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COMBINING THE ANTIDEPRESSANT DRUGS
943 Achilles tendon is repeatedly tapped, and how does this affect the results ? ’The first two or three reflex measurements of a single subject are often longer than those that follow. We achieved consistent results by recording 10-12 consecutive reflex measurements on each subject, discarding the first three, and accepting the measurement that occurred most frequently among the remaining ones as the final value. There was only minor variation from reflex to reflex in an individual (contrasted to
the
findings
in
neurosyphilis).
In summary, I believe that the Achilles reflex measurement (recorded by both electromagnetic and photocell techniques) has been carefully studied and shown to be comparable in accuracy to the standard diagnostic tests of thyroid function. The whys and wherefores of this interesting peripheral response to abnormal thyroid hormone levels remain unknown. University Hospitals, Madison, Wisconsin.
that of 75 female patients on prolonged phenothiazine therapy, approximately two-thirds showed a definite trend towards
leucopenia. We still believe that as a general principle combining the antidepressant drugs is contraindicated and that to administer a specific antidepressant drug for a specific syndrome or cluster of symptoms is more satisfactory. For example, Kiloh and Garside 15 have emphasised the independence of neurotic and endogenous depression, and Ball and Kiloh 16 demonstrated that patients diagnosed as having endogenous depression made a significantly better response to imipramine than those regarded as showing neurotic depression. Further combining the antidepressant drugs is dangerous.
Dr. Laurence 17states that " monoamineoxidase inhibitors ...
particularly versatile in their interactions and dangerous potentiation of a number of drugs may occur... with ephedrine, amphetamines, adrenaline and noradrenaline, causing arterial hypertension and convulsions ... with imipramine (’Tofranil’) causing sweating, salivation, excitement, coma and hyperthermia". Dr. Beresford Davies particularly stated that amphetamine may be safely combined with imipramine, amitriptyline, or a monoamineoxidase inhibitor given to many patients for months. In spite of this we would prefer to accept the view of Dr. Laurence, who further adds that " it may be thought better that a few warnings, later shown to have been are
Lewis, 1963.
A. Research and its
grave risks should be run". Dr. Denis Leigh 18 succinctly summarises the position thus: " The dangers associated -with these psychotropic drugs have only been fully recognized in the past two years. It has become essential for the doctor to distinguish symptoms and signs due to ’side-effects ’ from those resulting from the illness. Moreover, the dangerous effects produced by the co-administration of other drugs is only now being appreciated ... The monoamineoxidase inhibitors are particularly concerned, for severe reactions occur when the amphetamines, pethidine, morphine and imipramine are administered. It is unwise to combine a monoamineoxidase inhibitor with drugs of the imipramine group; a clear two weeks off medication should be allowed before one replaces the other." J. C. BARKER Shelton Hospital, M. DAVID ENOCH. Shrewsbury.
LAWRENCE SHERMAN.
COMBINING THE ANTIDEPRESSANT DRUGS SIR,-Dr. Beresford Davies and Dr. Boardman (Oct. 12) criticise us for expressing opinions (Sept. 28) differing from those of Dr. Sargant (Sept. 21). These were honest if strongly held views which we felt justified in " ventilating; indeed3 informed criticism ", as Sir Aubrey Lewis 12 has recently remarked, " is as valuable, or indispensable, in the advancement of psychiatry, as of any other field of knowledge ". Dr. Beresford Davies’ letter exhibits ambivalence towards our expressed views. On the one hand, he objects to our criticising the combination of antidepressant drugs, and on the other hand he emphasises the importance of possible side-effects occurring after prolonged drug therapy and specifically advocates their temperate use. These were precisely the points that we were trying to make. We should again like to emphasise the serious side-effects which may follow prolonged drug therapy, and which may not become apparent for a considerable time. An important example of this is the depression of the white blood-cells after phenothiazine therapy. IS 14 Preliminary studies here show
12.
groundless, should be given, than that potentially
Application in Psychiatry; p. 20. Glasgow,
13.
Arieti, S. American Handbook of Psychiatry; vol. ii, p. 1548. New York,
14. 15. 16. 17.
Sim, M. Guide to Psychiatry; p. 634. Edinburgh, 1963. Kiloh, L. G., Garside, R. F. Brit. J. Psychiat. 1963, 109, 451. Ball, J. R. B., Kiloh, L. G. Brit. med. J. 1959, ii, 1052. Laurence, D. R. Prescribers’ J. 1963, 3, 46.
1959.
LYONISATION OF THE X CHROMOSOME SIR,-You describe (Oct. 12) the difficulty of accounting for the developmental abnormalities in Turner’s and Klinefelter’s syndromes should Lyon’s hypothesis 19 be generally valid. This difficulty would plausibly be resolved if the X-linked genes in key cells governing development and growth in normal females were unaffected by Lyonisation. Aneuploidy involving the X chromosome would disturb the normal balance of repressor and of messenger R.N.A. synthesis from non-Lyonised regulator and structural genes respectively, and developmental abnormalities could then reasonably be attributed to this imbalance. We wish to suggest that there is much indirect evidence to support this view. It has already been shown 20 21 that the rate of somatic mutation in spontaneous disturbed tolerance’ autoimmunity can in females be twice (e.g., polyarthritis 20), four times (e.g., systemic sclerosis 21), and possibly eight times (e.g., systemic lupus erythematosus 21) the corresponding rates in males. These’ sex-differences are readily explained if somatic mutation affects genes at one, two, or three loci respectively on the X chromosome-provided of course that both homologous genes are " at risk " in the stem cells of normal XX females. Consequently, if Barr-body formation occurs in these cells, it appears not to affect the loci " at risk" with respect to the phenotypic expression of autoimmune disease .20 We could therefore account for the developmental defects in the above syndromes if the loci that are at risk with respect to autoimmunity are also implicated in ontogeny. One of us has summarised the evidence in support of his hypothesis 22 that the primary natural role of lymphoid tissue is related to morphostasis. It is envisaged that the development, growth, and relative size of many organs and tissues is regulated, at least in part, by a feed-back interaction between specific elements of lymphoid tissue and complementary differentiated target cells. A system of this kind requires that the controlling " agent should be able to recognise tissue-specific factors along both the receptor and effector pathways. In view of the great variety of differentiated tissues, the controlling agent must "
contain many specific elements, each of which has a different information content to enable it to identify the " tissue code ". The great range of specificities of antibodies would appear to be admirably suited to these recognition and control requirements. It has been suggested 20 that mitosis in target tissues and organs is to some extent regulated through a weak (or subimmune type) interaction between small lymphocytes carrying cell-bound antibody " and mitotically competent target tissue. In disturbed tolerance autoimmunity, we deduce that relevant mutation in the stem cells of the control tissue changes the polypeptide structure and hence the steric configuration of the 18. Leigh, D. Practitioner, 1963, 191, 431. "
19. 20. 21. 22.
Lyon, M. F. Nature, Lond. 1961, 190, 372. Burch, P. R. J. Lancet, 1963, i, 1253. Burch, P. R. J., Rowell, N. R. ibid. Sept. 7, 1963, p. 507. Burwell, R. G. ibid. July 13, 1963, p. 69.
the
findings
in
neurosyphilis).
In summary, I believe that the Achilles reflex measurement (recorded by both electromagnetic and photocell techniques) has been carefully studied and shown to be comparable in accuracy to the standard diagnostic tests of thyroid function. The whys and wherefores of this interesting peripheral response to abnormal thyroid hormone levels remain unknown. University Hospitals, Madison, Wisconsin.
that of 75 female patients on prolonged phenothiazine therapy, approximately two-thirds showed a definite trend towards
leucopenia. We still believe that as a general principle combining the antidepressant drugs is contraindicated and that to administer a specific antidepressant drug for a specific syndrome or cluster of symptoms is more satisfactory. For example, Kiloh and Garside 15 have emphasised the independence of neurotic and endogenous depression, and Ball and Kiloh 16 demonstrated that patients diagnosed as having endogenous depression made a significantly better response to imipramine than those regarded as showing neurotic depression. Further combining the antidepressant drugs is dangerous.
Dr. Laurence 17states that " monoamineoxidase inhibitors ...
particularly versatile in their interactions and dangerous potentiation of a number of drugs may occur... with ephedrine, amphetamines, adrenaline and noradrenaline, causing arterial hypertension and convulsions ... with imipramine (’Tofranil’) causing sweating, salivation, excitement, coma and hyperthermia". Dr. Beresford Davies particularly stated that amphetamine may be safely combined with imipramine, amitriptyline, or a monoamineoxidase inhibitor given to many patients for months. In spite of this we would prefer to accept the view of Dr. Laurence, who further adds that " it may be thought better that a few warnings, later shown to have been are
Lewis, 1963.
A. Research and its
grave risks should be run". Dr. Denis Leigh 18 succinctly summarises the position thus: " The dangers associated -with these psychotropic drugs have only been fully recognized in the past two years. It has become essential for the doctor to distinguish symptoms and signs due to ’side-effects ’ from those resulting from the illness. Moreover, the dangerous effects produced by the co-administration of other drugs is only now being appreciated ... The monoamineoxidase inhibitors are particularly concerned, for severe reactions occur when the amphetamines, pethidine, morphine and imipramine are administered. It is unwise to combine a monoamineoxidase inhibitor with drugs of the imipramine group; a clear two weeks off medication should be allowed before one replaces the other." J. C. BARKER Shelton Hospital, M. DAVID ENOCH. Shrewsbury.
LAWRENCE SHERMAN.
COMBINING THE ANTIDEPRESSANT DRUGS SIR,-Dr. Beresford Davies and Dr. Boardman (Oct. 12) criticise us for expressing opinions (Sept. 28) differing from those of Dr. Sargant (Sept. 21). These were honest if strongly held views which we felt justified in " ventilating; indeed3 informed criticism ", as Sir Aubrey Lewis 12 has recently remarked, " is as valuable, or indispensable, in the advancement of psychiatry, as of any other field of knowledge ". Dr. Beresford Davies’ letter exhibits ambivalence towards our expressed views. On the one hand, he objects to our criticising the combination of antidepressant drugs, and on the other hand he emphasises the importance of possible side-effects occurring after prolonged drug therapy and specifically advocates their temperate use. These were precisely the points that we were trying to make. We should again like to emphasise the serious side-effects which may follow prolonged drug therapy, and which may not become apparent for a considerable time. An important example of this is the depression of the white blood-cells after phenothiazine therapy. IS 14 Preliminary studies here show
12.
groundless, should be given, than that potentially
Application in Psychiatry; p. 20. Glasgow,
13.
Arieti, S. American Handbook of Psychiatry; vol. ii, p. 1548. New York,
14. 15. 16. 17.
Sim, M. Guide to Psychiatry; p. 634. Edinburgh, 1963. Kiloh, L. G., Garside, R. F. Brit. J. Psychiat. 1963, 109, 451. Ball, J. R. B., Kiloh, L. G. Brit. med. J. 1959, ii, 1052. Laurence, D. R. Prescribers’ J. 1963, 3, 46.
1959.
LYONISATION OF THE X CHROMOSOME SIR,-You describe (Oct. 12) the difficulty of accounting for the developmental abnormalities in Turner’s and Klinefelter’s syndromes should Lyon’s hypothesis 19 be generally valid. This difficulty would plausibly be resolved if the X-linked genes in key cells governing development and growth in normal females were unaffected by Lyonisation. Aneuploidy involving the X chromosome would disturb the normal balance of repressor and of messenger R.N.A. synthesis from non-Lyonised regulator and structural genes respectively, and developmental abnormalities could then reasonably be attributed to this imbalance. We wish to suggest that there is much indirect evidence to support this view. It has already been shown 20 21 that the rate of somatic mutation in spontaneous disturbed tolerance’ autoimmunity can in females be twice (e.g., polyarthritis 20), four times (e.g., systemic sclerosis 21), and possibly eight times (e.g., systemic lupus erythematosus 21) the corresponding rates in males. These’ sex-differences are readily explained if somatic mutation affects genes at one, two, or three loci respectively on the X chromosome-provided of course that both homologous genes are " at risk " in the stem cells of normal XX females. Consequently, if Barr-body formation occurs in these cells, it appears not to affect the loci " at risk" with respect to the phenotypic expression of autoimmune disease .20 We could therefore account for the developmental defects in the above syndromes if the loci that are at risk with respect to autoimmunity are also implicated in ontogeny. One of us has summarised the evidence in support of his hypothesis 22 that the primary natural role of lymphoid tissue is related to morphostasis. It is envisaged that the development, growth, and relative size of many organs and tissues is regulated, at least in part, by a feed-back interaction between specific elements of lymphoid tissue and complementary differentiated target cells. A system of this kind requires that the controlling " agent should be able to recognise tissue-specific factors along both the receptor and effector pathways. In view of the great variety of differentiated tissues, the controlling agent must "
contain many specific elements, each of which has a different information content to enable it to identify the " tissue code ". The great range of specificities of antibodies would appear to be admirably suited to these recognition and control requirements. It has been suggested 20 that mitosis in target tissues and organs is to some extent regulated through a weak (or subimmune type) interaction between small lymphocytes carrying cell-bound antibody " and mitotically competent target tissue. In disturbed tolerance autoimmunity, we deduce that relevant mutation in the stem cells of the control tissue changes the polypeptide structure and hence the steric configuration of the 18. Leigh, D. Practitioner, 1963, 191, 431. "
19. 20. 21. 22.
Lyon, M. F. Nature, Lond. 1961, 190, 372. Burch, P. R. J. Lancet, 1963, i, 1253. Burch, P. R. J., Rowell, N. R. ibid. Sept. 7, 1963, p. 507. Burwell, R. G. ibid. July 13, 1963, p. 69.