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.

Solar insolation in springtime influences age of onset of bipolar I disorder.

OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density. RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001). CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

Influence of birth cohort on age of onset cluster analysis in bipolar I disorder.

PURPOSE: Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. METHODS: The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared. RESULTS: There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups. CONCLUSION: These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

Age at onset in bipolar disorder: Investigation of the role of TaqIA polymorphism of DRD2 gene in a Sardinian sample.

Bipolar disorder (BD) is a highly heterogeneous and heritable psychiatric illness. Age at onset has been shown to be a powerful tool for dissecting both the phenotypic and genetic complexity of BD. In this article, we present findings from an association study between the DRD2 TaqIA polymorphism and age at onset, showing that both alleles and genotypes at this locus associate with early onset BD.

Carbamazepine augmentation in lithium-refractory bipolar patients: a prospective study on long-term prophlyactic effectiveness.

Twenty-two patients affected by bipolar or schizoaffective disorder, in whom carbamazepine was added to lithium after recurrence when on maintenance with lithium alone, were followed up prospectively for 2 to 13 years. The number of episodes, hospitalizations, and cumulative affective morbidity was markedly reduced after carbamazepine augmentation. Seventeen patients presented a better course during combined treatment than during lithium alone, and of these 15 had no further recurrences. Four patients did not appear to improve after carbamazepine augmentation, whereas one featured reemergence of affective episodes after having derived satisfactory benefit from combination for 7 years (delayed tolerance). Carbamazepine augmentation was associated with a reduction of lithium doses in some patients, including a subgroup who had not tolerated lithium at usual therapeutic levels. Carbamazepine significantly reduced serum thyrotropin concentrations, which were abnormally high in approximately one half of patients when on lithium alone. Total serum thyroxine concentrations were also decreased after carbamazepine augmentation, but free thyroid hormone concentrations did not change. Other significant carbamazepine-induced changes in laboratory tests included increases in total cholesterol concentrations and decreases in white blood cell counts.

Suicidal behavior on and off lithium prophylaxis in a group of patients with prior suicide attempts.

One hundred patients who had attempted suicide before commencing lithium prophylaxis were followed up. Outcome was analyzed in terms of attempted or completed suicide after a mean of 10 years since admission to the lithium clinics. Of 10 patients who committed suicide, 9 had discontinued adequate lithium prophylaxis for a period ranging from 2 weeks to 7 years before death. Having discontinued lithium therapy was associated with suicide also in the subgroup of patients for whom lithium had not completely prevented episodes during lithium treatment. Suicide risk was 24 times as high during periods off compared with periods on adequate lithium prophylaxis. Incidence of attempting suicide was similar during the periods before receiving or after discontinuing lithium treatment, whereas it was 5 to 6 times lower during prophylaxis. Continuous and adequate lithium prophylaxis should be considered in the presence of high suicide risk, even if the prophylactic effect on the underlying mood disorder may be incomplete.