Social support and enhanced suppression of adrenocorticotropic hormone and cortisol responses to hypothalamic-pituitary-adrenal function and thyrotropin-releasing hormone tests in patients with major depressive disorder.

The results of the thyrotropin-releasing hormone (TRH) stimulation test and the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test are believed to correlate with social support status in patients with major depressive disorder. We studied 41 consecutive patients hospitalized for major depressive disorder and tested their responses to DEX/CRH and TRH on hospital days 4-7. DeltaMAX TSH and DeltaMAX cortisol were measured. Multiple regression analysis found that social support questionnaire (SSQ-A) and SSQ-B scores were significantly related to DeltaMAX cortisol and DeltaMAX TSH, respectively, at the time of admission. Social support might contribute partially to the TRH and DEX/CRH test results in patients with major depressive disorder.

Administration of antisense DNA for ghrelin causes an antidepressant and anxiolytic response in rats.

RATIONALE: Ghrelin is a peptide of 28 amino acids found in mammals that increases the release of growth hormone, food intake, and body weight. OBJECTIVES: We investigated the relationship between ghrelin and the states of anxiety and depression by giving rats either antisense DNA for ghrelin, scrambled DNA or vehicle into the lateral ventricle of rats. RESULTS: In forced swimming tests, rats that received antisense DNA decreased the length of time that they were immobile in the water. Ghrelin antisense oligonucleotides produced an anxiolytic-like effects in the elevated plus maze test, black and white test, or conditioned fear tests. Treatment with antisense DNA for ghrelin significantly decreased rat body weight. No significant effect on general locomotor activity was seen. CONCLUSIONS: These results suggest that administration of antisense DNA for ghrelin causes an antidepressant and anxiolytic response in rats.

Anxiolytic suppression of repetitive transcranial magnetic stimulation-induced anxiety in the rats.

Repetitive transcranial magnetic stimulation (rTMS) is effective for treatment of several psychiatric disorders such as depression and anxiety disorder. However, some reports suggest that rTMS induced anxiety in normal volunteers. Consistent with this observation, we have reported that chronic rTMS induces anxiety in normal rats which was suppressed by chronic treatment, but not acute paroxetine treatment. The current study evaluates rTMS as animal model of anxiety by investigating the effect of rTMS on anxiety behaviors and the ability of standard anxiolytics to block expression of these behaviors. We found that 10-day rTMS induced anxiety in normal rats, as evidenced by expression of anxiety behaviors in the elevated plus-maze. This anxiety was suppressed by acute treatment with diazepam, alprazolam, or buspirone suggesting that chronic rTMS treatment provides a good animal model for anxiety.

Low risk of male suicide and lithium in drinking water.

OBJECTIVE: Recently, several epidemiologic studies reported that lithium in drinking water may be associated with lower rates of suicide mortality at the population level, but other studies failed to confirm the association. The objective of the present study is to determine whether lithium in drinking water is associated with lower suicide rate after adjustment of potential confounding factors. METHOD: From 2010 to 2013, 274 mean lithium levels of 434 lithium samples in drinking water were examined in relation to suicide standardized mortality ratios (SMRs) in 274 municipalities of Kyushu Island in Japan. Weighted least squares regression analysis adjusted for the size of each population was used to investigate the association of lithium levels with suicide SMRs. The associations of lithium levels in drinking water with suicide SMRs (total, male, and female) were investigated adjusting for proportion of elderly people, proportion of 1-person households, proportion of people with college education or more, and proportion of people engaging in primary industry (adjusted model 1), and further adjustment was performed with overall unemployment rate, annual marriage rate, annual mean temperature, and annual postal savings per person (adjusted model 2). RESULTS: Lithium levels in drinking water were significantly (ß = -.169, P = .019) and inversely associated with male suicide SMRs but not total or female SMRs in the adjusted model 2. CONCLUSIONS: The present findings suggest that lithium in drinking water may be associated with the low risk of male suicide in the general population. Further studies are required to confirm these findings and investigate gender differences.

Identification of the neural correlates of cyclothymic temperament using a working memory task in fMRI.

BACKGROUND: Recently, we reported a significantly negative association of cyclothymic temperament scores with activations of the left lingual gyrus during esthetic judgments of paintings, suggesting that cyclothymic temperament may be associated with the left lingual gyrus. In view of potential associations of cyclothymic temperament, bipolar disorder and dementia, this study examined the relationship of temperament to lingual gyrus activity using a working memory task as a new context. METHODS: N-back tasks (0-, 1-, 2- and 3-back tasks) were performed on 34 healthy subjects using functional MRI. Multiple regression analyses were applied to measure the association between cyclothymic temperament scores and each of 4 beta images corresponding to 0-, 1-, 2- and 3-back tasks with gender, age and the other temperament scores (depressive, hyperthymic, irritable and anxious) as covariates. RESULTS: The whole brain analysis corrected for multiple comparisons revealed a significant activation of the left lingual gyrus associated with cyclothymic temperament scores in a new context-working memory for both 2- and 3-back tasks. LIMITATIONS: The number of subjects was relatively small. The subjects were almost medical staff or students and the results should be interpreted with caution. CONCLUSIONS: The present findings reconfirm that cyclothymic temperament may be associated with the left lingual gyrus.

Spatial memory impairment in OLETF rats without cholecystokinin - a receptor.

Cholecystokinin (CCK) is one of the most abundant neurotransmitter peptides in the brain. As Otsuka Long-Evans Tokushima Fatty (OLETF) rats lack CCK-A receptor because of a genetic abnormality, we examined whether learning and memory were impaired in these animals using both Morris water maze (MWM) and step-through type passive avoidance (PA) learning test. In the MWM test, memory impairment was observed in OLETF rats. The number of errors was also significantly higher, and that of the correct choices was significantly lower in OLETF rats compared to the controls [Long-Evans Tokushima Otsuka (LETO)] rats. In PA, OLETF rats did not show facilitating response 24 h after training. From these observations, we concluded that a spatial memory was impaired in the OLETF rats.

Anxiogenic-like effect of corticotropin-releasing factor receptor 2 antisense oligonucleotides infused into rat brain.

Corticotropin-releasing factor (CRF) is widely distributed in the brain and coordinates behavioural responses to stress. Its receptor subtypes, CRF-R1 and CRF-R2, are expressed in the brain. For this study, we tested the effect of a continuous infusion of CRF-R2 antisense oligonucleotides into the lateral ventricle on anxiety-related behaviours in rats. Our results indicate that CRF-R2 antisense oligonucleotides produced an anxiogenic-like effect in elevated plus maze, black and white box and conditioned fear stress in rats. No significant effect on general locomotor activity was seen. These results indicate that inhibition of CRF-R2 induces an increase in anxiety-related behaviours suggesting an anxiogenic-like effect.

Association between affective temperaments and regional gray matter volume in healthy subjects.

BACKGROUND: Affective temperaments such as cyclothymic and hyperthymic temperaments have been regarded as potential antecedents of bipolar disorder but the neural substrates underlying these temperaments have not been identified. The aim of this study is to determine whether these temperaments are associated with specific neural substrates in regional brain morphology in healthy subjects. METHODS: We conducted a cross-sectional neuroimaging study of 60 healthy subjects (30 males and 30 females) with affective temperaments. All participants underwent the Mini-International Neuropsychiatric Interview (MINI) to screen for the past and present psychiatric disorder. The scores of cyclothymic and hyperthymic temperaments were measured by the Temperament Scale of Memphis, Pisa, Paris and San Diego-Autoquestionnaire. We analyzed the association between voxel-based morphometry of the brain and these affective temperaments. RESULTS: Subjects classified as having high cyclothymic scores had a significantly larger gray matter volume of the left medial frontal gyrus (MFG) than low cyclothymic subjects. High hyperthymic males also had significantly larger gray matter volume of the left MFG than low hyperthymic males, but there was no difference in females. Subjects with both high cyclothymic and high hyperthymic temperaments demonstrated significantly larger gray matter volume of the left MFG than their counterparts. Region of interest analysis revealed that peaks of these clusters showed a significant positive correlation of the regional volume with temperament scores. LIMITATIONS: The subjects were relatively young and the number was relatively small. Due to the nature of a cross-sectional research design, we could not determine the causal relationship between temperament and the volume changes. CONCLUSIONS: These findings suggest that cyclothymic and hyperthymic temperaments in healthy subjects may have their morphological basis in the left MFG.

Identification of the neural correlates of cyclothymic temperament using an esthetic judgment for paintings task in fMRI.

BACKGROUND: There is a well-known association between artistic creativity and cyclothymic temperament but the neural correlates of cyclothymic temperament have not yet been fully identified. Recently, we showed that the left lingual gyrus and bilateral cuneus may be associated with esthetic judgment of representational paintings, we therefore sought to investigate brain activity during esthetic judgment of paintings in relation to measures of cyclothymic temperament. METHODS: Regions of interest (ROI) were set at the left lingual gyrus and bilateral cuneus using automated anatomical labeling, and percent signal changes of the ROIs were measured by marsbar toolbox. The associations between percent signal changes of the ROIs during esthetic judgments of paintings and cyclothymic temperament scores were investigated by Pearson׳s coefficient. Moreover, the associations were further analyzed using multiple regression analysis whereby cyclothymic temperament scores were a dependent factor and percent signal changes of the 3 ROIs and the other 4 temperament scores were independent factors. RESULTS: There was a significantly negative association of cyclothymic temperament scores with the percent signal changes of the left lingual gyrus during esthetic judgments of paintings, but not with those of bilateral cuneus. Even after adjustment using multiple regression analysis, this finding remained unchanged. LIMITATIONS: The number of subjects was relatively small and the task was limited to appreciation of paintings. CONCLUSIONS: The present findings suggest that cyclothymic temperament may be associated with the left lingual gyrus.

Difference in brain activations during appreciating paintings and photographic analogs.

Several studies have investigated neural correlates of aesthetic appreciation for paintings but to date the findings have been heterogeneous. This heterogeneity may be attributed to previous studies' measurement of aesthetic appreciation of not only the beauty of paintings but also the beauty of motifs of the paintings. In order to better elucidate the beauty of paintings, it seems necessary to compare aesthetic appreciation of paintings and photographic analogs which included corresponding real images. We prepared for famous painters' pictures and their photographic analogs which were set up to resemble each painting in order to investigate the hypothesis that there exist specific neural correlates associated with the aesthetic appreciation for paintings. Forty-four subjects participated in functional magnetic resonance study which required comparisons of aesthetic appreciation of paintings of still life and landscape versus photographic analogs including corresponding real images of still life and landscape. Bilateral cuneus and the left lingual gyrus were activated in the comparison of aesthetic appreciation of paintings versus photographic analogs. In conclusion, the present findings suggest a possibility of the existence of specific neural correlates associated with the aesthetic appreciation for paintings and that bilateral cuneus and the left lingual gyrus may be involved.

Hyperthymic temperament and rapid reaction time in brightness preference.

BACKGROUND: It is well-known that Type A behavior pattern is characterized by hard-driving, competitive behavior and time urgency. Also, people with hyperthymic temperament are known to have high energy levels and are full of plans. It is therefore hypothesized that hyperthymic temperament is associated with rapid processing and fast reaction time in making decisions. METHODS: Using data from our previous experimental studies (N=58) examining brightness judgment and brightness preference, reaction time (RT) was investigated in relation to hyperthymic temperament scores and fMRI signal changes of the left inferior orbitofrontal cortex during brightness judgment. RESULTS: RT for brightness judgment was significantly shorter than RT for brightness preference. Significant associations were found between RT for brightness preference and hyperthymic temperament scores, and RT for brightness preference and fMRI signal changes of the left inferior orbitofrontal cortex whilst performing brightness preference task. Multiple regression analysis revealed that RT for brightness preference task was significantly and negatively associated with hyperthymic temperament scores, and significantly and positively associated with fMRI signal changes of the left inferior orbitofrontal cortex. LIMITATIONS: It is uncertain whether the findings of RT (around 1s) can be extrapolated to routine life (around 24h) and whether RT for brightness preference can be generalized to a variety of daily activities. CONCLUSIONS: The present findings suggest that hyperthymic temperament is associated with rapid processing. Further studies are required to overcome the above limitations.

Hyperthymic temperament and brightness preference in healthy subjects: further evidence for involvement of left inferior orbitofrontal cortex in hyperthymic temperament.

BACKGROUND: Hyperthymic temperament has been generally accepted as one of premorbid temperament of bipolar disorders. Although several studies indicate that subjects with hyperthymic temperament receive more illuminance, our recent study suggests that the threshold of brightness and darkness judgment is not different between more and less hyperthymic subjects, and that hyperthymic temperament may be associated with left inferior orbitofrontal cortex, which has been reported to be associated with bipolar disorder. Therefore, at the next stage, it can be hypothesized that hyperthymic subjects may prefer brightness (i.e., heliotropism) and thereby seek illuminance, and that percent signal changes of left inferior orbitofrontal cortex during the preference task may be associated with hyperthymic temperament scores. METHODS: We compared brightness preference and un-preference between more and less hyperthymic subjects, and investigated percent signal changes of left inferior orbitofrontal cortex during brightness preference judgment, brightness un-preference judgment, and control task by using functional Magnetic Resonance Imaging (fMRI). RESULTS: There were significant differences in brightness preference judgment and un-preference judgment, showing that more hyperthymic subjects preferred brighter illuminace levels and un-preferred darker illuminance levels than less hyperthymic subjects. Moreover, fMRI signal changes of left inferior orbitofrontal cortex was significantly and negatively associated with hyperthymic temperament scores. LIMITATIONS: It is unknown why left but not right inferior orbitofrontal cortex was associated with hyperthymic temperament scores. CONCLUSIONS: The present findings suggest that more hyperthymic subjects may prefer brightness and un-prefer darkness than less hyperthymic subjects (i.e., heliotropism), and reconfirm that hyperthymic temperament may be associated with left inferior orbitofrontal cortex, which have been reported to be associated with bipolar disorders.

Hyperthymic temperament and brightness judgment in healthy subjects: involvement of left inferior orbitofrontal cortex.

BACKGROUND: Hyperthymic temperament has been generally accepted as one of premorbid temperament of bipolar disorders. Since recent several studies indicate an association between illuminance and hyperthymic temperament, it can be hypothesized that more hyperthymic temperament subjects have a different threshold of brightness or darkness perception in comparison with less hyperthymic temperament subjects. METHODS: We compared the threshold of brightness and darkness judgment between more and less hyperthymic subjects, and by simultaneously using fMRI we compared activations of whole brain between these subjects by two sample t-test. Furthermore, the association between the activations and hyperthymic temperament scores was analyzed. RESULTS: Although there was no significant difference in the threshold of brightness or darkness judgment between more and less hyperthymic subjects, there was a significant difference in activations of the regions including left superior temporal gyrus, left inferior orbitofrontal cortex, left triangular inferior frontal gyrus and left insula between these subjects. Moreover, there was a significantly positive association between a cluster containing left inferior orbitofrontal cortex and hyperthymic temperament scores. The common activated region of these two analyses (categorical and continuous ones) was determined as left inferior orbitofrontal cortex. LIMITATIONS: Limitation of the present study is a lack of brightness and darkness preference experiment between more and less hyperthymic subjects. CONCLUSIONS: The present findings suggest that the threshold of brightness and darkness judgment is not different between more and less hyperthymic subjects, and that hyperthymic temperament may be associated with left inferior orbitofrontal cortex, which has been reported to be associated with bipolar disorder.

Aripiprazole augmentation in 13 patients with refractory obsessive-compulsive disorder: a case series.

OBJECTIVES: The primary treatment for obsessive-compulsive disorder (OCD) is selective serotonin reuptake inhibitors (SSRI). However, approximately a third of patients do not respond to SSRIs and remain chronically affected. METHODS: Therefore, we added aripiprazole to SSRI therapy for 13 patients with treatment-refractory OCD (subjects who failed to respond to SSRI therapy for at least 2 months, and for an average of 508 days). Participants underwent at least 7 weeks of treatment with aripiprazole augmentation. RESULTS: Patients were evaluated using the Y-BOCS and GAF scales. Aripiprazole (3-12 mg)/SSRI co-therapy significantly improved Y-BOCS and GAF scores. However, many patients needed to take antiparkinsonian drugs to control extrapyramidal symptoms. CONCLUSIONS: These results suggest that aripiprazole augmentation of SSRI therapy may be effective for treatment-refractory OCD.

Salivary alpha-amylase and cortisol responsiveness following electrical stimulation stress in major depressive disorder patients.

Major depressive disorder (MDD) is often associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis by chronic stress. In comparison, psychosocial stress-induced activation of salivary α-amylase (sAA) functions as a marker of sympathoadrenal medullary system (SAM) activity. However, in contrast to salivary cortisol, sAA has been less extensively studied in MDD patients. The present study measured sAA and salivary cortisol levels in patients with MDD. The authors determined Profile of Mood State (POMS) and State-Trait anxiety Inventory (STAI) scores, Heart Rate Variability (HRV), and sAA and salivary cortisol levels in 88 patients with MDD and 41 healthy volunteers following the application of electrical stimulation stress. Patients with major depressive disorder were 8 points or more on Hamilton Depression Scale (HAM-D) scores. Tension-Anxiety, Depression-Dejection, Anger-Hostility, Fatigue, and Confusion scores in patients with major depressive disorder were significantly increased compared to healthy controls. In contrast, Vigor scores in patients with MDD were significantly decreased compared with healthy controls. There was no difference in heart rate variability measures between MDD patients and healthy controls. The threshold of electrical stimulation applied in MDD patients was lower than that in healthy controls. SAA levels in female MDD patients were significantly elevated relative to controls both before and after electrical stimulation. Finally, there were no differences in salivary cortisol levels between major depressive patients and controls. In the present study only three time points were explored. Furthermore, the increased secretion of sAA before and after stimulation could allude to an increased responsiveness of novel and uncontrollable situations in patients with MDD. These preliminary results suggest that sAA might be a useful biological marker of MDD.

Infrared radiation has potential antidepressant and anxiolytic effects in animal model of depression and anxiety.

BACKGROUND: Bright light therapy has been shown to have antidepressant and anxiolytic effects in humans. OBJECTIVE: The antidepressant and anxiolytic effects of infrared radiation were evaluated using an experimental animal model. METHODS: Rats were randomly assigned to either an acutely or chronically exposed infrared radiation group or to a nonexposed control group. Acutely exposed rats were treated with an infrared radiation machine for one session, whereas chronically exposed animals were treated with an infrared radiation for 10 sessions. Control group rats were exposed to the sound of the infrared radiation machine as a sham treatment. After infrared radiation or control exposure, rats underwent behavioral evaluation, including elevated plus maze test, light/dark box, and forced swim test. RESULTS: Chronic infrared radiation exposure decreased indicators of depression- and anxiety-like behavior. No significant effect on general locomotor activity was observed. The number of BrdU-positive cells in CA1 of the hippocampus was significantly increased in both acutely and chronically exposed infrared radiation groups compared with the control group. CONCLUSIONS: These results indicate that chronic infrared radiation might produce antidepressant- and anxiolytic-like effects.

Serum hepatocyte growth factor levels and the effects of antidepressants in panic disorder.

Previous animal studies have suggested that hepatocyte growth factor (HGF) could be associated with depression- and anxiety-related behaviors. Our aim was to relate serum HGF levels with State-Trait Anxiety Inventory (STAI), Profile of Mood State (POMS), and Revised NEO Personality Inventory (NEO-PI-R) scores in patients with panic disorder (with or without agoraphobia) and healthy controls. We examined 67 patients with panic disorders and 97 controls. Patients were split into two groups according to whether they exhibited a 50% improvement in test scores (good/high response group: n = 26) or not (poor/low response group: n = 41). In both healthy control and panic disorder individuals, there were no significant associations between HGF serum levels and STAI or NEO-PI-R scores. However, there was a significant correlation between serum HGF levels and fatigue in healthy control subjects in as scored by POMS testing. HGF concentration in the good/high response group was significantly elevated compared to both the low/poor response group (p < 0.01) and the control group (p < 0.01). HGF levels in the poor response group did not differ from the control group (p = 0.48). These results indicate that increased serum HGF levels might be a requirement for antidepressant efficacy in patients with panic disorders.

Elevated salivary α-amylase and cortisol levels in unremitted and remitted depressed patients.

Abstract Objective. Major depressive disorder (MDD) is often associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis via chronic stress. Psychosocial stress-induced activation of salivary α-amylase (sAA) represents sympathoadrenal medullary system (SAM) activity, and sAA has become an emerging biomarker for sympathetic nervous system activity. In contrast to salivary cortisol, sAA has been less extensively studied in depressed patients. The present study sought to address this problem by measuring sAA and salivary cortisol levels in patients with major depressive disorder. Methods. The authors recorded Spielberger State-Trait Anxiety Inventory (STAI) scores along with, levels of sAA and salivary cortisol in 28 patients with unremitted major depressive disorder, 43 remitted patients and 103 healthy volunteers. Results. STAI (State or Trait) measurements in unremitted patients with MDD were significantly increased compared with healthy controls and remitted patients. SAA and cortisol levels in unremitted patients were also significantly elevated compared to controls and remitted patients. Finally, sAA levels were significantly correlated with HRSD in unremitted patients with MDD. Conclusion. These preliminary results suggest that sAA may be a state-dependent marker of major depressive disorder in addition to salivary cortisol.