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Plasma norepinephrine after a standardized test meal in acute and remitted patients with anorexia nervosa and in healthy controls
1074
BIOLPSYCHIATRY 1992;31:1074-1077
Plasma Norepinephdne After a Standardized Test Meal in Acute and Remitted Patients with Anorexia Nervosa and in Healthy Controls Karl M. Pirke, Michael Kellner, Elisabeth Philipp, Reinhold Laessle, Jfigen Christian Krieg, and Manfred M. Fichter
Introduction The reduced activity of the peripheral sympathetic nervous system of anorectic patients is reflected in low blood pressure, low pulse rate, hypothermia, etc. Norepinephrine and its membolites in plasma, urine, and cerebrospinal fluid show low concentrations (for ~eview see Pirke 1990). The reduced activity of the sympathetic nervous system can be stimulated by an orthostatic challenge (Kaye et al 1985; Heufelder et al 1985) and by exercise (Nudel et al 1984; Pirke et al 1989) although to a lesser extent than in controls. Kaye et al (1985) found decreased norepinephrine levels in plasma before and after an orthostatic challenge in long-term ( 6 - 72 months) weight recovered anorectic patients. These former patients had eitl~er intermediate or good outcome. Norepinephrine plays a role in the regulation of hunger and satiety (Leibowitz 1984) in many neuroendocrine and neurophysiological regulatory systems and it is correlated with mood disturbances in anorexia nervosa (Halmi et al
From the Max Planck Institute for Psychiatry, Munich, and the Psychosomatic Hospital, Roseneck, Prien, Germany. Address reprint requests to ProL K. M. Pirke, Center for Psychobiological and Psychosomatic Research, Dept. of Fsychoendocrinology, University of Trier, Building D, P. O. Box 3825, 5500 Trier, Germany. Received September 30, 1991; revised February 3, 1992.
© 1992 Society of Biological Psychiatry
1978; Laessle et al 1988). We have studied the response of plasma norepinephrine to a standardized test meal in acutely ill and in weightrecovered anorectics as well as in healthy controis.
Subjects and Methods Seven underweight inpatients with anorexia nervosa, 10 weight-recovered anorectics, as well as 12 healthy age-matched young women were studied. Diagnosis was made according to the DSM-III-R criteria. Patient- and control groups are described in Table 1. Controls were healthy young women without a history of eating disorders. Subjects who dieted currently, took medication (except from contraceptive pills), used drugs or alcohol, or exercised heavily were excluded. Patients, former patients, and controls came to the laboratory after an overnight fast. An indwelling catheter was inserted into a forearm vein and kept open by a saline drip. During the whole precedure subjects remained in a halfsupine position in bed. The first blood sample was taken after 30 min. Then the liquid test meal (750 kcal; 40% fat, 20% protein, 40% carbohydrate in the form of a milkshake with either coffee or vanilla flavor) was given and consumed by all patients and controls within I0 0006-322~/92/$05.00
Brief Reports
BIOL PSYCHIATRY 1992;31:1o74-Io77
min. Ten, 20, 30, 45, 60, 80, and 100 min after the test meal, additional blood samples of 10 ml each we~ taken, mixed with a small amount of EDTA, centrifuged immediately, and kept frozen at - 7 0 ° C until analyzed. Analysis was done by high pressure liquid chromatography (HPLC) including electrochemical detection as described earlier (Heufelder et al 1985). A standardized interview was conducted with all subjects. All completed the Three Factor Eating Questionnaire (Stunkard and Messink 1985). The restrained scale was evaluated. Subjects scoring above the 75th percentile of the normal control group can be classified as restrained eaters (Laessle et al 1989). Patients and former patients also completed the Eating Attitude Test (EAT) (Garner and Garfinkel 1979). The 26item questionnaire was used. For statistical evaluation the Kruskal Wallis test was used to study differences between three groups. The MannWhitney U test was applied for comparison of two groups. In the weight-recovered anorectics, body weight was normalized on the average for 4 years (Table 1). All patients had resumed menstmal cycles. The restraint score (Stunkard and Messink 1985) was significantly different between groups (p < 0.01). Weight-recovered anorectics had significantly lower values than acutely ill anorectics (8.3 _+ 5.6 versus 12.5.43.6) and significantly higher values than controis (3.4 +_. 1.9). The total EAT score in the low-weight anorectics was 34.4 -4- 21.6. In the weight-recovered anorectics the to~,alEAT score was significantly lower (7.8 -4:. 11.3). The EAT score was only slightly higher in the weightrecovered anorectics than the score observed by
1075
us earlier in 40 healthy young women (Laessle et al 1989). This normal group had an EAT score of 6.5 _+ 5.3. Figure 1 shows the plasma norepinephrine values before and after the test meal. Healthy controls had significantly higher norepinephrine baseline values than low-weight and weighsnormalized patients (p < 0.001). The increase as calculated from the area under the curve was significantly reduced in low-weight anorectics (p < 0.25). No difference in the area under the curve was found between weight-recovered patients and controls. When all three groups were considered together there was a significant correlation between baseline norepinephrine values and the restraint score (r = - 0.64, p < 0.001). When only patieats were considered the correlation was still significant (r = 0.5, p < 0.05). No correlation was found between the area under the postprandial norepinephrine curve and the restraint score.
Discussion The weight-recovered patients studied here had a good outcome. This conclusion is based on the normal weight, the reappearance of menstrual cycles, and the low EAT score. On the average they still had a significantly elevated restraint score. We have reported earlier that restrained eaters selected from a group of healthy young women by the Three Factor Eating Questionnaire (Stunkard and Messink 1985) had significantly lower norepinephrine values at all points in time after a standardized test meal (Pirke et
Table 1. Sample Description (mean + SD)
Acute AN n=7 Recovered AN n = 10 Controls n = 12
Age
BMI (kg/m2)
Duration of illness (years)
Vomiter/ restricter
2 2 . 9 _ 9.8
15.1 _ 1.5
?,.6 - 4.6
1/6
25.4 ± 3.7
20.0 ± 4.5
2.4 ± 1.5
2/8
23.5 ± 1.9
21.5 ± 1.4
Recovered (years)
4.0 ± 2.0
1076
Brief Reports
BIOL PSYCHIATRY 1992;3 !: 1074-1077
NE (pg/ml) 700 600 "500 400 300 200 100
0
!
basl ~line 10
!
i
i
!
i
i
20
30
45
60
80
100
--'--
controls
-~-
underweight AN
-e-
weight recov. AN
minutes after testmeal
Figure 1. Plasmanorepinephrine after a liquid test meal of 750 kcal in healthycontrols, low-weightanorectics, and weight-recovered anorectics. Mean and SEM are plotted.
al 1990). We can therefore conclude that the weight-recovered anorectics studied by us become restrained eaters, who have in common with "normal" restrained eaters not only strict cognitive control over eating but also low norepinephrine values. It remains unclear whether restrained eating causes low norepinephrine values. Baseline norepinephrine values do not necessarily reflect the activity of the sympathetic nervous system (Kopin 1978). It remains unclear whether changes in secretion, reuptake, or metabolism cause low plasma norepinephrine values in weight-recovered anorectics and re/ strained eaters. Low norepinephrine values have not only been found in acutely ill and weight-recovered anorectic patients but also in normal weight bulimics (Pirke et al 1985; Kaye et al 1990; Lesem et al 1989), in starving healthy subjects (Pirke and Ploog 1987), and in restrained eaters (Pirke et al 1990). These observations indicate that not only s~vere eating disorders but also subclinical forms of disturbed eating can suppress norepinephrine (NE) levels in plasma. We might speculate that eating behavior in anorectic patients with good outcome is still disturbed, causing low NE values. An alternative but also highly speculative
explanation is the assumption that low NE is a trait-del~ndent variable in anorexia nervosa and restrained eating.
References Garner DM, Garfinkel PE (1979): The eating attitude test: an index of symptoms of anorexia nervosa. Psychol Med 9:273-279. Halmi KA, Dekirmenjian H, Davis JM, Casper B, Goldberg S (1978): Catecbolamine metabolism in anorexia nervosa. Arch Gen Psychiatry 35:458460. KayeWH, JimersonDC, Lake CR, Ebert MH (1985): Altered norepinephrine metabolism following long term weight recovery in patients with anorexia nervosa. Psychiatry Res 14:333-342. Kaye WH, Gwirtsman HE, George DT, Jimerson DC, Ebert MH, Lake CR (1990): Disturbances of noradrenergic systems in normal weight bulimia: Relationship to diet and menses. Biol Psychiatry 27:4-21. Kopin IJ (1978): Plasma levels of norepinephrine. Ann Intern Med 88:671--680. Laessle RG, Schweiger U, Pirke KM (1988): Mood a,id orthostatic norepinephrine response in anorexia nervosa. Psychiatry Res 24:87-94. Laessle RG, Tuschl ILl, Waadt S, Pirke KM (1989): The specific psychopathologyof bulimia nervosa: A comparison with restrained and unrestrained
Brief Reports
(normal) eaters. J Consult Clin Psychol 57:772775. Leibowitz SF (1984): Noradrenergic function in the medial hypothalamus. Potential relation to anorexia nervosa and bulimia. In Pirke KM, Ploog D (eds), Psychobiology of Anorp_~iaNercosa Berlin: Springer-Verlag, pp 35-45. Lesem MD, Georgee DT, Kaye WH, Goldstein DS, Jimerson DC (1989): State-related changes in norepinephrine regulation in anorexia nervosa. Biol Psychiatry 25:509-512. Nudel DB, Gootman N, Nussbaum MP, Shenker IR (1984): Altered exercise performance and abnormal sympathetic responses to exercise in patients with anorexia nervosa. J Pediatr 105:34--37. Pi_tke KM (1_¢~0): The noradrenergic system in anorexia and bulimia nervosa. In Remschmidt H, Schmidt MH (eds), Child and Youth Psychiatry. European Perspectives, Vol 1 pp 30--44.
BIOL PSYCHIATRY 1992;31:1074-1077
1077
Pirke KM, Ploog D (1987): Biology of human starvation. In Beumont, Burrows, Casper (eds), Handbook of Eating Disorders Part I New York: Elsevier, pp 79-102. Pirke KM, Fichter MM, Pahl J (1985) Nomdrenaline, trijodthyronin, growth hormone and prolactine during weight gain in anorexia nervosa, lnt J Eat Disord 4:499-509. Pirke KM, Eckert M, Ofers B et al, (1989): Plasma norepinephrine response to exercise in bulimia, anorexia nervosa and in controls. Biol Psychiatry 25:799-802. Pirke KM, Tuschl RJ, Spyra B, et al, (1990): Endocrine Findings in restrained eaters. Physiol BeVy 47:903-906. Stunkard AJ, Messink S (1985): The three factor eating questionnaire to measure dietary restraint, disinhibition and hunger. J Psychosom l~es 29:71--. 81
BIOLPSYCHIATRY 1992;31:1074-1077
Plasma Norepinephdne After a Standardized Test Meal in Acute and Remitted Patients with Anorexia Nervosa and in Healthy Controls Karl M. Pirke, Michael Kellner, Elisabeth Philipp, Reinhold Laessle, Jfigen Christian Krieg, and Manfred M. Fichter
Introduction The reduced activity of the peripheral sympathetic nervous system of anorectic patients is reflected in low blood pressure, low pulse rate, hypothermia, etc. Norepinephrine and its membolites in plasma, urine, and cerebrospinal fluid show low concentrations (for ~eview see Pirke 1990). The reduced activity of the sympathetic nervous system can be stimulated by an orthostatic challenge (Kaye et al 1985; Heufelder et al 1985) and by exercise (Nudel et al 1984; Pirke et al 1989) although to a lesser extent than in controls. Kaye et al (1985) found decreased norepinephrine levels in plasma before and after an orthostatic challenge in long-term ( 6 - 72 months) weight recovered anorectic patients. These former patients had eitl~er intermediate or good outcome. Norepinephrine plays a role in the regulation of hunger and satiety (Leibowitz 1984) in many neuroendocrine and neurophysiological regulatory systems and it is correlated with mood disturbances in anorexia nervosa (Halmi et al
From the Max Planck Institute for Psychiatry, Munich, and the Psychosomatic Hospital, Roseneck, Prien, Germany. Address reprint requests to ProL K. M. Pirke, Center for Psychobiological and Psychosomatic Research, Dept. of Fsychoendocrinology, University of Trier, Building D, P. O. Box 3825, 5500 Trier, Germany. Received September 30, 1991; revised February 3, 1992.
© 1992 Society of Biological Psychiatry
1978; Laessle et al 1988). We have studied the response of plasma norepinephrine to a standardized test meal in acutely ill and in weightrecovered anorectics as well as in healthy controis.
Subjects and Methods Seven underweight inpatients with anorexia nervosa, 10 weight-recovered anorectics, as well as 12 healthy age-matched young women were studied. Diagnosis was made according to the DSM-III-R criteria. Patient- and control groups are described in Table 1. Controls were healthy young women without a history of eating disorders. Subjects who dieted currently, took medication (except from contraceptive pills), used drugs or alcohol, or exercised heavily were excluded. Patients, former patients, and controls came to the laboratory after an overnight fast. An indwelling catheter was inserted into a forearm vein and kept open by a saline drip. During the whole precedure subjects remained in a halfsupine position in bed. The first blood sample was taken after 30 min. Then the liquid test meal (750 kcal; 40% fat, 20% protein, 40% carbohydrate in the form of a milkshake with either coffee or vanilla flavor) was given and consumed by all patients and controls within I0 0006-322~/92/$05.00
Brief Reports
BIOL PSYCHIATRY 1992;31:1o74-Io77
min. Ten, 20, 30, 45, 60, 80, and 100 min after the test meal, additional blood samples of 10 ml each we~ taken, mixed with a small amount of EDTA, centrifuged immediately, and kept frozen at - 7 0 ° C until analyzed. Analysis was done by high pressure liquid chromatography (HPLC) including electrochemical detection as described earlier (Heufelder et al 1985). A standardized interview was conducted with all subjects. All completed the Three Factor Eating Questionnaire (Stunkard and Messink 1985). The restrained scale was evaluated. Subjects scoring above the 75th percentile of the normal control group can be classified as restrained eaters (Laessle et al 1989). Patients and former patients also completed the Eating Attitude Test (EAT) (Garner and Garfinkel 1979). The 26item questionnaire was used. For statistical evaluation the Kruskal Wallis test was used to study differences between three groups. The MannWhitney U test was applied for comparison of two groups. In the weight-recovered anorectics, body weight was normalized on the average for 4 years (Table 1). All patients had resumed menstmal cycles. The restraint score (Stunkard and Messink 1985) was significantly different between groups (p < 0.01). Weight-recovered anorectics had significantly lower values than acutely ill anorectics (8.3 _+ 5.6 versus 12.5.43.6) and significantly higher values than controis (3.4 +_. 1.9). The total EAT score in the low-weight anorectics was 34.4 -4- 21.6. In the weight-recovered anorectics the to~,alEAT score was significantly lower (7.8 -4:. 11.3). The EAT score was only slightly higher in the weightrecovered anorectics than the score observed by
1075
us earlier in 40 healthy young women (Laessle et al 1989). This normal group had an EAT score of 6.5 _+ 5.3. Figure 1 shows the plasma norepinephrine values before and after the test meal. Healthy controls had significantly higher norepinephrine baseline values than low-weight and weighsnormalized patients (p < 0.001). The increase as calculated from the area under the curve was significantly reduced in low-weight anorectics (p < 0.25). No difference in the area under the curve was found between weight-recovered patients and controls. When all three groups were considered together there was a significant correlation between baseline norepinephrine values and the restraint score (r = - 0.64, p < 0.001). When only patieats were considered the correlation was still significant (r = 0.5, p < 0.05). No correlation was found between the area under the postprandial norepinephrine curve and the restraint score.
Discussion The weight-recovered patients studied here had a good outcome. This conclusion is based on the normal weight, the reappearance of menstrual cycles, and the low EAT score. On the average they still had a significantly elevated restraint score. We have reported earlier that restrained eaters selected from a group of healthy young women by the Three Factor Eating Questionnaire (Stunkard and Messink 1985) had significantly lower norepinephrine values at all points in time after a standardized test meal (Pirke et
Table 1. Sample Description (mean + SD)
Acute AN n=7 Recovered AN n = 10 Controls n = 12
Age
BMI (kg/m2)
Duration of illness (years)
Vomiter/ restricter
2 2 . 9 _ 9.8
15.1 _ 1.5
?,.6 - 4.6
1/6
25.4 ± 3.7
20.0 ± 4.5
2.4 ± 1.5
2/8
23.5 ± 1.9
21.5 ± 1.4
Recovered (years)
4.0 ± 2.0
1076
Brief Reports
BIOL PSYCHIATRY 1992;3 !: 1074-1077
NE (pg/ml) 700 600 "500 400 300 200 100
0
!
basl ~line 10
!
i
i
!
i
i
20
30
45
60
80
100
--'--
controls
-~-
underweight AN
-e-
weight recov. AN
minutes after testmeal
Figure 1. Plasmanorepinephrine after a liquid test meal of 750 kcal in healthycontrols, low-weightanorectics, and weight-recovered anorectics. Mean and SEM are plotted.
al 1990). We can therefore conclude that the weight-recovered anorectics studied by us become restrained eaters, who have in common with "normal" restrained eaters not only strict cognitive control over eating but also low norepinephrine values. It remains unclear whether restrained eating causes low norepinephrine values. Baseline norepinephrine values do not necessarily reflect the activity of the sympathetic nervous system (Kopin 1978). It remains unclear whether changes in secretion, reuptake, or metabolism cause low plasma norepinephrine values in weight-recovered anorectics and re/ strained eaters. Low norepinephrine values have not only been found in acutely ill and weight-recovered anorectic patients but also in normal weight bulimics (Pirke et al 1985; Kaye et al 1990; Lesem et al 1989), in starving healthy subjects (Pirke and Ploog 1987), and in restrained eaters (Pirke et al 1990). These observations indicate that not only s~vere eating disorders but also subclinical forms of disturbed eating can suppress norepinephrine (NE) levels in plasma. We might speculate that eating behavior in anorectic patients with good outcome is still disturbed, causing low NE values. An alternative but also highly speculative
explanation is the assumption that low NE is a trait-del~ndent variable in anorexia nervosa and restrained eating.
References Garner DM, Garfinkel PE (1979): The eating attitude test: an index of symptoms of anorexia nervosa. Psychol Med 9:273-279. Halmi KA, Dekirmenjian H, Davis JM, Casper B, Goldberg S (1978): Catecbolamine metabolism in anorexia nervosa. Arch Gen Psychiatry 35:458460. KayeWH, JimersonDC, Lake CR, Ebert MH (1985): Altered norepinephrine metabolism following long term weight recovery in patients with anorexia nervosa. Psychiatry Res 14:333-342. Kaye WH, Gwirtsman HE, George DT, Jimerson DC, Ebert MH, Lake CR (1990): Disturbances of noradrenergic systems in normal weight bulimia: Relationship to diet and menses. Biol Psychiatry 27:4-21. Kopin IJ (1978): Plasma levels of norepinephrine. Ann Intern Med 88:671--680. Laessle RG, Schweiger U, Pirke KM (1988): Mood a,id orthostatic norepinephrine response in anorexia nervosa. Psychiatry Res 24:87-94. Laessle RG, Tuschl ILl, Waadt S, Pirke KM (1989): The specific psychopathologyof bulimia nervosa: A comparison with restrained and unrestrained
Brief Reports
(normal) eaters. J Consult Clin Psychol 57:772775. Leibowitz SF (1984): Noradrenergic function in the medial hypothalamus. Potential relation to anorexia nervosa and bulimia. In Pirke KM, Ploog D (eds), Psychobiology of Anorp_~iaNercosa Berlin: Springer-Verlag, pp 35-45. Lesem MD, Georgee DT, Kaye WH, Goldstein DS, Jimerson DC (1989): State-related changes in norepinephrine regulation in anorexia nervosa. Biol Psychiatry 25:509-512. Nudel DB, Gootman N, Nussbaum MP, Shenker IR (1984): Altered exercise performance and abnormal sympathetic responses to exercise in patients with anorexia nervosa. J Pediatr 105:34--37. Pi_tke KM (1_¢~0): The noradrenergic system in anorexia and bulimia nervosa. In Remschmidt H, Schmidt MH (eds), Child and Youth Psychiatry. European Perspectives, Vol 1 pp 30--44.
BIOL PSYCHIATRY 1992;31:1074-1077
1077
Pirke KM, Ploog D (1987): Biology of human starvation. In Beumont, Burrows, Casper (eds), Handbook of Eating Disorders Part I New York: Elsevier, pp 79-102. Pirke KM, Fichter MM, Pahl J (1985) Nomdrenaline, trijodthyronin, growth hormone and prolactine during weight gain in anorexia nervosa, lnt J Eat Disord 4:499-509. Pirke KM, Eckert M, Ofers B et al, (1989): Plasma norepinephrine response to exercise in bulimia, anorexia nervosa and in controls. Biol Psychiatry 25:799-802. Pirke KM, Tuschl RJ, Spyra B, et al, (1990): Endocrine Findings in restrained eaters. Physiol BeVy 47:903-906. Stunkard AJ, Messink S (1985): The three factor eating questionnaire to measure dietary restraint, disinhibition and hunger. J Psychosom l~es 29:71--. 81