Lower serum zinc in major depression is a sensitive marker of treatment resistance and of the immune/inflammatory response in that illness

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      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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        • Aggett J
        • Harris JT
        Current status of zinc in health and disease.
        Arch Dis Child. 1979; 54: 909-917
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Press, New York1987
        • Arborelius L
        • Nomikos GG
        • Grillner P
        • et al.
        5-HT1A receptor antagonists increase the activity of serotonergic cells in the dorsal raphe nucleus in rats treated acutely or chronically with citalopram.
        Naunyn Schiedebergs Arch Pharmacol. 1995; 352: 157-165
        • Bremner I
        • Beattie JH
        Copper and zinc metabolism in health and disease: Speciation and interactions.
        in: Proc Nutr Soc. 54. 1995: 489-499
        • Clabrese JR
        • Skwerer RG
        • Barna B
        • et al.
        Depression, immunocompetence, and prostaglandins of the E series.
        Psychiatry Res. 1986; 17: 41-47
        • Cousins RJ
        Systemic transport of zinc.
        in: Mills CF Zinc in Human Biology. Springer-Verlag, Washington, DC1989: 79-93
        • Cousins RJ
        • Leinart AS
        Tissue-specific regulation of zinc metabolism and metallothionein genes by interleukin-I.
        FASEB J. 1988; 2: 2884-2890
        • Couturier E
        • Praet JP
        • Vis HL
        • et al.
        The increase in zincaemia provoked by starvation does not influence the intestinal absorption of zinc.
        Clin Chim Acta. 1987; 163: 165-169
        • Duch DS
        • Woolf JH
        • Nichol CA
        • Davidson JR
        • Garbutt JC
        Urinary excretion of biopterin and neopterin in psychiatric disorders.
        Psychiatry Res. 1984; 11: 83-89
        • Dunbar PR
        • Hill J
        • Neale TJ
        • Mellsop GW
        Neopterin measurement provides evidence of altered cell-mediated immunity in patients with depression, but not with schizophrenia.
        Psychol Med. 1992; 22: 1051-1057
        • Dunn MA
        • Cousins RJ
        Kinetics of zinc metabolism in the rat: Effect of dibutyryl cAMP.
        Am J Physiol. 1989; 256: 420-430
        • Goode HF
        • Robertson DAF
        • Kelleher J
        • et al.
        Effects of fasting, self-selected and isocaloric glucose and fat meals and intravenous feeding on plasma zinc concentrations.
        Ann Clin Biochem. 1991; 28: 442-445
        • Grandjean P
        • Nielsen GD
        • Jorgensen PJ
        • et al.
        Reference intervals for trace elements in blood: Significance of risk factors.
        Scand J Clin Lab Invest. 1992; 52: 321-337
        • Hamilton M
        A rating scale for depression.
        J Neurol Neurosurg Psychiatry. 1960; 23: 56-61
        • Hamilton M
        Diagnosis and rating of anxiety.
        Br J Psychiatry. 1969; 3: 76-79
        • Hansen Jr, CR
        • Malecha M
        • Mackenzie TB
        • Kroll J
        Copper and zinc deficiencies in association with depression and neurological findings.
        Biol Psychiatry. 1983; 18: 395-401
        • Howell DC
        Multiple comparisons among treatment means.
        in: Howell DC Statistical Methods for Psychology. Duxbury Press, London1982: 289-307
        • Joyce PR
        • Hawes CR
        • Mulder RT
        • Sellman JD
        • Wilson DA
        • Boswell DR
        Elevated levels of acute phase plasma proteins in major depression.
        Biol Psychiatry. 1992; 32: 1035-1041
        • Kent S
        • Bluthé R-M
        • Kelley KW
        • Dantzer R
        Sickness behavior as a new target for drug development.
        Trends Pharmacol Sci. 1992; 13: 24-28
        • Lieb J
        • Karmali R
        Elevated levels of prostaglandin E2 and thromboxane B2 in depression.
        Prostaglandins Leukot Med. 1983; 10: 361-368
        • Linnoila M
        • Whorton R
        • Rubinow DR
        • Cowdry RW
        • Ninan PT
        • Waters RN
        CSF prostaglandin levels in depressed and schizophrenic patients.
        Arch Gen Psychiatry. 1983; 40: 405-406
        • Lowe NM
        • Bremner I
        • Jackson MJ
        Plasma 65Zn kinetics in the rat.
        Br J Nutr. 1991; 65: 445-455
        • Lowik MRH
        • Schrijver J
        • Odink J
        • et al.
        Nutrition and aging: Nutritional status of apparently healthy elderly (Dutch Nutrition Surveillance System).
        J Am Coll Nutr. 1990; 9: 18-27
        • Maes M
        Evidence for an immune response in major depression: A review and hypothesis.
        Prog Psychopharmacol Biol Psychiatry. 1995; 19: 11-38
        • Maes M
        • Bosmans E
        • Suy E
        • et al.
        Depression-related disturbances in mitogen-induced lymphocyte responses, interleukin-1β, and soluble interleukin-2-receptor production.
        Acta Psychiatr Scand. 1991; 84: 379-386
        • Maes M
        • Vandewoude M
        • Scharpé S
        • et al.
        Anthropometric and biochemical assessment of the nutritional state in depression: Evidence for lower visceral protein plasma levels in depression.
        J Affect Disord. 1991; 23: 25-33
        • Maes M
        • Lambrechts J
        • Bosmans E
        • et al.
        Evidence for a systemic immune activation during depression: Results of leukocyte enumeration by flow cytometry in conjunction with monoclonal antibody staining.
        Psychol Med. 1992; 22: 45-53
        • Maes M
        • Scharpé S
        • Bosmans E
        • et al.
        Disturbances in acute phase plasma proteins during melancholia: Additional evidence for the presence of an inflammatory process during that illness.
        Prog Neuropsychopharmacol Biol Psychiatry. 1992; 16: 501-515
        • Maes M
        • Scharpé S
        • Vamn Grootel L
        • et al.
        Higher α1-antitrypsin, haptoglobin, ceruloplasmin and lower retinol binding protein plasma levels during depression: Further evidence for the existence of an inflammatory response during that illness.
        J Affect Disord. 1992; 24: 183-192
        • Maes M
        • Meltzer HY
        • Scharpé S
        • et al.
        Psychomotor retardation, anorexia, weight loss, sleep disturbances and loss of energy: Psychopathological correlates of hyperhaptoglobinemia during major depression.
        Psychiatry Res. 1993; 47: 229-241
        • Maes M
        • Scharpé S
        • Meltzer HY
        • et al.
        Relationships between interleukin-6 activity, acute phase proteins and HPA-axis function in severe depression.
        Psychiatry Res. 1993; 49: 11-27
        • Maes M
        • Scharpé S
        • Meltzer HY
        • Cosyns P
        Relationships between increased haptoglobin plasma levels and activity of cell-mediated immunity.
        Biol Psychiatry. 1993; 34: 690-701
        • Maes M
        • Scharpé S
        • D'Haese W
        • De Broe M
        • Cosyns P
        Hypozincaemia in depression.
        J Affect Disord. 1994; 31: 135-140
        • Maes M
        • Scharpé S
        • Meltzer HY
        • Okayli G
        • D'Hondt P
        • Cosyns P
        Increased neopterin and interferon gamma secretion and lower L-tryptophan levels in major depression: Further evidence for immune activation in severe depression.
        Psychiatry Res. 1994; 54: 143-160
        • Maes M
        • Meltzer HY
        • Bosmans E
        • et al.
        Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression.
        J Affect Disord. 1995; 34: 301-309
        • Maes M
        • Scharpé S
        • Neels H
        • Wauters A
        • Van Gastel A
        • Cosyns P
        Total serum protein and serum protein fractions in major depression.
        J Affect Disord. 1995; 34: 61-69
        • McLoughlin IJ
        • Hodge JS
        Zinc in depressive disorder.
        Acta Psychiatr Scand. 1990; 82: 451-453
        • Morimoto A
        • Murakami N
        • Nakamori T
        • Sakata Y
        • Watanabe T
        Brain regions involved in the development of acute phase responses accompanying fever in rabbits.
        J Physiol. 1989; 416: 645-657
        • Morimoto A
        • Sakata Y
        • Watanabe T
        • Murakami N
        Characteristics of fever and acute-phase responses induced in rabbits by IL-1 and TNF.
        Am J Physiol. 1989; 256: 35-41
        • Muller N
        • Ackenheil M
        • Hofschuster E
        Altered T-cell number and reduced suppressor cell activity in patients with affective psychosis.
        in: Hadden JW Masek K Nistico G Interactions among Central Nervous System, Neuroendocrine and Immune Systems. Pythagora Press, Boston1989: 385-394
        • Muller N
        • Hofschuster E
        • Ackenheil M
        • Mempel W
        • Eckstein R
        Investigations of the cellular immunity during depression and the free interval: Evidence for an immune activation in affective psychosis.
        Prog Neuropsychopharmacol Biol Psychiatry. 1993; 17: 713-730
        • Mussalo-Rauhamaa H
        • Konttinen YT
        • Lehto J
        • Honkanen V
        Predictive clinical and laboratory parameters for serum zinc and copper in rheumatoid arthritis.
        Ann Rheum Dis. 1988; 47: 816-819
        • Nassberger L
        • Traskman-Bendz L
        Increased soluble interleukin-2 receptor concentrations in suicide attempters.
        Acta Psychiatr Scand. 1993; 88: 48-52
        • Rains TM
        • Shay NF
        Zinc status specifically changes preferences for carbohydrate and protein in rats selecting from separate carbohydrate-, protein-, and fat-containing diets.
        J Nutr. 1995; 125: 2874-2879
        • Rea IM
        Sex and age changes in serum zinc levels.
        Nutr Res. 1989; 9: 121-125
        • Schildkraut JJ
        The catecholamine hypothesis of affective disorders: A review of supporting evidence.
        Am J Psychiatry. 1965; 122: 509-522
        • Sluzewska A
        • Rybakowski JK
        • Laciak M
        • Mackiewicz A
        • Sobieska M
        • Wiktorowiz K
        Interleukin-6 serum levels in depressed patients before and after treatment with fluoxetine.
        Ann NY Acad Sci. 1995; 762: 474-476
      1. Sluzewska A, Rybakowski JK, Sobieska M, Bosmans E, Pollet H, Wiktorowicz K (in press): Increased levels of alpha-1-acid glycoprotein and interleukin-6 in refractory depression. Depression.

      2. Sluzewska A, Rybakowski JK, Sobieska M, Wiktorowicz K (in press): Concentrations and microheterogeneity glycophorms of alpha-1-acid glycoprotein in major depression. J Affect Disord.

      3. Sluzewska A, Rybakowski J, Bosmans E, et al (in press): Indicators of immune activation in major depression. Psychiatry Res.

        • Smith RS
        The macrophage theory of depression.
        Med Hypoth. 1991; 35: 298-306
        • Solomons NW
        Zinc and copper.
        in: Shils ME Young VR Modern Nutrition in Health and Disease. Lea & Febiger, Rome1988: 238-262
        • Song C
        • Dinan T
        • Leonard BE
        Changes in immunoglobulin, complement and acute phase protein levels in the depressed patients and normal controls.
        J Affect Disord. 1994; 30: 283-288
        • Spitzer RL
        • Williams JBW
        • Gibbon M
        • First MB
        Structured Clinical Interview according to DSM-III-R.
        American Press, Philadelphia1990
        • Srinivas U
        • Braconier JH
        • Jeppsson B
        • Abdulla M
        • Akesson B
        • Ockerman PA
        Trace element alterations in infectious diseases.
        Scand J Clin Lab Invest. 1988; 48: 495-500
        • Swartz CM
        Albumin decrement in depression and cholesterol decrement in mania.
        J Affect Disord. 1990; 19: 173-176
        • Thase ME
        • Rush AJ
        Treatment-resistant depression.
        in: Bloom FE Kupfer DJ Psychopharmacology, the Fourth Generation of Progress. Raven Press, New York1995: 1081-1098
        • Van Miert AS
        • Van Duin CT
        • Wensing T
        Fever and changes in plasma zinc and iron concentrations in the goat.
        J Comp Pathol. 1990; 103: 289-300
        • Wilson RL
        Zinc and iron in free radical pathology and cellular control.
        in: Mills CF Zinc in Human Biology. Springer-Verlag, New York1989: 147-172
        • Young DS
        Effects of Preanalytical Variables on Clinical Laboratory Tests.
        The American Association for Clinical Chemistry Press, London1993
        • Zweig MH
        • Campbell G
        Receiver operating characteristic (ROC) plots: A fundamental evaluation tool in clinical medicine.
        Clin Chem. 1993; 39: 561-577