Total sleep time and kynurenine metabolism associated with mood symptom severity in bipolar disorder.

OBJECTIVE: Chronic, low-level inflammation is associated with symptomatic bipolar disorder (BD) and with chronic insomnia. Disrupted sleep is a feature of episodes of both mania and depression. We examined the effect of neopterin, a marker of cellular immune activation, and kynurenine (KYN), an inflammatory byproduct of the serotonin pathway, on the association between total sleep time and depression severity in BD. METHOD: Twenty-one symptomatic BD participants and 28 healthy controls (HC) were recruited and followed during usual clinical care. At baseline and after symptomatic recovery, total sleep time was objectively measured with actigraphy for 1 week and blood plasma was collected to measure the serotonin precursor tryptophan (TRP), KYN, the KYN/TRP ratio, and neopterin levels. Statistical analyses were conducted using chi-square, independent t tests and hierarchical linear multiple regression models. RESULTS: Total sleep time was correlated positively with depressive severity and negatively with manic severity. TRP was significantly reduced in BD participants compared to HC. KYN, TRP, and the KYN/TRP ratio were associated with depressive severity when total sleep time and body mass index (BMI) were included in the model. The KYN/TRP ratio trended towards a negative association with mania symptoms, controlling for BMI and total sleep time, in acutely symptomatic BD participants. Neopterin was not associated with sleep or mood severity. After usual clinical care, BD participants showed significantly decreased clinical symptoms but no significant differences in sleep phenotype or biomarkers. CONCLUSION: Inflammation, sleep, and mood are closely intertwined. Future research into the effect of inflammation on sleep in BD may lead to clinical markers of outcome.

Low unesterified:esterified eicosapentaenoic acid (EPA) plasma concentration ratio is associated with bipolar disorder episodes, and omega-3 plasma concentrations are altered by treatment.

OBJECTIVES: Omega (n)-3 and n-6 polyunsaturated fatty acids (PUFAs) are molecular modulators of neurotransmission and inflammation. We hypothesized that plasma concentrations of n-3 PUFAs would be lower and those of n-6 PUFAs higher in subjects with bipolar disorder (BD) compared to healthy controls (HCs), and would correlate with symptom severity in subjects with BD, and that effective treatment would correlate with increased n-3 but lower n-6 PUFA levels. Additionally, we explored clinical correlations and group differences in plasma levels of saturated and monounsaturated fatty acids. METHODS: This observational, parallel group study compared biomarkers between HCs (n = 31) and symptomatic subjects with BD (n = 27) when ill and after symptomatic recovery (follow-up). Plasma concentrations of five PUFAs [linoleic acid (LA), arachidonic acid (AA), alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA)], two saturated fatty acids (palmitic acid and stearic acid) and two monounsaturated fatty acids (palmitoleic acid and oleic acid) were measured in esterified (E) and unesterified (UE) forms. Calculated ratios included UE:E for the five PUFAs, ratios of n-3 PUFAs (DHA:ALA, EPA:ALA and EPA:DHA), and the ratio of n-6:n-3 AA:EPA. Comparisons of plasma fatty acid levels and ratios between BD and HC groups were made with Student t-tests, and between the BD group at baseline and follow-up using paired t-tests. Comparison of categorical variables was performed using chi-square tests. Pearson's r was used for bivariate correlations with clinical variables, including depressive and manic symptoms, current panic attacks, and psychosis. RESULTS: UE EPA was lower in subjects with BD than in HCs, with a large effect size (Cohen's d = 0.86, p < 0.002); however, it was not statistically significant after correction for multiple comparisons. No statistically significant difference was seen in any plasma PUFA concentration between the BD and HC groups after Bonferroni correction for 40 comparisons, at p < 0.001. Neither depressive severity nor mania severity was correlated significantly with any PUFA concentration. Exploratory comparison showed lower UE:E EPA in the BD than the HC group (p < 0.0001). At follow-up in the BD group, UE, E DHA:ALA, and UE EPA:ALA were decreased (p < 0.002). Exploratory correlations of clinical variables revealed that mania severity and suicidality were positively correlated with UE:E EPA ratio, and that several plasma levels and ratios correlated with panic disorder and psychosis. Depressive severity was not correlated with any ratio. No plasma fatty acid level or ratio correlated with self-reported n-3 PUFA intake or use of medication by class. CONCLUSIONS: A large effect size of reduced UE EPA, and a lower plasma UE:E concentration ratio of EPA in the symptomatic BD state may be important factors in vulnerability to a mood state. Altered n-3 PUFA ratios could indicate changes in PUFA metabolism concurrent with symptom improvement. Our findings are consistent with preclinical and postmortem data and suggest testing interventions that increase n-3 and decrease n-6 dietary PUFA intake.

Subjective and objective sleep discrepancy in symptomatic bipolar disorder compared to healthy controls.

BACKGROUND: Bipolar disorder (BD) is associated with sleep misperception. The objective of this study was to investigate the correlation between subjective and objective measures of sleep in persons with symptomatic bipolar disorder (BDS) compared to healthy controls (HC). METHODS: We studied 24 BDS and 30 HC subjects similar in age, race and sex. Subjective sleep was measured with Pittsburgh Sleep Quality Index (PSQI) and objective sleep with 7-days of actigraphy. Absolute discrepancy variables were calculated by subtracting objective sleep latency (SL) and total sleep time (TST) on actigraphy from their respective subjective estimates from PSQI. Mood symptoms were measured with Young Mania Rating Scale and Hamilton Depression Rating Scale. RESULTS: In the BDS group, subjective TST did not significantly correlate with objective TST, while it correlated in the HC group. The BDS group had significantly higher absolute discrepancy between subjective and objective SL and TST compared to the HC group. Multivariable regression analysis showed that severity of depression was associated with greater absolute discrepancy between subjective and objective TST within the BDS group. LIMITATIONS: Subjects are from a tertiary care center and were on medications for treatment of BD symptoms. CONCLUSION: There is low correlation between subjective and objective TST in BDS subjects and more severe depressive symptoms are associated with greater absolute discrepancy in TST. Objective rather than subjective measures of sleep, such as actigraphy, may be needed to evaluate sleep in BD subjects. Cognitive-behavioral interventions to address sleep misperception and associated depressed mood may be indicated in BD.

Peripheral zinc and neopterin concentrations are associated with mood severity in bipolar disorder in a gender-specific manner.

Bipolar disorder (BD) is a recurrent, episodic mood disorder for which there are no current diagnostic, prognostic or theranostic biomarkers. Two peripheral markers of the acute phase immune response, zinc and neopterin, are consistently associated with severity of depression in literature. Given gender differences in clinical presentation of BD and in inflammatory processes, we aimed to explore the interaction between gender and immune biomarkers to predict mood severity in BD. Participants with DSM IV BD I and II were recruited through the Pennsylvania Psychiatric Institute during an acute mood episode. Healthy controls (HC) were recruited through advertisements. Participants fasted for at least 6h when blood was drawn for biomarkers. We found that zinc concentrations were significantly lower in the BD group at baseline (p<.05), and there was also a significant interaction between gender and zinc (p<.05), associated with depression severity. Also, we found a significant interaction between gender and neopterin, associated with mania severity (p<.05). We found that mania severity was associated with neopterin in men, while depression severity was positively associated with zinc in women. Our report bears replication in larger samples and highlights the potential for differences in the underlying pathophysiology between men and women with BD.

Daily mood monitoring of symptoms using smartphones in bipolar disorder: A pilot study assessing the feasibility of ecological momentary assessment.

BACKGROUND: Personal device technology has facilitated gathering data in real-time using Ecological momentary assessment (EMA). We hypothesized that using smartphones to measure symptoms in auto-generated surveys twice a day would be feasible in a group with bipolar disorder (BD). A second exploratory objective of this study was to compare potential differences in core symptoms between BD and healthy control (HC) groups. METHODS: A two-arm, parallel group, observational study was designed to measure completion rates of surveys of symptoms of mood, energy, speed of thought, impulsivity, and social stress in BD (N=10) and HC (N=10) participants. The surveys were auto-generated twice a day for fourteen days, and subjects could also perform self-generated surveys. Completion rates were compared between BD and HC groups. Scores were averaged for each participant over the 14 day period, and group medians were compared. RESULTS: Median completion rates did not differ between groups: 95% in BD, 88% in HC (p=0.68); the median completion rate of auto-generated surveys in the BD group was 79% and in the HC group was 71% (p=0.22). The BD group had significantly lower median mood score (p=0.043) and energy score (p=0.007) than the HC group. Median scores of speed of thoughts (p=0.739), impulsivity (p=0.123) and social stress (p=0.056) did not significantly differ between BD and HC. The BD group had significantly higher range of variability of group median mood (p=0.043), speed of thoughts (p=0.002) and impulsivity (p=0.005) scores over the course of 14 days than HC, while range of variability of energy (p=0.218) and social stress (p=0.123) scores did not differ. Results were not significantly different between auto-generated and self-generated surveys for BD or HC. LIMITATIONS: This pilot study was conducted for a short time and with a small sample. CONCLUSIONS: This study demonstrates feasibility of using EMA with a smartphone to gather data on BD symptoms.