Folate Deficiency in Psychiatric Practice JAMES
S. HOWARD, III, M.D.*
The standard textbooks of psychiatry as well as biochemistry and neurology contain no reference to psychological or ncurological manifestations of folic acid deficiency.1.2 Likewise, most medical schools still teach that folate has a hematopoietic but not a neurological effect and therefore should be withheld in favor of Vitamin Bl~ in case of megaloblastic anemia. This ostensibly is to prevent subacute combined degeneration of the spinal cord and other neurological damage which is indeed the case in deficiency of the latter. 3 On the other hand literature has been accumulating for several years now showing that deficiency of either may produce major psychiatric and neurological changes. 4 This literature may roughly be divided into causes, psychiatric and neurological manifestations, clinical procedures for elucidating the deficiency state, and metabolic importance. Although folate is common in most foodstuffs,!' deficiency may come about thru anorexia or intentional restriction of intake. Likewise, conditions of physical or psychological stress are known to increase folate utilization. 6 Malabsorption syndromes such as sprue, celiac disease and chronic diarrhea may produce a deficiency due to diminished transport of folate across the wall of the jejunum. Congenital or postoperative blind loops may bring about a similar state due to increased demands for folate by bacterial flora in these area.7,10 Pregnancy, as it progresses has likewise been shown to be implicated in folate deficiency, due not only to the demands of the fetus, but also to the increase of hormonal dependent folate carrier proteins, particularly transferrin,u At the same time induction of a macromolecular folate binder occurs in both serum and leukocytes during pregnancy which tends to lower the effective level of reduced folates as well as the metabolic coenzyme, dihydrofolate. 12 Oral contraceptives and estrogen preparations have been shown to reduce folate by similar mechanisms.13.14.1li.16 Finally several anticonvulsants such as Dilantin, Phenobarbital, Primidone and Carbamazepine which exert at least part of their effect thru the reduction of folate,17.18 have been implicated in folate deficiency. This is mainly thru liver enzyme induction with subsequent greater demand for tetrahydrofolate, decreased • Clinical Director-Psychiatric Division 11 and Medical-
Surgical Services, Eastern State Hospital, Williamsburg, Virginia. 112
intestinal absorption of food folates and/or a specific effect on the cerebrospinal folate pump.19.20.23 The latter is especially important as approximately five to seven times the concentration of folate is normally found in the spinal fluid than is present in the blood. 24 .25 Among state hospital populations the incidence of folate deficiency is generally thought to be around 25 % 26·28.30 with the highest incidence among alcoholics, followed by the geriatric population, then schizophrenics. None of these disorders, however, has been shown to have a more specific causative relationship to the disease than frequently a reduction of dietary intake. Likewise it has been shown that treatment with neuroleptics, even on a long-term basis does not depress serum folate concentrations. 29 At any rate, however, it would appear that at least some of the signs and symptoms frequently attributed to these disease states may at times be more appropriately ascribed to deficiency of folic acid. Psychiatric symptoms of folate deficient patients include insomnia, anorexia, forgetfulness, hyperirritability, apathy, fatigue, withdrawal, confusion, lack of motivation, anxiety, delusions, dementia, disorientation, concreteness, psychosis, and depression both with and without psychomotor retardation. Alertness, concentration, self confidence, independence, and socialability are impaired. Speed of cerebration, as indicated by speech, thought, and action is slowed. 31 .40 Neurological symptoms which may be seen are progressive weakness, numbness, stiffness and spasticity, both with and without muscular atrophy. This may be generalized or restricted to the lower extremities. Bradykinesia, dystonia, ataxia, and vertigo make walking and standing difficult. Vibration sense, proprioception, and light touch are impaired as well as general motor and sensory conduction. Parasthesias, hyperasthesias and hypasthesias are known to occur. Deep tendon reflexes may either be diminished or hyperactive. Babinski and/or Romberg signs may be present as well as urinary incontinence.31.35.36.40,41.43 These symptoms together with pathological material suggest involvement or damage to the cerebellum, cerebrum, optic tracts, and especially the pyramidal tracts, posterior columns, and root pouches of the spinal cord.31.36.40.41.42 Other physical signs include pallor or yellowish skin discoloration, and atrophic glossitis or depapillation of the tongue. 4 Volume XVI
FOLATE DEFICIENCY-HOWARD
Figure I Tyrosine
Tyrosine Hydrozylase Pteridine Cofactor
Laboratory confirmation of folic acid deficiency may be obtained by low serum folate, macrocytosis, and megaloblastic marrow. Anemia may be present but is not necessary for neurological effects, as these are thought due to metabolic and endocrine disfunction. Elevated levels of formimino glutamic acid (FIGLU) are found in the urine, and the electroencephalogram frequently shows an abnormally slow dominant activity of 5 to 7 cycles per second with at times random bursts of 2 cycles per second slowing occasional1y seen. This may be generalized or localized to one or more areas of the brain. 44 A serum Vitamin BIz level would also be of value due to the similarities of the two deficiency states. Folic acid (pteroyl glutamic acid) is known to play ? key role in the metabolism and endocrinology of the brain, and many of the signs and symptoms of the deficiency state may be explained on this basis. First, the production of the sympathetic catechol amines is mediated thru the rate limiting step of tyrosine hydroxylation. This step requires not only tyrosine hydroxlase but also a pteridine cofactor, and both folic acid and dihydrobiopterin have been shown to function in this regard. 34 •40 ,46 Thus it would appear then that in folate deficiency the hydroxylation of tyrosine would likely be impaired with a subsequent decline in brain dopamine. This may explain possibly the bradykinesia, weakness, dystonias and other signs of Parkinsonism seen in association in this condition. Likewise, in keeping with the biogenic theory of affective disorders, depletion of dopamine, the norepinephrine precursor, would give rise to the depressive features of this illness, and explain why antidepressants which potentiate the action of norepinephrine but do not stimulate its synthesis are not usual1y successful. 33 In addition, the synthesis of brain epinephrine is known to occur from dopamine by way of the intermediary epinine. For this, not only is dopamine -nmethylating enzyme required, but also 5-methyl tetrahydrofolate as the methyl donor. In this way deficiency of folate would appear likely to further reduce the synthesis of this hormoneY At the same time folate plays a key role in the production of y-amino butyric acid (GABA), the important inhibitor of neurotransmission in the brain. This is accomplished thru the conversion of histidine to glutamic acid thru the intermediary formiminoglutamic acid July / August/September, 1975
~Dopamine
~ Norepinephrine
~ Epinephrine
(FIGLU). In the presence of folic acid, FIGLU is converted to glutamic acid which is then decarboxylated to form GABA. 48 During periods of folate deficiency, GABA would then be reduced yielding signs of possible central disinhibition. Figure II
Dopamine
DopamineN - Methylating Enzyme
-+ Epinine
~ Epinephrine
5 - Methyl THFA
A similar folate dependency occurs in the case of glycine, a major inhibitory neurotransmitter of the spinal cord. 48 Here tetrahydrofolic acid (THFA) is required in the interconversion of serine to glycine. 6 Decreased levels of glycine in the spinal cord may then be offered in partial explanation of the spasticity, Babinski and other long tract signs associated with this disease. Glycine also serves several other important functions such as the detoxification of certain endogenous amines which when present tend to decrease oxygen consumption in the brain. 6 On the other hand both serine and glycine are involved in the encoding of experience at the macromolecular level, along with other DNA & RNA synthesis. A direct requirement for folate occurs also in this regard. 49 Therefore in folate deficiency, synthesis of both nucleic acids would likely be reduced with DNA being affected more severely. During these times the DNA /RNA ratio may increase from its normal value of .30 up to .85 or more, the disproportionate fall in DNA synthesis being due to decreased amounts of folate-dependent thymidine available for encoding. 48 Memory loss, slow cerebration, and other signs of cerebral dysfunction associated with the disorder could be explained on this basis. Treatment consists of adequate intake of folate either thru diet or by supplement, using 2 to 5 milligrams folic acid per day, whereas between 50 micrograms and I milligram per day are thought necessary to prevent deficiency symptoms. The response is often striking and immediate with beneficial effects frequently noted within a few days. For this reason it is essential that laboratory screening for this disorder be done as soon as possible after admission to the hos113
PSYCHOSOMATICS
pital, for several adequate meals may significantly alter the clinical picture, as may discontinuance of the offending medication. Excessive intake of supplementary folate on the other hand should be avoided due to increased susceptability for seizures. The ingestion of excessive folate may also cause a paradoxical decrease of tyrosine hydroxylase activity.4 6 From the above it would seem that folate deficiency then should be included among the physical disorders producing mental and emotional, as well as neurologic symptoms commonly seen by the practicing psychiatrist. Persons suffering with this disorder have been diagnosed: senile dementia, presenile dementia, alcoholic deterioration, involutional melancholia, neurotic depressive reaction, schizoid personality, hysterical, paranoid. immature personality, post partum depression, schizophrenia. schizo-affective schizophrenia, endogenous depression, and parkinsonism. 26 Should this continue to be the case? BIBLIOGRAPHY
1. Cecil·Loeb, Textbook of Medicine, ed. P. B. Beesm and W. McDermott, 13th edition, P. 1472, Phila., Saunders, 197!. 2. DeGrudy, G. C., Clinical Haematology In Medical Prac· tice, :lrd edition, P. 138, Edinburgh, Blackwell, 197. 3. Cecil-Loeb, Textbook of Medicine, ed. P. B. Beesm and W. McDermott, 13th edition, P. 1466·1470, Phila., Saunders, 1971. 4. Pincus, Jonathan H., et ai, Subacute Combined System Degeneration With Folate Deficiency, JAMA, July 31, 1972, Vol. 221, No.5, 496-497. 5. Santini, Rafael, et aI, The Distribution of Folic Acid Active Compounds in Individual Foods, Amer. Jour. of Clin. Nutrition, Vol. 14, April 1964, 205-210. 6. Sourkes, T. L., Biochemistry of Mental Disease, Harper & Rowe, Publ., New York, 1962, 22·25. 7. Klipstein, Frederick A., Folate Deficiency Secondary to Disease of the Intestinal Tract, Bull., New York Acad. Med., Vol. 42, No.8, 1966. 8. Goldstein, F., et al. Clinical Syndrome Resembling Tropical Sprue in Life Long Residents of Temperate Zone, Dige~tive Diseases, Vol. 17, No.5, (May 1972) 407-414. 9. Olsen, W. A., A Practical Approach To Diagnosis of Disorders of Intestinal Absorption, New Engl., Jour. of Med, Vol. 285, No. 24, 1358-136!. 10. Goodwin, M. S., et aI, Malabsorption and Cerebal Dysfunction: A Multivariate and Comparative Study of AutIstic Children, Journal of Autism and Childhood Schizophrenia, 1971, I, I, 48-62. 11. Markkanen, T., et ai, Binding of Folic Acid to Serum Proteins, Acta Haemat., 50:85-91, (1973), 85-91. 12. DaCosta, M., Appearance of A Folate Binder in Leuco· cytes and Serum of Women Who are Pregnant or Taking Oral Contraceptives, J. Lab. Clin. Med, Feb, 1974, 207· 214. 13. Ryser, J. E., et aI, Megaloblastic Anemia Due to Folic Acid Deficiency in A Young Woman on Oral Contraceptives, Acta Haemat., 45:319·324, (1971), 319·324, 14. Corrocker, R., et ai, Hepatic Protein Binding of Folate, Clin. Science and Molecular Medicine, (1974), 46, 551554. 114
15. Buhac, I., et aI, Folsauremangelanamie Als Folge des Langfristigen Gebrauchs Peroraler Kontrazeptiver Mittel, Schweiz. Med. Wschr., 101, 1879-1881, (1971). 16. Necheles, T. F., et aI, Malabsorption of Folate Polyg· lwamates Associated with Oral Contraceptive Therapy, New Engl., Jour. Med., Vol. 282, No. 15. 858-859. 17. Reynolds, E. H., Anticonvulsallls, Folic Acid, and Epilepsy, Lancet, June 16, 1973. 1376-1378. 18. Reynolds, E. H., et aI, Anticonl'ulsant Therapy, Folic Acid and Vitamin B I1 Metabolism and Mental Symptoms, Epilepsia, 7, (1966), 261·270. 19. Mortimer, P. E., et aI, Enzyme Induction and Folate De· ficienc)', Brit. Med. Jour., 26 Feb, 1972, 567. 20. Latham, A. N., et aI, Lil'er Enzyme Induction by Anticonvulsant Dru1?s. and Its Relationship To Dislllrbed Calcium and Folic Acid Metabolism, J. Clin, Pharmacol, 13, (8·9):337-342, (Aug·Sept), 1973. 21. Markkanen, T., et aI, Binding of Folic Acid to Serum Proteins, Acta. Haemat. 50: 284-292, (1973). 22. Reizenstein, P., et aI, Effect of AllIiconvulsant Drugs on Folate Absorption and The Cerebrospinal Folate Pump, Scand. J. Haematol. 11:158·165, 1973. 23. Rosenberg, t. H., Dru1!s and Folic Acid Absorption, Gastroenterolgy, Vol. 63, No.2, August 1972, 353. 24. Houben, P. F. M., et aI, Anticonvulsant Drugs and Folic Acid in Young Mentally Retarded Epileptic Patiellls, Epilepsia, 1971, 12:235·247. 25. Mattson, R. H., et ai, Folate Therapy in Epilepsy, Arch Neurol, Vol. 29, Aug. 1973, 78·8!. 26. Kallstrom, B., et aI, Vitamin B I1 and Folic Acid in Psychiatric Disorders, Acta Psychiat. Scan., Vol. 45, 137152. 27. Kallstrom, T., Serum B 12 and Folate Concentrations in Mental Patients, Acta Psychiat. Scand., 45, (1969), 19. 28. Hunter, R., et ai, Serum B I! and Folate Concentrations in in Mental Patients, Brit. J. Psychiat., 113, (1967), 1291. 29. Gundersen, H. J., Serum Folate in Psychiatric Patients Under Long·Term Treatment with Tricycles Neuroleptic Druf!.f, Acta Psychiat. Scand., Vol. 45, No.2, 1969, 133136. 30. Hunter, R., et ai, Serum B Il and Folate Concentration in Mental Patients, Brit. J. Psychiat., (1967), 113, 1291· 1295. 31. Reynolds, E. H., Mental Effects of Anticonvulsants and Folic Acid Metabolism, Brain. Vol. 91, Part 2, June 1968, 197·214. 32. Reynolds, E. H., Vitamin Bit and Folate Deficiencies, Brit. J. Psychiat., Vol. 113, 681·683. 33. Reynolcl~, E. H., Folate Metabolism in Epileptic and Psychiatric Patients, J. Neurol. Neurosurg. Psychiat., 1971, 34, 726-732. 34. Reynolds, E. H., Anticonvulsant Drugs, Folic Acid Me· tabolism, Fit Frequency and Psychiatric Illness, Psychiatria Neurologia, Neurochirurgia, 74, (1971), 167·174. 35. Ahmed, M., Neurological Disease and Folate Deficiency, Brit. Med. Jour. 15 Jan '72, 181. 36. Reynolds, E. H., et ai, Neurological Disease Associated with Folate Deficiency, Brit. Med. Jour., 19 May 1973, 398-400. 37. Reynolds, E. H., et ai, Folate Deficiency in Depressive Illness, Brit. J. Psychiat., (1970), 117, 287·92. 38. Callaghan, N., et aI, The Relationship of Serum Folic Acid and Vitamin BI! Levels to Psychosis in Epilepsy, t. J. Med. Sc 7th Series, Vol. 2 No. 10, Oct. 1969, 497· 505. 39. Carney, M. W. P., Serum Folate Values in 423 Psychiatric Patients, Brit. Med. Jour., 1967, 4, 512-516. Volume XVI
FOLATE DEFICIENCY-HOWARD 40. Grant, H. C., Folate Deficiency and Neurological Disease, Lancet, Oct. 16, 1965, 763-767. 41. Hansen, H. A., et aI, Megaloblastic Anemia and Neurologic Disturbances Combined with Folic Acid Deficiency, Acta. Medica. Scandinavica, Vol. 176, Fasc. 2, 1964, 243-251. 42. Reynolds, E. H., Neurological Disease Associated with Folate Deficiency, Brit. Med. Jour., May 19, 1973, 398400. 43. Fehling. c., et aI, Folate Deficiency and Neurological Disease, Arch. Neurol., Vol. 30, March 1974, 263-265. 44. Strachan, R. W., et aI, Dementia and Folate Deficiency, Quarterly Journa. of Medicine, New Series XXXVI, No. 142, April 1967, 189-204. 45. McGeer, P. L., et ai, A Clinical Trial of Folic Acid in
46.
47.
48. 49.
50.
Parkinson's Disease, C.M.A. Journal, Jan. 22, 1972. Vol. 106, 145. Ellenbogen, L., et aI, On The Role of Pteridines As Cofactors For Tyrosine Hydroxylase, Biochem. and Bio· phys. Research Comm., Vol. 19, No.6, 1965, 708-715. Laduron, P., N-Methylations of Dopamine to Epinine in Brain Tissue Using N-Methyl Tetrahydrofolic Acid as the Methyl Donor, Nature New Biology, Vol. 238, August 16, 1972, 212-213. White, A., et ai, editor, Principles of Biochemistry, 5th Edition, McGraw-Hili Book Co., New York, 1973. Dickerman, H. W., The Role of Folate Coenzymes In the Initiation of Protein Synthesis, Annals, New York Academy of Sciences, Vol. 186, P. 70-84, 30 Nov. 1971. Herbert, Victor, Folic Acid, Ann. Rev. Med., 16, 1965, 359-371.
Temple University Symposium
The Temple University School of Medicine announces The First Annual Weiss-English Psychosomatic Symposium. Entitled "Psychosomatic Links in Cardiovascular Disease". The date is Saturday, October 11, 1975 and the place is the Faculty-Student Union at Broad and Ontario Street in Philadelphia. This symposium will honor the memory of Dr. Edward Weiss, Clinical Professor of Medicine at Temple and Dr. O. Spurgeon English, co-author with Dr. Weiss of the textbook "Psychosomatic Medicine" and Emeritus Professor of Psychiatry at Temple as well as Chairman of the Department of Psychiatry. Both are considered pioneers in formulating the concepts of psychosomatic medicine. What is most significant is that Dr. Edward Weiss remained an internist. Speakers include: Dr. Pametta, currently Professor and Chairman, Department of Psychiatry at Temple; Dr. Barney Olin, Clinical Professor of Psychiatry at Temple and Program Chairman; Dr. Wilfred Dorfman, Editor-in-Chief of Psychosomatics, Brooklyn, N.Y.; Dr. Alfred A. Bove, Assistant Professor of Medicine at Temple; Dr. Seymour ScholZ, Field Representative for the Committee on Graduate Medical Education of the AMA, who will speak on "My heart attack"-a personal history. The afternoon session will feature Dr. H. Keith Fischer, Clinical Professor of Psychiatry at Temple and President-Elect of the Academy of Psychosomatic Medicine; Dr. Louis Soloff, Emeritus Chief, Section of Cardiology, Temple University; Dr. Bernard Engel, Chief of Behavioral Sciences, National Institute of Aging, Johns Hopkins University, Baltimore; and Dr. George Engel, Professor of Psychiatry as well as Professor of Medicine at the University of Rochester, Rochester, N.Y. Further information and application forms for registration can be obtained from Dr. Albert Finestone, Assistant Dean, Continuing Medical Education, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, Pa. 19140.
July/August/September, 1975
115
S. HOWARD, III, M.D.*
The standard textbooks of psychiatry as well as biochemistry and neurology contain no reference to psychological or ncurological manifestations of folic acid deficiency.1.2 Likewise, most medical schools still teach that folate has a hematopoietic but not a neurological effect and therefore should be withheld in favor of Vitamin Bl~ in case of megaloblastic anemia. This ostensibly is to prevent subacute combined degeneration of the spinal cord and other neurological damage which is indeed the case in deficiency of the latter. 3 On the other hand literature has been accumulating for several years now showing that deficiency of either may produce major psychiatric and neurological changes. 4 This literature may roughly be divided into causes, psychiatric and neurological manifestations, clinical procedures for elucidating the deficiency state, and metabolic importance. Although folate is common in most foodstuffs,!' deficiency may come about thru anorexia or intentional restriction of intake. Likewise, conditions of physical or psychological stress are known to increase folate utilization. 6 Malabsorption syndromes such as sprue, celiac disease and chronic diarrhea may produce a deficiency due to diminished transport of folate across the wall of the jejunum. Congenital or postoperative blind loops may bring about a similar state due to increased demands for folate by bacterial flora in these area.7,10 Pregnancy, as it progresses has likewise been shown to be implicated in folate deficiency, due not only to the demands of the fetus, but also to the increase of hormonal dependent folate carrier proteins, particularly transferrin,u At the same time induction of a macromolecular folate binder occurs in both serum and leukocytes during pregnancy which tends to lower the effective level of reduced folates as well as the metabolic coenzyme, dihydrofolate. 12 Oral contraceptives and estrogen preparations have been shown to reduce folate by similar mechanisms.13.14.1li.16 Finally several anticonvulsants such as Dilantin, Phenobarbital, Primidone and Carbamazepine which exert at least part of their effect thru the reduction of folate,17.18 have been implicated in folate deficiency. This is mainly thru liver enzyme induction with subsequent greater demand for tetrahydrofolate, decreased • Clinical Director-Psychiatric Division 11 and Medical-
Surgical Services, Eastern State Hospital, Williamsburg, Virginia. 112
intestinal absorption of food folates and/or a specific effect on the cerebrospinal folate pump.19.20.23 The latter is especially important as approximately five to seven times the concentration of folate is normally found in the spinal fluid than is present in the blood. 24 .25 Among state hospital populations the incidence of folate deficiency is generally thought to be around 25 % 26·28.30 with the highest incidence among alcoholics, followed by the geriatric population, then schizophrenics. None of these disorders, however, has been shown to have a more specific causative relationship to the disease than frequently a reduction of dietary intake. Likewise it has been shown that treatment with neuroleptics, even on a long-term basis does not depress serum folate concentrations. 29 At any rate, however, it would appear that at least some of the signs and symptoms frequently attributed to these disease states may at times be more appropriately ascribed to deficiency of folic acid. Psychiatric symptoms of folate deficient patients include insomnia, anorexia, forgetfulness, hyperirritability, apathy, fatigue, withdrawal, confusion, lack of motivation, anxiety, delusions, dementia, disorientation, concreteness, psychosis, and depression both with and without psychomotor retardation. Alertness, concentration, self confidence, independence, and socialability are impaired. Speed of cerebration, as indicated by speech, thought, and action is slowed. 31 .40 Neurological symptoms which may be seen are progressive weakness, numbness, stiffness and spasticity, both with and without muscular atrophy. This may be generalized or restricted to the lower extremities. Bradykinesia, dystonia, ataxia, and vertigo make walking and standing difficult. Vibration sense, proprioception, and light touch are impaired as well as general motor and sensory conduction. Parasthesias, hyperasthesias and hypasthesias are known to occur. Deep tendon reflexes may either be diminished or hyperactive. Babinski and/or Romberg signs may be present as well as urinary incontinence.31.35.36.40,41.43 These symptoms together with pathological material suggest involvement or damage to the cerebellum, cerebrum, optic tracts, and especially the pyramidal tracts, posterior columns, and root pouches of the spinal cord.31.36.40.41.42 Other physical signs include pallor or yellowish skin discoloration, and atrophic glossitis or depapillation of the tongue. 4 Volume XVI
FOLATE DEFICIENCY-HOWARD
Figure I Tyrosine
Tyrosine Hydrozylase Pteridine Cofactor
Laboratory confirmation of folic acid deficiency may be obtained by low serum folate, macrocytosis, and megaloblastic marrow. Anemia may be present but is not necessary for neurological effects, as these are thought due to metabolic and endocrine disfunction. Elevated levels of formimino glutamic acid (FIGLU) are found in the urine, and the electroencephalogram frequently shows an abnormally slow dominant activity of 5 to 7 cycles per second with at times random bursts of 2 cycles per second slowing occasional1y seen. This may be generalized or localized to one or more areas of the brain. 44 A serum Vitamin BIz level would also be of value due to the similarities of the two deficiency states. Folic acid (pteroyl glutamic acid) is known to play ? key role in the metabolism and endocrinology of the brain, and many of the signs and symptoms of the deficiency state may be explained on this basis. First, the production of the sympathetic catechol amines is mediated thru the rate limiting step of tyrosine hydroxylation. This step requires not only tyrosine hydroxlase but also a pteridine cofactor, and both folic acid and dihydrobiopterin have been shown to function in this regard. 34 •40 ,46 Thus it would appear then that in folate deficiency the hydroxylation of tyrosine would likely be impaired with a subsequent decline in brain dopamine. This may explain possibly the bradykinesia, weakness, dystonias and other signs of Parkinsonism seen in association in this condition. Likewise, in keeping with the biogenic theory of affective disorders, depletion of dopamine, the norepinephrine precursor, would give rise to the depressive features of this illness, and explain why antidepressants which potentiate the action of norepinephrine but do not stimulate its synthesis are not usual1y successful. 33 In addition, the synthesis of brain epinephrine is known to occur from dopamine by way of the intermediary epinine. For this, not only is dopamine -nmethylating enzyme required, but also 5-methyl tetrahydrofolate as the methyl donor. In this way deficiency of folate would appear likely to further reduce the synthesis of this hormoneY At the same time folate plays a key role in the production of y-amino butyric acid (GABA), the important inhibitor of neurotransmission in the brain. This is accomplished thru the conversion of histidine to glutamic acid thru the intermediary formiminoglutamic acid July / August/September, 1975
~Dopamine
~ Norepinephrine
~ Epinephrine
(FIGLU). In the presence of folic acid, FIGLU is converted to glutamic acid which is then decarboxylated to form GABA. 48 During periods of folate deficiency, GABA would then be reduced yielding signs of possible central disinhibition. Figure II
Dopamine
DopamineN - Methylating Enzyme
-+ Epinine
~ Epinephrine
5 - Methyl THFA
A similar folate dependency occurs in the case of glycine, a major inhibitory neurotransmitter of the spinal cord. 48 Here tetrahydrofolic acid (THFA) is required in the interconversion of serine to glycine. 6 Decreased levels of glycine in the spinal cord may then be offered in partial explanation of the spasticity, Babinski and other long tract signs associated with this disease. Glycine also serves several other important functions such as the detoxification of certain endogenous amines which when present tend to decrease oxygen consumption in the brain. 6 On the other hand both serine and glycine are involved in the encoding of experience at the macromolecular level, along with other DNA & RNA synthesis. A direct requirement for folate occurs also in this regard. 49 Therefore in folate deficiency, synthesis of both nucleic acids would likely be reduced with DNA being affected more severely. During these times the DNA /RNA ratio may increase from its normal value of .30 up to .85 or more, the disproportionate fall in DNA synthesis being due to decreased amounts of folate-dependent thymidine available for encoding. 48 Memory loss, slow cerebration, and other signs of cerebral dysfunction associated with the disorder could be explained on this basis. Treatment consists of adequate intake of folate either thru diet or by supplement, using 2 to 5 milligrams folic acid per day, whereas between 50 micrograms and I milligram per day are thought necessary to prevent deficiency symptoms. The response is often striking and immediate with beneficial effects frequently noted within a few days. For this reason it is essential that laboratory screening for this disorder be done as soon as possible after admission to the hos113
PSYCHOSOMATICS
pital, for several adequate meals may significantly alter the clinical picture, as may discontinuance of the offending medication. Excessive intake of supplementary folate on the other hand should be avoided due to increased susceptability for seizures. The ingestion of excessive folate may also cause a paradoxical decrease of tyrosine hydroxylase activity.4 6 From the above it would seem that folate deficiency then should be included among the physical disorders producing mental and emotional, as well as neurologic symptoms commonly seen by the practicing psychiatrist. Persons suffering with this disorder have been diagnosed: senile dementia, presenile dementia, alcoholic deterioration, involutional melancholia, neurotic depressive reaction, schizoid personality, hysterical, paranoid. immature personality, post partum depression, schizophrenia. schizo-affective schizophrenia, endogenous depression, and parkinsonism. 26 Should this continue to be the case? BIBLIOGRAPHY
1. Cecil·Loeb, Textbook of Medicine, ed. P. B. Beesm and W. McDermott, 13th edition, P. 1472, Phila., Saunders, 197!. 2. DeGrudy, G. C., Clinical Haematology In Medical Prac· tice, :lrd edition, P. 138, Edinburgh, Blackwell, 197. 3. Cecil-Loeb, Textbook of Medicine, ed. P. B. Beesm and W. McDermott, 13th edition, P. 1466·1470, Phila., Saunders, 1971. 4. Pincus, Jonathan H., et ai, Subacute Combined System Degeneration With Folate Deficiency, JAMA, July 31, 1972, Vol. 221, No.5, 496-497. 5. Santini, Rafael, et aI, The Distribution of Folic Acid Active Compounds in Individual Foods, Amer. Jour. of Clin. Nutrition, Vol. 14, April 1964, 205-210. 6. Sourkes, T. L., Biochemistry of Mental Disease, Harper & Rowe, Publ., New York, 1962, 22·25. 7. Klipstein, Frederick A., Folate Deficiency Secondary to Disease of the Intestinal Tract, Bull., New York Acad. Med., Vol. 42, No.8, 1966. 8. Goldstein, F., et al. Clinical Syndrome Resembling Tropical Sprue in Life Long Residents of Temperate Zone, Dige~tive Diseases, Vol. 17, No.5, (May 1972) 407-414. 9. Olsen, W. A., A Practical Approach To Diagnosis of Disorders of Intestinal Absorption, New Engl., Jour. of Med, Vol. 285, No. 24, 1358-136!. 10. Goodwin, M. S., et aI, Malabsorption and Cerebal Dysfunction: A Multivariate and Comparative Study of AutIstic Children, Journal of Autism and Childhood Schizophrenia, 1971, I, I, 48-62. 11. Markkanen, T., et ai, Binding of Folic Acid to Serum Proteins, Acta Haemat., 50:85-91, (1973), 85-91. 12. DaCosta, M., Appearance of A Folate Binder in Leuco· cytes and Serum of Women Who are Pregnant or Taking Oral Contraceptives, J. Lab. Clin. Med, Feb, 1974, 207· 214. 13. Ryser, J. E., et aI, Megaloblastic Anemia Due to Folic Acid Deficiency in A Young Woman on Oral Contraceptives, Acta Haemat., 45:319·324, (1971), 319·324, 14. Corrocker, R., et ai, Hepatic Protein Binding of Folate, Clin. Science and Molecular Medicine, (1974), 46, 551554. 114
15. Buhac, I., et aI, Folsauremangelanamie Als Folge des Langfristigen Gebrauchs Peroraler Kontrazeptiver Mittel, Schweiz. Med. Wschr., 101, 1879-1881, (1971). 16. Necheles, T. F., et aI, Malabsorption of Folate Polyg· lwamates Associated with Oral Contraceptive Therapy, New Engl., Jour. Med., Vol. 282, No. 15. 858-859. 17. Reynolds, E. H., Anticonvulsallls, Folic Acid, and Epilepsy, Lancet, June 16, 1973. 1376-1378. 18. Reynolds, E. H., et aI, Anticonl'ulsant Therapy, Folic Acid and Vitamin B I1 Metabolism and Mental Symptoms, Epilepsia, 7, (1966), 261·270. 19. Mortimer, P. E., et aI, Enzyme Induction and Folate De· ficienc)', Brit. Med. Jour., 26 Feb, 1972, 567. 20. Latham, A. N., et aI, Lil'er Enzyme Induction by Anticonvulsant Dru1?s. and Its Relationship To Dislllrbed Calcium and Folic Acid Metabolism, J. Clin, Pharmacol, 13, (8·9):337-342, (Aug·Sept), 1973. 21. Markkanen, T., et aI, Binding of Folic Acid to Serum Proteins, Acta. Haemat. 50: 284-292, (1973). 22. Reizenstein, P., et aI, Effect of AllIiconvulsant Drugs on Folate Absorption and The Cerebrospinal Folate Pump, Scand. J. Haematol. 11:158·165, 1973. 23. Rosenberg, t. H., Dru1!s and Folic Acid Absorption, Gastroenterolgy, Vol. 63, No.2, August 1972, 353. 24. Houben, P. F. M., et aI, Anticonvulsant Drugs and Folic Acid in Young Mentally Retarded Epileptic Patiellls, Epilepsia, 1971, 12:235·247. 25. Mattson, R. H., et ai, Folate Therapy in Epilepsy, Arch Neurol, Vol. 29, Aug. 1973, 78·8!. 26. Kallstrom, B., et aI, Vitamin B I1 and Folic Acid in Psychiatric Disorders, Acta Psychiat. Scan., Vol. 45, 137152. 27. Kallstrom, T., Serum B 12 and Folate Concentrations in Mental Patients, Acta Psychiat. Scand., 45, (1969), 19. 28. Hunter, R., et ai, Serum B I! and Folate Concentrations in in Mental Patients, Brit. J. Psychiat., 113, (1967), 1291. 29. Gundersen, H. J., Serum Folate in Psychiatric Patients Under Long·Term Treatment with Tricycles Neuroleptic Druf!.f, Acta Psychiat. Scand., Vol. 45, No.2, 1969, 133136. 30. Hunter, R., et ai, Serum B Il and Folate Concentration in Mental Patients, Brit. J. Psychiat., (1967), 113, 1291· 1295. 31. Reynolds, E. H., Mental Effects of Anticonvulsants and Folic Acid Metabolism, Brain. Vol. 91, Part 2, June 1968, 197·214. 32. Reynolds, E. H., Vitamin Bit and Folate Deficiencies, Brit. J. Psychiat., Vol. 113, 681·683. 33. Reynolcl~, E. H., Folate Metabolism in Epileptic and Psychiatric Patients, J. Neurol. Neurosurg. Psychiat., 1971, 34, 726-732. 34. Reynolds, E. H., Anticonvulsant Drugs, Folic Acid Me· tabolism, Fit Frequency and Psychiatric Illness, Psychiatria Neurologia, Neurochirurgia, 74, (1971), 167·174. 35. Ahmed, M., Neurological Disease and Folate Deficiency, Brit. Med. Jour. 15 Jan '72, 181. 36. Reynolds, E. H., et ai, Neurological Disease Associated with Folate Deficiency, Brit. Med. Jour., 19 May 1973, 398-400. 37. Reynolds, E. H., et ai, Folate Deficiency in Depressive Illness, Brit. J. Psychiat., (1970), 117, 287·92. 38. Callaghan, N., et aI, The Relationship of Serum Folic Acid and Vitamin BI! Levels to Psychosis in Epilepsy, t. J. Med. Sc 7th Series, Vol. 2 No. 10, Oct. 1969, 497· 505. 39. Carney, M. W. P., Serum Folate Values in 423 Psychiatric Patients, Brit. Med. Jour., 1967, 4, 512-516. Volume XVI
FOLATE DEFICIENCY-HOWARD 40. Grant, H. C., Folate Deficiency and Neurological Disease, Lancet, Oct. 16, 1965, 763-767. 41. Hansen, H. A., et aI, Megaloblastic Anemia and Neurologic Disturbances Combined with Folic Acid Deficiency, Acta. Medica. Scandinavica, Vol. 176, Fasc. 2, 1964, 243-251. 42. Reynolds, E. H., Neurological Disease Associated with Folate Deficiency, Brit. Med. Jour., May 19, 1973, 398400. 43. Fehling. c., et aI, Folate Deficiency and Neurological Disease, Arch. Neurol., Vol. 30, March 1974, 263-265. 44. Strachan, R. W., et aI, Dementia and Folate Deficiency, Quarterly Journa. of Medicine, New Series XXXVI, No. 142, April 1967, 189-204. 45. McGeer, P. L., et ai, A Clinical Trial of Folic Acid in
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Parkinson's Disease, C.M.A. Journal, Jan. 22, 1972. Vol. 106, 145. Ellenbogen, L., et aI, On The Role of Pteridines As Cofactors For Tyrosine Hydroxylase, Biochem. and Bio· phys. Research Comm., Vol. 19, No.6, 1965, 708-715. Laduron, P., N-Methylations of Dopamine to Epinine in Brain Tissue Using N-Methyl Tetrahydrofolic Acid as the Methyl Donor, Nature New Biology, Vol. 238, August 16, 1972, 212-213. White, A., et ai, editor, Principles of Biochemistry, 5th Edition, McGraw-Hili Book Co., New York, 1973. Dickerman, H. W., The Role of Folate Coenzymes In the Initiation of Protein Synthesis, Annals, New York Academy of Sciences, Vol. 186, P. 70-84, 30 Nov. 1971. Herbert, Victor, Folic Acid, Ann. Rev. Med., 16, 1965, 359-371.
Temple University Symposium
The Temple University School of Medicine announces The First Annual Weiss-English Psychosomatic Symposium. Entitled "Psychosomatic Links in Cardiovascular Disease". The date is Saturday, October 11, 1975 and the place is the Faculty-Student Union at Broad and Ontario Street in Philadelphia. This symposium will honor the memory of Dr. Edward Weiss, Clinical Professor of Medicine at Temple and Dr. O. Spurgeon English, co-author with Dr. Weiss of the textbook "Psychosomatic Medicine" and Emeritus Professor of Psychiatry at Temple as well as Chairman of the Department of Psychiatry. Both are considered pioneers in formulating the concepts of psychosomatic medicine. What is most significant is that Dr. Edward Weiss remained an internist. Speakers include: Dr. Pametta, currently Professor and Chairman, Department of Psychiatry at Temple; Dr. Barney Olin, Clinical Professor of Psychiatry at Temple and Program Chairman; Dr. Wilfred Dorfman, Editor-in-Chief of Psychosomatics, Brooklyn, N.Y.; Dr. Alfred A. Bove, Assistant Professor of Medicine at Temple; Dr. Seymour ScholZ, Field Representative for the Committee on Graduate Medical Education of the AMA, who will speak on "My heart attack"-a personal history. The afternoon session will feature Dr. H. Keith Fischer, Clinical Professor of Psychiatry at Temple and President-Elect of the Academy of Psychosomatic Medicine; Dr. Louis Soloff, Emeritus Chief, Section of Cardiology, Temple University; Dr. Bernard Engel, Chief of Behavioral Sciences, National Institute of Aging, Johns Hopkins University, Baltimore; and Dr. George Engel, Professor of Psychiatry as well as Professor of Medicine at the University of Rochester, Rochester, N.Y. Further information and application forms for registration can be obtained from Dr. Albert Finestone, Assistant Dean, Continuing Medical Education, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, Pa. 19140.
July/August/September, 1975
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