Illness trajectory from prodromal symptoms to incident bipolar disorder and schizophrenia

Background: The concept of prodrome is highly variable but, when applied retrospectively in cohorts who progress to meet diagnostic criteria for bipolar disorder (BD) and schizophrenia (SZ), it can contribute to clarify early origins and trajectory of the illness. In the context of race and ethnicity, studies with population-based and registry-based cohorts, such as the Rochester Epidemiology Project (REP), can potentially identify, through retrospective assessment of the prodromes of BD and SZ, differences while addressing the heterogeneous nature of the illness. Objective: We aim to describe and compare the illness trajectories of individuals with BD or SZ prior to the incident case. Additionally, we assessed for differences in access to healthcare in racially diverse patients and within those with schizophrenia, we sought to analyze differences in prodrome duration based on place of birth (U.S. born vs. foreign born). Methods: Using a records-linkage system from Minnesota, we searched for subjects born after 1985 that had been diagnosed with BD or SZ. Cases were ascertained for diagnosis and identification of the first episode of mania or psychosis. Using the medical records we extracted data from their medical history prior to their first episode. Results: We identified 205 cases with the first episode of psychosis or mania (SZ = 131; BD = 74). The mean age of onset for BD was 21.34 years and 20.45 years for SZ. We did not find a difference between the mean duration of the trajectory of mental health problems to a first episode. Both disorders were preceded by high healthcare utilization and had similar rates of psychiatric diagnoses, substance use, and prescriptions of psychiatric medications. SZ was more common in Non-white patients and in immigrants and BD had a higher rate of depressive disorder and adjustment disorders. Conclusions: Results from this study provide critical information on social and clinical features that precede a first manic or psychotic episode that may help early illness detection, identification of individuals at high risk of BD and SZ and address health disparities

Racial differences in pathways to care preceding first episode mania or psychosis: a historical cohort prodromal study

BackgroundThere is evidence suggesting racial disparities in diagnosis and treatment in bipolar disorder (BD) and schizophrenia (SZ). The purpose of this study is to compare psychiatric diagnoses and psychotropic use preceding a first episode of mania (FEM) or psychosis (FEP) in racially diverse patients.MethodsUsing a comprehensive medical records linkage system (Rochester Epidemiology Project, REP), we retrospectively identified individuals diagnosed with BD or SZ and a documented first episode of mania or psychosis. Illness trajectory before FEP/FEM were characterized as the time from first visit for a mental health complaint to incident case. Pathways to care and clinical events preceding FEP/FEM were compared based on subsequent incident case diagnosis (BD or SZ) and self-reported race (White vs. non-White).ResultsA total of 205 (FEM = 74; FEP = 131) incident cases were identified in the REP. Duration of psychiatric antecedents was significantly shorter in non-White patients, compared to White patients (2.2 ± 4.3 vs. 7.4 ± 6.6 years; p < 0.001) with an older age at time of first visit for a mental health complaint (15.7 ± 6.3 vs. 11.1 ± 6.0 years; p = 0.005). There were no significant differences by race in FEM pathway to care or age of first seeking mental health. Overall non-White patients had lower rates of psychotropic use.ConclusionThese data are unable to ascertain reasons for shorter duration of psychiatric antecedents and later age of seeking care, and more broadly first age of initial symptom presentation. If symptoms are confirmed to be earlier than first time seeking care in both groups, it would be important to identify barriers that racial minorities face to access timely psychiatric care and optimize early intervention strategies

Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study

Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = −0.14; 95% confidence interval [CI]: −0.24 to −0.03; p value = 0.010) and MDD (β = −0.16; 95% CI: −0.27 to −0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34–1.93; p value = 2e−7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Genetic contributions to bipolar disorder: Current status and future directions

Abstract Bipolar disorder (BD) is a highly heritable mental disorder and is estimated to affect about 50 million people worldwide. Our understanding of the genetic etiology of BD has greatly increased in recent years with advances in technology and methodology as well as the adoption of international consortiums and large population-based biobanks. It is clear that BD is also highly heterogeneous and polygenic and shows substantial genetic overlap with other psychiatric disorders. Genetic studies of BD suggest that the number of associated loci is expected to substantially increase in larger future studies and with it, improved genetic prediction of the disorder. Still, a number of challenges remain to fully characterize the genetic architecture of BD. First among these is the need to incorporate ancestrally-diverse samples to move research away from a Eurocentric bias that has the potential to exacerbate health disparities already seen in BD. Furthermore, incorporation of population biobanks, registry data, and electronic health records will be required to increase the sample size necessary for continued genetic discovery, while increased deep phenotyping is necessary to elucidate subtypes within BD. Lastly, the role of rare variation in BD remains to be determined. Meeting these challenges will enable improved identification of causal variants for the disorder and also allow for equitable future clinical applications of both genetic risk prediction and therapeutic interventions

Shear-wave velocity of the patellar tendon and quadriceps muscle is increased immediately after maximal eccentric exercise

PURPOSE: To determine whether stiffness of the patellar tendon and quadriceps muscles is altered immediately after and 48 h after a single bout of maximal eccentric exercise of the knee extensor muscles. METHODS: Thirteen healthy individuals [group mean (SD) age 22.4 (3.5) years; 7 female] performed a single bout of maximal eccentric exercise of the non-dominant knee extensors, using an isokinetic dynamometer. Shear-wave velocity (an index of tissue stiffness) was recorded from the patellar tendon, vastus medialis (VM), rectus femoris (RF) and vastus lateralis (VL), before, following (post0), and 48 h after (post48) exercise. To investigate features of exercise induced muscle damage, maximal voluntary isometric contraction (MVIC) and self-reported pain and stiffness (numerical rating scales 0 = no pain/stiffness to 100 = worst imaginable pain/stiffness) were measured before, post0, and post48 exercise. Serum creatine kinase (CK) was measured before and post48 exercise. RESULTS: Compared to preexercise, MVIC decreased and self-reported pain and stiffness increased at post0 and post48 and CK levels increased at post48 (all p

Long-Term Lithium Therapy and Thyroid Disorders in Bipolar Disorder: A Historical Cohort Study

Lithium has been a cornerstone treatment for bipolar disorder (BD). Despite descriptions in the literature regarding associations between long-term lithium therapy (LTLT) and development of a thyroid disorder (overt/subclinical hypo/hyperthyroidism, thyroid nodule, and goiter) in BD, factors such as time to onset of thyroid abnormalities and impact on clinical outcomes in the course of illness have not been fully characterized. In this study we aimed to compare clinical characteristics of adult BD patients with and without thyroid disorders who were on LTLT. We aimed to identify the incidence of thyroid disorders in patients with BD on LTLT and response to lithium between patients with and without thyroid disorders in BD. The Cox proportional model was used to find the median time to the development of a thyroid disorder. Our results showed that up to 32% of patients with BD on LTLT developed a thyroid disorder, of which 79% developed hypothyroidism, which was corrected with thyroid hormone replacement. We did not find significant differences in lithium response between patients with or without thyroid disorders in BD. Findings from this study suggest that patients with BD and comorbid thyroid disorders when adequately treated have a response to lithium similar to patients with BD and no thyroid disorders

Association of schizophrenia polygenic risk score with manic and depressive psychosis in bipolar disorder

Abstract Bipolar disorder (BD) is highly heterogeneous in symptomatology. Narrowing the clinical phenotype may increase the power to identify risk genes that contribute to particular BD subtypes. This study was designed to test the hypothesis that genetic overlap between schizophrenia (SZ) and BD is higher for BD with a history of manic psychosis. Analyses were conducted using a Mayo Clinic Bipolar Biobank cohort of 957 bipolar cases (including 333 with history of psychosis during mania, 64 with history of psychosis only during depression, 547 with no history of psychosis, and 13 with unknown history of psychosis) and 778 controls. Polygenic risk score (PRS) analysis was performed by calculating a SZ-PRS for the BD cases and controls, and comparing the calculated SZ risk between different psychosis subgroups and bipolar types. The SZ-PRS was significantly higher for BD-I cases with manic psychosis than BD-I cases with depressive psychosis (Nagelkerke’s R 2 = 0.021; p = 0.045), BD-I cases without psychosis (R 2 = 0.015; p = 0.007), BD-II cases without psychosis (R 2 = 0.014; p = 0.017), and controls (R 2 = 0.065; p = 2 × 10−13). No other significant differences were found. Our results show that BD-I with manic psychosis is genetically more similar to SZ than any other tested BD subgroup. Further investigations on genetics of distinct clinical phenotypes composing major psychoses may help refine the current diagnostic classification system