Correction of depression-associated circadian rhythm abnormalities is associated with lithium response in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is characterized by episodes of depression and mania and disrupted circadian rhythms. Lithium is an effective therapy for BD, but only 30%-40% of patients are fully responsive. Preclinical models show that lithium alters circadian rhythms. However, it is unknown if the circadian rhythm effects of lithium are essential to its therapeutic properties. METHODS: In secondary analyses of a multi-center, prospective, trial of lithium for BD, we examined the relationship between circadian rhythms and therapeutic response to lithium. Using standardized instruments, we measured morningness, diurnal changes in mood, sleep, and energy (circadian rhythm disturbances) in a cross-sectional study of 386 BD subjects with varying lithium exposure histories. Next, we tracked symptoms of depression and mania prospectively over 12 weeks in a subset of 88 BD patients initiating treatment with lithium. Total, circadian, and affective mood symptoms were scored separately and analyzed. RESULTS: Subjects with no prior lithium exposure had the most circadian disruption, while patients stable on lithium monotherapy had the least. Patients who were stable on lithium with another drug or unstable on lithium showed intermediate levels of disruption. Treatment with lithium for 12 weeks yielded significant reductions in total and affective depression symptoms. Lithium responders (Li-Rs) showed improvement in circadian symptoms of depression, but non-responders did not. There was no difference between Li-Rs and nonresponders in affective, circadian, or total symptoms of mania. CONCLUSIONS: Exposure to lithium is associated with reduced circadian disruption. Lithium response at 12 weeks was selectively associated with the reduction of circadian depressive symptoms. We conclude that stabilization of circadian rhythms may be an important feature of lithium's therapeutic effects. CLINICAL TRIALS REGISTRY: NCT0127253.

Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study.

BACKGROUND: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. METHODS: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. RESULTS: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. CONCLUSIONS: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

Global Posttrauma Symptoms: A Systematic Review of Qualitative Literature.

Exposure to potentially traumatic events is a global health problem, especially in low- and middle-income countries. Assessments for symptoms resulting from trauma exposure rely heavily on the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) criteria for post-traumatic stress disorder (PTSD), which may not be relevant in all regions of the globe. We examined posttrauma symptoms that were not limited to Western constructs of mental health (i.e., PTSD). In a systematic review, we searched nine databases to identify posttrauma symptoms arising in qualitative literature published before July 17, 2017. A total of 17,938 records were identified and 392 met inclusion criteria. The 392 studies represented data on 400 study populations from 71 different nationalities/ethnicities. The presence and frequency of posttrauma symptoms were examined across all regions. Fisher's exact tests were also conducted to compare frequencies in posttrauma symptoms across region and gender. Based on a weighted analysis across regions, a list of global posttrauma symptoms (N = 85) was compiled into an item bank. We found that the majority of DSM-5 PTSD symptoms were mentioned across regions (with the exception of inability to recall specific aspects of the trauma and blame of self or others for the event). Across all regions, we also found a number of symptoms mentioned that were not part of PTSD and its associated features. Findings suggest that assessing posttrauma symptoms solely based on PTSD may be limiting to global populations. Research, policy, and practice implications are discussed.

The association between lithium use and neurocognitive performance in patients with bipolar disorder.

Lithium remains the gold standard for the treatment of bipolar disorder (BD); however, its use has declined over the years mainly due to the side effects and the subjective experience of cognitive numbness reported by patients. In the present study, we aim to methodically test the effects of lithium on neurocognitive functioning in the largest single cohort (n = 262) of BD patients reported to date by harnessing the power of a multi-site, ongoing clinical trial of lithium monotherapy. At the cross-sectional level, multivariate analysis of covariance (MANCOVA) was conducted to examine potential group differences across neurocognitive tests [California Verbal Learning Test (CVLT trials 1-5,CVLT delayed recall), Wechsler Digit Symbol, Trail-making Test parts A and B (TMT-A; TMT-B), and a global cognition index]. At the longitudinal level, on a subset of patients (n = 88) who achieved mood stabilization with lithium monotherapy, we explored the effect of lithium treatment across time on neurocognitive functioning. There were no differences at baseline between BD patients that were taking lithium compared with those that were not. At follow-up a significant neurocognitive improvement in the global cognitive index score [F = 31.69; p < 0.001], CVLT trials 1-5 [F = 29.81; p < 0.001], CVLT delayed recall [F = 15.27; p < 0.001], and TMT-B [F = 6.64, p = 0.012] was detected. The cross-sectional and longitudinal (on a subset of 88 patients) investigations suggest that lithium may be beneficial to neurocognitive functioning in patients with BD and that at the very least it does not seem to significantly impair cognition when used therapeutically.

Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder.

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

Test-retest reliability of a new questionnaire for the retrospective assessment of long-term lithium use in bipolar disorder.

BACKGROUND: The identification of predictors of treatment response holds tremendous potential for the improvement of clinical outcomes in bipolar disorder (BP). The goal of this project is to evaluate the test-retest reliability of a new clinical tool, the Lithium Questionnaire (LQ), for the retrospective assessment of long-term lithium use in research participants with BP. METHODS: Twenty-nine individuals with BP-I (n=27), major depression (n=1), or schizoaffective disorder (n=1) were recruited for participation. The LQ was administered to all participants at two time-points, spaced 17 months apart on average, and used to determine each subject׳s score on the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder Scale, or the Alda Scale. Scores were confirmed through a best-estimate procedure, and test-retest reliability (intra-class correlation coefficient [ICC]) of the LQ was calculated. RESULTS: The correlation between the total Alda Scale scores at the two time-points was in the moderate range (ICC=0.60). Relevant clinical factors such as age or presence of Axis I psychiatric comorbidity did not influence the reliability. LIMITATIONS: The validity of the LQ was not examined. Inclusion of two participants with non-BP diagnoses may have affected the LQ׳s reliability, but re-analysis of our data after exclusion of these participants did not influence the reliability. The absence of measures of mood and cognition at time of LQ may be a limitation of this work. CONCLUSIONS: The LQ holds promise for the standardization of the retrospective assessment of long-term treatment in BP.