Changes in pain during a depressive episode and relationship to cytokine levels in major depressive disorder.

BACKGROUND: Depressed patients have an increased incidence of pain. A pathophysiological connection between depression and pain is still not revealed. Immunological activation has been found in both depression and pain. There are few studies of pain and immune activation in patients with depression, without inflammatory and autoimmune disorders. METHODS: This is a naturalistic follow-up study of 50 patients with a major depressive disorder (MDD) depressive episode, without any inflammatory or autoimmune conditions. We have previously reported on the relationship between depression and cytokine levels. In this study, we obtained data of depression, pain and cytokine levels before and after 12 weeks of depression treatment. All patients were medication-free at inclusion. RESULTS: At inclusion three out of four patients experienced pain, and the pain scores correlated with the depression scores. After treatment, as depression was relieved, the pain scores dropped significantly and were no longer correlated to the depression scores. There were no correlations between pain scores and cytokine levels. Pain level at inclusion did not correlate with depression treatment outcome. CONCLUSION: Our findings indicate that pain is a feature of depression. Pain levels and cytokine values didn't correlate. Pain at inclusion did not predict depression treatment outcome.

Increased plasma levels of competing amino acids, rather than lowered plasma tryptophan levels, are associated with a non-response to treatment in major depression.

Lowered plasma tryptophan (TRP) and TRP/competing amino acid (CAA) ratio may be involved in the pathophysiology of major depression (MDD). Increased cortisol and immune-inflammatory mediators in MDD may affect the availability of TRP to the brain. We investigated whether baseline or post-treatment TRP, CAAs and TRP/CAA ratio are associated with a treatment response in MDD and whether these effects may be mediated by cortisol or immune biomarkers. We included 50 medication-free MDD patients with a depressive episode (DSM diagnosis) and assessed symptom severity with the Inventory of Depressive Symptomatology (IDS) before and after treatment as usual for 12 weeks (endpoint). Plasma levels of TRP, CAAs, the ratio, cortisol, CRP and 6 selected cytokines were assayed. The primary outcome was a 50% reduction in the IDS, while the secondary was a remission of the depressive episode. In IDS non-responders, CAAs increased and the TRP/CAA ratio decreased, while in IDS responders CAAs decreased and the TRP/CAA ratio increased from baseline to endpoint. In patients who were still depressed at endpoint TRP and CAAs levels had increased from baseline, while in remitted patients no such effects were found. Increases in CAAs were inversely correlated with changes in interleukin-1 receptor antagonist levels. The results show that increased CAA levels from baseline to endpoint are associated with a non-response to treatment in MDD patients. This suggests that the mechanism underpinning the CAA-related treatment resistance may be related to changes in immune pathways. CAA levels and amino acid metabolism may be new drug targets in depression.

Ongoing episode of major depressive disorder is not associated with elevated plasma levels of kynurenine pathway markers.

BACKGROUND: It has been suggested that the development of depressive symptoms as a result of cytokine therapy is attributable to cytokine-induced elevated activity of the kynurenine pathway. The few studies of this mechanism in patients with common major depressive disorder (MDD) have yielded inconsistent results. The aim of the present study was to identify markers of the kynurenine pathway in a clinical MDD sample with increased cytokine levels. METHODS: Fifty medication-free MDD patients with a depressive episode and 34 healthy controls were included at baseline; the patients were followed for 12 weeks. Before initiating treatment, the patients were diagnosed and assessed for depressive symptoms and their blood was analyzed for tryptophan and its metabolites in the kynurenine pathway. The clinical assessments and metabolite measurements were repeated after 12 weeks of "treatment as usual". RESULTS: We did not find significant elevation of kynurenine plasma markers in patients with a depressive episode compared to healthy controls, despite elevated cytokine levels in the patients. Clinical depression scores were significantly reduced after 12 weeks, but no significant change in the plasma kynurenine pathway plasma markers was observed. CONCLUSION: The obtained results do not support the hypothesis that MDD depressive episodes are associated with elevated activity in the kynurenine pathway. This suggests that the pathophysiology underlying depressive episodes in common MDD differs from that of interferon induced depression. Our results warrant further study of the interplay between the kynurenine pathway and the cytokine activation patterns in these conditions.

The plasma levels of various cytokines are increased during ongoing depression and are reduced to normal levels after recovery.

BACKGROUND: Cytokines are implicated in the pathophysiology of major depressive disorder (MDD). However, the pattern of alterations in cytokine levels is still unclear. The current study investigated the plasma levels of a range of cytokines in a follow-up design, with the aim of determining their involvement in depression. METHODS: Fifty medication-free MDD patients with a depressive episode and 34 healthy controls were included at baseline; the patients were followed up after 12 weeks. Before initiating treatment, the patients were diagnosed and assessed for depressive symptoms and blood for cytokine analysis was obtained. The same clinical assessments and cytokine measurements were performed after 12 weeks of "treatment as usual." RESULTS: The cytokines interleukin (IL)-1ß, IL-1 receptor antagonist (IL-1Ra), IL-5, IL-6, IL-7, IL-8, IL-10, granulocyte colony-stimulating factor (G-CSF), and interferon gamma (IFNγ) were significantly elevated (p=0.01-0.047) in depressed patients at baseline compared to healthy controls. After 12 weeks of treatment, the plasma levels of seven of these nine cytokines (IL-1Ra, IL-6, IL-7, IL-8, IL-10, G-CSF, and IFNγ had decreased significantly compared to baseline and did not differ from those in the healthy controls. The depressive symptoms were simultaneously significantly reduced. In addition, the reduction to normal cytokines levels occurred only in those who met the recovery criteria. CONCLUSION: A more general pattern of elevated cytokine levels is described herein relative to what has been described previously shown in MDD. Furthermore, recovery from depression was associated with reduction to normal levels of the majority of the measured cytokines. These results strongly support the notion that a complex network of cytokines is involved in the pathophysiology of MDD.

Experiences of guided Internet-based cognitive-behavioural treatment for depression: a qualitative study.

BACKGROUND: Internet-based self-help treatment with minimal therapist contact has been shown to have an effect in treating various conditions. The objective of this study was to explore participants' views of Internet administrated guided self-help treatment for depression. METHODS: In-depth interviews were conducted with 12 strategically selected participants and qualitative methods with components of both thematic analysis and grounded theory were used in the analyses. RESULTS: Three distinct change processes relating to how participants worked with the treatment material emerged which were categorized as (a) Readers, (b) Strivers, and (c) Doers. These processes dealt with attitudes towards treatment, views on motivational aspects of the treatment, and perceptions of consequences of the treatment. CONCLUSIONS: We conclude that the findings correspond with existing theoretical models of face-to-face psychotherapy within qualitative process research. Persons who take responsibility for the treatment and also attribute success to themselves appear to benefit more. Motivation is a crucial aspect of guided self-help in the treatment of depression.

Intermittent pneumatic compression enhances neurovascular ingrowth and tissue proliferation during connective tissue healing: a study in the rat.

Intermittent pneumatic compression (IPC) is a treatment method to decrease venous stasis and stimulate blood flow. Recently, it was hypothesized that IPC may exert positive effects on tissue healing, a process highly dependent upon adequate circulation. In this study, we investigated the effects of daily 1-h IPC treatment during 2 and 4 weeks post-rat Achilles tendon rupture. The tendons were subjectively and semiquantitatively analyzed for collagen organization, fibroblast density, angiogenesis, and the occurrence of sensory neuropeptides, substance P (SP) and calcitonine gene related peptide (CGRP), as well as for a nerve regeneration marker, growth associated protein 43 (GAP-43). After 2 weeks of treatment, fibroblast density increased by 53% (p = 0.0004), vessel density by 64% (p = 0.022), and the occurrence of SP by 110% (p = 0.047) and CGRP by 47% (p = 0.0163) compared to untreated controls. Following 4 weeks of treatment, both the occurrence of sensory neuropeptides and the vessel density remained significantly higher (p < 0.05), whereas fibroblast density returned to normal. However, at 4 weeks the treated tendons displayed a higher degree of organized parallel collagen fibers, a sign of increased maturation. Daily IPC treatment improves neurovascular ingrowth and fibroblast proliferation in the healing tendon and may accelerate the repair process.

Pronociceptive and antinociceptive neuromediators in patellar tendinopathy.

BACKGROUND: The occurrence of nerve ingrowth and its relation to chronic tendon pain (tendinopathy) are still largely unknown. In healthy tendons, the innervation is confined to the paratenon, whereas the tendon proper is devoid of nerve fibers. In this study on the pathogenesis of tendinopathy, the authors examined sensory and sympathetic nerve fiber occurrence in the patellar tendon. HYPOTHESIS: Nerve ingrowth and altered expression of sensory and sympathetic neuromediators play a major role in the pathophysiology of pain in patellar tendinopathy. STUDY DESIGN: Case control study; Level of evidence, 3. METHODS: Biopsies from the patellar tendon in patients with patellar tendinopathy (n = 10) were compared with biopsies from a control group (n = 10) without any previous or current knee symptoms compatible with patellar tendinopathy. The biopsies were stained immunohistochemically for sensory and autonomic nerve markers. The biopsies from the 2 groups were compared using subjective and semiquantitative methods. RESULTS: Chronic painful patellar tendons exhibited increased occurrence of sprouting nonvascular sensory, substance P-positive nerve fibers and a decreased occurrence of vascular sympathetic nerve fibers, positive to tyroxin hydroxylase, a marker for noradrenaline. CONCLUSION: The altered sensory-sympathetic innervation suggests a role in the pathophysiology of tendinopathy. Ingrowth of sprouting substance P fibers presumably reflects a nociceptive and maybe a proliferative role, possibly as reactions to repeated microtraumata, whereas the decreased occurrence of tyroxin hydroxylase may represent a reduced antinociceptive role. These findings could be used to develop targeted pharmacotherapy for the specific treatment of tendinopathy.