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.

Prospective study of major depressive disorder with white matter hyperintensity: comparison of patients with and without lacunar infarction.

OBJECTIVE: To investigate clinical characteristics, outcome, and risk factor for cerebrovascular disease in patients who had major depressive disorder and white matter hyperintensity (WMHI). METHOD: A total of 123 new patients diagnosed with major depressive disorder by semi-structured interview underwent magnetic resonance imaging (MRI) and were placed into one of three groups based on results. Patients with no abnormal findings (NF), patients with WMHI and no lacunar infarction (WMHI), and patients with lacunar infarction (LI). RESULTS: In the WMHI group, age at initial onset of depression and age at time of interview were both higher than in the NF group, as was severity of depression. Hamilton Rating Scale for Depression (HRSD) scores were significantly higher in the WMHI group than in the NF group. Total WMHI was significantly correlated only with age at initial onset of depression and age at time of interview. In the WMHI group, age at interview was lower than in the LI group and systolic and diastolic blood pressures were lower. Survival analysis regarding the clinical outcome of remission was conducted, but no significant differences were discovered among the three groups, WMHI, LI, and NF. However, the suicide rate was significantly higher in the LI group than in the other two groups. CONCLUSIONS: The origin and clinical characteristics of depression accompanied by WMHI may be specific; additional stringent study in comparison with individuals with LI is needed.

Enhanced suppression of adrenocorticotropic hormone and cortisol responses to hypothalamic-pituitary-adrenal function and thyrotropin-releasing hormone tests after stressful life events in patients with major depressive disorder.

BACKGROUND: It is commonly believed that there exists a relationship between the outcome of thyrotropin-releasing hormone (TRH) test, the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test and stressful life events (SLEs) in major depressive disorder. OBJECTIVE: SLEs influence the TRH and DEX/CRH tests in major depressive disorder when administered at the time of admission and improvement. METHODS: The TRH and DEX/CRH tests were administered to patients hospitalized for major depressive disorders - on the 4th through the 7th hospital day and at the time of improvement. We measured DeltaMAX TSH, DeltaMAX ACTH, ACTH AUC, DeltaMAX cortisol, cortisol AUC, DeltaMAX ACTH/DeltaMAX TSH and DeltaMAX cortisol/DeltaMAX TSH. RESULTS: SLEs were significantly negatively associated with DeltaMAX ACTH, ACTH AUC and cortisol AUC at the time of admission. However, these relationships lost significance at the time of improvement. The sample (41 patients at the time of admission, 18 patients at the time of improvement) was relatively small, which may have contributed to false-negative results. CONCLUSION: SLEs may be negatively associated with the outcome of the DEX/CRH tests in major depressive disorder. The hypothalamic-pituitary-adrenal axis in the DEX/CRH test was modulated by SLEs.

Assessment of the dexamethasone/CRH test as a state-dependent marker for hypothalamic-pituitary-adrenal (HPA) axis abnormalities in major depressive episode: a Multicenter Study.

There is compelling evidence for the involvement of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in depression. Growing evidence has suggested that the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test is highly sensitive to detect HPA axis abnormalities. We organized a multicenter study to assess the DEX/CRH test as a state-dependent marker for major depressive episode in the Japanese population. We conducted the DEX/CRH test in 61 inpatients with major depressive episode (Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV)) and 57 healthy subjects. In all, 35 patients were repeatedly assessed with the DEX/CRH test on admission and before discharge. The possible relationships between clinical variables and the DEX/CRH test were also examined. Significantly enhanced pituitary-adrenocortical responses to the DEX/CRH test were observed in patients on admission compared with controls. Such abnormalities in patients were significantly reduced after treatment, particularly in those who underwent electroconvulsive therapy (ECT) in addition to pharmacotherapy. Age and female gender were associated with enhanced hormonal responses to the DEX/CRH test. Severity of depression correlated with DEX/CRH test results, although this was explained, at least in part, by a positive correlation between age and severity in our patients. Medication per se was unrelated to DEX/CRH test results. These results suggest that the DEX/CRH test is a sensitive state-dependent marker to monitor HPA axis abnormalities in major depressive episode during treatment. Restoration from HPA axis abnormalities occurred with clinical responses to treatment, particularly in depressed patients who underwent ECT.

Predicting efficacy of electroconvulsive therapy in major depressive disorder.

The aim of this study was to investigate methods for predicting the efficacy of electroconvulsive therapy (ECT) in patients with major depressive disorder. Subjects comprised 24 inpatients with major depressive disorder diagnosed according to DSM-IV criteria who were resistant to antidepressant therapy or who, due to adverse reactions, could not undergo pharmacotherapy at adequate doses for sufficient durations. ECT was generally performed 12 times using a sinusoidal-wave device. Efficacy of ECT was evaluated using the 17-item Hamilton Rating Scale for Depression (HRSD). Multiple regression analysis was performed, using the final rate of improvement with ECT as the dependent variable, and improvement rate at completion of three ECT sessions and adequacy of pharmacotherapy before ECT as independent variables. Significant positive correlations were seen between final improvement rate with ECT and improvement rate at completion of three ECT sessions (partial correlation coefficient, 0.50, P<0.02), and significant negative correlations were seen between final improvement rate and adequacy of pharmacotherapy before ECT (partial correlation coefficient, -0.51, P<0.02). No significant differences were identified between responders and non-responders with respect to age, sex, duration of index episode, number of previous depressive episodes, whether depression was melancholia-type, whether depression was accompanied by psychotic features, total HRSD score immediately before ECT, and HRSD retardation or agitation scores. These results suggest that history of pharmacotherapy prior to ECT and improvement rate at completion of three ECT sessions may offer predictors for the final rate of improvement with ECT.

Simultaneous use of thyrotropin-releasing hormone test and combined dexamethasone/corticotropine-releasing hormone test for severity evaluation and outcome prediction in patients with major depressive disorder.

We performed a prospective study designed to examine whether or not evaluation of the severity and prediction of treatment outcome in major depressive disorder would be enabled by simultaneous use of the thyrotropin-releasing hormone (TRH) test and the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test. We studied consecutive patients hospitalized for major depressive disorder. The patients received the TRH test and the DEX/CRH test on the 4th through the 7th hospital days and at the time of improvement. None of the indices in these tests at the time of admission correlated with the Hamilton rating scale for depression (HRSD) or the Global Assessment for Function (GAF). However, since the DeltaMAXACTH, ACTHAUC, DeltaMAXcortisol, and CortisolAUC showed significant decreases at the time of improvement compared with the time of admission, suggesting that the DEX/CRH test can be a state marker. DeltaMAXTSH showed no significant change. Prediction of improvement within 3 months after admission was not possible with either test alone. However, the quotient which divided DeltaMAXACTH by DeltaMAXTSH was predictive of clinical improvement with a sensitivity of 50% and a specificity of 100%. The simultaneous use of the TRH test and the DEX/CRH test seems to provide a more useful biological marker than the separate use of either test alone in patients with major depressive disorder.

Contributing factors to changes of cerebral blood flow in major depressive disorder.

BACKGROUND: Results of single photon emission computed tomography (SPECT) regarding mood disorders have been inconsistent. The aim of the study was to elucidate factors contributing to changes in cerebral blood flow in patients with major depressive disorder. METHODS: A total of 89 consecutive patients diagnosed with major depressive disorder using DSM-IV semistructured interviews were evaluated using single photon emission computed tomography, the 17-item Hamilton Rating Scale for Depression (HRSD), and the Global Assessment of Function (GAF) scale. Nineteen of these patients also underwent the same tests during remission. RESULTS: Global cerebral blood flow (gCBF) was significantly higher during remission than at the time of enrollment. Significant correlations were seen between gCBF and age, duration of previous episode of depression, and hypochondriasis. However, no correlation was seen between gCBF and HRSD, GAF, severity and duration of depressive episode, or melancholia-type depression. Correlations between gCBF and age were seen only at enrollment and disappeared during remission. No differences in regional cerebral blood flow at any site were seen between time of enrollment and remission for the same patient. LIMITATION: Analysis that adequately accounts for these factors to changes of cerebral blood flow in major depressive disorder will require a large subject population. CONCLUSIONS: These results suggest that although there is a decrease in gCBF in major depressive disorder, the level of the decrease is determined by conditions present before episode onset, rather than by the characteristics of the episode itself. The findings also suggest that the correlation between gCBF and age is state-dependent.

Coping behavior in patients with panic disorder.

The purpose of the present paper was to investigate the role of coping behavior in patients with panic disorder (PD). This was done by evaluating three items of coping behavior (seeking of social support, wishful thinking and avoidance) in the Ways of Coping Checklist. The subjects consisted of 30 patients with PD (26 with agoraphobia). Coping behavior and the severity of PD was investigated at baseline and at 24 months (the final outcome). At baseline there were no gender differences in coping behavior. The severity of panic attacks significantly correlated with that of agoraphobia. The baseline severity of PD (panic attacks and agoraphobia) did not correlate with coping behavior. At the outcome assessment there was no significant correlation between the severity of panic attack and coping behavior. The severity of agoraphobia at final outcome and the coping behavior (seeking of social support) at baseline were significantly correlated. In the group that had remission in agoraphobia (the good outcome group), the severity of agoraphobia at baseline was significantly lower and the seeking of social support coping behavior was significantly higher than that of the poor outcome group. No significant difference in panic attack severity was noted between the good and poor outcome groups. Discriminant analysis revealed that seeking of social support coping behavior was a significant discriminant factor of agoraphobia. Although these are preliminary data, special coping behavior might be related to improvement of agoraphobia in patients with PD.

Reduced anxious behavior in mice lacking the CCK2 receptor gene.

Cholecystokinin 2 (CCK2) receptors have been implicated as mediators of anxiety in standard mouse models such as exploratory behavior both in black and white test boxes and in elevated plus-mazes. We investigated the role of the CCK2 receptor in anxiety by evaluating the behavior of mice lacking the gene for this receptor in these standard anxiety models (i.e., exploratory behavior in a black and white test box and exploratory behavior in an elevated plus-maze). In the black and white test box, mice lacking the CCK2 receptor gene showed significantly increased numbers of transitions between the boxes compared to control mice. In the elevated plus-maze, mice lacking the CCK2 receptor gene displayed significantly more head dips than control mice. These results suggest that mice lacking the CCK2 receptor gene are less anxious than normal mice.

Coping behavior in depressed patients: a longitudinal study.

The relationship of coping behavior to outcome in depressed patients was examined. Subjects (n=105) with major depressive disorder (n=85), depressive disorder not otherwise specified (n=7) or major depressive disorder with axis I comorbidity (n=13) were followed for 6 months. Their coping behavior (i.e. rumination, active distraction, cognitive distraction and dangerous activities) was defined using the Comprehensive Assessment List for Affective Disorders. Based on their Hamilton Rating Scale for Depression (HRSD) scores at 6 months, the patients were categorized as having had a good or a poor outcome. Severity of depression and coping behavior were similar among the three diagnostic groups. At baseline assessment, coping behavior was not correlated with either HRSD score or age. However, males were significantly more likely to be engaged in dangerous activity as a coping behavior than females. Patients with a good outcome at 6 months were significantly more likely to use rumination as a coping behavior while patients with a poor outcome were significantly more likely to use dangerous activity. Multiple regression analysis confirmed this finding, indicating that rumination and dangerous activity were significant predictors of outcome at 6 months. Rumination might be associated with good outcomes in depressed patients while dangerous activity might be associated with poor outcomes.

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.

Discrepancy between subjective and objective sleep in patients with depression.

The literature investigating the relationship between objective and subjective sleep in depressed patients is limited and the results are inconsistent. Furthermore, many factors that influence the aforementioned relationship have not been investigated. The present study was carried out to clarify the characteristics of self-estimation of sleep in depressed patients. Sleep was estimated concurrently using a sleep log and polysomnography for 5 consecutive days to investigate the relationship between subjective sleep estimation and objective sleep estimation in 23 patients with major depression (Diagnostic and Statistical Manual of Mental Disorders, 3rd edn, revised; DSM-III-R). Factors related to a discrepancy between both types of estimation were identified. The subjective total sleep time showed a significant, but moderate, positive correlation (correlation coefficient: 0.63) with the objective total sleep time. The degree of discrepancy was significantly correlated with various objective sleep variables and severity of depression. In the underestimation group in which the subjective total sleep time was shorter than the objective total sleep time, the objective total sleep time and slow-wave sleep time were shorter, age was greater and the extroversion score (Maudsley Personality Inventory) was lower than in the overestimation group in which the subjective total sleep time was longer than the objective total sleep time. The data suggest that subjective sleep estimation in depressed patients is influenced by their objective sleep, severity of depression, age and personality.

Frontal brain hypoactivity as a biological substrate of anxiety in patients with panic disorders.

Frontal brain asymmetry is associated with differences in the basic dimensions of emotion. It seems to reflect the activation of specialized systems for avoidance-withdrawal behavior. Since patients with panic disorder are characterized by having both negative emotions and avoidance-withdrawal behavior, we expected them to show greater asymmetry in the frontal hemisphere change activation. Near-infrared reflection spectroscopy was recorded from the left and right frontal regions of 23 patients with panic disorder without depression and from 31 healthy control participants in the following conditions: confrontation at rest with neutral (mushroom), anxiety-relevant (spider and snake) or anxiety-irrelevant but emotionally relevant stimuli (erotic picture). Emotional states and traits were assessed by the State-Trait Anxiety Inventory. The left frontal oxyhemoglobin in patients was significantly lower than in control subjects when confronted with anxiety-relevant or anxiety-irrelevant but emotionally relevant stimuli. There was no frontal brain asymmetry when patients or control subjects observed any stimuli. These data suggest that patients with panic disorder are characterized by having a greater decrease in the activation of a left frontal avoidance-withdrawal system in situations with a negative valence. The findings are interpreted as biological evidence for a disturbed cortical processing in patients with panic disorder.

Association between the CCK-A receptor gene and panic disorder.

Cholecystokinin (CCK) is one of the most abundant neurotransmitter peptides in the brain. CCK appears to play an important role in the neurobiology of anxiety and panic disorders (PD) in both humans and animals. Recently, we reported that lack of CCKAR had a significant anxiogenic-like effect in rats. In this study, to investigate the role of CCKAR in PD, we compared the CCKAR gene in PD patients and normal controls. Subjects who fulfilled the DSM-IV criteria for PD were 17 males and 26 females. The sequence containing the Pst I polymorphic site in the boundary between intron 1 and exon 2 of the CCKAR gene was studied. Pst I digestion of the PCR products gave two individual alleles: A1 and A2. The A1 allele was the undigested fragment and the A2 allele was the digested one with two variant bands at 264 and 180 bp. Genotypic frequencies were 20.9% (A1-A1), 55.8% (A1-A2), and 41.7% (A2-A2) in patients, and 20.5% (A1-A1), 46.2% (A1-A2), and 33.3% (A2-A2) in controls. Allelic frequencies were 48.8% (A1) and 51.2% (A2) in patients, and 43.6% (A1) and 56.4% (A2) in controls. The chi-square test did not show a significant difference in either genotypic or allelic frequencies between patients and control subjects. The Pst polymorphism of CCKAR may not be associated with PD.

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.

Effect of repetitive transcranial magnetic stimulation on forced swimming test.

Repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive shock (ECS) have been shown to affect mood in health and disease. Evidence to date has demonstrated an antidepressant potential for rTMS and electroconvulsive therapy (ECT). The present experiment, aimed at comparing the effects of ECS and rTMS in rats, employed one test used for screening of antidepressant activity: the forced swimming test (FST). In this study, the authors investigated whether chronic rTMS influenced active behavior in the rat FST, similar to ECS. Male Wistar rats received rTMS treatment daily, for 10 days as is commonly used for ECT treatment. Control rats received sham treatment by placing the stimulation coil in a perpendicular position to the rat's head. Passing a current through earclip electrodes for 1 s induced ECS. The control animals were treated identically, but current was not applied. The FST was carried out 24 h after the last rTMS or ECS. The immobility time in the FST was not significantly affected by rTMS and ECS for 1 day. The immobility time in the FST was significantly shortened at rTMS and ECS for 10 days. Chronic treatment with rTMS, similar to chronic treatment with ECS, decreased the immobility time in the FST. These results indicate that chronic treatment with rTMS might have antidepressant effect similar to chronic treatment with ECS.