1233
Hypothesis VASOPRESSIN IN AFFECTIVE ILLNESS PHILIP W. GOLD
Clinical Psychobiology Branch, National Institute of Mental Health, 9000 Rockville Pike, Building 10, Room 4S239, Bethesda, Maryland 20014
Fig. 5-Structural feature of the «-G.H.L"
50% of maltase activity2 is much less affected by
a-G.H.I.
(my unpublished observations). 200 mg of &agr;-G.H.I. effectively decreased postprandial glucose levels after sucrose ingestion and prevented the late postprandial dip in blood-glucose. The latter can be explained by the reduced insulin response to sucrose in the presence of :x-G.H.I.6 x-G.H.i. not only delayed glucose absorption, as observed in patients on treatment with biguanides,10 but also resulted in malabsorption of sucrose as shown by increased breath-H2 production. Similar rises in breath-H2 concentration seen in this study have been reported in lactase-deficient patients after ingestion of lactose7,9 or in sucrase-isomaltase deficient patients after a sucrose load.3 In order to quantitate the amount of sucrose that is not absorbed in the presence of the a-G.H.1., breath-H2 concentrations produced by sucrose and the inhibitor were compared with H2 concentrations produced by the non-absorbable disaccharide lactulose. The integrated H2-output (integration of area below curves in fig. 4) produced by 100 g of sucrose and &agr;-G.H.I. was 2.014-fold higher than that produced by 20 g of lactulose. On the assumption that lactulose and sucrose are fermented by colonic bacteria at equal rates, maldigestion and malabsorption must have resulted in approximately 40 g of the 100 g sucrose load being left behind for fermentation by colonic bacteria. This new compound is an interesting tool by which the effects of carbohydrate maldigestion, and hence malabsorption, in animals and man can be studied. It may be a useful agent for retarding carbohydrate absorption in some diseases, such as, diabetes mellitis, obesity, and hyperlipldxmia. The I.
FREDERICK K. GOODWIN
x-G.H.I. (Bay g 5421) was provided by Dr P. Berchtold, Dr Hillebrandt, and Dr W. Puls (Bayer Pharmaceutical Company,
VICTOR I. REUS
Biological Psychiatry Branch, National Institute of Mental Health, 9000 Rockville Pike, Building 10, Room 3S239, Bethesda, Maryland 20014
Summary
Animal studies have revealed
two
impor-
aspects of vasopressin function which make this peptide a suitable candidate for involvement in complex behavioural syndromes: (1) vasopressin deficiency produces deficits of behaviour which are reversed by vasopressin; (2) well-developed systems exist for the distribution of vasopressin throughout the central nervous system (C.N.S.) via either peptidergic neurons or the cerebrospinal fluid (C.S.F.) and provide the means by which vasopressin may regulate cells controlling behavioural or physiological processes. Among the processes which vasopressin can influence are several of significance in the symptom-complex of affective illness, including alterations in memory, changes in pain sensitivity, synchronisation of biological rhythms, the timing and quality of R.E.M. sleep, and the regulation of fluid and electrolyte balance. In addition, vasopressin is functionally linked to monoamine neurotransmitter systems and, like them, is altered by pharmacological agents which affect mood. Some of the pharmacological and clinical data suggest that vasopressin function is diminished in depression and augmented in mania; sometimes, however, alterations in vasopressin function may be detectable only during crucial periods of the tant
manic-depressive cycle. The hypothesis that vasopressin plays a role in disorders of human behaviour, particularly manic-depressive illness, can now be directly tested by radioimmunoassays of vasopressin in C.S.F. and plasma and by the administration of specific vasopressin analogues and inhibitors.
Wuppertal, Germany). VASOPRESSIN AND PSYCHOACTIVE AGENTS
commonly used to treat affective illeffects on vasopressin function. For potent an antimanic example, lithium, agent, decreases the of vasopressin receptors (and can cause sensitivity diabetes insipidus), while certain tricyclic nephrogenic as used antidepressive agents, increase central agents, release.2 These pharmacological data sugvasopressin that central vasopressin gest activity may be increased in mania and reduced in depression. However, although lithium is most successful when used as an antimanic drug, it also possesses some antidepressant properties;3 moreover, a preliminary report suggests that one tricycTHE
drugs
most
ness exert
REFERENCES
1.
Crane, R. K., Menard, D., Preiser, H., Cerda, J. in Membranes and Diseases (edited by L. Bolis, J. F. Hoffman, and A. Leaf), p. 229. New York, 1976. 2. Gray, G. M. New Engl. J. Med. 1975, 292, 1225. 3. Metz, G., Jenkins, D. J. A., Newman, A., Blendis, L. M. Lancet, 1976, i, 119. 4.
Schmidt, D. D., Frommer, W., Junge, B., Müller, L., Wingender, W., Truscheit, E., Schäfer, D. ibid. p. 535. 5. Caspary, W. F. Abstracts of the Meeting of the European Society for Clinical Investigation held in Rotterdam, 1978. 6. Puls, W., Keup, U., Krause, H. P., Thomas, G., Hoffmeister, F. Naturwissenschaften, 1977, 64, 536. 7. Bond, J. H., Levitt, M. D. Am. J. dig. Dis. 1977, 22, 379. 8. Metz, G., Gassull, M. A., Leeds, A. R., Blendis, L. M., Jenkins, D. J. A. Clin Sci. molec. Med. 1976, 50, 237. 9. Newcomer, A. D., Thomas, P. J., McGill, D. B., Hofmann, A. F. New Engl. J. Med. 1975, 293, 1232. 10. Caspary, W. F. Acta hepato-gastroenter. 1977, 24, 473.
lic (carbamazepine) may have both antimanic and anudepressant properties.4 Thus, some of the clinical effects of lithium and carbamazepine cannot be easily related to
1234
decreases or increases in vasopressin activity, but lie instead in the capacity of these drugs to initiate may adaptive changes in vasopressin activity, a property by which lithium and tricyclics have been said to promote homoeostasis in other systems.s Moreover, the multiple therapeutic effects attributed to these drugs may result from their influence not only on vasopressin activity, but also on other central neuroregulatory systems.
simple
VASOPRESSIN
AND MEMORY
Endogenously depressed patients have difficulty in retrieving previously adaptive behaviour and in retaining newly learned material.6 The cognitive deficits in mania have been less formally studied, but manic patients clearly show alterations in arousal, attention, and in the rate and continuity of ideation. The role of vasopressin in the regulation of memory has been well described by de Wied and his colleagues.7,8 Rats with hereditary absence of vasopressin have difficulty in maintaining learned avoidance-task responses, a deficit which is promptly reversed by vasopressin or its analogues. Moreover, vasopressin will reverse experimentally induced amnesia of avoidance learning in rats, and inhibition of central vasopressin function by intrathecal administration of its antiserum will induce an almost complete deficit in passive avoidbehaviour. The memory deficits in depressed patients are compatible with a hypothesis of decreased central vasopressin function in this group. Whether increases in central vasopressin function are related to the cognitive changes seen in mania is conjectural although there has been one report of hypomania in a subject receiving exogenous vasopressin for the treatment of amnesia.9 Animal as well as some clinical data suggest an important role for noradrenergic systems in the memory ance
process. 10, 11 Vasopressin regulates noradrenergic systems in dorsal, septal, parafascicular, hippocampal, and lateral thalamic nuclei, regions that have been identified as important in the process of rnemory.’2 Thus, it is likely that the effect of vasopressin on memory processes relates to its regulation of these specific noradrenergic systems, a suggestion that is compatible with current theories of central peptide action." Moreover, modification of behaviour by regulation of noradrenergic systems provides a link between vasopressin function and the postulated role of catecholamines in the pathophysiology of affective illness. The effect of vasopressin on memory may also relate to its regulation of hippocampal theta frequencies during rapid eye movement (R.E.M.) sleep,’4 a stage of sleep which appears to be especially important for long-term memory, and which is often disturbed in affective illness.15,16 Drugs which enhance memory produce changes in R.E.M. sleep similar to those induced by vaso-
pressin.17 Although knowledge
of the action of vasopressin on the central nervous system has been based mainly on animal data, there are clinical reports of the efficacy of a vasopressin analogue in the treatment of amnesia and memory loss secondary to senile dementia.9,18 In addition, carbamazepine, a potent releaser of vasopressin, has been shown to improve symptoms relating to alertness and mental function in a group of epileptic
patients.19 Conversely, drugs which interfere with vasopressin action may adversely affect learning and memory in human subjects; for example, ethanol, a potent inhibitor of vasopressin release,20 disrupts various aspects of memory processes.21 Lithium carbonate may also have some, adverse effects on memory,22 probably related to the ability of lithium to depress vasopressin function. VASOPRESSIN, ENDOGENOUS OPIATES, AND PAIN
endogenous opiate peptides influence brain involved in the perception and experience of pleasure and pain, as well as in the mediation of information relating to reward; since these processes seem to be altered in patients with affective illness, both endorphin and endorphin antagonists have been given to manic and depressed subjects. To date, one preliminary uncontrolled study has suggested an antidepressant effect of beta-endorphin, 23 while a more controlled study has reported an antimanic effect on the specific endorThe
centres
phin antagonist, naloxone. 24 There is extensive evidence of a complex and close relation between the endorphinergic system and vasopressin, and it seems plausible that vasopressin may mediate certain effects attributed to the endorphins or modify some of the actions of central opiate peptides. The acute administration of narcotics causes antidiuresis in experimental animals and man,25 a finding consistent with a report that endorphin,,given to experimental animals stimulates vasopressin release .26 Conversely, narcotic antagonists cause diuresis in animals and man. 17 Moreover, one patient with refractory inappropriate vasopressin release finally responded to the narcotic antagonist, oxilorphan.2 Thus, the weight of available evidence suggests that activation of the endorphin system stimulates vasopressin release, while inhibition of endorphin activity via its specific antagonists inhibits vasopressin function. Hence, one can postulate that the possible antidepressant effects of endorphin, like those of tricyclics, are mediated through vasopressin, while the antimanic effects of naloxone, like those of lithium, are mediated by an inhibition of vasopressin. These interactions represent further circumstantial evidence for a hypothesis of decreased vasopressin function in depression and augmented vasopressin function in mania. It has also been reported that vasopressin stimulates opiate peptide release by anterior pituitary tumour cells in culture.28 Thus, the opiate peptides and vasopressin may participate in a regulatory loop in which each affects the other’s release. This interrelation between vasopressin and the endorphins is also reflected in reports that vasopressin plays a role in the processing of information relating to reward and pain perception. Thus, vasopressin decreases heroin self-stimulation behaviour29 and facilitates the development of tolerance to the analgesic action of morphine in experimental animals.10 These data may mean a direct action of vasopressin on the reward centre or an increased release of endogenous opiate peptide after vasopressin; either way, one would expect the animal’s urge for exogenous narcotic to be diminished. Incidentally, analgesics as disparate as morphine, aspirin, and paracetamol all potentiate the actions of vasopressin, although by different
1235
mechanisms.2 VASOPRESSIN,
BIOLOGICAL
RHYTHMS,
AND AFFECTIVE
ILLNESS
Biological rhythms are involved in affective disorder in two ways. Firstly, disturbances in the 24-h (circadian) rhythms of activity, sleep, and neuroendocrine function have been reported.31 The altered pattern of the activityrest cycle in depressed and manic subjects has given rise to the preliminary suggestion that circadian rhythms are slowed during depression and accelerated in mania.3’ A second disturbance of biological rhythms is reflected in the episodic nature of affective illness which suggests a disturbance in long-term biological cycles. More specifically, some cases of recurrent affective disorder appear to be pathological expressions of normal monthly, seasonal, or annual rhythms.3’ Animal studies suggest that vasopressin may be one of the neuroregulators involved in the synchronisation of circadian rhythms. Vasopressin is an important constituent of the suprachiasmatic nucleus,32 which is thought to be the site of the endogenous circadian biological clock.33 Moreover, drugs which affect vasopressin function are among the few agents which affect the periodicity of circadian rhythms. Thus, lithium and ethanol, which interfere with vasopressin function, prolong the circadian cycle;34 moreover, indirect evidence suggests that tricyclic agents, which enhance vasopressin function, may speed the circadian clock.35 These pharmacological data indicate that impaired vasopressin function may be associated with a slowed circadian clock, and enhanced vasopressin function with an accelerated circadian pacemaker. Evidence that tricyclic drugs significantly increase the frequency of manic and depressive episodes are compatible with a role for vasopressin in controlling the cycles in manic-depressive illness.36 Moreover, the prophylactic role of lithium can be seen as a reduction in the cycle frequency of mania, and per-
CONCLUSION
variety of evidence suggests that vasopressin plays neuroregulatory role in the pathophysiology of affective illness. Pharmacological data support the hypothesis that vasopressin function is diminished in depression and augmented in mania. Studies showing impaired memory in depression and the case-report of vasopressin-induced hypomania support this suggestion. This hypothesis is also consistent with the possible role of vasopression in the regulation of the circadian clock and the preliminary finding that circadian rhythms may be slowed in depression and accelerated in mania. This vasopressin hypothesis of affective illness can be easily tested. Radioimmunoassays for vasopressin in human c.s.F. and plasma allow quantitative studies for investigating vasopressin function in psychiatric patients. Since the c.s.F. appears to represent an important pathway through which vasopressin may exert its central effects,37 studies of c.s.F. vasopressin levels may be especially informative. Fortunately, levels of c.s.F. vasopressin in normal subjects fall within a very narrow range,38 so that a useful comparison can be made with manic-depressive subjects. Plasma-vasopressin studies will also help elucidate various aspects of central vasoA
before the switch into mania. The verification of this hypothesis would lead to specific treatments for affective illness. 1-deamino-8-darginine vasopressin (D.D.A.V.P.), a potent excitatory vasopressin analogue free of vasoactive properties,41> is already available for administration to humans and could be given to patients with diminished central vasopressin function, while it is conceivable that specific inhibitors of vasopressin function such as vasopressinoic acid4l could be used to treat disorders due to augmented central vasopressin function.
REFERENCES 1. Singer, I., Rotenberg, D., Puschett, J. J. clin. Invest. 1972, 51, 1081. 2. Moses, A. M., Miller, M., Streeten, D. H. P. Metabolism, 1976, 25, 697. 3. Goodwin, F. K., Murphy, D. L., Dunner, D. L., Bunney, W. E., Jr. Am.
haps depression.
a
pressin regulation. For instance, the centrally mediated set point for vasopressin response to changes in plasmaosmolality can be determined by measuring the plasmavasopressin response to a graded infusion of hypertonic saline.39 Even subtle changes in the sensitivity of the osmoreceptor can be detected by such a procedure. This kind of dynamic study can be used to explore the often conflicting reports of fluid and electrolyte imbalance in patients with affective illness and to study the possible differences in osmoreceptor function in patients during depression and mania and after recovery. The strategy of following various aspects of vasopressin function during each phase of an illness is obviously important. However, since central peptides are thought to be long-term regulators of neuronal systems,’3 the functional activity of vasopressin may be altered for only a short time, yet still induce relatively long-term changes in behaviour. For instance, enhanced vasopressin function in patients with affective illness may be detectable only at crucial periods in the cycle, perhaps just
J. Psychiat. 1972, 129, 44. 4. Ballenger, J. C., Post, R. M. Commun. Psychopharmac. (In the press). 5. Mandell, A. in Neurobiological Mechanisms of Adaptation and Behavior (edited by A. Mandell); p. 1. New York, 1975. 6. Stromgren, L. S. Acta psychiat. scand. 1977, 56, 109 7. de Wied, D. Life Sci. 1976, 19, 685. 8. de Wied, D. ibid. 1977, 20, 195. 9. Oliveros, J. C., Jandoli, M. K., Timsit-Berthler, M., Remy, R., Benghezala, A., Audibert, A., Moeglen, J. M. Lancet, 1978, i, 42. 10. McGaugh, J. L. Ann. Rev. Pharmac. 1973, 13, 229. 11. Henry, G. M., Weingartner, H., Murphy, D. L. Am. J. Psychiat. 1973, 130, 1966.
Tanaka, M., de Kloet, E. R., de Wied, D., Versteeg, D. M. Life Sci. 1977, 20, 1799. 13. Barker, J. L. in Peptides in Neurobiology (edited by Harold Gainer); p. 295. New York, 1977. 14. Urban, I., de Wied, D. Pharmac. Biochem. Behav. 1978, 8, 51. 15. Kupfer, J. Biol. Psychiat. 1977, 11, 159. 16. Vogel, G. Paper presented at the 17th annual meeting for the Psychophysical Study of Sleep, held in Houston, 1977. 17. Long, V. G., Loizzo, A. in Pharmacology and the Nature of Man (edited by F. E. Bloom and J. H. Acheson); p. 46. Basle, 1973. 18. Legros, J., Gilot, P., Seron, X., Claessers, J., Adam, A., Moeglen, J. M., Audibert, A., Berchier, P. Lancet, 1978, i, 41. 19. Dadrill, C. B., Troupin, A. S. Neurology, 1977, 27, 1023. 20. Kleeman, C. R., Rubini, M. E., Lambdin, E., Epstein, G. H. J. clin. Invest. 1955, 34, 448. 21. Ryback, R. S. Q.Jl Stud. Alcohol, 1971, 32, 995. 22. Kusomo, K. S., Vaughan, M. Br. J. Psychiat. 1977, 131, 453. 23. Kline, N. S., Li, C. H., Lehmann, H. E., Lajtha, A., Laski, E., Cooper, T. Archs gen. Psychiat. 1977, 34, 1111. 24. Janowski, D. in Endorphins and Mental Health Research (edited by E.
12.
Usdin, W. E. Bunney, Jr., N. S. Klein); New York (in the press).
-
°
1236 reflux. All of these patients also showed reflux of methylene blue. 3 other patients who were X-ray negative had methyleneblue reflux. The other 18 patients showed neither barium nor methylene-blue reflux. A control group of 22 children of comparable age, admitted to hospital for elective surgery not involving the respiratory or gastrointestinal tract, also had methylene-blue tests. Barium X-rays were not done since they were not clinically indicated; previous studies in a similar control group have shown reflux to be uncommon.’ 3 of the controls (13%) had reflux of methylene blue; 19 (87%) did not.
Methods and Devices DIAGNOSIS OF GASTRO-ŒSOPHAGEAL REFLUX IN INFANTS AND CHILDREN BY METHYLENE-BLUE TEST GUIDO GIRARDI LEON VIAL
EDUARDO FRITIS ERWIN HEVIA
Department of Respiratory Diseases (Thoracic Unit), E. Gonzalez Cortes Hospital, Santiago, Chile MARCO OTERO Instituto Nacional de
Enfermedades Respiratorias y Cirugia Toracica, Santiago, Chile
POPE, II
Veterans Administration
Hospital and Department of Medicine, University of Washington, Seattle, Washington, U.S.A.
GASTRO-CESOPHAGEAL reflux in children and infants may present in many ways’ and pulmonary symptoms may predominate.z3 A safe and inexpensive test which does not require radiation is needed for the diagnosis of reflux in children. Such a test, which uses methylene blue, has been developed.
Technique
ml/kg body weight of a 1% solution of methylene blue in mol/I HCI is introduced into the fasting stomach through a nasogastric tube, which is then withdrawn and quinalbarbitone (secobarbital), 6 mg/kg, given orally. A test catheter, consisting of a polyvinyl tube, 2 mm outer diameter, with several openings cut along its length and containing a cotton thread, 5 0.1
is passed transnasally until the tip is estimated to lie in the lower portion of the oesophagus. The patient lies supine for two hours, then sits up, and the tube is rapidly withdrawn. The cotton thread is removed. If there has been any reflux of methylene blue during the test period, the thread will be stained opposite the holes made in the tube. Capillary action will not stain the entire length of thread; therefore the thread will not be stained along its length if the end of the tube dips into the stomach. Validation
of Method 70 infants and children, and 22 were aged 2-5 y,
46 of whom
were aged 6 mo to 2 being investigated for symptoms of reflux by a standardised barium X-ray examination and the methylene-blue test. 49 were shown by X-ray to have
y
Reflux
equally well detected by methylene blue and in the same patients; methylene blue may be slightly more sensitive than X-ray. The 13% incidence of methyleneblue reflux in the controls is similar to that found by pH probe in symptom-free adults.4 We were unable to compare methylene blue with a pH probe because we did not have the equtpment. Since this study, another 490 patients have been given methylene blue without complications. It is hoped that the use of methylene blue will further the study of reflux m infants and children. Correspondence should be addressed to C. E. P., Veterans Administration Hospital, 4435 Beacon Avenue South, Seattle, Washington was
X-ray and
AUGUSTO LARRAIN
CHARLES E.
Discussion
were
98108, U.S.A. REFERENCES
1. Euler, A. R., Ament, M. D. Pediat. Ann. 1976, 5, 678. 2. Casar, C., Ceruti, E., Diaz, A. Revta. Chil. Pediat. 1973, 44, 337. 3. Danus, O., Casar, C., Larrain, A., Pope II, C. E. J. Pediat. 1976, 89, 720. 4. Venkatachalam, B., DaCosta, L. R., Ip, S. K. L., Beck, I. T. Gastroenter-
ology, 1972, 62, 521.
JEJUNAL BIOPSY WITHOUT THE NEED FOR SCREENING G. HOLDSTOCK* ROYAL VICTORIA
HOSPITAL, BOSCOMBE, BOURNEMOUTH
WITH the increased awareness of coeliac disease, the number of jejunal biopsies being performed is steadily increasing. The procedure can, however, be a time-consuming and an unpleasant experience for the patient. With the standard Crosby capsule’ (with or without modifications) or multiple sampling devices,2 relatively long periods of screening time may be required, even when metoclopramide is used.’ The time required for the procedure can be reduced by use of the new direct able device,4 but this is relatively expensive. A method in which gastroscope, biopsy capsule, and screening are used has
25. Schneider, H., Blackmore, E. K. Br. J. Pharmac. 1955, 10, 45. 26. Weitzman, R. E., Fisher, D. W., Minisck, S., Ling, N., Guillemin, R. Endoc-
rinology, 1977, 101, 1643. Nutt, J. G., Jasinski, D. R. Clin. Pharmac. Ther. 1974,15, 36. Mata, M., Gainer, H., Klee, W. Life Sci. 1977, 21, 1159. van Ree, J., de Wied, D. ibid. 1977, 21, 315. de Wied, D., Gispin, W. H. Psychopharmacologia, 1977, 46, 27. Wehr, T. A. Ann. intern Med. 1977, 87, 319. Zimmerman, E. A., Robinson, A. G. Kidney Int. 1976, 10, 12. Stetson, M. H., Watson-Whitmyre, M. Science, 1976, 191, 197. Ruzak, B., Zucker, I. Ann. Rev. Psychol. 1975, 26, 137. Baltzer, V., Weiskrantz, L. Biol. Psychtat. 1975, 10, 199. Wehr, T. A., Goodwin, F. K. Psychopharmac. Bull. (in the press). Van Wimersma Greidanus, T. B., de Wied, D. in Biochemical Correlates of Brain Function (edited by A. N. Davison), p. 36. London, 1977. 38. Luerssen, R. L., Shelton, R. L., Robertson, G. L. Clin. Research, 1977, 1,
27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.
14. 39. Robertson, G. L., Shelton, R. L., Athar, A. Kidney Int. 1976, 10, 25. 40. Robinson, A. G. New Engl. J. Med. 1976, 294, 507 41. Dousa, T. P., Hechter, O., Wlater, R., Schwartz, I. L. Science, 1970, 1134.
167,
*Present address: Professorial Medical General Hospital, Southampton SO9 4XY.
Unit, Centre Block, Southampton
Gastroscope with biopsy capsule
in
position.
Hypothesis VASOPRESSIN IN AFFECTIVE ILLNESS PHILIP W. GOLD
Clinical Psychobiology Branch, National Institute of Mental Health, 9000 Rockville Pike, Building 10, Room 4S239, Bethesda, Maryland 20014
Fig. 5-Structural feature of the «-G.H.L"
50% of maltase activity2 is much less affected by
a-G.H.I.
(my unpublished observations). 200 mg of &agr;-G.H.I. effectively decreased postprandial glucose levels after sucrose ingestion and prevented the late postprandial dip in blood-glucose. The latter can be explained by the reduced insulin response to sucrose in the presence of :x-G.H.I.6 x-G.H.i. not only delayed glucose absorption, as observed in patients on treatment with biguanides,10 but also resulted in malabsorption of sucrose as shown by increased breath-H2 production. Similar rises in breath-H2 concentration seen in this study have been reported in lactase-deficient patients after ingestion of lactose7,9 or in sucrase-isomaltase deficient patients after a sucrose load.3 In order to quantitate the amount of sucrose that is not absorbed in the presence of the a-G.H.1., breath-H2 concentrations produced by sucrose and the inhibitor were compared with H2 concentrations produced by the non-absorbable disaccharide lactulose. The integrated H2-output (integration of area below curves in fig. 4) produced by 100 g of sucrose and &agr;-G.H.I. was 2.014-fold higher than that produced by 20 g of lactulose. On the assumption that lactulose and sucrose are fermented by colonic bacteria at equal rates, maldigestion and malabsorption must have resulted in approximately 40 g of the 100 g sucrose load being left behind for fermentation by colonic bacteria. This new compound is an interesting tool by which the effects of carbohydrate maldigestion, and hence malabsorption, in animals and man can be studied. It may be a useful agent for retarding carbohydrate absorption in some diseases, such as, diabetes mellitis, obesity, and hyperlipldxmia. The I.
FREDERICK K. GOODWIN
x-G.H.I. (Bay g 5421) was provided by Dr P. Berchtold, Dr Hillebrandt, and Dr W. Puls (Bayer Pharmaceutical Company,
VICTOR I. REUS
Biological Psychiatry Branch, National Institute of Mental Health, 9000 Rockville Pike, Building 10, Room 3S239, Bethesda, Maryland 20014
Summary
Animal studies have revealed
two
impor-
aspects of vasopressin function which make this peptide a suitable candidate for involvement in complex behavioural syndromes: (1) vasopressin deficiency produces deficits of behaviour which are reversed by vasopressin; (2) well-developed systems exist for the distribution of vasopressin throughout the central nervous system (C.N.S.) via either peptidergic neurons or the cerebrospinal fluid (C.S.F.) and provide the means by which vasopressin may regulate cells controlling behavioural or physiological processes. Among the processes which vasopressin can influence are several of significance in the symptom-complex of affective illness, including alterations in memory, changes in pain sensitivity, synchronisation of biological rhythms, the timing and quality of R.E.M. sleep, and the regulation of fluid and electrolyte balance. In addition, vasopressin is functionally linked to monoamine neurotransmitter systems and, like them, is altered by pharmacological agents which affect mood. Some of the pharmacological and clinical data suggest that vasopressin function is diminished in depression and augmented in mania; sometimes, however, alterations in vasopressin function may be detectable only during crucial periods of the tant
manic-depressive cycle. The hypothesis that vasopressin plays a role in disorders of human behaviour, particularly manic-depressive illness, can now be directly tested by radioimmunoassays of vasopressin in C.S.F. and plasma and by the administration of specific vasopressin analogues and inhibitors.
Wuppertal, Germany). VASOPRESSIN AND PSYCHOACTIVE AGENTS
commonly used to treat affective illeffects on vasopressin function. For potent an antimanic example, lithium, agent, decreases the of vasopressin receptors (and can cause sensitivity diabetes insipidus), while certain tricyclic nephrogenic as used antidepressive agents, increase central agents, release.2 These pharmacological data sugvasopressin that central vasopressin gest activity may be increased in mania and reduced in depression. However, although lithium is most successful when used as an antimanic drug, it also possesses some antidepressant properties;3 moreover, a preliminary report suggests that one tricycTHE
drugs
most
ness exert
REFERENCES
1.
Crane, R. K., Menard, D., Preiser, H., Cerda, J. in Membranes and Diseases (edited by L. Bolis, J. F. Hoffman, and A. Leaf), p. 229. New York, 1976. 2. Gray, G. M. New Engl. J. Med. 1975, 292, 1225. 3. Metz, G., Jenkins, D. J. A., Newman, A., Blendis, L. M. Lancet, 1976, i, 119. 4.
Schmidt, D. D., Frommer, W., Junge, B., Müller, L., Wingender, W., Truscheit, E., Schäfer, D. ibid. p. 535. 5. Caspary, W. F. Abstracts of the Meeting of the European Society for Clinical Investigation held in Rotterdam, 1978. 6. Puls, W., Keup, U., Krause, H. P., Thomas, G., Hoffmeister, F. Naturwissenschaften, 1977, 64, 536. 7. Bond, J. H., Levitt, M. D. Am. J. dig. Dis. 1977, 22, 379. 8. Metz, G., Gassull, M. A., Leeds, A. R., Blendis, L. M., Jenkins, D. J. A. Clin Sci. molec. Med. 1976, 50, 237. 9. Newcomer, A. D., Thomas, P. J., McGill, D. B., Hofmann, A. F. New Engl. J. Med. 1975, 293, 1232. 10. Caspary, W. F. Acta hepato-gastroenter. 1977, 24, 473.
lic (carbamazepine) may have both antimanic and anudepressant properties.4 Thus, some of the clinical effects of lithium and carbamazepine cannot be easily related to
1234
decreases or increases in vasopressin activity, but lie instead in the capacity of these drugs to initiate may adaptive changes in vasopressin activity, a property by which lithium and tricyclics have been said to promote homoeostasis in other systems.s Moreover, the multiple therapeutic effects attributed to these drugs may result from their influence not only on vasopressin activity, but also on other central neuroregulatory systems.
simple
VASOPRESSIN
AND MEMORY
Endogenously depressed patients have difficulty in retrieving previously adaptive behaviour and in retaining newly learned material.6 The cognitive deficits in mania have been less formally studied, but manic patients clearly show alterations in arousal, attention, and in the rate and continuity of ideation. The role of vasopressin in the regulation of memory has been well described by de Wied and his colleagues.7,8 Rats with hereditary absence of vasopressin have difficulty in maintaining learned avoidance-task responses, a deficit which is promptly reversed by vasopressin or its analogues. Moreover, vasopressin will reverse experimentally induced amnesia of avoidance learning in rats, and inhibition of central vasopressin function by intrathecal administration of its antiserum will induce an almost complete deficit in passive avoidbehaviour. The memory deficits in depressed patients are compatible with a hypothesis of decreased central vasopressin function in this group. Whether increases in central vasopressin function are related to the cognitive changes seen in mania is conjectural although there has been one report of hypomania in a subject receiving exogenous vasopressin for the treatment of amnesia.9 Animal as well as some clinical data suggest an important role for noradrenergic systems in the memory ance
process. 10, 11 Vasopressin regulates noradrenergic systems in dorsal, septal, parafascicular, hippocampal, and lateral thalamic nuclei, regions that have been identified as important in the process of rnemory.’2 Thus, it is likely that the effect of vasopressin on memory processes relates to its regulation of these specific noradrenergic systems, a suggestion that is compatible with current theories of central peptide action." Moreover, modification of behaviour by regulation of noradrenergic systems provides a link between vasopressin function and the postulated role of catecholamines in the pathophysiology of affective illness. The effect of vasopressin on memory may also relate to its regulation of hippocampal theta frequencies during rapid eye movement (R.E.M.) sleep,’4 a stage of sleep which appears to be especially important for long-term memory, and which is often disturbed in affective illness.15,16 Drugs which enhance memory produce changes in R.E.M. sleep similar to those induced by vaso-
pressin.17 Although knowledge
of the action of vasopressin on the central nervous system has been based mainly on animal data, there are clinical reports of the efficacy of a vasopressin analogue in the treatment of amnesia and memory loss secondary to senile dementia.9,18 In addition, carbamazepine, a potent releaser of vasopressin, has been shown to improve symptoms relating to alertness and mental function in a group of epileptic
patients.19 Conversely, drugs which interfere with vasopressin action may adversely affect learning and memory in human subjects; for example, ethanol, a potent inhibitor of vasopressin release,20 disrupts various aspects of memory processes.21 Lithium carbonate may also have some, adverse effects on memory,22 probably related to the ability of lithium to depress vasopressin function. VASOPRESSIN, ENDOGENOUS OPIATES, AND PAIN
endogenous opiate peptides influence brain involved in the perception and experience of pleasure and pain, as well as in the mediation of information relating to reward; since these processes seem to be altered in patients with affective illness, both endorphin and endorphin antagonists have been given to manic and depressed subjects. To date, one preliminary uncontrolled study has suggested an antidepressant effect of beta-endorphin, 23 while a more controlled study has reported an antimanic effect on the specific endorThe
centres
phin antagonist, naloxone. 24 There is extensive evidence of a complex and close relation between the endorphinergic system and vasopressin, and it seems plausible that vasopressin may mediate certain effects attributed to the endorphins or modify some of the actions of central opiate peptides. The acute administration of narcotics causes antidiuresis in experimental animals and man,25 a finding consistent with a report that endorphin,,given to experimental animals stimulates vasopressin release .26 Conversely, narcotic antagonists cause diuresis in animals and man. 17 Moreover, one patient with refractory inappropriate vasopressin release finally responded to the narcotic antagonist, oxilorphan.2 Thus, the weight of available evidence suggests that activation of the endorphin system stimulates vasopressin release, while inhibition of endorphin activity via its specific antagonists inhibits vasopressin function. Hence, one can postulate that the possible antidepressant effects of endorphin, like those of tricyclics, are mediated through vasopressin, while the antimanic effects of naloxone, like those of lithium, are mediated by an inhibition of vasopressin. These interactions represent further circumstantial evidence for a hypothesis of decreased vasopressin function in depression and augmented vasopressin function in mania. It has also been reported that vasopressin stimulates opiate peptide release by anterior pituitary tumour cells in culture.28 Thus, the opiate peptides and vasopressin may participate in a regulatory loop in which each affects the other’s release. This interrelation between vasopressin and the endorphins is also reflected in reports that vasopressin plays a role in the processing of information relating to reward and pain perception. Thus, vasopressin decreases heroin self-stimulation behaviour29 and facilitates the development of tolerance to the analgesic action of morphine in experimental animals.10 These data may mean a direct action of vasopressin on the reward centre or an increased release of endogenous opiate peptide after vasopressin; either way, one would expect the animal’s urge for exogenous narcotic to be diminished. Incidentally, analgesics as disparate as morphine, aspirin, and paracetamol all potentiate the actions of vasopressin, although by different
1235
mechanisms.2 VASOPRESSIN,
BIOLOGICAL
RHYTHMS,
AND AFFECTIVE
ILLNESS
Biological rhythms are involved in affective disorder in two ways. Firstly, disturbances in the 24-h (circadian) rhythms of activity, sleep, and neuroendocrine function have been reported.31 The altered pattern of the activityrest cycle in depressed and manic subjects has given rise to the preliminary suggestion that circadian rhythms are slowed during depression and accelerated in mania.3’ A second disturbance of biological rhythms is reflected in the episodic nature of affective illness which suggests a disturbance in long-term biological cycles. More specifically, some cases of recurrent affective disorder appear to be pathological expressions of normal monthly, seasonal, or annual rhythms.3’ Animal studies suggest that vasopressin may be one of the neuroregulators involved in the synchronisation of circadian rhythms. Vasopressin is an important constituent of the suprachiasmatic nucleus,32 which is thought to be the site of the endogenous circadian biological clock.33 Moreover, drugs which affect vasopressin function are among the few agents which affect the periodicity of circadian rhythms. Thus, lithium and ethanol, which interfere with vasopressin function, prolong the circadian cycle;34 moreover, indirect evidence suggests that tricyclic agents, which enhance vasopressin function, may speed the circadian clock.35 These pharmacological data indicate that impaired vasopressin function may be associated with a slowed circadian clock, and enhanced vasopressin function with an accelerated circadian pacemaker. Evidence that tricyclic drugs significantly increase the frequency of manic and depressive episodes are compatible with a role for vasopressin in controlling the cycles in manic-depressive illness.36 Moreover, the prophylactic role of lithium can be seen as a reduction in the cycle frequency of mania, and per-
CONCLUSION
variety of evidence suggests that vasopressin plays neuroregulatory role in the pathophysiology of affective illness. Pharmacological data support the hypothesis that vasopressin function is diminished in depression and augmented in mania. Studies showing impaired memory in depression and the case-report of vasopressin-induced hypomania support this suggestion. This hypothesis is also consistent with the possible role of vasopression in the regulation of the circadian clock and the preliminary finding that circadian rhythms may be slowed in depression and accelerated in mania. This vasopressin hypothesis of affective illness can be easily tested. Radioimmunoassays for vasopressin in human c.s.F. and plasma allow quantitative studies for investigating vasopressin function in psychiatric patients. Since the c.s.F. appears to represent an important pathway through which vasopressin may exert its central effects,37 studies of c.s.F. vasopressin levels may be especially informative. Fortunately, levels of c.s.F. vasopressin in normal subjects fall within a very narrow range,38 so that a useful comparison can be made with manic-depressive subjects. Plasma-vasopressin studies will also help elucidate various aspects of central vasoA
before the switch into mania. The verification of this hypothesis would lead to specific treatments for affective illness. 1-deamino-8-darginine vasopressin (D.D.A.V.P.), a potent excitatory vasopressin analogue free of vasoactive properties,41> is already available for administration to humans and could be given to patients with diminished central vasopressin function, while it is conceivable that specific inhibitors of vasopressin function such as vasopressinoic acid4l could be used to treat disorders due to augmented central vasopressin function.
REFERENCES 1. Singer, I., Rotenberg, D., Puschett, J. J. clin. Invest. 1972, 51, 1081. 2. Moses, A. M., Miller, M., Streeten, D. H. P. Metabolism, 1976, 25, 697. 3. Goodwin, F. K., Murphy, D. L., Dunner, D. L., Bunney, W. E., Jr. Am.
haps depression.
a
pressin regulation. For instance, the centrally mediated set point for vasopressin response to changes in plasmaosmolality can be determined by measuring the plasmavasopressin response to a graded infusion of hypertonic saline.39 Even subtle changes in the sensitivity of the osmoreceptor can be detected by such a procedure. This kind of dynamic study can be used to explore the often conflicting reports of fluid and electrolyte imbalance in patients with affective illness and to study the possible differences in osmoreceptor function in patients during depression and mania and after recovery. The strategy of following various aspects of vasopressin function during each phase of an illness is obviously important. However, since central peptides are thought to be long-term regulators of neuronal systems,’3 the functional activity of vasopressin may be altered for only a short time, yet still induce relatively long-term changes in behaviour. For instance, enhanced vasopressin function in patients with affective illness may be detectable only at crucial periods in the cycle, perhaps just
J. Psychiat. 1972, 129, 44. 4. Ballenger, J. C., Post, R. M. Commun. Psychopharmac. (In the press). 5. Mandell, A. in Neurobiological Mechanisms of Adaptation and Behavior (edited by A. Mandell); p. 1. New York, 1975. 6. Stromgren, L. S. Acta psychiat. scand. 1977, 56, 109 7. de Wied, D. Life Sci. 1976, 19, 685. 8. de Wied, D. ibid. 1977, 20, 195. 9. Oliveros, J. C., Jandoli, M. K., Timsit-Berthler, M., Remy, R., Benghezala, A., Audibert, A., Moeglen, J. M. Lancet, 1978, i, 42. 10. McGaugh, J. L. Ann. Rev. Pharmac. 1973, 13, 229. 11. Henry, G. M., Weingartner, H., Murphy, D. L. Am. J. Psychiat. 1973, 130, 1966.
Tanaka, M., de Kloet, E. R., de Wied, D., Versteeg, D. M. Life Sci. 1977, 20, 1799. 13. Barker, J. L. in Peptides in Neurobiology (edited by Harold Gainer); p. 295. New York, 1977. 14. Urban, I., de Wied, D. Pharmac. Biochem. Behav. 1978, 8, 51. 15. Kupfer, J. Biol. Psychiat. 1977, 11, 159. 16. Vogel, G. Paper presented at the 17th annual meeting for the Psychophysical Study of Sleep, held in Houston, 1977. 17. Long, V. G., Loizzo, A. in Pharmacology and the Nature of Man (edited by F. E. Bloom and J. H. Acheson); p. 46. Basle, 1973. 18. Legros, J., Gilot, P., Seron, X., Claessers, J., Adam, A., Moeglen, J. M., Audibert, A., Berchier, P. Lancet, 1978, i, 41. 19. Dadrill, C. B., Troupin, A. S. Neurology, 1977, 27, 1023. 20. Kleeman, C. R., Rubini, M. E., Lambdin, E., Epstein, G. H. J. clin. Invest. 1955, 34, 448. 21. Ryback, R. S. Q.Jl Stud. Alcohol, 1971, 32, 995. 22. Kusomo, K. S., Vaughan, M. Br. J. Psychiat. 1977, 131, 453. 23. Kline, N. S., Li, C. H., Lehmann, H. E., Lajtha, A., Laski, E., Cooper, T. Archs gen. Psychiat. 1977, 34, 1111. 24. Janowski, D. in Endorphins and Mental Health Research (edited by E.
12.
Usdin, W. E. Bunney, Jr., N. S. Klein); New York (in the press).
-
°
1236 reflux. All of these patients also showed reflux of methylene blue. 3 other patients who were X-ray negative had methyleneblue reflux. The other 18 patients showed neither barium nor methylene-blue reflux. A control group of 22 children of comparable age, admitted to hospital for elective surgery not involving the respiratory or gastrointestinal tract, also had methylene-blue tests. Barium X-rays were not done since they were not clinically indicated; previous studies in a similar control group have shown reflux to be uncommon.’ 3 of the controls (13%) had reflux of methylene blue; 19 (87%) did not.
Methods and Devices DIAGNOSIS OF GASTRO-ŒSOPHAGEAL REFLUX IN INFANTS AND CHILDREN BY METHYLENE-BLUE TEST GUIDO GIRARDI LEON VIAL
EDUARDO FRITIS ERWIN HEVIA
Department of Respiratory Diseases (Thoracic Unit), E. Gonzalez Cortes Hospital, Santiago, Chile MARCO OTERO Instituto Nacional de
Enfermedades Respiratorias y Cirugia Toracica, Santiago, Chile
POPE, II
Veterans Administration
Hospital and Department of Medicine, University of Washington, Seattle, Washington, U.S.A.
GASTRO-CESOPHAGEAL reflux in children and infants may present in many ways’ and pulmonary symptoms may predominate.z3 A safe and inexpensive test which does not require radiation is needed for the diagnosis of reflux in children. Such a test, which uses methylene blue, has been developed.
Technique
ml/kg body weight of a 1% solution of methylene blue in mol/I HCI is introduced into the fasting stomach through a nasogastric tube, which is then withdrawn and quinalbarbitone (secobarbital), 6 mg/kg, given orally. A test catheter, consisting of a polyvinyl tube, 2 mm outer diameter, with several openings cut along its length and containing a cotton thread, 5 0.1
is passed transnasally until the tip is estimated to lie in the lower portion of the oesophagus. The patient lies supine for two hours, then sits up, and the tube is rapidly withdrawn. The cotton thread is removed. If there has been any reflux of methylene blue during the test period, the thread will be stained opposite the holes made in the tube. Capillary action will not stain the entire length of thread; therefore the thread will not be stained along its length if the end of the tube dips into the stomach. Validation
of Method 70 infants and children, and 22 were aged 2-5 y,
46 of whom
were aged 6 mo to 2 being investigated for symptoms of reflux by a standardised barium X-ray examination and the methylene-blue test. 49 were shown by X-ray to have
y
Reflux
equally well detected by methylene blue and in the same patients; methylene blue may be slightly more sensitive than X-ray. The 13% incidence of methyleneblue reflux in the controls is similar to that found by pH probe in symptom-free adults.4 We were unable to compare methylene blue with a pH probe because we did not have the equtpment. Since this study, another 490 patients have been given methylene blue without complications. It is hoped that the use of methylene blue will further the study of reflux m infants and children. Correspondence should be addressed to C. E. P., Veterans Administration Hospital, 4435 Beacon Avenue South, Seattle, Washington was
X-ray and
AUGUSTO LARRAIN
CHARLES E.
Discussion
were
98108, U.S.A. REFERENCES
1. Euler, A. R., Ament, M. D. Pediat. Ann. 1976, 5, 678. 2. Casar, C., Ceruti, E., Diaz, A. Revta. Chil. Pediat. 1973, 44, 337. 3. Danus, O., Casar, C., Larrain, A., Pope II, C. E. J. Pediat. 1976, 89, 720. 4. Venkatachalam, B., DaCosta, L. R., Ip, S. K. L., Beck, I. T. Gastroenter-
ology, 1972, 62, 521.
JEJUNAL BIOPSY WITHOUT THE NEED FOR SCREENING G. HOLDSTOCK* ROYAL VICTORIA
HOSPITAL, BOSCOMBE, BOURNEMOUTH
WITH the increased awareness of coeliac disease, the number of jejunal biopsies being performed is steadily increasing. The procedure can, however, be a time-consuming and an unpleasant experience for the patient. With the standard Crosby capsule’ (with or without modifications) or multiple sampling devices,2 relatively long periods of screening time may be required, even when metoclopramide is used.’ The time required for the procedure can be reduced by use of the new direct able device,4 but this is relatively expensive. A method in which gastroscope, biopsy capsule, and screening are used has
25. Schneider, H., Blackmore, E. K. Br. J. Pharmac. 1955, 10, 45. 26. Weitzman, R. E., Fisher, D. W., Minisck, S., Ling, N., Guillemin, R. Endoc-
rinology, 1977, 101, 1643. Nutt, J. G., Jasinski, D. R. Clin. Pharmac. Ther. 1974,15, 36. Mata, M., Gainer, H., Klee, W. Life Sci. 1977, 21, 1159. van Ree, J., de Wied, D. ibid. 1977, 21, 315. de Wied, D., Gispin, W. H. Psychopharmacologia, 1977, 46, 27. Wehr, T. A. Ann. intern Med. 1977, 87, 319. Zimmerman, E. A., Robinson, A. G. Kidney Int. 1976, 10, 12. Stetson, M. H., Watson-Whitmyre, M. Science, 1976, 191, 197. Ruzak, B., Zucker, I. Ann. Rev. Psychol. 1975, 26, 137. Baltzer, V., Weiskrantz, L. Biol. Psychtat. 1975, 10, 199. Wehr, T. A., Goodwin, F. K. Psychopharmac. Bull. (in the press). Van Wimersma Greidanus, T. B., de Wied, D. in Biochemical Correlates of Brain Function (edited by A. N. Davison), p. 36. London, 1977. 38. Luerssen, R. L., Shelton, R. L., Robertson, G. L. Clin. Research, 1977, 1,
27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.
14. 39. Robertson, G. L., Shelton, R. L., Athar, A. Kidney Int. 1976, 10, 25. 40. Robinson, A. G. New Engl. J. Med. 1976, 294, 507 41. Dousa, T. P., Hechter, O., Wlater, R., Schwartz, I. L. Science, 1970, 1134.
167,
*Present address: Professorial Medical General Hospital, Southampton SO9 4XY.
Unit, Centre Block, Southampton
Gastroscope with biopsy capsule
in
position.
