Is serum Cu a “trait marker” of unipolar depression? A preliminary clinical study

ArticleinPolish journal of pharmacology 51(6):535-8 · November 1999with 46 Reads
Source: PubMed
Abstract
Depression is not a homogenous illness and is diagnosed in only one in three persons suffering from this disorder. Besides psychological-psychiatric diagnostic methods (e.g. Hamilton's, Beck's rating scales), some biochemical measures have been introduced as markers of depression. However, the sensitivity of even the best characterized dexamethasone suppression test is as low as 40-50%. A search for better markers is continuously in progress. In the present study, we investigated alterations in serum copper concentrations in depressive patients before, during and after antidepressant treatment and compared these values with the concentrations in healthy volunteers. The serum copper concentration in depression is significantly higher (by 21%) than in the control. However, effective antidepressant treatments (which reduced symptoms by ca. 50% measured by Hamilton Depression Rating Scale) did not affect (did not normalize) this increased copper concentration. The present data indicate that serum copper is a "trait marker" (remains constant regardless of successful treatment) of unipolar depression.

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  • ... (14) In support, several studies also reported that changes in serum copper level is associated with depression during pregnancy, postpartum, and major depression. (15)(16)(17)(18)(19) Lower micronutrient density diet is more prevalent among pregnant women in developing countries and in low socioeconomic area. (20) There is yet no study on Copper intake in Iranian general population diet (21); However, low levels of serum copper had been detected in Iranian pregnant women especially those who live in poor socioeconomic areas and have hemoglobin more than 13.2 gr/dl. ...
  • ... (14) In support, several studies also reported that changes in serum copper level is associated with depression during pregnancy, postpartum, and major depression. (15)(16)(17)(18)(19)Lower micronutrient density diet is more prevalent among pregnant women in developing countries and in low socioeconomic area. (20) There is yet no study on Copper intake in Iranian general population diet (21); However, low levels of serum copper had been detected in Iranian pregnant women especially those who live in poor socioeconomic areas and have hemoglobin more than 13.2 gr/dl. ...
    ... Furthermore, Cu as a part of dopamine mono-oxygenase, an enzyme involved in neurotransmitter synthesis, can play an important role in catecholaminergic pathways in brain which is involved in pathophysiology of depression [14]. In support, several studies also reported that changes in serum Cu level are associated with depression during pregnancy, postpartum, and major depression [15][16][17][18][19]. Lower micronutrient density diet is more prevalent among pregnant women in developing countries and in low socioeconomic area [20]. ...
    Objective: To evaluate the effects of copper supplementation during pregnancy on the rupture of membranes and pregnancy outcomes. Method: Study was conducted as a triple blind randomized clinical trial. In one group copper in a dose of 1000 milligram per day and in the other group, placebo was prescribed orally from 16th week of pregnancy. Results: The women of the 2 groups did not have significant difference according to age, gestational age at recruitment, BMI, and socioeconomic conditions. There was no statistically significant difference between case and control group regarding the incidence of PPROM, PROM, preterm labor, vaginal bleeding during pregnancy, pre-eclampsia and the incidence of placenta abruption. There was a 75% and 90% decrease in depressive symptoms in 2nd trimester and 3rd trimester in supplemented group respectively. Also, there was a 45% and 80% decrease in anxiety symptoms in 2nd trimester and 3rd trimester in the supplemented group respectively. The rate of infection during pregnancy was significantly higher in control group (P: 0.046). There was no difference between the 2 groups according to neonatal outcomes. Conclusion: Copper supplementation during pregnancy could not influence positively on ROM, however, could improve some mood status of the women.
  • Chapter
    Elements (bioelements) are necessary factors required for the physiological function of organisms. They are critically involved in fundamental processes of life. Extra- and intracellular message and metabolic pathway factors as well as structural components include one or many elements in their functional structure. Recent years have seen an intensification in terms of knowledge gained about the roles of elements in anxiety disorders. In this chapter we present a review of the most important current data concerning the involvement of zinc, magnesium, copper, lithium, iron, and manganese, and their deficiency, in the pathophysiology and treatment of anxiety.
  • Chapter
    Chocolate and mood are strongly intertwined in the popular imagination. The strong body of chocolate lore is not matched by a strong body of evidence. Theoretically, chocolate bears many substances and properties that could influence mood, favorably and adversely. The balance of favorable to adverse effects could differ by individual and timing after chocolate consumption. Favorable effects on mood might be mediated by methylxanthines (caffeine and theobromine), catechins, biogenic amines like serotonin and ethylamine, and cannabinoid receptor agonists like anandamine. Antioxidant functions and cell energy support through mitochondrial biogenesis (mediated by epicatechin) might support positive mood. Detrimental effects on mood might be mediated by methylxanthine excess or withdrawal, effects of copper, or effects of trans-fatty acids (where these have polluted the chocolate product). Empirically, few studies in humans have examined the relation of chocolate to mood. Based on the scant extant literature, mood associations appear to be favorable immediately after eating chocolate that is perceived as palatable. In studies not focused upon the immediate effect, greater chocolate consumption has been linked to lower mood, but it is not clear which (if either) drives which.
  • ... High Cu concentration is observed in Alzheimer's, Parkinson's, and Wilson's diseases and may also lead to decline in intelligence in young adolescents[8,9]. Limited data also suggests the potential importance of copper in the development of neuropsychiatric disorders, including depression[6,[11][12][13][14][15][16], and several compelling arguments can confirm this fact. Firstly, copper is an essential component of some enzymes (monoamine oxidase—MAO, dopamine β-hydroxylaze— DBH, and tyrosine hydroxylase) involved in the proper turnover of catecholamines, which disturbances can lead to the development of depression[17,18]. ...
    ... However, in theMaes et al.'s trial, there was a decline of copper levels in depressive patients following the antidepressant treatment, while we did not perform any corresponding analyses. Partly consistent with our findings are also the results obtained by Schlegel-Zawadzka et al.[15,16]. Although, in the study, which enrolled 19 MDD patients and 16 healthy, was shown elevated levels of copper in depressed people. ...
    ... Although, in the study, which enrolled 19 MDD patients and 16 healthy, was shown elevated levels of copper in depressed people. However, just like in our study, there was not any correlation between copper levels and severity of depression measured by HDRS, and moreover, effective antidepressant was without effect on this measure[15,16]. Interesting observations, which in part are consistent with our results, have also been made in the cross-sectional analysis by Crayton and Walsh[11], the study to which 813 (485 women and 328 men) depressed patients and 54 (28 women and 26 men) control subjects between 30 and 60 years were selected; significant increase in the serum copper concentration in depressed women compared to the matched control was demonstrated. Additionally, it has been shown that women with a history of postpartum depression (PPD) exhibited significantly higher Cu level than those without PPD history. ...
    Article
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    Copper may be involved in the pathophysiology of depression. Clinical data on this issue are very limited and not conclusive. The purpose of the study was to determine the copper concentration in the serum of patients with major depressive disorder and to discuss its potential clinical usefulness as a biomarker of the disease. A case-control clinical study included 69 patients with current depressive episode, 45 patients in remission and 50 healthy volunteers. Cu concentration was measured by electrothermal atomic absorption spectrometry (ETAAS). The mean serum copper level in depressed patients was slightly lower (by 11 %; not statistically significant) than in the control group. Furthermore, there was no significant difference in Cu(2+) concentration between depressive episode and remission, nor between remission and control group. In the remission group were observed significant correlations between copper levels and the average number of relapses over the past years or time of remission. There was no correlation between serum copper and severity of depression, as measured by HDRS and MADRS. The obtained results showed no significant differences between the copper concentration in the blood serum of patients (both with current depressive episode and in remission) and healthy volunteers, as well as the lack of correlations between the copper level in the active stage of the disease and clinical features of the population. Our study is the first conducted on such a large population of patients, so the results may be particularly important and reliable source of knowledge about the potential role of copper in depression.
  • Article
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    Our previous study showed that dietary zinc restriction induces depression-like behavior with concomitant up-regulation of the N-methyl-D-aspartate receptor (NMDAR). Because metal ions, oxidative stress, and inflammation are involved in depression/NMDAR function, in the present study, bio-elements (zinc, copper, iron, magnesium, and calcium), oxidative (thiobarbituric acid-reactive substances; protein carbonyl content), and inflammatory (IL-1α, IL-1β) factors were measured in serum, hippocampus (Hp), and prefrontal cortex (PFC) of male Sprague-Dawley rats subjected to a zinc-adequate (ZnA) (50 mg Zn/kg) or a zinc-deficient (ZnD) (3 mg Zn/kg) diet for 4 or 6 weeks. Both periods of dietary zinc restriction reduced serum zinc and increased serum iron levels. At 4 weeks, lowered zinc level in the PFC and Hp as well as lowered iron level in the PFC of the ZnD rats was observed. At 6 weeks, however, iron level was increased in the PFC of these rats. Although at 6 weeks zinc level in the PFC did not differ between the ZnA and ZnD rats, extracellular zinc concentration after 100 mM KCl stimulation was reduced in the PFC of the ZnD rats and was accompanied by increased extracellular iron and glutamate levels (as measured by the in vivo microdialysis). The examined oxidative and inflammatory parameters were generally enhanced in the tissue of the ZnD animals. The obtained data suggest dynamic redistribution of bio-elements and enhancement of oxidative/inflammatory parameters after dietary zinc restriction, which may have a link with depression-like behavior/NMDAR function/neurodegeneration.
  • ... Patients with Wilson's disease often suffer from depression, anxiety and psychosis [16], and there is a case of a patient with WD with late onset, in which major depression was the first and the only clinical manifestation of the disease [17]. Moreover, serum copper has been suggested as a trait marker of unipolar depression [18]. The question then arises, what role does copper play in the course of affective disorders? ...
    ... Study design Number of participants Age [years] Questionnaire used to identify mood disturbances Method used to estimate amount of copper Results References Copper A case–control study 31 cases 62 controls n/a n/a (diagnosed patients attending the outpatients neuropsychiatric clinic) Plasma copper measurements (atomic absorption spectrophotometry) The plasma copper levels in depressed patients were significantly higher as compared to controls (by 22%) [31] A case–control study 35 cases (21 males, 14 females) 35 controls n/a Hamilton depression rating scale Plasma copper measurements (atomic absorption spectrophotometry) The plasma copper levels in depressed patients were significantly higher as compared to controls (by 14%). After recovery, copper levels decreased significantly (by 15%) [30] A case–control study 19 cases 16 controls n/a Hamilton depression rating scale Plasma copper measurements (atomic absorption spectrophotometry) The plasma copper levels in depressed patients were significantly higher as compared to controls (by 21%) [18] A case–control study 31 cases 15 controls n/a Hamilton depression rating scale Plasma copper measurements (atomic absorption spectrophotometry) Antidepressant treatment significantly reduced serum copper levels [11] ...
    Article
    In this paper we continue to discuss the involvement of essential elements in depression and anxiety, and the possible mechanisms that link elements to the neurobiology underlying depression/anxiety. The present paper is focused on copper, selenium, manganese, iodine and vanadium. Different aspects of relationship between elements and depression or anxiety are reviewed, e.g. the association of the amount of an element in a diet or the serum level of an element and depressive or anxiety-like symptoms. Moreover, the relation of selected elements to the pathophysiology of depression or anxiety is discussed in the context of enzymes which require these elements as co-factors and are involved in the underlying pathophysiology of these disorders.
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    Depression is the leading psychiatric disorder with a high risk of morbidity and mortality. Clinical studies report lower serum zinc in depressed patients, suggesting a strong link between zinc and mood disorders. Also copper as an antagonistic element to zinc seems to play a role in depression, where elevated concentration is observed. In the present study we investigated serum copper and zinc concentration after acute or chronic antidepressant (AD) treatment under pathological/zinc-deficient conditions. Zinc deficiency in mice was induced by a special diet administered for 6 weeks (zinc adequate diet - ZnA, contains 33.5 mgZn/kg; zinc deficient diet - ZnD, contains 0.2 mgZn/kg). Animals received acute or chronically saline (control), imipramine, escitalopram, reboxetine or bupropion. To evaluate changes in serum copper and zinc concentrations the total reflection X-ray fluorescence (TXRF) and flame atomic absorption spectrometry (FAAS) was performed. In ZnD animals serum zinc level was reduced after acute ADs treatment (similarly to vehicle treatment), however, as demonstrated in the previous study after chronic ADs administration no differences between both ZnA and ZnD groups were observed. Acute ADs in ZnD animals caused different changes in serum copper concentration with no changes after chronic ADs treatment. The calculated serum Zn/Cu ratio is reduced in ZnD animals (compared to ZnA subjects) treated with saline (acutely or chronically) and in animals treated acutely with ADs. However, chronic treatment with ADs normalized (by escitalopram, reboxetine or bupropion) or increased (by imipramine) this Zn/Cu ratio. Observed in this study normalization of serum Zn/Cu ratio in depression-like conditions by chronic (but not acute) antidepressants suggest that this ratio may be consider as a marker of depression or treatment efficacy.
  • Article
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    To assess plasma Zn and Cu levels in individuals with depression. Plasma from 73 clinically depressed individuals, 38 individuals with anxiety and 16 controls were tested for plasma Zn and Cu concentration using inductively-coupled plasma-mass spectrometry. Depressed individuals, with and without secondary anxiety, had decreased plasma Zn and elevated plasma Cu compared to controls. Zn normalized (increased to the level of normal controls) but Cu increased in individuals with depression (with and without secondary anxiety), after Zn therapy, whereas both plasma Zn increased and Cu levels decreased in anxiety, with and without secondary depression, after Zn therapy. Individuals with depression,with and without secondary anxiety, had significantly higher symptom severity when compared to neurotypical controls. Symptom severity in individuals with anxiety (both with and without secondary depression) significantly decreased after Zn therapy, whereas symptoms remained the same in individuals with primary depression. These data show an association between Zn and Cu plasma levels and clinically depressed individuals, and suggest that high Cu levels are associated with high symptom severity.
  • ... Besides, of course, confirming results with an increased sample size, a deeper investigation of the relationship of the two copper pools with clinical status is recommended. In fact, Schlegel-Zawadzka et al. reported that total copper concentrations, which they found 21% higher in depressives than in controls, do not appear to return to normal after effective antidepressant treatments (Schlegel-Zawadzka et al., 1999). Unfortunately, their study did not consider bound and free copper separately, and did not clarify the relationship of the specific drugs examined with copper, so that a targeted time-study of the free copper levels appears useful. ...
    Article
    Background: Several neuropsychiatric pathologies have been recently linked to oxidative stress. In this study, we investigated the relationship between depression, markers of oxidative stress and neurotransmission, as expressed by sensory cortex excitability. Methods: Serum levels of oxidative stress markers and somatosensory magnetic fields, evoked by external galvanic stimulation, were measured in 13 depressed patients and 13 controls. Results: Depressives had higher levels of total and free copper than controls and lower levels of transferrin. They also showed lower sensory cortex excitability, which correlated with copper levels in controls, but not in patients. Transferrin correlated with sensory cortex excitability in both patients and controls, although in opposite ways. Copper level results associated with the patients' clinical status. Limitations: Small sample size and possible sampling bias in patient selection. Conclusions: Pro-oxidant agents appear to affect neuronal excitability and clinical state of depressed patients, as free copper excess alters their cortical glutamatergic neurotransmission.
  • In the present study we report the results of investigations into the serum copper levels in a clinical study of 19 patients with unipolar depression; 16 normal controls and three animal models of depression: chronic severe stress (CSS), chronic mild stress (CMS) and olfactory bulbectomy (OB) in rats. Unipolar depressed patients exhibit significantly higher serum copper levels than the appropriate controls (depression 1·15±0·17 mg/l; control 0·95±0·09 mg/l). There was no alteration in that value in rat models of depression. The data indicate that the increased serum copper level in the depressed patients might potentially be a marker of that illness. Moreover, animal models of human depression do not show changes in this marker. Copyright © 1999 John Wiley & Sons, Ltd.
  • Article
    Blood copper, zinc, magnesium and lead levels were determined by atomic absorption spectroscopy for 15 males and 16 females suffering from depression, 6 males and 1 female with mental retardation and 3 males and 4 females with seizure disorders. They were all under no medication and belonged to low income groups. No difference in copper levels was found between the sexes in any of the groups. The levels in all the groups were significantly higher than in the normals. In depressives, males had significantly higher zinc levels than females and only female depressives had significantly different (lower) levels from normals. In both depressives and normals, males had higher magnesium levels than females but no group of patients had significantly different levels from normals. Lead levels were significantly higher in female depressives and for those with seizure disorders than for controls. At least one metal abnormality was found in 21 (67.7%) depressive, 5 (71.4%) of those with mental retardation and 6 (85.7%) with seizure disorders.
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    NMDA antagonists mimic the effects of clinically effective antidepressants in both preclinical tests predictive of antidepressant action and procedures designed to model aspects of depressive symptomatology. These findings led to experiments demonstrating that chronic administration of NMDA antagonists to rodents results in a downregulation of cortical beta-adrenoceptors, a phenomenon also observed following chronic treatment with many antidepressants. These neurochemical and behavioral similarities between antidepressants and NMDA antagonists prompted us to examine the impact of chronic antidepressant treatment on NMDA receptors. Chronic (14 days) but not acute (1 day) administration of seventeen different antidepressants to mice produced adaptive changes in radioligand binding to NMDA receptors. Detailed studies with three antidepressants (imipramine, citalopram, and electroconvulsive shock) show that these changes develop slowly, persist for some time after cessation of treatment, and (for imipramine and citalopram) are dose dependent. Moreover, following chronic treatment with imipramine, these changes in radioligand binding to NMDA receptors appear restricted to the cerebral cortex. Based on the consistency of these effects across antidepressant treatments, we propose that adaptive changes in NMDA receptors may be the final common pathway for antidepressant action. The recent demonstration (Nowak et al., 1995) that radioligand binding to NMDA receptors is altered in frontal cortex of suicide victims (compared to age and post-mortem interval matched controls) is consistent with the hypothesis (Trullas and Skolnick, 1990) that this family of ligand gated ion channels is involved in the pathophysiology of depression.
  • Article
    The aims of the present study were to examine i) serum zinc (Zn) and copper (Cu) in treatment resistant depression (TRD); ii) the effects of subchronic antidepressant therapy on these trace elements; and iii) the relationships between serum Zn and Cu and immune/inflammatory markers. Serum Zn was significantly lower in TRD than in normal controls. There was a significant inverse correlation between baseline serum Zn and staging of depression based on severity of prior treatment resistance. There were no significant effects of antidepressive treatment on serum Zn, whereas serum Cu was significantly reduced. There were highly significant correlations between serum Zn and the CD4+/CD8+ T-cell ratio (negative), and total serum protein, serum albumin, and transferrin (all positive). The results suggest that lower serum Zn is a marker of TRD and of the immune/inflammatory response in depression. It is suggested that treatment resistance may bear a relationship with the immune/inflammatory alterations in major depression.
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    We investigated the effects of repeated electroconvulsive shock or imipramine treatment on inositol phosphate accumulation and on the reactivity of neurons to metabotropic glutamate (mGlu) receptor agonists in rat hippocampal slices. (1S,3R)-1-carboxycyclopentane-3-acetic acid (1S,3R-ACPD), a nonselective mGlu receptor agonist, caused a concentration-dependent increase in inositol phosphate in slices from the CA1 region of the hippocampus, an effect that was not modified by imipramine or electroconvulsive shock treatment. 1S,3R-ACPD or the selective agonist of the I group of mGlu receptor, (R,S)-3,5-dihydroxyphenylglycine ((R,S)-3,5-DHPG), produced a concentration-dependent increase of the population spike recorded in the CA1 cell layer. This effect of 1S,3R-ACPD was markedly attenuated by both repeated imipramine and electroconvulsive shock treatment, and the action of (R,S)-3,5-DHPG was markedly attenuated by prolonged imipramine treatment (electroconvulsive shock was not tested). Our results indicate that antidepressant treatment may induce a subsensitivity of group I mGlu receptors when assessed by electrophysiological but not biochemical measures.
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