A double-blind comparative trial of oxaprotiline with amitriptyline and placebo in outpatients with moderate depression: relationship of urinary MHPG levels

  • The Oxaprotiline Study Group


The use of urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) as a predictor of clinical responsiveness to oxaprotiline or amitriptyline was determined in a double-blind, placebo-controlled, multicenter trial involving outpatients with moderate depression. Using the total Hamilton Depression Rating Scale (HDRS), oxaprotiline and amitriptyline were found to be equally effective and both were statistically superior to placebo. At the final visit, oxaprotiline, but not amitriptyline, was statistically superior to placebo for the Anxiety/Somatization Factor of the HDRS. At the same time, amitriptyline was statistically superior to oxaprotiline and placebo for the Sleep Disturbance Factor. The number of patients who were discontinued from the trial as a result of side-effects was significantly higher in the amitriptyline group than in the oxaprotiline group. Baseline urinary (MHPG) levels were divided into four subgroups and the success to failure ratio for each treatment was calculated for each subgroup. The rate of response to oxaprotiline was particularly high (72%) in the subgroup of patients with baseline urinary MHPG levels of 1501–2500 μg/24 h. In contrast, the rate of response to amitriptyline was quite low (30%) in the subgroup.


Hamilton Depression Rate Scale Moderate Depression Mandelic Acid Hamilton Depression Rate Scale Score Failure Ratio 
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  1. Bareggi, S.R., Marc, V. and Morselli, P.L. (1974). Urinary excretion of 3-methoxy-4-hydroxyphenylglycol sulfate in rats after intraventricular injection of 6-OHDA. Brain Res., 75:177–180PubMedCrossRefGoogle Scholar
  2. Beckmann, H. and Goodwin, F.K. (1975). Antidepressant response to tricyclics and urinary MHPG in unipolar patients. Archs Gen. Psychiat. 32:17–21Google Scholar
  3. Blombery, P.A., Kopin, I.J., Gordon, E.K., Markey, S.P. and Ebert, M.E. (1980). Conversion of MHPG to Vanillyl-mandelic acid. Archs Gen. Psychiat., 37:1095–1098Google Scholar
  4. Bond, P.A., Jenner, F.A. and Sampson, G.A. (1972). Daily variations of the urine content of MHPG in two manic-depressive patients. Psychol. Med., 2:81–85Google Scholar
  5. Breese, G.R., Prange, A.J., Howard, J.L. and Lipton, M.A. (1972). Noradrenaline metabolite excretion after central sympathectomy with 6-hydroxydopamine. Nature (New Biol.), 240:286–287CrossRefGoogle Scholar
  6. Buchsbaum, M., Landau, S., Murphy, D. and Goodwin, F. (1973). Average evoked response in bipolar and unipolar affective disorders: relationship to sex, age of onset, and monoamine oxidase. Biol. Psychiat., 7(3):199–212Google Scholar
  7. Buchsbaum, M.S. and Rieder, R.O. (1979). Biological heterogeneity and psychiatric research: platelet MAO activity as a case study. Archs Gen. Psychiat., 36:1163–1169Google Scholar
  8. Bunney, W.E., Jr. and Davis, J.M. (1965). Norepinephrine in depressive reactions: a review. Archs Gen. Psychiat., 13:483494Google Scholar
  9. Cobbin, D.M., Requin-Blow, B., Williams, L.R. and Williams, W.O. (1979). Urinary MHPG levels and tricyclic antidepressant drug selection. Archs Gen. Psychiat., 36:1111–1115Google Scholar
  10. Cohn, C.K., Dunner, D.L. and Axelrod, J. (1970). Reduced cathechol-0-methyltransferase activity in red blood cells of women with primary affective disorder. Science, 170:1323–1324Google Scholar
  11. Coppen, A., Rana Rao, V.A., Ruthven, C.R.J., Goodwin, B.L. and Sandler, M. (1979). Urinary 4-hydroxy-3-methoxyphenylglycol is not a predictor for clinical response to amitriptyline in depressive illness. Psychopharmacology, 64:95–97PubMedCrossRefGoogle Scholar
  12. Davidson, J.R.T., McLeod, M.N., Turnbill, C.D., White, H.L. and Feuer, E.V. (1980). Platelet monoamine oxidase activity and the classification of depression. Archs Gen. Psychiat., 37:771–773Google Scholar
  13. Dunner, D.L., Cohn, C.K., Gershon, E.S. and Goodwin, F.K. (1971). Differential cathechol-0-methyltransferase activity in unipolar and bipolar affective illness. Archs Gen. Psychiat., 25:348–353Google Scholar
  14. Dunner, D.L., Goodwin, F.K., Gershon, E.S., Murphy, D.L. and Bunney, W.E. (1972). Excretion of 17-hydroxy-corticosteroids in unipolar and bipolar depressed patients. Archs Gen. Psychiat., 26:360–363Google Scholar
  15. Gershon, E.S. and Jones, W.Z. (1975). Erythrocyte soluble catechol-0-methyltransferase activity in primary affective disorder. Archs Gen. Psychiat., 32:1351–1356Google Scholar
  16. Greenspan, J., Schildkraut, J.J., Gordon, E.K., Baer, L., Aronoff, M.S. and Durell, J. (1970). Catecholamine metabolism in affective disorders. III. 3-Methoxy-4-hydroxyphenylglycol and other catecholamine metabolites in patients treated with lithium carbonate. J. Psychiat. Res., 7:171–183Google Scholar
  17. Jones, F., Maas, J.W., Dekirmenjian, H. and Fawcett, J.A. (1973). Urinary catecholamine metabolites during behavioral changes in a patient with manic depressive cycles. Science, 179:300–302PubMedCrossRefGoogle Scholar
  18. Karoum, F., Neff, N.H. and Wyatt, R.J. (1976). Distribution and turnover rate of vanillylmandelic acid and 3-methoxy-4-hydroxyphenylglycol in rat brain. J. Neurochem., 27:33–35Google Scholar
  19. Karoum, F., Wyatt, R. and Costa, E. (1974). Estimation of the contribution of peripheral and central noradrenergic neurons to urinary 3-methoxy-4-hydroxyphenylglycol in the rat. Neuropharmacology, 13:165–176PubMedCrossRefGoogle Scholar
  20. Kopin, I.J. (1978). Measuring turnover of neurotransmitters in human brains. In M.A. Lipton, A. DiMascio and Killiam, K.P. (eds.), Psychopharmacology: A Generation of Progress, Raven Press, New York, p.933Google Scholar
  21. Korf, J., Aghajanian, G.K. and Roth, R.H. (1973). Stimulation and destruction of the locus coeruleus: Opposite effects on 3-methoxy-4-hydroxyphenylglycol sulfate levels in the rat cerebral cortex. Eur. J. Pharmacol., 21:305–310Google Scholar
  22. Landowski, J., Lysiak, W. and Angielski, S. (1975). Monoamine oxidase activity in blood platelets from patients with cyclophrenic depressive syndromes. Biochem. Med., 14:347–354Google Scholar
  23. Logue, J.N., Sachais, B.A. and Feighner, J.P. (1979). Comparisons of maprotiline with imipramine in severe depression: A multicenter controlled trial. J. Clin. Pharmacol., 19:64–74Google Scholar
  24. Maas, J.W. (1978). Clinical and biochemical heterogeneity of depressive disorders. Ann. Intern. Med., 88:556–563Google Scholar
  25. Maas, J.W., Dekirmenjian, H., Garver, D., Redmond, D.E. Jr. and Landis, D.H. (1973). Excretion of catecholamine metabolites following intracentricular injection of 6-hydroxydopamine in the Macaca speciosa. Eur. J. Pharmacol., 23:121–130Google Scholar
  26. Maas, J.W., Fawcett, J.A. and Dekirmenjian, H. (1968a). Catecholamine metabolism and the depressive states. Annual Meeting of the American Psychiatric Association, Boston.Google Scholar
  27. Maas, J.W., Fawcett, J.A. and Dekirmenjian, E. (1968b). 3-Methoxy-4-hydroxyphenylglycol (MHPG) excretion in depressive states. Archs Gen. Psychiat., 19:129–134Google Scholar
  28. Maas, J.W., Fawcett, J.A. and Dekirmenjian, H. (1972). Catecholamine metabolism depressive illness and drug response. Archs Gen. Psychiat., 26:252–262Google Scholar
  29. Maas, J.W., Green, N.M., Hattox, S.E. and Roth, R.H. (1979). Neurotransmitter metabolite production by human brain. In E. Usdin, I.J. Kopin and J. Barchas (eds.), Catecholamines: Basic and Clinical Frontiers, Pergamon Press, New York, p. 1878CrossRefGoogle Scholar
  30. Maas, J.W. and Landis, D.E. (1968). In vivo studies of the metabolism of norepinephrine in the central nervous system. J. Pharmacol. Exp. Ther., 163:147–162Google Scholar
  31. Maitre, L., Waldmeier, P.C., Greengrass, P.M., Jackel, J., Sedlucek, S. and Delini-Stola, A. (1975). Maprotiline — Its position as an antidepressant in the light of recent neuropharmacological and neurobiochemical findings. J. Int. Med. Res., 3 (suppl 2): 2–15Google Scholar
  32. Mannarino, E., Kirshner, N. and Nashold, B.S. (1963). The metabolism of [C14] noradrenaline by cat brain in vivo. J. Neurochem., 10:373–379Google Scholar
  33. Mardh, G., Sjögvist, B. and Anggard, E. (1981). Norepinephrine metabolism in man using deuterium labeling: the conversion of 4-hydroxy-3-methoxyphenylglycol to 4-hydroxy-3-methoxymandelic acid. J. Neurochem., 36:1181–1185Google Scholar
  34. Mattsson, B., Mjörndal, T., Oreland, L. and Perris, C. (1974). Catechol-0-methyltransferase and plasma monoamine oxidase in patients with affective disorders. Acta Psychiat. Scand., suppl. 255, 187–192Google Scholar
  35. Meek, J.L. and Neff, N.H. (1973). The rate of formation of 3-methoxy-4-hydroxyphenylethyleneglycol sulfate in brain as an estimate of the rate of formation of norepinephrine. J. Pharmacol. Exp. Ther., 184(3):570–575Google Scholar
  36. Murphy, D.L. and Weiss, R. (1972). Reduced monoamine oxidase activity in blood platelets from bipolar depressed patients. Am. J. Psychiat., 128:1351–1357Google Scholar
  37. Pickar, D., Sweeney, D.R., Maas, J.W. and Heninger, G.R. (1978). Primary affective disorder, clinical state change and MHPG excretion: A longitudinal study. Archs Gen. Psychiat., 35:1378–1383Google Scholar
  38. Post, R.M., Stoddard, F.J., Gillin, J.C., Buchsbaum, M., Runkle, D.C., Black, R.E. and Bunney, W.E. Jr. (1977). Slow and rapid alterations in motor activity, sleep and biochemistry in a cycling manic-depressive patient. Archs Gen. Psychiat., 34:470–477Google Scholar
  39. Rosenbaum, A.E., Schatzberg, A.F., Maruta, T., Orsulak, P.J., Cole, J.O., Grab, E.L. and Schildkraut, J.J. (1980). MHPG as a predictor of antidepressant response to imipramine and maprotiline. Am. J. Psychiat., 137:1090–1092Google Scholar
  40. Schanberg, S.M., Breese, G.R., Schildkraut, J.J., Gordon, E.K. and Kopin, I.J. (1968). 3-Methoxy-4-hydroxyphenylglycol sulfate in brain and cerebrospinal fluid. Biochem. Pharmacol., 17:2006–2008Google Scholar
  41. Schatzberg, A.T., Rosenbaum, A.H., Orsulak, P.J., Rohde, W.A., Maruta, T., Kruger, E.R., Cole, J.O. and Schildkraut, J.J. (1981). Pretreatment urinary MHPG levels as predictors of response to treatment with maprotiline. Psychopharmacology, 75:34–38PubMedCrossRefGoogle Scholar
  42. Schildkraut, J.J. (1965). The catecholamine hypothesis of affective disorders: A review of supporting evidence. Am. J. Psychiat., 122:509–522Google Scholar
  43. Schildkraut, J.J. (1970). Neuropsychopharmacology and the Affective Disorders, Little, Brown and Co., BostonGoogle Scholar
  44. Schildkraut, J.J. (1973). Norepinephrine metabolites as biochemical criteria for classifying depressive disorders and predicting responses to treatment: preliminary findings. Am. J. Psychiat., 130:695–698Google Scholar
  45. Shopsin, B., Wilk, S., Gershon, S., Roffman, M. and Goldstein, M. (1974). Collaborative psychopharmacologic studies exploring catecholamine metabolism in psychiatric disorders. In E. Usdin and S. Snyder (eds.), Frontiers in Catecholamine Research, Pergamon Press, New York, pp. 1173–1179Google Scholar
  46. Sjöqvist, B. (1975). Mass, fragmentographic determination of 4-hydroxy-3-methoxymandelic acid in human urine, cerebrospinal fluid, brain and serum using a deuterium-labelled internal standard. J. Neurochem., 24:199–201Google Scholar
  47. Spiker, D.C., Edwards, D., Hanin, I., Neil, J.F. and Kupfer, D.J. (1980). Urinary MHPG and clinical response to amitriptyline in depressed patients. Am. J. Psychiat., 137:1183–1187Google Scholar
  48. Sullivan, J.L., Maltbie, A., Cavenar, J.O. and Stanfield, C. (1977). Platelet monoamine oxidase activity predicts response to lithium in manic-depressive illness. Lancet, 2:1325–1322PubMedCrossRefGoogle Scholar
  49. Waldmeier, P.C., Baumann, P., Greengrass, P.M. and Maitre, L. (1976). Effects of clomipramine and other tricyclic antidepressants on biogenic amine uptake and turnover. Postgrad. Med. J., 52(suppl.3):33–39Google Scholar
  50. Waldmeier, P.C., Baumann, P.A., Wilheim, M., Bernasconi, R. and Maitre, L. (1977). Selective inhibition of noradrenaline and serotonin uptake by C 49802B Ba and CGP 6085A. Eur. J. Pharmacol., 46:387–391Google Scholar
  51. White, K., Shih, J., Fong, T.L., Young, H., Gelfand, R., Boyd, J., Simpson, G. and Sloane, R.B. (1980). Elevated platelet monoamine oxidase activity in patients with nonendogenous depression. Am. J. Psychiat., 137(10):1258–1259Google Scholar

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