Timing of movements in depressed patients and healthy controls

BACKGROUND: Psychomotor disturbances are fundamental psychopathological features of major depression and observable components of behaviour. Human behaviour is segmented into action units with duration of a few seconds due to central nervous motor processing. Timing may depend on cognitive and emotional functions which are affected in depression. Therefore, time structure of action units in depressed patients was compared to healthy controls. METHODS: Included were patients with major depression and melancholic features. Upper limb movements (total n = 566) of depressed patients and matched controls were evaluated using videotaped interviews and frame-by-frame analysis with a temporal resolution of 40 ms. RESULTS: Behaviour of depressed patients in interview sessions was organised in action units with a narrow time span of only a few seconds. Single, non-repetitive action units were significantly shorter (median = 1.20 s) and repetitive units longer (median = 4.92 s) in patients compared to controls (median = 2.08 and 2.96, respectively). LIMITATIONS: Behaviour in interview sessions might differ from activities of daily living. DISCUSSION: Altered temporal segmentation of movements appears to be an observable, measurable sign of melancholic depression and may allow further insights in pathophysiological dysfunctions of the disease. Clinical implications of these motor changes for differential diagnosis, course and treatment of depression are discussed and need further evaluation.     

Amygdala volumes in a sample of current depressed and remitted depressed patients and healthy controls

BackgroundMajor Depressive Disorder is associated with amygdala volumetric alterations. To date, it is still unclear (I) whether amygdala volumetric alterations constitute a state or a trait marker of MDD; (II) what influences the direction of amygdala morphometric changes (i.e., enlargement versus shrinkage); and (III) what the role of laterality is in amygdala volumetric alterations in MDD.MethodsWe investigated amygdala volume in a sample of 31 currently depressed patients (cMDD), 31 healthy subjects with a previous diagnosis of MDD (rMDD) and 31 healthy controls, using images obtained from a 1.5 Tesla MRI scanner. The groups were matched for age and gender.ResultsWe found that left amygdala volumes of rMDD subjects were significantly larger as compared to healthy controls, and tended to be larger when compared to cMDD subjects. There was no difference in left amygdala volumes between cMDD patients and healthy controls. Right amygdala volumes did not differ between groups.ConclusionsGiven that amygdala alterations were present only in remitted patients, we suggest that such alterations appear to be a state marker of MDD. Further, we found evidence of a lateralization effect, with changes in the left hemisphere only. Left amygdala enlargement in the rMDD group may represent a neurobiological marker of vulnerability to relapse, or may reflect recovery from MDD, whereby volumetric changes have resulted from stress associated with the last depressive episode.     

The effect of age on cortisol and plasma dexamethasone concentrations in depressed patients and controls

The aim of this study was to identify any relationships between various patient factors such as age, gender and concurrent medication that may affect plasma cortisol or dexamethasone (DEX) concentrations. Multiple regression analysis was used to formulate an equation to predict plasma DEX levels to identify factors that may influence DEX bioavailability. Pre- and post-DST cortisol levels did not increase with age, but DEX levels were higher in elderly depressed patients. Neither gender nor psychotropic medication affected plasma cortisol or DEX levels. There was no indication that pre-DST cortisol levels influenced plasma DEX levels to account for the lower DEX values in non-suppressors. Age was the only significant factor found in this study to influence DEX levels and it could be argued that the dose of DEX should be lowered when administering the DST to elderly patients to reduce plasma DEX variability.     

Similar sleep EEG topography in middle-aged depressed patients and healthy controls

OBJECTIVES: One of the early hypotheses relating sleep disturbances in depression to a model of sleep regulation is the S-deficiency hypothesis. It is postulated that, in depressed patients, sleep propensity during wakefulness does not rise to the level attained by nondepressed subjects, resulting in altered sleep structure or changes in the electroencephalogram during sleep. We aimed to test this hypothesis by assessing topographic changes in the sleep electroencephalogram associated with depression. DESIGN: Cross-sectional clinical study. SETTING: Mental Health Clinical Research Center. PARTICIPANTS: Sixteen unmedicated depressed outpatients (mean age: 41.2 years) and 16 pair-matched healthy controls (mean age: 41.1 years). Interventions: None. MEASUREMENTS: Baseline sleep electroencephalogram recordings were obtained from a central referential electrode and from 3 bipolar derivations (frontocentral, centroparietal, parietooccipital) along the anteroposterior axis. RESULTS: Symptoms of depression at the time of sleep recordings were moderate (24-item Hamilton Rating Scale of Depression range: 16-31). No differences between patients and controls were found in sleep variables and all-night electroencephalogram spectra in non-rapid-eye-movement and rapid-eye-movement sleep. The ultradian modulation of slow-wave activity (power within 0.75-4.5 Hz), as well as the exponential decline of slow-wave activity, during sleep did not differ between the groups. The statistical analyses of electroencephalogram power gradients between adjacent derivations revealed no Group x Derivation interactions. An anterior dominance in non-rapid-eye-movement sleep power was present in the 0.75- to 2-Hz range, which diminished throughout the night. CONCLUSIONS: These findings in moderately depressed patients do not support the existence of an S-deficiency during sleep. Because the build up of sleep propensity during waking can be dissociated from its decline, future studies need to investigate the waking electroencephalogram spectra in depression.     

A neuroendocrine study of serotonin function in depressed stroke patients compared to non depressed stroke patients and healthy controls.

OBJECTIVES: We employed a neuroendocrine challenge paradigm to study serotonergic abnormalities associated with poststroke depression. METHOD: Twelve depressed stroke patients (major depression N= 5, minor depression N = 7), 8 nondepressed stroke patients and 12 healthy volunteers completed a single-blind, placebo-controlled, challenge tests. Baseline cortisol (CORT) and prolactin (PRL) values, and these hormonal responses to 30 mg of oral d-FEN and placebo over a 4 hour period were measured in the three groups. RESULTS: There were intergroup differences for baseline adjusted PRL responses (change scores from baseline) to d-FEN (group effect F = 4.38, df = 2,29, p = 0.02) while these responses to placebo were comparable between groups (group effect F = 1.82, df = 2,29, p = 0.18). Peak PRL responses (post d-FEN maximal PRL change from baseline scores) in depressed stroke patients were significantly greater than in nondepressed patients (p = 0.005) but comparable to healthy normals (p = 0.47). However, these responses between major and minor depression were not significant (p = 0.34). There was a trend suggesting a negative correlation between peak PRL response and severity of depression (p = 0.056). Depressed patients were younger than the controls (p = 0.054). Also, the depressed group was more functionally impaired (p = 0.04) and more likely to have right-sided lesions (p = 0.009) compared with the nondepressed group. Differences in baseline adjusted PRL changes between depressed and nondepressed groups became non significant when the influence of laterality of lesions was covaried, whereas covariation of functional scores and age did not alter the significance. CORT responses did not show intergroup differences. LIMITATIONS: The study group was small and was heterogenous in lesion characteristics, time since stroke and type of depression. A fixed-order design was used in the challenge test paradigm. CONCLUSIONS: When laterality of stroke lesion was taken into account, depressed and nondepressed stroke patients did not differ in PRL responses to d-FEN.     

Insulin-induced hypoglycaemic response and release of growth hormone in depressed patients and healthy controls

As part of the Collaborative Study of the Psychobiology of Depression, we have examined the pretreatment growth hormone response (delta GH) to insulin (0.1 U/kg) and the magnitude of the hypoglycaemic response in a large number of well-defined depressed patients (N = 132) and healthy controls (N = 80). After applying rigorous exclusion criteria, data were analysed from 93 patients and 66 controls for blood glucose response and from 56 patients and 52 controls for delta GH. Depressed patients, either unipolar or bipolar, showed less of a fall in glucose than controls. A weak association was found between the magnitude of the fall in glucose and the severity of depression. No significant differences were found in values for delta GH between the unipolar or bipolar depressed patients and controls either for males, pre-menopausal or post-menopausal females, or the total female group. These data do not support previous claims of a lowered delta GH response to insulin in depressed patients. However, the resistance to hypoglycaemia seen in the depressed patients is consistent with previous reports.     

Effects of metyrapone and dexamethasone upon pro-gamma-MSH plasma levels in depressed patients and healthy controls

There is current controversy over the mechanisms underlying hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in depression. Pro-gamma-melanocyte-stimulating hormone (MSH), a portion of the N-terminal region of pro-opiomelanocortin, has been shown to act synergistically with adrenocorticotropic hormone (ACTH) in stimulating corticosteroid secretion both in vitro and in vivo. Pro-gamma-MSH and ACTH plasma levels were measured in 30 drug-free male patients with a DSM-IIIR major depressive disorder and 21 healthy controls. The baseline levels were similar in the two groups. After single-dose metyrapone stimulation, both hormones increased, but pro-gamma-MSH was significantly higher in control subjects than in depressives. After overnight 1-mg dexamethasone, ACTH was significantly less suppressed in depressives than controls. These results suggest that HPA axis dysregulation in depression may involve peptides other than ACTH and be more complex than previously reported.     

Delta sleep EEG in depressed adolescent females and healthy controls

BACKGROUND: Quantitative EEG studies have identified a number of sleep abnormalities in adults with major depressive disorders (MDD), including a reduction in the amplitude of delta activity during NREM sleep. To date, these methodologies have not been used in early onset MDD. METHODS: Delta activity during NREM sleep was compared in eight symptomatic but unmedicated adolescent females with MDD and eight age- and gender-matched healthy controls. RESULTS: The depressed group showed significantly lower delta amplitude and power in the first NREM sleep period. By contrast, standard sleep architecture did not differentiate between groups. LIMITATIONS: Given the sample size, this study is best viewed as tentative. In addition, it has yet to be determined whether adolescent males with MDD also show delta sleep abnormalities. Further, failure to find between-group differences in REM latency or other macroarchitectural measures may be due to the small sample size. CONCLUSIONS: The findings of this study underscore the utility of quantitative sleep EEG techniques in early onset MDD. The results of the present study do, however, diverge from reports in adults with MDD, where delta abnormalities are more prevalent in men. Such findings suggest that the maturational time course of sleep EEG disturbances may differ for males and females with depression. Early emergence of delta abnormalities in depression may be of relevance to clinical course of illness.     

Dopamine transporter availability in symptomatic depressed patients with seasonal affective disorder and healthy controls.

BACKGROUND: During recent years hypotheses about the pathophysiology of seasonal affective disorder/winter type (SAD) have focused monoaminergic mechanisms. There is substantial evidence that serotonergic systems play an important role. The potential role of catecholaminergic pathways has not been fully explored. METHODS: Eleven drug-free, symptomatic depressed patients with SAD and 11 healthy age- and gender-matched healthy controls were invited to participate in a 123Ibeta-CIT single photon emission computed tomography (SPECT) study to assess striatal density of dopamine transporters (DATs). The cerebellum was used as reference region. Ratios were calculated between mean counts in left and right striatum and cerebellum. These ratios minus I represent specific/non-displaceable binding and are assumed to be directly related to DAT availability at the time of binding equilibrium. RESULTS: Displaceable 153Ibeta-CIT binding in the area corresponding to the left striatum was significantly reduced in SAD patients compared to healthy controls (10.49+/-0.91 v. 1195+/-1.54, respectively; 2-tailed P = 0.017, Mann-Whitney U test). CONCLUSIONS: These data suggest reductions in the availability of striatal DAT binding sites in untreated symptomatic depressed SAD patients. It remains unclear whether these reductions represent a primary defect or an attempt to overcome a state of possible lowered dopamine availability in the synaptic cleft during a depressive episode of SAD. However, these findings provide evidence that brain dopaminergic systems may be involved in the pathophysiology of SAD.     

Age effects on cortisol levels in depressed patients with and without comorbid post-traumatic stress disorder, and healthy volunteers

BACKGROUND: Post-traumatic stress disorder (PTSD) and major depression are frequently comorbid. Age and major depression are associated with higher cortisol levels and dexamethasone resistance, whereas PTSD is associated with lower cortisol and dexamethasone supersensitivity. Therefore, we examined the effect of age on the hypothalamic-pituitary-adrenal (HPA) system in depressed patients with and without PTSD. METHODS: Thirty-one depressed patients without PTSD, 12 depressed patients with PTSD, and 23 healthy volunteers were studied on 2 days. Subjects received single-blind placebo on day 1 and fenfluramine on day 2. Cortisol levels were drawn before challenge and for 5 h thereafter. RESULTS: Cortisol levels increase with age in depressed patients without PTSD but not in depressed patients with PTSD or in healthy volunteers. Number of previous major depressive episodes was a predictor of the cortisol response to fenfluramine administration in depressed patients without PTSD. CONCLUSIONS: The results of our study highlight the importance of considering age in psychobiology. Further research is needed to fully delineate the role of age in abnormalities of the HPA axis found in major depression and PTSD.     

Examining the effects of sleep delay on depressed males and females and healthy controls

Individuals with major depressive disorder typically exhibit sleep electroencephalograpy abnormalities which have been shown to vary by sex. Recent research has shown that depressed males display deficits in slow wave sleep and delta electroencephalograph (EEG) activity that are not apparent in depressed females. This may suggest that males and females with depression vary with respect to their homeostatic regulation of sleep. Utilizing archival data, the present study examined the effects of a 3‐h sleep delay, which represents a mild sleep challenge, on slow wave activity in healthy controls and individuals with depression. All participants slept in the laboratory for three sequential nights. On the third night in the laboratory, the participants' bedtime was delayed by 3 h. Slow wave activity was calculated utilizing power spectral analysis and compared across groups. Following the sleep delay, males with depression exhibited the lowest slow wave activity compared to all other groups. These results may suggest that males with depression are at a greater risk for homeostatic dysregulation than females, and may require specialized intervention.     

Plasma HVA levels in depressed patients and controls

Plasma levels of the dopamine metabolite homovanillic acid (HVA) were examined in depressed patients and controls. There were no significant differences between the groups. In particular, there were no significant differences for plasma HVA levels between depressed patients with and without melancholia or between depressed patients who were cortisol nonsuppressors or suppressors.     

Platelet [3H]imipramine binding in depressed patients and its circadian variations in healthy controls

Platelet [3H]imipramine binding was determined in 28 patients with major depression, 11 with bipolar disorders, and 28 healthy controls. The mean maximum number of binding sites (Bmax) in depressed patients was significantly lower than in healthy controls. A significant negative correlation was found between the Bmax values and the total scores of the 17-item Hamilton depression rating scale in major depression. Our results suggest that the Bmax values in major depression may be related to severity of depression. There were significant circadian variations in the Bmax values of [3H]imipramine binding on human platelets from six healthy controls. The mean Bmax values were significantly low in the dark phase and high in the light phase.     

Effects of personal controls on cortisol secretion during stress processes

This study investigated effects of personal control on psychobiological stress responses. Salivary cortisol was used as an index of hypothalamic pituitary-adrenocortical axis response. Healthy males (N = 20) were exposed five times serially to a psychosocial stressor: mental arithmetic under time pressure. "Chance control", "other powerful controls" and "internality" were reported personality-dependent aspects of personal controls; "personal control as coping" under the psychosocial stress situation was also assessed with a questionnaire after the session ended. Cortisol response showed significant increase (F (16,304) = 6.69, p < 0.01). From the view point of personality, the high "chance control" score group showed higher levels of cortisol compared to the low score group before stressful tasks. On the other hand, the high "personal control as coping" score group showed higher levels of cortisol compared to the low score group after the stressful tasks. We inferred that the high "personal control as coping" score group conducted stressful tasks with high concentration and effort. The effects of such personal controls as personality and as ways of coping were demonstrated in this experiment through cortisol secretion in different stress-process phases.     

Hypothermic, ACTH, and cortisol responses to ipsapirone in patients with mania and healthy controls.

BACKGROUND: The selective 5-HT1A receptor agonist ipsapirone causes dose-dependent decrease in body temperature and increase in adrenocorticotropic hormone (ACTH) and cortisol release in humans. These responses are attenuated by 5-HT1A receptor antagonists, suggesting that hypothermia, ACTH and cortisol release induced by ipsapirone are indeed mediated by 5-HT1A receptors and that these responses provide a valid index of 5-HT1A receptor function in humans. METHODS: To examine the 5-HT1A receptor sensitivity in patients with mania, we studied six manic patients and six age and sex matched healthy controls. After obtaining a blood sample for baseline hormone levels and measuring body temperature, a single dose of 0.3 mg/kg of ipsapirone was given orally to all the subjects and further bloods and temperature reading were obtained every 30 minutes for 3 hours. RESULTS: We found that ACTH and cortisol responses to ipsapirone were significantly increased in mania when compared to healthy controls, but there was no significant difference in hypothermic response to ipsapirone between the two groups. LIMITATIONS: A lack of placebo control, heterogeneity of patients, and a small sample size are the limitations. CONCLUSIONS: Our findings suggest that manic patients may have enhanced postsynaptic 5-HT1A receptor sensitivity, but presynaptic 5-HT1A receptors are unaltered in this condition. Further placebo-controlled studies with a larger number of manic patients are needed to verify this.     

CSF GABA in depressed patients and normal controls.

The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has been implicated in the pathophysiology of depression. Therefore, we examined cerebrospinal fluid (CSF) levels of GABA in depressed patients (N = 25) and normal controls (N = 20). There was no significant difference between the groups. However, among the depressed patients the subgroup of unipolar melancholic patients (N = 13) had significantly lower CSF levels of GABA than the rest of the depressed patients (N = 12). There was no significant difference for CSF levels of GABA between depressed patients who were (N = 14) or were not (N = 11) cortisol non-suppressors. It was of interest that among the controls there was a significant negative correlation between CSF levels of GABA and CSF levels of norepinephrine.     

Dysphoria: self-devaluative and affective components in recovered depressed patients and never depressed controls.

BACKGROUND: The Interacting Cognitive Subsystems analysis of cognitive vulnerability to depression predicts that subjective experiences of dysphoria in recovered depressed patients will be qualitatively different from those of controls. This study tested this prediction using a new instrument, the Depressed States Checklist. METHODS: Twenty-three recovered recurrently depressed patients and 54 never depressed controls rated the affective and self-devaluative components of a dysphoric experience. RESULTS: Groups reported similar levels of affective component but recovered depressed patients reported higher self-devaluative dysphoric experience. At zero affective component of dysphoria neither group reported any self-devaluative feelings. With increasing affective component of dysphoria, the self-devaluative component increased significantly more in recovered patients than in controls. The ratio of self-devaluative to affective components of dysphoria significantly differentiated recovered depressed patients from controls. CONCLUSIONS: As predicted, dysphoria in recovered depressed patients is qualitatively different from controls in ways that increase vulnerability to major depression. The Depressed States Checklist is a new, brief, measure of cognitive vulnerability to depression that may be particularly useful in large, prospective, epidemiological studies.     

Platelet 3H-imipramine binding sites in depressed patients and healthy controls: a comparison between morning and afternoon samples

Platelet 3H-imipramine binding was compared between 19 hospitalized, depressed patients and age-matched controls (n = 11). For each individual person blood samples were withdrawn at 8 a.m. and 3 p.m. on two separate occasions (day 0 and day 28). Mean Bmax and Kd values did not differ between depressed patients and healthy controls at any of the four time-points tested, and no significant differences could be established between the different time-points, though there were irregular intraindividual variations.     

The effects of glucocorticoids on the availability of L-tryptophan and tyrosine in the plasma of depressed patients

There is evidence that a functional deficit of serotonin/noradrenaline and/or of their precursors L-tryptophan (L-TRP)/tyrosine and disorders in the hypothalamic-pituitary-adrenal (HPA) axis are linked to the pathophysiology of severe depressions. Several reports suggest a reciprocal relationship between these neurotransmitters and HPA axis activity. In order to investigate the effect of glucocorticoid excess on the availability of L-TRP and tyrosine to the brain, we measured urinary cortisol (UC) excretion in 24-h urine, and the availability of both amino acids before and after treatment with 1 mg dexamethasone in 26 depressed patients. We found no relationship between UC excretion and the availability of either amino acid. Dexamethasone significantly suppressed the availability of L-TRP (P less than 10(-5] and of tyrosine (P = 0.005). Major depressed patients with melancholia exhibited a significantly lower availability of L-TRP than minor depressives (P = 0.007).     

Platelet accumulation of histamine in controls, depressed and lithium-treated patients

The accumulation of histamine into blood platelets of depressed patients, lithium-treated patients and controls was determined using radio-labelled histamine. All groups had significantly different mean accumulation rates: the depressives had the lowest, the controls had the highest while the lithium-treated patients had intermediate rates. No significant difference in histamine accumulation rates was detected between drug-free depressed patients or depressed patients receiving psychotropic medication apart from lithium. Histamine accumulation rates of depressed patients did not appear to have been influenced by their age or severity or endogenicity of their illness; no difference in histamine accumulation was detected between those patients who had an abnormal or normal dexamethasone suppression test response. We have concluded that while the biological significance of these results is unclear it would appear to be a very sensitive test for depression, especially in women. It would appear that prophylactic lithium treatment increased the rate of histamine accumulation: this result is discussed with reference to histamine's association with allergic disorders.