, y actualmente se están llevando a cabo ensayos clínicos para evaluar tanto este aspecto como el impacto del fármaco en la esfera cognitiva y en la funcionalidad de los pacientes. En conclusión, el uso de cariprazina en el TB está plenamente justificado desde un punto de vista científico, con unos beneficios globales que sobrepasan ampliamente el perfil de efectos adversos. (AU)

Cariprazine is a new generation antipsychotic that acts as a partial agonist of dopamine D2 and D3 receptors and serotonin 5HT1A receptors.Cariprazine has now been approved by the Spanish Medicines Association (Asociación Española del Medicamento (AEM)) for the treatment of schizophrenia, and by the Food and Drug Administration (FDA) for the treatment of the manic, depressive, and mixed states associated with bipolar disorder (BD). The available scientific evidence, and several international guidelines attest to the efficacy, safety, and tolerability of this drug and endorse its use in any type of acute BD episode, with or without mixed symptoms.The most frequent adverse effects are extrapyramidal symptoms, especially akithisia. Studies propose individualising the dose of cariprazine to the type and severity of the episode, and the patient’s tolerability. The most recent studies also seem to indicate a potential benefit in the prevention of relapse in the euthymia phase, and clinical trials are currently underway to evaluate this and the impact of the drug on patients’ cognitive sphere and functionality. To conclude, the use of cariprazine in bipolar disorder is fully justified from a scientific perspective, with overall benefits that far outweigh the adverse effects profile. (AU)

The U-shaped relationship between parental age and the risk of bipolar disorder in the offspring: A systematic review and meta-analysis.

Parenthood age may affect the risk for the development of different psychiatric disorders in the offspring, including bipolar disorder (BD). The present systematic review and meta-analysis aimed to appraise the relationship between paternal age and risk for BD and to explore the eventual relationship between paternal age and age at onset of BD. We searched the MEDLINE, Scopus, Embase, PsycINFO online databases for original studies from inception, up to December 2021. Random-effects meta-analyses were conducted. Sixteen studies participated in the qualitative synthesis, of which k = 14 fetched quantitative data encompassing a total of 13,424,760 participants and 217,089 individuals with BD. Both fathers [adjusted for the age of other parent and socioeconomic status odd ratio - OR = 1.29(95%C.I. = 1.13-1.48)] and mothers aged ≤ 20 years [(OR = 1.23(95%C.I. = 1.14-1.33)] had consistently increased odds of BD diagnosis in their offspring compared to parents aged 25-29 years. Fathers aged ≥ 45 years [adjusted OR = 1.29 (95%C.I. = 1.15-1.46)] and mothers aged 35-39 years [OR = 1.10(95%C.I. = 1.01-1.19)] and 40 years or older [OR = 1.2(95% C.I. = 1.02-1.40)] likewise had inflated odds of BD diagnosis in their offspring compared to parents aged 25-29 years. Early and delayed parenthood are associated with an increased risk of BD in the offspring. Mechanisms underlying this association are largely unknown and may involve a complex interplay between psychosocial, genetic and biological factors, and with different impacts according to sex and age range. Evidence on the association between parental age and illness onset is still tentative but it points towards a possible specific effect of advanced paternal age on early BD-onset.