Eduard Suy

Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-adrenal axis in severe depression

Recent studies from this laboratory have provided some evidence that major depression, in particular melancholia, may be accompanied by an immune response. The present study was designed to investigate whether severe depression is characterized by increased interleukin-6 (Il-6) activity and whether Il-6 production is related to altered levels of acute phase reactants and to abnormal function of the hypothalamic-pituitary-adrenal (HPA) axis. Measurements were made in 8 healthy control subjects and 24 depressed inpatients of Il-6 production in culture supernatants of mitogen-stimulated peripheral leukocytes and plasma levels of haptoglobin (Hp), transferrin (Tf), and postdexamethasone cortisol. Il-6 activity was significantly higher in melancholic subjects than in healthy control subjects and in patients with minor depression or nonmelancholic major depression. Il-6 production was significantly correlated with Hp (positively) and Tf (negatively) plasma levels. There were significant and positive correlations between Il-6 activity and postdexamethasone cortisol values. The findings may suggest that increased Il-6 activity in severe depression is related to hypotransferrinemia, hyperhaptoglobinemia, and hyperactivity of the HPA axis.

Depression-related disturbances in mitogen-induced lymphocyte responses and interleukin-1β and soluble interleukin-2 receptor production

In an attempt to delineate the pathophysiology underpinning the previously reported blunted lymphocyte responses to mitogenic stimulation in depressed patients, we measured the following immune variables in 28 depressives and 10 healthy controls: pre‐ and postdexamethasone (1 mg orally) lymphocyte responses to various mitogens, such as phytohaemagglutinin (PHA), and the PHA‐induced accumulation of interleukin‐1β (Il‐1β) and soluble interleukin‐2‐receptors (sIl‐2Rs) in culture supernatants. In the predexamethasone state, we found significantly more mitogen‐stimulated blastogenesis in minor depressives vs healthy controls and major depressives. In depressed subjects there was a significant inverse relationship between the severity of illness and the mitogen‐induced lymphocyte responses. Melancholics exhibited significantly more Il‐1β accumulation in PHA culture supernatant than healthy controls. In healthy controls – but not in depressed patients – the sIl‐2R accumulation perfectly reflects the magnitude of the PHA‐induced lymphocyte stimulation. Dexamethasone administration significantly suppressed the lectin‐induced blastogenesis and the Il‐1β production rate in normal volunteers, whereas depressives exhibited dexamethasone nonsuppression in those factors. Healthy controls exhibited significantly less postdexamethasone blast transformation, Il‐1β and sIl‐2Rs accumulation in culture supernatant than the depressed patients.

Relationships between lower plasma L-tryptophan levels and immune-inflammatory variables in depression

Despite much research, the pathophysiology underlying lower L-tryptophan (L-TRP) availability in major depression has remained elusive. The present study investigates whether lower L-TRP availability in major depression is related to immune activation which may occur in that illness and is known to modulate L-TRP metabolism. Toward this end, the authors have measured the following in depressed patients and normal control subjects: plasma levels of L-TRP, and the competing amino acids (CAA) valine, leucine, isoleucine, tyrosine, and phenylalanine, together with indices of immune function such as haptoglobin (Hp) and transferrin (Tf) plasma levels, dipeptidyl peptidase IV (DPP IV) serum activity, and mitogen-induced culture supernatant interleukin-6 (Il-6) production. Both plasma levels of L-TRP and the L-TRP/CAA ratio were significantly lower in major depressed subjects as compared with healthy control subjects. There were significant correlations between plasma L-TRP levels, on the one hand, and Tf plasma levels, DPP IV activity (both positive), Il-6 production, and Hp plasma levels (both negative), on the other. Up to 63.7% of the variance in L-TRP plasma concentrations could be explained by DPP IV, Hp, Il-6 values, and gender. Up to 50% of the variance in the L-TRP/CAA ratio could be explained by Hp values (negative correlation) and gender. It is hypothesized that lower plasma L-TRP availability in major depression may be related to the immune response in that illness.

Disturbances in acute phase plasma proteins during melancholia: Additional evidence for the presence of an inflammatory process during that illness

1. Leukocyte enumeration through flow cytometry has revealed that severe depression may be accompanied by a systemic immune activation, indicative of an inflammatory response. The latter condition allegedly involves an important modification of acute phase plasma protein (APP) equilibrium. 2. In order to elucidate whether the state of severe depression is represented by alterations in APPs, the authors measured: alpha 1 antitrypsin (alpha 1 AT), alpha 2 macroglobulin (alpha 2 M), haptoglobin (Hp), alpha 1 acid glycoprotein (alpha 1 S), transferrin (Tf), complement component 4 (C4) and C-reactive protein (CRP). Interleukin-1-beta (II-1 beta) and interleukin-6 (II-6) circulating levels were determined. 3. Hyperhaptoglobinemia and hypotransferrinemia are hallmarks for major depression and depression per se, respectively. The disorders in Hp and Tf circulating levels are highly sensitive to (83%) and specific for (100%) melancholia as opposed to the healthy state. 4. Disorders in both APPs are significantly related to the absolute number of blood monocytes. 5. The authors observed a trend towards lower alpha 2M and higher alpha 1S values in severely depressed subjects. Severity of depression was significantly related to Hp and alpha 1S (both positively) and to alpha 2M and Tf (both negatively) values. 6. No significant intercategory differences in C4 could be established, whilst only a few subjects exhibited measurable CRP, II-1 beta and II-6 circulating levels. 7. Our findings may support the hypothesis that depression is accompanied by an inflammatory response.

Antiphospholipid, antinuclear, epstein-barr and cytomegalovirus antibodies, and soluble interleukin-2 receptors in depressive patients

To determine whether depression might be associated with serologic indices of autoimmune processes or active virus infections, we measured the following parameters in healthy controls, minor, simple major and melancholic patients: antiphospholipid (anticardiolipin, antiphosphatidylserine), antinuclear, and Epstein-Barr (EBV) and cytomegalovirus (CMV) antibodies. In addition, the soluble interleukin-2 receptor (sIL-2R) circulating levels in serum were measured and used as a marker of T cell activation. The anticardiolipin antibody titers were higher in melancholics than in healthy controls and minor depressives. Antinuclear antibodies were present significantly more frequently in depressed patients than in normal volunteers. The anticardiolipin and antinuclear antibody titers were significantly and positively intercorrelated. Depression is characterized by increased serum circulating levels of sIL-2Rs compared to the healthy state. Antinuclear-positive subjects exhibited significantly higher sIL-2Rs than those without detectable antinuclear titers. There was a positive correlation between anticardiolipin activity and sIL-2Rs. We found no evidence that depression is linked to EBV or CMV infection.

The dexamethasone suppression test, the Hamilton Depression Rating Scale and the DSM-III depression categories

The Hamilton Depression Rating Scale (HDRS) score and plasma cortisol values were measured in 100 depressed patients at 8 a.m., 4 p.m. and 11 p.m. after oral administration of 1 mg dexamethasone the previous night. The patients were categorized according to DSM-III as suffering from either minor depression (including dysthymic disorder, 300.40; adjustment disorder with depressed mood, 309.00; atypical depression, 296.82) or major depression (without melancholia, 296.X2; with melancholia, 296.X3; with psychotic features, 296.X4). Plasma cortisol levels of greater than or equal to 3.5 micrograms/dl at 8 a.m. were found to be the most sensitive (56.9%) and specific (94.3%) discriminator between minor and major depression. Plasma cortisol levels at 4 p.m. and 11 p.m. or the combination of several cortisol values also differentiated between minor and major depression; however, the results were not so conclusive. According to the ratings on the Hamilton Depression Scale the patients with major depression were more severely depressed (P less than 0.001) than patients suffering from minor depression. Cortisol values at 8 a.m., 4 p.m., 11 p.m. and the highest levels were significantly (P less than 0.001) correlated with the HDRS score. A maximum of 20.2% of the score variance could be explained by the correlation with the highest cortisol value observed. Severity of illness does not exclusively account for the biological differences between minor and major depression.

Seasonality in severity of depression: relationships to suicide and homicide occurrence

Some previous studies have reported seasonal or monthly variations in the occurrence of depressive syndromes. The present study was carried out in order to investigate seasonality in severity of depression. Toward this end, the authors measured the Zung Self‐Rating Depression (ZD) and Anxiety (ZA) Scales scores in 104 consecutively admitted depressed patients between November 1983 and April 1985. The data were analyzed by means of spectral analysis of a single time series. Up to 47.9% of the variance in the weekly average of the ZD scores could be explained by two significant rhythms of 51 (circannual) and 7 weeks. Peaks in ZD scores were observed in April‐May, with lows occurring in August–September. Up to 30.8% of the variance in the weekly average of ZA scores was explained by a circannual rhythm. Our results show that there is a true seasonality in the severity of illness of depressed subjects. There were significant correlations between the weekly average in severity of illness and the chronograms of suicide (positively) and homicide (negatively) occurrence in Belgium.

An evaluation of basal hypothalamic-pituitary-thyroid axis function in depression: Results of a large-scaled and controlled study

In order to evaluate the function of the hypothalamic-pituitary-thyroid (HPT)-axis in unipolar depression, the authors measured basal 0800h plasma levels of free thyroxine (FT4), free triiodothyronine (FT3), and thyroid stimulating hormone (TSH) by means of the new, ultrasensitive assays (TSH-IRMA) in 69 healthy controls, 62 minor, 101 simple major, and 57 melancholic depressed subjects. Basal HPT-axis hormone levels of almost all (96.8%) unipolar depressed patients fell within the normal, euthyroid range. None of the major depressed subjects showed subclinical hypothyroidism. It was found that 8.8% of the melancholic subjects exhibited some degree of subclinical hyperthyroidism. Basal TSH-IRMA values were significantly lower in melancholic patients than in healthy controls, minor and simple major depressed patients, and in major vs. minor depressed subjects. FT4 circulating levels were significantly higher in melancholic patients than in all other subjects. Basal TSH-IRMA and FT4 levels were significantly correlated with severity of illness. In depression, there was a significant and negative correlation between basal TSH-IRMA values and FT4 concentrations. No significant gender- or age-related differences in TSH-IRMA or thyroid hormones were detected in depression. It is argued that--in depression research--the assays of basal TSH-IRMA should replace thyrotropin releasing hormone tests.

Decreased serum dipeptidyl peptidase IV activity in major depression

It has been recently shown that severe depression is characterized by immune dysfunctions such as blunted mitogen-induced blast transformation, which is linked to interleukin-2 (IL-2) mechanisms, and to autoimmune responses. In order to explore one of the putative pathophysiological mechanisms underlying both factors, we have measured the predexamethasone and postdexamethasone serum dipeptidyl-peptidase IV (DPP IV) activity in depressed inpatients and normal controls. This enzyme is an important mediator of IL-2-related blast proliferation, and it may play a role in autoimmunity. We found significantly lower DPP IV levels in major depressives as compared with healthy controls, and melancholics exhibited significantly lower enzyme activity than minor depressives. There was a significant negative correlation between serum DPP IV activity and the severity of illness. However, we were unable to detect any significant relationships between DPP IV on the one hand, and mitogen-induced blast transformation, soluble IL-2 receptor accumulation in PHA culture supernatant, total number of leukocytes and lymphocytes, T lymphocytes, CD4+ and CD25+ cells, on the other. Men exhibited significantly higher serum DPP IV levels than women.

Autoimmunity in depression: increased antiphospholipid autoantibodies

Some groups have recently reported higher titers of autoantibodies in depressed subjects than in normal controls. The present study investigates whether depressed patients exhibit increased antiphospholipid antibody titers compared with normal controls. The authors measured the binding index (BI) of antiphosphatidylserine (APSA), antipartial thromboplastin (APTA) and anticardiolipin (ACA) in 22 minor, 23 simple major and 20 melancholic depressives, 10 healthy controls and 104 normal controls with negative autoantibody sera. Depressed subjects exhibited significantly higher APSA and APTA antibody titers compared with normal controls. A large number of depressed subjects (± 54%) showed APTA and APSA positivity, defined as BI≥2 standard deviations above the mean BI of normal controls. There was a significant discrimination (≥2.8 standard deviations) between melancholic subjects and healthy controls with respect to BI of ACA, APSA and APTA. However, by using a more conservative value for phospholipid positivity (i.e., BI≥5 standard deviations above the mean BI of a reference sample of normal sera), the subjects autoantibody titers were, on the whole, within the normal range. Our results point towards a higher expression of antiphospholipid antibodies during depression but a much lower incidence of positive patients than in classical autoimmune disorders, such as systemic lupus erythematosus.