487
and Epstein-Barr virus capsid antigen and by ELISA for HIV p24 (Abbott); and their sera were negative for antibody to herpes simplex virus 1 and 2 and of low titre to VZV and CMV 6 months before and 2 weeks after transplantation. The level of antibody to Epstein-Barr virus increased after immunosuppression, but we did not detect antibody to virus capsid antigen in monocytes. The HHV-6 antibody titre rose slightly in patient 1 from 20 before to 40 after transplantation and remained low in patient 2 (below 20). The detection of HHV-6 in co-cultivated monocytes from a patient with circulating HHV-6 antibody titre below 20 is notable. The source of the HHV-6 is unknown. One possibility3 is transfer from donor to recipient during organ transplantation but in neither patient were symptoms of acute HHV-6 infection observed. Donor sera and cells were not tested for HHV-6. In these two patients pre-existing HHV-6 may have been reactivated by immunosuppression. Despite serological evidence of widespread HHV-6 infection in the general population virus antigen in or virus isolation from peripheral blood monocytes is not common. The presence of HHV-6 in the monocytes of transplant recipients raised the possibility that some of the frequently encountered posttransplant lymphoproliferative disorders could be linked to infection with this virus. We thank Dr F. Rapp and Dr K. D. Cockley for valuable discussions; Dr R. C. Gallo (Laboratory of Tumour Cell Biology, NIH) for generously providing HHV-6 strain GS and HSB-2 cells; Dr S. Josephs (NIH) for providing the sequences for the synthesis of primers and a probe for HHV-6 detection; and Dr Z. Wroblewska and Dr E. Gonczol (Wistar Institute, Philadelphia, Dr B. Conner (Pennsylvania State University, College of Medicine), and Ms M. Smithgall for virus tests. This work was supported by CA 34479 from the National Institutes of Health.
Department of Microbiology and Immunology, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
HELENA WRZOS JOSEPH GIBBONS PETER L. ABT
Section of Transplantation, Department of Surgery, College of Medicine, Pennsylvania State University
ROBERT R. M. GIFFORD HAROLD C. YANG
1. Yanianishi K, Okuno T, Shiraki K, et al. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet 1988; i: 1065-67. 2. Josephs SF, Buchbinder A, Streicher HZ, et al. Detection of human B-lymphotropic virus (human herpes virus 6) sequences in B cell lymphoma tissues of three patients. Leukemia 1988; 2: 132-35. 3 Morris DJ, Littler E, Arrand JR, et al. Human herpesvirus 6 infection m renal transplant recipients. N Engl J Med 1989; 320: 1560-61. 4. Ward KN, Gray JJ, Efstathiou S. Brief report: primary human herpesvirus 6 infection in a patient following liver transplantation from a seropositive donor. J Med Virol
1989; 28: 69-72. 5. Ablashi DV, Lusso P, Hung C-L, et al. Utilization of human
hematopoietic cell lines for the propagation and characterization of HBLV (human herpesvirus 6). Int J Cancer 1988; 42: 787-91. 6. Maniatis T, Fritsch EF, Sambrook J, eds. Molecular cloning: a laboratory manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 1984. 7. Hewlett IK, Ruta M, Cristiano K, Hawthorne CA, Epstein JS. Co-amplification of multiple regions of the HIV-1 genome by the polymerase chain reaction: potential use in multiple diagnosis. Oncogene 1989; 4: 1149-51. 8. Buchbinder A, Josephs SF, Ablashi D, et al. Polymerase chain reaction amplification and in situ hybridization for the detection of human B-lymphotropic virus. J Virol Methods 1988; 21: 191-98.
Nibbling
at the
cherry
SiR,—Your Jan 27 editorial asks about the weight gain seen during a gorging pattern of eating compared with a nibbling regimen in man. Dallosso et all are cited (correctly) as showing a greater weight gain (0 79 kg over 14 days) in young men overfed twice a day than the same men fed the same diet in six meals per day, when they showed a loss of 0-1 kg in 14 days. You say (incorrectly) that we have reported a greater rate of weight loss in obese women fed 3-4 MJ per day in five meals rather than in one meal daily.2 In fact, weight loss was greater on one meal than on five meals, and on 10% protein than on 15% protein, but we showed that the larger weight loss was attributable to greater loss of lean tissue, not fat-adisadvantage to the obese patients. Other investigators have failed to find any significant effect of meal frequency on weight loss.3 I believe that the correct answer to your question is that for a given energy intake hunger is greater on the infrequent meal intake.
When the experiment was done in a closed metabolic ward,4 where subjects could not obtain extra food, there was little effect on weight loss, but there were many bitter complaints of hunger in the single-meal phase of the experiment, and consequently the highest drop-out rate I have experienced in any protocol. Dallosso and colleagues’ study showed that meal frequency does not affect energy expenditure so either the weight gain indicates extra food intake (where that is possible) or an increase of body water. I can think of no plausible explanation for an increase in body water, but hunger may explain the covert increase in food intake when the experiment is done in free-living subjects. Rank Department of Human Nutrition, St Bartholomew’s Hospital Medical College, London EC1M 6BQ, UK
J. S. GARROW
HM, Murgatroyd PR, James WPT. Feeding frequency and energy balance in adult males. Hum Nutr Clin Nutr 1982; 36c: 25-39. 2. Garrow JS, Durrant ML, Blaza S, Wilkins D, Royston P, Sunkin S. The effect of meal frequency and protein concentration on the composition of the weight lost by obese subjects. Br J Nutr 1981; 45: 5-16. 3. Young CM, Hutter LF, Scanlan SS, Rand CE, Lutwak L, Simko V. Metabolic effects of meal frequency on normal young men. J Am Diet Assoc 1972; 61: 391-98. 4. Garrow JS, Durrant ML, Mann S, Stalley SF, Warwick PM. Factors determining weight loss in obese patients in a metabolic ward. Int J Obes 1978; 2: 441-47. 1. Dallosso
Lisinopril overdose SIR,-During a randomised crossover comparison of captopril and lisinopril in hypertension in general practices in New South Wales, a 57-year-old man was recruited to the study following a series of blood pressure (BP) readings averaging 184/100 mm Hg. His hypertension was untreated and he gave no history of coexisting disease; he had had biliary colic and a back injury sustained at work some years earlier. Apart from obesity, there were no abnormal physical or laboratory signs and he had a normal ECG. He was randomised to captopril first, and after dose titration to 50 mg daily his BP fell. During the placebo washout BP (supine) rose to 198/ 100 mm Hg. He started on lisinopril 10 mg daily on Feb 2,1989. The dose was increased to 20 mg daily after a week and on Feb 24 his BP was well controlled at 148/80 mm Hg (supine). He continued on this dose without adverse response up to April 7 when the formal study ended. During the trial extension period he was on 20 mg lisinopril daily. On May 11 at 1130 h, after an argument with his wife, he ingested nine 25 mg tablets of amitriptyline (his wife’s) together with all the lisinopril tablets remaining in a bottle of 110 x 10 mg. Assuming compliance, 68 tablets would have been ingested by May 11, leaving 42 (420 mg). If compliance had not been perfect, a larger dose would have been available. A reasonable estimate of the lisinopril ingested between 420 and 500 mg. On arrival at hospital Ih after the overdose he was drowsy, responding to command but confused. There were no localising neurological signs and the pupils were equal and reactive. He had a sinus tachycardia of 100/min with atrial ectopic beats and a QRS interval of 110 ms. His lying BP was 95/60 mm Hg. Gastric lavage did not produce tablets or fragments and 50 g activated charcoal in sorbitol was put down the tube. He was put on intravenous saline and transferred to the Royal Newcastle Hospital. Conscious level rapidly improved. His BP 241 h after the overdose (after lavage and about 400 ml intravenous saline) was 130/90 mm Hg (lying). It was 160/90, 154/80, and 150/86 mm Hg at 32, 6, and 7 h, respectively, from the time of ingestion. His BP rose to pretreatment levels during the second day in hospital but settled by discharge late that evening. The patient is now well with reasonable BP control from was
captopril 50 mg daily. Blood samples were taken at 75, 115, 19 25, and 72-0 h after ingestion for lisinopril radioimmunoassay in the department of medicine, Austin Hospital and revealed plasma concentrations of over 500, 472, 214, and 24 ng/ml, respectively. Peak plasma concentrations of lisinopril are reached 6 h after administration, and stable blood levels are achieved after 3 days of dosing. The usual therapeutic range is 20-70 ng/ml.l Lisinopril is eliminated almost entirely by renal excretion. The half-life of plasma clearance was estimated at 14h, which is not very different from that obtained with standard doses (12 h).
488
Single doses of up to 160 mg lisinopril have been given in dose-ranging studies but we can be confident that our patient took at least 400 mg (but almost certainly not more than 500 mg). Despite this his hypotension was never profound and treatment with activated charcoal and intravenous saline were accompanied by rapid improvement. The amitryptiline he took would, if anything, have compounded the hypotension. As in reports of overdose with captopril and enalapril complete recovery is probable with intestinal decontamination and intravenous saline. Pressor agents have not been needed.
Discipline of Clinical Pharmacology, University of Newcastle, David Maddison Clinical Sciences Building, Royal Newcastle Hospital, Newcastle, NSW 2300, Australia Austin
Hospital, Heidelberg, Victoria
A. H. DAWSON D. HARVEY A. J. SMITH M. TAYLOR I. M. WHYTE
C. I. JOHNSON R. B. CUBELA
Plasma melatonin
response to dim
(depressed) (euthymic).
treatment ICI Australia Pty Ltd, Melbourne, Victoria
M.
J.
ROBERTS
Jackson B, Cubela RB, Conway EL, Johnston CI. Lisinopril pharmacokinetics in chronic renal failure. Br J Clin Pharmacol 1988; 25: 719-24. 2. Lau C. Attempted suidde with enalapril. N Engl J Med 1986; 315: 197. 3. Waeber G, Nussberger J, Brunner HR. Self poisoning with enalapril. Br Med J 1984; 1.
288: 287-88.
4. Augenstein NW, Kulig KW, Rumack BH. Captopril over-dose resulting in hypotension. JAMA 1988; 259: 3302-05. 5. Varughese A, Taylor AA, Nelson EB. Consequences of angiotensin converting enzyme inhibitor overdose. Am J Hypert 1989; 2: 355-57. 6. Turhan A, Grateau G, Kamoun P, Grunfeld JP. Intoxication volontaire par le captopril. Presse Méd 1984; 13: 2707.
Melatonin supersensitivity to dim light in seasonal affective disorder SIR,-A 57-year-old woman had presented with a long-standing history of winter depressions, weight gain, carbohydrate craving and increased appetite, reduced physical activity, reduced energy, and increased somnolence (3-4 hours more sleep in winter months compared with spring/summer months). She had spring/summer remission. Seasonal affective disorder (SAD) was diagnosed. In the current episode she had been drug-free for 3 months before taking part in a bright light treatment programme. The phototherapy consisted of exposure to bright artificial light every morning from 0600 to 0800 hours for 2 weeks. Response was assessed by modified Hamilton rating scale (Williams J; New York State Psychiatric Institute) and a modified Carroll self-rating scale Both ratings confirmed the clinical impression of significant improvement in symptoms, the Hamilton score falling from 25 before treatment to 1 after treatment and the Carroll score from 25 to 2. The patient consented to two nights (2100 to 0500 hours) of blood collection for the measurement of plasma melatonin, one when the patient was depressed before phototherapy and the other after 2 weeks of successful therapy. Melatonin was measured in plasma by radioimmunoassay.3,4 At midnight on both nights, the patient was exposed to 60 min of dim light (200 lux). This procedure had no significant effect on plasma melatonin concentrations in healthy volunteers. Our patient exhibited a supersensitive melatonin response to dim light exposure both before and after phototherapy (figure). The response, calculated as the percentage change from midnight concentration to the nadir during exposure, was 67% before and 37% after phototherapy. Both responses are abnormal and are more akin to responses seen in patients with bipolar affective disorder.6,7 However, the suppression by dim light was much less in the night after successful phototherapy. A further difference between the two nights was the rate at which melatonin concentrations returned to pre-light levels. Before phototherapy melatonin remained suppressed until 0130 hours and slowly recovered to pre-light levels by 0300; after phototherapy melatonin levels were no different from pre-light concentrations an hour sooner, at 0200. These results suggest that melatonin suppression
by dim light may be a marker of depression in patients with
SAD.
light exposure before and after successful phototherapy
Both a phase delay$and a reduced melatonin production9 have been reported during the depression of SAD. Some investigators have suggested a phase advance (or normalisation) of melatonin’s circadian rhythm after phototherapy8,10 but on our data it is difficult to conclude unequivocally that such a change occurred. Our data do seem to substantiate the claim’ that melatonin production is increased on recovery from depression since almost all concentrations were higher after successful treatment than they had been at equivalent times before phototherapy. If patients with SAD do indeed exhibit supersensitivity to light what might that mean for SAD as a separate diagnostic entity under DSM-111-R? A biological feature such as melatonin supersensitivity, common to bipolar disorder and SAD, might suggest a common neurochemical cause. Given that most of the original SAD patients defmed by Rosenthal et al" also met criteria for bipolar disorder, our fmdings should not surprise. However, the reduced sensitivity to dim light following successful phototherapy and the rate of melatonin recovery following dim light suggest a "state" marker of depression in SAD, at odds with the suggestion that response to dim light in bipolars is a "trait" marker. Clearly, the results discussed require confirmation in larger numbers of
patients. Department of Psychiatry, University of Melbourne and Psychoendocrine Research Unit, Division of Psychological Medicine, Austin Hospital, Heidelberg, Victoria 3084, Australia
IAIN M. MCINTYRE TREVOR R. NORMAN GRAHAM D. BURROWS
Department of Psychology and Brain Behaviour Reseach Institute, La Trobe University, Bundoora, Victoria 1. 2.
STUART M. ARMSTRONG
McIntyre I, Johns M, Norman T, Armstrong S. A portable light source for bright light treatment. Sleep (in press). McIntyre I, Armstrong S, Norman T, Burrows G. Treatment of seasonal affective disorder with light: preliminary Australian experience. Aust NZJ Psychiatry 1989; 23: 369-72
3. Fraser S, Cowen P, Franklin U, Franey C, Arendt J. A direct radioimmunoassay for melatonin Clin Chem 1983; 29: 396-99. 4. McIntyre I, Judd F, Norman T, Burrows G. Plasma melatonin concentrations in depression. Aust NZ J Psychiatry 1986; 20: 381-83. 5 McIntyre I, Norman T, Burrows G, Armstrong S. Human melatonin suppression by light intensity dependent. J Pineal Res 1989; 6: 149-56. 6. Lewy A, Wehr T, Goodwin F, Newsome D, Rosenthal N. Manic-depressive patients may be supersensitive to light Lancet 1981; i: 383-84. 7. Lewy A, Numberger J, Wehr T, Pack D, Becker L, Powell R, Newsome D Supersensitivity to light: possible trait marker for manic depressive illness. AmJ Psychiatry 1985; 142: 725-27. 8. Lewy A, Sack R, Miller S, Hoban T. Antidepressant and circadian phase-shifting effects of light. Science 1987; 235: 352-54. 9. Skwerer R, Jacobsen F, Duncan C, et al. Neurobiology of seasonal effective disorder and phototherapy. In: Rosenthal NE, Blehar MC, eds. Seasonal affective disorders and phototherapy. New York: Guilford Press, 1989: 311-32. 10. Terman M, Terman J, Quitkin F, et al. Response of the melatonin cycle to phototherapy for seasonal affective disorder. J Neural Transm 1988; 72: 147-65. 11. Rosenthal NE, Sack DA,Gillin C, et al. Seasonal affective disorder: a description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 1984; 41: 72-80.
and Epstein-Barr virus capsid antigen and by ELISA for HIV p24 (Abbott); and their sera were negative for antibody to herpes simplex virus 1 and 2 and of low titre to VZV and CMV 6 months before and 2 weeks after transplantation. The level of antibody to Epstein-Barr virus increased after immunosuppression, but we did not detect antibody to virus capsid antigen in monocytes. The HHV-6 antibody titre rose slightly in patient 1 from 20 before to 40 after transplantation and remained low in patient 2 (below 20). The detection of HHV-6 in co-cultivated monocytes from a patient with circulating HHV-6 antibody titre below 20 is notable. The source of the HHV-6 is unknown. One possibility3 is transfer from donor to recipient during organ transplantation but in neither patient were symptoms of acute HHV-6 infection observed. Donor sera and cells were not tested for HHV-6. In these two patients pre-existing HHV-6 may have been reactivated by immunosuppression. Despite serological evidence of widespread HHV-6 infection in the general population virus antigen in or virus isolation from peripheral blood monocytes is not common. The presence of HHV-6 in the monocytes of transplant recipients raised the possibility that some of the frequently encountered posttransplant lymphoproliferative disorders could be linked to infection with this virus. We thank Dr F. Rapp and Dr K. D. Cockley for valuable discussions; Dr R. C. Gallo (Laboratory of Tumour Cell Biology, NIH) for generously providing HHV-6 strain GS and HSB-2 cells; Dr S. Josephs (NIH) for providing the sequences for the synthesis of primers and a probe for HHV-6 detection; and Dr Z. Wroblewska and Dr E. Gonczol (Wistar Institute, Philadelphia, Dr B. Conner (Pennsylvania State University, College of Medicine), and Ms M. Smithgall for virus tests. This work was supported by CA 34479 from the National Institutes of Health.
Department of Microbiology and Immunology, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
HELENA WRZOS JOSEPH GIBBONS PETER L. ABT
Section of Transplantation, Department of Surgery, College of Medicine, Pennsylvania State University
ROBERT R. M. GIFFORD HAROLD C. YANG
1. Yanianishi K, Okuno T, Shiraki K, et al. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet 1988; i: 1065-67. 2. Josephs SF, Buchbinder A, Streicher HZ, et al. Detection of human B-lymphotropic virus (human herpes virus 6) sequences in B cell lymphoma tissues of three patients. Leukemia 1988; 2: 132-35. 3 Morris DJ, Littler E, Arrand JR, et al. Human herpesvirus 6 infection m renal transplant recipients. N Engl J Med 1989; 320: 1560-61. 4. Ward KN, Gray JJ, Efstathiou S. Brief report: primary human herpesvirus 6 infection in a patient following liver transplantation from a seropositive donor. J Med Virol
1989; 28: 69-72. 5. Ablashi DV, Lusso P, Hung C-L, et al. Utilization of human
hematopoietic cell lines for the propagation and characterization of HBLV (human herpesvirus 6). Int J Cancer 1988; 42: 787-91. 6. Maniatis T, Fritsch EF, Sambrook J, eds. Molecular cloning: a laboratory manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 1984. 7. Hewlett IK, Ruta M, Cristiano K, Hawthorne CA, Epstein JS. Co-amplification of multiple regions of the HIV-1 genome by the polymerase chain reaction: potential use in multiple diagnosis. Oncogene 1989; 4: 1149-51. 8. Buchbinder A, Josephs SF, Ablashi D, et al. Polymerase chain reaction amplification and in situ hybridization for the detection of human B-lymphotropic virus. J Virol Methods 1988; 21: 191-98.
Nibbling
at the
cherry
SiR,—Your Jan 27 editorial asks about the weight gain seen during a gorging pattern of eating compared with a nibbling regimen in man. Dallosso et all are cited (correctly) as showing a greater weight gain (0 79 kg over 14 days) in young men overfed twice a day than the same men fed the same diet in six meals per day, when they showed a loss of 0-1 kg in 14 days. You say (incorrectly) that we have reported a greater rate of weight loss in obese women fed 3-4 MJ per day in five meals rather than in one meal daily.2 In fact, weight loss was greater on one meal than on five meals, and on 10% protein than on 15% protein, but we showed that the larger weight loss was attributable to greater loss of lean tissue, not fat-adisadvantage to the obese patients. Other investigators have failed to find any significant effect of meal frequency on weight loss.3 I believe that the correct answer to your question is that for a given energy intake hunger is greater on the infrequent meal intake.
When the experiment was done in a closed metabolic ward,4 where subjects could not obtain extra food, there was little effect on weight loss, but there were many bitter complaints of hunger in the single-meal phase of the experiment, and consequently the highest drop-out rate I have experienced in any protocol. Dallosso and colleagues’ study showed that meal frequency does not affect energy expenditure so either the weight gain indicates extra food intake (where that is possible) or an increase of body water. I can think of no plausible explanation for an increase in body water, but hunger may explain the covert increase in food intake when the experiment is done in free-living subjects. Rank Department of Human Nutrition, St Bartholomew’s Hospital Medical College, London EC1M 6BQ, UK
J. S. GARROW
HM, Murgatroyd PR, James WPT. Feeding frequency and energy balance in adult males. Hum Nutr Clin Nutr 1982; 36c: 25-39. 2. Garrow JS, Durrant ML, Blaza S, Wilkins D, Royston P, Sunkin S. The effect of meal frequency and protein concentration on the composition of the weight lost by obese subjects. Br J Nutr 1981; 45: 5-16. 3. Young CM, Hutter LF, Scanlan SS, Rand CE, Lutwak L, Simko V. Metabolic effects of meal frequency on normal young men. J Am Diet Assoc 1972; 61: 391-98. 4. Garrow JS, Durrant ML, Mann S, Stalley SF, Warwick PM. Factors determining weight loss in obese patients in a metabolic ward. Int J Obes 1978; 2: 441-47. 1. Dallosso
Lisinopril overdose SIR,-During a randomised crossover comparison of captopril and lisinopril in hypertension in general practices in New South Wales, a 57-year-old man was recruited to the study following a series of blood pressure (BP) readings averaging 184/100 mm Hg. His hypertension was untreated and he gave no history of coexisting disease; he had had biliary colic and a back injury sustained at work some years earlier. Apart from obesity, there were no abnormal physical or laboratory signs and he had a normal ECG. He was randomised to captopril first, and after dose titration to 50 mg daily his BP fell. During the placebo washout BP (supine) rose to 198/ 100 mm Hg. He started on lisinopril 10 mg daily on Feb 2,1989. The dose was increased to 20 mg daily after a week and on Feb 24 his BP was well controlled at 148/80 mm Hg (supine). He continued on this dose without adverse response up to April 7 when the formal study ended. During the trial extension period he was on 20 mg lisinopril daily. On May 11 at 1130 h, after an argument with his wife, he ingested nine 25 mg tablets of amitriptyline (his wife’s) together with all the lisinopril tablets remaining in a bottle of 110 x 10 mg. Assuming compliance, 68 tablets would have been ingested by May 11, leaving 42 (420 mg). If compliance had not been perfect, a larger dose would have been available. A reasonable estimate of the lisinopril ingested between 420 and 500 mg. On arrival at hospital Ih after the overdose he was drowsy, responding to command but confused. There were no localising neurological signs and the pupils were equal and reactive. He had a sinus tachycardia of 100/min with atrial ectopic beats and a QRS interval of 110 ms. His lying BP was 95/60 mm Hg. Gastric lavage did not produce tablets or fragments and 50 g activated charcoal in sorbitol was put down the tube. He was put on intravenous saline and transferred to the Royal Newcastle Hospital. Conscious level rapidly improved. His BP 241 h after the overdose (after lavage and about 400 ml intravenous saline) was 130/90 mm Hg (lying). It was 160/90, 154/80, and 150/86 mm Hg at 32, 6, and 7 h, respectively, from the time of ingestion. His BP rose to pretreatment levels during the second day in hospital but settled by discharge late that evening. The patient is now well with reasonable BP control from was
captopril 50 mg daily. Blood samples were taken at 75, 115, 19 25, and 72-0 h after ingestion for lisinopril radioimmunoassay in the department of medicine, Austin Hospital and revealed plasma concentrations of over 500, 472, 214, and 24 ng/ml, respectively. Peak plasma concentrations of lisinopril are reached 6 h after administration, and stable blood levels are achieved after 3 days of dosing. The usual therapeutic range is 20-70 ng/ml.l Lisinopril is eliminated almost entirely by renal excretion. The half-life of plasma clearance was estimated at 14h, which is not very different from that obtained with standard doses (12 h).
488
Single doses of up to 160 mg lisinopril have been given in dose-ranging studies but we can be confident that our patient took at least 400 mg (but almost certainly not more than 500 mg). Despite this his hypotension was never profound and treatment with activated charcoal and intravenous saline were accompanied by rapid improvement. The amitryptiline he took would, if anything, have compounded the hypotension. As in reports of overdose with captopril and enalapril complete recovery is probable with intestinal decontamination and intravenous saline. Pressor agents have not been needed.
Discipline of Clinical Pharmacology, University of Newcastle, David Maddison Clinical Sciences Building, Royal Newcastle Hospital, Newcastle, NSW 2300, Australia Austin
Hospital, Heidelberg, Victoria
A. H. DAWSON D. HARVEY A. J. SMITH M. TAYLOR I. M. WHYTE
C. I. JOHNSON R. B. CUBELA
Plasma melatonin
response to dim
(depressed) (euthymic).
treatment ICI Australia Pty Ltd, Melbourne, Victoria
M.
J.
ROBERTS
Jackson B, Cubela RB, Conway EL, Johnston CI. Lisinopril pharmacokinetics in chronic renal failure. Br J Clin Pharmacol 1988; 25: 719-24. 2. Lau C. Attempted suidde with enalapril. N Engl J Med 1986; 315: 197. 3. Waeber G, Nussberger J, Brunner HR. Self poisoning with enalapril. Br Med J 1984; 1.
288: 287-88.
4. Augenstein NW, Kulig KW, Rumack BH. Captopril over-dose resulting in hypotension. JAMA 1988; 259: 3302-05. 5. Varughese A, Taylor AA, Nelson EB. Consequences of angiotensin converting enzyme inhibitor overdose. Am J Hypert 1989; 2: 355-57. 6. Turhan A, Grateau G, Kamoun P, Grunfeld JP. Intoxication volontaire par le captopril. Presse Méd 1984; 13: 2707.
Melatonin supersensitivity to dim light in seasonal affective disorder SIR,-A 57-year-old woman had presented with a long-standing history of winter depressions, weight gain, carbohydrate craving and increased appetite, reduced physical activity, reduced energy, and increased somnolence (3-4 hours more sleep in winter months compared with spring/summer months). She had spring/summer remission. Seasonal affective disorder (SAD) was diagnosed. In the current episode she had been drug-free for 3 months before taking part in a bright light treatment programme. The phototherapy consisted of exposure to bright artificial light every morning from 0600 to 0800 hours for 2 weeks. Response was assessed by modified Hamilton rating scale (Williams J; New York State Psychiatric Institute) and a modified Carroll self-rating scale Both ratings confirmed the clinical impression of significant improvement in symptoms, the Hamilton score falling from 25 before treatment to 1 after treatment and the Carroll score from 25 to 2. The patient consented to two nights (2100 to 0500 hours) of blood collection for the measurement of plasma melatonin, one when the patient was depressed before phototherapy and the other after 2 weeks of successful therapy. Melatonin was measured in plasma by radioimmunoassay.3,4 At midnight on both nights, the patient was exposed to 60 min of dim light (200 lux). This procedure had no significant effect on plasma melatonin concentrations in healthy volunteers. Our patient exhibited a supersensitive melatonin response to dim light exposure both before and after phototherapy (figure). The response, calculated as the percentage change from midnight concentration to the nadir during exposure, was 67% before and 37% after phototherapy. Both responses are abnormal and are more akin to responses seen in patients with bipolar affective disorder.6,7 However, the suppression by dim light was much less in the night after successful phototherapy. A further difference between the two nights was the rate at which melatonin concentrations returned to pre-light levels. Before phototherapy melatonin remained suppressed until 0130 hours and slowly recovered to pre-light levels by 0300; after phototherapy melatonin levels were no different from pre-light concentrations an hour sooner, at 0200. These results suggest that melatonin suppression
by dim light may be a marker of depression in patients with
SAD.
light exposure before and after successful phototherapy
Both a phase delay$and a reduced melatonin production9 have been reported during the depression of SAD. Some investigators have suggested a phase advance (or normalisation) of melatonin’s circadian rhythm after phototherapy8,10 but on our data it is difficult to conclude unequivocally that such a change occurred. Our data do seem to substantiate the claim’ that melatonin production is increased on recovery from depression since almost all concentrations were higher after successful treatment than they had been at equivalent times before phototherapy. If patients with SAD do indeed exhibit supersensitivity to light what might that mean for SAD as a separate diagnostic entity under DSM-111-R? A biological feature such as melatonin supersensitivity, common to bipolar disorder and SAD, might suggest a common neurochemical cause. Given that most of the original SAD patients defmed by Rosenthal et al" also met criteria for bipolar disorder, our fmdings should not surprise. However, the reduced sensitivity to dim light following successful phototherapy and the rate of melatonin recovery following dim light suggest a "state" marker of depression in SAD, at odds with the suggestion that response to dim light in bipolars is a "trait" marker. Clearly, the results discussed require confirmation in larger numbers of
patients. Department of Psychiatry, University of Melbourne and Psychoendocrine Research Unit, Division of Psychological Medicine, Austin Hospital, Heidelberg, Victoria 3084, Australia
IAIN M. MCINTYRE TREVOR R. NORMAN GRAHAM D. BURROWS
Department of Psychology and Brain Behaviour Reseach Institute, La Trobe University, Bundoora, Victoria 1. 2.
STUART M. ARMSTRONG
McIntyre I, Johns M, Norman T, Armstrong S. A portable light source for bright light treatment. Sleep (in press). McIntyre I, Armstrong S, Norman T, Burrows G. Treatment of seasonal affective disorder with light: preliminary Australian experience. Aust NZJ Psychiatry 1989; 23: 369-72
3. Fraser S, Cowen P, Franklin U, Franey C, Arendt J. A direct radioimmunoassay for melatonin Clin Chem 1983; 29: 396-99. 4. McIntyre I, Judd F, Norman T, Burrows G. Plasma melatonin concentrations in depression. Aust NZ J Psychiatry 1986; 20: 381-83. 5 McIntyre I, Norman T, Burrows G, Armstrong S. Human melatonin suppression by light intensity dependent. J Pineal Res 1989; 6: 149-56. 6. Lewy A, Wehr T, Goodwin F, Newsome D, Rosenthal N. Manic-depressive patients may be supersensitive to light Lancet 1981; i: 383-84. 7. Lewy A, Numberger J, Wehr T, Pack D, Becker L, Powell R, Newsome D Supersensitivity to light: possible trait marker for manic depressive illness. AmJ Psychiatry 1985; 142: 725-27. 8. Lewy A, Sack R, Miller S, Hoban T. Antidepressant and circadian phase-shifting effects of light. Science 1987; 235: 352-54. 9. Skwerer R, Jacobsen F, Duncan C, et al. Neurobiology of seasonal effective disorder and phototherapy. In: Rosenthal NE, Blehar MC, eds. Seasonal affective disorders and phototherapy. New York: Guilford Press, 1989: 311-32. 10. Terman M, Terman J, Quitkin F, et al. Response of the melatonin cycle to phototherapy for seasonal affective disorder. J Neural Transm 1988; 72: 147-65. 11. Rosenthal NE, Sack DA,Gillin C, et al. Seasonal affective disorder: a description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 1984; 41: 72-80.
