Jenna Griffiths

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-1β) 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-1β 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-1β 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.

A prospective study of neuroendocrine and immune alterations associated with the stress of an oral academic examination among graduate students

Stressful experiences may influence neuroendocrine, immune and cytokine functioning, as well as physical and psychological well being. The present prospective investigation assessed physiological and behavioral variations in anticipation of a critical oral academic examination among graduate students (i.e. related to a dissertation or comprehensive defense). Relative to matched control subjects, plasma cortisol levels were elevated among graduate students, especially females, 1 h prior to the oral examination, but not 6-8 weeks earlier (at about the time of the submission of the written document). In contrast, mitogen-stimulated (Con-A) lymphocyte proliferation was only reduced 6-8 weeks before the examination. Neither adrenocorticotrophic hormone (ACTH), prolactin, serum interleukin-1beta (IL-1beta) nor mitogen stimulated IL-1beta production was influenced at any time. Although, graduate students did not differ from controls with respect to perceived stress and feelings of mastery, they reported more frequent malaise (e.g. headaches, sore throat, fatigue) than did controls. The present findings suggest that during the course of lengthy anticipatory periods preceding a scheduled stressor, different stress-sensitive, situation-dependent biological processes may be engendered. It is further suggested that cortisol release is most closely aligned with immediate threats, while the immune alterations are sensitive to more distal events, or are subject to adaptation in response to a protracted stressor.

Interleukin-1β production in dysthymia before and after pharmacotherapy

Abstract Background: Like major depression, dysthymia has been associated with elevated production of interleukin-1 (IL-1β) in mitogen-stimulated lymphocytes. In the present investigation, we assessed whether the elevated IL-1β production in dysthymic patients would normalize following treatment with sertraline. Methods: The production of IL-1β 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-1β 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-1β production. Conclusions: While dysthymia is associated with elevated IL-1β production, the failure for the cytokine to normalize following symptom alleviation suggests that either the IL-1β 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-1β, the possibility ought to be explored that increased IL-1β production may play a role in the pathophysiology of dysthymia.

Stressful life events and coping styles in relation to dysthymia and major depressive disorder : variations associated with alleviation of symptoms following pharmacotherapy

1. Both major depression and dysthymia (chronic, low grade depression) were associated with increased reports of minor stressors (daily hassles), and feelings of loneliness, reduced uplifts, as well as the use of inappropriate coping strategies (i.e., emotion-focussed rather than problem-oriented coping). 2. Although major depressive and dysthymic patients shared several features with respect to symptomatology, dysthymics tended to report a greater number of hassles than major depressives. 3. Treatment with serotonin reuptake inhibitors over an 8-week period resulted in a marked alleviation of the depressive symptoms in both patient groups, although the clinical effectiveness of the drugs appeared somewhat later in dysthymics. 4. The attenuation of the depressive symptoms was accompanied by a modest, but significant diminution in reports of minor stressors, while the perception of uplifts remained unchanged. Moreover, recovery from depression was associated with changes in coping style, such that patients relied less on inappropriate emotion-focussed coping strategies.

Dysthymia: a review of pharmacological and behavioral factors

Although dysthymia, a chronic, low-grade form of depression, has a morbidity rate as high as that of major depression, and increases the risk for major depressive disorder, limited information is available concerning the etiology of this illness. In the present report we review literature concerning the biological and characterological features of dysthymia, the effectiveness of antidepressant treatments, the influence of stressors in the precipitation and maintenance of the disorder, and both quality of life and psychosocial correlates of the illness. We also provisionally suggest that dysthymia may stem from disturbances of neuroendocrine and neurotransmitter functioning (eg, corticotropin releasing hormone and arginine vasopressin within the hypothalamus, or alternatively monoamine variations within several extrahypothalamic sites), and may also involve cytokine activation. The central disturbances may reflect phenotypic variations of neuroendocrine processes or sensitization of such mechanisms. It is suggested that chronic stressor experiences or stressors encountered early in life lead to the phenotypic neurochemical alterations, which then favor the development of the dysthymic state. Owing to the persistence of the neurochemical disturbances, vulnerability to double depression is increased, and in this instance treatment with antidepressants may attenuate the symptoms of major depression but not those of the basal dysthymic state. Moreover, the residual features of depression following treatment may be indicative of underlying neurochemical disturbances, and may also serve to increase the probability of illness recurrence or relapse.

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.

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.

Circulating lymphocyte subsets in obsessive compulsive disorder, major depression and normal controls

BACKGROUND Obsessive compulsive disorder (OCD) shares several features with depressive illness (e.g., comorbidity, early escape from dexamethasone suppression, effectiveness of serotonergic pharmacotherapy). It was of interest to establish whether OCD, like major depression, was also associated with immune alterations, notably elevations of circulating natural killer (NK) cells. METHOD Circulating lymphocytes were determined from morning blood samples taken from OCD and major depressive patients, as well as from age- and sex-matched controls. Stress perception and coping styles were evaluated in order to assess whether such variables accompanied the NK alterations. Finally, in a subset of patients, symptoms of the illness, stress/coping, and circulating lymphocytes, were also evaluated following 12 weeks of antidepressant medication (serotonergic reuptake inhibitor). RESULTS The major depressive and OCD patients reported increased perception of day-to-day stresses, coupled with reliance on emotion focused coping styles. Moreover, circulating NK cells were elevated among male OCD and major depressive patients, whereas only a modest increase of NK cells was seen in female major depressives. Twelve weeks of medication alleviated depressive and OCD symptoms, and resulted in normalization of NK cells in the major depressives. However, in OCD patients the reduction of symptoms was not accompanied by significant variations of circulating NK cells. CONCLUSIONS Although major depression and OCD are both accompanied by elevated circulating NK cells, at least in males, normalization of NK cells following treatment was only evident in depression. The persistent elevations of NK cells among male OCD patients may reflect either a trait characteristic of the illness, or symptom reduction and not true remission. LIMITATIONS Although elevations of lymphocyte subsets in major depressive and OCD patients were observed, conclusions concerning immune status in OCD ought to be held in abeyance pending assessment of other indices of immune and cytokine functioning.

Influence of acute tryptophan depletion on mood and immune measures in healthy males

Depressive illness has been associated with variations of several aspects of immune functioning, as well as alterations of cytokine production in stimulated lymphocytes. In the present investigation we sought to determine whether pharmacologically-induced reductions of mood in healthy, male subjects would be associated with alterations in the levels of circulating IL-1 beta or IL-6 or to in vitro lymphocyte proliferation in response to T cell mitogens, PHA and Con A. Lowering tryptophan levels by means of a tryptophan-deficient amino acid mixture, which reduced plasma tryptophan and serotonin (5-HT) levels, produced a lowering of mood in a subset of male subjects (that had no personal or family history of depression) relative to subjects that received a balanced amino acid mixture. Correlational analyses revealed that the change of mood (particularly depression and anger) in subjects that received the tryptophan-free mixture was related to the extent of the tryptophan or 5-HT reductions. However, while fenfluramine administration resulted in recovery of tryptophan and 5-HT levels, this was not accompanied by recovery of mood. Furthermore, it was observed that the lowering of tryptophan levels and the reduced mood were not accompanied by variations of the cytokine levels or cell proliferation. Evidently, transient and modest alterations of 5-HT or mood induced by a tryptophan-free amino acid mixture were insufficient to promote variations of immune activity or circulating IL-1 beta or IL-6 levels. Even if depression were related to immune disturbances, the mood and 5-HT alterations associated with this type of manipulation may be too brief to promote immune changes comparable with those ordinarily associated with severe or chronic depressive illness.

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.