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.

Changes in cytokine and chemokine expression distinguish dysthymic disorder from major depression and healthy controls.

An important area of uncertainty is the inflammatory degree to which depression occurring as part of dysthymic disorder may differ from major depression. Using a 27-plex cytokine assay, we analyzed the serum of 12 patients with dysthymic disorder, 12 with major depression, and an age-, sex-, and body mass index-matched control group of 20 healthy volunteers. We observed that patients with dysthymic disorder exhibited aberrant cytokine and chemokine expression compared with healthy controls and patients with major depression. The levels of interferon-γ-induced protein 10 highly predicted dysthymic disorder. Network analyses revealed that in patients with dysthymic disorder, the vertices were more sparsely connected and adopted a more hub-like architecture, and the connections from neighboring vertices of interleukin 2 and eotaxin-1 increased. After treatment with the same antidepressant, there was no difference between dysthymic disorder and major depression regarding any of the cytokines or chemokines analyzed. For dysthymic disorder, changes in the levels of interferon-γ-induced protein 10 and macrophage inflammatory protein-1α correlated with depression improvement. The findings suggest that the cytokine milieu in dysthymic disorder differs either at the level of individual expression or in network patterns. Moreover, chemokines play an important role in driving the pathophysiology of dysthymic disorder.

Discovery of serum biomarkers predicting development of a subsequent depressive episode in social anxiety disorder.

Although social anxiety disorder (SAD) is strongly associated with the subsequent development of a depressive disorder (major depressive disorder or dysthymia), no underlying biological risk factors are known. We aimed to identify biomarkers which predict depressive episodes in SAD patients over a 2-year follow-up period. One hundred sixty-five multiplexed immunoassay analytes were investigated in blood serum of 143 SAD patients without co-morbid depressive disorders, recruited within the Netherlands Study of Depression and Anxiety (NESDA). Predictive performance of identified biomarkers, clinical variables and self-report inventories was assessed using receiver operating characteristics curves (ROC) and represented by the area under the ROC curve (AUC). Stepwise logistic regression resulted in the selection of four serum analytes (AXL receptor tyrosine kinase, vascular cell adhesion molecule 1, vitronectin, collagen IV) and four additional variables (Inventory of Depressive Symptomatology, Beck Anxiety Inventory somatic subscale, depressive disorder lifetime diagnosis, BMI) as optimal set of patient parameters. When combined, an AUC of 0.86 was achieved for the identification of SAD individuals who later developed a depressive disorder. Throughout our analyses, biomarkers yielded superior discriminative performance compared to clinical variables and self-report inventories alone. We report the discovery of a serum marker panel with good predictive performance to identify SAD individuals prone to develop subsequent depressive episodes in a naturalistic cohort design. Furthermore, we emphasise the importance to combine biological markers, clinical variables and self-report inventories for disease course predictions in psychiatry. Following replication in independent cohorts, validated biomarkers could help to identify SAD patients at risk of developing a depressive disorder, thus facilitating early intervention.

Comparison of steady state development and reduction of menopausal symptoms after oral or transdermal delivery of 17-ß-estradiol in young healthy symptomatic menopausal women.

OBJECTIVE: There is a renewed interest in the delivery of estradiol (E2) for the reduction of menopausal symptoms in young symptomatic menopausal women. This paper compares experimentally and theoretically obtained E2 plasma values by oral and transdermal delivery and compares them with relevant menopausal symptoms. STUDY DESIGN: Two independent previously published studies were compared, which each contained 42 young symptomatic menopausal women. Experimentally obtained plasma values at days 1, 7 and 21 were compared with a theoretical model, taken from the literature, for describing plasma values for an oral immediate release formulation, consecutively for 21 days. Menopausal symptoms were determined in the steady state for oral and transdermal delivery with the Kuppermann index, previously not reported. In the case of oral delivery, estradiol was compared with estradiol valerate. RESULTS: Previously published results for transdermal delivery of E2 showed that the matrix system establishes a steady state condition with the application of the first patch. Excellent agreement between theoretically predicted and experimentally obtained E2 plasma values for oral delivery in menopausal women was obtained. Circadian E2 plasma levels were observed continuously for transdermal delivery, were seen in oral delivery during first application and disappeared when steady state was achieved. Application of the prodrug E2-valerate delayed the maximum plasma peak from 1 pm to 4 pm, similar to the transdermal matrix patch. Investigating menopausal symptoms determined with the Kuppermann index did not reveal differences between oral or transdermal "E2 kinetic (hot flushes) relationship". This relationship was similar to symptomatic women suffering from hot flushes in untreated menopausal women or premenopausal women. Different menopausal symptoms required different E2 plasma levels: the average E2 levels higher than 23 pg/mL in plasma did abolish insomnia in 50% of postmenopausal women, with 28 pg/mL is needed to suppress 50% of dysthymia; however, rather high levels of 41 pg/mL are needed to suppress 50% of hot flushes, suggesting a rather complex mechanism beyond an E2 receptor mediated process. CONCLUSION: There is a difference in the steady state between oral and transdermal E2 delivery. Steady state condition is achieved in the first application of a matrix patch, whereas with the application of a tablet the steady state is achieved in transdermal delivery within 12-14 days. Our reported calculated missed intake of a E2 tablet shows that E2 plasma levels drop for 4 days consecutively. Our conducted study has several limitations: firstly, no cross-over was conducted, but a rather cumbersome mathematical modeling; secondly, healthy women with no accompanying severe diseases were included in this study. The higher the oral dose, the higher the E2 steady state levels, but the time to achieve steady state levels is independent from the E2 dose.

Plasma levels of brain-derived neurotrophic factor and interleukin-6 in patients with dysthymic disorder: comparison with age- and sex-matched major depressed patients and healthy controls.

In the present study, we investigated the serum BDNF levels and plasma IL-6 levels in patients with dysthymic disorder, major depressive disorder and control subjects. Eighteen patients who met the DSM-IV criteria (American Psychiatric Association, 1994) for dysthymic disorder (male/female: 5/13; age: 36 ± 9 year) and 20 patients (male/female: 7/13; age: 38 ± 10 year) who met the criteria for major depressive disorder were enrolled. The serum BDNF levels in patients with dysthymic and major depressive disorder were significantly lower than those in the control subjects. However, no difference was found between the dysthymic group and major depression group. The plasma IL-6 levels in the dysthymic group and major depression group were significantly higher than those in the control group. No difference was observed in the plasma IL-6 levels between the dysthymic group and major depression group. These results suggest that the pathophysiology of dysthymic disorder and major depression might be similar in terms of the blood levels of BDNF and IL-6.

Pessimistic, anxious, and depressive personality traits predict all-cause mortality: the Mayo Clinic cohort study of personality and aging.

OBJECTIVE: To study the association between several personality traits and all-cause mortality. METHODS: We established a historical cohort of 7216 subjects who completed the Minnesota Multiphasic Personality Inventory (MMPI) for research at the Mayo Clinic from 1962 to 1965, and who resided within a 120-mile radius centered in Rochester, MN. A total of 7080 subjects (98.1%) were followed over four decades either actively (via a direct or proxy telephone interview) or passively (via review of medical records or by obtaining their death certificates). We examined the association of pessimistic, anxious, and depressive personality traits (as measured using MMPI scales) with all-cause mortality. RESULTS: A total of 4634 subjects (65.5%) died during follow-up. Pessimistic, anxious, and depressive personality traits were associated with increased all-cause mortality in both men and women. In addition, we observed a linear trend of increasing risk from the first to the fourth quartile for all three scales. Results were similar in additional analyses considering the personality scores as continuous variables, in analyses combining the three personality traits into a composite neuroticism score, and in several sets of sensitivity analyses. These associations remained significant even when personality was measured early in life (ages 20-39 years). CONCLUSIONS: Our findings suggest that personality traits related to neuroticism are associated with an increased risk of all-cause mortality even when they are measured early in life.

Adjunctive lithium treatment in the prevention of suicidal behaviour in depressive disorders: a randomised, placebo-controlled, 1-year trial.

OBJECTIVE: Evidence based on controlled studies is still limited for treatment strategies that prevent recurrence of suicide attempts. Findings from observational as well as meta-analytic studies strongly suggest that lithium may have suicide-protective properties. METHOD: Patients with a recent suicide attempt in the context of an affective spectrum disorder (n = 167) were treated with either lithium or placebo during a 12-month period. RESULTS: Survival analysis showed no significant difference of suicidal acts between lithium and placebo-treated individuals (adjusted hazard ratio 0.517; 95% CI 0.18-1.43). However, post hoc analysis revealed that all completed suicides had occurred in the placebo group accounting for a significant difference in incidence rates (P = 0.049). CONCLUSION: Results indicate that lithium treatment might be effective in reducing the risk of completed suicide in adult patients with affective disorders. Our findings contribute to the growing body of evidence suggesting a specific antisuicidal effect of lithium.

ROC analysis of dexamethasone suppression test threshold in suicide prediction after attempted suicide.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis function is associated with suicidal behavior. In suicide attempters with mood disorder, the non-suppressor status in the dexamethasone suppression test (DST) is associated with suicide indicating that HPA-axis hyperactivity is a biological risk factor for suicide and may be a useful predictor. The threshold of 5 microg/dl for cortisol levels measured at 08:00 a.m. or 4:00 p.m. following dexamethasone at 11:00 p.m. to define the DTS nonsuppression was derived as being optimal for the separation of melancholia and nonmelancholic conditions rather than the prediction of suicide. A different threshold may offer a better identification of suicide. The aim of this study was to find the optimal threshold level of post DST plasma cortisol at 4 p.m. for suicide prediction using receiver operating characteristics (ROC) analysis. A cohort of 106 depressed inpatients with an index suicide attempt admitted to the department of Psychiatry at the Karolinska University Hospital between 1980 and 2000, were submitted to DST and followed up for causes of death. During the follow-up (mean 17 years), 25 suicides (24%) were identified. The ROC analysis revealed that a lower threshold of 3.3 microg/dl for the nonsuppressor status predicted 17 of 25 suicides (sensitivity of 68%) compared with 15 of 25 suicides (sensitivity 60%) with a conventional threshold of 5 microg/dl at 4:00 p.m. In male suicide attempters the lower threshold for pathological DST result (3.3 microg/dl) changed the Odds ratio from 6.7 till 18. In female suicide attempters a higher threshold (7.3 microg/dl) optimised the value of DST as a biological test for suicide prediction indicating a gender difference.

Prenatal dysthymia versus major depression effects on maternal cortisol and fetal growth.

To determine differences between pregnant women diagnosed with Dysthymia versus Major Depression, depressed pregnant women (N=102) were divided by their diagnosis into Dysthymic (N=48) and Major Depression (N=54) groups and compared on self-report measures (depression, anxiety, anger, daily hassles and behavioral inhibition), on stress hormone levels (cortisol and norepinephrine), and on fetal measurements. The Major Depression group had more self-reported symptoms. However, the Dysthymic group had higher prenatal cortisol levels and lower fetal growth measurements (estimated weight, femur length, abdominal circumference) as measured at their first ultrasound (M=18 weeks gestation). Thus, depressed pregnant women with Dysthymia and Major Depression appeared to have different prenatal symptoms.

Neuropsychological correlates of homocysteine levels in euthymic bipolar patients.

BACKGROUND: We have previously reported that homocysteine levels are elevated in euthymic bipolar patients with functional deterioration. The current study was designed to extend this finding by examining the relationship between neuropsychological functioning and homocysteine levels in euthymic bipolar patients. METHODS: Fifty-seven euthymic bipolar outpatients were assessed for serum levels of homocysteine, folic acid, and vitamin B-12 and administered a battery of neuropsychological tests. RESULTS: We found that male bipolar subjects showed higher average homocysteine levels than a comparison group of normal subjects, that poorer functioning on a task of executive function (Wisconsin Card Sort) was related to higher homocysteine levels, and that folic acid or vitamin B-12 levels did not significantly affect neuropsychological functioning. LIMITATIONS: These results, while suggesting some relationship between higher homocysteine levels, bipolar illness, and impairment in cognitive function do not establish any causative effects. CONCLUSIONS: The findings of this study confirm that in euthymic bipolar patients, higher homocysteine levels are associated with poorer performance in some neuropsychological tests. Treatment trials will be required before it will be known if the putative decrements in the executive function of bipolar patients can be reversed, or at least retarded, if homocysteine levels are reduced (as, for example, by dietary addition of B vitamin supplements).

Leptin in depressed women: cross-sectional and longitudinal data from an epidemiologic study.

BACKGROUND: There is conflicting evidence regarding levels of leptin in depression. In this study we aimed to investigate the relationship between serum leptin level and depression in a community sample of women using both cross-sectional and longitudinal data. METHODS: From among 510 women aged 20-78 yr, 83 were identified with a lifetime history of major depressive disorder or dysthymia, ascertained using the Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition (SCID-I/NP). Serum leptin levels were measured by radioimmunoassay. Medication use and lifestyle were self-reported and body mass index (BMI) determined from measures of height and weight. RESULTS: Using multiple linear regression, serum leptin levels were greater among women with a lifetime history of depression compared to women without any history of depression, independent of BMI. Adjusted geometric mean values of serum leptin were 16.37 (95%CI 14.70-18.23) ng/mL for depressed and 14.46 (95%CI 13.79-15.16) ng/mL for non-depressed women (P=0.039). The hazard ratio (HR) for a de novo depressive disorder over five years increased 2.56-fold for each standard deviation increase in log-transformed serum leptin among non-smokers and this was not explained by differences in BMI, medications or other lifestyle factors (HR=2.56, 95%CI 1.52-4.30). No association was observed for smokers. LIMITATIONS: There is potential for unrecognised confounding, recall bias and transient changes in body composition. CONCLUSION: Women with a lifetime history of depression have elevated levels of serum leptin, and elevated serum leptin predicts subsequent development of a depressive disorder.

Serum brain-derived neurotrophic factor level in dysthymia: a comparative study with major depressive disorder.

In this present work, it is aimed to demonstrate BDNF serum concentrations in patients with dysthymia and to compare them with BDNF serum concentrations in patients with major depressive disorder and healthy subjects. The study was carried out in Celal Bayar University Hospital, Manisa, Turkey. Seventeen patients with dysthymia, 24 patients with major depressive disorder and 26 subjects without any psychiatric diagnosis and any psychiatric treatment were included in the study. The severity of depression was assessed with 17-item HAM-D. All subjects were asked to give their written consent. Blood samples were collected at baseline. Serum BDNF was kept at -70 degrees C before testing, and assayed with an ELISA Kit (Promega; Madison, WI, USA), after dilution with the Block and Sample solution provided with the kit. The data were subjected to the analysis of variance. The BDNF serum concentrations of the dysthymia group (mean=28.9+/-9.2 ng/ml) were significantly higher than that of the major depressive disorder group (21.2+/-11.3 ng/ml) (p=0.002), and it was not different from the level of the control group (31.4+/-8.8 ng/ml). BDNF serum concentrations and HAM-D score did not have any significant correlation in the dysthymia and major depression groups (r=-0.276, p=0.086). The low level of BDNF in patients with dysthymic disorder seems to point out that BDNF changes in mood disorders are state-dependent and vary according to the severity of depressive episodes.

Plasma testosterone and dehydroepiandrosterone sulfate in male and female patients with dysthymic disorder.

BACKGROUND: Depressive symptomatology has been connected with an activation of the hypothalamus-pituitary-adrenal axis and, in several studies, with reduced androgen levels, while administration of androgens, usually in older subjects, may have positive effects on mood, both in males and females. Regarding dysthymic disorder (DD), low serum testosterone levels have been reported in older males, while information on younger male or on female patients is lacking. METHODS: We assessed the serum levels of testosterone (T), dehydroepiandrosterone sulfate (DHEAS) and cortisol in male and female patients with DD, and compared them to the levels of sex and age matched controls. Eighteen male and 43 female patients in the age range of 22 to 71 years were studied and diagnosed according to the Scheduled Diagnostic Interview for DSM-IV axis I disorders (SCID). Depressive symptomatology was assessed using the Hamilton Depression Rating Scale. Subgroups with subjects below or over 50 years of age were also built and compared. RESULTS: Serum T levels were lower than controls mainly in the subjects aged below 50 years, in both genders. More pronounced were reductions in DHEAS levels both in male and female patients, while cortisol levels were normal or reduced. T levels were positively correlated to both DHEAS and cortisol. The negative correlations of DHEAS and T to age were significant for all groups and subgroups, except in the group of male patients. Four male patients (22%) had T levels below 2.0 ng/ml. CONCLUSIONS: Male and female patients with DD aged below 50 years show reduced gonadal and adrenal androgen levels, and normal to low cortisol levels. These neuroendocrine characteristics differentiate DD from depression, and place this diagnostic group closer to posttraumatic stress disorder.

Divalproex sodium reduces overall aggression in youth at high risk for bipolar disorder.

INTRODUCTION: The psychopharmacology of aggression in youth is relatively unexplored, even though such maladaptive aggression manifests across many different diagnoses. METHODS: This study was a 12-week, open-label trial with divalproex sodium (DVPX) in 24 bipolar offspring 6-18 years of age (mean age = 11.3 years; 17 boys) with mixed diagnoses of major depression, cyclothymia, attention-deficit/hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD). The Overt Aggression Scale (OAS) was used to measure aggression in 4-week intervals. We measured serum gamma-butyric acid (GABA) and glutamate levels at baseline and week 12. RESULTS: Seventy-one percent of evaluable subjects were considered responders to DVPX treatment by the OAS. There was a significant correlation between the Young Mania Rating Scale (YMRS) and OAS scores at week 0 (p = 0.036) and week 12 (p = 0.025). Serum DVPX level did not correlate with treatment response. CONCLUSIONS: These youths who are at high risk for bipolar disorder experienced an overall decrease in aggressive behavior in response to DVPX. Age or gender did not predict a positive response to DVPX. This study is the first report of treatment efficacy of a mood stabilizer for aggression in youth at high risk for bipolar disorder.

Defining the boundaries of atypical depression: evidence from the HPA axis supports course of illness distinctions.

BACKGROUND: Treatment outcome and brain laterality differ between early onset (<20 years) chronically (no well-being >2 months) depressed patients with atypical features (early/chronic atypical) and those with either later onset or less chronic illness (late/nonchronic atypical). Because hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been hypothesized to distinguish atypical depression from melancholia, we examined whether HPA measures would also differentiate these two groups of depressed patients with atypical features. METHODS: Three-hour afternoon cortisol levels, stimulation of cortisol by afternoon dextroamphetamine, and suppression of cortisol by dexamethasone were investigated in 85 depressed patients with atypical features. The latter group was divided into early/chronic atypical and late/nonchronic atypical based on chart review of course of illness. RESULTS: Patients with early/chronic atypical had significantly lower mean 3 h afternoon cortisol levels (N=21) and 4:00 p.m. post-dexamethasone cortisol levels (N=20) than did those with late/nonchronic atypical (N=43 with afternoon cortisol; N=26 with post-dexamethasone cortisol). Post-dextroamphetamine cortisol levels were numerically higher in the early/chronic atypical group (N=15 vs. 19), but this failed to reach conventional significance (0.05

The dexamethasone suppression test as a predictor of suicidal behavior in unipolar depression.

BACKGROUND: Non-suppression on the dexamethasone suppression test (DST) in unipolar depression has been found to be associated with completed suicide, with less consistent data for attempted suicide and hospitalizations for suicidality. The purpose of this study was to examine DST non-suppression as a predictor of these three aspects of suicidal behavior. METHODS: Records were reviewed for 101 patients who met criteria for major depressive disorder and/or dysthymic disorder and had a DST performed. All patients were treated naturalistically and were followed for an average of 2 years. DST suppressors and non-suppressors were compared with respect to three outcomes: (1) completed suicide; (2) attempted suicide; and (3) hospitalizations for suicidality. RESULTS: DST non-suppressors were significantly more likely to have completed suicide or be hospitalized for suicidality than DST suppressors, with a non-significant trend for attempts. Total suicidal events were also significantly more frequent in the non-suppressor group. LIMITATIONS: Axis II diagnoses and severity of illness were not assessed. Knowledge of DST results may have influenced the decision to hospitalize patients. CONCLUSIONS: DST non-suppression identifies unipolar depressed patients with a higher risk for future suicide completion or hospitalization for suicidality. Performance of DST upon initiation of treatment may be a useful adjunct in identifying suicidal risk.

Low yield of thyroid-stimulating hormone testing in elderly patients with depression.

Although hypothyroidism is purportedly an important cause of depression, prior studies have involved small samples of young people and produced conflicting results. We examined the yield of thyroid-stimulating hormone (TSH) testing in a large group of elderly patients with major depression or dysthymic disorder. The study sample comprised 883 outpatients aged 60 years or older from 18 primary care sites enrolled in the intervention arm of a clinical trial of depression management. Thyroid function was assessed by a single TSH value. Depressive diagnoses were confirmed with the Structured Clinical Interview for DSM-IV (SCID) and depression severity was assessed with the HSCL-20, a modified depression scale of the Hopkins Symptom Checklist. TSH results were available for 725 (82.1%) participants. Although 32 (4.4%) of those tested had TSH>5 mIU/L, the vast majority (27/32) had marginally elevated results (5.1-9.4 mIU/L). Only five patients (0.7%) had TSH levels >10 mIU/L. Patients with elevated TSH did not differ from those with TSH < or = 5 mIU/L in the severity or symptom pattern of depression as measured by the baseline HSCL-20 score (P=.37) or SCID score (P=.44). These findings should caution physicians against acceptance of borderline TSH values as the primary cause of a patient's clinical depression.

Lipid and lipoprotein levels in depressive disorders with melancholic feature or atypical feature and dysthymia.

The purpose of the present study was to explore the relationship between serum lipid and lipoprotein levels and clinical subtypes in patients with depressive disorders. A total of 207 patients who were admitted for general health screening were assessed by using the semistructured clinical interview for Diagnostic and Statistical Manual of Mental Disorders (4th edn; DSM-IV) criteria for the possibility of having depressive disorders. Blood and physical examinations were done to rule out systemic diseases. A total of 142 patients without systemic diseases was recruited for further analysis, including dysthymia (n = 35), major depressive disorder with melancholic feature (n = 22), major depressive disorder with atypical feature (n = 46) and normal controls (n = 39). Analysis of covariance after age adjustment reveals significant differences in patients with melancholic feature and patients with atypical feature in serum concentrations of triglyceride (TG) and very-low-density-lipoprotein cholesterol (VLDL) in men, and high-density-lipoprotein cholesterol (HDL) in women. This suggests that the TG, VLDL and HDL levels might be used as biological markers to differentiate between major depressive patients with melancholic feature or atypical feature.

Low testosterone levels in elderly men with dysthymic disorder.

OBJECTIVE: A decline in hypothalamic-pituitary-gonadal (HPG) axis function is often seen in elderly men, and dysthymic disorder is common. Symptoms of both HPG axis hypofunction and dysthymic disorder include dysphoria, fatigue, and low libido. The authors compared total testosterone levels in three groups of elderly men. METHOD: Total testosterone levels were measured in subjects who met DSM-IV criteria for major depressive disorder (N=13) or dysthymic disorder (N=32) and a comparison group (N=175) who had participated in an epidemiological study of male aging and had scored below the median on the Center for Epidemiologic Studies Depression Scale, a well-validated, self-report depression symptom inventory. RESULTS: There were no differences among the three groups in measured demographic variables, including age and weight. Median testosterone levels varied for those with dysthymic disorder (295 ng/dl), major depressive disorder (425 ng/dl), and no depression (423 ng/dl). A test for differences in central tendency showed a statistically significant difference among the three groups. Post hoc pairwise comparisons revealed statistically significant differences between those with dysthymic disorder and those with major depressive disorder and no depression. CONCLUSIONS: Total testosterone levels were lower in elderly men with dysthymic disorder than in men with major depressive disorder and men without depressive symptoms. Dysthymic disorder in elderly men may be related to HPG axis hypofunction.

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.