Simultaneous monitoring of activity and heart rate variability in depressed patients: A pilot study using a wearable monitor for 3 consecutive days.

INTRODUCTION: Reduced activity and sleep-wake rhythm disturbances are essential features of depressive episodes. In addition, alterations in heart rate variability (HRV) have been implicated in depression. By using a wearable sensor that monitors 3-dimensional acceleration and HRV simultaneously, we examined the activity and HRV indices in depressive episode of mood disorders. METHODS: Participants were 19 patients (13 major depressive disorder [MDD] and 6 bipolar depression; 11 females) and 18 controls (9 females) matched for age and ethnicity (all Japanese) who completed 3 consecutive days of all-day monitoring by a small and light device attached to the chest. RESULTS: Activity magnitude was significantly reduced while lying/resting time was increased in depressed patients, compared with controls. When males and females were examined separately, male, but not female, patients showed significant reduction in activity. HRV indices such as R-R interval and high-frequency power (a parameter for the parasympathetic system) were significantly decreased in patients than in controls. Significant differences in activity and HRV indices were seen only in males. Sympathetic load during sleep significantly correlated with damped rest-activity rhythm in depressed patients. LIMITATIONS: The number of participants was small, and the majority of the participants were taking psychotropic medications. CONCLUSIONS: We obtained evidence for reduced activity, increased lying/resting time, and reduced HRV indices in male depressed patients. The simultaneous monitoring for activity and HRV suggested greater sympathetic load during sleep is associated with damped rest-activity rhythm (increased activity during sleep and decreased daytime activity), which might be a characteristic pathology of depression.

Altered polyunsaturated fatty acid levels in relation to proinflammatory cytokines, fatty acid desaturase genotype, and diet in bipolar disorder.

Inflammation and altered polyunsaturated fatty acid (PUFA) levels have been implicated in bipolar disorder (BD). A recent genome-wide association study identified a locus in the fatty acid desaturase (FADS) gene cluster conferring susceptibility to BD. In this study, we examined PUFA levels in patients with BD in relation to proinflammatory cytokines, FADS genotype, and dietary habits. We enrolled 83 patients with BD and 217 healthy controls who underwent plasma PUFA measurement. A subsample of 65 patients and 90 controls underwent plasma interleukin (IL)-6 and tumor necrosis factor alpha (TNFα) measurement, and three FADS single nucleotide polymorphisms (SNPs) were genotyped. Information on fish consumption was obtained by a self-reported diet history questionnaire. In comparing PUFA levels between patients and controls, significant differences were found for all 7 PUFAs tested. Specifically, n-3 eicosapentaenoic acid (EPA) level was decreased, and n-6 arachidonic acid level was increased in the patients (p < 0.0001 for both). Plasma IL-6 and TNFα levels were both significantly increased in the patients. Plasma EPA level was negatively correlated with IL-6 and TNFα levels. The FADS genotype, which was associated with increased n-6 PUFA levels, was also associated with marked elevation in TNFα levels. Less frequent fish intake was associated with low EPA and high IL-6 level. Taken together, our results provide strong evidence for altered plasma PUFA and proinflammatory cytokine levels in patients with BD. Furthermore, FADS genotype and fish consumption may contribute not only to altered PUFA levels but also to inflammation in BD.

Bifidobacterium and Lactobacillus Counts in the Gut Microbiota of Patients With Bipolar Disorder and Healthy Controls.

Background: Although the pathophysiology of bipolar disorder remains elusive, growing evidence suggests the beneficial effects of Bifidobacterium and Lactobacillus in the gut microbiota on stress response and depressive symptoms. In the present study, we examined Bifidobacterium and Lactobacillus counts for association with bipolar disorder and serum cortisol levels. Methods: Bacterial counts in fecal samples were examined in 39 patients with bipolar disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edn. and 58 healthy controls using bacterial rRNA-targeted reverse transcription-quantitative polymerase chain reaction. Results: No significant difference was found in either bacterial counts between the two groups. However, we found a significantly negative correlation between Lactobacillus counts and sleep (ρ = -0.45, P = 0.01). Furthermore, a significant negative correlation was found between Bifidobacterium counts and cortisol levels (ρ = -0.39, P = 0.02) in the patients, although such a correlation was not found for Lactobacillus counts. Conclusions: Our results suggest that Bifidobacterium or Lactobacillus counts may not play a major role in the pathophysiology of bipolar disorder in our sample. However, the observed negative correlation between Lactobacillus counts and sleep and that between Bifidobacterium counts and serum cortisol levels point to the possible roles of these bacteria in sleep and stress response of the patients.

Plasma amino acid profile in major depressive disorder: Analyses in two independent case-control sample sets.

Some amino acids act as neurotransmitters themselves, or are precursors of neurotransmitters. Previous studies reported inconsistent results regarding their changes in blood in major depressive disorder (MDD), which prompted us to examine plasma levels of amino acids and related molecules in two independent case-control sample sets. In total, 511 subjects were recruited. Sample set A consisted of 164 patients with MDD (147 currently depressed [dMDD]; 17 in remission, DSM-IV) and 217 healthy controls. Sample set B consisted of 65 patients (51 dMDD; 14 in remission) and 65 controls. Plasma amino acid levels were measured using high-performance liquid chromatography for set A and liquid chromatography/mass spectrometry for set B. We further analyzed the relationships between plasma amino acid levels and clinical variables. In sample set A, plasma asparagine, histidine+1-methylhistidine, methionine, phenylalanine, tryptophan, and tyrosine levels were decreased, while plasma glutamate and phosphoethanolamine were elevated in dMDD compared to controls (all P < 0.0005), even after correcting for multiple testing. Plasma leucine levels were associated with "psychic anxiety." In sample set B, glutamate and methionine levels were also altered in the same direction to that in sample set A (both P < 0.05). In the integrative analysis, plasma glutamate and methionine levels were found to be significantly associated with the diagnosis of MDD with small to medium effect sizes (both P < 1.0E-6). In conclusion, several amino acids and related molecules were altered in patients with MDD. Decreased methionine and increased glutamate levels were found consistently in the two sample sets, suggesting their involvement in MDD. Further investigations are warranted on the possible role of amino acids in the pathophysiology of MDD.

A personality-based latent class typology of outpatients with major depressive disorder: association with symptomatology, prescription pattern and social function.

BACKGROUND: While major depressive disorder (MDD) is considered to be a heterogeneous disorder, the nature of the heterogeneity remains unclear. Studies have attempted to classify patients with MDD using latent variable techniques, yet the empirical approaches to symptom-based subtyping of MDD have not provided conclusive evidence. Here we aimed to identify homogeneous classes of MDD based on personality traits, using a latent profile analysis. METHODS: We studied 238 outpatients with DSM-IV MDD recruited from our specialized depression outpatient clinic and assessed their dimensional personality traits with the Temperament and Character Inventory. Latent profile analysis was conducted with 7 dimensions of the Temperament and Character Inventory as indicators. Relationships of the identified classes with symptomatology, prescription pattern, and social function were then examined. RESULTS: The latent profile analysis indicated that a 3-class solution best fit the data. Of the sample, 46.2% was classified into a "neurotic" group characterized by high harm avoidance and low self-directedness; 30.3% into an "adaptive" group characterized by high self-directedness and cooperativeness; and 23.5% into a "socially-detached" group characterized by low reward dependence and cooperativeness and high self-transcendence. The 2 maladaptive groups, namely neurotic and socially-detached groups, demonstrated unique patterns of symptom expression, different classes of psychotropic medication use, and lower social functioning. LIMITATIONS: Generalizability of the findings was limited since our patients were recruited from the specialized depression outpatient clinic. CONCLUSIONS: Our personality-based latent profile analysis identified clinically meaningful 3 MDD groups that were markedly different in their personality profiles associated with distinct symptomatology and functioning.

Possible association of Bifidobacterium and Lactobacillus in the gut microbiota of patients with major depressive disorder.

BACKGROUND: Bifidobacterium and Lactobacillus in the gut have been suggested to have a beneficial effect on stress response and depressive disorder. We examined whether these bacterial counts are reduced in patients with major depressive disorder (MDD) than in healthy controls. METHOD: Bifidobacterium and Lactobacillus counts in fecal samples were estimated in 43 patients and 57 controls using bacterial rRNA-targeted reverse transcription-quantitative polymerase chain reaction RESULTS: The patients had significantly lower Bifidobacterium counts (P=0.012) and tended to have lower Lactobacillus counts (P=0.067) than the controls. Individuals whose bacterial counts below the optimal cut-off point (9.53 and 6.49log10 cells/g for Bifidobacterium and Lactobacillus, respectively) were significantly more common in the patients than in the controls for both bacteria (Bifidobacterium: odds ratio 3.23, 95% confidence interval [CI] 1.38-7.54, P=0.010; Lactobacillus: 2.57, 95% CI 1.14-5.78, P=0.027). Using the same cut-off points, we observed an association between the bacterial counts and Irritable bowel syndrome. Frequency of fermented milk consumption was associated with higher Bifidobacterium counts in the patients. LIMITATIONS: The findings should be interpreted with caution since effects of gender and diet were not fully taken into account in the analysis. CONCLUSION: Our results provide direct evidence, for the first time, that individuals with lower Bifidobacterium and/or Lactobacillus counts are more common in patients with MDD compared to controls. Our findings provide new insight into the pathophysiology of MDD and will enhance future research on the use of pro- and prebiotics in the treatment of MDD.

24-h activity rhythm and sleep in depressed outpatients.

Disturbances in sleep and circadian rest-activity rhythms are key features of depression. Actigraphy, a non-invasive method for monitoring motor activity, can be used to objectively assess circadian rest-activity rhythms and sleep patterns. While recent studies have measured sleep and daytime activity of depressed patients using wrist-worn actigraphy, the actigraphic 24-h rest-activity rhythm in depression has not been well documented. We aimed to examine actigraphically measured sleep and circadian rest-activity rhythms in depressed outpatients. Twenty patients with DSM-IV major depressive episode and 20 age- and sex-matched healthy controls participated in this study. Participants completed 7 consecutive days of all-day actigraphic activity monitoring while engaging in usual activities. For sleep parameters, total sleep time, wake after sleep onset, and sleep fragmentation index were determined. Circadian rhythms were estimated by fitting individual actigraphy data to a cosine curve of a 24-h activity rhythm using the cosinor method, which generated three circadian activity rhythm parameters, i.e., MESOR (rhythm-adjusted mean), amplitude, and acrophase. Subjective sleep was also assessed using a sleep diary and the Pittsburgh Sleep Quality Index. Patients showed significantly lower MESOR and more dampened amplitude along with significant sleep disturbances. Logistic regression analysis revealed that lower MESOR and more fragmented sleep emerged as the significant predictors of depression. Correlations between subjectively and actigraphically measured parameters demonstrated the validity of actigraphic measurements. These results indicate marked disturbances in sleep and circadian rest-activity rhythms of depression. By simultaneously measuring sleep and rest-activity rhythm parameters, actigraphy might serve as an objective diagnostic aid for depression.

Plasma L-tryptophan concentration in major depressive disorder: new data and meta-analysis.

OBJECTIVE: Tryptophan, an essential amino acid, is the precursor to serotonin and is metabolized mainly by the kynurenine pathway. Both serotonin and kynurenine have been implicated in the pathophysiology of major depressive disorder (MDD). However, plasma tryptophan concentration in patients with MDD has not unequivocally been reported to be decreased, which prompted us to perform a meta-analysis on previous studies and our own data. DATA SOURCES: We searched the PubMed database for case-control studies published until August 31, 2013, using the search terms plasma AND tryptophan AND synonyms for MDD. An additional search was performed for the term amino acid instead of tryptophan. We obtained our own data in 66 patients with MDD (DSM-IV) and 82 controls who were recruited from March 2011 to July 2012. The majority of the patients were medicated (N = 53). Total plasma tryptophan concentrations were measured by the liquid chromatography/mass spectrometry method. STUDY SELECTION: We scrutinized 160 studies for eligibility. Original articles that were written in English and documented plasma tryptophan values in patients and controls were selected. DATA EXTRACTION: We included 24 studies from the literature and our own data in the meta-analysis, which involved a total of 744 patients and 793 controls. Data on unmedicated patients (N = 156) and their comparison subjects (N = 203) were also extracted. To see the possible correlation between tryptophan concentrations and depression severity, meta-regression analysis was performed for 10 studies with the Hamilton Depression Rating Scale 17-item version score. RESULTS: In our case-control study, mean (SD) plasma tryptophan level was significantly decreased in the MDD patients versus the controls (53.9 [10.9] vs 57.2 [11.3] µmol/L; P = .03). The meta-analysis after adjusting for publication bias showed a significant decrease in patients with MDD with a modest effect size (Hedges g, -0.45). However, analysis on unmedicated subjects yielded a large effect (Hedges g, -0.84; P = .00015). We found a weak association with depression severity in the meta-regression analysis (P = .049). CONCLUSIONS: This meta-analysis provides convincing evidence for reduced plasma tryptophan levels in patients with MDD, particularly in unmedicated patients.

Cognitive effects of the ANK3 risk variants in patients with bipolar disorder and healthy individuals.

BACKGROUND: Genetic variants within the ankyrin 3 gene (ANK3) have been identified as a risk factor for bipolar disorder. ANK3 influences action potential generation by clustering sodium gated channels and plays an integral role in neurotransmission. Thus, this gene may influence cognition, a process compromised in bipolar disorder. We investigated whether genetic variants of ANK3 would be associated with an array of cognitive functions in patients with bipolar disorder and healthy individuals. METHODS: In a sample of 49 patients with bipolar disorder and 633 healthy subjects, we examined possible effects of 2 risk variants within ANK3, rs10994336 and rs10761482, on 7 neurocognitive domains. RESULTS: Compared to healthy subjects, patients with bipolar disorder demonstrated significantly poorer performance on most of the cognitive domains examined. The risk C-allele of rs10761482 was significantly associated with worse performance on verbal comprehension, logical memory and processing speed in patients. This allele was significantly associated with worse performance on executive function and visual memory in healthy individuals. No significant association was observed between rs10994336 and cognition either in patients or healthy individuals. LIMITATIONS: The sample size of patients with bipolar disorder was small, and most of the patients were on psychotropic medication. CONCLUSIONS: These results indicate that a risk variant within ANK3 may have an impact on neurocognitive function, suggesting a mechanism by which ANK3 confers risk for bipolar disorder.

Psychological coping in depressed outpatients: association with cortisol response to the combined dexamethasone/CRH test.

BACKGROUND: Depression is associated with dysfunctional coping styles and dysregulated hypothalamic-pituitary-adrenal (HPA) axis function. Studies have shown that maladaptive coping strategies relate to abnormal HPA axis function; however, such a relationship has been under-studied in patients with depression. We aimed to examine whether dysfunctional coping styles in depression would be associated with abnormal cortisol reactivity. METHODS: Seventy-four outpatients with major depressive disorder and 133 age- and sex-matched healthy individuals were recruited. Coping was assessed by the Ways of Coping Checklist. Psychological distress was assessed by the Hopkins Symptom Checklist. Cortisol reactivity was measured by the combined dexamethasone/corticotropin-releasing hormone test. RESULTS: Compared to healthy individuals, depressed patients demonstrated significantly less use of problem-solving, positive reappraisal and social support coping styles and more use of self-blame and wishful thinking styles. Such a pattern of coping styles was significantly associated with patients' greater distress. Partial correlation analysis in patients, controlling for age and sex, revealed a significant correlation between more use of escape-avoidance coping and lower levels of reactive cortisol measures. A stepwise multiple regression analysis predicting cortisol reactivity from age, sex, distress, symptom severity and coping styles revealed that escape-avoidance coping was a significant predictor. LIMITATIONS: The neuroendocrine challenge test was administered only once, based on a simple test protocol. CONCLUSIONS: More use of escape-avoidance coping in depressed patients was associated with less cortisol reactivity. Our findings shed light on the heterogeneity of depression in terms of low and high levels of avoidance associated with exaggerated and blunted HPA axis reactivity, respectively.

Validation of computer-administered clinical rating scale: Hamilton Depression Rating Scale assessment with Interactive Voice Response technology--Japanese version.

AIM: The aim of this study was to examine the reliability and validity of the Interactive Voice Response (IVR) program to rate the 17-item Hamilton Rating Scale for Depression (HAM-D) score in Japanese depressive patients. METHODS: Depression severity was assessed in 60 patients by a clinician and psychologists using HAM-D. Scoring by the IVR program was conducted on the same and the following days. Test-retest reliability, internal consistency, and concurrent validity for total HAM-D scores were examined by calculating intraclass correlation coefficient, Cronbach's alpha, and Pearson's correlation coefficient. Inter-rater consistency for each HAM-D item was examined by Cohen's kappa. RESULTS: Test-retest reliability of the IVR program was high (intraclass correlation coefficient: 0.93). Internal consistency of each total score obtained by the clinician, psychologists, and IVR program was high (Cronbach's alpha: 0.77, 0.79, 0.78, and 0.83). Regarding concurrent validity, correlation coefficients between total scores obtained by the clinician versus IVR and that by the clinician versus psychologists were high (0.81 and 0.93). The HAM-D total score rated by the clinician was 3 points lower than that of IVR. Inter-rater consistency for each HAM-D item evaluated by the clinician versus IVR was estimated to be fair (Cohen's kappa coefficient: 0.02-0.50). CONCLUSION: Our results suggest that the Japanese IVR HAM-D program is reliable and valid to assess 17-item HAM-D total score in Japanese depressive patients. However, the current program tends to overestimate depression severity, and the score of each item did not always show high agreement with clinician's rating, which warrants further improvement in the program.

Difference in Temperament and Character Inventory scores between depressed patients with bipolar II and unipolar major depressive disorders.

BACKGROUND: Although some core personality variables are known to be characteristic of unipolar or bipolar depression, few studies have compared the personality profile between these two disorders. METHODS: Temperament and Character Inventory (TCI) was employed to assess the personality of 36 depressed patients with bipolar II disorder (BPII), 90 patients with unipolar major depressive disorder (UP), and 306 healthy controls. The TCI was administered during the depressive episode in BPII and UP patients so that the results can be applied in a clinical setting. RESULTS: Significantly higher scores in harm avoidance (p<0.0001) and lower scores in self-directedness (p<0.0001) and cooperativeness (p<0.05) were observed in both BPII and UP patients compared to controls. Lower novelty seeking in UP patients compared to BPII patients and controls was observed in females (p<0.0001, p<0.01, respectively). A significant difference in self-transcendence score was observed between BPII and UP patients in females (p<0.0005), with higher scores in BPII (p=0.009) and lower scores in UP (p=0.046) patients compared to controls. A logistic regression model predicted BPII in depressed females based on novelty seeking and self-transcendence scores with a sensitivity of 89% and a specificity of 73%, but did not accurately predict BPII in males. LIMITATIONS: Patients in our study were limited to those receiving outpatient treatments, and bipolar patients were limited to those with BPII. CONCLUSIONS: Novelty seeking and self-transcendence scores of TCI might be useful in the differentiation of UP and BPII in female patients.