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. 1983;15(Suppl 3):393S–405S. doi: 10.1111/j.1365-2125.1983.tb02130.x

5-Hydroxytryptamine and depression

A model for the interaction of normal variance with pathology

F K Goodwin, R M Post
PMCID: PMC1427648  PMID: 6190490

Abstract

1 Theories linking 5-hydroxytryptamine (5-HT) with depression are briefly reviewed. The various experimental strategies adopted to investigate this relationship, examination of autopsy data, CSF metabolite data, 5-HT re-uptake patterns in human blood platelets and imipramine binding studies in human platelets, are discussed.

2 Recent studies of 5-hydroxyindole acetic acid (5-HIAA) levels in cerebrospinal fluid have revealed a linkage between low 5-HIAA levels and suicide, aggression and impulsivity. Decreases in the number of imipramine binding sites have also been found in brains of suicide victims.

3 The available data lead to the conclusion that decreased 5-hydroxytryptaminergic function may be associated with an increased risk of depression, suicide, and some types of aggression.

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Selected References

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  1. Agren H. Symptom patterns in unipolar and bipolar depression correlating with monoamine metabolites in the cerebrospinal fluid: I. General patterns. Psychiatry Res. 1980 Oct;3(2):211–223. doi: 10.1016/0165-1781(80)90038-4. [DOI] [PubMed] [Google Scholar]
  2. Agren H. Symptom patterns in unipolar and bipolar depression correlating with monoamine metabolites in the cerebrospinal fluid: II. Suicide. Psychiatry Res. 1980 Oct;3(2):225–236. doi: 10.1016/0165-1781(80)90039-6. [DOI] [PubMed] [Google Scholar]
  3. Asberg M., Ringberger V. A., Sjöqvist F., Thorén P., Träskman L., Tuck J. R. Monoamine metabolites in cerebrospinal fluid and serotonin uptake inhibition during treatment with chlorimipramine. Clin Pharmacol Ther. 1977 Feb;21(2):201–207. doi: 10.1002/cpt1977212201. [DOI] [PubMed] [Google Scholar]
  4. Asberg M., Thorén P., Träskman L., Bertilsson L., Ringberger V. "Serotonin depression"--a biochemical subgroup within the affective disorders? Science. 1976 Feb 6;191(4226):478–480. doi: 10.1126/science.1246632. [DOI] [PubMed] [Google Scholar]
  5. Asberg M., Träskman L., Thorén P. 5-HIAA in the cerebrospinal fluid. A biochemical suicide predictor? Arch Gen Psychiatry. 1976 Oct;33(10):1193–1197. doi: 10.1001/archpsyc.1976.01770100055005. [DOI] [PubMed] [Google Scholar]
  6. Ashcroft G. W., Blackburn I. M., Eccleston D., Glen A. I., Hartley W., Kinloch N. E., Lonergan M., Murray L. G., Pullar I. A. Changes on recovery in the concentrations of tryptophan and the biogenic amine metabolites in the cerebrospinal fluid of patients with affective illness. Psychol Med. 1973 Aug;3(3):319–325. doi: 10.1017/s0033291700049606. [DOI] [PubMed] [Google Scholar]
  7. Ashcroft G. W., Crawford T. B., Eccleston D., Sharman D. F., MacDougall E. J., Stanton J. B., Binns J. K. 5-hydroxyindole compounds in the cerebrospinal fluid of patients with psychiatric or neurological diseases. Lancet. 1966 Nov 12;2(7472):1049–1052. doi: 10.1016/s0140-6736(66)92028-9. [DOI] [PubMed] [Google Scholar]
  8. Ashcroft G. W., Glen A. I. Mood and neuronal functions: a modified amine hypothesis for the etiology of affective illness. Adv Biochem Psychopharmacol. 1974;11(0):335–339. [PubMed] [Google Scholar]
  9. Banki C. M. Correlation of anxiety and related symptoms with cerebrospinal fluid 5-hydroxyindoleacetic acid in depressed women. J Neural Transm. 1977;41(2-3):135–143. doi: 10.1007/BF01670278. [DOI] [PubMed] [Google Scholar]
  10. Berger P. A., Faull K. F., Kilkowski J., Anderson P. J., Kraemer H., Davis K. L., Barchas J. D. CSF monoamine metabolites in depression and schizophrenia. Am J Psychiatry. 1980 Feb;137(2):174–180. doi: 10.1176/ajp.137.2.174. [DOI] [PubMed] [Google Scholar]
  11. Berrettini W. H., Nurnberger J. I., Jr, Post R. M., Gershon E. S. Platelet 3H-imipramine binding in euthymic bipolar patients. Psychiatry Res. 1982 Oct;7(2):215–219. doi: 10.1016/0165-1781(92)90094-j. [DOI] [PubMed] [Google Scholar]
  12. Bioulac B., Benezech M., Renaud B., Noel B., Roche D. Serotoninergic dysfunction in the 47, XYY syndrome. Biol Psychiatry. 1980 Dec;15(6):917–923. [PubMed] [Google Scholar]
  13. Bioulac B., Benezech M., Renaud B., Roche D., Noël B. Biogenic amines in 47, XYY syndrome. Neuropsychobiology. 1978;4(6):366–370. doi: 10.1159/000117653. [DOI] [PubMed] [Google Scholar]
  14. Bourne H. R., Bunney W. E., Jr, Colburn R. W., Davis J. M., Davis J. N., Shaw D. M., Coppen A. J. Noradrenaline, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid in hindbrains of suicidal patients. Lancet. 1968 Oct 12;2(7572):805–808. doi: 10.1016/s0140-6736(68)92459-8. [DOI] [PubMed] [Google Scholar]
  15. Bowers M. B., Jr CSF acid monoamine metabolities as a possible reflection of central MAO activity in chronic schizophrenia. Biol Psychiatry. 1976 Apr;11(2):245–249. [PubMed] [Google Scholar]
  16. Bowers M. B., Jr, Heninger G. R., Gerbode F. Cerebrospinal fluid 5-hydroxyindoleactiic acid and homovanillic acid in psychiatric patients. Int J Neuropharmacol. 1969 May;8(3):255–262. doi: 10.1016/0028-3908(69)90046-x. [DOI] [PubMed] [Google Scholar]
  17. Briley M. S., Langer S. Z., Raisman R., Sechter D., Zarifian E. Tritiated imipramine binding sites are decreased in platelets of untreated depressed patients. Science. 1980 Jul 11;209(4453):303–305. doi: 10.1126/science.7384806. [DOI] [PubMed] [Google Scholar]
  18. Brown G. L., Ebert M. H., Goyer P. F., Jimerson D. C., Klein W. J., Bunney W. E., Goodwin F. K. Aggression, suicide, and serotonin: relationships to CSF amine metabolites. Am J Psychiatry. 1982 Jun;139(6):741–746. doi: 10.1176/ajp.139.6.741. [DOI] [PubMed] [Google Scholar]
  19. Brown G. L., Goodwin F. K., Ballenger J. C., Goyer P. F., Major L. F. Aggression in humans correlates with cerebrospinal fluid amine metabolites. Psychiatry Res. 1979 Oct;1(2):131–139. doi: 10.1016/0165-1781(79)90053-2. [DOI] [PubMed] [Google Scholar]
  20. Bunney W. E., Jr, Davis J. M. Norepinephrine in depressive reactions. A review. Arch Gen Psychiatry. 1965 Dec;13(6):483–494. doi: 10.1001/archpsyc.1965.01730060001001. [DOI] [PubMed] [Google Scholar]
  21. Coppen A., Prange A. J., Jr, Whybrow P. C., Noguera R. Abnormalities of indoleamines in affective disorders. Arch Gen Psychiatry. 1972 May;26(5):474–478. doi: 10.1001/archpsyc.1972.01750230084016. [DOI] [PubMed] [Google Scholar]
  22. Coppen A., Swade C., Wood K. Platelet 5-hydroxytryptamine accumulation in depressive illness. Clin Chim Acta. 1978 Jul 1;87(1):165–168. doi: 10.1016/0009-8981(78)90071-2. [DOI] [PubMed] [Google Scholar]
  23. Coppen A. The biochemistry of affective disorders. Br J Psychiatry. 1967 Nov;113(504):1237–1264. doi: 10.1192/bjp.113.504.1237. [DOI] [PubMed] [Google Scholar]
  24. Eichelman B. S., Jr, Thoa N. B. The aggressive monoamines. Biol Psychiatry. 1973 Apr;6(2):143–164. [PubMed] [Google Scholar]
  25. FOTHERBY K., ASHCROFT G. W., AFFLECT J. W., FORREST A. D. Studies on sodium transfer and 5-hydroxyindoles in depressive illness. J Neurol Neurosurg Psychiatry. 1963 Feb;26:71–73. doi: 10.1136/jnnp.26.1.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. GLOWINSKI J., AXELROD J. INHIBITION OF UPTAKE OF TRITIATED-NORADRENALINE IN THE INTACT RAT BRAIN BY IMIPRAMINE AND STRUCTURALLY RELATED COMPOUNDS. Nature. 1964 Dec 26;204:1318–1319. doi: 10.1038/2041318a0. [DOI] [PubMed] [Google Scholar]
  27. Goodwin F. K., Post R. M. Studies of amine metabolites in affective illness and in schizophrenia: a comparative analysis. Res Publ Assoc Res Nerv Ment Dis. 1975;54:299–332. [PubMed] [Google Scholar]
  28. Goodwin F. K., Post R. M., Wehr T. Clinical approaches to the evaluation of brain amine function in mental illness: some conceptual issues. Essays Neurochem Neuropharmacol. 1977;2:71–104. [PubMed] [Google Scholar]
  29. Gottfries C. G., von Knorring L., Perris C. Neurophysiological measures related to levels of 5-hydroxyindoleacetic acid, homovanillic acid and tryptophan in cerebrospinal fluid of psychiatric patients. Neuropsychobiology. 1976;2(1):1–8. doi: 10.1159/000117523. [DOI] [PubMed] [Google Scholar]
  30. Hodge G. K., Butcher L. L. 5-Hydroxytryptamine correlates of isolation-induced aggression in mice. Eur J Pharmacol. 1974 Oct;28(2):326–337. doi: 10.1016/0014-2999(74)90286-6. [DOI] [PubMed] [Google Scholar]
  31. Hodge G. K., Butcher L. L. Catecholamine correlates of isolation-induced aggression in mice. Eur J Pharmacol. 1975 Mar;31(1):81–93. doi: 10.1016/0014-2999(75)90081-3. [DOI] [PubMed] [Google Scholar]
  32. Jimerson D. C., Post R. M., Goodwin F. K. Antidepressant treatments and alterations in central serotonin turnover in affective illness. Monogr Neural Sci. 1976;3:15–22. doi: 10.1159/000399329. [DOI] [PubMed] [Google Scholar]
  33. Jori A., Dolfini E., Casati C., Argenta G. Effect of ECT and imipramine treatment on the concentration of 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in the cerebrospinal fluid of depressed patients. Psychopharmacologia. 1975 Oct 14;44(1):87–90. doi: 10.1007/BF00421189. [DOI] [PubMed] [Google Scholar]
  34. Knapp S., Mandell A. J. Cocaine and lithium: neurobiological antagonism in the serotonin biosynthetic system in rat brain. Life Sci. 1976 Apr 1;18(7):679–683. doi: 10.1016/0024-3205(76)90178-8. [DOI] [PubMed] [Google Scholar]
  35. Korf J., Van Praag H. M. Amine metabolism in the human brain: further evaluation of the probenecid test. Brain Res. 1971 Dec 10;35(1):221–230. doi: 10.1016/0006-8993(71)90607-x. [DOI] [PubMed] [Google Scholar]
  36. Korf J., van Praag H. M. Retarded depression and the dopamine metabolism. Psychopharmacologia. 1971;19(2):199–203. doi: 10.1007/BF00402643. [DOI] [PubMed] [Google Scholar]
  37. Langer S. Z., Moret C., Raisman R., Dubocovich M. L., Briley M. High-affinity [3H]imipramine binding in rat hypothalamus: association with uptake of serotonin but not of norepinephrine. Science. 1980 Dec 5;210(4474):1133–1135. doi: 10.1126/science.7444441. [DOI] [PubMed] [Google Scholar]
  38. Langer S. Z., Raisman R., Briley M. S. Stereoselective inhibition of 3H-imipramine binding by antidepressant drugs and their derivatives. Eur J Pharmacol. 1980 May 30;64(1):89–90. doi: 10.1016/0014-2999(80)90373-8. [DOI] [PubMed] [Google Scholar]
  39. Lapin I. P., Oxenkrug G. F. Intensification of the central serotoninergic processes as a possible determinant of the thymoleptic effect. Lancet. 1969 Jan 18;1(7586):132–136. doi: 10.1016/s0140-6736(69)91140-4. [DOI] [PubMed] [Google Scholar]
  40. Lloyd K. G., Farley I. J., Deck J. H., Hornykiewicz O. Serotonin and 5-hydroxyindoleacetic acid in discrete areas of the brainstem of suicide victims and control patients. Adv Biochem Psychopharmacol. 1974;11(0):387–397. [PubMed] [Google Scholar]
  41. Mandell A. J. Neurobiologocal mechanisms of presynaptic metabolic adaptation and their organization: implications for a pathophysiology of the affective disorders. Adv Biochem Psychopharmacol. 1975;13:1–32. [PubMed] [Google Scholar]
  42. Meltzer H. Y., Arora R. C., Baber R., Tricou B. J. Serotonin uptake in blood platelets of psychiatric patients. Arch Gen Psychiatry. 1981 Dec;38(12):1322–1326. doi: 10.1001/archpsyc.1981.01780370024002. [DOI] [PubMed] [Google Scholar]
  43. Mendels J., Frazer A., Fitzgerald R. G., Ramsey T. A., Stokes J. W. Biogenic amine metabolites in cerebrospinal fluid of depressed and manic patients. Science. 1972 Mar 24;175(4028):1380–1382. doi: 10.1126/science.175.4028.1380. [DOI] [PubMed] [Google Scholar]
  44. Oreland L., Wiberg A., Asberg M., Träskman L., Sjöstrand L., Thorén P., Bertilsson L., Tybring G. Platelet MAO activity and monoamine metabolites in cerebrospinal fluid in depressed and suicidal patients and in healthy controls. Psychiatry Res. 1981 Feb;4(1):21–29. doi: 10.1016/0165-1781(81)90004-4. [DOI] [PubMed] [Google Scholar]
  45. Papeschi R., McClure D. J. Homovanillic and 5-hydroxyindoleacetic acid in cerebrospinal fluid of depressed patients. Arch Gen Psychiatry. 1971 Oct;25(4):354–358. doi: 10.1001/archpsyc.1971.01750160066012. [DOI] [PubMed] [Google Scholar]
  46. Pare C. M., Yeung D. P., Price K., Stacey R. S. 5-hydroxytryptamine, noradrenaline, and dopamine in brainstem, hypothalamus, and caudate nucleus of controls and of patients committing suicide by coal-gas poisoning. Lancet. 1969 Jul 19;2(7612):133–135. doi: 10.1016/s0140-6736(69)92442-8. [DOI] [PubMed] [Google Scholar]
  47. Paul S. M., Rehavi M., Skolnick P., Ballenger J. C., Goodwin F. K. Depressed patients have decreased binding of tritiated imipramine to platelet serotonin "transporter". Arch Gen Psychiatry. 1981 Dec;38(12):1315–1317. doi: 10.1001/archpsyc.1981.01780370017001. [DOI] [PubMed] [Google Scholar]
  48. Paul S. M., Rehavi M., Skolnick P., Goodwin F. K. Demonstration of specific "high affinity" binding sites for [3H] imipramine on human platelets. Life Sci. 1980 Mar 24;26(12):953–959. doi: 10.1016/0024-3205(80)90116-2. [DOI] [PubMed] [Google Scholar]
  49. Post R. M., Goodwin F. K. Estimation of brain amine metabolism in affective illness: cerebrospinal fluid studies utilizing probenecid. Psychother Psychosom. 1974;23(1-6):142–158. doi: 10.1159/000286638. [DOI] [PubMed] [Google Scholar]
  50. Praag H. M. The Harold E. Himwich Memorial Lecture. Significance of biochemical parameters in the diagnosis, treatment, and prevention of depressive disorders. Biol Psychiatry. 1977 Feb;12(1):101–131. [PubMed] [Google Scholar]
  51. Prange A. J., Jr, Wilson I. C., Lynn C. W., Alltop L. B., Stikeleather R. A. L-tryptophan in mania. Contribution to a permissive hypothesis of affective disorders. Arch Gen Psychiatry. 1974 Jan;30(1):56–62. doi: 10.1001/archpsyc.1974.01760070040006. [DOI] [PubMed] [Google Scholar]
  52. Rehavi M., Ittah Y., Rice K. C., Skolnick P., Goodwin F. K., Paul S. M. 2-nitroimipramine: a selective irreversible inhibitor of [3H] serotonin uptake and [3H] imipramine binding in platelets. Biochem Biophys Res Commun. 1981 Apr 15;99(3):954–959. doi: 10.1016/0006-291x(81)91255-9. [DOI] [PubMed] [Google Scholar]
  53. Schildkraut J. J. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry. 1965 Nov;122(5):509–522. doi: 10.1176/ajp.122.5.509. [DOI] [PubMed] [Google Scholar]
  54. Sedvall G., Fyrö B., Gullberg B., Nybäck H., Wiesel F. A., Wode-Helgodt B. Relationships in healthy volunteers between concentrations of monoamine metabolites in cerebrospinal fluid and family history of psychiatric morbidity. Br J Psychiatry. 1980 Apr;136:366–374. doi: 10.1192/bjp.136.4.366. [DOI] [PubMed] [Google Scholar]
  55. Shaw D. M., Camps F. E., Eccleston E. G. 5-Hydroxytryptamine in the hind-brain of depressive suicides. Br J Psychiatry. 1967 Dec;113(505):1407–1411. doi: 10.1192/bjp.113.505.1407. [DOI] [PubMed] [Google Scholar]
  56. Sheard M. H. Lithium in the treatment of aggression. J Nerv Ment Dis. 1975 Feb;160(2-1):108–118. doi: 10.1097/00005053-197502000-00005. [DOI] [PubMed] [Google Scholar]
  57. Sheard M. Effect of lithium on human aggression. Nature. 1971 Mar 12;230(5289):113–114. doi: 10.1038/230113a0. [DOI] [PubMed] [Google Scholar]
  58. Sjöström R. 5-Hydroxyindole acetic acid and homovanillic acid in cerebrospinal fluid in manic-depressive psychosis and the effect of probenecid treatment. Eur J Clin Pharmacol. 1973 Aug;6(2):75–80. doi: 10.1007/BF00562430. [DOI] [PubMed] [Google Scholar]
  59. Sjöström R., Roos B. E. 5-Hydroxyindolacetic acid and homovanillic acid in cerebrospinal fluid in manic-depressive psychosis. Eur J Clin Pharmacol. 1972 Jun;4(3):170–176. doi: 10.1007/BF00561141. [DOI] [PubMed] [Google Scholar]
  60. Stahl S. M., Meltzer H. Y. A kinetic and pharmacologic analysis of 5-hydroxytryptamine transport by human platelets and platelet storage granules: comparison with central serotonergic neurons. J Pharmacol Exp Ther. 1978 Apr;205(1):118–132. [PubMed] [Google Scholar]
  61. Stanley M., Virgilio J., Gershon S. Tritiated imipramine binding sites are decreased in the frontal cortex of suicides. Science. 1982 Jun 18;216(4552):1337–1339. doi: 10.1126/science.7079769. [DOI] [PubMed] [Google Scholar]
  62. Subrahmanyam S. Role of biogenic amines in certain pathological conditions. Brain Res. 1975 Apr 11;87(2-3):355–362. doi: 10.1016/0006-8993(75)90433-3. [DOI] [PubMed] [Google Scholar]
  63. Takahashi S., Yamane H., Kondo H., Tani N., Kato N. CSF monoamine metabolites in alcoholism: a comparative study with depression. Folia Psychiatr Neurol Jpn. 1974;28(4):347–354. doi: 10.1111/j.1440-1819.1974.tb02312.x. [DOI] [PubMed] [Google Scholar]
  64. Träskman L., Asberg M., Bertilsson L., Sjöstrand L. Monoamine metabolites in CSF and suicidal behavior. Arch Gen Psychiatry. 1981 Jun;38(6):631–636. doi: 10.1001/archpsyc.1981.01780310031002. [DOI] [PubMed] [Google Scholar]
  65. Tuomisto J., Tukiainen E., Ahlfors U. G. Decreased uptake of 5-hydroxytryptamine in blood platelets from patients with endogenous depression. Psychopharmacology (Berl) 1979 Oct;65(2):141–147. doi: 10.1007/BF00433040. [DOI] [PubMed] [Google Scholar]
  66. Tupin J. P., Smith D. B., Clanon T. L., Kim L. I., Nugent A., Groupe A. The long-term use of lithium in aggressive prisoners. Compr Psychiatry. 1973 Jul-Aug;14(4):311–317. doi: 10.1016/0010-440x(73)90022-9. [DOI] [PubMed] [Google Scholar]
  67. Vestergaard P., Sørensen T., Hoppe E., Rafaelsen O. J., Yates C. M., Nicolaou N. Biogenic amine metabolites in cerebrospinal fluid of patients with affective disorders. Acta Psychiatr Scand. 1978 Jul;58(1):88–96. doi: 10.1111/j.1600-0447.1978.tb06924.x. [DOI] [PubMed] [Google Scholar]
  68. van Praag H. M., Korf J. A pilot study of some kinetic aspects of the metabolism of 5-hydroxytryptamine in depressive patients. Biol Psychiatry. 1971;3(2):105–112. [PubMed] [Google Scholar]
  69. van Praag H. M., Korf J., Puite J. 5-Hydroxyindoleacetic acid levels in the cerebrospinal fluid of depressive patients treated with probenecid. Nature. 1970 Mar 28;225(5239):1259–1260. doi: 10.1038/2251259b0. [DOI] [PubMed] [Google Scholar]
  70. van Praag H. M., Korf J., Schut D. Cerebral monoamines and depression. An investigation with the Probenecid technique. Arch Gen Psychiatry. 1973 Jun;28(6):827–831. doi: 10.1001/archpsyc.1973.01750360053007. [DOI] [PubMed] [Google Scholar]
  71. van Praag H. M., de Haan S. Central serotonin metabolism and frequency of depression. Psychiatry Res. 1979 Dec;1(3):219–224. doi: 10.1016/0165-1781(79)90002-7. [DOI] [PubMed] [Google Scholar]

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