Lukas Propper

Brain structural signature of familial predisposition for bipolar disorder: replicable evidence for involvement of the right inferior frontal gyrus.

BACKGROUND To translate our knowledge about neuroanatomy of bipolar disorder (BD) into a diagnostic tool, it is necessary to identify the neural signature of predisposition for BD and separate it from effects of long-standing illness and treatment. Thus, we examined the associations among genetic risk, illness burden, lithium treatment, and brain structure in BD. METHODS This is a two-center, replication-design, structural magnetic resonance imaging study. First, we investigated neuroanatomic markers of familial predisposition by comparing 50 unaffected and 36 affected relatives of BD probands as well as 49 control subjects using modulated voxel-based morphometry. Second, we investigated effects of long-standing illness and treatment on the identified markers in 19 young participants early in the course of BD, 29 subjects with substantial burden of long-lasting BD and either minimal lifetime (n = 12), or long-term ongoing (n = 17) lithium treatment. RESULTS Five groups, including the unaffected and affected relatives of BD probands from each center as well as participants early in the course of BD showed larger right inferior frontal gyrus (rIFG) volumes than control subjects (corrected p < .001). The rIFG volume correlated negatively with illness duration (corrected p < .01) and, relative to the controls, was smaller among BD individuals with long-term illness burden and minimal lifetime lithium exposure (corrected p < .001). Li-treated subjects had normal rIFG volumes despite substantial illness burden. CONCLUSIONS Brain structural changes in BD may result from interplay between illness burden and compensatory processes, which may be enhanced by lithium treatment. The rIFG volume could aid in identification of subjects at risk for BD even before any behavioral manifestations.

Striatal volumes in affected and unaffected relatives of bipolar patients - high-risk study

BACKGROUND Striatal volume changes reported in bipolar disorders could represent artifacts of medication or comorbid conditions, or illness related changes, either biological predispositions or consequences of illness burden. We conducted volumetric high-risk study to investigate whether striatal volume changes represent primary biological risk factor for bipolar disorders. METHODS High-risk (HR) participants (age range 15-30 years) were recruited from families multiply affected with bipolar disorders. They included 20 affected and 26 unaffected offspring of parents with primary mood disorders, matched by age and sex with 31 controls without a personal or family history of psychiatric disorders. Striatal volumes were measured on 1.5T 3D anatomical MRI images using standard methods. RESULTS There was a significant difference between groups (affected, unaffected HR and control subjects) in caudate volumes (F=3.50, DF=2; 74 and p=0.04) in absence of putamen volume changes. The caudate volumes were largest in unaffected HR subjects without differences between affected and control or affected and unaffected HR subjects. The maximum changes were found in the head of the caudate. Controlling for non-independence of observations in multiple subjects per family yielded non-significant differences. CONCLUSIONS Despite the biological plausibility, partial agreement with previous studies and nominal statistical significance, controlling for non-independence of observations within families changed the increased caudate volumes among unaffected subjects to non-significant. We thus present these findings as negative, pending further replication. Striatal volume abnormalities did not meet criteria for endophenotype in this study.

Amygdala and hippocampal volumes in relatives of patients with bipolar disorder: a high-risk study.

Objective: Bipolar disorders (BD) have a strong genetic underpinning, yet no biological vulnerability markers for BD have yet been identified. To test whether amygdala or hippocampal volumes represent an endophenotype for BD, we measured mesiotemporal volumes in young affected and unaffected relatives of patients with BD (high-risk design). Method: High-risk participants (aged 15 to 30 years) were recruited from families multiply affected with BD. They included 20 affected and 26 unaffected offspring of parents with primary mood disorders, matched by age and sex with 31 control subjects without a personal or family history of psychiatric disorders. Amygdala and hippocampal volumes were measured on 1.5 Tesla 3-dimensional anatomical magnetic resonance images using standard methods. Results: We found comparable amygdala and hippocampal volumes among unaffected relatives, affected high-risk patients, and control subjects. The exclusion of 6 medicated patients did not change the results. There were no differences between participants with family history of BD I, compared with participants with family history of BD II, or between subjects with family history of BD with psychotic symptoms, compared with subjects with family history of BD without psychotic symptoms. Conclusions: Hippocampal and amygdala volume abnormalities were absent in unaffected and affected relatives of patients with BD and thus did not meet criteria for endophenotype.

A familial risk enriched cohort as a platform for testing early interventions to prevent severe mental illness

BackgroundSevere mental illness (SMI), including schizophrenia, bipolar disorder and severe depression, is responsible for a substantial proportion of disability in the population. This article describes the aims and design of a research study that takes a novel approach to targeted prevention of SMI. It is based on the rationale that early developmental antecedents to SMI are likely to be more malleable than fully developed mood or psychotic disorders and that low-risk interventions targeting antecedents may reduce the risk of SMI.Methods/DesignFamilies Overcoming Risks and Building Opportunities for Well-being (FORBOW) is an accelerated cohort study that includes a large proportion of offspring of parents with SMI and embeds intervention trials in a cohort multiple randomized controlled trial (cmRCT) design. Antecedents are conditions of the individual that are distressing but not severely impairing, predict SMI with moderate-to-large effect sizes and precede the onset of SMI by at least several years. FORBOW focuses on the following antecedents: affective lability, anxiety, psychotic-like experiences, basic symptoms, sleep problems, somatic symptoms, cannabis use and cognitive delay. Enrolment of offspring over a broad age range (0 to 21 years) will allow researchers to draw conclusions on a longer developmental period from a study of shorter duration. Annual assessments cover a full range of psychopathology, cognitive abilities, eligibility criteria for interventions and outcomes. Pre-emptive early interventions (PEI) will include skill training for parents of younger children and courses in emotional well-being skills based on cognitive behavioural therapy for older children and youth. A sample enriched for familial risk of SMI will enhance statistical power for testing the efficacy of PEI.DiscussionFORBOW offers a platform for efficient and unbiased testing of interventions selected according to best available evidence. Since few differences exist between familial and ’sporadic’ SMI, the same interventions are likely to be effective in the general population. Comparison of short-term efficacy of PEI on antecedents and the long term efficacy for preventing the onset of SMI will provide an experimental test of the etiological role of antecedents in the development of SMI.

White matter hyperintensities in affected and unaffected late teenage and early adulthood offspring of bipolar parents: A two-center high-risk study

BACKGROUND White matter hyperintensities (WMHs) are among the most replicated neuroimaging findings in bipolar disorder (BD). It is not clear whether these lesions are an artifact of comorbid conditions, or whether they are directly associated with the disorder, or even represent biological risk factor for BD. METHODS To test whether WMHs meet criteria for an endophenotype of BD, we conducted a high-risk design study and recruited 35 affected, 44 unaffected relatives of bipolar probands (age range 15-30 years), matched by age and sex with 49 healthy controls without any personal or family history of psychiatric disorders. The presence of WMHs was determined from Fluid Attenuated Inversion Recovery (FLAIR) scans acquired on a 1.5 Tesla scanner using a validated semi-quantitative scale. RESULTS We found mostly low grade WMHs in all groups. The proportion of WMH-positive subjects was comparable between the unaffected high-risk, affected familial and control groups. CONCLUSION White matter hyperintensities did not meet criteria for an endophenotype of BD. Bipolar disorder in young subjects without comorbid conditions was not associated with increased rate of WMHs.

Early-onset and very-early-onset bipolar disorder: distinct or similar clinical conditions?

This study aimed to examine differences in the clinical presentation of very‐early‐onset (VEO) and early‐onset (EO) bipolar disorder (BD) not fully explored previously.

Stimulant Medication and Psychotic Symptoms in Offspring of Parents With Mental Illness

BACKGROUND: Stimulants, such as methylphenidate, are among the most commonly used medications in children and adolescents. Psychotic symptoms have been reported as rare adverse reactions to stimulants but have not been systematically inquired about in most previous studies. Family history of mental illness may increase the vulnerability to drug-induced psychotic symptoms. We examined the association between stimulant use and psychotic symptoms in sons and daughters of parents with major mood and psychotic disorders. METHODS: We assessed psychotic symptoms, psychotic-like experiences, and basic symptoms in 141 children and youth (mean ± SD age: 11.8 ± 4.0 years; range: 6–21 years), who had 1 or both parents with major depressive disorder, bipolar disorder, or schizophrenia, and of whom 24 (17.0%) had taken stimulant medication. RESULTS: Psychotic symptoms were present in 62.5% of youth who had taken stimulants compared with 27.4% of participants who had never taken stimulants. The association between stimulant use and psychotic experiences remained significant after adjustment for potential confounders (odds ratio: 4.41; 95% confidence interval: 1.82–10.69; P = .001) and was driven by hallucinations occurring during the use of stimulant medication. A temporal relationship between use of stimulants and psychotic symptoms was supported by an association between current stimulant use and current psychotic symptoms and co-occurrence in cases that were assessed on and off stimulants. CONCLUSIONS: Psychotic symptoms should be monitored during the use of stimulants in children and adolescents. Family history of mood and psychotic disorders may need to be taken into account when considering the prescription of stimulants.

Disruptive mood dysregulation disorder in offspring of parents with depression and bipolar disorder

BackgroundIt has been suggested that offspring of parents with bipolar disorder are at increased risk for disruptive mood dysregulation disorder (DMDD), but the specificity of this association has not been established.AimsWe examined the specificity of DMDD to family history by comparing offspring of parents with (a) bipolar disorder, (b) major depressive disorder and (c) a control group with no mood disorders.MethodWe established lifetime diagnosis of DMDD using the Schedule for Affective Disorders and Schizophrenia for School Aged Children for DSM-5 in 180 youth aged 6-18 years, including 58 offspring of parents with bipolar disorder, 82 offspring of parents with major depressive disorder and 40 control offspring.ResultsDiagnostic criteria for DMDD were met in none of the offspring of parents with bipolar disorder, 6 of the offspring of parents with major depressive disorder and none of the control offspring. DMDD diagnosis was significantly associated with family history of major depressive disorder.ConclusionsOur results suggest that DMDD is not specifically associated with a family history of bipolar disorder and may be associated with parental depression.

255. Greater Gyrification of the Inferior Frontal Gyrus as a Marker of Genetic Risk for Bipolar Disorders

To bridge these lines of research we sought to map a transcriptome-based polygenic risk score (PRS) onto MRIassessed dlPFC function and whole-brain structural covariance network properties. Methods: Using the GTEx database, we developed a PRS based on 243 common cis-eQTL SNPs which bias gene expression in the dlPFC towards a depression-like molecular phenotype. We next examined the effect of this PRS on dlPFC activity during a working memory task (n5183) in the Duke Neurogenetics Study. We further conducted a structural covariance network analysis (n51063) to probe potentially development-mediated PRS effects on dlPFC network hub status, as well as whole-brain network clustering (transitivity) and integration capacity (mean path length). Results: Higher PRS was associated with greater left dlPFC activity in the absence of performance differences during a working memory task, but only in participants reporting high childhood trauma (p 50.03). Structural covariance analyses revealed higher PRS was independently associated with decreased left dlPFC “hubness” and increased mean network path length. Conclusions: Our results suggest a depression-like transcriptome polygenic risk score is associated with inefficient dlPFC activity supporting working memory, particularly in individuals exposed to early life stress. The same molecular phenotype may also disrupt developmentally mediated shared structural plasticity between the dlPFC and other regions, leading to long-term whole-brain network reorganization consistent with reduced integration capacity. Supported By: YSN is supported by a Banting Postdoctoral Fellowship (CIHR) and NARSAD Young Investigator Grant. ARH is supported by R01-DA033369 and R01AG049789. ES is supported by NIH Grant R01-MH077159