Little is known about the impact of insulin resistance on bipolar disorder.
To examine the relationships between insulin resistance, type 2 diabetes and clinical course and treatment outcomes in ...bipolar disorder.
We measured fasting glucose and insulin in 121 adults with bipolar disorder. We diagnosed type 2 diabetes and determined insulin resistance. The National Institute of Mental Health Life Chart was used to record the course of bipolar disorder and the Alda scale to establish response to prophylactic lithium treatment.
Patients with bipolar disorder and type 2 diabetes or insulin resistance had three times higher odds of a chronic course of bipolar disorder compared with euglycaemic patients (50% and 48.7% respectively v. 27.3%, odds ratio (OR) = 3.07, P = 0.007), three times higher odds of rapid cycling (38.5% and 39.5% respectively v. 18.2%, OR = 3.13, P = 0.012) and were more likely to be refractory to lithium treatment (36.8% and 36.7% respectively v. 3.2%, OR = 8.40, P<0.0001). All associations remained significant after controlling for antipsychotic exposure and body mass index in sensitivity analyses.
Comorbid insulin resistance may be an important factor in resistance to treatment in bipolar disorder.
Abstract Objective To identify specific treatment-emergent symptoms in response to antidepressant therapy in depression preceding bipolar disorder. Methods Retrospective chart review of response to ...antidepressants in “pre-bipolar” depression, compared to a matched unipolar sample. Results Family history of completed suicide ( p = 0.0003) and bipolar disorder ( p = 0.004) were more common in the pre-bipolar subgroup. Earlier age of onset of diagnosed depression ( p = 0.005) as well as even earlier episodes of untreated retrospectively diagnosed major depression ( p < 0.0001) were associated with a future bipolar course. The pre-bipolar group was less likely to respond to antidepressant treatment ( p = 0.009). Treatment-emergent “mixed” symptoms (two or more symptoms of DSM IV mania, mood lability, irritability/rage with co-existing depression) and in particular, “serious symptoms” (treatment emergent or increased agitation, rage or suicidality) occurred more commonly in the bipolar group. The two variables that best accounted for the between-group differences in logistic regression, were early age at first symptoms of depression and treatment-emergent agitation. Conclusions Family history of completed suicide and/or bipolar disorder, early onset of depressive symptoms as well as treatment-emergent “mixed” symptoms are common in depression preceding the diagnosis of bipolar disorder.
Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with ..."exemplary phenotypes"-those whose clinical features are reliably associated with LiR and non-response (LiNR)-are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a "clinical exemplar score," which measures the degree to which a subject's clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the "best clinical exemplars") were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the "poor clinical exemplars"). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR 0.83, 0.98), compared to 0.66 0.61, 0.80 (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer's amyloid-secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers.
The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence ...of such a relationship. To clarify this, we performed an exploratory study of the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi
Gen, N = 2374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. Overall, we observed relatively weak associations (p < 1 × 10
) with BP phenotypes within immune-related genes. Network and functional enrichment analyses of the top findings from the association analyses of Li response variables showed an overrepresentation of pathways participating in cell adhesion and intercellular communication. These appeared to converge on the well-known Li-induced inhibition of GSK-3β. Association analyses of age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation suggested modest contributions of genes such as RTN4, XKR4, NRXN1, NRG1/3 and GRK5 to disease characteristics. PGS analyses returned weak associations (p < 0.05) between inflammation markers and the studied BP phenotypes. Our results suggest a modest relationship between immunity and clinical features in BP. More research is needed to assess the potential therapeutic relevance.
BackgroundLittle is known about the impact of insulin resistance on bipolardisorder.AimsTo examine the relationships between insulin resistance, type 2 diabetesand clinical course and treatment ...outcomes in bipolar disorder.MethodWe measured fasting glucose and insulin in 121 adults with bipolardisorder. We diagnosed type 2 diabetes and determined insulin resistance.The National Institute of Mental Health Life Chart was used to record thecourse of bipolar disorder and the Alda scale to establish response toprophylactic lithium treatment.ResultsPatients with bipolar disorder and type 2 diabetes or insulin resistancehad three times higher odds of a chronic course of bipolar disordercompared with euglycaemic patients (50% and 48.7% respectivelyv. 27.3%, odds ratio (OR) = 3.07, P= 0.007), three times higher odds of rapid cycling (38.5% and 39.5%respectively v. 18.2%, OR = 3.13, P =0.012) and were more likely to be refractory to lithium treatment (36.8%and 36.7% respectively v. 3.2%, OR = 8.40,P<0.0001). All associations remained significantafter controlling for antipsychotic exposure and body mass index insensitivity analyses.ConclusionsComorbid insulin resistance may be an important factor in resistance totreatment in bipolar disorder.
Group 3 innate lymphoid cell (ILC3)-mediated production of the cytokine interleukin-22 (IL-22) is critical for the maintenance of immune homeostasis in the gastrointestinal tract. Here, we find that ...the function of ILC3s is not constant across the day, but instead oscillates between active phases and resting phases. Coordinate responsiveness of ILC3s in the intestine depended on the food-induced expression of the neuropeptide vasoactive intestinal peptide (VIP). Intestinal ILC3s had high expression of the G protein-coupled receptor vasoactive intestinal peptide receptor 2 (VIPR2), and activation by VIP markedly enhanced the production of IL-22 and the barrier function of the epithelium. Conversely, deficiency in signaling through VIPR2 led to impaired production of IL-22 by ILC3s and increased susceptibility to inflammation-induced gut injury. Thus, intrinsic cellular rhythms acted in synergy with the cyclic patterns of food intake to drive the production of IL-22 and synchronize protection of the intestinal epithelium through a VIP-VIPR2 pathway in ILC3s.
Objective:
Bipolar disorders increase the risk of dementia and show biological and brain alterations, which resemble accelerated aging. Lithium may counter some of these processes and lower the risk ...of dementia. However, until now no study has specifically investigated the effects of Li on brain age.
Methods:
We acquired structural magnetic resonance imaging scans from 84 participants with bipolar disorders (41 with and 43 without Li treatment) and 45 controls. We used a machine learning model trained on an independent sample of 504 controls to estimate the individual brain ages of study participants, and calculated BrainAGE by subtracting chronological from the estimated brain age.
Results:
BrainAGE was significantly greater in non-Li relative to Li or control participants, F(2, 125) = 10.22, p < 0.001, with no differences between the Li treated and control groups. The estimated brain age was significantly higher than the chronological age in the non-Li (4.28 ± 6.33 years, matched t(42) = 4.43, p < 0.001), but not the Li-treated group (0.48 ± 7.60 years, not significant). Even Li-treated participants with partial prophylactic treatment response showed lower BrainAGE than the non-Li group, F(1, 64) = 4.80, p = 0.03.
Conclusions:
Bipolar disorders were associated with greater, whereas Li treatment with lower discrepancy between brain and chronological age. These findings support the neuroprotective effects of Li, which were sufficiently pronounced to affect a complex, multivariate measure of brain structure. The association between Li treatment and BrainAGE was independent of long-term thymoprophylactic response and thus may generalize beyond bipolar disorders, to neurodegenerative disorders.
Clinical immunity to P. falciparum malaria is non‐sterilizing, with adults often experiencing asymptomatic infection. Historically, asymptomatic malaria has been viewed as beneficial and required to ...help maintain clinical immunity. Emerging views suggest that these infections are detrimental and constitute a parasite reservoir that perpetuates transmission. To define the impact of asymptomatic malaria, we pursued a systems approach integrating antibody responses, mass cytometry, and transcriptional profiling of individuals experiencing symptomatic and asymptomatic P. falciparum infection. Defined populations of classical and atypical memory B cells and a TH2 cell bias were associated with reduced risk of clinical malaria. Despite these protective responses, asymptomatic malaria featured an immunosuppressive transcriptional signature with upregulation of pathways involved in the inhibition of T‐cell function, and CTLA‐4 as a predicted regulator in these processes. As proof of concept, we demonstrated a role for CTLA‐4 in the development of asymptomatic parasitemia in infection models. The results suggest that asymptomatic malaria is not innocuous and might not support the induction of immune processes to fully control parasitemia or efficiently respond to malaria vaccines.
Synopsis
Asymptomatic Plasmodium falciparum malaria infection supports protective humoral responses, but it also features an immunosuppressive transcriptional signature with upregulation of pathways involved in the inhibition of T‐cell function.
Asymptomatic malaria is thought to be beneficial for maintaining clinical immunity and remains untreated.
Despite supporting protective humoral immune responses, asymptomatic malaria infections feature an immunosuppressive blood transcriptional signature with upregulation of pathways involved in the control of T‐cell function.
These results suggest that asymptomatic malaria is not innocuous and might not support immune processes to fully control parasitemia or efficiently respond to malaria vaccines.
Asymptomatic Plasmodium falciparum malaria infection supports protective humoral responses, but it also features an immunosuppressive transcriptional signature with upregulation of pathways involved in the inhibition of T‐cell function.
Abstract Background The objective of this study was to evaluate effectiveness of commonly used prophylactic treatments for bipolar disorder in a naturalistic setting and to explore factors associated ...with treatment response. Methods We reviewed charts of 120 patients with a confirmed diagnosis of bipolar I or bipolar II disorder. The sample consisted of 37 males and 83 females, in the age range of 20 to 81 years (mean age 45 ± 14 years), treated at an outpatient psychiatry program in a teaching hospital. In contrast to controlled clinical trials, we did not exclude subjects with co-morbid conditions and/or substance abuse. Treatment outcome was evaluated using a scale for retrospective assessment of prophylactic treatment response. The scale rates the degree of improvement in the course of treatment weighted by the likelihood of response being attributable to the treatment. The inter-reliability of the assessments was good with concordance of ratings of 90% and weighted kappa of 0.8. Results Rates of full response to individual mood stabilizers were: lithium 30%, carbamazepine 0%, valproate 13%, lamotrigine 11%, and olanzapine 25%. Lithium responders were more likely to be bipolar II, and had a typically episodic course of illness with earlier onset in comparison with non-responders. Responders to valproate had higher rates of psychosis. Limitations Data were obtained by chart reviews. Conclusions Less than one-third of patients treated with lithium achieved remission; the effectiveness of other treatments in this naturalistic sample was even lower.
Objectives
We sought to study the underlying dynamic processes involved in mood regulation in subjects with bipolar disorder and healthy control subjects using time‐series analysis and to then ...analyze the relation between anxiety and mood using cross‐correlation techniques.
Methods
We recruited 30 healthy controls and 30 euthymic patients with bipolar disorder. Participants rated their mood, anxiety, and energy levels using a paper‐based visual analog scale; and they also recorded their sleep and any life events. Information on these variables was provided over a three‐month period on a daily basis, twice per day. We analyzed the data using Box–Jenkins time series analysis to obtain information on the autocorrelation of the series (for mood) and cross‐correlation (mood and anxiety series).
Results
Throughout the study, we analyzed 10,170 data points. Self‐ratings for mood, anxiety, and energy were normally distributed in both groups. Autocorrelation functions for mood in both groups were governed by the autoregressive integrated moving average (ARIMA) (1,1,0) model, which means that current values in the series were related to one previous point only. We also found a negative cross‐correlation between mood and anxiety.
Conclusions
Mood can be considered a memory stochastic process; it is a flexible, dynamic process that has a ‘short memory’ both in healthy controls and euthymic patients with bipolar disorder. This process may be quite different in untreated patients or in those acutely ill. Our results suggest that nonlinear measures can be applied to the study of mood disorders.
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