Weight gain as a predictor of frontal and temporal lobe volume loss in bipolar disorder: A prospective MRI study.

OBJECTIVES: A sizable fraction of people with bipolar I disorder (BDI) experience a deteriorating clinical course with increasingly frequent mood episodes and chronic disability. This is believed to result from neurobiological illness progression, or neuroprogression. Excessive weight gain predicts neuroprogression across multiple brain illnesses, but no prospective studies have investigated this in BDI. The objective of this study was to determine whether BDI patients who experienced clinically significant weight gain (CSWG; gaining ≥7% of baseline weight) over 12 months had greater 12-month brain volume loss in frontal and temporal regions important to BDI. METHODS: In 55 early-stage BDI patients we measured (i) rates of CSWG, (ii) the number of days with mood symptoms, using NIMH LifeCharts, and (iii) baseline and 12-month brain volumes, using 3T MRI. We quantified brain volumes using the longitudinal processing stream in FreeSurfer v6.0. We used general linear models for repeated measures to investigate whether CSWG predicted volume loss, adjusting for potentially confounding clinical and treatment variables. RESULTS: After correction for multiple comparisons, CSWG in patients predicted greater volume loss in the left orbitofrontal cortex (effect size [ES; Cohen's d] = -1.01, P = 0.002), left cingulate gyrus (ES = -1.31, P < 0.001), and left middle temporal gyrus (ES = -0.96, P = 0.004). Middle temporal volume loss predicted more days with depression (ß = -0.406, P = 0.010). CONCLUSIONS: These are the first prospective data on weight gain and neuroprogression in BDI. CSWG predicted neuroprogression, and neuroprogression predicted a worse clinical illness course. Trials of weight loss interventions are needed to confirm the causal direction of the weight gain-neuroprogression relationship, and to determine whether weight loss is a disease-modifying treatment.

Structural brain changes in first episode mania with and without psychosis: Data from the Systematic Treatment Optimization Program for Early Mania (STOP-EM).

OBJECTIVES: The neurobiological underpinnings of bipolar I disorder are not yet understood. Previous structural neuroimaging studies of bipolar disorder have produced rather conflicting results. We hypothesise that clinical sub-phenotypes of bipolar I disorder defined by their psychotic symptoms, especially those with mood-incongruent psychotic features, may have more extensive structural brain abnormalities. METHODS: We investigated structural brain alterations in patients with first-episode mania (n = 55) with mood-congruent (n = 16) and mood-incongruent (n = 32) psychotic features, as well as those without psychotic symptoms (n = 7), relative to healthy subjects (n = 56). RESULTS: Total intracranial volume was significantly reduced in patients with mood-incongruent psychosis compared to healthy subjects while cerebrospinal fluid (CSF) volume was significantly increased. Patients with mood-congruent psychosis showed significant reduction in total white matter volume and significant CSF volume increase. Patients with psychosis had significant volume reduction in anterior cingulate and medial prefrontal cortices. Relative to mood-congruent psychotic features, mood-incongruent psychotic features were associated with volume reduction in the left middle temporal gyrus, right inferior parietal gyrus, right fusiform gyrus, left middle orbitofrontal gyrus and cerebellum. CONCLUSIONS: While preliminary, our findings suggest that the presence and type of psychosis in first-episode mania may be phenotypic markers of underlying biological variants of bipolar disorder.

A Positron Emission Tomography Study of Norepinephrine Transporter Occupancy and Its Correlation with Symptom Response in Depressed Patients Treated with Quetiapine XR.

Background: Quetiapine is effective in treating depressive symptoms in major depressive disorder and bipolar disorder, but the mechanisms underlying its antidepressants effects are unknown. Norquetiapine, a metabolite of quetiapine, has high affinity for norepinephrine transporter, which might account for its therapeutic efficacy. Methods: In this study, we used positron emission tomography with (S,S)-[11C]O-methyl reboxetine to estimate norepinephrine transporter density and assess the relationship between norepinephrine transporter occupancy by quetiapine XR and improvement in depression in patients with major depressive disorder (n=5) and bipolar disorder (n=5). After the baseline positron emission tomography scan, patients were treated with quetiapine XR with a target dose of 150 mg in major depressive disorder and 300 mg in bipolar disorder. Patients had a second positron emission tomography scan at the end of week 2 and a final scan at week 7. Results: Norepinephrine transporter density was significantly lower in locus ceruleus in patients compared with healthy subjects. Further, there was a significant positive correlation between quetiapine XR dose and norepinephrine transporter occupancy in locus ceruleus at week 2. The norepinephrine transporter occupancy at week 2 in hypothalamus but not in other regions predicted improvement in depression as reflected by reduction in MADRS scores from baseline to week 7. The estimated dose of quetiapine XR associated with 50% norepinephrine transporter occupancy in hypothalamus at week 2 was 256 mg and the estimated plasma levels of norquetiapine to achieve 50% norepinephrine transporter occupancy was 36.8 µg/L. Conclusion: These data provide preliminary support for the hypothesis that norepinephrine transporter occupancy by norquetiapine may be a contributor to the antidepressant effects of quetiapine.

The impact of psychosis on brain anatomy in bipolar disorder: A structural MRI study.

BACKGROUND: Bipolar disorder (BD) is a major psychiatric illness characterized by heterogeneous symptoms including psychotic features. Up until now, neuroimaging studies investigating cerebral morphology in patients with BD have underestimated the potential impact of psychosis on brain anatomy in BD patients. In this regard, psychotic and non-psychotic BD may represent biologically different subtypes of the disorder, being possibly associated with specific cerebral features. METHODS: In the present study, magnetic resonance imaging (MRI) at 3T was used to identify the neuroanatomical correlates of psychosis in an International sample of BD patients. A large sample of structural MRI data from healthy subjects (HC) and BD patients was collected across two research centers. Voxel based morphometry was used to compare gray matter (GM) volume among psychotic and non-psychotic BD patients and HC. RESULTS: We found specific structural alterations in the two patient groups, more extended in the psychotic sample. Psychotic patients showed GM volume deficits in left frontal cortex compared to HC, and in right temporo-parietal cortex compared to both HC and non-psychotic patients (p < 0.001, > 100 voxels). Psychotic patients also exhibited enhanced age-related GM volume deficits in a set of subcortical and cortical regions. LIMITATIONS: The integration of multiple datasets may have affected the results. CONCLUSIONS: Overall, our results confirm the importance of classifying BD based on psychosis. The knowledge of the neuronal bases of psychotic symptomatology in BD can provide a more comprehensive picture of the determinants of BD, in the light of the continuum characteristic of major psychoses.

Trajectories of body mass index change in first episode of mania: 3-year data from the Systematic Treatment Optimization Program for Early Mania (STOP-EM).

BACKGROUND: Overweight/obesity is common in patients with bipolar disorder (BD). However, little is known about longitudinal trends in body mass index (BMI) in patients with BD. Furthermore, most studies on the association between BMI and clinical outcomes are restricted by retrospective and cross-sectional designs. This study uses prospectively-gathered data from a first episode mania (FEM) cohort to examine the trajectories of BMI change and analyze their association with clinical outcomes during a 3-year period. METHODS: A total of 110 FEM patients receiving maintenance treatment and 57 healthy subjects were included. The comparisons of BMI trajectories were examined using linear mixed-effects models. The effects of BMI on time to any mood episode were assessed by Cox proportional-hazards models. RESULTS: The estimated mean BMI in FEM patients significantly increased from 24.0kg/m2 to 25.4kg/m2 within 6 months. FEM patients had a significant BMI increase trend over the entire 3 years follow-up, which was not observed in the control group. No significant difference in BMI trajectory between patient subgroups (baseline normal-weight vs. overweight/obese; male vs. female) was observed. BMI increase predicted an increased risk of recurrence during follow-up visits (HR=1.50, 95% CI: 1.06-2.13; p=0.02). LIMITATIONS: Naturalistic design does not allow the accurate assessments of the impact of pharmacologic treatments on BMI. CONCLUSIONS: FEM patients showed a significantly increased BMI trajectory compared to healthy subjects. Furthermore, BMI increase is independently associated with an increased risk of recurrence to a new mood episode during 3-year follow-up. Thus, weight control prevention is needed in the early course of BD.

A Longitudinal Study of the Relationships Between Mood Symptoms, Body Mass Index, and Serum Adipokines in Bipolar Disorder.

OBJECTIVE: There is a bidirectional relationship between obesity and mood disorders, with each increasing the risk of developing the other. This relationship suggests that they have overlapping pathophysiologic mechanisms. Adipose tissue-derived hormones, or adipokines, regulate appetite and metabolism and have activity in limbic brain regions, making them potential shared etiologic factors between elevated body mass index (BMI) and mood disorders. However, the precise relationships between BMI, mood, and adipokines are unknown. METHODS: We measured the serum levels of adiponectin, lipocalin-2, resistin, adipsin, and leptin in 53 people with early-stage DSM-IV-defined bipolar disorder, diagnosed with the Mini-International Neuropsychiatric Interview, and 22 healthy comparison subjects. Participants were followed at the University of British Columbia Mood Disorders Centre between June 2004 and June 2012. We were primarily interested in determining, in patients, (1) whether BMI and recent mood episodes predicted adipokine levels and (2) whether adipokine levels in turn predicted subsequent mood relapses and change in BMI. RESULTS: Using linear regression, we found that (1) past-6-month mood episodes predicted lower adiponectin (ß = -0.385, P = .04) and adipsin (ß = -0.376, P = .03) levels and higher lipocalin-2 levels (ß = 0.411, P = .03), (2) BMI did not predict adipokine levels, and (3) treatment with second-generation antipsychotics was associated with higher resistin levels (ß = 0.482, P < .01). Furthermore, lower adiponectin (ß = -0.353, P = .01) and leptin (ß = -0.332, P = .02) levels predicted depressive relapse over 12 months, while higher adipsin (ß = 0.496, P < .01) and leptin (ß = 0.421, P < .01) levels predicted BMI gain. CONCLUSIONS: Our results suggest that mood episodes and medication treatment contribute to adipokine abnormalities in bipolar disorder and that adipokines influence psychiatric illness course and BMI change. Adipokines may represent a novel pathophysiologic mechanism linking elevated BMI and mood disorders and deserve further study as potential mood-regulating molecules.

Association of peripheral inflammation with body mass index and depressive relapse in bipolar disorder.

Bipolar I disorder (BD) is associated with increased inflammation, which is believed to be central to disease etiology and progression. However, BD patients also have high rates of obesity, itself an inflammatory condition, and the relative contributions of mood illness and obesity to inflammation are unknown. Moreover, the impact of inflammation on clinical illness course has not been well studied. The objectives of this analysis were therefore: (1) to determine if inflammation in BD is mood illness-related or secondary to elevated body mass index (BMI), and (2) to investigate the impact of inflammation on prospectively-ascertained relapse into depression and mania. We measured the serum levels of 7 inflammatory cytokines (TNF-α, γ-interferon, monocyte chemoattractant protein-1 [MCP-1], IL-1α, IL-2, IL-6, and IL-8) and 2 anti-inflammatory cytokines (IL-4 and IL-10) in 52 early-stage BD patients and 22 healthy subjects. In patients, a multivariate multiple regression model that controlled for psychotropic medications found that higher BMI, but not recent (past-6-month) mood episodes, predicted greater inflammatory cytokines (p=.05). Healthy subjects also had a BMI-related increase in inflammatory cytokines (p<.01), but it was counter-balanced by a compensatory increase in anti-inflammatory cytokines (p=.02), reducing their total inflammatory burden from higher BMI. In patients, linear regression showed that two inflammatory cytokines predicted depressive relapse in the 12 months after cytokine measurement: IL-1α (p<.01) and MCP-1 (p<.01). These results suggest that elevated BMI is a significant contributor to inflammation in BD, more so even than recent mood illness severity. They also point to inflammation as an important predictor of illness course, particularly depressive relapse.