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Acute tryptophan depletion in autistic disorder: A controlled case study
I~IOLPSYCHIATRY 1993;33:547-550
547
CASE REPORT
Acute Tryptophan Depletion in Autistic Disorder: A Controlled Case Study Christopher J. McDougle, Susan T. Naylor, Wayne K. Goodman, Fred R. Volkmar, Donald J. Cohen, and Lawrence H. Price
Introduction Autistic disorder is characterized by a disturbance in social relatedness (Kanner 1943), often accompanied by obsessivecompulsive symptoms, and aggressive/impulsive behavior. A number of lines of evidence suggest that abnormalities in the serotonin (5-hydroxytryptamine [5-HT]) system may contribute to the pathophysiology of autism. Decreased central 5-1-I"1"responsivity has been demonstrated in children (Hoshino et al 1984) and adults (McBride et al 1989) with autistic disorder, as reflected by a decreased prolactin response to L-5-hydroxytryptophan and fenflurarnine, respectively. Elevated whole blood 5-HT levels have been found in 30%-40% of autistic patients studied (Anderson et al 1987). Antibodies dh-ected against 5-HT neurons were identified in the blood and cerebrospinal fluid in 7 of 13 autistic patients in one study (Todd and Ciaranello 1985). A recent investigation, however, found that elevated blood 5-HT in autistic patients was not closely related to inhibition of 5-HT binding by antibody-rich blood fractions (Yuwiler et al 1992). The synthesis of 5-HT is dependent on dietary intake of its precursor, the essential amino acid tryptophan (Gal and Dreses 1962). Data suggest that dietary tryptophan aepletion may specifically reduce brain 5-HT function (Fernstrom 1977). It was recently demonstrated that the combination of a low-tryptophan diet and a tryptophan-free amino acid mixture can rapidly reduce plasma tryptophan levels by up to 80%; this effect was co=eiated with the rapid reversal of the clinical response to antidepressants in recently remitted depressed patients (Delgado et al 1990). Based on evidence indicating a potential dysregulation of 5-HT function in autistic disorder, an adult with autism underwent acute tryptophan depletion with this method.
Fromthe Departmentof Psychiatry.YaleUniversitySchoolof Medicine(CJM, STN, WKG, LHP) and ClinicalNeuroscienceResearchUnit, Connecticut MentalHealthCenter;andYaleChildStudyCenter(FRV,DJC),NewHaven. CT. Addressreprintrequeststo ChristopherJ. McDougle,MD, YaleUniversitySchool of Medicine,ConnecticutMHC,ClinicalNeuroseienceResearchUnit.34 Park St., New Haven,~ 06519. ReceivedAugust8. 1992;revisedJanuary 12, 1993. © 1993Societyof BiologicalPsychiatry
Case Report Ms. A., a 35-year-old woman, presented for treatment because of a life-long inability to relate to other people, a chronic heightened sensitivity to auditory stimuli, persistent interfering obsessional thoughts and preoccupations, and extreme anxiety. She was not demonstrating aggressivity on hospitalization. At the time of admission, Ms. A. met the following DSM-III-R (American Psychiatric Association 1987) criteria for autistic disorder: A. 4,5; B. 2,4,5,6; and C. 2,3,4,5. She had a total score of 95 on the Autism Behavior Checklist (Krug et.al 1980). The patient's father reported that Ms. A. did not speak until the age of 2.5 years, tha~ she demonstrated very poor eye contact throughout childhood and adolescence, that she preferred contact with objects rather than people, and that she resisted being touched or held. Ms A. showed aggressive behaviors such as hitting and biting other people and throwing objects. She was institutionalized between the ages of 10--15 years, lived in a group home until the age of 20, and subsequently moved into her own apartment. Admiss~.on physical examination, routine laboratory tests of blood and urine, and electrocardiogram were normal. Full-scale IQ on the Wechsler Adult Intelligence Scale (WAIS-R) (Wechsier i98i) was 105. Ms A.'s past medical history wag ur~-em~kable and no identifiable etiology of autistic disorder had been found. No significantfamily history of neuropsychiatric disorders was elicited. Mental status examination revealed a short, androgynousappearing woman with increased psychomotor activity who made only momentary eye contact. Speech was monotone and increased in volume. The patient's mood was described as "nervous" and her affect was constricted. Thought processes were ctrcumstantial and, although not psychotic, the patient demonstrated an intense preoccupation with the need to keep "noisy children" off of the unit and to perform her dally routines according to her set schedule. Ms. A.'s intelligence was average and her short- and long-term memory were excellent, but her concentration was impaired. Two weeks following admission, and after signing voluntary written informed consent, Ms. A. was entered into the acute tryptophan depletion study. She was medication-free throughout 0006-3223/93/$06.00
5~l,q
BIOL PSYCHIATRY 1g~)3;33:547-550
C.J. McDougle et al
Table I. Behavioral Response to Active and Sham Acute Tryptophan Depletion
Visual analog scalC Talkative Happy Drowsy Nervous Sad Calm Depressed Anxious Energetic Fearful Mellow High Angry Irritable Tired HungD Agitation Ham-At' Ham-D~ Y-BOCSd CGF
Active depletion (peak change from baseline)
Sham depletion
0 - 50 0 + 14 + 25 - 50 + 64 + 25 0 - 25 0 0 + 50 + 50 - 25 0 + 75 + 11 + II +I "'very. much worse"
- 25 0 0 + 11 0 0 0 - 25 + 25 - 25 0 0 0 0 + 25 0 - 25 - 7 - 4 0 "rainimally improved"
~17-item, lO0-mmscale(rangingfrom0 = "not at all" to 100 = "mostever"). bHamilton Rating Scale for Anxiety. 'Hamilton Rating Scale for Depression. JYale-BrownObsessive CompulsiveScale. "ClinicalGlobalImpressionsScale(7 = "verymuch worse,"4 = "no change," I - "vet,. much improved").
the testing period and had not taken any psychoactive medication during the preceding 15 years. Active tryptophan depletion consisted of a 24-hr, 160 mg/day iow-tryptophan diet with placebo capsules given with each meal, followed the next morning by a tryptophan-free, 15-amino acid drink. Sham testing consisted of a 24-hr, 160 mg/day low-tryptophan diet supplemented with capsules containing 500 mg of tryptophan given with each meal, followed the next morning by a 16-amino acid drink containing 2.3 gs of tryptophan. The patient returned to normal dietary intake at 5 PM on the day of each testing session. The active and sham testing sessions were separated by 7 days and randomized double-blind conditions were maintained throughout. Behavioral ratings were obtained at 15 min before and 3, 5, and 7 hr after the amino acid drink. Plasma for total tryptophan measurement, assayed by high-performance liquid chromatography, was obtained 15 min before and 5 hr after the drink.
Results Changes in behavioral ratings following active and sham tryptophan depletion are shown in Table 1. Active tryptophan depletion in contrast to sham depletion resulted in a marked ex-
acerbation of anxiety, depression, auger, irritability, agitation, and ~rseveration. The patient aid not become physically aggressive. Figure 1 displays mean results from the Ritvo-Freeman Real-Life Scale (Freeman et al 1986), which is specifically designed to measure changes in severity of a variety of behaviors characteristic of autistic disorder. Following active tryptophan depletion, the patient demonstrated a worsening of the symptoms of autism in association with an 88% reduction in total plasma tryptophan level (10.1 I.~ mol/L to 1.2 la. mol/L), in contrast, sham depletion resulted in mild improvement in clinical state, and a 27% increase in total plasma tryptophan level (10.7 ix mol/L to 14.6 Ix reel/L).
Discussion Serotonin function is involved in social interactive (McGuire and Raleigh 1985), obsessive-compulsive (Clomipramine Collaborative Study Group 1991), and aggressive/impulsive phenomena (Stanley and Stanley 1990). Preliminary open-label studies and case reports suggest that drugs which affect 5-HT neurotransmission such as fluvoxamine (McDougle et al 1990), fluoxetine (Mehlinger et al 1990; Ghaziuddin et al 1991; Hamdan-Allen 1991, Todd 1991; Cook ¢t al 1992), clomipramine (Gordon et al 1992; McDougle ct al 1992), and buspirone (Realmuto et al 1989; Ratey et al 1989) may reduce the problematic social interactive, obsessive-compulsive, and aggressive/impulsive phenomena characteristic of patients with autistic disorder. In light of evidence that a dysregulation in brain 5-HT function may contribute to the pathophysiology of autistic disorder, and that drugs which facilitate 5-HT neurotransmission may improve some of the disabling symptoms of autism, rapid depletion of endogenous 5-HT stores might be expected to alter behavioral indices of 5-HT function in patients with this condition. Dietary tryptophan depletion has been shown to increase pain sensitivity (Lytle et al 1975), acoustic startle (Waiters et al 1979), and muricidal behavior (Gibbons et al 1979) in laboratory- animals. Administration of tryptophan-free amino acid mixtures to vervet monkeys decreases plasma levels of tryptophan and cerebrospinal fluid (CSF) levels of tryptophan and 5-HIAA, with no change in CSF levels of homo,a, fiii~,: acid ~H:.'.'., .;r ,-iaethoxy~-hydroxypbenylethylene glycol (MHPG) (Young et al 1989). The acute depletion of tryptophan, and presumably brain 5-HT, in this autistic patient resulted in an acute worsening of her disorder. It is possible, however, that in addition to affecting 5-HT, acute tryptophan depletion may have affected neuropeptides, second messenger systems, receptor synthesis, or some other nonspecific aspect of brain function. In addition, it is possible that tryptophan depletion a~d the consequent reduction of 5-HT may have altered some balance between 5-HT and other neurotransmitter systems, such as the noradrenergic and dopaminergic systems. Finally, it is clear that changes m c|inica- state following acute tryptophan depletion are not unique to autistic disorder (Delgado et al 1990). Based on the evidence reviewed above, however, it appears that continued investigation into the role of 5-HT in the treatment and pathophysiology of autistic disorder may prove fruitful.
Tryptophan Depletion in Autism
BIOLPSYC~ltATRV 1993;33:547-550
0.4"
-~
03"
549
ShamDepletion Active Depletion
9.2"
,=,
o.1 -O.O
~ ~
-0.1' -0,2
~
-0.3 *0.4
"l
"
H=
I"
I ' 1
= i ' l ' l ' a °
I = 1 " 1
baseline
" 1 " 1
" l ' l ' l "
I ' 1 "
3
I"
| ' 1 " 1 " 1 =
5
I ' 1 " 1 "
I ' 1
"
7
TIME (bourn) Figure 1. Mean results from the Ritvo-Freeman Real-Life Scale.
References American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington DC: American Psychiatric Press. Anderson GM, Freedman DX, Cohen DJ, et ai (1987): Whole blood serotonin in autistic and normal subjects. J Child Psychol Psychiatry 28:885-900. Clomipramine Collaborative Study Group (1991 ): Clomipramine in the treatment of patients with obsessive-compulsive disorder. Arch Gen Psychiatry 48:730-738. Cook EH, Rowlett R, Jaselskis C, Leventhal BL (1992): Fluoxetine treatment of children and adults with autistic disorder and mental retardation. J AM 4cad ChiM Adolesc Psychiatry 31:739-745. Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR (1990): Serotonin function and the mechanism of antidepressant action: Reversal of antidepressant-induced remission by ~pid depletior, of plasma tryptophan. Arch Gen Psychiatry 47:411-418. Fernstrom JD (1977): Effects of the diet on brain neurotransmitters. Metabolism 26:207-223. Freeman BJ, Ritvo ER, Yokota A, Ritvo A (1986): A scale for rating symptoms of patients with the syndrome of autism in real life settings. J Am Acad Child Adolesc Psychiatry 25:130136. Gal EM, Dreses PA (1962): Studies on the metabolism of 5hydroxytryptamine (serotonin), ,~.lw',-...~-,~ . . . . v.r ._j. . .r,,vv.._t,~nhandeficiency in ra:s. Proc Soc Exp Biol Med 110:368-371. Ghaziuddin M, Tsai L, Ghaziuddin N (1991): Fluoxetine in autism with depression (letter). J Am Acad Child Adolesc Psychiatry 30:3.
Gibbons JL, Barr GA, Bridger WH Leibowitz SF (1979): Manipulations of dietary tryptophan: Effects on mouse killing and brain serotonin in the rat. Brain Res 169:139-153. Gordon CT, Rapoport JL, Hamburger SD, State RC, Mannheim GB (1992): Differential response of seven subjects with autistic disorder to clomipramine and desipramine. Am J Psy'chiatry 149:363-366. Hamdan-Allen G (1991): Brief report: Trichotillomania in an autistic male. J Autism Dev Disord 21:79-82. Hoshino Y, Tachibana R, Watanabe M, et al (1984): Serotonin metabolism and hypothalamic-pituitary function in children and infantile autism and minimal brain dysfunction. Jpn J Psychiatry Neurol 26:937-945. Kanne~ L (i943): Autistic disturbances of affective contact. J Nervous Child 2:217-250. Krug DA, Arick JR, Almond PJ (1980): Autism Screening Instrument for Education Planning. Portland, OR: ASIEP Educational Co. Lytle LD, Messing RB, Fisher L, Phebus L (1975): Effects of long-term corn consumption on brain serotonin and the response to electric shock. Science 90:692-694. McBride PA, Anderson GM, Hertzig ME, et al (1989): Se,'otonergic responsivity in male young adults with autistic disorder. Results of a pilot study. Arch Gen Psychiatry 46:213221. McDougle CJ, Price LH, Goodman WK (1990): Fluvoxamine treatment of coincident autistic disorder and obsessive compulsive disorder: A case report. J Autism Dev Disord 20:537543. McDougle CJ, Price LH, Volkmar FR, et al (1992): Clomipra-
550
C,J. McDougle et
BIOL PSYCHIATRY |9~3;33:547- 550
mine in autism: Preliminary evidence of efficacy. J Am Acad Child Adolesc P~,chiatry 31:746-750. McGuire MT, Raleigh MJ (1985): Serotonin-behavior interactions in yet'vet monkeys. Psychopharmacol Bull 21:458--463. Mehlinger R, Scheftner WA, Poznanski E (1990): Fluoxetine and autism (letter). J Am Acad Child Adolesc Psychiatry 29:985. Ratey JJ, Sovner R, Mikkelsen E, Chmielinski HE (1989): Buspirone therapy for maladaptive behavior and anxiety in developmentally disabled persons. J Clin Psychiatry 50:382384. Realmuto GM, August G J, Garlinkel BD (1989): Clinical effect of buspirone in autistic children. J Clin Psychopharmacol 9:122-125. Stanley M, Stanley B (1990): Postmortem evidence for serotonin's role in suicide. J Clin Psychiatry 51 [suppl]:22-28. Todd RD (1991): Fluoxetine in autism (letter). Am J Psychiatry 148:1089.
al
Todd RD, Ciaranello RD (1985): Demonstration of inter- and intraspecies differences in setotonin binding sites by antibodies from an autistic child. Proc NatlAcad Sci USA 82:6 ! 2616. Waiters JK, Davis M, Sheard MH (1979): Tryptophan-free diet: Effects on the acoustic startle reflex in rats. Psychopharmacology 62:103-109. Wechsler D (198 !)" Manual for the Wechsler Adult Intelligence Scale--Revised.San Antonio, TX: The Psychological Cor-
poration. Young SN, Ervin FR, Pihl RO, Finn P (1989): Biochemical aspects of tryptophan depletion in primates. Psychopharmacology 98:508-511. Yuwiler A, Shih JC, Chert C-H (1992): Hyperserotoninemia and antiserotonin antibodies in autism and other disorders. J Autism Dev Disord 22:33--45.
547
CASE REPORT
Acute Tryptophan Depletion in Autistic Disorder: A Controlled Case Study Christopher J. McDougle, Susan T. Naylor, Wayne K. Goodman, Fred R. Volkmar, Donald J. Cohen, and Lawrence H. Price
Introduction Autistic disorder is characterized by a disturbance in social relatedness (Kanner 1943), often accompanied by obsessivecompulsive symptoms, and aggressive/impulsive behavior. A number of lines of evidence suggest that abnormalities in the serotonin (5-hydroxytryptamine [5-HT]) system may contribute to the pathophysiology of autism. Decreased central 5-1-I"1"responsivity has been demonstrated in children (Hoshino et al 1984) and adults (McBride et al 1989) with autistic disorder, as reflected by a decreased prolactin response to L-5-hydroxytryptophan and fenflurarnine, respectively. Elevated whole blood 5-HT levels have been found in 30%-40% of autistic patients studied (Anderson et al 1987). Antibodies dh-ected against 5-HT neurons were identified in the blood and cerebrospinal fluid in 7 of 13 autistic patients in one study (Todd and Ciaranello 1985). A recent investigation, however, found that elevated blood 5-HT in autistic patients was not closely related to inhibition of 5-HT binding by antibody-rich blood fractions (Yuwiler et al 1992). The synthesis of 5-HT is dependent on dietary intake of its precursor, the essential amino acid tryptophan (Gal and Dreses 1962). Data suggest that dietary tryptophan aepletion may specifically reduce brain 5-HT function (Fernstrom 1977). It was recently demonstrated that the combination of a low-tryptophan diet and a tryptophan-free amino acid mixture can rapidly reduce plasma tryptophan levels by up to 80%; this effect was co=eiated with the rapid reversal of the clinical response to antidepressants in recently remitted depressed patients (Delgado et al 1990). Based on evidence indicating a potential dysregulation of 5-HT function in autistic disorder, an adult with autism underwent acute tryptophan depletion with this method.
Fromthe Departmentof Psychiatry.YaleUniversitySchoolof Medicine(CJM, STN, WKG, LHP) and ClinicalNeuroscienceResearchUnit, Connecticut MentalHealthCenter;andYaleChildStudyCenter(FRV,DJC),NewHaven. CT. Addressreprintrequeststo ChristopherJ. McDougle,MD, YaleUniversitySchool of Medicine,ConnecticutMHC,ClinicalNeuroseienceResearchUnit.34 Park St., New Haven,~ 06519. ReceivedAugust8. 1992;revisedJanuary 12, 1993. © 1993Societyof BiologicalPsychiatry
Case Report Ms. A., a 35-year-old woman, presented for treatment because of a life-long inability to relate to other people, a chronic heightened sensitivity to auditory stimuli, persistent interfering obsessional thoughts and preoccupations, and extreme anxiety. She was not demonstrating aggressivity on hospitalization. At the time of admission, Ms. A. met the following DSM-III-R (American Psychiatric Association 1987) criteria for autistic disorder: A. 4,5; B. 2,4,5,6; and C. 2,3,4,5. She had a total score of 95 on the Autism Behavior Checklist (Krug et.al 1980). The patient's father reported that Ms. A. did not speak until the age of 2.5 years, tha~ she demonstrated very poor eye contact throughout childhood and adolescence, that she preferred contact with objects rather than people, and that she resisted being touched or held. Ms A. showed aggressive behaviors such as hitting and biting other people and throwing objects. She was institutionalized between the ages of 10--15 years, lived in a group home until the age of 20, and subsequently moved into her own apartment. Admiss~.on physical examination, routine laboratory tests of blood and urine, and electrocardiogram were normal. Full-scale IQ on the Wechsler Adult Intelligence Scale (WAIS-R) (Wechsier i98i) was 105. Ms A.'s past medical history wag ur~-em~kable and no identifiable etiology of autistic disorder had been found. No significantfamily history of neuropsychiatric disorders was elicited. Mental status examination revealed a short, androgynousappearing woman with increased psychomotor activity who made only momentary eye contact. Speech was monotone and increased in volume. The patient's mood was described as "nervous" and her affect was constricted. Thought processes were ctrcumstantial and, although not psychotic, the patient demonstrated an intense preoccupation with the need to keep "noisy children" off of the unit and to perform her dally routines according to her set schedule. Ms. A.'s intelligence was average and her short- and long-term memory were excellent, but her concentration was impaired. Two weeks following admission, and after signing voluntary written informed consent, Ms. A. was entered into the acute tryptophan depletion study. She was medication-free throughout 0006-3223/93/$06.00
5~l,q
BIOL PSYCHIATRY 1g~)3;33:547-550
C.J. McDougle et al
Table I. Behavioral Response to Active and Sham Acute Tryptophan Depletion
Visual analog scalC Talkative Happy Drowsy Nervous Sad Calm Depressed Anxious Energetic Fearful Mellow High Angry Irritable Tired HungD Agitation Ham-At' Ham-D~ Y-BOCSd CGF
Active depletion (peak change from baseline)
Sham depletion
0 - 50 0 + 14 + 25 - 50 + 64 + 25 0 - 25 0 0 + 50 + 50 - 25 0 + 75 + 11 + II +I "'very. much worse"
- 25 0 0 + 11 0 0 0 - 25 + 25 - 25 0 0 0 0 + 25 0 - 25 - 7 - 4 0 "rainimally improved"
~17-item, lO0-mmscale(rangingfrom0 = "not at all" to 100 = "mostever"). bHamilton Rating Scale for Anxiety. 'Hamilton Rating Scale for Depression. JYale-BrownObsessive CompulsiveScale. "ClinicalGlobalImpressionsScale(7 = "verymuch worse,"4 = "no change," I - "vet,. much improved").
the testing period and had not taken any psychoactive medication during the preceding 15 years. Active tryptophan depletion consisted of a 24-hr, 160 mg/day iow-tryptophan diet with placebo capsules given with each meal, followed the next morning by a tryptophan-free, 15-amino acid drink. Sham testing consisted of a 24-hr, 160 mg/day low-tryptophan diet supplemented with capsules containing 500 mg of tryptophan given with each meal, followed the next morning by a 16-amino acid drink containing 2.3 gs of tryptophan. The patient returned to normal dietary intake at 5 PM on the day of each testing session. The active and sham testing sessions were separated by 7 days and randomized double-blind conditions were maintained throughout. Behavioral ratings were obtained at 15 min before and 3, 5, and 7 hr after the amino acid drink. Plasma for total tryptophan measurement, assayed by high-performance liquid chromatography, was obtained 15 min before and 5 hr after the drink.
Results Changes in behavioral ratings following active and sham tryptophan depletion are shown in Table 1. Active tryptophan depletion in contrast to sham depletion resulted in a marked ex-
acerbation of anxiety, depression, auger, irritability, agitation, and ~rseveration. The patient aid not become physically aggressive. Figure 1 displays mean results from the Ritvo-Freeman Real-Life Scale (Freeman et al 1986), which is specifically designed to measure changes in severity of a variety of behaviors characteristic of autistic disorder. Following active tryptophan depletion, the patient demonstrated a worsening of the symptoms of autism in association with an 88% reduction in total plasma tryptophan level (10.1 I.~ mol/L to 1.2 la. mol/L), in contrast, sham depletion resulted in mild improvement in clinical state, and a 27% increase in total plasma tryptophan level (10.7 ix mol/L to 14.6 Ix reel/L).
Discussion Serotonin function is involved in social interactive (McGuire and Raleigh 1985), obsessive-compulsive (Clomipramine Collaborative Study Group 1991), and aggressive/impulsive phenomena (Stanley and Stanley 1990). Preliminary open-label studies and case reports suggest that drugs which affect 5-HT neurotransmission such as fluvoxamine (McDougle et al 1990), fluoxetine (Mehlinger et al 1990; Ghaziuddin et al 1991; Hamdan-Allen 1991, Todd 1991; Cook ¢t al 1992), clomipramine (Gordon et al 1992; McDougle ct al 1992), and buspirone (Realmuto et al 1989; Ratey et al 1989) may reduce the problematic social interactive, obsessive-compulsive, and aggressive/impulsive phenomena characteristic of patients with autistic disorder. In light of evidence that a dysregulation in brain 5-HT function may contribute to the pathophysiology of autistic disorder, and that drugs which facilitate 5-HT neurotransmission may improve some of the disabling symptoms of autism, rapid depletion of endogenous 5-HT stores might be expected to alter behavioral indices of 5-HT function in patients with this condition. Dietary tryptophan depletion has been shown to increase pain sensitivity (Lytle et al 1975), acoustic startle (Waiters et al 1979), and muricidal behavior (Gibbons et al 1979) in laboratory- animals. Administration of tryptophan-free amino acid mixtures to vervet monkeys decreases plasma levels of tryptophan and cerebrospinal fluid (CSF) levels of tryptophan and 5-HIAA, with no change in CSF levels of homo,a, fiii~,: acid ~H:.'.'., .;r ,-iaethoxy~-hydroxypbenylethylene glycol (MHPG) (Young et al 1989). The acute depletion of tryptophan, and presumably brain 5-HT, in this autistic patient resulted in an acute worsening of her disorder. It is possible, however, that in addition to affecting 5-HT, acute tryptophan depletion may have affected neuropeptides, second messenger systems, receptor synthesis, or some other nonspecific aspect of brain function. In addition, it is possible that tryptophan depletion a~d the consequent reduction of 5-HT may have altered some balance between 5-HT and other neurotransmitter systems, such as the noradrenergic and dopaminergic systems. Finally, it is clear that changes m c|inica- state following acute tryptophan depletion are not unique to autistic disorder (Delgado et al 1990). Based on the evidence reviewed above, however, it appears that continued investigation into the role of 5-HT in the treatment and pathophysiology of autistic disorder may prove fruitful.
Tryptophan Depletion in Autism
BIOLPSYC~ltATRV 1993;33:547-550
0.4"
-~
03"
549
ShamDepletion Active Depletion
9.2"
,=,
o.1 -O.O
~ ~
-0.1' -0,2
~
-0.3 *0.4
"l
"
H=
I"
I ' 1
= i ' l ' l ' a °
I = 1 " 1
baseline
" 1 " 1
" l ' l ' l "
I ' 1 "
3
I"
| ' 1 " 1 " 1 =
5
I ' 1 " 1 "
I ' 1
"
7
TIME (bourn) Figure 1. Mean results from the Ritvo-Freeman Real-Life Scale.
References American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington DC: American Psychiatric Press. Anderson GM, Freedman DX, Cohen DJ, et ai (1987): Whole blood serotonin in autistic and normal subjects. J Child Psychol Psychiatry 28:885-900. Clomipramine Collaborative Study Group (1991 ): Clomipramine in the treatment of patients with obsessive-compulsive disorder. Arch Gen Psychiatry 48:730-738. Cook EH, Rowlett R, Jaselskis C, Leventhal BL (1992): Fluoxetine treatment of children and adults with autistic disorder and mental retardation. J AM 4cad ChiM Adolesc Psychiatry 31:739-745. Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR (1990): Serotonin function and the mechanism of antidepressant action: Reversal of antidepressant-induced remission by ~pid depletior, of plasma tryptophan. Arch Gen Psychiatry 47:411-418. Fernstrom JD (1977): Effects of the diet on brain neurotransmitters. Metabolism 26:207-223. Freeman BJ, Ritvo ER, Yokota A, Ritvo A (1986): A scale for rating symptoms of patients with the syndrome of autism in real life settings. J Am Acad Child Adolesc Psychiatry 25:130136. Gal EM, Dreses PA (1962): Studies on the metabolism of 5hydroxytryptamine (serotonin), ,~.lw',-...~-,~ . . . . v.r ._j. . .r,,vv.._t,~nhandeficiency in ra:s. Proc Soc Exp Biol Med 110:368-371. Ghaziuddin M, Tsai L, Ghaziuddin N (1991): Fluoxetine in autism with depression (letter). J Am Acad Child Adolesc Psychiatry 30:3.
Gibbons JL, Barr GA, Bridger WH Leibowitz SF (1979): Manipulations of dietary tryptophan: Effects on mouse killing and brain serotonin in the rat. Brain Res 169:139-153. Gordon CT, Rapoport JL, Hamburger SD, State RC, Mannheim GB (1992): Differential response of seven subjects with autistic disorder to clomipramine and desipramine. Am J Psy'chiatry 149:363-366. Hamdan-Allen G (1991): Brief report: Trichotillomania in an autistic male. J Autism Dev Disord 21:79-82. Hoshino Y, Tachibana R, Watanabe M, et al (1984): Serotonin metabolism and hypothalamic-pituitary function in children and infantile autism and minimal brain dysfunction. Jpn J Psychiatry Neurol 26:937-945. Kanne~ L (i943): Autistic disturbances of affective contact. J Nervous Child 2:217-250. Krug DA, Arick JR, Almond PJ (1980): Autism Screening Instrument for Education Planning. Portland, OR: ASIEP Educational Co. Lytle LD, Messing RB, Fisher L, Phebus L (1975): Effects of long-term corn consumption on brain serotonin and the response to electric shock. Science 90:692-694. McBride PA, Anderson GM, Hertzig ME, et al (1989): Se,'otonergic responsivity in male young adults with autistic disorder. Results of a pilot study. Arch Gen Psychiatry 46:213221. McDougle CJ, Price LH, Goodman WK (1990): Fluvoxamine treatment of coincident autistic disorder and obsessive compulsive disorder: A case report. J Autism Dev Disord 20:537543. McDougle CJ, Price LH, Volkmar FR, et al (1992): Clomipra-
550
C,J. McDougle et
BIOL PSYCHIATRY |9~3;33:547- 550
mine in autism: Preliminary evidence of efficacy. J Am Acad Child Adolesc P~,chiatry 31:746-750. McGuire MT, Raleigh MJ (1985): Serotonin-behavior interactions in yet'vet monkeys. Psychopharmacol Bull 21:458--463. Mehlinger R, Scheftner WA, Poznanski E (1990): Fluoxetine and autism (letter). J Am Acad Child Adolesc Psychiatry 29:985. Ratey JJ, Sovner R, Mikkelsen E, Chmielinski HE (1989): Buspirone therapy for maladaptive behavior and anxiety in developmentally disabled persons. J Clin Psychiatry 50:382384. Realmuto GM, August G J, Garlinkel BD (1989): Clinical effect of buspirone in autistic children. J Clin Psychopharmacol 9:122-125. Stanley M, Stanley B (1990): Postmortem evidence for serotonin's role in suicide. J Clin Psychiatry 51 [suppl]:22-28. Todd RD (1991): Fluoxetine in autism (letter). Am J Psychiatry 148:1089.
al
Todd RD, Ciaranello RD (1985): Demonstration of inter- and intraspecies differences in setotonin binding sites by antibodies from an autistic child. Proc NatlAcad Sci USA 82:6 ! 2616. Waiters JK, Davis M, Sheard MH (1979): Tryptophan-free diet: Effects on the acoustic startle reflex in rats. Psychopharmacology 62:103-109. Wechsler D (198 !)" Manual for the Wechsler Adult Intelligence Scale--Revised.San Antonio, TX: The Psychological Cor-
poration. Young SN, Ervin FR, Pihl RO, Finn P (1989): Biochemical aspects of tryptophan depletion in primates. Psychopharmacology 98:508-511. Yuwiler A, Shih JC, Chert C-H (1992): Hyperserotoninemia and antiserotonin antibodies in autism and other disorders. J Autism Dev Disord 22:33--45.