Comparing different non-invasive brain stimulation interventions for bipolar depression treatment: A network meta-analysis of randomized controlled trials.

Non-invasive brain stimulation (NIBS) is a promising treatment for bipolar depression. We systematically searched for randomized controlled trials on NIBS for treating bipolar depression (INPLASY No: 202340019). Eighteen articles (N = 617) were eligible for network meta-analysis. Effect sizes were reported as standardized mean differences (SMDs) or odds ratios (ORs) with 95% confidence intervals (CIs). Anodal transcranial direct current stimulation over F3 plus cathodal transcranial direct current stimulation over F4 (a-tDCS-F3 +c-tDCS-F4; SMD = -1.18, 95%CIs = -1.66 to -0.69, N = 77), high-definition tDCS over F3 (HD-tDCS-F3; -1.17, -2.00 to -0.35, 25), high frequency deep transcranial magnetic stimulation (HF-dTMS; -0.81, -1.62 to -0.001, 25), and high frequency repetitive TMS over F3 plus low frequency repetitive TMS over F4 (HF-rTMS-F3 +LF-rTMS-F4; -0.77, -1.43 to -0.11, 38) significantly improved depressive symptoms compared to sham controls. Only a-tDCS-F3 +c-tDCS-F4 (OR = 4.53, 95%CIs = 1.51-13.65) and HF-rTMS-F3 +LF-rTMS-F4 (4.69, 1.02-21.56) showed higher response rates. No active NIBS interventions exhibited significant differences in dropout or side effect rates, compared with sham controls.

Sex differences in bipolar disorder: The dorsolateral prefrontal cortex as an etiopathogenic region.

Bipolar disorder (BD) is worldwide a prevalent mental illness and a leading risk factor for suicide. Over the past three decades, it has been discovered that sex differences exist throughout the entire panorama of BD, but the etiologic regions and mechanisms that generate such differences remain poorly characterized. Available evidence indicates that the dorsolateral prefrontal cortex (DLPFC), a critical region that controls higher-order cognitive processing and mood, exhibits biological disparities between male and female patients with psychiatric disorders, which are highly correlated with the co-occurrence of psychotic symptoms. This review addresses the sex differences in BD concerning epidemiology, cognitive impairments, clinical manifestations, neuroimaging, and laboratory abnormalities. It also provides strong evidence linking DLPFC to the etiopathogenesis of these sex differences. We emphasize the importance of identifying gene signatures using human brain transcriptomics, which can depict sexually different variations, explain sex-biased symptomatic features, and provide novel targets for sex-specific therapeutics.

Polymicrogyria: An Unusual Case of Secondary Mania.

BACKGROUND: Secondary mania refers to a manic episode that arises during a medical illness other than bipolar disorder or in response to a drug or medication. As the psychopathological features of secondary mania resemble those of mania due to bipolar disorder, misdiagnosis is frequent. PURPOSE AND BASIC PROCEDURES: We present the case of a 20-year-old woman who developed a manic episode with psychotic symptoms, in whom polymicrogyria, a malformation of the cortical development with abnormal electroencephalographic activity, was documented. After initiating antiepileptic management, the affective symptoms completely subsided. MAIN FINDINGS: To date, no specific recommendations are available concerning when to perform advanced studies in patients with a manic episode; however, as our case shows, these are much needed. PRINCIPAL CONCLUSION: Because the treatment of secondary conditions largely depends on finding the underlying cause, patients with a new-onset mania should undergo a thorough assessment for secondary causes.

Commentary: Mania in Medically Ill Patients.

Patients may present with manic symptoms in medical settings such as emergency rooms and on inpatient medical floors, leading to psychiatric consultation to try to determine the etiology of the symptoms. It is crucial to clarify whether the mania is secondary to a medical illness or whether the patient's symptoms are from a primary bipolar disorder. In this issue, we publish 2 case reports of patients presenting with manic symptoms in medical settings. The first case involves polymicrogyria in the frontal lobe of the brain as a cause of secondary mania. The second case involves a patient who was previously diagnosed with bipolar disorder and subsequently developed symptoms of Behçet's disease. In this case, it appears likely that the bipolar disorder was primary, and that the Behçet disease and the bipolar disorder may have exacerbated each other. Given the complexities involved in assessing and treating patients, especially in acute or emergency settings, it is important for primary medical and psychiatric providers to collaborate and communicate well in assuring that they obtain a thorough history of their patients' symptoms and that patients receive a comprehensive medical evaluation before psychiatric treatment is started.

Impact of Early-Life Factors on Risk for Schizophrenia and Bipolar Disorder.

BACKGROUND AND HYPOTHESIS: Schizophrenia (SCZ) and bipolar disorder (BD) have shared genetic risk and clinical symptoms, yet the extent to which environmental risk factors are shared is not well known. We aimed to examine the associations of early-life environmental exposures with the risk of SCZ and BD. STUDY DESIGN: We conducted a Swedish register-based nested case-control study using 4184 SCZ and 18 681 BD cases diagnosed 1988-2013, individually matched to 5 population-based controls by birth year, sex and birthplace. Conditional logistic regression was used to evaluate the risk of SCZ and BD by seasonality, severe prenatal infections, and perinatal factors. STUDY RESULTS: Seasonality had similar patterns of risk for both disorders: Higher risk for births November-December; lower risk April-June. Experiencing any perinatal factor was associated with a significantly higher risk of SCZ (incidence rate ratio [IRR] 1.19, 95%CI 1.11-1.63) and to a lesser extent BD (IRR 1.08, 95%CI 1.05-1.12). Prenatal infections were only associated with a greater risk of SCZ (IRR 1.30, 95%CI 1.04-1.63). In the mutually adjusted model, only perinatal factors were associated with outcomes. Several perinatal factors were associated with both disorders, but estimates were significantly higher for SCZ for low birth weight, low APGAR, and high parity. Congenital malformations were only associated with risk of SCZ, and jaundice with BD. CONCLUSIONS: Adverse perinatal factors and winter birth were the risk factors for both disorders, while severe prenatal infections were only risk a factor for SCZ. Early-life exposures were associated with a higher risk of both disorders, but may play a larger role in the development of SCZ than BD.

Sex-specific risk profiles for suicide mortality in bipolar disorder: incidence, healthcare utilization and comorbidity.

BACKGROUND: Evidence on sex-specific incidence and comorbidity risk factors of suicide among patients with bipolar disorder is scarce. This study investigated the sex-specific risk profiles for suicide among the bipolar disorder population in terms of incidence, healthcare utilization and comorbidity. METHODS: Using data from the Taiwan National Health Insurance Research Database between 1 January 2000 and 31 December 2016, this nationwide cohort study included patients with bipolar disorder (N = 46 490) and individuals representative of the general population (N = 185 960) matched by age and sex at a 1:4 ratio. Mortality rate ratios (MRRs) of suicide were calculated between suicide rates of bipolar disorder cohort and general population. In addition, a nested case-control study (1428 cases died by suicide and 5710 living controls) was conducted in the bipolar disorder cohort to examine the sex-specific risk of healthcare utilization and comorbidities. RESULTS: Suicide risk was considerably higher in the cohort (MRR = 21.9) than in the general population, especially among women (MRR = 35.6). Sex-stratified analyses revealed distinct healthcare utilization patterns and physical comorbidity risk profiles between the sexes. Although female patients who died by suicide had higher risks of nonhypertensive cardiovascular disease, pneumonia, chronic kidney disease, peptic ulcer, irritable bowel syndrome, and sepsis compared to their living counterparts, male patients who died by suicide had higher risks of chronic kidney disease and sepsis compared to the living controls. CONCLUSIONS: Patients with bipolar disorder who died by suicide had sex-specific risk profiles in incidence and physical comorbidities. Identifying these modifiable risk factors may guide interventions for suicide risk reduction.

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.

Staging the bipolar disorders: Are early stages at too early a stage for intervention?

OBJECTIVES: A number of staging models have been generated for the bipolar disorders, which include pre-onset as well as post-onset stages. Some models propose treatments for those at the pre-onset stage, a recommendation which is critiqued here. METHODS: Several exemplar staging models are overviewed, and a critique is provided. RESULTS: The critique argues against intervention at a pre-onset stage, in light of there being limited risk factors, unquantified sensitivity and specificity data for most putative onset illness risk factors, and thus there is the risk of overtreatment. Also, it is possible that many of the recommended interventions for those at risk of a bipolar disorder may have general non-specific benefits for those at risk. CONCLUSIONS: While retaining a pre-onset phase in the staging model, it would appear wiser for it to not be populated with recommended interventions until they have a firmer empirical base.

Bipolar type I diagnosis after a manic episode secondary to SARS-CoV-2 infection: A case report.

RATIONALE: Our objective is to provide awareness about psychotic vulnerability in patients infected with SARS-CoV-2 and to better understand the role of steroid withdrawal in manic episodes, especially with its common usage in respiratory disease caused by SARS-CoV-2. PATIENT CONCERNS: We present the case of a patient who was hospitalized twice after discontinuing steroid therapy for SARS-CoV-2 infection and presented with a manic episode despite not having a psychiatric history. DIAGNOSIS: The patient tested positive on a polymerase chain reaction test for SARS-CoV-2 and developed pneumonia. Other organic differential diagnoses such as encephalitis were also investigated and excluded. Manic episodes were diagnosed according to DSM-V criteria. Subsequently, the patient was diagnosed with type I bipolar disorder. INTERVENTIONS: According to the protocols, supplemental oxygen therapy, prophylactic enoxaparin and intravenous (IV) steroids were administered. Steroid dosage was gradually reduced under supervision. During the acute mania, antipsychotics and benzodiazepines were administered. OUTCOMES: After discharge, the patient was admitted to the psychiatric consultation service. He first received mood stabilizer therapy and then received supportive psychotherapy. LESSONS: Psychotic symptoms commonly occur after the discontinuation of high-dose steroid therapy; however, controlled tapering may prevent these side effects. Only a few cases have reported concomitant SARS-CoV-2 infection and manic episodes, often with an apparent relationship with steroid withdrawal syndrome. In this case, we considered psychotic vulnerability a condition that is often underestimated. In consideration of the SARS-CoV-2 pandemic, the case may represent an underlying trigger for psychotic decompensation, which, in concert with neuroinflammation, may induce a manic episode.

Association of Etiological Factors for Hypomanic Symptoms, Bipolar Disorder, and Other Severe Mental Illnesses.

Importance: Subsyndromal hypomanic symptoms are relatively common in the general population and are linked to the onset of bipolar disorder. Little is known about their etiology and whether this is shared with the etiology of bipolar disorder or other mental illnesses. Objective: To examine the genetic and environmental architecture of hypomanic symptoms in a nonclinical youth sample and compare estimates at varying severity levels and their association with diagnosed bipolar disorder. Design, Setting, and Participants: This cohort study used phenotypic and genetic data from the Child and Adolescent Twin Study in Sweden and included individuals with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis of psychiatric disorders from national registries for residents of Sweden. Associations between hypomania and polygenic risk scores for bipolar disorder, major depressive disorder and schizophrenia were also investigated. Analysis began November 2018 and ended October 2021. Main Outcomes and Measures: Hypomanic symptoms were assessed using the parent-rated Mood Disorders Questionnaire when the twins were aged 18 years. Bipolar disorder diagnosis and/or lithium prescription were ascertained from national registries for residents of Sweden. Polygenic risk scores for psychiatric disorders were calculated using independent discovery genetic data. Results: A total of 8568 twin pairs aged 18 years (9381 [54.7%] female) were included in the study. The hypomania heritability estimate was 59% (95% CI, 52%-64%) for male individuals and 29% (95% CI, 16%-44%) for female individuals. Unique environmental factors accounted for 41% (95% CI, 36%-47%) of the hypomania variance in male individuals and 45% (95% CI, 40%-50%) in female individuals. Shared environmental factors were only detected for female individuals and explained 26% (95% CI, 13%-38%) of the variance. The heritability estimates were fairly consistent across different hypomania severity groups. Moderate genetic (0.40; 95% CI, 0.21-0.58) and shared environmental (0.41; 95% CI, 0.03-0.75) correlations between hypomania and diagnosed bipolar disorder were found. Hypomania was significantly associated with the polygenic risk scores for schizophrenia (ß = 0.08; SE = 0.026; P = .002) and major depressive disorder (ß = 0.09; SE = 0.027; P = .001) but not bipolar disorder (ß = 0.017; SE = 0.03; P = 0.57) (bipolar disorder I [ß = 0.014; SE = 0.029; P = .64] or bipolar disorder II [ß = 0.045; SE = 0.027; P = .10]). Conclusions and Relevance: Higher heritability for hypomania was found for male compared with female individuals. The results highlight the shared etiologies between hypomanic symptoms, bipolar disorder, major depression, and schizophrenia in youths. Future research should focus on identifying specific shared genetic and environmental factors. These findings support a possible dimensional model of bipolar disorder, with hypomania representing a continuous trait underlying the disorder.

Repetitive transcranial magnetic stimulation (rTMS) in bipolar disorder: A systematic review.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) is commonly used in unipolar depression; yet, its evidence in bipolar disorder (BD) is limited. We sought to review the evidence on the use of rTMS across the different stages of BD. METHODS: MEDLINE database was systematically searched using the PubMed interface following the PRISMA guidelines. Inclusion criteria were as follows: (i) randomized clinical trials (RCTs), open-label studies, and case series; (ii) specific evaluation of the treatment outcomes using psychometric scales; (iii) clinical studies in adults; and (iv) articles in the English language. The systematic review has been registered on PROSPERO (CRD42020192788). RESULTS: Thirty-one papers were included in the review. Most studies included participants diagnosed with a bipolar depressive episode (N = 24), have yielded mixed findings, and have yet to reach a consensus on the most effective rTMS protocol. Few studies examined the effect of rTMS during manic (N = 5) or mixed episode (N = 1), or as maintenance treatment (N = 1). The limited data thus far suggest rTMS to be relatively safe and well tolerated. Small sample sizes, heterogeneity among study designs, patients and control groups recruited, rTMS parameters, and outcome measures are among the most significant limitations to these studies. CONCLUSION: The current data regarding the application of rTMS in BD patients remain limited. More adequately powered sham-controlled studies are required to verify its efficacy. Large-scale clinical trials are needed to also determine whether its effects extend to manic and mixed episodes, as well as its role in mood stabilization and amelioration of suicidal behavior.

Poststroke Bipolar Disorder.

ABSTRACT: Various diseases that impact different systems and organs in the body may trigger manic episodes. Strokes are often associated with psychiatric symptoms, particularly depressive and, more rarely, manic. We herein report a case of bipolar disorder secondary to cerebrovascular disease in a 67-year-old man with no personal or family history of psychiatric illness who, at the age of 64, had a bilateral ischemic stroke in the middle cerebral artery territory. About 20 days after this stroke, he experienced a manic episode. Three years later, he experienced a second manic episode, with another hospitalization in a psychiatric ward. With this case, we intend to emphasize that, although rare, the diagnosis of mania after stroke should not be forgotten, and most important, one should be aware of the recurrence of affective episodes just as in non-medical-caused bipolar disorder.

Organic bipolar disorder secondary to central neurocytoma resection: a case report.

entral neurocytoma is a neuroepithelial tumor described by Hassoun in 1982, predominantly located in the midline at the level of the septum pellucidum, or in the lateral ventricles wall1. They represent approximately 50% of intraventricular lesions in adults, and they are in total 0.25-0.5% of intracranial tumors.

A behavioral protocol to assess the relationship between three cognitive biases and future depression severity.

According to the cognitive model of depression, memory bias, interpretation bias, and attention bias are associated with the development and maintenance of depression. Here, we present a protocol for investigating whether and how the novel coronavirus disease 2019 (COVID-19) pandemic may affect the relationship between current cognitive biases and future depression severity in a population with non-clinical depression. This protocol can also be used in other contexts, including cognitive bias-related studies and depression-related functional magnetic resonance imaging (fMRI) studies. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2021).

Association between polygenic propensity for psychiatric disorders and nutrient intake.

Despite the observed associations between psychiatric disorders and nutrient intake, genetic studies are limited. We examined whether polygenic scores for psychiatric disorders are associated with nutrient intake in UK Biobank (N = 163,619) using linear mixed models. We found polygenic scores for attention-deficit/hyperactivity disorder, bipolar disorder, and schizophrenia showed the highest number of associations, while a polygenic score for autism spectrum disorder showed no association. The relatively weaker obsessive-compulsive disorder polygenic score showed the greatest effect sizes suggesting its association with diet traits may become more apparent with larger genome-wide analyses. A higher alcohol dependence polygenic score was associated with higher alcohol intake and individuals with higher persistent thinness polygenic scores reported their food to weigh less, both independent of socioeconomic status. Our findings suggest that polygenic propensity for a psychiatric disorder is associated with dietary behaviour. Note, nutrient intake was self-reported and findings must therefore be interpreted mindfully.

Elevated Mood States in Patients With Parkinson's Disease Treated With Deep Brain Stimulation: Diagnosis and Management Strategies.

OBJECTIVE: Deep brain stimulation (DBS) is an effective surgical treatment for patients with Parkinson's disease (PD). DBS therapy, particularly with the subthalamic nucleus (STN) target, has been linked to rare psychiatric complications, including depression, impulsivity, irritability, and suicidality. Stimulation-induced elevated mood states can also occur. These episodes rarely meet DSM-5 criteria for mania or hypomania. METHODS: The investigators conducted a chart review of 82 patients with PD treated with DBS. RESULTS: Nine (11%) patients developed stimulation-induced elevated mood. Five illustrative cases are described (all males with STN DBS; mean age=62.2 years [SD=10.5], mean PD duration=8.6 years [SD=1.6]). Elevated mood states occurred during or shortly after programming changes, when more ventral contacts were used (typically in monopolar mode) and lasted minutes to months. Four patients experienced elevated mood at low amplitudes (1.0 V/1.0 mA); all had psychiatric risk factors (history of impulse-control disorder, dopamine dysregulation syndrome, substance use disorder, and/or bipolar diathesis) that likely contributed to mood destabilization. CONCLUSIONS: Preoperative DBS evaluations should include a thorough assessment of psychiatric risk factors. The term "stimulation-induced elevated mood states" is proposed to describe episodes of elevated, expansive, or irritable mood and psychomotor agitation that occur during or shortly after DBS programming changes and may be associated with increased goal-directed activity, impulsivity, grandiosity, pressured speech, flight of ideas, or decreased need for sleep and may persist beyond stimulation adjustments. This clinical phenomenon should be considered for inclusion in the bipolar disorder category in future DSM revisions, allowing for increased recognition and appropriate management.

Old Age Bipolar Disorder-Epidemiology, Aetiology and Treatment.

Data regarding older age bipolar disorder (OABD) are sparse. Two major groups are classified as patients with first occurrence of mania in old age, the so called "late onset" patients (LOBD), and the elder patients with a long-standing clinical history, the so called "early onset" patients (EOBD). The aim of the present literature review is to provide more information on specific issues concerning OABD, such as epidemiology, aetiology and treatments outcomes. We conducted a Medline literature search from 1970-2021 using the MeSH terms "bipolar disorder" and "aged" or "geriatric" or "elderly". The additional literature was retrieved by examining cross references and by a hand search in textbooks. With sparse data on the treatment of OABD, current guidelines concluded that first-line treatment of OABD should be similar to that for working-age bipolar disorder, with specific attention to side effects, somatic comorbidities and specific risks of OABD. With constant monitoring and awareness of the possible toxic drug interactions, lithium is a safe drug for OABD patients, both in mania and maintenance. Lamotrigine and lurasidone could be considered in bipolar depression. Mood stabilizers, rather than second generation antipsychotics, are the treatment of choice for maintenance. If medication fails, electroconvulsive therapy is recommended for mania, mixed states and depression, and can also be offered for continuation and maintenance treatment. Preliminary results also support a role of psychotherapy and psychosocial interventions in old age BD. The recommended treatments for OABD include lithium and antiepileptics such as valproic acid and lamotrigine, and lurasidone for bipolar depression, although the evidence is still weak. Combined psychosocial and pharmacological treatments also appear to be a treatment of choice for OABD. More research is needed on the optimal pharmacological and psychosocial approaches to OABD, as well as their combination and ranking in an evidence-based therapy algorithm.