Correlation of Antibodies to Neurotransmitters in the Sera of Women with Alcohol Dependence and Depressive Disorders.

Comparative analysis of blood sera from women with alcohol dependence and depressive disorders or from conditionally healthy women revealed reduced level of antibodies to dopamine, norepinephrine, serotonin, glutamate, and GABA in blood serum in women with dysthymic disorder and a depressive episode and their increased content in women with alcohol dependence in combination with depressive disorders.

A shift toward T helper 2 responses and an increase in modulators of innate immunity in depressed patients treated with escitalopram.

Depression is hypothesized to involve inflammatory processes, and identifying the key cytokines targeted by antidepressant drugs is critical for tailoring treatment to specific cases. However, investigating a limited number of cytokines at one time cannot provide a broad picture of antidepressant-associated immunomodulation. Cytokines act in a network where one could demonstrate pleiotropism, redundancy, synergy, and antagonism with other cytokine functions. This study was aimed at determining whether escitalopram functions as an anti-inflammatory agent and, if so, how it influences cytokine networks. A total of 24 healthy controls and 26 patients with clinical depression requiring inpatient treatment were recruited. A multiplex assay, an efficient tool to simultaneously measure 27 cytokines, was applied in patients with depression before and after 4-week escitalopram treatment. Healthy controls did not take escitalopram and completed cytokine analyses once. We demonstrated that escitalopram increased the levels of interleukin (IL)-1 receptor antagonist and IL-2. Moreover, escitalopram contributed to a shift toward T helper 2 responses and an increase in modulators of innate immunity, leading to a decrease of immune system activation, both innate and adaptive. We suggest that escitalopram modulates the balance of IL-1 and IL-1 receptor antagonist and improves the function and number of T regulatory cells. However, diverse conclusions could be drawn if only a few cytokines were assessed or different significance levels were used. Further studies should investigate a wide range of cytokines in a reliable and valid way, which is key to disentangling the effects of different antidepressants on inflammatory processes.

Natural killer cell cytotoxity and course of illness in depressed mood.

There is now some evidence that depressed mood is associated with activation of the immune system. First, we evaluated, within a cross-sectional design, NKCA (in vitro) in 49 subjects meeting inclusion criteria either for a major depressive episode, for dysthymia, or for "double depression". We found that recent and long depressive episodes (dysthymia) are associated with a lower immunodepression. Second, we compared two subset of subjects: 14 patients meeting criteria of major depression to 14 healthy controls. The data show a significant improvement in major depression when compared to controls througout a treatment combining supportive psychotherapy and 8 mg Reboxetine™.

Neopterin levels and dexamethasone suppression test in obsessive-compulsive disorder.

Neopterin, a biopterin precursor that is released by macrophages, is an important immunological marker in psychiatric disorders. It has been reported that glucocorticoids may cause suppression of cell-mediated immunity and consequently result in decreased neopterin levels. In the present study, we evaluated whether dexamethasone suppression test (DST) and neopterin findings were associated with pure obsessive-compulsive disorder (OCD) patients (OCD-D group) and the concomitant OCD and depression (OCD+D group). The sample comprised 44 patients with OCD (27 with OCD-D and 17 with OCD+D) and 30 control subjects. There was significantly higher DST nonsuppression in the OCD+D group than in the OCD-D group. With regard to mean neopterin levels, there was no significant difference between the OCD-D group and the control group, but there was a statistically significant difference between the OCD+D group and the control group. The OCD+D group had significantly lower neopterin levels than the 20 OCD-D group. We suggest that this distinction may reflect the fact that glucocorticoids can lead to suppression of cell-mediated immunity and consequently can result in decreased neopterin levels. In conclusion, our results suggest that not the OCD-D group had normal neopterin levels and DST results, and also that OCD may be a heterogeneous subtype characterized by some biological indicators or anxiety and affective disorders.

Monocytic parameters in patients with dysthymia versus major depression.

BACKGROUND: The studies on monocytic function during depression are controversial. A better knowledge of affective disorders may improve the differential diagnosis of depression subtypes. Our goals are to examine if there are differences in monocytic function in patients with major depression and dysthymia. METHOD: Twenty-two depressed patients (12 dysthymia and 10 major depression) and 15 healthy controls participated in the study. We analyzed monocyte count, monocyte subsets (CD14+, CD16+, and HLA class-II+), respiratory burst activity, phagocytic index and the interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNFalpha) production. RESULTS: Depressed patients showed elevated IL-1beta (P<0.05) and IL-6 (P<0.01), elevated monocytic respiratory burst activity (P<0.01); and reduced surface molecule expression HLA class-II and phagocytosis (P<0.01) compared with controls. We found no differences in any monocytic parameters between dysthymia and major depression. LIMITATIONS: The small sample size and the short wash-out reduce the reliability of the results. CONCLUSIONS: Major depression and dysthymia show similar signs of both monocytic activation and suppression. These alterations may be due to the depressive syndrome and not to the characteristics of depression subtypes studied.

Interleukin-1beta and tumor necrosis factor-alpha in children with major depressive disorder or dysthymia.

BACKGROUND: Immune function is altered in adult depressed patients. The aim of our study was to see whether or not cytokine secretion is impaired at a very young phase of development of depressive disorders, possibly being pathogenetically involved in their course. METHODS: Basal plasma concentrations of interleukin-1beta (Il-1beta) and tumor necrosis factor-alpha (TNF-alpha) were measured radioimmunologically in 22 drug-free children-adolescents, 11 with recurrent major depressive disorders (MDD) and 11 with dysthymia (DYS), and in 11 psychophysically healthy age-sex matched controls. Depression was monitored using the Poznanski Rating Scale and Anxiety with the Reynold Rating Scale. RESULTS: Il-1beta levels were not significantly different in MDD from controls and significantly higher than normal in DYS subjects. TNF-alpha levels were not significantly different in MDD patients from controls and significantly lower than normal in DYS patients. Cytokine concentrations were correlated with anxious and depressive symptomatology in MDD but not in DYS patients. CONCLUSIONS: There is a cytokine pathology in depressive disorders of obscure etiopathogenetical significance.

Analysis of IL-1alpha, IL-1beta, and IL-1RA [correction of IL-RA] polymorphisms in dysthymia.

Investigators of independent studies reported alterations in cytokine serum levels in patients with different mood disorders. Several polymorphisms associated with neuropsychiatric disorders such as schizophrenia and Alzheimer's disease have been reported at the interleukin-1 (IL-1) panel. Here we report the results of three specific polymorphisms at the IL-1alpha, IL-1beta, and IL-1RA genes, which were analyzed in 128 Brazilian subjects: 59 dysthymic patients and 69 normal controls. We found a statistically significant difference (p = 0.002) in the frequency of haplotypes with alleles 2+ (IL-1RA), T+ (IL-1alpha), and C+ (IL-1beta) in patients as compared to controls. We also observed that haplotype IL-1RA1.2/IL-1alpha CT/IL-1beta CC, present in 6 dysthymic patients (10%) was absent in the normal control group (p = 0.012). These results suggest that these polymorphisms might confer a greater susceptibility to develop dysthymia in Brazilian patients. However, to validate these data it will be of great interest to repeat this study in larger samples and other ethnic groups.

Lymphocyte proliferation among major depressive and dysthymic patients with typical or atypical features.

BACKGROUND: Depressive illness may be associated with immune and cytokine alterations. However, data are unavailable concerning functional immune changes associated with chronic, low-grade depression (dysthymia). Moreover, the contribution of the neurovegetative features of depression (e.g., altered sleep, eating) to the immune alterations remains to be determined. METHODS: Mitogen-stimulated cell proliferation was assessed in major depressive and dysthymic patients exhibiting either typical or atypical features. In a subset of patients, lymphocyte proliferation was also assessed before and after pharmacotherapy to determine whether alleviation of symptoms would be accompanied by normalization of immune functioning. RESULTS: Lymphocyte proliferation was reduced to a greater extent among dysthymic than among major depressive patients. Among dysthymic patients reduced cell proliferation was evident irrespective of symptom typicality; however, among major depressive patients the contribution of neurovegetative features varied with the specific mitogen used. Symptom alleviation following antidepressant treatment was not accompanied by normalization of cell proliferation. LIMITATIONS: Patients received 12 weeks of antidepressant treatment, and more sustained therapy may be required for normalization of immune activity. As well, conclusions concerning normalization of immune functioning in drug-treated major depressive patients requires that a greater number of patients be assessed. CONCLUSIONS: As the immune variations were more pronounced in dysthymia than in major depression, chronicity of illness may be a pertinent factor in promoting immune disturbances. This does not exclude the possibility that depression is associated with immune activation, which then provokes suppression of other aspects of immunity. As well, it is conceivable that immune alterations indirectly contribute to the symptoms accompanying depressive state, although it does not appear that variations of lymphocyte proliferation are associated with neurovegetative status.

Endocrine and cytokine correlates of major depression and dysthymia with typical or atypical features.

Depression has been associated with both suppression and enhancement of various aspects of immune functioning. It was of interest to determine whether cytokine alterations associated with depression, including interleukin-1 (IL-1beta) and interleukin-2 (IL-2), were related to the neurovegetative symptom profile or to the chronicity of the illness. Circulating ACTH, cortisol, norepinephrine (NE) and epinephrine levels, and production of IL-1beta and IL-2 from mitogen-stimulated lymphocytes were assessed in classical major depression, atypical depression (ie, with reversed neurovegetative features), and dysthymia (chronic depression without comorbid major depression) with either typical or atypical profiles, as well as nondepressed control subjects. Among atypical depressives, plasma ACTH levels were elevated while cortisol was reduced relative to controls. Irrespective of neurovegetative profile, IL-1beta production was increased in dysthymic patients, and was highly correlated with age-of-onset and duration of illness. In contrast, IL-2 production was reduced in each of the groups, although less so among atypical major depressives. Moreover, IL-2 production in the depressive groups was directly related to plasma NE levels. While neither depressed mood per se nor neurovegetative features accounted for this effect, it seemed likely that chronicity of illness or age-of-onset were associated with cytokine alterations. Given that circulating cytokines influence neuroendocrine functioning, and may affect neurovegetative features, a role for interleukins may exist with respect to the pathophysiology of certain subtypes of depression.

Interleukin-1 beta production in dysthymia before and after pharmacotherapy.

BACKGROUND: Like major depression, dysthymia has been associated with elevated production of interleukin-1 (IL-1 beta) in mitogen-stimulated lymphocytes. In the present investigation, we assessed whether the elevated IL-1 beta production in dysthymic patients would normalize following treatment with sertraline. METHODS: The production of IL-1 beta was determined in dysthymic patients and in nondepressed control subjects. Patients then received 12 weeks of doses of either sertraline or placebo in a double-blind trial, after which cytokine production was again determined. RESULTS: Basal IL-1 beta was elevated in dysthymic patients relative to control subjects. Cytokine production was modestly correlated with the severity of symptoms and with the age of illness onset. Relative to placebo treatment, sertraline attenuated the symptoms of depression; however, this was not accompanied by normalization of IL-1 beta production. CONCLUSIONS: While dysthymia is associated with elevated IL-1 beta production, the failure for the cytokine to normalize following symptom alleviation suggests that either the IL-1 beta may be a trait marker of the illness, or that more sustained treatment is necessary to reduce cytokine production. Given the neuroendocrine and central neurochemical consequences of exogenously administered IL-1 beta, the possibility ought to be explored that increased IL-1 beta production may play a role in the pathophysiology of dysthymia.

Circulating lymphocyte subsets in major depression and dysthymia with typical or atypical features.

OBJECTIVE: Inconsistent results have been reported concerning circulating lymphocyte subsets in depression. To establish whether the immune alterations in depression could be related to neurovegetative symptoms, lymphocyte subsets were assessed in major depressive and dysthymic patients who exhibited either typical or atypical features (ie, the latter characterized by mood reactivity and reversed neurovegetative features). METHOD: Blood was collected from major depressive, atypical depressive, typical dysthymic, or atypical dysthymic patients and from nondepressed control subjects. Circulating lymphocyte subsets (CD3, CD4, CD8, CD19, CD16/CD56) were determined by flow cytometry. In a subset of patients, lymphocyte subsets were also determined after a 12-week course of antidepressant medication. RESULTS: Although T and B cell populations did not differ between the depressive subtypes and control subjects, circulating natural killer (NK) cells were elevated in depressive illness, and varied as a function of depressive subtype and sex. Among male patients, NK cells were elevated to a greater extent in typical than in atypical depression, and more so in major depressive than in dysthymic patients. Among female patients, circulating NK cells were lower than in male patients, and only among the typical major depressive patients did NK cells exceed those of controls. Normalization of NK cells occurred with successful pharmacotherapy. CONCLUSIONS: Depression may be associated with elevated levels of circulating NK cells. Although the neurovegetative features associated with depression, particularly altered eating, may have contributed to the elevated NK cells, depressive affect itself also contributed in this respect. However, the relative contributions of these factors varied between male and female patients.

Neuroendocrine measures and lymphocyte subsets in depressive illness: influence of a clinical interview concerning life experiences.

The effects of a clinical interview concerning either positive or negative day-to-day events on lymphocyte subpopulations, and on plasma cortisol, ACTH and norepinephrine, were determined in depressive patients (major depressive and dysthymic) and in normal controls. Irrespective of its content, the interview provoked an elevation of circulating natural killer (NK) cells, suggesting that this effect was related to either a change in mood state (regardless of its valence) or to the stress associated with the interview procedure. Since the interview did not influence plasma cortisol, ACTH or norepinephrine, it is likely that the NK cell variations were independent of these endocrines. Although basal NK cells were elevated in the depressive group relative to controls, the extent of the NK cell increase provoked by the interview was comparable in depressive and control subjects. The failure to detect differences between these populations could not be attributed to ceiling effects precluding more pronounced alterations in the depressed subjects. Indeed, variations of circulating cell subtypes were found to be exquisitely sensitive to differences in stressor intensity. In a subset of control subjects, a more potent stressor (anticipation of an academic examination) increased the plasma endocrine levels, increased circulating NK cell number beyond that associated with the interview stress, and provoked an increase of several T cell subsets (CD3, CD4 and CD8). Evidently, while a clinical interview may be sufficiently stressful to influence circulating NK cells, the stress of such a procedure seems no greater in depressed than in control subjects. It is suggested that although depressed patients may exhibit higher basal NK levels, this effect is likely not related to increased reactivity to stressors.

Variations of lymphocyte subsets associated with stress in depressive populations.

Major depression and dysthymia have been associated with increased perception of day-to-day stressors, greater reliance on emotion-focused coping efforts, and reduced perception of uplifting events. Moreover, it has been observed that levels of circulating natural killer (NK) cells were elevated in depressed patients. Given that mild stressors may increase circulating NK cells, it is conceivable that the elevated NK cells in depression may be secondary to the increased stress perception associated with the illness. In the present investigation a laboratory stressor, comprising a mathematical challenge, increased circulating NK cells; however, the extent of the increase was comparable in depressive, dysthymic and control subjects. Moreover, the increased NK cells induced by the stressor procedure appeared to be independent of variations of plasma cortisol, ACTH or norepinephrine. Interestingly, although the NK changes were not differentially influenced by stressors in the subject populations, in the major depressive patients correspondence existed between NK cell levels and emotion-focused coping styles. Likewise, the response to a laboratory stressor was directly related to the severity of depression and to the use of coping styles involving cognitive restructuring or problem solving.

Primary dysthymia: a study of several psychosocial, endocrine and immune correlates.

The relationship between primary dysthymia (chronic, low grade depression) and indices of major and minor life stresses, uplifts and coping styles was examined. Additionally, circulating lymphocyte subsets were assessed in dysthymic patients to determine their relationship to stress/coping factors or plasma levels of cortisol, ACTH or norepinephrine. Primary dysthymia was found to be associated with increased minor stressors (daily hassles), reduced uplifts, as well as particular reliance on emotion-focused rather than problem-oriented coping strategies. Interestingly, among dysthymics, the early onset group exhibited a greater degree of hassles and greater emotion-focused coping compared to the late onset subgroup. Although hassles and coping styles were correlated with depressed mood, only coping styles predicted severity of depressed affect. It seems that although dysthymia is characterized by increased hassles and reduced uplifts, these variables do not distinguish between the severity of the depressive affect, whereas the coping styles employed in the face of the increased hassles and reduced uplifts are more closely aligned with depression severity. Dysthymia was associated with elevated levels of circulating natural killer (NK) cells. Since levels of plasma cortisol, ACTH or norepinephrine were not increased in the dysthymic subjects, it is likely that the elevated NK cell number was unrelated to these neuroendorcrine measures. In control subjects circulating NK cells were inversely related to the severity of hassles recently encountered, while in dysthymic patients stress and coping factors were unrelated to NK cell numbers. Thus, it appears that the altered NK cells in dysthymic patients were not related to the increased stress perception and altered coping which characterize these patients.

Increased serum interleukin-1-receptor-antagonist concentrations in major depression.

Recently, it has been shown that major depression may be accompanied by an increased production of interleukin-1 beta (IL-1 beta), an acute phase (AP) response and simultaneous signs of activation and suppression of cell-mediated immunity. The interleukin-1-receptor antagonist (IL-1-rA) is released in vivo during an AP response and serum levels are increased in many immune disorders. The release of IL-1-rA may limit the pro-inflammatory effects of IL-1. This study has been carried out to examine serum IL-1-Ra in 68 depressed subjects (21 minor, 25 simple major and 22 melancholic subjects) vs. 22 normal controls. Depressed subjects showed significantly higher serum IL-1-rA concentrations than healthy controls. 29% of all depressed subjects had serum IL-1-rA levels higher than the mean value +2 standard deviations of normal controls; 44% depressed subjects had IL-1-rA values greater than 0.215 ng/ml with a specificity of 90%. In depressed subjects, there was a significant and positive relationship between serum IL-1-rA and severity of illness. In depression, there were no significant relationships between serum IL-1-rA concentrations and indicants of hypothalamic-pituitary-adrenal (HPA)-axis activity, such as 24-h urinary cortisol and postdexamethasone cortisol values. Women had significantly higher serum IL-1-rA levels than men. The findings support the thesis that depression is accompanied by an immune-inflammatory response.