Abstract
5′-Methyltetrahydrofolic acid (5′- MTHF) in addition to standard psychotropic medication significantly improved clinical recovery in depressed patients with borderline or definite folate deficiency, and significantly reduced depressive symptoms in elderly normofolatemic patients after 3 weeks of treatment. In this equivalence study the effect of 5′- MTHF on depressive symptoms and cognitive status was compared to Trazodone (TRZ) in normofolatemic elderly patients with mild to moderate dementia and depression. Ninety-six patients with dementia, scoring 12–23 at the Mini Mental State Examination (MMSE) and ≥18 at the Hamilton Depression Rating Scale (HDRS) after a 2-week placebo run-in, were randomized to receive either 5′-MTHF (50 mg/day p.o.) (47 patients) or TRZ (100 mg/day p.o.) (49 patients) in a double-blind design for 8 weeks. HDRS was assessed before, after 4 weeks and at the end of treatment; Rey’s Verbal Memory (RVM) test for immediate and delayed recall was evaluated before and after treatment. After 4 weeks of treatment HDRS score was reduced from 23±5 to 20±6 in the 5′-MTHF (p<0.05 vs baseline), and from 23±3 to 21±4 in the TRZ group (p<0.05 vs baseline). p]A further significant decrease to 18±6 and 19±5 respectively was obtained at the end of the treatment period (p<0.05 vs week 4) with 5′-MTHF and TRZ. HDRS was administered again after a 4-week, drug-free, follow-up period: no change vs the post treatment scores was observed either in the 5′-MTHF or in the TRZ group (18±7 and 19±5 respectively). RVM test for immediate recall was significantly improved (p<0.05) at week 8 vs baseline in the 5′-MTHF group whereas no significant change occurred in the TRZ group. No change in delayed recall was observed after treatment in either group. Tolerability was good for both treatments. This study shows that 5′-MTHF and TRZ are equally effective in improving depressive symptoms in patients with mild to moderate dementia and suggests that pharmacological doses of 5′-MTHF may exert psychotropic effects irrespective of folate status. (Aging Clin. Exp. Res. 1: 63–71, 1993)
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Tomlinson B.E., Blessed G., Roth M.: Observations on the brains of demented old people. J. Neurol. Sci. 11: 205–242, 1970.
Fischer P., Simanyi M., Danielczyk W.: Depression in Dementia of the Alzheimer type and in Multi-In- farct Dementia. Am. J. Psychiatry 147: 1484–1487, 1990.
Reifler B.V., Larson E., Teri L., Poulsen M.: Dementia of the Alzheimer’s type and depression. J. Am. Geriatr. Soc. 34: 855–859, 1986.
Reifler B.V., Teri L., Raskind M., Veith R., Barnes R., White E., McLean P.: Double-blind trial of imipramine in Alzheimer’s disease patients with and without depression. Am. J. Psychiatry 146: 45–49, 1989.
Rovner B.W., Broadhead J., Spencer M., Carson K., Folstein M.F.: Depression and Alzheimer’s disease. Am. J. Psychiatry 146: 350–353, 1989.
Greenwald B.S., Kramer-Ginsberg E., Marin D.B., Laitman L.B., Hermann C.K., Mohs R., Davis K.L.: Dementia with Coexistent Major Depression. Am. J. Psychiatry 146: 1472–1478, 1989.
Potter W.Z., Rudorfer H.V., Manji H.: The pharmacologic treatment of depression. N. Engl. J. Med. 325: 633–642, 1991.
Altamura A.C., Mauri M.C., Colacurcio F., Scapicchio P.L., Hadjchristos C., Carucci G., Minervini M., Montanini R., Perini M., Rudas N., Carpiniello B., D’Aloise A., Malinconico A.: Trazodone in late life depressive states: a double-blind multicenter study versus amitriptyline and mionserim. Psychopharmacology 95: 534–536, 1988.
Godfrey P.S.A., Toone B.K., Carney M.W.P., Flynn T.G., Bottiglieri T., Laundy M., Chanarin I., Reynolds E.H.: Enhancement of recovery from psychiatric illness by methylfolate. Lancet 336: 392–395, 1990.
Guaraldi G.P., Fava M., Mazzi F., La Greca P.: Open study on 5 methyltetrahydrofolic acid in the treatment of depression in the elderly. Eur. J. Clin. Invest. 22: A30, 1992.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (ed. 3-revised) Washington, D.C., 1987, pp. 119-123.
Folstein M.F.: The Mini Mental State Examination. In: Crook T.H., Ferris S., Bartus R. (Eds.), Assessment in geriatric Psychopharmachology. Madison, Coon, Mark Powley Associates, 1983.
Folstein M.F., Folstein S.E., McHugh P.R.: “Mini Mental State”: a practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12: 189–198, 1975.
Hamilton M.: A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23: 56, 1960.
Hachinski V.C.: Cerebral blood flow in dementia. Arch. Neurol. 32: 632–637, 1975.
Quitkin F.M., Rabkin J.G.: Methodological problems in studies of depressive disorder: utility of the discontinuation design. J. Clin. Psychopharmacol. 1: 283–288, 1981.
Bell K.M., Pion L., Bunney W.E., Potkin S.G.: S- Adenosylmethionine treatment of depression: a controlled clinical trial. Am. J. Psychiatry 145: 1110–1114, 1988.
Rey A.: Memorisation d’une série de 15 mots en 5 repetitions. In: Rey A. (Ed.), L’examen clinique en psychologie. Presse Universitaire de France, Paris, 1958.
Fraser R.M., Glass I.B.: Unilateral and bilateral ECT in elderly patients: a comparative study. Acta Psychiatr. Scand. 62: 13–31, 1980.
Georgotas A., McCue R.E., Hapworth W.: Comparative efficacy and safety of MAOIs versus TCAs in treating depression in the elderly. Biol. Psychiatry 21: 1155–1166, 1986.
Murphy E.: The prognosis of depression in old age. Br. J. Psychiatry 142: 111–119, 1983.
Quitkin F.M., Rabkin J.G., Stewart J.W., Mc Grath P.J., Harrison W., Ross D.C., Tricarno E., Fleiss J., Markowitz J., Klein D.F.: Heterogeneity of clinical response during placebo treatment. Am. J. Psychiatry 148: 193–196, 1991.
Quitkin F.M., McGrath P.J., Rabkin J.G., Stewart J.W., Harrison W., Ross D.C., Tricarno E., Fleiss J., Markowitz J., Klein D.F.: Different types of placebo response in patients receiving antidepressants. Am. J. Psychiatry 148: 197–203, 1991.
Dannenbaum S., Parkinson S., Inman V.: Short-term forgetting: comparison between patients with dementia of the Alzheimer type, depressed and normal elderly. Cognitive Neuropsychology 5: 213–233, 1988.
Rubin E.H., Kinscherf D.A., Grant E.A., Storandt M.: The influence of major depression on clinical and psychometric assessment of senile dementia of the Alzheimer type. Am. J. Psychiatry 148: 1164–1171, 1991.
Reding M., Haycox J., Blass J.: Depression in patients referred to a dementia clinic: a three year prospective study. Arch. Neurol. 42: 894–896, 1985.
Danielczyk W.: Psychiatrische komplikationen beim Morbus Parkinson: kranktreitssymptome, Folge der Alterung order der Therapie? Neuropsychiatr. Clin. 3: 145–155, 1984.
Reynolds E.H.: Cerebrospinal fluid folate: Clinical studies. In: Botez M.I., Reynolds E.H. (Eds.), Folic Acid in Neurology, Psychiatry and Internal Medicine. Raven Press, New York, 1979, pp. 195–203.
Korevaar W.C., Geyer M.A., Knapp S., Hsu L., Mandell A.J.: Regional distribution of 5′-Methyltetrahydrofolic Acid in brain. Nature 245: 244–245, 1973.
Shorvon S.D., Carney M.W.P., Chanarin I., Reynolds E.H.: The neuropsychiatry of megaloblastic anaemia. Br. Med. J. 281: 1036–1042, 1980.
Carney M.W.P.: Serum folate values in 423 psychiatric patients. Br. Med. J. 4: 512–516, 1967.
Carney M.W.P., Sheffield B.F.: Serum folic acid and B12 in 272 psychiatric in-patients. Psychol. Med. 8: 139–144, 1978.
Carney M.W.P., Chary T.K.N., Laundy M., Bottiglieri T., Chanarin I., Reynolds E.H., Toone B.: Red folate concentrations in psychiatric patients. J. Affective Disorders 19: 207–213, 1990.
Botez M.I., Young S.N., Bachevalier J., Gauthier S.: Folate deficiency and decreased brain 5-hydroxytryptamine synthesis in man and rat. Nature 278: 182–183, 1989.
Coppen A., Swade C., Jones S.A., Armstrong R.A., Blair J.A., Leening R.J.: Depression and tetrahydrobiopterin: the folate connection. J. Affective Disorders 16: 103–107, 1989.
Levine R.A., Lovenberg W.: CFS tetrahydrobiopterin levels in patients with affective disorders. Lancet I: 283, 1984.
Argentiero V., Tavolato B.: Dopamine (DA) and serotonin metabolic levels in the cerebrospinal fluid (CSF) in Alzheimer’s presenile dementia under basic conditions and after stimulation with cerebral cortex phospholipids (BC-PL). J. Neurol. 224: 53–58, 1980.
Soininen H., MacDonald E., Rekonen M., Riekkinen P.J.: Homovanillic acid and 5-hydroxyindoleacetic acid levels in cerebrospinal fluid of patients with senile dementia of Alzheimer type. Acta Neurol. Scand. 64: 101–107, 1981.
Palmer A.M., Sins N.R., Bowen D.N., Neary D., Palo J., Wikstrom J., Davison A.N.: Monoamine metabolite concentrations in lumbar cerebrospinal fluid of patients with histologically verified Alzheimer’s dementia. J. Neurol. Neurosurg. Psychiatry 47: 481–484, 1984.
Volicer L., Langlais P.J., Matson W.R., Mark K.A., Gamache P.H.: Serotoninergic system in dementia of the Alzheimer type. Abnormal forms of 5′-hydroxytriptophan and serotonin in cerebrospinal fluid. Arch. Neurol. 42: 1158–1161, 1985.
Molchan S.E., Lawlor B.A., Hill J.L., Martinez R.A., Davis C.L., Mellow A.M., Rubinow D.R., Sunderland T.: CSF Monoamine metabolites and somatostatin in Alzheimer’s disease and major depression. Biol. Psychiatric 29: 1110–1118, 1991.
Reynolds E.H., Carney M.W.P., Toone B.K.: Methylation and mood. Lancet II: 196–198 1984.
Bell K.M., Pion L., Bunney W.E.: S-Adenosylmethionine treatment of depression: a controlled clinical trial. Am. J. Psychiatry 145: 1110–1114, 1984.
Kagan B.L., Sultzer D.L., Rosenclicht N.: Oral S-Adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. Am. J. Psychiatry 147: 591–595, 1990.
Rosenbaum J.F., Fava M., Falk W.E., Pollack M.H., Cohen L.S., Cohen B.M., Zubenko G.S.: The antidepressant potential of oral S-adenosyl-L-methionine. Acta Psychiatr. Scand. 81: 432–436, 1990.
Bottiglieri T., Godfrey P., Flynn T., Carney M.W.P., Toone B.K., Reynolds E.H.: Cerebrospinal fluid S- adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J. Neurol. Neurosurg. Psychiatry 53: 1096–1098, 1990.
Procter A.: Enhancement of recovery from psychiatric illness by methylfolate. Br. J. Psychiatry 159: 271–272, 1991.
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Passen, M., Cucinotta, D., Abate, G. et al. Oral 5′-methyltetrahydrofolic acid in senile organic mental disorders with depression: Results of a double-blind multicenter study. Aging Clin Exp Res 5, 63–71 (1993). https://doi.org/10.1007/BF03324128
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DOI: https://doi.org/10.1007/BF03324128