Major Depression and Metabolic Encephalopathy: Syndromes More Alike Than Not?

  • Brian H. Harvey


The seminal discovery of the antidepressant imipramine in 1958, the mood-stabilizing actions of lithium ion in 1949, and that these drugs work by increasing or modulating synaptic levels of one or more monoamine such as serotonin (5HT), noradrenaline (NA) or dopamine (DA), have set the gold standard for drug research and treatment in mania and depression. However, drug discovery has not realized its full potential and in many ways is decades behind our understanding of psychiatric illness. Our newest drugs for these disorders, such as the 5HT reuptake inhibitors (SRI, e.g., fluoxetine (Prozac®)), are not any more effective than imipramine in the treatment of depression (Geddes et al., 2000) while after more than 50 years, lithium salts still remain the bench mark treatment for manic ­depression (Compton and Nemeroff, 2000).

The advent of sophisticated techniques in molecular neuroscience and molecular psychiatry has uncovered a wealth of knowledge pertaining to the...


Nitric Oxide NMDA Receptor Hepatic Encephalopathy Fabry Disease Acute Tryptophan Depletion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The author’s work in the area of depression and stress is supported by the South African Medical Research Council (MRC) and the National Research Foundation (grant number 2073038).


  1. Ahboucha, S. and Butterworth, R.F. 2007. The neurosteroid system: an emerging therapeutic target for hepatic encephalopathy. Metab. Brain Dis. 22:291–308.PubMedCrossRefGoogle Scholar
  2. Albrecht, J. and Jones, E.A. 1999. Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome. J. Neurol. Sci. 170:138–146.PubMedCrossRefGoogle Scholar
  3. Altamura, C., Maes, M., Dai, J., and Meltzer, H.Y. 1995. Plasma concentrations of excitatory amino acids, serine, glycine, taurine and histidine in major depression. Eur. Neuropsychopharmacol. 5:71–75.PubMedCrossRefGoogle Scholar
  4. Bansky, G., Meier, P.J., Ziegler, W.H., Walser, H., Schmid, M., and Huber, M. 1985. Reversal of hepatic coma by benzodiazepine antagonist (Ro 15-1788). Lancet 1:132–1325.Google Scholar
  5. Barbosa, L., Berk, M., and Vorster, M. 2003. A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. J. Clin. Psychiatry 64:403–407.PubMedCrossRefGoogle Scholar
  6. Basile, A.S., Hughes, R.D., Harrison, P.M., Murata, Y., Pannell, L., Jones, E.A., Williams, R., and Skolnick, P. 1991. Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure. N. Engl. J. Med. 325:473–478.PubMedCrossRefGoogle Scholar
  7. Bassett, M.L., Mullen, K.D., Skolnick, P., and Jones, E.A. 1987. Amelioration of hepatic encephalopathy by pharmacologic antagonism of the GABAA-benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure. Gastroenterology 93:1069–1077.PubMedGoogle Scholar
  8. Bell, C., Abrams, J., and Nutt, D. 2001. Tryptophan depletion and its implications for psychiatry. Br. J. Psychiatry 178:399–405.PubMedCrossRefGoogle Scholar
  9. Benkert, O., Grunder, G., Wetzel, H., and Hackett, D. 1996. A randomized, double-blind comparison of a rapidly escalating dose of venlafaxine and imipramine in inpatients with major depression and melancholia. J. Psychiatr. Res. 30:441–451.PubMedCrossRefGoogle Scholar
  10. Benkert, O., Szegedi, A., and Kohnen, R. 2000. Mirtazapine compared with paroxetine in major depression. J. Clin. Psychiatry 61:656–663.PubMedCrossRefGoogle Scholar
  11. Bergqvist, P.B., Hjorth, S., Audet, R.M., Apelqvist, G., Bengtsson, F., and Butterworth, R.F. 1996. Ammonium acetate challenge in experimental chronic hepatic encephalopathy induces a transient increase of brain 5-HT release in vivo. Eur. Neuropsychopharmacol. 6:317–322.PubMedCrossRefGoogle Scholar
  12. Berk, M., Plein, H., and Ferreira, D. 2001. Platelet glutamate receptor supersensitivity in major depressive disorder. Clin. Neuropharmacol. 24:129–132.PubMedCrossRefGoogle Scholar
  13. Berton, O. and Nestler, E.J. 2006. New approaches to antidepressant drug discovery: beyond monoamines. Nat. Rev. Neurosci. 7:137–151.PubMedCrossRefGoogle Scholar
  14. Bertsch, T., Mielke, O., Höly, S., Zimmer, W., Casarin, W., Aufenanger, J., Walter, S., Muehlhauser, F., Kuehl, S., Ragoschke, A., and Fassbender, K. 2001. Homocysteine in cerebrovascular disease: an independent risk factor for subcortical vascular encephalopathy. Clin Chem Lab Med 39:721–724.PubMedGoogle Scholar
  15. Bilici, M., Efe, H., Koroglu, M.A., Uydu, H.A., Bekaroglu, M., and Deger, O. 2001. Antioxidative enzyme activities and lipid peroxidation in major depression: alterations by antidepressant treatments. J. Affect. Disord. 64:43–51.PubMedCrossRefGoogle Scholar
  16. Blier, P. 2003. The pharmacology of putative early-onset antidepressant strategies. Eur. Neuropsychopharmacol. 13:57–66.PubMedCrossRefGoogle Scholar
  17. Booij, L., Van der Does, A.J., and Riedel, W.J. 2003. Monoamine depletion in psychiatric and healthy populations: review. Mol. Psychiatry 8:951–973.PubMedCrossRefGoogle Scholar
  18. Borkowska, H.D., Oja, S.S., Oja, O.S., Saransaari, P., Hilgier, W., and Albrecht, J. 1999. N-methyl-d-aspartate-evoked changes in the striatal extracellular levels of dopamine and its metabolites in vivo in rats with acute hepatic encephalopathy. Neurosci. Lett. 268:151–154.PubMedCrossRefGoogle Scholar
  19. Bottiglieri, T. 2005. Homocysteine and folate metabolism in depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 29:1103–1112.PubMedCrossRefGoogle Scholar
  20. Boyer, P.A., Skolnick, P., and Fossom, L.H. 1998. Chronic administration of imipramine and citalopram alters the expression of NMDA receptor subunit mRNAs in mouse brain. A quantitative in situ hybridization study. J. Mol. Neurosci. 10:219–233.PubMedCrossRefGoogle Scholar
  21. Cangiano, C., Cardelli-Cangiano, P., James, J.H., Rossi-Fanelli, F., Patrizi, M.A., Brackett, K.A., Strom, R., and Fischer, J.E. 1983. Brain microvessels take up large neutral amino acids in exchange for glutamine. Cooperative role of Na+-dependent and Na+-independent systems. J. Biol. Chem. 258:8949–8954.PubMedGoogle Scholar
  22. Capuron, L. and Dantzer, R. 2003. Cytokines and depression: the need for a new paradigm. Brain Behav. Immun. 17(Suppl. 1):S119–S124.PubMedCrossRefGoogle Scholar
  23. Carpenter, L.L., Yasmin, S., and Price, L.H. 2002. A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. Biol. Psychiatry 51:183–188.PubMedCrossRefGoogle Scholar
  24. Cauli, O., Rodrigo, R., Piedrafita, B., Boix, J., and Felipo, V. 2007. Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with portacaval shunts. Hepatology 46:51–519.PubMedCrossRefGoogle Scholar
  25. Chamberlin, E. and Tsai, G.E. 1998. A glutamatergic model of ECT-induced memory dysfunction. Harv Rev Psychiatry 5:307–317.PubMedCrossRefGoogle Scholar
  26. Chan, K.H., Cheung, R.T., Au-Yeung, K.M., Mak, W., Cheng, T.S., and Ho, S.L. 2005. Wilson’s disease with depression and parkinsonism. J. Clin. Neurosci. 12:303–305.PubMedCrossRefGoogle Scholar
  27. Chen, F., Larsen, M.B., Sanchez, C., and Wiborg, O. 2005. The S-enantiomer of R,S-citalopram, increases inhibitor binding to the human serotonin transporter by an allosteric mechanism. Comparison with other serotonin transporter inhibitors. Eur. Neuropsychopharmacol. 15:193–198.PubMedCrossRefGoogle Scholar
  28. Chrapko, W.E., Jurasz, P., Radomski, M.W., Lara, N., Archer, S.L., and Le Melledo, J.M. 2004. Decreased platelet nitric oxide synthase activity and plasma nitric oxide metabolites in major depressive disorder. Biol. Psychiatry 56:129–134.PubMedCrossRefGoogle Scholar
  29. Ciranna, L. 2006. Serotonin as a modulator of glutamate- and GABA-mediated neurotransmission: implications in physiological function in pathology. Curr. Neuropharmacol. 4:101–114.PubMedCrossRefGoogle Scholar
  30. Compton, M.T. and Nemeroff, C.B. 2000. The treatment of bipolar depression. J. Clin. Psychiatry 61(Suppl. 9):57–67.PubMedGoogle Scholar
  31. Cooper, J.R., Bloom, F.E., and Roth, R.H. 1996. The Biochemical Basis of Neuropharmacology. New York: Oxford University Press.Google Scholar
  32. D’Sa, C. and Duman, R.S. 2002. Antidepressants and neuroplasticity. Bipolar Disord. 4:183–194.PubMedCrossRefGoogle Scholar
  33. Dager, S.R., Friedman, S.D., Parow, A., Demopulos, C., Stoll, A.L., Lyoo, I.K., Dunner, D.L., and Renshaw, P.F. 2004. Brain metabolic alterations in medication-free patients with bipolar disorder. Arch. Gen. Psychiatry 61:450–458.PubMedCrossRefGoogle Scholar
  34. Dall’Olio, R., Gandolfi, O., and Gaggi, R. 2000. d-Cycloserine, a positive modulator of NMDA receptors, inhibits serotonergic function. Behav. Pharmacol. 11:631–637.PubMedCrossRefGoogle Scholar
  35. Dantzer, R. 2001. Cytokine-induced sickness behavior: where do we stand? Brain Behav. Immun. 15:7–24.PubMedCrossRefGoogle Scholar
  36. Delgado, P.L., Miller, H.L., Salomon, R.M., Licinio, J., Krystal, J.H., Moreno, F.A., Heninger, G.R., and Charney, D.S. 1999. Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. Biol. Psychiatry 46:212–220.PubMedCrossRefGoogle Scholar
  37. Devanand, D.P., Shapira, B., Petty, F., Kramer, G., Fitzsimons, L., Lerer, B., and Sackeim, H.A. 1995. Effects of electroconvulsive therapy on plasma GABA. Convulsive Ther. 11:3–13.Google Scholar
  38. Di Cara, B., Dusticier, N., Forni, C., Lievens, J.C., and Daszuta, A. 2001. Serotonin depletion produces long lasting increase in striatal glutamatergic transmission. J. Neurochem. 78:240–248.PubMedCrossRefGoogle Scholar
  39. Di Martini, A., Dew, M.A., Javed, L., Fitzgerald, M.G., Jain, A., and Day, N. 2004. Pretransplant psychiatric and medical comorbidity of alcoholic liver disease patients who received liver transplant. Psychosomatics 45:517–523.CrossRefGoogle Scholar
  40. Dimopoulos, N., Piperi, C., Salonicioti, A., Psarra, V., Gazi, F., Papadimitriou, A., Lea, R.W., and Kalofoutis, A. 2007. Correlation of folate, vitamin B12 and homocysteine plasma levels with depression in an elderly Greek population. Clin Biochem 40:60–608.PubMedCrossRefGoogle Scholar
  41. Domek-Łopacíska, K. and Strosznajder, J.B. 2005. Cyclic GMP metabolism and its role in brain physiology. J. Physiol. Pharmacol. 56(Suppl. 2):15–34.Google Scholar
  42. Drevets, W.C., Thase, M.E., Moses-Kolko, E.L., Price, J., Frank, E., Kupfer, D.J., and Mathis, C. 2007. Serotonin-1A receptor imaging in recurrent depression: replication and literature review. Nucl Med Biol 34:865–877.PubMedCrossRefGoogle Scholar
  43. Dunn, A. 2001. Effects of cytokines and infections on brain neurochemistry. In Psycho­neuroimmunology, ed. R. Ader, D. Felten, and N. Cohen, pp. 649–666. San Diego: Academic.Google Scholar
  44. Eggers, B., Hermann, W., Barthel, H., Sabri, O., Wagner, A., and Hesse, S. 2003. The degree of depression in Hamilton rating scale is correlated with the density of presynaptic serotonin transporters in 23 patients with Wilson’s disease. J. Neurol. 250:576–580.PubMedCrossRefGoogle Scholar
  45. Engelmann, M., Wolf, G., and Horn, T.F. 2002. Release patterns of excitatory and inhibitory amino acids within the hypothalamic supraoptic nucleus in response to direct nitric oxide administration during forced swimming in rats. Neurosci. Lett. 324:252–254.PubMedCrossRefGoogle Scholar
  46. Entsuah, R., Derivan, A., and Kikta, D. 1998. Early onset of antidepressant action of venlafaxine: pattern analysis in intent-to-treat patients. Clin. Ther. 20:517–526.PubMedCrossRefGoogle Scholar
  47. Erceg, S., Monfort, P., Hernandez-Viadel, M., Rodrigo, R., Montoliu, C., and Felipo, V. 2005. Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts. Hepatology 41:299–306.PubMedCrossRefGoogle Scholar
  48. Felipo, V., Grau, E., Minana, M.D., and Grisolia, S. 1993. Hyperammonemia decreases protein-kinase-C-dependent phosphorylation of microtubule-associated protein 2 and increases its binding to tubulin. Eur. J. Biochem. 214:243–249.PubMedCrossRefGoogle Scholar
  49. Folstein, M., Liu, T., Peter, I., Buell, J., Arsenault, L., Scott, T., and Qiu, W.W. 2007. The homocysteine hypothesis of depression. Am J Psychiatry 164:861–867.PubMedCrossRefGoogle Scholar
  50. Forton, D.M., Thomas, H.C., and Taylor-Robinson, S.D. 2004. Central nervous system involvement in hepatitis C virus infection. Metab. Brain Dis. 19:383–391.PubMedCrossRefGoogle Scholar
  51. Frankenburg, F.R. 2007. The role of one-carbon metabolism in schizophrenia and depression. Harv Rev Psychiatry 15:146–160.PubMedCrossRefGoogle Scholar
  52. Frieling, H., Romer, K.D., Beyer, S., Hillemacher, T., Wilhelm, J., Jacoby, G.E., de Zwaan, M., Kornhuber, J., and Bleich, S. 2006. Depressive symptoms may explain elevated plasma levels of homocysteine in females with eating disorders. J Psychiatr Res, Dec 18; doi:10.1016/j.jpsychires.2006.10.007 [Epub ahead of print].Google Scholar
  53. Gammal, S.H., Basile, A.S., Geller, D., Skolnick, P., and Jones, E.A. 1990. Reversal of the behavioral and electrophysiological abnormalities of an animal model of hepatic encephalopathy by benzodiazepine receptor ligands. Hepatology 11:371–378.PubMedCrossRefGoogle Scholar
  54. Gardner, A., Johansson, A., Wibom, R., Nennesmo, I., von Dobeln, U., Hagenfeldt, L., and Hallstrom, T. 2003. Alterations of mitochondrial function and correlations with personality traits in selected major depressive disorder patients. J. Affect. Disord. 76:55–68.PubMedCrossRefGoogle Scholar
  55. Geddes, J.R., Freemantle, N., Mason, J., Eccles, M.P., and Boynton, J. 2000. SSRIs versus other antidepressants for depressive disorder. Cochrane Database Syst. Rev. CD001851.Google Scholar
  56. Guelfi, J.D., White, C., Hackett, D., Guichoux, J.Y., and Magni, G. 1995. Effectiveness of venlafaxine in patients hospitalized for major depression and melancholia. J. Clin. Psychiatry 56:450–458.PubMedGoogle Scholar
  57. Gutiérrez-Aguilar, G., Abenia-Usón, P., García-Cazorla, A., Vilaseca, M.A., and Campistol, J. 2005. Encephalopathy with methylmalonic aciduria and homocystinuria secondary to a deficient exogenous supply of vitamin B12. Rev. Neurol. 40:605–608.PubMedGoogle Scholar
  58. Ha, J.H. and Basile, A.S. 1996. Modulation of ligand binding to components of the GABAA receptor complex by ammonia: implications for the pathogenesis of hyperammonemic syndromes. Brain Res. 720:35–44.PubMedCrossRefGoogle Scholar
  59. Harkin, A.J., Bruce, K.H., Craft, B., and Paul, I.A. 1999. Nitric oxide synthase inhibitors have antidepressant-like properties in mice. 1. Acute treatments are active in the forced swim test. Eur. J. Pharmacol. 372:207–213.PubMedCrossRefGoogle Scholar
  60. Harkin, A., Connor, T.J., Burns, M.P., and Kelly, J.P. 2004. Nitric oxide synthase inhibitors augment the effects of serotonin re-uptake inhibitors in the forced swimming test. Eur. Neuropsychopharmacol. 14:27–281.PubMedCrossRefGoogle Scholar
  61. Harkin, A., Nowak, G., and Paul, I.A. 2000. Noradrenergic lesion antagonizes desipramine-induced adaptation of NMDA receptors. Eur. J. Pharmacol. 389:187–192.PubMedCrossRefGoogle Scholar
  62. Harvey, B.H. 1996. Affective disorders and nitric oxide: a role in pathways to relapse and refractoriness. Hum. Psychopharmacol. 11:309–319.CrossRefGoogle Scholar
  63. Harvey, B.H., Jonker, L.P., Brand, L., Heenop, M., and Stein, D.J. 2002. NMDA receptor involvement in imipramine withdrawal-associated effects on swim stress, GABA levels and NMDA receptor binding in rat hippocampus. Life Sci. 71:43–54.PubMedCrossRefGoogle Scholar
  64. Harvey, B.H., McEwen, B.S., and Stein, D.J. 2003. Neurobiology of antidepressant withdrawal: implications for the longitudinal outcome of depression. Biol. Psychiatry 54:1105–1117.PubMedCrossRefGoogle Scholar
  65. Harvey, B.H., Oosthuizen, F., Brand, L., Wegener, G., and Stein, D.J. 2004. Stress–restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus. Psychopharmacology (Berl.) 175:49–502.CrossRefGoogle Scholar
  66. Harvey, B.H., Retief, R., Korff, A., and Wegener, G. 2006. Increased hippocampal nitric oxide synthase activity and stress responsiveness after imipramine discontinuation: role of 5HT 2A/C-receptors. Metab. Brain Dis. 21:211–220.PubMedCrossRefGoogle Scholar
  67. Heiberg, I.L., Wegener, G., and Rosenberg, R. 2002. Reduction of cGMP and nitric oxide has antidepressant-like effects in the forced swimming test in rats. Behav. Brain Res. 134:479–484.PubMedCrossRefGoogle Scholar
  68. Heresco-Levy, U., Javitt, D.C., Gelfin, Y., Gorelik, E., Bar, M., Blanaru, M., and Kremer, I. 2006. Controlled trial of d-cycloserine adjuvant therapy for treatment-resistant major depressive disorder. J. Affect. Disord. 93:239–243.PubMedCrossRefGoogle Scholar
  69. Hesse, S., Barthel, H., Hermann, W., Murai, T., Kluge, R., Wagner, A., Sabri, O., and Eggers, B. 2003. Regional serotonin transporter availability and depression are correlated in Wilson’s disease. J. Neural Transm. 110:923–933.PubMedCrossRefGoogle Scholar
  70. Hilgier, W., Puka, M., and Albrecht, J. 1992. Characteristics of large neutral amino acid-induced release of preloaded l-glutamine from rat cerebral capillaries in vitro: effects of ammonia, hepatic encephalopathy, and gamma-glutamyl transpeptidase inhibitors. J. Neurosci. Res. 32:221–226.PubMedCrossRefGoogle Scholar
  71. House, J.D., Jacobs, R.L., Stead, L.M., Brosnan, M.E., and Brosnan, J.T. 1999. Regulation of homocysteine metabolism. Adv. Enzyme Regul. 39:69–91.PubMedCrossRefGoogle Scholar
  72. Ishizuka, Y., Ishida, Y., Jin, Q.H., Mitsuyama, Y., and Kannan, H. 2000. GABA(A) and GABA(B) receptors modulating basal and footshock-induced nitric oxide releases in rat prefrontal cortex. Brain Res. 872:266–270.PubMedCrossRefGoogle Scholar
  73. Jones, E.A. 2002. Ammonia, the GABA neurotransmitter system, and hepatic encephalopathy. Metab. Brain Dis. 17:275–281.PubMedCrossRefGoogle Scholar
  74. Kaneko, K., Kurumaji, A., Watanabe, A., Yamada, S., and Toru, M. 1998. Changes in high K+-evoked serotonin release and serotonin 2A/2C receptor binding in the frontal cortex of rats with thioacetamide-induced hepatic encephalopathy. J. Neural Transm. 105:13–30.PubMedCrossRefGoogle Scholar
  75. Kasper, S., Spadone, C., Verpillat, P., and Angst, J. 2006. Onset of action of escitalopram compared with other antidepressants: results of a pooled analysis. Int. Clin. Psychopharmacol. 21:105–110.PubMedCrossRefGoogle Scholar
  76. Kendler, K.S., Thornton, L.M., and Gardner, C.O. 2001. Genetic risk, number of previous depressive episodes, and stressful life events in predicting onset of major depression. Am. J. Psychiatry 158:582–586.PubMedCrossRefGoogle Scholar
  77. Kim, Y.K., Paik, J.W., Lee, S.W., Yoon, D., Han, C., and Lee, B.H. 2006. Increased plasma nitric oxide level associated with suicide attempt in depressive patients. Prog. Neuropsychopharmacol. Biol. Psychiatry 30:1091–1096.PubMedCrossRefGoogle Scholar
  78. Kocsis, J.H. 2003. Pharmacotherapy for chronic depression. J. Clin. Psychol. 59:885–892.PubMedCrossRefGoogle Scholar
  79. Kosenko, E., Kaminsky, Y., Grau, E., Minana, M.D., Grisolia, S., and Felipo, V. 1995. Nitroarginine, an inhibitor of nitric oxide synthetase, attenuates ammonia toxicity and ammonia-induced alterations in brain metabolism. Neurochem. Res. 20:451–456.PubMedCrossRefGoogle Scholar
  80. Kosenko, E., Kaminsky, Y., Grau, E., Minana, M.D., Marcaida, G., Grisolia, S., and Felipo, V. 1994. Brain ATP depletion induced by acute ammonia intoxication in rats is mediated by activation of the NMDA receptor and Na+,K(+)-ATPase. J. Neurochem. 63:2172–2178.PubMedCrossRefGoogle Scholar
  81. Kosenko, E., Kaminsky, Y., Lopata, O., Muravyov, N., Kaminsky, A., Hermenegildo, C., and Felipo, V. 1998. Nitroarginine, an inhibitor of nitric oxide synthase, prevents changes in superoxide radical and antioxidant enzymes induced by ammonia intoxication. Metab. Brain Dis. 13:29–41.PubMedCrossRefGoogle Scholar
  82. Kroczka, B., Branski, P., Palucha, A., Pilc, A., and Nowak, G. 2001. Antidepressant-like properties of zinc in rodent forced swim test. Brain Res. Bull. 55:297–300.PubMedCrossRefGoogle Scholar
  83. Kruse, J., Petrak, F., Herpertz, S., Albus, C., Lange, K., and Kulzer, B. 2006. Diabetes and depression – a life-endangering interaction. Z. Psychosom. Med. Psychother. 52:289–309.PubMedGoogle Scholar
  84. Krystal, J.H., Sanacora, G., Blumberg, H., Anand, A., Charney, D.S., Marek, G., Epperson, C.N., Goddard, A., and Mason, G.F. 2002. Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Mol. Psychiatry 7(Suppl. 1):S71–S80.PubMedCrossRefGoogle Scholar
  85. Law, A.J. and Deakin, J.F. 2001. Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses. Neuroreport 12:2971–2974.PubMedCrossRefGoogle Scholar
  86. Leinonen, E., Skarstein, J., Behnke, K., Agren, H., and Helsdingen, J.T. 1999. Efficacy and tolerability of mirtazapine versus citalopram: a double-blind, randomized study in patients with major depressive disorder. Nordic Antidepressant Study Group. Int. Clin. Psychopharmacol. 14:329–337.PubMedCrossRefGoogle Scholar
  87. Leonard, B.E. 2003. Fundamentals of Psychopharmacology. Chichester: Wiley.CrossRefGoogle Scholar
  88. Levine, J., Sela, B.A., Osher, Y., and Belmaker, R.H. 2005. High homocysteine serum levels in young male schizophrenia and bipolar patients and in an animal model. Prog. Neuropsychopharmacol. Biol. Psychiatry 29:1181–1191.PubMedCrossRefGoogle Scholar
  89. Lipton, S.A., Kim, W.K., Choi, Y.B., Kumar, S., D’Emilia, D.M., Rayudu, P.V., Arnelle, D.R., and Stamler, J.S. 1997. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-d-aspartate receptor. Proc. Natl Acad. Sci. USA 94:5923–5928.PubMedCrossRefGoogle Scholar
  90. Madrigal, J.L., Garcia-Bueno, B., Caso, J.R., Perez-Nievas, B.G., and Leza, J.C. 2006. Stress-induced oxidative changes in brain. CNS Neurol. Disord. Drug Targets 5:561–568.PubMedCrossRefGoogle Scholar
  91. Maes, M., D’Haese, P.C., Scharpe, S., D’Hondt, P., Cosyns, P., and De Broe, M.E. 1994. Hypozincemia in depression. J. Affect. Disord. 31:135–140.PubMedCrossRefGoogle Scholar
  92. Maes, M., Verkerk, R., Vandoolaeghe, E., Lin, A., and Scharpe, S. 1998. Serum levels of excitatory amino acids, serine, glycine, histidine, threonine, taurine, alanine and arginine in treatment-resistant depression: modulation by treatment with antidepressants and prediction of clinical responsivity. Acta Psychiatr. Scand. 97:302–308.PubMedCrossRefGoogle Scholar
  93. Manji, H.K., Drevets, W.C., and Charney, D.S. 2001. The cellular neurobiology of depression. Nat. Med. 7:541–547.PubMedCrossRefGoogle Scholar
  94. McDaniel, W.W., Sahota, A.K., Vyas, B.V., Laguerta, N., Hategan, L., and Oswald, J. 2006. Ketamine appears associated with better word recall than etomidate after a course of 6 electroconvulsive therapies. J. ECT 22:103–106.PubMedCrossRefGoogle Scholar
  95. McLeod, T.M., Lopez-Figueroa, A.L., and Lopez-Figueroa, M.O. 2001. Nitric oxide, stress, and depression. Psychopharmacol. Bull. 35:2–41.PubMedGoogle Scholar
  96. Michalak, A., Chatauret, N., and Butterworth, R.F. 2001. Evidence for a serotonin transporter deficit in experimental acute liver failure. Neurochem. Int. 38:163–68.PubMedCrossRefGoogle Scholar
  97. Michalak, A., Rose, C., Butterworth, J., and Butterworth, R.F. 1996. Neuroactive amino acids and glutamate (NMDA) receptors in frontal cortex of rats with experimental acute liver failure. Hepatology 24:908–913.PubMedCrossRefGoogle Scholar
  98. Miller, A.H., Capuron, L., and Raison, C.L. 2005. Immunologic influences on emotion regulation. Clin. Neurosci. Res. 4:325–333.CrossRefGoogle Scholar
  99. Mitchell, A.J. 2006. Two-week delay in onset of action of antidepressants: new evidence. Br. J. Psychiatry 188:105–106.PubMedCrossRefGoogle Scholar
  100. Montoliu, C., Piedrafita, B., Serra, M.A., del Olmo, J.A., Rodrigo, J.M., and Felipo, V. 2007. A single transient episode of hyperammonemia induces long-lasting alterations in protein kinase A. Am. J. Physiol Gastrointest Liver Physiol 292: G305–14.CrossRefGoogle Scholar
  101. Mousseau, D.D., Baker, G.B., and Butterworth, R.F. 1997. Increased density of catalytic sites and expression of brain monoamine oxidase A in humans with hepatic encephalopathy. J. Neurochem. 68:1200–1208.PubMedCrossRefGoogle Scholar
  102. Mousseau, D.D., Perney, P., Layrargues, G.P., and Butterworth, R.F. 1993. Selective loss of pallidal dopamine D2 receptor density in hepatic encephalopathy. Neurosci. Lett. 162:192–196.PubMedCrossRefGoogle Scholar
  103. Muller, N., Schwarz, M.J., Dehning, S., Douhe, A., Cerovecki, A., Goldstein-Muller, B., Spellmann, I., Hetzel, G., Maino, K., Kleindienst, N., Moller, H.J., Arolt, V., and Riedel, M. 2006. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol. Psychiatry 11:680–684.PubMedCrossRefGoogle Scholar
  104. Nelson, J.C., Mazure, C.M., Jatlow, P.I., Bowers, M.B., Jr., and Price, L.H. 2004. Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: a double-blind, randomized study. Biol. Psychiatry 55:296–300.PubMedCrossRefGoogle Scholar
  105. Nilsson, K., Gustafson, L., and Hultberg, B. 2007. Elevated plasma homocysteine concentration in elderly patients with mental illness is mainly related to the presence of vascular disease and not the diagnosis. Dement. Geriatr. Cogn. Disord. 24:162–168.PubMedCrossRefGoogle Scholar
  106. Norenberg, M.D. and Martinez-Hernandez, A. 1979. Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res. 161:303–310.PubMedCrossRefGoogle Scholar
  107. Norris, E.R., Smallwood, G.A., Connor, K., McDonell, K., Martinez, E., Stieber, A.C., and Heffron, T.G. 2002. Prevalence of depressive symptoms in patients being evaluated for liver transplantation. Transplant. Proc. 34:3285–3286.PubMedCrossRefGoogle Scholar
  108. Nowak, G., Ordway, G.A., and Paul, I.A. 1995. Alterations in the N-methyl-d-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims. Brain Res. 675:157–164.PubMedCrossRefGoogle Scholar
  109. Ohkuma, S., Narihara, H., Katsura, M., Hasegawa, T., and Kuriyama, K. 1995. Nitric oxide-induced [3H] GABA release from cerebral cortical neurons is mediated by peroxynitrite. J. Neurochem. 65:1109–1114.PubMedCrossRefGoogle Scholar
  110. Olasmaa, M., Rothstein, J.D., Guidotti, A., Weber, R.J., Paul, S.M., Spector, S., Zeneroli, M.L., Baraldi, M., and Costa, E. 1990. Endogenous benzodiazepine receptor ligands in human and animal hepatic encephalopathy. J. Neurochem. 55:2015–2023.PubMedCrossRefGoogle Scholar
  111. Packman, W., Wilson, C.T., Riesner, A., Fairley, C., and Packman, S. 2006. Psychological complications of patients with Gaucher disease. J. Inherit. Metab. Dis. 29:99–105.PubMedCrossRefGoogle Scholar
  112. Pandey, G.N., Conley, R.R., Pandey, S.C., Goel, S., Roberts, R.C., Tamminga, C.A., Chute, D., and Smialek, J. 1997. Benzodiazepine receptors in the post-mortem brain of suicide victims and schizophrenic subjects. Psychiatry Res. 71:137–149.PubMedCrossRefGoogle Scholar
  113. Perez, V., Gilaberte, I., Faries, D., Alvarez, E., and Artigas, F. 1997. Randomised, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment. Lancet 349:159–1597.PubMedCrossRefGoogle Scholar
  114. Perlmutter, J.B., Frishman, W.H., and Feinstein, R.E. 2000. Major depression as a risk factor for cardiovascular disease: therapeutic implications. Heart Dis. 2:75–82.PubMedGoogle Scholar
  115. Prast, H. and Philippu, A. 2001. Nitric oxide as modulator of neuronal function. Prog. Neurobiol. 64:51–68.PubMedCrossRefGoogle Scholar
  116. Rao, V.L. and Butterworth, R.F. 1994. Alterations of [3H]8-OH-DPAT and [3H]ketanserin binding sites in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Neurosci. Lett. 182:69–72.PubMedCrossRefGoogle Scholar
  117. Rao, V.L., Giguere, J.F., Layrargues, G.P., and Butterworth, R.F. 1993. Increased activities of MAOA and MAOB in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Brain Res. 621:349–352.PubMedCrossRefGoogle Scholar
  118. Ratnakumari, L., Audet, R., Qureshi, I.A., and Butterworth, R.F. 1995. Na+,K(+)-ATPase activities are increased in brain in both congenital and acquired hyperammonemic syndromes. Neurosci. Lett. 197:89–92.PubMedCrossRefGoogle Scholar
  119. Regenold, W.T., Hisley, K.C., Obuchowski, A., Lefkowitz, D.M., Marano, C., and Hauser, P. 2005. Relationship of white matter hyperintensities to cerebrospinal fluid glucose polyol pathway metabolites – a pilot study in treatment-resistant affective disorder patients. J. Affect. Disord. 85:341–350.PubMedCrossRefGoogle Scholar
  120. Regenold, W.T., Phatak, P., Kling, M.A., and Hauser, P. 2004. Post-mortem evidence from human brain tissue of disturbed glucose metabolism in mood and psychotic disorders. Mol. Psychiatry 9:731–733.PubMedCrossRefGoogle Scholar
  121. Riedel, G., Platt, B., and Micheau, J. 2003. Glutamate receptor function in learning and memory. Behav. Brain Res. 140:1–47.PubMedCrossRefGoogle Scholar
  122. Rogoz, Z., Dziedzicka-Wasylewska, M., Daniel, W.A., Wojcikowski, J., Dudek, D., Wrobel, A., and Zieba, A. 2004. Effects of joint administration of imipramine and amantadine in patients with drug-resistant unipolar depression. Pol. J. Pharmacol. 56:735–742.PubMedCrossRefGoogle Scholar
  123. Rogoz, Z., Skuza, G., Maj, J., and Danysz, W. 2002. Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats. Neuropharmacology 42:102–1030.PubMedCrossRefGoogle Scholar
  124. Rozanski, A., Blumenthal, J.A., and Kaplan, J. 1999. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation 99:2192–2217.PubMedCrossRefGoogle Scholar
  125. Sadek, J., Shellhaas, R., Camfield, C.S., Camfield, P.R., and Burley, J. 2004. Psychiatric findings in four female carriers of Fabry disease. Psychiatr. Genet. 14:199–201.PubMedCrossRefGoogle Scholar
  126. Sanacora, G., Mason, G.F., Rothman, D.L., Hyder, F., Ciarcia, J.J., Ostroff, R.B., Berman, R.M., and Krystal, J.H. 2003. Increased cortical GABA concentrations in depressed patients receiving ECT. Am. J. Psychiatry 160:577–579.PubMedCrossRefGoogle Scholar
  127. Sanchez, C. 2006. The pharmacology of citalopram enantiomers: the antagonism by R-citalopram on the effect of S-citalopram. Basic Clin. Pharmacol. Toxicol. 99:91–95.PubMedCrossRefGoogle Scholar
  128. Sapolsky, R.M. 2000. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch. Gen. Psychiatry 57:925–935.PubMedCrossRefGoogle Scholar
  129. Saran, T., Hilgier, W., Kocki, T., Urbanska, E.M., Turski, W.A., and Albrecht, J. 1998. Acute ammonia treatment in vitro and in vivo inhibits the synthesis of a neuroprotectant kynurenic acid in rat cerebral cortical slices. Brain Res. 787:348–350.PubMedCrossRefGoogle Scholar
  130. Saransaari, P. and Oja, S.S. 1997. Enhanced GABA release in cell-damaging conditions in the adult and developing mouse hippocampus. Int. J. Dev. Neurosci. 15:163–174.PubMedCrossRefGoogle Scholar
  131. Sargent, P.A., Kjaer, K.H., Bench, C.J., Rabiner, E.A., Messa, C., Meyer, J., Gunn, R.N., Grasby, P.M., and Cowen, P.J. 2000. Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch. Gen. Psychiatry 57:17–180.PubMedCrossRefGoogle Scholar
  132. Schliess, F., Gorg, B., and Haussinger, D. 2006. Pathogenetic interplay between osmotic and oxidative stress: the hepatic encephalopathy paradigm. Biol. Chem. 387:1363–1370.PubMedCrossRefGoogle Scholar
  133. Scollo-Lavizzari, G. and Steinmann, E. 1985. Reversal of hepatic coma by benzodiazepine antagonist (Ro 15-1788). Lancet 1:132–1325.CrossRefGoogle Scholar
  134. Shiah, I.S. and Yatham, L.N. 1998. GABA function in mood disorders: an update and critical review. Life Sci. 63:1289–1303.PubMedCrossRefGoogle Scholar
  135. Skolnick, P. 1999. Antidepressants for the new millennium. Eur. J. Pharmacol. 375:31–40.PubMedCrossRefGoogle Scholar
  136. Skolnick, P., Layer, R.T., Popik, P., Nowak, G., Paul, I.A., and Trullas, R. 1996. Adaptation of N-methyl-d-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry 29:23–26.PubMedCrossRefGoogle Scholar
  137. Stahl, S. 1996. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Cambridge: Cambridge University Press.Google Scholar
  138. Stahl, S.M., Nierenberg, A.A., and Gorman, J.M. 2001. Evidence of early onset of antidepressant effect in randomized controlled trials. J. Clin. Psychiatry 62(Suppl. 4):17–23.PubMedGoogle Scholar
  139. Starkman, M.N., Gebarski, S.S., Berent, S., and Schteingart, D.E. 1992. Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing’s syndrome. Biol. Psychiatry 32:756–765.PubMedCrossRefGoogle Scholar
  140. Starkman, M.N., Giordani, B., Berent, S., Schork, M.A., and Schteingart, D.E. 2001. Elevated cortisol levels in Cushing’s disease are associated with cognitive decrements. Psychosom. Med. 63:985–993.PubMedGoogle Scholar
  141. Starkman, M.N., Giordani, B., Gebarski, S.S., Berent, S., Schork, M.A., and Schteingart, D.E. 1999. Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing’s disease. Biol. Psychiatry 46:1595–1602.PubMedCrossRefGoogle Scholar
  142. Stewart, C.A. and Reid, I.C. 2002. Antidepressant mechanisms: functional and molecular correlates of excitatory amino acid neurotransmission. Mol. Psychiatry 7(Suppl. 1):S15–S22.PubMedCrossRefGoogle Scholar
  143. Stryjer, R., Strous, R.D., Shaked, G., Bar, F., Feldman, B., Kotler, M., Polak, L., Rosenzcwaig, S., and Weizman, A. 2003. Amantadine as augmentation therapy in the management of treatment-resistant depression. Int. Clin. Psychopharmacol. 18:93–96.PubMedCrossRefGoogle Scholar
  144. Suzuki, E., Yagi, G., Nakaki, T., Kanba, S., and Asai, M. 2001. Elevated plasma nitrate levels in depressive states. J. Affect. Disord. 63:221–224.PubMedCrossRefGoogle Scholar
  145. Suzuki, E., Yoshida, Y., Shibuya, A., and Miyaoka, H. 2003. Nitric oxide involvement in depression during interferon-alpha therapy. Int. J. Neuropsychopharmacol. 6:415–419.PubMedCrossRefGoogle Scholar
  146. Tagliaferro, P., Ramos, A.J., Lopez-Costa, J.J., Lopez, E.M., Saavedra, J.P., and Brusco, A. 2001. Increased nitric oxide synthase activity in a model of serotonin depletion. Brain Res. Bull. 54:199–205.PubMedCrossRefGoogle Scholar
  147. Tao, R. and Auerbach, S.B. 2000. Regulation of serotonin release by GABA and excitatory amino acids. J. Psychopharmacol. 14:100–113.PubMedCrossRefGoogle Scholar
  148. Thompson, C. 2002. Onset of action of antidepressants: results of different analyses. Hum. Psychopharmacol. 17(Suppl. 1):S27–S32.PubMedCrossRefGoogle Scholar
  149. Tome, M.B., Isaac, M.T., Harte, R., and Holland, C. 1997. Paroxetine and pindolol: a randomized trial of serotonergic autoreceptor blockade in the reduction of antidepressant latency. Int. Clin. Psychopharmacol. 12:81–89.PubMedCrossRefGoogle Scholar
  150. Vaquero, J. and Butterworth, R.F. 2006. The brain glutamate system in liver failure. J. Neurochem. 98:661–669.PubMedCrossRefGoogle Scholar
  151. Vester-Blokland, E. and Van Oers, H. 2002. Mirtazapine orally disintegrating tablets versus sertraline: response and remission in a prospective onset-of-action trial. Eur. Neuropsychopharmacol. 12:S186.CrossRefGoogle Scholar
  152. Vogels, B.A., Maas, M.A., Daalhuisen, J., Quack, G., and Chamuleau, R.A. 1997. Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats. Hepatology 25:820–827.PubMedCrossRefGoogle Scholar
  153. Wegener, G., Volke, V., Harvey, B.H., and Rosenberg, R. 2003. Local, but not systemic, administration of serotonergic antidepressants decreases hippocampal nitric oxide synthase activity. Brain Res. 959:128–134.PubMedCrossRefGoogle Scholar
  154. Wheatley, D.P., van Moffaert, M., Timmerman, L., and Kremer, C.M. 1998. Mirtazapine: efficacy and tolerability in comparison with fluoxetine in patients with moderate to severe major depressive disorder. Mirtazapine–Fluoxetine Study Group. J. Clin. Psychiatry 59:306–312.CrossRefGoogle Scholar
  155. Wheeler, D., Boutelle, M.G., and Fillenz, M. 1995. The role of N-methyl-d-aspartate receptors in the regulation of physiologically released dopamine. Neuroscience 65:767–774.PubMedCrossRefGoogle Scholar
  156. Wichers, M.C. and Maes, M. 2004. The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-alpha-induced depression. J. Psychiatry Neurosci. 29:11–17.PubMedGoogle Scholar
  157. Wysmyk, U., Oja, S.S., Saransaari, P., and Albrecht, J. 1992. Enhanced GABA release in cerebral cortical slices derived from rats with thioacetamide-induced hepatic encephalopathy. Neurochem. Res. 17:1187–1190.PubMedCrossRefGoogle Scholar
  158. Yamada, J., Saitow, F., Satake, S., Kiyohara, T., and Konishi, S. 1999. GABA(B) receptor-mediated presynaptic inhibition of glutamatergic and GABAergic transmission in the basolateral amygdala. Neuropharmacology 38:1743–1753.PubMedCrossRefGoogle Scholar
  159. Yurdaydin, C., Herneth, A.M., Puspok, A., Steindl, P., Singer, E., and Ferenci, P. 1996. Modulation of hepatic encephalopathy in rats with thioacetamide-induced acute liver failure by serotonin antagonists. Eur. J. Gastroenterol. Hepatol. 8:667–671.PubMedGoogle Scholar
  160. Zanardi, R., Serretti, A., Rossini, D., Franchini, L., Cusin, C., Lattuada, E., Dotoli, D., and Smeraldi, E. 2001. Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-HTTLPR in delusional and nondelusional depression. Biol. Psychiatry 50:323–330.PubMedCrossRefGoogle Scholar
  161. Zarate, C.A., Jr., Singh, J.B., Carlson, P.J., Brutsche, N.E., Ameli, R., Luckenbaugh, D.A., Charney, D.S., and Manji, H.K. 2006. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 63:856–864.PubMedCrossRefGoogle Scholar
  162. Zieve, L. 1987. Pathogenesis of hepatic encephalopathy. Metab. Brain Dis. 2:147–165.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Brian H. Harvey
    • 1
  1. 1.Division of Pharmacology, School of PharmacyNorth-West UniversityPotchefstroomSouth Africa

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