Publications

The aim of this study was to determine platelet α<sub>2</sub>-adrenergic receptor (α<sub>2</sub>-AR) binding sites in fibromyalgia both before and after treatment with sertraline or placebo. The maximum number of binding sites (B<sub>max</sub>) and their affinity (K<sub>d</sub>) for [<sup>3</sup>H]rauwolscine, a selective α<sub>2</sub>-AR antagonist, were measured in 13 normal volunteers and 22 fibromyalgia patients. Severity of illness was evaluated by means of the Hamilton Depression Rating Scale (HDRS) and dolorimetric assessments of tenderness at tender points. Fibromyalgia patients had repeated measurements of [<sup>3</sup>H]rauwolscine binding characteristics both before and after subchronic treatment with sertraline or placebo for 12 weeks. [<sup>3</sup>H]rauwolscine binding K<sub>d</sub> values were significantly higher in fibromyalgia patients than in normal volunteers. There were significant inverse correlations between [<sup>3</sup>H]rauwolscine binding K<sub>d</sub> values and duration of illness, age and lower energy. Significantly higher [<sup>3</sup>H]rauwolscine binding K<sub>d</sub> values were found in fibromyalgia patients in an early phase of illness (<3 years) than in fibromyalgia patients with a protracted illness (>3 years). Repeated administration of sertraline had no significant effects on [<sup>3</sup>H]rauwolscine binding B<sub>max</sub> or K<sub>d</sub> values. The results suggest that fibromyalgia and, in particular, fibromyalgia in an early phase of illness, is accompanied by lowered affinity of platelet α<sub>2</sub>-ARs.

There is now evidence that major depression is accompanied by an induction of inflammatory and oxidative and nitrosative stress (IO&NS) pathways and by a lowered antioxidant status. Coenzyme Q10 (CoQ10) is a strong antioxidant that has anti-inflammatory effects.This paper examines the plasma concentrations of CoQ10 in 35 depressed patients and 22 normal volunteers and the relationships between plasma CoQ10 and treatment resistant depression (TRD), the severity of illness as measured by means of the Hamilton Depression Rating Scale (HDRS) and the presence of chronic fatigue syndrome (CFS).We found that plasma CoQ10 was significantly (p=0.0002) lower in depressed patients than in normal controls. 51.4% of the depressed patients had plasma CoQ10 values that were lower than the lowest plasma CoQ10 value detected in the controls. Plasma CoQ10 was significantly lower in patients with TRD and with CFS than in the other depressed patients. There were no significant correlations between plasma CoQ10 and the HDRS.The results show that lower CoQ10 plays a role in the pathophysiology of depression and in particular in TRD and CFS accompanying depression. It is suggested that depressed patients may benefit from CoQ10 supplementation. The findings that lower CoQ10 is a risk factor to coronary artery disease and chronic heart failure (CHF) and mortality due to CHF suggest that low CoQ10 is another factor explaining the risk to cardiovascular disorder in depression. Since statins significantly lower plasma CoQ10, depressed patients and in particular those with TRD and CFS represent populations at risk to statin treatment.

To examine associations between IgA responses to Gram-negative gut commensal bacteria and peri-menstrual symptoms and sex hormone levels during the menstrual cycle in women with and without premenstrual symptoms.Forty women aged 18-45 years completed the Daily Record of Severity of Problems (DRSP) during all 28 consecutive days of the menstrual cycle. We assayed, in plasma, IgA responses to six Gram-negative bacteria, that is, Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii, Klebsiella pneumoniae, Pseudomonas putida and Citobacter koseri, progesterone and oestradiol at days 7, 14, 21 and 28 of the menstrual cycle.Significant changes in Δ (actual - 1 week earlier) IgA to lipopolysaccharides (LPS) of the six Gram-negative bacteria during the menstrual cycle were observed with peak IgA levels at T4 (day 28) and lows at T1 or T2 (day 7 or 14). The ΔIgA changes in H. alvei, M. Morganii, P. putida during the menstrual cycle were significantly and positively associated with changes in the total DRSP score, and severity of physio-somatic, anxiety and breast-craving, but not depressive, symptoms. The changes in IgA responses to LPS were largely predicted by changes in progesterone and steady-state levels of progesterone averaged over the luteal phase.Menstrual cycle-associated changes in IgA directed against LPS and by inference bacterial translocation may be driven by the effects of progesterone on transcellular, paracellular and vascular pathways (leaky gut) thereby contributing to the severity of physio-somatic and anxiety symptoms as well as fatigue, breast swelling and food cravings.

There is now evidence that the pathophysiology of chronic fatigue syndrome (CFS) is related to inflammation and oxidative & nitrosative stress (ION and b) dam- age to membrane lipids, functional proteins and DNA by ON Pseudomonas Aeruginosa, Morganella Morganii, Pseudomonas Putida, Citrobacter Koseri, and Klebsielle Pneumoniae are significantly increased in patients with CFS. This suggests that in CFS there is an increased LPS translocation through a weakened tight junction barrier with subsequent gut-derived inflammation. This condition indicates an increased gut permeability or leaky gut. Treatment for 10-14 months with specific anti- inflammatory and -oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc, with or without immunoglobins intravenously (IVIg), significantly attenuates the initially increased IgA and IgM responses to LPS, showing that the gut-derived inflamma- tion is attenuated and thus that the weakened tight junction barrier is partly restored. The attenuation of gut-derived inflammation predicts the clinical improvement 10-14 months after intake of NAIOSs. The above findings show that an increased translocation of gram negative bacteria with subsequent inflammation is a new pathway that contributes to the systemic IO&NS responses in CFS.

The dexamethasone suppression test has been carried out in 111 depressed inpatients. Fasting, 8 a.m. plasma levels of Cortisol and adrenocorticotropic hormone (ACTH) were determined before and after administration of 1 mg dexamethasone. In 64 subjects multisequential (1-17,1-24,1-39) ACTH, and in 47 subjects intact (1-39) ACTH has been determined. Patients with melancholia exhibited significantly higher postdexamethasone Cortisol and intact ACTH values as compared with minor and simple major depressives. Severity of illness was significantly and positively related to postdexamethasone intact ACTH - but not to multisequential ACTH. Cortisol nonsuppressors showed higher postdexamethasone (only intact) ACTH values than Cortisol suppressors. Both postdexamethasone ACTH values were significantly and positively related with the postdexamethasone Cortisol values. We have established that Cortisol nonsuppression during melancholia is determined by an augmented escape of ACTH from suppression by dexamethasone. Intact ACTH showed the most significant clinical relevance for depression and Cortisol nonsuppression. In the clinical practice we advize the use of postdexamethasone intact ACTH in stead of plasma Cortisol or multisequential ACTH.