Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A high proportion of cancer and hepatitis C patients who receive cytokine immunotherapy develop symptoms of depression that are indistinguishable from those found in major depressive disorders. These symptoms are alleviated by anti-depressant treatment. Moreover, preventive treatment with anti-depressants, in particular selective serotonin reuptake inhibitors (SSRIs) attenuates IFN-alpha-associated symptoms of depression, anxiety, and neurotoxicity. The intermediate mechanisms of these effects are still unclear. Studies suggest that the state of depression is associated with an increase in plasma levels of various cytokines and soluble cytokine receptors. Furthermore, anti-depressants have been shown to shift the cytokine network towards a decreased production of pro-inflammatory cytokines and an increased production of anti-inflammatory cytokines. Other studies suggest that anti-depressants can also modify immune reactivity by acting on neural structures involved in neuroimmunomodulation. It is possible that anti-depressants could help to normalize the serotoninergic neurotransmission that is likely disrupted during immunotherapy due to the potent effects of cytokines on the metabolism of the amino acid precursor tryptophan. Further work is needed to optimize strategies for preventing neuropsychiatric side effects of cytokine immunotherapy, to clarify the mechanisms involved in the alleviating effects of anti-depressants on cytokine-induced depression, as well as to assess the possible consequences of anti-depressant therapy on the efficacy of immunotherapy on the disease process.
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PMID:Treatment of cytokine-induced depression. 1240 71

The prognosis of hepatocellular carcinoma(HCC) invading the major branches of the portal vein(Vp3 or 4) is extremely poor. Recently, we reported the efficacy of the combination therapy with subcutaneous interferon(IFN)-alpha and intra-arterial 5-FU for intractable HCC with Vp3 or Vp4. Forty-eight consecutive patients with HCC and Vp3 or 4 were treated with the combination therapy consisting of continuous arterial infusion of 5-FU(450-500 mg/day, 5 days/week, for the initial 2 weeks) and subcutaneous injection of IFN(5 MIU, 3 times/week, 4 weeks). The treatment outcome of these cases was very good. In addition, it is considered direct antitumor effect, the angiogenesis depression effect, and the indirect antitumor effect through immunocompetent cell, may concerned, as the mechanism. In conclusion, combination therapy with subcutaneous IFN and intra-arterial 5-FU is therefore a promising treatment modality for intractable HCC with Vp3 or 4.
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PMID:[Development and research of the new therapy for hepatocellular carcinoma--combined interferon and 5-fluorouracil therapy]. 1244 Jan 36

Administration of the cytokines interferon-alpha and interleukin-2 is used for the treatment of various disorders, such as hepatitis C and various forms of cancer. The most serious side-effects are symptoms associated with depression, including fatigue, increased sleepiness, irritability, loss of appetite as well as cognitive changes. However, great differences exist in the prevalence of the development of depressive symptoms across studies. Differences in doses and duration of therapy may be sources of variation as well as individual differences of patients, such as a history of psychiatric illness. In addition, sensitization effects may contribute to differential responses of patients to the administration of cytokines. In animals administration of pro-inflammatory cytokines induces a pattern of behavioural alterations called 'sickness behaviour' which resembles the vegetative symptoms of depression in humans. Changes in serotonin (5-HT) receptors and in levels of 5-HT and its precursor tryptophan in depressed people support a role for 5-HT in the development of depression. In addition, evidence exists for a dysregulation of the noradrenergic system and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis in depression. Some mechanisms exist which make it possible for cytokines to cross the blood-brain barrier. Pro-inflammatory cytokines such as IL-1beta, IFN-alpha, IFN-gamma and TNF-alpha affect the 5-HT metabolism directly and/or indirectly by stimulating the enzyme indoleamine 2,3-dioxygenase which leads to a peripheral depletion of tryptophan. IL-1, IL-2 and TNF-alpha influence noradrenergic activity and IL-1, IL-6 and TNF-alpha are found to be potent stimulators of the HPA axis. Altogether, administration of cytokines may induce alterations in the brain resembling those found in depressed patients, which leads to the hypothesis that cytokines induce depression by their influence on the 5-HT, noradrenergic and HPA system.
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PMID:The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. 1246 36

Interferon-alpha (IFN-alpha) administration induces major depression in a significant number of patients undergoing treatment for viral illnesses and other chronic diseases. Non-steroidal anti-inflammatory drugs (NSAIDs) are known to counteract a number of IFN-alpha-induced side effects, including pro-inflammatory cytokine activation and stress hormone release. To investigate this possibility further, we sought to determine the effect of the NSAID diclofenac sodium on monoamine turnover in brain induced by acute IFN-alpha exposure. Eleven male, Wistar rats (8 weeks old) were pretreated with diclofenac (20 mg/kg, s.c.) or saline, followed by intracerebroventricular (i.c.v.) infusion of IFN-alpha (1000 IU in 5 microl) or vehicle. The prefrontal cortex, striatum, and hippocampus were isolated and samples were assayed for monoamines and major metabolites by high-pressure liquid chromatography with electrochemical detection. The data show that acute IFN-alpha increased serotonin turnover in prefrontal cortex and increased dopamine turnover in hippocampus, while pre-treatment with diclofenac completely prevented these neurochemical responses. Importantly, these changes were recorded in two brain areas known to be important in depression and antidepressant action. These data offer support for a novel role of NSAIDs in modulating IFN-alpha-induced neurochemical alterations, and raise the possibility of the use of NSAIDs for the prevention of IFN-alpha-induced depression.
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PMID:The non-steroidal anti-inflammatory drug diclofenac sodium attenuates IFN-alpha induced alterations to monoamine turnover in prefrontal cortex and hippocampus. 1278 15

Immunotherapy with interferon-alpha (IFN-alpha) induces neuropsychiatric side effects, most notably depression. One of the presumed pathophysiological mechanisms is an effect on tryptophan metabolism. As tryptophan is the precursor of serotonin, decreased availability of tryptophan to the central nervous system could result in serotonin deficiency. Tetrahydrobiopterin (BH((4))) is a cofactor for one of the enzymes synthesizing serotonin. We conducted an exploratory study into the serum concentrations of large neutral amino acids (AA), biopterin (BIOP) and neopterin (NEOP), of 67 patients with high-risk melanoma, who were either treated with two different doses of IFN-alpha or were part of an observation-only control group. We found evidence for IFN-alpha to decrease concentrations of all AA except phenylalanine. The decrease in tryptophan concentration was most prominent and consistent. These changes persisted throughout a year of maintenance treatment. Concentrations of NEOP rose sharply, whereas, those of BIOP did not change. Except for the increase in NEOP and the increase in the ratio between phenylalanine (PHE) and tyrosine (TYR), no support for derangement in BH((4)) metabolism was found. The increase in the ratio between PHE and TYR suggests inhibition of the enzyme phenylalanine hydroxylase. Patients with IFN-alpha induced anxiety and depression had higher pretreatment concentrations of NEOP. Changes in tryptophan metabolism may play a role in the pathophysiology of the neuropsychiatric side effects of IFN-alpha, and further research into the predictive potential of NEOP is warranted.
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PMID:Serum amino acids, biopterin and neopterin during long-term immunotherapy with interferon-alpha in high-risk melanoma patients. 1286 Mar 66

Interferon alpha (IFN-alpha), an immunomodulatory cytokine, is used for the treatment of several disorders including chronic hepatitis or malignant melanoma. During the therapy IFN-alpha may cause severe neuropsychiatric syndromes including depression with suicidal ideation, paranoid psychoses or confusional states. The reasons and management of these side effects are widely unknown. The underlying pathogenetic mechanisms include various effects on neuroendocrine, cytokine and neurotransmitter systems. This review summarizes therapeutic strategies against IFN-alpha associated psychiatric syndromes. Zolpidem or Zopiclon can be used for the treatment of sleeping disturbances. Serotonin-reuptake-inhibitors including citalopram or paroxetine were shown to be effective for acute treatment of IFN-alpha associated depression. The efficacy of prophylactic treatment for prevention of IFN-alpha induced depression has to be proven in future trials. In an interdisciplinary setting, psychiatric disorders and drug addiction should not prevent patients from interferon-alpha treatment. Furthermore, interdisciplinary care should improve quality of life, adherence and therapeutic outcome of interferon-alpha treated patients.
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PMID:[Incidence, pathoetiology and treatment of interferon-alpha induced neuro-psychiatric side effects]. 1297 32

It has been postulated that interferon induces depression via a nitric oxide-related system. The purpose of this study was to test whether there was a difference in the effects of interferon-alpha (IFN-alpha) on nitric oxide production between patients with and without interferon-induced depression. The subjects had chronic hepatitis C and were being treated with IFN-alpha. We measured plasma nitrate, a marker of nitric oxide production in vivo, before, during, and after interferon therapy. Of 146 patients, 9 developed depression within the first 4 wk of interferon therapy, and 8 developed depression later. In the former group, a significant plasma nitrate increase was observed during therapy, followed by a decrease to baseline after discontinuation. This, however, was not the case with the latter group or those who had no psychiatric symptoms. These results suggest nitric oxide involvement in at least some forms of IFN-alpha-induced depression.
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PMID:Nitric oxide involvement in depression during interferon-alpha therapy. 1460 57

Interferon alpha (IFN-alpha) is a cytokine that is widely used for the treatment of chronic viral infection or malignant disorders. During treatment with IFN-alpha, severe neuropsychiatric syndromes may occur such as depression with suicidal ideation, paranoid psychoses or confusional states. The neurobiological correlates of these side effects are widely unknown. Besides induction of other cytokines and hormonal changes, IFN-alpha has been shown to modulate the opioid, serotonin, dopamine and glutamate neurotransmitter system. Positive therapeutic effects of antidepressants such as selective serotonin-reuptake-inhibitors (SSRI) or of opioid receptor antagonists support the hypothesis that neurotransmitter changes play an important role in the development of IFN-alpha associated neuropsychiatric side effects. We review recent research about IFN-associated neurotransmitter changes in the central nervous system and discuss treatment strategies.
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PMID:Neurotransmitter changes by interferon-alpha and therapeutic implications. 1467 80

It has been suggested that patients with subclinical mood symptoms prior to initiating cytokine treatment (as revealed by elevated baseline scores on depression rating scales) are more likely to become clinically depressed during the course of cytokine therapy. The present study was designed to identify which specific preexisting symptoms predict development of depressive symptomatology during treatment with the cytokines, interleukin-2 (IL-2) and/or interferon-alpha (IFN-alpha), in patients with cancer. Thirty-two patients with renal cell carcinoma or malignant melanoma eligible to receive treatment with IL-2 and/or IFN-alpha were enrolled in the study. At baseline and after one month of cytokine therapy (endpoint), depressive symptoms were assessed using the clinician-administered Montgomery-Asberg depression rating scale (MADRS). Illness-related coping strategies, social support, somatic complaints, quality of sleep and demographic factors were also assessed as relevant baseline predictive factors. MADRS scores significantly increased during cytokine therapy. Patients with moderate to marked depressive symptomatology at study endpoint exhibited higher baseline scores in dimensions of the MADRS scale assessing emotional (especially reported sadness), cognitive (especially pessimistic thoughts) and neurovegetative (sleep disturbances) symptoms compared to patients who remained free of depressive symptoms during cytokine therapy. Interestingly, only emotional symptoms and sleep disturbance at baseline, along with low social support, predicted severity of depressive symptoms at the end of the first month of therapy. By documenting specific behavioral vulnerability factors for cytokine-induced depressive symptoms, these findings may help identify patients at risk for mood disturbances during cytokine treatment and help target specific patient populations and specific symptoms for preventative strategies.
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PMID:Baseline mood and psychosocial characteristics of patients developing depressive symptoms during interleukin-2 and/or interferon-alpha cancer therapy. 1505 Jun 47

Members of the ADAR (adenosine deaminases acting on RNA) gene family are involved in one type of RNA editing that converts adenosine residues to inosine. The A-to-I editing of serotonin receptor subtype 2C (5-HT(2C)R) mRNA leads to replacement of three amino acid residues located within the intracellular loop II domain, resulting in dramatic alterations in G-protein coupling functions of the receptor. It has been speculated that RNA editing may play a role in several pharmacological and behavioral processes where the serotonergic plasticity is mediated through 5-HT(2C)R. Interferon-alpha (IFN-alpha) often causes severe depression in patients treated for chronic viral hepatitis and certain malignancies. In this study, we examined the effects of IFN-alpha on RNA editing in human glioblastoma cell lines, which express 5-HT(2C)R mRNAs. ADAR1 expression and the pattern of the 5-HT(2C)R mRNA editing rapidly changed in response to IFN-alpha, leading to the dominant expression of the 5-HT(2C)R-VSI isoform predicted to have reduced G-protein coupling functions. Our results support the hypothesis that 5-HT(2C)R mRNA editing has causative relevance in the pathophysiology of depression associated with cytokine therapy.
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PMID:Altered RNA editing of serotonin 5-HT2C receptor induced by interferon: implications for depression associated with cytokine therapy. 1509 87


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