Effects of pregnancy and delivery on serum prolyl endopeptidase (PEP) activity: alterations in serum PEP are related to increased anxiety in the early puerperium and to postpartum depression.

BACKGROUND: There is now some evidence that anxiety or anxiety disorders are related to increased activity of serum prolyl endopeptidase (PEP) and that major depression is related to lower serum PEP. The aims of the present study were to examine (i) the effects of pregnancy and delivery on serum PEP and (ii) the relationships between serum PEP and postpartum depression, anxiety in the early puerperium and a past history of depression. METHODS: Serum PEP activity was measured in 11 healthy nonpregnant and in 98 pregnant women 3 days before delivery and 1 and 3 days after delivery. On the same occasions, pregnant females completed the Spielberger State Anxiety Inventory (STAI) and were divided into high and low anxiety responders, as defined by changes in the STAI. The presence of a previous depression and postpartum depression within 3 months of delivery was assessed by means of DSM-IV criteria. RESULTS: Serum PEP activity was significantly higher 1 and 3 days after delivery than before. Women with a past history of depression as well as anxiety responders had significantly increased serum PEP activity over nonpregnant women and puerperae with a negative history and anxiety nonresponders, respectively. Parturients who developed a postpartum major, but not minor, depression had significantly lower serum PEP than parturients without postpartum depression. The results were controlled for maternal and labor variables, such as type of analgesia and delivery, induction of labor, breast feeding, parity, and duration of pregnancy and labor. CONCLUSIONS: Our results show that, in puerperae, increased serum PEP is related to increased state anxiety in the early puerperium and that lowered serum PEP is related to a subsequent postpartum major depression. INTERPRETATION: The results suggest that increased serum PEP may be related to postpartum anxious blues and that lowered serum PEP may predispose toward postpartum major depression.

Effects of pregnancy and delivery on serum concentrations of Clara Cell Protein (CC16), an endogenous anticytokine: lower serum CC16 is related to postpartum depression

There is now some evidence that lower serum concentrations of Clara Cell Protein (CC16) are related to stress-induced anxiety, psychoses and major depression. This study was developed to determine whether serum CC16 is lowered in the early puerperium and whether Postnatal Depression and Postnatal Blues are associated with lower levels of serum CC16. Serum concentrations of CC16 were assayed in 17 non-pregnant women and in 98 pregnant women before delivery and 1 and 3 days after delivery. On each occasion the parturients completed the State version of the Spielberger State-Trait Anxiety Inventory (STAI) and the Zung Depression Rating Scale (ZDS). Serum CC16 was significantly lower in pregnant women, at the end of pregnancy as well as 1 and 3 days after delivery, than in the non-pregnant women. Serum CC16 was somewhat, although significantly, higher 1 and 3 days after delivery than before delivery. Parturients who developed a postpartum depression had significantly lower serum CC16 concentrations than women who did not. There were no significant differences in serum CC16 between the puerperal women whose STAI or ZDS scores increased in the puerperium and those whose scores did not. It is concluded that in puerperal women there is a decreased anti-inflammatory capacity in the serum, in part caused by lowered serum CC16, and that the latter may be related to the development of postpartum depression.

Changes in platelet alpha-2-adrenoceptors in fibromyalgia: effects of treatment with antidepressants.

The aim of this study was to determine platelet alpha(2)-adrenergic receptor (alpha(2)-AR) binding sites in fibromyalgia both before and after treatment with sertraline or placebo. The maximum number of binding sites (B(max)) and their affinity (K(d)) for [(3)H]rauwolscine, a selective alpha(2)-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 [(3)H]rauwolscine binding characteristics both before and after subchronic treatment with sertraline or placebo for 12 weeks. [(3)H]rauwolscine binding K(d) values were significantly higher in fibromyalgia patients than in normal volunteers. There were significant inverse correlations between [(3)H]rauwolscine binding K(d) values and duration of illness, age and lower energy. Significantly higher [(3)H]rauwolscine binding K(d) 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 [(3)H]rauwolscine binding B(max) or K(d) values. The results suggest that fibromyalgia and, in particular, fibromyalgia in an early phase of illness, is accompanied by lowered affinity of platelet alpha(2)-ARs.

The immune-inflammatory pathophysiology of fibromyalgia: increased serum soluble gp130, the common signal transducer protein of various neurotrophic cytokines.

Fibromyalgia is a chronic, painful musculoskeletal disorder characterized by widespread pain, pressure hyperalgesia, morning stiffness and by an increased incidence of depressive symptoms. The etiology, however, has remained elusive. The aim of the present study was to examine the inflammatory response system (IRS) in fibromyalgia. Serum interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), sgp130, sIL-1R antagonist (IL-1RA) and sCD8 were determined in 33 healthy volunteers and in 21 fibromyalgia patients, classified according to the American College of Rheumatology criteria. Severity of illness was measured with several pain scales, dolorimetry and the Hamilton Depression Rating Scale (HDRS). Serum sgp130 was significantly higher and serum sCD8 significantly lower in fibromyalgia patients than in healthy volunteers. Serum sIL-6R and sIL-1RA were significantly higher in fibromyalgia patients with an increased HDRS score (> or = 16) than in normal volunteers and fibromyalgia patients with a HDRS score < 16. In fibromyalgia patients, an important part of the variance in sCD8 (50.3%) and IL-1RA (19.3%) could be explained by the HDRS score; 74.3% of the variance in sIL-6R was explained by the combined effects of pain symptoms and the HDRS score; and 25.9% of the variance in serum sgp130 was explained by stiffness. The results support the contention that pain and stiffness in fibromyalgia may be accompanied by a suppression of some aspects of the IRS and that the presence of clinically significant depressive symptoms in fibromyalgia is associated with some signs of IRS activation.

Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalized major depressed patients, including those with treatment resistance.

The aims of this study were to examine whether pindolol, a serotonin (5-hydroxytryptamine [5-HT])-1A receptor antagonist, and mianserin, a 5-HT2A/C and alpha2-adrenoceptor (alpha2-AR) antagonist, may augment the clinical efficacy of fluoxetine, a selective serotonin reuptake inhibitor, and shorten the latency of onset of antidepressive activity in the treatment of major and treatment-resistant depression (TRD). Ten days after admission to the hospital, 31 major depressed patients were randomly assigned using a double-blind, controlled design to receive fluoxetine 20 mg daily, fluoxetine 20 mg daily plus pindolol 7.5 mg daily, or fluoxetine 20 mg plus mianserin 30 mg daily for 5 weeks. The 17-item Hamilton Rating Scale for Depression (HAM-D) score was the primary outcome measure. Analysis of efficacy was conducted according to the intent-to-treat analysis principle considering the change from baseline to endpoint. It was found that fluoxetine plus pindolol and fluoxetine plus mianserin were significantly more effective than fluoxetine alone. Using an outcome measure of 50% reduction in the HAM-D, a 60% response rate was found in patients treated with either fluoxetine plus pindolol or fluoxetine plus mianserin compared with a 9% response rate in patients treated with fluoxetine alone. The HAM-D score 1 week after starting fluoxetine plus mianserin decreased more than 4 points and was significantly greater than that obtained by fluoxetine alone. The results suggest that pindolol and mianserin augment the efficacy of fluoxetine in the treatment of TRD and that mianserin, but not pindolol, may significantly shorten the latency of onset of antidepressive action when combined with fluoxetine.

Lower serum activity of prolyl endopeptidase in fibromyalgia is related to severity of depressive symptoms and pressure hyperalgesia.

BACKGROUND: The aims of the present study were to examine serum activities of peptidases, i.e. prolyl endopeptidase (PEP) and dipeptidyl peptidase IV (DPP IV), in patients with fibromyalgia and to examine the effects of subchronic treatment with sertraline on these variables. METHOD: Serum PEP and DPP IV activity were measured in 28 normal volunteers and 21 fibromyalgia patients, classified according to the American College of Rheumatology criteria. Tenderness at tender points was evaluated by means of dolorimetry. Fibromyalgia patients had repeated measurements of serum PEP and DPP IV both before and after repeated administration of sertraline or placebo for 12 weeks. RESULTS: Patients with fibromyalgia had significantly lower serum PEP activity than normal volunteers. There were significantly negative correlations between serum PEP activity and severity of pressure hyperalgesia and the non-somatic, cognitive symptoms of the Hamilton Depression Rating Scale. Fibromyalgia patients with severe pressure hyperalgesia had significantly lower PEP activity than normal controls and fibromyalgia patients with less severe hyperalgesia. Fibromyalgia patients with severe non-somatic depressive symptoms had significantly lower serum PEP activity than normal volunteers. There were no significant changes in serum DPP IV activity in fibromyalgia. There were no significant effects of repeated administration of sertraline on serum PEP and DPP IV activity in patients with fibromyalgia. CONCLUSIONS: The results show that fibromyalgia, and aberrant pain perception and depressive symptoms in fibromyalgia are related to lower serum PEP activity. It is hypothesized that lower serum PEP activity may play a role in the biophysiology of fibromyalgia through diminished inactivation of algesic and depression-related peptides.

Immune markers in fibromyalgia: comparison with major depressed patients and normal volunteers.

BACKGROUND: There is a high degree of comorbidity between fibromyalgia and major depression. The latter is characterized by signs of immune activation, whereas the immune status in fibromyalgia is not yet elucidated. The aims of the present study were to examine (i) neopterin and biopterin excretion in 24-h urine of patients with fibromyalgia compared with normal volunteers and patients with major depression; and (ii) the effects of subchronic treatment with sertraline (11 weeks) on the urinary excretion of neopterin and biopterin. METHODS: Measurements of neopterin, biopterin, pseudouridine, creatinine and uric acid in 24-h urine were performed by means of HPLC in 14 fibromyalgia and ten major depressed patients and 17 normal volunteers. RESULTS: There were no significant differences in urine excretion of the above five analytes between patients with fibromyalgia and normal volunteers. Patients with major depression showed significantly higher urinary neopterin excretion than normal volunteers and fibromyalgia patients. Patients with fibromyalgia and major depression had a significantly increased neopterin/creatinine ratio. Fibromyalgia patients had significantly lower urinary excretion of creatinine than patients with major depression. In fibromyalgia patients, there were no significant effects of sertraline treatment on any of the urine analytes. CONCLUSIONS: The findings suggest that fibromyalgia, in contrast to major depression, may not be accompanied by activation of cell-mediated immunity. LIMITATION: Other immune markers should be measured in fibromyalgia before drawing definite conclusions. CLINICAL RELEVANCE: Increased urinary excretion of neopterin can be used as a marker for major depression, but not fibromyalgia.