738
BIOL PSYCHIATRY 1991 ;29:738-744
Whole Blood Serotonin in Juvenile Obsessive-Compulsive Disorder Gregory L. Hanna, Arthur Yuwiler, and Dennis P. Cantwell
Whole blood serotonin (5-HT) concentration was assessed in 16 children and adolescents with severe obsessive--compulsive disorder (OCD) and in 14 normal adolescent controls. There was no difference in blood 5-HT content between the OCD patients and the normal controls. However, the OCD patients with a family history of OCD had significantly higher blood 5-HT levels than did either the OCD patients without a family history of OCD or the normal controls. Blood 5-HT content was not associated with a history of major depressive disorder or chronic tic disorder. These preliminary results suggest that studies of serotonergic ~nctioning in OCD may need to control for family history of OCD and that blood 5-HT may be a useful biochemical measure in family-genetic studies of OCO.
Introduction Obsessive-compulsive disorder (OCD) is one of the more chronic and prevalent conditions in psychiatry (Goodwin et al 1969; Karno et al 1988). It appears to be similar in children and adults in its clinical presentation and response to pharmacological treatment (Rapoport 1986; Flament et al 1985; Leonard et al 1989). The therapeutic response to serotonergic antidepressants has sugge3ted that a serotonergic dysfunction is involved in the pathophysiology of OCD, but this response does not necessarily implicate a primary serotonergic abnormality in OCD (Murphy et al 1989). Few studies of OCD have measured serotonin (5-hydroxytryptamine, 5-HT) in blood platelets or 5-hydroxyindoleacetic acid (5-HIAA), the principal 5-HT metabolite in cerebrcspinal fluid (CSF). Yuryura-Tobias et al (1977) reported that whole blood 5-HT concentrations were significantly lower in OCD patients than in normal controls. In contrast, Ha,neat et a! (1987) found no difference between juvenile OCD patients and normal controls in platelet 5-HT levels. They found a significant negative correlation, however, between platelet 5HI" content and severity of obsessive-compulsive symptoms, lnsel et al (1985) reported that CSF 5-HIAA levels were significantly higher in 8 OCD patients than in 23 controls. ...I~ tuu~.,,...12rger "''~,e~mnioc ~'"r .h.~. .,.u. ~. .,., ~ r , O.~r~ tnntionte ~ n d n n r m ~ l ~-nntro! s did n n t d l f f p r in ~...~..
5-HIAA levels (Thoren et al 1980; Lydiard et al 1990).
From the Department of Psychiatry and Biobehavioral Sciences, School of Medicine, U:.iversity of California at Los Angeles (GLH, AY, DPC) and the Neurobiochemistry Laboratory, Brentwood Division, West Los Angeles Veterans Administration Medical Center, Los Angeles, CA (AY). Address reprint requests to Dr. Gregory L. Hanna, UCLA Neuropsychiatric Institute, 760 Westwood Plaza, LOs Angeles, CA 90024. Received July 20, 1990; revised November 13, 1990. © 1991 Society of Biological Psychiatry
0006-3223/91/$03.50
Serotonin in Juvenile OCD
nIOLps¥cmA'm¥ 1991:29:73~-'M4
739
The discrepancies in these findings led us to compare whole blood 5-HT c o n c e n ~ o n s in juvenile OCD patients and normal controls, and to examine the clinical correlates of the 5-HT levels in the OCD patients.
Methods The sample consisted of 16 patients with severe OCD (11 boys and 5 girls) and 14 normal controls (10 boys and 4 girls). The age range was 9-17 years for the patients and 1317 years for the controls. The patients were evaluated and treated as outpatients at U C ~ NPI between 1987 and 1989. In addition to an unstructured clinical interview, all patients and at least 1 of each patient's parents were interviewed with the Diagnostic Interview for Children and Adolescents (DICA-C and DICA-P) (Welner et al 1987). The controls were healthy volunteers recruited through newspaper advertisements for a study of adolescent depression during the same period of time. All controls and at least 1 of each subject's parents were interviewed with the Schedule for Affective Disorders and Schizophrenia for School-Age Children, Epidemiologic Version (K-SADS-E) (Orvaschel and Puig-Antich 1987). The patients met DSM-III-R criteria for OCD (American Psychiatric Association 1987) and had at least a l-year history of obsessive-compulsive symptoms. Other inclusion criteria were a NIMH global obsessive-compulsive scale score (GOCS) of ~>7 (Murphy et al 1982), a 16-item children's Yale-Brown obsessive-compulsive scale score (CYBOCS) of I>16 (Goodman et al 1989a, 1989b), and a 17-item Hamilton depression rating scale score (HDRS) of ~ 16 (Hamilton 1967). Exclusion criteria included major medical illness, mental retardation, organic mental disorder, pervasive development~ disorder, schizophrenia or other psychoses, schizotypal personality disorder, bipolar disorder, primary major depression, panic disorder, agoraphobia, eating disorder, and suicidal behavior. None of the subjects had received any medications for at least 2 weeks prior to clinical assessment and blood s :unpling. During the clinical interview, the parents of the OCD patients were interviewed re. . . , ~`~ . . . . . . -,-r o~=,essions, compulsions, and tics in all firstgarding the c u ~ n t and e,~, ,,,~,,,,J degree and second-degree relatives of the patients. OCD was diagnosed only if obsessions or compulsions resulted in distress and impairment of occupational or social functioning. If obsessive-compulsive symptoms were described that did not cause marked distress and significant interference with occupational or social functioning, the diagnosis of obsessivecompulsive symptoms (OCS) was made. Blood from each subject was collected by venipuncture with a 21-gauge needle into a plastic syringe between 8 AM and 4 e i . The blood was immediately transferred to an EDTA blood collection tube which was gently inverted and placed in ice. The sample was then stored in a plastic tube at - 8 0 ° C until the time of batch assay. Blood 5-HT concentration was determined with the fluorometric procedure of Yuwiler et al (1970). All samples were run in duplicate on 0.7--0.9 ml of whole blood. Assays were performed blind to proband status -and family history. The intraassay coefficient of variation was 1.7%, and the interassay coefficient of variation was 1.8%. Blood 5-HT levels for a single individual in childhood or adolescence are constant over several months, and are not affected by ordinary changes in diet (Ritvo et al 1970; Badcock et al 1987). Even when subjects are acutely loaded with tryptophan, the precursor of 5-HT, changes in blood 5-HT are transient and return to baseline levels within 8 hr (Yuwiler et al 1981). Consequently, diet was not controlled. Prior work has shown that
740
G.L. Hanna et al
BIOL PSYCHL~~'RY 1991;29:738-744
Table 1. Clinical and Biochemical Characteristics of OCD Patients and Normal Control Subjects
Age, yr (mean) Male (%) Whole blood serotonin, I~g/ml (mean) Age at onset, yr (mean) CY-BOCS score (mean) NIMH GOCS score (mean) HDRS score (mean) History of pharmacotherapy (%) History of behavior therapy (%)
Familial OCD (n = 6)
Sporadic OCD (n = 10)
Normal controls (n = 14)
14.8 100 0.201 11.0 25.2 9.5 4.0 5n 16.7
13.2 50 O. 122 10.2 26.3 9.5 3.9 5~ 20.0
15.0 71.4 0.151
there is no significant diurnal variation in blood 5-HT content (Tuldainen 1981; Kremer et al 1990). Differenee~ ~tween groups were tested with either one-way ~,..a,,o~ of v~riance (ANOVA) or Student's t-test. Pearson product-moment ¢orrelation coefficients were computed between clinical severity ratings and whole blood 5-HT concentrations. All probability values reported are two-tailed. .
.
.
.
.
.
. . . .
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7
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. . . .
Results Table 1 summarizes the demographic, clinical, and bioch*.mical characteristics of the OCD patients and the n o d a l control subjects. Six male patients had a family history of OCD or OCS so that fandlial OCD was confined exclusively to male proba~ds rather than randomly distributed between the sexes. Two patients had 2 first-degree relatives with OCD, and 2 had 1 first-degree relative with OCD. One patient had a second-de~ee ielative with OCD, and 1 patient had a first-degre~e relative with OCS. The sporadic OCD group consisted of 5 male and 5 female OCD patients. Five patients formed a TS/OCD group which was contrasted with the OCD group without a personal or family history of chronic tic disorder (Pauls et al 1986). Two male patients had Tourette's syndrome (TS), and 1 female patient had a past history of TS. These 3 patients had had obvious, but relatively infrequent, motor and vocal tics which had not been treated. One male patient had a first-degree relative with TS, and 1 female patient had a first-degree relative with chronic motor tic disorder. The OCD patients were somewhat younger than the normal controls in mean age (13.8 ± 2.4 versus 15.0 ± 1.2 years, t = 1.74, df = 28, p = 0.09). The two groups did not differ with respect to gender. Blood 5-HT concentrations were not related to age, gender, or time of blood sampling in either group. Blood 5-HT levels in the OCD patients were not associated with age at onset, duration or severity of OCS, severity of depressive symptoms, or history of major depressive disorder or chronic tic disorder. The overall difference in mean whole blood 5-HT concentrations between the OCD patients and the normal controls was not statistically significant (0.151 _ 0.063 versus 0.151 ± 0.045 I.~g/ml). However, when the OCD patients were divided according to family history of OCD or OCS, the blood 5-HT levels in the resultant groups were significantly different (F = 5.01, p < 0.02). The familial OCD patients had significantly
toOL~ ¥ ~ T R Y
S e m t o n i n in Juvenile O C D
741
1991 ;29:'738-?44
.300
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Figure I Whole blood serotonin in familial OCD patients, sporadic OCD patients, and normal controis. Male subjects (0); female su~ects (©); the mean ( ).
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| Fomiliol OCD
~_1 I
I Sporodic OCD
L I'4ormo! Controls
higher 5-HT levels than did either the sporadic OCD patients (0.201 + 0 . ~ versus 0.122 + 0.056 p.g/ml, t = 3.00, p < 0.01) or the normal controls (0.201 + 0.040 versus 0.151 + 0.045 p.g/ml, t = 2.32, p < 0.05). There was no overlap in blood 5HT levels between the males with familial OCD and those with sporadic OCD. In addition, there were no detectable differences between the familial OCD patients and the sporadic OCD patients in age, age at onset, duration or severity of OCS, severity of depressive symptoms, history of major depressive disorder or chronic tic disorder, treatment history, or time of blood sampling. Finally, there were no differences in 5-HT levels among the TS/OCS patiemo, the OCD patients without a h~,ory of chronic tic disorder, and the normal controls (Figure l).
Discussion These findings are preliminary and consequently, should be interpreted with caution. The sample size was small, especially for those with familial OCD, so that the possibility of sampling error exists. The normal controls were not age matched. The family history method, rather than blind direct family interviews, was used to ascertain a family history of obsessions, compulsions, and tics. Diet and time of sampfing were not rigorously controlled. Only male OCD patients in this sample had a family history of OCD, with 37.5% of the total OCD sample (55% of the male sample) having a positive family history. A previous study of a larger sample of juveniles with OCD found that 30% had at least I first-degree relative with OCD and that the majority of the probands with a positive family history were male (Swedo et al 1989; Lenane et al 1990). Thus, it appears that the prevalence of ~CD in parents of children with OCD is considerably higher than the
742
BIOLPSYCHIATRY 1991;29:738-744
G.L. Hanna et al
lifetime prevalence rate of 2% to 3% found in the Epidemiologic Catchment Area study (Karno et al 1988). These figures suggest that an, e~iy onset of OCD may be associated with increased f~,~,iliai aggregation. This finding requires replication with a controlled family study that directly and blindly interviews all first-degree relatives with appropriate structured interviews. The similarity in the mean whole blood 5-HT concentrations in the OCD patients and the normal controls is consistent with the report on platelet 5-HT in juveniles with OCD (Flament et al 1987), but is contrary to the report on blood 5-14"1"in adults with OCD (Yuryura-Tobias et al 1977). Blood 5-HT declines with age to stable adult levels by age 12 and the slope from ages 10 to 12 is shallow (Ritvo et al 1971). Two of the 5 0 C D patients under age 13 had a family history of OCD. However, their blood 5-HT levels were not appreciably higher than those of the 4 familial OCD patients over age 13 and do not account for the significant difference between the familial and sporadic OCD patients. A personal or family history of chronic tic disorder in the OCD patients was not associated with abnornaal blood 5-HT levels. This is consistent with a previous study which found no difference between TS patients and normal controls in mean blood 5HT levels (Leckman et al 1984). It is possible that significant differences in 5-HT metabolism between children and adults with OCD may account for some of the discrepant reports in the literature on blood 5-HT, platelet 5-HT, and CSF 5-HIAA. In addition, if serotonergic activity differs between familial and sporadic OCD patients, it is plausible that some of these discrepancies may derive from the proportion of familial and sporadic OCD cases in the various OCD samples. Finally, the reports of low blood 5-HT levels (Yuryura-Tobias et al 1977) and high CSF 5-HIAA levels (lnsel et al 1985) in adults with OCD may be consistent. Dominance and aggression in monkeys are associated with high blood 5-HT levels (Raleigh et al 1984) but low CSF 5-HIAA levels (Yodyingyuad et al 1985). High blood 5HT levels in autistic adults has been associated with low central 5-HT activity (McBride et al 1989). However, the relationship of blood 5-HT to central serotonergic activity remains undetermined. The preliminary finding of increased blood 5-HT concentration in familial OCD requires replication in a larger sample in which diet and the timing of the blood samples are standardized, the OCD and normal control groups are more closely matched on age and gender, and family history is obtained in the manner described above. A larger sample should also include females with familial OCD. This finding raises the possibility that studies of serotonergic functioning in OCD may need to control for family history of GCD and that, conversely, whole blood 5-HT may be a useful biochemical measure in family-genetic studies of OCD. Supported in part through a grant from Ciba-GeigyPharmaceuticals, Inc.
References American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington: APA. Badcock NR, Spence JG, Stern LM (1987): Blood serotonin levels in adults, autistic and nonautistic child~er~--with a comparison of different methodologies. Ann Clin Biochem 24:625-634.
Serotonin in Juvenile OCD
BlOt. PSYCHIATRY" 1991;29:'/38-744
7~3
Flament MF, Rapoport JL, Berg CB, et al (I 985): Clomipramine treatment of c h i l ~ ~sessivecompulsive disorder: A double-blind controlled study. Arch Gen Psychiawy 42:977-983. Flament MF, Rapoport JL, Murphy DL, Berg CB, Lake CR (1987): Biochemical changes during clomipramine treatment of childhood obsessive-compulsive disorder. Arch Gen P~,chiany 44:219-:. 225. Goodman WK, Price LH, Rasmussen SA, et al (1989a): The Yale-Brown Obsessive Comp~sive Scale I: Development, use, reliability. Arch Gen Psychiatry 46:1006-1011. Goodman WK, Price LH, Rasmussen SA, et al ¢19~9b): The Yale-Brown Obsessive Compulsive Scale II. Validity. Arch Gen Psychiatry 46:1012-1~!6~ Goodwin DW, Guze SB, Robins E (1969): Follow-up studies in obsessional neurosis. Arch Gen Psychiatry 20:182-187. Hamilton M (1967): Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 6:278-296. Insel TR, Mueller EA III, Alterman I, Linnoila M, Murphy DL (1985): Obsessive-compulsive disorder and serotonin: Is there a connection? Biol Psychiatry 20:1174-1188. Kamo M, Golding IM, Sorenson SB, Burnam MA (1988): The epidemiology of obsessive-compulsive disorder in five U.S. communities. Arch Gen Psychiatry 45:1094-1099. Kremer HPH, Goekoop JG, Van Kempen GMJ (1990): Clinical use of the determination of serotomn in whole blood. J Clin Psychopharmacol 10:83-87. Leckman JF, Anderson GM, Cohen DJ, et al (1984): Whole blood serotonin and tryptophan levels in Tourette's disorder: Effects of acute and chronic clonidine treatment. Life Sci 35:2497-2503. Lenane MC, Swedo SE, Leonard H, Pauls DL, Sceery W, Rapoport JL (1990): Psychiatric disorders in first-degree relatives of children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 3:407-412. Leonard HL, Swedo SE, Rapoport JL, et al (1989): Treatment of obsessive-compulsive disorder with clomipramine and desipramine in children and adolescents: A double-blind crossover comparison. Arch Gen Psychiatry 46:1088-1092. Lydiard RB, B~llenger JC, Ellinwood EH, Laraia MT, Austin LS, Fossey MD (1990): CSF monoamine ~etabolites in obsessive-compulsive disorder. Presented at the American Psychiatric Association, May 15, New York, NY. McBride PA, ,~xtderson GM, Hertzig ME, et al (1989): Serotonergic responsivity in male young adults with ~utistic disorder. Arch Gen Psychia~y 46:213-221. Murphy DL, Pickar D, Alterman IS (1982): Methods for the quantitative assessment of depressive and manic behavior. In Burdock El, Sudilovski A, Gershon S (eds), The Behavior of Psychiatric Patients. New York: Marcel Dekker Inc, pp 351-391. Murphy DL, Zohar J, Benkelfat C, Pato MT, Pigott TA, Insel TR (1989): Obsessive-compulsive u*~sorder as a 5-HT subsystem-related behavioural disorder. Br J Psychiatry 155:15-24. Orvaschel H, Puig-Antich J (1987): Schedule for Affective Disorders and Schizophrenia for SchoolAge Children, Epidemiologic Version. Pittsburgh: Western Psychiatric Institute and Clinics. Pauls DL, Towbin KE, Leckman JF, Zalmer GEP, Cohen DJ (1986): Gilles de la Tourette's syndrome and obsessive-compulsive disorder. Arch Gen Psychiatry 43:! !80-I 182. Raleigh MJ, Brammer GL, McGuire MT, Yuwiler A (!984): Dominant social status facilitates the behavioral effects of serotonergic agonists. Brain Res 348:274-281. Rapoport JL (1986): Annotation: Childhood obsessive-compulsive disorder. J Child Psychol Psychiatry 27:289-295. Ritvo ER, Y-,~,i!er A~ Geller E (1970): Increased blood serotonin and platelets in early infantile autism. Arch Gen Psychiatry 23:566-572. Ritvo ER, Yuwiler A, Geller E, Plotkin S, Mason A, Saegar K (1971): Maturational changes in blood serotonin levels and platelet counts. Biochem Med 5:90-96. Swedo SE, Rapoport JL, Leonard H, Lenane M, Cheslow D (1989): Obsessive-compulsive disorder in children and adolescents. Arch Gen Psychiatry 46:335-341.
744
BIOLPSYCHIATRY 199 i ;29:738-744
G.L. Hanna et al
Thoren P, Asberg M, Bertilsson L, Mellstrom B, Sjogvist F, Traskman L (1980): Clomipramine treatment of obsessive-compulsive disorder. 11: Biochemical aspects. Arch Gen Psychiatry 37:12891294. Tukiainen E (1981): Effect of hypophysectomy and adrenalectomy on 5-hydmxycyptamine uptake by rat hypothalamic synaptosomes and blood platelets. Acta Pharmacol Toxico148:139-144. Welner Z, Rich W, Herjanic B, Jung K, Amado H (1987): Reliability, validity and child agreement studies of the Diagnostic Interview for Children and Adolescents (DICA). J Am Acad Child Adolesc Psychiatry 26:649-653. Yodyingy~ad U, De laRiva DH, Herbert J, Keveme EB (1985): Relationship between dominance hierarchy, cerebrospina] fluid Ic'~'~Is of ~,-',Ane~.tr~n~mittermetabofites (5-hydroxyindole acetic acid and homovanillic acid) and plasma cortisoi in monkeys. Neuroscience 16:851-858. Yuryura-Tobias JA, Bebirian RJ, Neziroglu FA, Bhagavan I-iN (1977): Obsessive-compulsive disorders as a serotonergic defect. Res Commun Psychol Psychiatry Behav 2:279-286. Yuwiler A, Plotkin S, Geller F~ Ritvo ER (1970): A rapid accurate procedure for the determination of serotonin in whole h u ~ , bi~-~,~.~.ochem Med 3:426--436. Yuwiler A, Brammer GL, Morley JE, Raleigh MJ, Flannery JW, Geller E (1981): Short-term and repetitive administration of oral wyptophan in normal men. Arch Gen Psychiatry 38:619-626.
BIOL PSYCHIATRY 1991 ;29:738-744
Whole Blood Serotonin in Juvenile Obsessive-Compulsive Disorder Gregory L. Hanna, Arthur Yuwiler, and Dennis P. Cantwell
Whole blood serotonin (5-HT) concentration was assessed in 16 children and adolescents with severe obsessive--compulsive disorder (OCD) and in 14 normal adolescent controls. There was no difference in blood 5-HT content between the OCD patients and the normal controls. However, the OCD patients with a family history of OCD had significantly higher blood 5-HT levels than did either the OCD patients without a family history of OCD or the normal controls. Blood 5-HT content was not associated with a history of major depressive disorder or chronic tic disorder. These preliminary results suggest that studies of serotonergic ~nctioning in OCD may need to control for family history of OCD and that blood 5-HT may be a useful biochemical measure in family-genetic studies of OCO.
Introduction Obsessive-compulsive disorder (OCD) is one of the more chronic and prevalent conditions in psychiatry (Goodwin et al 1969; Karno et al 1988). It appears to be similar in children and adults in its clinical presentation and response to pharmacological treatment (Rapoport 1986; Flament et al 1985; Leonard et al 1989). The therapeutic response to serotonergic antidepressants has sugge3ted that a serotonergic dysfunction is involved in the pathophysiology of OCD, but this response does not necessarily implicate a primary serotonergic abnormality in OCD (Murphy et al 1989). Few studies of OCD have measured serotonin (5-hydroxytryptamine, 5-HT) in blood platelets or 5-hydroxyindoleacetic acid (5-HIAA), the principal 5-HT metabolite in cerebrcspinal fluid (CSF). Yuryura-Tobias et al (1977) reported that whole blood 5-HT concentrations were significantly lower in OCD patients than in normal controls. In contrast, Ha,neat et a! (1987) found no difference between juvenile OCD patients and normal controls in platelet 5-HT levels. They found a significant negative correlation, however, between platelet 5HI" content and severity of obsessive-compulsive symptoms, lnsel et al (1985) reported that CSF 5-HIAA levels were significantly higher in 8 OCD patients than in 23 controls. ...I~ tuu~.,,...12rger "''~,e~mnioc ~'"r .h.~. .,.u. ~. .,., ~ r , O.~r~ tnntionte ~ n d n n r m ~ l ~-nntro! s did n n t d l f f p r in ~...~..
5-HIAA levels (Thoren et al 1980; Lydiard et al 1990).
From the Department of Psychiatry and Biobehavioral Sciences, School of Medicine, U:.iversity of California at Los Angeles (GLH, AY, DPC) and the Neurobiochemistry Laboratory, Brentwood Division, West Los Angeles Veterans Administration Medical Center, Los Angeles, CA (AY). Address reprint requests to Dr. Gregory L. Hanna, UCLA Neuropsychiatric Institute, 760 Westwood Plaza, LOs Angeles, CA 90024. Received July 20, 1990; revised November 13, 1990. © 1991 Society of Biological Psychiatry
0006-3223/91/$03.50
Serotonin in Juvenile OCD
nIOLps¥cmA'm¥ 1991:29:73~-'M4
739
The discrepancies in these findings led us to compare whole blood 5-HT c o n c e n ~ o n s in juvenile OCD patients and normal controls, and to examine the clinical correlates of the 5-HT levels in the OCD patients.
Methods The sample consisted of 16 patients with severe OCD (11 boys and 5 girls) and 14 normal controls (10 boys and 4 girls). The age range was 9-17 years for the patients and 1317 years for the controls. The patients were evaluated and treated as outpatients at U C ~ NPI between 1987 and 1989. In addition to an unstructured clinical interview, all patients and at least 1 of each patient's parents were interviewed with the Diagnostic Interview for Children and Adolescents (DICA-C and DICA-P) (Welner et al 1987). The controls were healthy volunteers recruited through newspaper advertisements for a study of adolescent depression during the same period of time. All controls and at least 1 of each subject's parents were interviewed with the Schedule for Affective Disorders and Schizophrenia for School-Age Children, Epidemiologic Version (K-SADS-E) (Orvaschel and Puig-Antich 1987). The patients met DSM-III-R criteria for OCD (American Psychiatric Association 1987) and had at least a l-year history of obsessive-compulsive symptoms. Other inclusion criteria were a NIMH global obsessive-compulsive scale score (GOCS) of ~>7 (Murphy et al 1982), a 16-item children's Yale-Brown obsessive-compulsive scale score (CYBOCS) of I>16 (Goodman et al 1989a, 1989b), and a 17-item Hamilton depression rating scale score (HDRS) of ~ 16 (Hamilton 1967). Exclusion criteria included major medical illness, mental retardation, organic mental disorder, pervasive development~ disorder, schizophrenia or other psychoses, schizotypal personality disorder, bipolar disorder, primary major depression, panic disorder, agoraphobia, eating disorder, and suicidal behavior. None of the subjects had received any medications for at least 2 weeks prior to clinical assessment and blood s :unpling. During the clinical interview, the parents of the OCD patients were interviewed re. . . , ~`~ . . . . . . -,-r o~=,essions, compulsions, and tics in all firstgarding the c u ~ n t and e,~, ,,,~,,,,J degree and second-degree relatives of the patients. OCD was diagnosed only if obsessions or compulsions resulted in distress and impairment of occupational or social functioning. If obsessive-compulsive symptoms were described that did not cause marked distress and significant interference with occupational or social functioning, the diagnosis of obsessivecompulsive symptoms (OCS) was made. Blood from each subject was collected by venipuncture with a 21-gauge needle into a plastic syringe between 8 AM and 4 e i . The blood was immediately transferred to an EDTA blood collection tube which was gently inverted and placed in ice. The sample was then stored in a plastic tube at - 8 0 ° C until the time of batch assay. Blood 5-HT concentration was determined with the fluorometric procedure of Yuwiler et al (1970). All samples were run in duplicate on 0.7--0.9 ml of whole blood. Assays were performed blind to proband status -and family history. The intraassay coefficient of variation was 1.7%, and the interassay coefficient of variation was 1.8%. Blood 5-HT levels for a single individual in childhood or adolescence are constant over several months, and are not affected by ordinary changes in diet (Ritvo et al 1970; Badcock et al 1987). Even when subjects are acutely loaded with tryptophan, the precursor of 5-HT, changes in blood 5-HT are transient and return to baseline levels within 8 hr (Yuwiler et al 1981). Consequently, diet was not controlled. Prior work has shown that
740
G.L. Hanna et al
BIOL PSYCHL~~'RY 1991;29:738-744
Table 1. Clinical and Biochemical Characteristics of OCD Patients and Normal Control Subjects
Age, yr (mean) Male (%) Whole blood serotonin, I~g/ml (mean) Age at onset, yr (mean) CY-BOCS score (mean) NIMH GOCS score (mean) HDRS score (mean) History of pharmacotherapy (%) History of behavior therapy (%)
Familial OCD (n = 6)
Sporadic OCD (n = 10)
Normal controls (n = 14)
14.8 100 0.201 11.0 25.2 9.5 4.0 5n 16.7
13.2 50 O. 122 10.2 26.3 9.5 3.9 5~ 20.0
15.0 71.4 0.151
there is no significant diurnal variation in blood 5-HT content (Tuldainen 1981; Kremer et al 1990). Differenee~ ~tween groups were tested with either one-way ~,..a,,o~ of v~riance (ANOVA) or Student's t-test. Pearson product-moment ¢orrelation coefficients were computed between clinical severity ratings and whole blood 5-HT concentrations. All probability values reported are two-tailed. .
.
.
.
.
.
. . . .
~glt|Qdt
7
~Jt~
~
. . . .
Results Table 1 summarizes the demographic, clinical, and bioch*.mical characteristics of the OCD patients and the n o d a l control subjects. Six male patients had a family history of OCD or OCS so that fandlial OCD was confined exclusively to male proba~ds rather than randomly distributed between the sexes. Two patients had 2 first-degree relatives with OCD, and 2 had 1 first-degree relative with OCD. One patient had a second-de~ee ielative with OCD, and 1 patient had a first-degre~e relative with OCS. The sporadic OCD group consisted of 5 male and 5 female OCD patients. Five patients formed a TS/OCD group which was contrasted with the OCD group without a personal or family history of chronic tic disorder (Pauls et al 1986). Two male patients had Tourette's syndrome (TS), and 1 female patient had a past history of TS. These 3 patients had had obvious, but relatively infrequent, motor and vocal tics which had not been treated. One male patient had a first-degree relative with TS, and 1 female patient had a first-degree relative with chronic motor tic disorder. The OCD patients were somewhat younger than the normal controls in mean age (13.8 ± 2.4 versus 15.0 ± 1.2 years, t = 1.74, df = 28, p = 0.09). The two groups did not differ with respect to gender. Blood 5-HT concentrations were not related to age, gender, or time of blood sampling in either group. Blood 5-HT levels in the OCD patients were not associated with age at onset, duration or severity of OCS, severity of depressive symptoms, or history of major depressive disorder or chronic tic disorder. The overall difference in mean whole blood 5-HT concentrations between the OCD patients and the normal controls was not statistically significant (0.151 _ 0.063 versus 0.151 ± 0.045 I.~g/ml). However, when the OCD patients were divided according to family history of OCD or OCS, the blood 5-HT levels in the resultant groups were significantly different (F = 5.01, p < 0.02). The familial OCD patients had significantly
toOL~ ¥ ~ T R Y
S e m t o n i n in Juvenile O C D
741
1991 ;29:'738-?44
.300
.25C E
o
o
v
z z 0 p. 0 t~ to t~ r~ 0 0 _J tD
.200
®
$
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.150
8 8 $
o • 100
Figure I Whole blood serotonin in familial OCD patients, sporadic OCD patients, and normal controis. Male subjects (0); female su~ects (©); the mean ( ).
o
L0 ..J 0 "r
o o o
.050
| Fomiliol OCD
~_1 I
I Sporodic OCD
L I'4ormo! Controls
higher 5-HT levels than did either the sporadic OCD patients (0.201 + 0 . ~ versus 0.122 + 0.056 p.g/ml, t = 3.00, p < 0.01) or the normal controls (0.201 + 0.040 versus 0.151 + 0.045 p.g/ml, t = 2.32, p < 0.05). There was no overlap in blood 5HT levels between the males with familial OCD and those with sporadic OCD. In addition, there were no detectable differences between the familial OCD patients and the sporadic OCD patients in age, age at onset, duration or severity of OCS, severity of depressive symptoms, history of major depressive disorder or chronic tic disorder, treatment history, or time of blood sampling. Finally, there were no differences in 5-HT levels among the TS/OCS patiemo, the OCD patients without a h~,ory of chronic tic disorder, and the normal controls (Figure l).
Discussion These findings are preliminary and consequently, should be interpreted with caution. The sample size was small, especially for those with familial OCD, so that the possibility of sampling error exists. The normal controls were not age matched. The family history method, rather than blind direct family interviews, was used to ascertain a family history of obsessions, compulsions, and tics. Diet and time of sampfing were not rigorously controlled. Only male OCD patients in this sample had a family history of OCD, with 37.5% of the total OCD sample (55% of the male sample) having a positive family history. A previous study of a larger sample of juveniles with OCD found that 30% had at least I first-degree relative with OCD and that the majority of the probands with a positive family history were male (Swedo et al 1989; Lenane et al 1990). Thus, it appears that the prevalence of ~CD in parents of children with OCD is considerably higher than the
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G.L. Hanna et al
lifetime prevalence rate of 2% to 3% found in the Epidemiologic Catchment Area study (Karno et al 1988). These figures suggest that an, e~iy onset of OCD may be associated with increased f~,~,iliai aggregation. This finding requires replication with a controlled family study that directly and blindly interviews all first-degree relatives with appropriate structured interviews. The similarity in the mean whole blood 5-HT concentrations in the OCD patients and the normal controls is consistent with the report on platelet 5-HT in juveniles with OCD (Flament et al 1987), but is contrary to the report on blood 5-14"1"in adults with OCD (Yuryura-Tobias et al 1977). Blood 5-HT declines with age to stable adult levels by age 12 and the slope from ages 10 to 12 is shallow (Ritvo et al 1971). Two of the 5 0 C D patients under age 13 had a family history of OCD. However, their blood 5-HT levels were not appreciably higher than those of the 4 familial OCD patients over age 13 and do not account for the significant difference between the familial and sporadic OCD patients. A personal or family history of chronic tic disorder in the OCD patients was not associated with abnornaal blood 5-HT levels. This is consistent with a previous study which found no difference between TS patients and normal controls in mean blood 5HT levels (Leckman et al 1984). It is possible that significant differences in 5-HT metabolism between children and adults with OCD may account for some of the discrepant reports in the literature on blood 5-HT, platelet 5-HT, and CSF 5-HIAA. In addition, if serotonergic activity differs between familial and sporadic OCD patients, it is plausible that some of these discrepancies may derive from the proportion of familial and sporadic OCD cases in the various OCD samples. Finally, the reports of low blood 5-HT levels (Yuryura-Tobias et al 1977) and high CSF 5-HIAA levels (lnsel et al 1985) in adults with OCD may be consistent. Dominance and aggression in monkeys are associated with high blood 5-HT levels (Raleigh et al 1984) but low CSF 5-HIAA levels (Yodyingyuad et al 1985). High blood 5HT levels in autistic adults has been associated with low central 5-HT activity (McBride et al 1989). However, the relationship of blood 5-HT to central serotonergic activity remains undetermined. The preliminary finding of increased blood 5-HT concentration in familial OCD requires replication in a larger sample in which diet and the timing of the blood samples are standardized, the OCD and normal control groups are more closely matched on age and gender, and family history is obtained in the manner described above. A larger sample should also include females with familial OCD. This finding raises the possibility that studies of serotonergic functioning in OCD may need to control for family history of GCD and that, conversely, whole blood 5-HT may be a useful biochemical measure in family-genetic studies of OCD. Supported in part through a grant from Ciba-GeigyPharmaceuticals, Inc.
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