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Decreased platelet monoamine oxidase activity in female bulimia nervosa
European Neuropsychopharmacology 10 (2000) 113–117 www.elsevier.com / locate / euroneuro
Decreased platelet monoamine oxidase activity in female bulimia nervosa ´ ´ MD a , Eric Hollander MD b , Jesus ´ Cesar ´ Jose´ Luis Carrasco MD a , *, Marina Dıaz-Marsa MD c , ´ Jeronimo Saiz-Ruiz MD d b
a ´ Jimenez ´ ´ Hospital, Madrid, Spain Dıaz Department of Psychiatry, Fundacion Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA c ´ y Cajal, Madrid, Spain Department of Haematology, Hospital Ramon d ´ y Cajal, Madrid, Spain Department of Psychiatry, Hospital Ramon
Received 29 June 1999; received in revised form 19 October 1999; accepted 26 October 1999
Abstract The involvement of brain serotonin systems in the pathophysiology of eating disorders has been repeatedly demonstrated in recent studies. Platelet MAO activity is an index of brain serotonin activity and lowered platelet MAO levels have been found in association with impulsive behaviors. In addition, some preliminary reports indicate that platelet MAO could be lowered in eating disorder patients. Methods: 47 patients with DSM-IV eating disorders were studied, including 30 with bulimia nervosa and 17 with anorexia nervosa binge eating–purging type. Platelet MAO activity was measured by isotopic methods using C-14 benzylamine and compared with a control group of 30 healthy subjects. Impulsive personality features were studied with specific rating scales. Results: Platelet MAO activity was significantly lower (4.462.4 nmol / h / 10 8 platelets) in the bulimic patients than in the control group (6.962.5) ( p,0.001). No significant differences were found between pure bulimics and binge eating–purging anorectics. Platelet MAO was inversely and significantly correlated with scores on impulsivity scales and with borderline personality disorder characteristics. Conclusions: Platelet MAO activity is lowered in patients with bulimia, which may reflect dysfunction in impulse control mechanisms. Since platelet MAO has a predominant genetic component, there is need for studies on the association of low platelet MAO and higher risk for developing eating disorders. 2000 Elsevier Science B.V. All rights reserved. Keywords: Bulimia nervosa; Platelet monoamineoxidase (MAO); Serotonin; Psychobiology; Personality; Impulsivity
1. Introduction Despite considerable evidence suggesting a link between serotonin (5-HT) function and eating disorders, studies on the functional activity of serotonin are inconclusive. Studies on 5-HT transmission in anorexia nervosa have yielded contradictory results. While some reports have found increased levels of plasma 5-HT and of spinal 5-HIAA in anorectic patients (Kaye et al., 1991), reports on lowered 5-HT function in anorexia nervosa are also described (Hassanyeh and Marshall, 1991). In this sense blunted prolactin concentrations after m-cpp and tryptophan administration have been found (Brewerton et
*Corresponding author. Fax: 134-91-634-2575. E-mail address: [email protected] (J.L. Carrasco)
al., 1990; Monteleone et al., 1998) suggesting a decreased serotonin receptor sensitivity in anorexia nervosa. Most studies have described decreased 5-HT function in patients with bulimia nervosa (Smith et al., 1999). Baseline concentrations of prolactin are lowered in bulimic patients and the response of prolactin has been consistently described as blunted after administration of tryptophan, m-cpp, and fenfluramine (Brewerton et al., 1992; Goldbloom et al., 1996; Kaye et al., 1998; Monteleone et al., 1998) Platelet monoamine oxidase activity (MAO) has been proposed as an index of cerebral 5-HT activity (Oreland and Shaskan, 1983) and has been studied in relation with various psychiatric disorders. Lowered platelet MAO has been repeatedly found in patients with impulsive features, including violent offenders (Alm et al., 1994; Castrogiovanni et al., 1994), impulsive drug users (Von
0924-977X / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0924-977X( 99 )00061-9
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Knorring and Oreland, 1985), pathological gamblers (Moreno et al., 1991; Carrasco et al., 1994) and borderline personality disorder (Verkes et al., 1996). Preliminary reports indicate that impulsive bulimia could be associated with lowered platelet MAO (Hallman et al., 1990; Verkes et al., 1996). Low platelet MAO in bulimic patients has been interpreted as a confirmation of decreased 5-HT turnover in these patients. However, the above mentioned studies are inconclusive, due to the small samples of patients and the lack of uniformity of diagnostic criteria of anorexia and bulimia used in the different studies (Biederman et al., 1984). To confirm these results, a study of platelet MAO activity was designed in a sample of 47 patients with impulsive bulimia, strictly delimited according to DSM-IV diagnostic criteria and including those with bulimia nervosa and those with bulimia associated to anorexia nervosa.
2. Methods and materials Forty seven patients with DSM-IV eating disorders (mean age6S.D.: 21.5364.2 years) and 30 healthy controls (mean age6S.D.: 2361 years) were studied. Patients were consecutively included in the study at admission in the ´ y Cajal hospital. Eating outpatient clinic of the Ramon disorders were classified according to DSM-IV diagnostic criteria, resulting in 30 patients with bulimia nervosa and 17 with anorexia nervosa binge eating–purging type. All the patients were drug free for one month before the study. Patients with current major depressive episodes were excluded as well as patients with lifetime bipolar disorder, psychotic disorders or history of alcoholism or substance abuse disorders. Since platelet MAO concentrations vary among sexes, only female patients and female controls were included in the study.
tive measurement of specific features of each personality condition.
2.2. Biological studies – Measurement of platelet MAO activity Participants were asked to refrain from taking coffee or other stimulating beverages the night before the study. Blood samplings were collected at 9:00 h, after a 12 h fast and after a one night sleep of at least 7 h duration. Thirty ml of blood were obtained by antecubital venipuncture and were collected in tubes containing 0.129 M trisodium citrate as anticoagulant (Vacutainer). The samples were immediately processed by centrifugation for 15 min, obtaining platelet-rich plasma (PRP) free from red and white blood cells. The concentration of platelets in PRP was measured by electronic count (Coulter Thrombocounter).The measurements of platelet MAO were made immediately after sampling, following the basic technique of (Murphy et al. (1976). PRP was transferred to test tubes containing 0.1 ml of potassium phosphate buffer (1.0 mol / l, pH 7.4). Every duplicate tube also contained 0.1 ml of pargyline (2.4 mmol / l, in 1 mmol / l HCl). After preincubation at 378C for 10 min, 100 micromol of 14C-benzylamine (4.0 mmol / l, 600 microCi / mmol, Amersham International) was added and incubated for 30 min at 378. The reaction was stopped by the addition of 0.3 ml of 3 M Hcl in each tube. The reaction products were recovered with heptane, centrifuged and added to 10 ml of scintillation liquid for radioactivity determination. C-14 activity was expressed as disintegrations per min per ml of reaction product. Isotopic counting due to MAO activity was calculated as the difference between the tubes with and without pargyline. Platelet MAO activity is reported as nmol of product per hour per 10 8 platelets. Both inter and intra-assay coefficients were less than 10%. Measurements were made simultaneously in patients and controls, intercalating individuals from both groups to avoid biases due to variations in environmental conditions.
2.1. Psychological measurements 2.3. Statistical analysis All subjects underwent a psychopathological assessment with the Eating Disorders Inventory (EDI) (Garner et al., 1983) and the Bulimic Investigation Test Edinburgh (BITE) (Henderson and Freeman, 1987) to quantify the symptoms of abnormal eating behavior. Concomitant depression and anxiety were rated with the Hamilton Anxiety and Depression scales. Impulsive features were evaluated with the Barrat’s Impulsiveness Scale (Barrat, 1972), a self-control scale (Rosembaum, 1980) and with analogue visual scales specifically designed. The structured Interview for Personality Disorders (SCID-II) was administered to patients and controls for diagnosis of comorbid personality disorders and for quantita-
Differences in MAO activity and on the psychological variables between patients and controls were calculated by two-tailed Mann-Whithney U test for nonparametric variables. ANOVA and two-tailed t-tests were used to evaluate the differences of platelet MAO between patients and controls. ANCOVA of platelet MAO was also used to evaluate the influence of other variables such as tobacco smoking and menstrual cycle on platelet MAO variance. Linear correlations were used for analysis of relationships of biological and psychological variables, with twotailed significance at p,0.05.
J.L. Carrasco et al. / European Neuropsychopharmacology 10 (2000) 113 – 117 Table 1 Clinical and impulsive variables in patients and controls
Weight BITE EDI Ham-A Ham-D Barrat’s scale Self-control scale
Control group
ANb-p
BN
55.065.2 7.362.1 25.665.3 5.862.2 7.162.0 20.0569.3 20.065.8
42.5618.5 26615.6 a 90.666.4 a 16.0612.9 18.5612.4 28.5611.7 23.069.1
58.668.0 33.8613.7 a 98.566.3 a 15.6610.7 14.169.2 31.59612.0 a 25.069.0 a
EDI: Eating Disorder Inventory; BITE: Bulimic Investigation Test Edinburgh; Ham-A: Hamilton anxiety scale; Ham-D: Hamilton depression scale; Barrat: Barrat’s Impulsivness scale; Anr: Anorexia nervosa restrictive type; Anb-p: Anorexia nervosa, binge eating-purging type; BN; Bulimia nervosa. a Significant difference from controls ( p,0.05).
3. Results As expected, patients with eating disorders had significantly higher EDI and BITE total scores than controls (Table 1). Although some patients had at the time high scores on Hamilton anxiety and depression scales, none of them met criteria for mood or anxiety disorders. Impulsivity was significantly higher in the group of bulimia nervosa patients compared with anorectic patients and controls ( p,0.05) (Table 1) Platelet MAO was significantly lower in the group of bulimic patients (mean 4.4, S.D. 2.2 nmol / h / 10 8 platelets) than in the control group (mean 6.9, S.D. 2.5 nmol / h / 10 8 platelets) (Student’s test, p,0.001). When patients are separated according to diagnosis, no significant differences were found between patients with bulimia nervosa (mean 4.2, S.D. 2.0) and patients with anorexia nervosa compulsive-binge eating type (mean 4.9, S.D. 2.6) (Table 2). Platelet MAO was inversely and significantly correlated with the scores on the BITE, that is, with the intensity of bulimic symptoms (r520.19; p,0.05), but not with other symptoms of eating behavior or with the length of illness, age, weight or BMI of the patients. Platelet MAO was negatively correlated with the scores on the Barrat impulsivity scale (r520.22; p,0.05) and on the impulsivity visual analogic scale (r520.24, p,0.05) and with the number of borderline personality features in patients (r 5 2 0.27; p,0.05). Since platelet MAO activity can be influenced by Table 2 MAO activity in DSM-IV eating disorders subgroups MAO activity Anorexia nervosa, binge eating– purging type Bulima nervosa Total patients Control group a
n: 17
4.9, S.D. 2.6 a
n: 30 n: 47 n: 30
4.2, S.D. 2.0 a 4.4, S.D. 2.2 a 6.9, S.D. 2.5
Significant difference vs. control group ( p,0.001).
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variables such as anxiety, depression, weight, menstrual cycle (Zeller et al., 1976) and cigarette smoking (Von Knorring et al., 1984), analysis of covariance (ANCOVA) for MAO activity was performed using the average daily cigarette consumption and the periods of menstrual cycle as covariates. ANCOVA demonstrated no significant influence of these variables on MAO concentration. No correlation was found between platelet MAO activity and scores on Hamilton depression or anxiety scales.
4. Discussion A major role for 5-HT activity in the pathophysiology of bulimia nervosa is widely accepted among researchers and clinicians. Biochemical indexes such as CSF 5-HIAA and prolactin response to 5-HT agonists (Smith et al., 1999; Brewerton et al., 1992; Kaye et al., 1998; Monteleone et al., 1998; Goldbloom et al., 1996) are reduced in this group of patients, indicating that 5-HT function is to some extent associated with bulimia. Further support for the serotonergic hypothesis of bulimia comes from evidence of a satisfactory response to treatment with selective serotonin reuptake inhibitors (SSRI) in these patients (Goldbloom, 1997; Goldbloom and Olmsted, 1993; Hudson et al., 1998). By contrast, the importance of disturbance of 5-HT function in anorexia nervosa is less uniformly demonstrated. Some studies have found a blunted prolactin response to 5-HT agonists (Monteleone et al., 1998) and also low concentrations of cerebrospinal fluid 5-HIAA (Kaye et al., 1988). Others have reported high levels of 5-HIAA (Kaye et al., 1991) or could not find alterations in the prolactin response to 5-HT agonists (Goodwin et al., 1989). In addition, treatment studies with SSRIs have not demonstrated significant efficacy in restrictive anorectic patients (Goldbloom, 1997). In our study, platelet MAO could not discriminate between strictly bulimic patients and binge eating–purging anorectic patients, as diagnosed according to the criteria of DSM-IV. However, platelet MAO discriminated clearly between patients and controls, suggesting that bulimic symptoms are associated with lowered platelet MAO. The role of platelet MAO in psychiatric disorders have yet to be clarified. Low activity of platelet MAO have been found in some forms of depression (Fieve, 1980; Wahlund et al., 1995) and schizophrenia (Wyatt et al., 1980; Kendler and Davis, 1981), but these results have been poorly replicated. In addition, the influence of some contaminant variables such as tobacco smoking, personality traits or pharmacological treatment were not analyzed in these studies. Platelet MAO is also lowered in patients with impulsive disorders such as pathological gambling (Carrasco et al., 1994) and borderline personality disorder (Brewerton et al., 1992) and is correlated with an accen-
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tuation of impulsive and sensation seeking temperament traits in normal individuals (Fowler et al., 1980; Carrasco et al., 1994). Platelet MAO activity in our study is inversely and significantly correlated with the occurrence and intensity of bulimic symptoms, as rated by the BITE. This is in accordance with the previously reported association of low platelet MAO activity and impulsive features (Barrat and Patton, 1983; Soloff et al., 1991; Coccaro and Siever, 1995; Verkes et al., 1996), since binge eating is phenomenologically similar to impulsive symptoms. This is further supported by the significant correlation of scores in the BITE with scores in the Barrat’s impulsivity scale in our study. Therefore, as previously described in the literature, decrease of platelet MAO in bulimic patients might be reflecting an accentuated impulsivity in these patients. Platelet MAO could have been affected by other factors such as tobacco smoking, menstrual cycle or treatment. However, after the analysis, no significant variance of platelet MAO could be attributed to these factors. Selecting a non smoking sample before the study might not be representative of the entire behavioral spectrum of the patients with eating disorders. The physiological significance of platelet MAO is still unclear. It has been considered as an index of brain serotonin activity, since it is correlated with concentrations of CSF 5-HIAA and with prolactin levels (Kleinman et al., 1979). According to this explanation, the lowered platelet MAO found in our sample of bulimic patients suggests that a 5-HT disturbance is present. However, the possibility that platelet MAO is not reflecting just 5-HT function has also to be considered. While serotonin is metabolized by MAO A (Fowler and Tipton, 1984), only MAO B is present in platelets, which questions the relationship of platelet MAO with 5-HT activity. MAO is also involved in the metabolism of norepinephrine (NE) which, in turn, plays a role in the regulation of eating and appetite. Also, some evidence for a NE dysfunction in eating disorders has been suggested in several clinical studies (Kaye et al., 1990a,b). Finally, the idea that low platelet MAO activity might be the manifestation of dysregulation of second and third messenger levels, affecting nonspecifically several psychiatric disorders, should not be ignored. The larger part of platelet MAO variance is genetically determined (Oreland and Shaskan, 1983). Therefore, the lowered platelet MAO activity in the bulimic patients could reflect a predisposition of these individuals to develop the disorder. Other authors have proposed that low platelet MAO might reflect a nonspecific risk factor for the occurrence of psychiatric disorders (Barrat and Patton, 1983). In other words, lowered platelet MAO could differentiate those youngsters with socially acceptable anorectic habits from those who develop the full expression of the eating disorder.
5. Conclusion A significantly decreased platelet MAO activity was found in the whole sample of bulimic patients compared with healthy controls. Decreased MAO activity correlates with bulimic symptoms and with impulsive features. Although preliminary, these results suggest a possible role for platelet MAO as a risk factor in the development of clinically significant eating disorders in young adolescents with initial anorectic and bulimic habits. However, the predictive significance of platelet MAO in eating disorders needs further studies with larger samples.
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J.L. Carrasco et al. / European Neuropsychopharmacology 10 (2000) 113 – 117 Goldbloom, D.S., Olmsted, M.P., 1993. Pharmacotherapy of bulimia nervosa with fluoxetine: Assessment of clinically significant attitudinal change. Am. J. Psychiatry 150, 770–774. Goldbloom, D.S., Garfinkel, P.E., Katz, R., Brown, G.M., 1996. The hormonal response to intravenous 5-hydrosytryptophan in bulimia. J. Psychosom. Res. 40 (3), 289–297. Goodwin, G.M., Shapiro, C.M., Bennie, J. et al., 1989. The neuroendocrine responses and psychological of infusion of L-tryptophan in anorexia nervosa. Pychol. Med. 19, 857–864. Hallman, J., Sakurai, E., Oreland, L., 1990. Blood platelet monoamine oxidase activity, serotonin uptake and release in anorexia and bulimia patients and healthy controls. Acta. Psychiatr. Scand. 81, 73–77. Hassanyeh, F., Marshall, E.F., 1991. Measures of serotonin metabolism in anorexia nervosa. Acta. Psychiatr. Scand. 84, 561–563. Henderson, M., Freeman, C.P.L., 1987. A self-rating scale for bulimia. The ‘‘BITE’’. Br. J. Psychiatry 150, 8–25. Hudson, J.I., Mc Elroy, S.L., Raymond, N.C., Crow, S., Keck, Jr. P.E. et al., 1998. Fluvoxamine in the treatment of binge eating disorder: a multicenter placebo-controlled, double-blind trial. Am. J. Psychiatry 155 (12), 1756–1762. Kaye, W.H., Gwirtsman, H.E., George, D.T. et al., 1988. Concentrations in anorexia nervosa: reduced values in underweight subjects normalize after weight gain. Biol. Psychiatry 23, 102–105. Kaye, W.H., Ebert, M.H., Gwirtsman, H.E. et al., 1990a. CSF monoamine levels in normal weight bulimia: evidence for abnormal noradrenergic activity. Am. J. Psychiatry 147, 225–229. Kaye, W.H., George, D.T., Gwirtsman, H.E. et al., 1990b. Isoproterenol ´ test in anorexia nervosa: assesment of pre and post-betanoradinfusion renergic receptor activity. Psychopharmacol. Bull. 26, 355–359. Kaye, W.H., Gwirstman, H.E., George, D.T. et al., 1991. Altered serotonin activity in anorexia nervosa after long-term weight restoration. Arch. Gen. Psychiatry 48, 556–562. Kaye, W.H., Greeno, C.G., Moss, H., Fernstrom, J., Lilenfeld, L.R., Weltzin, T.E., Mann, J.J.L., 1998. Alterations in serotonin activity and psychiatric symptoms after recovery from bulimia nervosa. Arch. Gen. Psychiatry 55 (10), 927–935. Kendler, K.S., Davis, K.L., 1981. The genetics and biochemistry of paranoid schizophrenia and other paranoid psychoses. Schizophr. Bull. 7, 689–699. Kleinman, J.E., Potkin, S.G., Rogola, A., 1979. A correlation between platelet monoamine oxidase activity and plasma prolactin concentracions in man. Science 206, 479–481.
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Monteleone, P., Brambilla, F., Bortolotti, F., La Rocca, A., Maj, J., 1998. Prolactin response to d-fenfluramineis blunted in people with anorexia nervosa. Br. J. Psychiatry 172, 438–442. Monteleone, P., Brambilla, F., Bortolotti, F., Ferraro, F., Maj, M., 1998. Plasma prolactin response to D-fenfluramine is blunted in bulimic patients with frequent binge episodes. Psychol. Med. 28 (4), 975–983. ´ ´ Moreno, I., Saiz-Ruiz, J., Lopez-Ibor, J.J., 1991. Serotonin and gambling dependence. Hum. Psychopharmacol. 6 (Suppl.), 9–12. Murphy, D.L., Wright, C., Buchsbaum, M.S., Nichols, A., Costa, J.L., Wyatt, R.J., 1976. Platelet and plasma amine oxidase activity in 680 normals: sex and age differences and stability over time. Biochem. Med. 16, 254–265. Oreland, L., Shaskan, E.G., 1983. Some rational behind the use of monoamine oxidase activity as a biological marker. Trends in Pharmacological Sciences 4, 339–341. Rosembaum, M., 1980. A schedule for assessing self-control behaviors. Preliminary findings. Behavior Therapy 11, 109–121. Smith, K.A., Fairburn, C.G., Cowen, P.J., 1999. Symptomatic relapse in bulimia nervosa following acute tryptophan depletion. Arch. Gen. Psychiatry 56 (2), 171–176. Soloff, P.H., Cornelius, J., Foglia, J., George, A., Perel, J.M., 1991. Platelet MAO in borderline personality disorder. Biol. Psychiatry 29 (5), 499–502. Verkes, R.J., Pijl, H., Meinders, E.A., Van Kempen, G.M.J., 1996. Borderline personality, impulsiveness and platelet monoamine measures in bulimia nervosa and recurrent suicidal behavior. Biol. Psychiatry 40, 173–180. Von Knorring, L., Oreland, L., 1985. Personality traits and platelets MAO in tobacco smokers. Psychol. Med. 15, 327–334. Von Knorring, L., Oreland, L., Winblad, B., 1984. Personality traits related to monoamine oxidase (MAO) activity in platelets. Psychiatric Res. 12, 11–26. Wahlund, B., Saaf, J., Wetterberg, L., 1995. Clinical symptoms and platelet monoamine oxidase in sibgroups and different states of affective disorders. J. Affect. Disord. 35 (1-2), 75–87. Wyatt, R.J., Potkin, S.G., Bridge, T.P., Murphy, D.L., 1980. Monoamine oxidase in schizophrenia: An overview. Schizophr. Bull. 6, 199–207. Zeller, E.A., Boshes, B., Arbit, J., Bieber, M., Blonsky, E.R., Dolkart, M., Huprikar, S.V., 1976. Molecular biology of neurological and psychiatric disorders. I. Effect of parkinsonism, age, sex and L-dopa on platelet monoamine oxidase. J. Neural Transmission 39, 63–77.
Decreased platelet monoamine oxidase activity in female bulimia nervosa ´ ´ MD a , Eric Hollander MD b , Jesus ´ Cesar ´ Jose´ Luis Carrasco MD a , *, Marina Dıaz-Marsa MD c , ´ Jeronimo Saiz-Ruiz MD d b
a ´ Jimenez ´ ´ Hospital, Madrid, Spain Dıaz Department of Psychiatry, Fundacion Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA c ´ y Cajal, Madrid, Spain Department of Haematology, Hospital Ramon d ´ y Cajal, Madrid, Spain Department of Psychiatry, Hospital Ramon
Received 29 June 1999; received in revised form 19 October 1999; accepted 26 October 1999
Abstract The involvement of brain serotonin systems in the pathophysiology of eating disorders has been repeatedly demonstrated in recent studies. Platelet MAO activity is an index of brain serotonin activity and lowered platelet MAO levels have been found in association with impulsive behaviors. In addition, some preliminary reports indicate that platelet MAO could be lowered in eating disorder patients. Methods: 47 patients with DSM-IV eating disorders were studied, including 30 with bulimia nervosa and 17 with anorexia nervosa binge eating–purging type. Platelet MAO activity was measured by isotopic methods using C-14 benzylamine and compared with a control group of 30 healthy subjects. Impulsive personality features were studied with specific rating scales. Results: Platelet MAO activity was significantly lower (4.462.4 nmol / h / 10 8 platelets) in the bulimic patients than in the control group (6.962.5) ( p,0.001). No significant differences were found between pure bulimics and binge eating–purging anorectics. Platelet MAO was inversely and significantly correlated with scores on impulsivity scales and with borderline personality disorder characteristics. Conclusions: Platelet MAO activity is lowered in patients with bulimia, which may reflect dysfunction in impulse control mechanisms. Since platelet MAO has a predominant genetic component, there is need for studies on the association of low platelet MAO and higher risk for developing eating disorders. 2000 Elsevier Science B.V. All rights reserved. Keywords: Bulimia nervosa; Platelet monoamineoxidase (MAO); Serotonin; Psychobiology; Personality; Impulsivity
1. Introduction Despite considerable evidence suggesting a link between serotonin (5-HT) function and eating disorders, studies on the functional activity of serotonin are inconclusive. Studies on 5-HT transmission in anorexia nervosa have yielded contradictory results. While some reports have found increased levels of plasma 5-HT and of spinal 5-HIAA in anorectic patients (Kaye et al., 1991), reports on lowered 5-HT function in anorexia nervosa are also described (Hassanyeh and Marshall, 1991). In this sense blunted prolactin concentrations after m-cpp and tryptophan administration have been found (Brewerton et
*Corresponding author. Fax: 134-91-634-2575. E-mail address: [email protected] (J.L. Carrasco)
al., 1990; Monteleone et al., 1998) suggesting a decreased serotonin receptor sensitivity in anorexia nervosa. Most studies have described decreased 5-HT function in patients with bulimia nervosa (Smith et al., 1999). Baseline concentrations of prolactin are lowered in bulimic patients and the response of prolactin has been consistently described as blunted after administration of tryptophan, m-cpp, and fenfluramine (Brewerton et al., 1992; Goldbloom et al., 1996; Kaye et al., 1998; Monteleone et al., 1998) Platelet monoamine oxidase activity (MAO) has been proposed as an index of cerebral 5-HT activity (Oreland and Shaskan, 1983) and has been studied in relation with various psychiatric disorders. Lowered platelet MAO has been repeatedly found in patients with impulsive features, including violent offenders (Alm et al., 1994; Castrogiovanni et al., 1994), impulsive drug users (Von
0924-977X / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0924-977X( 99 )00061-9
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J.L. Carrasco et al. / European Neuropsychopharmacology 10 (2000) 113 – 117
Knorring and Oreland, 1985), pathological gamblers (Moreno et al., 1991; Carrasco et al., 1994) and borderline personality disorder (Verkes et al., 1996). Preliminary reports indicate that impulsive bulimia could be associated with lowered platelet MAO (Hallman et al., 1990; Verkes et al., 1996). Low platelet MAO in bulimic patients has been interpreted as a confirmation of decreased 5-HT turnover in these patients. However, the above mentioned studies are inconclusive, due to the small samples of patients and the lack of uniformity of diagnostic criteria of anorexia and bulimia used in the different studies (Biederman et al., 1984). To confirm these results, a study of platelet MAO activity was designed in a sample of 47 patients with impulsive bulimia, strictly delimited according to DSM-IV diagnostic criteria and including those with bulimia nervosa and those with bulimia associated to anorexia nervosa.
2. Methods and materials Forty seven patients with DSM-IV eating disorders (mean age6S.D.: 21.5364.2 years) and 30 healthy controls (mean age6S.D.: 2361 years) were studied. Patients were consecutively included in the study at admission in the ´ y Cajal hospital. Eating outpatient clinic of the Ramon disorders were classified according to DSM-IV diagnostic criteria, resulting in 30 patients with bulimia nervosa and 17 with anorexia nervosa binge eating–purging type. All the patients were drug free for one month before the study. Patients with current major depressive episodes were excluded as well as patients with lifetime bipolar disorder, psychotic disorders or history of alcoholism or substance abuse disorders. Since platelet MAO concentrations vary among sexes, only female patients and female controls were included in the study.
tive measurement of specific features of each personality condition.
2.2. Biological studies – Measurement of platelet MAO activity Participants were asked to refrain from taking coffee or other stimulating beverages the night before the study. Blood samplings were collected at 9:00 h, after a 12 h fast and after a one night sleep of at least 7 h duration. Thirty ml of blood were obtained by antecubital venipuncture and were collected in tubes containing 0.129 M trisodium citrate as anticoagulant (Vacutainer). The samples were immediately processed by centrifugation for 15 min, obtaining platelet-rich plasma (PRP) free from red and white blood cells. The concentration of platelets in PRP was measured by electronic count (Coulter Thrombocounter).The measurements of platelet MAO were made immediately after sampling, following the basic technique of (Murphy et al. (1976). PRP was transferred to test tubes containing 0.1 ml of potassium phosphate buffer (1.0 mol / l, pH 7.4). Every duplicate tube also contained 0.1 ml of pargyline (2.4 mmol / l, in 1 mmol / l HCl). After preincubation at 378C for 10 min, 100 micromol of 14C-benzylamine (4.0 mmol / l, 600 microCi / mmol, Amersham International) was added and incubated for 30 min at 378. The reaction was stopped by the addition of 0.3 ml of 3 M Hcl in each tube. The reaction products were recovered with heptane, centrifuged and added to 10 ml of scintillation liquid for radioactivity determination. C-14 activity was expressed as disintegrations per min per ml of reaction product. Isotopic counting due to MAO activity was calculated as the difference between the tubes with and without pargyline. Platelet MAO activity is reported as nmol of product per hour per 10 8 platelets. Both inter and intra-assay coefficients were less than 10%. Measurements were made simultaneously in patients and controls, intercalating individuals from both groups to avoid biases due to variations in environmental conditions.
2.1. Psychological measurements 2.3. Statistical analysis All subjects underwent a psychopathological assessment with the Eating Disorders Inventory (EDI) (Garner et al., 1983) and the Bulimic Investigation Test Edinburgh (BITE) (Henderson and Freeman, 1987) to quantify the symptoms of abnormal eating behavior. Concomitant depression and anxiety were rated with the Hamilton Anxiety and Depression scales. Impulsive features were evaluated with the Barrat’s Impulsiveness Scale (Barrat, 1972), a self-control scale (Rosembaum, 1980) and with analogue visual scales specifically designed. The structured Interview for Personality Disorders (SCID-II) was administered to patients and controls for diagnosis of comorbid personality disorders and for quantita-
Differences in MAO activity and on the psychological variables between patients and controls were calculated by two-tailed Mann-Whithney U test for nonparametric variables. ANOVA and two-tailed t-tests were used to evaluate the differences of platelet MAO between patients and controls. ANCOVA of platelet MAO was also used to evaluate the influence of other variables such as tobacco smoking and menstrual cycle on platelet MAO variance. Linear correlations were used for analysis of relationships of biological and psychological variables, with twotailed significance at p,0.05.
J.L. Carrasco et al. / European Neuropsychopharmacology 10 (2000) 113 – 117 Table 1 Clinical and impulsive variables in patients and controls
Weight BITE EDI Ham-A Ham-D Barrat’s scale Self-control scale
Control group
ANb-p
BN
55.065.2 7.362.1 25.665.3 5.862.2 7.162.0 20.0569.3 20.065.8
42.5618.5 26615.6 a 90.666.4 a 16.0612.9 18.5612.4 28.5611.7 23.069.1
58.668.0 33.8613.7 a 98.566.3 a 15.6610.7 14.169.2 31.59612.0 a 25.069.0 a
EDI: Eating Disorder Inventory; BITE: Bulimic Investigation Test Edinburgh; Ham-A: Hamilton anxiety scale; Ham-D: Hamilton depression scale; Barrat: Barrat’s Impulsivness scale; Anr: Anorexia nervosa restrictive type; Anb-p: Anorexia nervosa, binge eating-purging type; BN; Bulimia nervosa. a Significant difference from controls ( p,0.05).
3. Results As expected, patients with eating disorders had significantly higher EDI and BITE total scores than controls (Table 1). Although some patients had at the time high scores on Hamilton anxiety and depression scales, none of them met criteria for mood or anxiety disorders. Impulsivity was significantly higher in the group of bulimia nervosa patients compared with anorectic patients and controls ( p,0.05) (Table 1) Platelet MAO was significantly lower in the group of bulimic patients (mean 4.4, S.D. 2.2 nmol / h / 10 8 platelets) than in the control group (mean 6.9, S.D. 2.5 nmol / h / 10 8 platelets) (Student’s test, p,0.001). When patients are separated according to diagnosis, no significant differences were found between patients with bulimia nervosa (mean 4.2, S.D. 2.0) and patients with anorexia nervosa compulsive-binge eating type (mean 4.9, S.D. 2.6) (Table 2). Platelet MAO was inversely and significantly correlated with the scores on the BITE, that is, with the intensity of bulimic symptoms (r520.19; p,0.05), but not with other symptoms of eating behavior or with the length of illness, age, weight or BMI of the patients. Platelet MAO was negatively correlated with the scores on the Barrat impulsivity scale (r520.22; p,0.05) and on the impulsivity visual analogic scale (r520.24, p,0.05) and with the number of borderline personality features in patients (r 5 2 0.27; p,0.05). Since platelet MAO activity can be influenced by Table 2 MAO activity in DSM-IV eating disorders subgroups MAO activity Anorexia nervosa, binge eating– purging type Bulima nervosa Total patients Control group a
n: 17
4.9, S.D. 2.6 a
n: 30 n: 47 n: 30
4.2, S.D. 2.0 a 4.4, S.D. 2.2 a 6.9, S.D. 2.5
Significant difference vs. control group ( p,0.001).
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variables such as anxiety, depression, weight, menstrual cycle (Zeller et al., 1976) and cigarette smoking (Von Knorring et al., 1984), analysis of covariance (ANCOVA) for MAO activity was performed using the average daily cigarette consumption and the periods of menstrual cycle as covariates. ANCOVA demonstrated no significant influence of these variables on MAO concentration. No correlation was found between platelet MAO activity and scores on Hamilton depression or anxiety scales.
4. Discussion A major role for 5-HT activity in the pathophysiology of bulimia nervosa is widely accepted among researchers and clinicians. Biochemical indexes such as CSF 5-HIAA and prolactin response to 5-HT agonists (Smith et al., 1999; Brewerton et al., 1992; Kaye et al., 1998; Monteleone et al., 1998; Goldbloom et al., 1996) are reduced in this group of patients, indicating that 5-HT function is to some extent associated with bulimia. Further support for the serotonergic hypothesis of bulimia comes from evidence of a satisfactory response to treatment with selective serotonin reuptake inhibitors (SSRI) in these patients (Goldbloom, 1997; Goldbloom and Olmsted, 1993; Hudson et al., 1998). By contrast, the importance of disturbance of 5-HT function in anorexia nervosa is less uniformly demonstrated. Some studies have found a blunted prolactin response to 5-HT agonists (Monteleone et al., 1998) and also low concentrations of cerebrospinal fluid 5-HIAA (Kaye et al., 1988). Others have reported high levels of 5-HIAA (Kaye et al., 1991) or could not find alterations in the prolactin response to 5-HT agonists (Goodwin et al., 1989). In addition, treatment studies with SSRIs have not demonstrated significant efficacy in restrictive anorectic patients (Goldbloom, 1997). In our study, platelet MAO could not discriminate between strictly bulimic patients and binge eating–purging anorectic patients, as diagnosed according to the criteria of DSM-IV. However, platelet MAO discriminated clearly between patients and controls, suggesting that bulimic symptoms are associated with lowered platelet MAO. The role of platelet MAO in psychiatric disorders have yet to be clarified. Low activity of platelet MAO have been found in some forms of depression (Fieve, 1980; Wahlund et al., 1995) and schizophrenia (Wyatt et al., 1980; Kendler and Davis, 1981), but these results have been poorly replicated. In addition, the influence of some contaminant variables such as tobacco smoking, personality traits or pharmacological treatment were not analyzed in these studies. Platelet MAO is also lowered in patients with impulsive disorders such as pathological gambling (Carrasco et al., 1994) and borderline personality disorder (Brewerton et al., 1992) and is correlated with an accen-
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J.L. Carrasco et al. / European Neuropsychopharmacology 10 (2000) 113 – 117
tuation of impulsive and sensation seeking temperament traits in normal individuals (Fowler et al., 1980; Carrasco et al., 1994). Platelet MAO activity in our study is inversely and significantly correlated with the occurrence and intensity of bulimic symptoms, as rated by the BITE. This is in accordance with the previously reported association of low platelet MAO activity and impulsive features (Barrat and Patton, 1983; Soloff et al., 1991; Coccaro and Siever, 1995; Verkes et al., 1996), since binge eating is phenomenologically similar to impulsive symptoms. This is further supported by the significant correlation of scores in the BITE with scores in the Barrat’s impulsivity scale in our study. Therefore, as previously described in the literature, decrease of platelet MAO in bulimic patients might be reflecting an accentuated impulsivity in these patients. Platelet MAO could have been affected by other factors such as tobacco smoking, menstrual cycle or treatment. However, after the analysis, no significant variance of platelet MAO could be attributed to these factors. Selecting a non smoking sample before the study might not be representative of the entire behavioral spectrum of the patients with eating disorders. The physiological significance of platelet MAO is still unclear. It has been considered as an index of brain serotonin activity, since it is correlated with concentrations of CSF 5-HIAA and with prolactin levels (Kleinman et al., 1979). According to this explanation, the lowered platelet MAO found in our sample of bulimic patients suggests that a 5-HT disturbance is present. However, the possibility that platelet MAO is not reflecting just 5-HT function has also to be considered. While serotonin is metabolized by MAO A (Fowler and Tipton, 1984), only MAO B is present in platelets, which questions the relationship of platelet MAO with 5-HT activity. MAO is also involved in the metabolism of norepinephrine (NE) which, in turn, plays a role in the regulation of eating and appetite. Also, some evidence for a NE dysfunction in eating disorders has been suggested in several clinical studies (Kaye et al., 1990a,b). Finally, the idea that low platelet MAO activity might be the manifestation of dysregulation of second and third messenger levels, affecting nonspecifically several psychiatric disorders, should not be ignored. The larger part of platelet MAO variance is genetically determined (Oreland and Shaskan, 1983). Therefore, the lowered platelet MAO activity in the bulimic patients could reflect a predisposition of these individuals to develop the disorder. Other authors have proposed that low platelet MAO might reflect a nonspecific risk factor for the occurrence of psychiatric disorders (Barrat and Patton, 1983). In other words, lowered platelet MAO could differentiate those youngsters with socially acceptable anorectic habits from those who develop the full expression of the eating disorder.
5. Conclusion A significantly decreased platelet MAO activity was found in the whole sample of bulimic patients compared with healthy controls. Decreased MAO activity correlates with bulimic symptoms and with impulsive features. Although preliminary, these results suggest a possible role for platelet MAO as a risk factor in the development of clinically significant eating disorders in young adolescents with initial anorectic and bulimic habits. However, the predictive significance of platelet MAO in eating disorders needs further studies with larger samples.
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