-
Biological Psychiatry Jul 2023Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric conditions that can involve symptoms of psychosis and cognitive dysfunction. The 2 conditions share...
BACKGROUND
Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric conditions that can involve symptoms of psychosis and cognitive dysfunction. The 2 conditions share symptomatology and genetic etiology and are regularly hypothesized to share underlying neuropathology. Here, we examined how genetic liability to SCZ and BD shapes normative variations in brain connectivity.
METHODS
We examined the effect of the combined genetic liability for SCZ and BD on brain connectivity from two perspectives. First, we examined the association between polygenic scores for SCZ and BD for 19,778 healthy subjects from the UK Biobank and individual variation in brain structural connectivity reconstructed by means of diffusion weighted imaging data. Second, we conducted genome-wide association studies using genotypic and imaging data from the UK Biobank, taking SCZ-/BD-involved brain circuits as phenotypes of interest.
RESULTS
Our findings showed brain circuits of superior parietal and posterior cingulate regions to be associated with polygenic liability for SCZ and BD, circuitry that overlaps with brain networks involved in disease conditions (r = 0.239, p < .001). Genome-wide association study analysis showed 9 significant genomic loci associated with SCZ-involved circuits and 14 loci associated with BD-involved circuits. Genes related to SCZ-/BD-involved circuits were significantly enriched in gene sets previously reported in genome-wide association studies for SCZ and BD.
CONCLUSIONS
Our findings suggest that polygenic liability of SCZ and BD is associated with normative individual variation in brain circuitry.
Topics: Humans; Schizophrenia; Bipolar Disorder; Genome-Wide Association Study; Connectome; Genetic Predisposition to Disease
PubMed: 36803976
DOI: 10.1016/j.biopsych.2022.11.006 -
Molecular Psychiatry Nov 2023Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome... (Review)
Review
Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome side-effects, and unclear mechanisms of action. Advances in drug development for the treatment of bipolar disorder remain incremental and have come largely from repurposing drugs used for other psychiatric conditions, a strategy that has failed to find truly revolutionary therapies, as it does not target the mood instability that characterises the condition. The lack of therapeutic innovation in the bipolar disorder field is largely due to a poor understanding of the underlying disease mechanisms and the consequent absence of validated drug targets. A compelling new treatment target is the Ca-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme. CaMKK2 is highly enriched in brain neurons and regulates energy metabolism and neuronal processes that underpin higher order functions such as long-term memory, mood, and other affective functions. Loss-of-function polymorphisms and a rare missense mutation in human CAMKK2 are associated with bipolar disorder, and genetic deletion of Camkk2 in mice causes bipolar-like behaviours similar to those in patients. Furthermore, these behaviours are ameliorated by lithium, which increases CaMKK2 activity. In this review, we discuss multiple convergent lines of evidence that support targeting of CaMKK2 as a new treatment strategy for bipolar disorder.
Topics: Animals; Humans; Mice; Bipolar Disorder; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Mutation, Missense
PubMed: 37730845
DOI: 10.1038/s41380-023-02260-3 -
Journal of the American Academy of... Jun 2024Pediatric bipolar disorder (PBD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur and share dysfunctions in affective and cognitive domains. As... (Meta-Analysis)
Meta-Analysis Comparative Study
Shared and Distinct Neurobiological Bases of Bipolar Disorder and Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: A Comparative Meta-Analysis of Structural Abnormalities.
OBJECTIVE
Pediatric bipolar disorder (PBD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur and share dysfunctions in affective and cognitive domains. As the neural substrates underlying their overlapping and dissociable symptomatology have not been well delineated, a meta-analysis of whole-brain voxel-based morphometry studies in PBD and ADHD was conducted.
METHOD
A systematic literature search was performed in PubMed, Web of Science, and Embase. The seed-based d mapping toolbox was used to identify altered clusters of PBD or ADHD and obtain their conjunctive and comparative abnormalities. Suprathreshold patterns were subjected to large-scale network analysis to identify affected brain networks.
RESULTS
The search revealed 10 PBD studies (268 patients) and 32 ADHD studies (1,333 patients). Decreased gray matter volumes in the right insula and anterior cingulate cortex relative to typically developing individuals were conjunctive in PBD and ADHD. Reduced volumes in the right inferior frontal gyrus, left orbitofrontal cortex, and hippocampus were more substantial in PBD, while decreased volumes in the left precentral gyrus, left inferior frontal gyrus, and right superior frontal gyrus were more pronounced in ADHD. Neurodevelopmental effects modulated patterns of the left hippocampus in PBD and those of the left inferior frontal gyrus in ADHD.
CONCLUSION
These findings suggest that PBD and ADHD are characterized by both common and distinct patterns of gray matter volume alterations. Their overlapping abnormalities may represent a transdiagnostic problem of attention and emotion regulation shared by PBD and ADHD, whereas the disorder-differentiating substrates may contribute to the relative differences in cognitive and affective features that define the 2 disorders.
PLAIN LANGUAGE SUMMARY
Pediatric bipolar disorder (BD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur, with overlapping changes in emotional and cognitive functioning. This meta-analysis summarizes findings from 10 articles on BD and 32 articles on ADHD to identify similarities and differences in brain structure between youth with BD and youth with ADHD. The authors found that both disorders share decreased gray matter volumes in the right insula and anterior cingulate cortex, which play important roles in emotion processing and attention, respectively. Youth with BD had decreased gray matter volume in the right inferior frontal gyrus, left orbitofrontal gyrus, and left hippocampus, while youth with ADHD had decreased volumes in the left precentral gyrus, left inferior frontal gyrus, and right superior frontal gyrus.
STUDY PREREGISTRATION INFORMATION
Structural Brain Abnormalities of Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder in Children/Adolescents: An Overlapping Meta-analysis; https://osf.io; trg4m.
Topics: Humans; Attention Deficit Disorder with Hyperactivity; Bipolar Disorder; Child; Adolescent; Magnetic Resonance Imaging; Brain; Gray Matter; Cerebral Cortex; Gyrus Cinguli
PubMed: 38072245
DOI: 10.1016/j.jaac.2023.09.551 -
Schizophrenia Research Oct 2023Prior studies report increased risk of schizophrenia (SCZ) in migrants relative to the native-born population; however, few have investigated bipolar disorder (BD) and...
OBJECTIVE
Prior studies report increased risk of schizophrenia (SCZ) in migrants relative to the native-born population; however, few have investigated bipolar disorder (BD) and migrant characteristics which may influence risk. We aimed to examine the risk of SCZ and BD in migrants and their children relative to those of Swedish ancestry, and whether risk varied by age at migration, region of origin, sex, and parental migrant status.
METHODS
We conducted a nested case-control study using 5539 SCZ cases and 20,577 BD cases diagnosed 1988-2013, individually matched to five population-based controls by birth year and sex. Conditional logistic regression was used to evaluate the risk of SCZ and BD by migrant status, region of origin and age at migration, with models stratified by sex.
RESULTS
First-generation migrants had increased risk of SCZ and decreased risk of BD. There was a distinct pattern of risk for SCZ by age at migration. Childhood migrants from all regions had increased risk of SCZ, particularly those from Africa. In contrast, risk for BD declined with age at migration, with increased risk only in Nordic child migrants. SCZ and BD diagnoses were decreased in adult migrants, elevated in second-generation migrants (with risk differing by number of migrant parents and greater for those with migrant fathers) and higher in male migrants (vs. female).
CONCLUSIONS
Age at migration, sex, and region of origin affect risk of SCZ and BD. Further research is required to determine how migration-related factors influence disease etiology and the receipt of these diagnoses.
Topics: Adult; Child; Humans; Male; Female; Schizophrenia; Bipolar Disorder; Case-Control Studies; Sweden; Transients and Migrants
PubMed: 37666061
DOI: 10.1016/j.schres.2023.08.022 -
Journal of Affective Disorders Oct 2023Suicidal behavior is strongly associated with major affective disorders, but there is a need to quantify and compare specific risk and protective factors in bipolar...
BACKGROUND
Suicidal behavior is strongly associated with major affective disorders, but there is a need to quantify and compare specific risk and protective factors in bipolar disorder (BD) and major depressive disorder (MDD).
METHODS
In 4307 extensively evaluated major affective-disorder participants with BD (n = 1425) or MDD (n = 2882) diagnosed by current international criteria, we compared characteristics among those with versus without suicidal acts from illness-onset through 8.24 years of follow-up.
RESULTS
Suicidal acts were identified in 11.4 % of participants; 25.9 % were violent and 6.92 % (0.79 % of all participants) were fatal. Associated risk factors included: diagnosis (BD > MDD), manic/psychotic features in first-episodes, family history of suicide or BD, separation/divorce, early abuse, young at illness-onset, female sex with BD, substance abuse, higher irritable, cyclothymic or dysthymic temperament ratings, greater long-term morbidity, and lower intake functional ratings. Protective factors included marriage, co-occurring anxiety disorder, higher ratings of hyperthymic temperament and depressive first episodes. Based on multivariable logistic regression, five factors remained significantly and independently associated with suicidal acts: BD diagnosis, more time depressed during prospective follow-up, younger at onset, lower functional status at intake, and women > men with BD.
LIMITATIONS
Reported findings may or may not apply consistently in other cultures and locations.
CONCLUSIONS
Suicidal acts including violent acts and suicides were more prevalent with BD than MDD. Of identified risk (n = 31) and protective factors (n = 4), several differed with diagnosis. Their clinical recognition should contribute to improved prediction and prevention of suicide in major affective disorders.
Topics: Male; Humans; Female; Depressive Disorder, Major; Prospective Studies; Suicidal Ideation; Protective Factors; Suicide; Temperament; Risk Factors; Puerperal Disorders
PubMed: 37301296
DOI: 10.1016/j.jad.2023.06.018 -
Pushing the Frontiers: Optogenetics for Illuminating the Neural Pathophysiology of Bipolar Disorder.International Journal of Biological... 2023Bipolar disorder (BD), a disabling mental disorder, is featured by the oscillation between episodes of depression and mania, along with disturbance in the biological... (Review)
Review
Bipolar disorder (BD), a disabling mental disorder, is featured by the oscillation between episodes of depression and mania, along with disturbance in the biological rhythms. It is on an urgent demand to identify the intricate mechanisms of BD pathophysiology. Based on the continuous progression of neural science techniques, the dysfunction of circuits in the central nervous system was currently thought to be tightly associated with BD development. Yet, challenge exists since it depends on techniques that can manipulate spatiotemporal dynamics of neuron activity. Notably, the emergence of optogenetics has empowered researchers with precise timing and local manipulation, providing a possible approach for deciphering the pathological underpinnings of mental disorders. Although the application of optogenetics in BD research remains preliminary due to the scarcity of valid animal models, this technique will advance the psychiatric research at neural circuit level. In this review, we summarized the crucial aberrant brain activity and function pertaining to emotion and rhythm abnormities, thereby elucidating the underlying neural substrates of BD, and highlighted the importance of optogenetics in the pursuit of BD research.
Topics: Animals; Humans; Bipolar Disorder; Optogenetics; Central Nervous System
PubMed: 37781027
DOI: 10.7150/ijbs.84923 -
Frontiers in Public Health 2024Problematic cannabis use is highly prevalent among people with mood disorders. This underscores the need to understand the effects of cannabis and cannabinoids in this...
BACKGROUND
Problematic cannabis use is highly prevalent among people with mood disorders. This underscores the need to understand the effects of cannabis and cannabinoids in this population, especially considering legalization of recreational cannabis use.
OBJECTIVES
We aimed to (1) systematically evaluate cross-sectional and longitudinal studies investigating the interplay between cannabis use, cannabis use disorder (CUD), and the occurrence of mood disorders and symptoms, with a focus on major depressive disorder (MDD) and bipolar disorder (BD) and; (2) examine the effects of cannabis on the prognosis and treatment outcomes of MDD and BD.
METHODS
Following PRISMA guidelines, we conducted an extensive search for English-language studies investigating the potential impact of cannabis on the development and prognosis of mood disorders published from inception through November 2023, using EMBASE, PsycINFO, PubMed, and MEDLINE databases.
RESULTS
Our literature search identified 3,262 studies, with 78 meeting inclusion criteria. We found that cannabis use is associated with increased depressive and manic symptoms in the general population in addition to an elevated likelihood of developing MDD and BD. Furthermore, we observed that cannabis use is linked to an unfavorable prognosis in both MDD or BD.
DISCUSSION
Our findings suggest that cannabis use may negatively influence the development, course, and prognosis of MDD and BD. Future well-designed studies, considering type, amount, and frequency of cannabis use while addressing confounding factors, are imperative for a comprehensive understanding of this relationship.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023481634.
Topics: Humans; Depressive Disorder, Major; Mood Disorders; Bipolar Disorder; Marijuana Abuse; Cross-Sectional Studies; Marijuana Use; Longitudinal Studies; Prognosis
PubMed: 38655516
DOI: 10.3389/fpubh.2024.1346207 -
Journal of Affective Disorders Nov 2023Bipolar disorder (BD) is a severe psychiatric illness with an increasing prevalence worldwide. Although the pathological mechanism of and pharmacological interventions... (Review)
Review
Bipolar disorder (BD) is a severe psychiatric illness with an increasing prevalence worldwide. Although the pathological mechanism of and pharmacological interventions for BD have been extensively investigated in preclinical and clinical studies, a scientometric analysis of the developmental trends, interdisciplinary frontiers, and research hotspots in this field has not yet been conducted. Therefore, we performed a comprehensive scientometric review of 55,358 published studies on BD over the past two decades (2002-2021) to identify the most frequently used keywords and explore research hotspots and trajectories. The present findings revealed the main distribution, knowledge structure, topic evolution, and emerging topics of BD research. Analysing the risk factors, pathogenesis, key brain regions, comorbid conditions, and treatment strategies for BD contributed to understanding of the aetiology, progression, and treatment of this disorder. These findings provided substantial support for continued research in this area.
Topics: Humans; Bipolar Disorder; Risk Factors
PubMed: 37595897
DOI: 10.1016/j.jad.2023.08.069 -
The British Journal of Psychiatry : the... Oct 2023Pharmacological treatment patterns for bipolar disorder have changed during recent years, but for better or worse?
BACKGROUND
Pharmacological treatment patterns for bipolar disorder have changed during recent years, but for better or worse?
AIMS
To investigate the comparative real-world effectiveness of antipsychotics and mood stabilisers in bipolar disorder.
METHOD
Register-based cohort study including all Finnish residents aged 16-65 with a diagnosis of bipolar disorder from in-patient care, specialised out-patient care, sickness absence and disability pensions registers between 1996 and 2018, with a mean follow-up of 9.3 years (s.d. = 6.4). Antipsychotic and mood stabiliser use was modelled using the PRE2DUP method and risk for hospital admission for psychiatric and non-psychiatric reasons when using versus not using medications was estimated using within-individual Cox models.
RESULTS
Among 60 045 individuals (56.4% female; mean age 41.7 years, s.d. = 15.8), the five medications associated with lowest risk of psychiatric admissions were olanzapine long-acting injection (LAI) (aHR = 0.54, 95% CI 0.37-0.80), haloperidol LAI (aHR = 0.62, 0.47-0.81), zuclopenthixol LAI (aHR = 0.66, 95% CI 0.52-0.85), lithium (aHR = 0.74, 95% CI 0.71-0.76) and clozapine (aHR = 0.75, 95% CI 0.64-0.87). Only ziprasidone (aHR = 1.26, 95% CI 1.07-1.49) was associated with a statistically higher risk. For non-psychiatric (somatic) admissions, only lithium (aHR = 0.77, 95% CI 0.74-0.81) and carbamazepine (aHR = 0.91, 95% CI 0.85-0.97) were associated with significantly reduced risk, whereas pregabalin, gabapentin and several oral antipsychotics, including quetiapine, were associated with an increased risk. Results for a subcohort of first-episode patients (26 395 individuals, 54.9% female; mean age 38.2 years, s.d. = 13.0) were in line with those of the total cohort.
CONCLUSIONS
Lithium and certain LAI antipsychotics were associated with lowest risks of psychiatric admission. Lithium was the only treatment associated with decreased risk of both psychiatric and somatic admissions.
Topics: Humans; Female; Adult; Male; Bipolar Disorder; Lithium; Cohort Studies; Antipsychotic Agents; Clozapine
PubMed: 37395140
DOI: 10.1192/bjp.2023.75 -
Genes Jul 2023Immune gene variants are known to be associated with the risk of psychiatric disorders, their clinical manifestations, and their response to therapy. This narrative... (Review)
Review
Immune gene variants are known to be associated with the risk of psychiatric disorders, their clinical manifestations, and their response to therapy. This narrative review summarizes the current literature over the past decade on the association of polymorphic variants of cytokine genes with risk, severity, and response to treatment for severe mental disorders such as bipolar disorder, depression, and schizophrenia. A search of literature in databases was carried out using keywords related to depressive disorder, bipolar disorder, schizophrenia, inflammation, and cytokines. Gene lists were extracted from publications to identify common genes and pathways for these mental disorders. Associations between polymorphic variants of the , , and genes were the most replicated and relevant in depression. Polymorphic variants of the , , , , , and genes have been associated with schizophrenia. Bipolar disorder has mainly been associated with polymorphic variants of the gene. Interestingly, the gene polymorphism (rs2228145) was associated with all three diseases. Some cytokine genes have also been associated with clinical presentation and response to pharmacotherapy. There is also evidence that some specific polymorphic variants may affect the expression of cytokine genes. Thus, the data from this review indicate a link between neuroinflammation and severe mental disorders.
Topics: Humans; Polymorphism, Single Nucleotide; Bipolar Disorder; Interleukin-6; Genetic Predisposition to Disease; Schizophrenia; Depression; Cytokines
PubMed: 37510364
DOI: 10.3390/genes14071460