Prediction of lithium response using clinical data.

OBJECTIVE: Promptly establishing maintenance therapy could reduce morbidity and mortality in patients with bipolar disorder. Using a machine learning approach, we sought to evaluate whether lithium responsiveness (LR) is predictable using clinical markers. METHOD: Our data are the largest existing sample of direct interview-based clinical data from lithium-treated patients (n = 1266, 34.7% responders), collected across seven sites, internationally. We trained a random forest model to classify LR-as defined by the previously validated Alda scale-against 180 clinical predictors. RESULTS: Under appropriate cross-validation procedures, LR was predictable in the pooled sample with an area under the receiver operating characteristic curve of 0.80 (95% CI 0.78-0.82) and a Cohen kappa of 0.46 (0.4-0.51). The model demonstrated a particularly low false-positive rate (specificity 0.91 [0.88-0.92]). Features related to clinical course and the absence of rapid cycling appeared consistently informative. CONCLUSION: Clinical data can inform out-of-sample LR prediction to a potentially clinically relevant degree. Despite the relevance of clinical course and the absence of rapid cycling, there was substantial between-site heterogeneity with respect to feature importance. Future work must focus on improving classification of true positives, better characterizing between- and within-site heterogeneity, and further testing such models on new external datasets.

Larger right inferior frontal gyrus volume and surface area in participants at genetic risk for bipolar disorders.

BACKGROUND: Larger grey matter volume of the inferior frontal gyrus (IFG) is among the most replicated biomarkers of genetic risk for bipolar disorders (BD). However, the IFG is a heterogeneous prefrontal region, and volumetric findings can be attributable to changes in cortical thickness (CT), surface area (SA) or gyrification. Here, we investigated the morphometry of IFG in participants at genetic risk for BD. METHODS: We quantified the IFG cortical grey matter volume in 29 affected, 32 unaffected relatives of BD probands, and 42 controls. We then examined SA, CT, and cortical folding in subregions of the IFG. RESULTS: We found volumetric group differences in the right IFG, with the largest volumes in unaffected high-risk and smallest in control participants (F2,192 = 3.07, p = 0.01). The volume alterations were localized to the pars triangularis of the IFG (F2,97 = 4.05, p = 0.02), with no differences in pars opercularis or pars orbitalis. Pars triangularis volume was highly correlated with its SA [Pearson r(101) = 0.88, p < 0.001], which significantly differed between the groups (F2,97 = 4.45, p = 0.01). As with volume, the mean SA of the pars triangularis was greater in unaffected (corrected p = 0.02) and affected relatives (corrected p = 0.05) compared with controls. We did not find group differences in pars triangularis CT or gyrification. CONCLUSIONS: These findings strengthen prior knowledge about the volumetric findings in this region and provide a new insight into the localization and topology of IFG alterations. The unique nature of rIFG morphology in BD, with larger volume and SA early in the course of illness, could have practical implications for detection of participants at risk for BD.

Glatiramer acetate treatment directly targets CD11b(+)Ly6G(-) monocytes and enhances the suppression of autoreactive T cells in experimental autoimmune encephalomyelitis.

Glatiramer acetate (GA) is used for the treatment of relapsing-remitting multiple sclerosis (MS) and can suppress experimental autoimmune encephalomyelitis in animals. Effective GA treatment is associated with the induction of anti-inflammatory T(H)2 responses and antigen-specific expansion of CD25(+)/Foxp3(+) Tregs through the modulation of antigen-presenting cells. Here, we show that intravenous injection of fluorochrome-labelled GA resulted in rapid and specific binding of GA to CD11b(+) F4/80(lo) Ly6G(-) blood monocytes via an MHC class II-independent mechanism. Intravenous GA treatment enhanced the intrinsic capability of these monocytes to directly suppress T cell proliferation in vitro. The suppressive function correlated with reduced proliferation of myelin-specific T cells in vivo after intravenous GA treatment. In contrast, subcutaneous treatment with GA inhibited the pro-inflammatory IFNγ-producing T cell phenotype rather than suppressing T cell proliferation. These data indicate that (1) GA engages directly with circulating monocytes to induce type II monocyte suppressor function; and (2) the therapeutic efficacy of GA may be expanded by employing different routes of GA administration to engage alternative mechanisms of suppression of autoreactive T cells in MS.