n~ psvc~v

467

1991~ 7 4 7 ~ I

Platelet 3H-Imipramine Binding Sites in Obsessive--Compulsive Behavior Suck Won Kim, Maurice W. Dysken, Ghanshyam N. P dey, and John M. Davis

Several studies indicate a serotonergic @sfunction in patients with obsessive-compulsive disorder (OCD). We examined serotonergic function in OCD by determining platelet 3Himpiramine binding sites in patients with OCD during a drug-free baseline period as well as normal control volunteers. The maximum number of binding sites (B,~) and apparent dissociation constant (K~ was determined using JH-imipramine (IMl) as the binding ligand. We observed that the mean JH-IM! binding B ~ ffmol/mg protein)determined in 24 patients with OCD was not significantly different from that in 23 normal control subjects. There were no significant differences in the Kd between patients with OCD and normal control subjects. Our results are thus similar to those reported by lnsel et al (1985) and Black et al (1990), who observed no significant differences in platelet JH-IM! binding between OCD patients and controls; but different from those reported by Weizmann et al (1986), who observed decreased 3H-IMl B ~ in OCD patients. The discrepancy in the results is not clear, but may be related to several factors. Our results thus indicate that any abnormality in serotonergic function present in patients with OCD is not related to imipramine binding sites in the platelets. However, the possibility that there may be an abnormal platelet serotonin uptake or other serotonergic function in OCD cannot be ruled out.

Introduction ' r h ~ nh©#r~at~t~n t h a t ,r'.lnmlmr-'~mlm~ R H v n Y ~ m i n ~

~rtcl f l | l n x e l i r l e _ w h i c h are ~ n t

block-

ers of serotonin ( 5 - h y d r o x ~ t a m i n e [5-HT]) uptake, are also effective in the treatment of obsessive-compulsive disorder (OCD) (~zk et al ! 98g; Kim ~ Dysken 1988; Y ~ Tobias and Neziroglu 1975; Ananth et al 1979) has |ed to ~ hypothesis th~ a dysfunction in the serotonergic system may be associated with the pathophysiology of OCD (Insel et al 1985). Evidence related to the role of 5-HT neurowansmJssion in ~ D has been provided by the studies of cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacefic acid ( 5 - ~ ) (Thoren et al 1980; Insel et al 1985), platelet 5-HT levels (Flament et al 1985), and

From the Department of Psychiau'y. Hennepin County Medical Center, Mim-teapotis, MN 55414 (SWK, MWD) and m ~ State Psychiaffic Institute and University of Illinois, Chicago, IL 60612 ~GNP, IMD). Address reprint requests to Ghanshyam N. Pandey, Ph.D., Hlinois State P s y c ~ c Instiuae, 1601 West Taylor Street, Chicago, IL 60612. Received November 30, 1990; ~vised March 20. 1991.

© 1991 Society of Biological Psychiatry

(]~(~>-3223/91/$03.50

468

BIOL [~yCIL][ATRY 19~1;30:467-474

S.W. Kim et al

neuroendocrine (Zohar et al 1987; Hollander et al 1988) and platelet imipramine binding studies (Insel et al 1985: Weizman et al 1986; Black et al 1990). Meta-chlorophenylpiperazine fMCPP)-induced changes in pmlactin and cottisol release and worsening of OCD symptoms has been used to study semtonergic function in OCD ( ~ et ai 1987; Hollander et al 1988; Chamey et al 1988). ~though the precise mechanism by which MCPP causes changes in prolactin and ~ s o l levels is unclear, setotonergic mechanisms are generally believed to be involved (Mueller at al 1985a, 1985b). Another strategy used for studying setotonin function is the determination of platelet aH-imipramine (IMI) binding sites, which have been linked to the setotonin transporter system (Davis 1984) and has been studied in depression and OCD. Many studies, but not all, observed decreased IMI binding sites in the platelets of depressed patients (Briley et al 1980; Paul et al 1981; Baron et al 1983; Kanof et al 1987; Mellerup et al 1982). insel et al (1985) and Black et al (1990) did not find any significant differences in SH. IMI binding sites between f..CD patients and normal controls, but Weizman et ai (1986) observed a significant decrease in platelet aH-IMI binding sites in OCD patients. In order to further examine the role of 3H-IMI binding sites in OCD, we determined 3H-IMI binding sites in platelets obtained from patients with OCD during a drug-free period as well as normal control subjects.

Methods

Subjects ~ e subjects for the study were 24 outpatients (13 women, 11 men) who met the DMSIII criteria for OCD. The diagnosis was also based on a structured interview using the Schedule for Affective Disorders and Schizophrenia lifetime version (SADS-L) (Spitzer and Endicott 1978). Patients were recruited by physician referral during a multicenter OCD clomipramine study. Initial evaluation of the patients included psychiatric interview and aciministration of Leyton Obsessional Inventory (LOI) (Cooper 1970), Symptom Checklist-90-Obsessive Compulsive Subscale (SCL-90-OC) (Derogatis ¢t al 1973), YaleBlown Obsessive Compulsive Scale (Y-BOCS) (Goodman et al 1989a, 1989b) and Hamilton Depression Rating Scale (HDRS) (Hamilton 1960). Those patients who developed depression prior to the development of OCD symptoms, or clinically depressed patients, .qnc] tht~

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study. Other exclusion criteria included the presence of major psychiatric disorders, recent electro.zonvulsive therapy, presence of significant medical illnesses such as heart, lung, kidney, or liver disease, and a history of recent substance abuse. Twenty-three normal controls (13 women, 10 men) were recruited by advertising in the media and on hospital bulletin boards. Normal control subjects were screened by a psychiatric interview and were free of any personal or family history of psychiatric disorders, were generally in good health and had no history of substance abuse, and were not on prescription drugs during the study. Informed consent was obtained from all subjects. Blood was drawn for 3H-IMI binding after at least a 4-week drug-free period.

Separation of Platelets and Determination of 3H-lmipramine Binding Sites Blood (30 ml) was obtained from the OCD patients during the first 2 weeks after placebo period in a tube containing 0.5 ml of 0.15 mol/L EDTA. The blood was mixed and then

P|at~let S H - I m i p r a m i n c B i n d i n g in

OCD

B~g. PSYCHiATrY

centrifuged at 210 g for 10 rain at 4°C. The platelet-rich plasma was removed ~ was centrifuged at 4000 g for I0 rain at 4 ~ . After aspirating of the plasma, t ~ platelet pellet was washed two times with isotonic saline and then frozen un~ assayed. 3H-ir~Wamine binding in platelets was carried out according to the nmdified procedure as described R~sman et al (1979) as follows: the platelet pellet was suspended in 3 wl of ~ ~ L tris buffer (pH 7.5) containing 5 mmoFL EDTA ~ ~,~s h o ~ e n ~ z e d by ~ ~ setting at 8 for 20 see. The suspe~.sion was cen~fuged at 49,000 g f ~ tO ~,q at 4°C. T ' ~ platelet membrane was then resuspended in 3 nd of incubation ~ f f e r ( ~ m . ~ t / L ~ s , 120 mmol/L NaCI, 5 mmol/L KCI, pH 7.4) and spun at 4 9 , ~ g for 10 rain at 4°C. The pellet was finally suspended in !.5-2.5 ml of incubation buffer depending upon size of the membrane pellets. The incubation was carried ~ t ~n ~plicate ~n rubes containing 100 ~1 (150-300 ~g ?roSe,n) of membrane suspension ~ ~ H - ~ (0.5-2..5 nmol/L) with or without desipramine (100 ~mol/L) in a total v o l u ~ of 0.4 ~ incubation buffer and incubated at 0°C for I hr. The reaction was terminated by the addition of 4 ml of ice-cold incabation buffer and by rapid filtration through GE~F filters u n ~ r vacuum pressure followed by three washes of 4 nd of incubation buffer. The filters were then placed in vials containing 10 ml of BBS cocktail and stored in a cold room ovemigh~ before counting in liquid scintillation spectrometer. The ~'~cubations were can~ed out ag five to seven different concentrations of 3H-IMI. The specific binding was defined ~ difference in ~H-IMI bound in the presence or absence of d e s i ~ ( I ~ ~mol/L) ranged from 60% to 85% of the tonal binding depending on the c o n c e n ~ o n of ligand. "11 ~ maximum number of 3H-IMI binding sites ( 8 ~ and apparent association constant (Ka) was obtained by Scatchard Analysis (Scatchard 1949). Protein was determined by method of Lowry et al (! 95 l). Results In order to examine day-to-day variability, we dete~ined K d a n d Bmax of platelet 3HIMI binding in six individuals, each at two timepoints at least I week apart. The means for Kd at the two ~hnepoints were 0.87 and 0.88, while for B ~ (fmoFmg ~ i n ) t h e means were 976.67 and 9/7.67; there was no evidence of any difference in the between the two timepoints. A two-factor (individual × fin.e) v ~ e component model was fit to each of these two measures to indicate the amount of tom vanab~ty that was a . . - , ^ I.+..h . k ~ ;.,A;,,;AI,.~! .mA ,,~ , ~

Hm,~ ,~f ~cc+.ccrru-nt i~nr h,~th v~r/~h|o~% t h e : ~ n t

of variability attributable to time was clearly nonsi~ificant; for Ka, a s i ~ c a n t effect of individual was not observed, but for B ~ the individual effect was ~ g ~ y s i ~ c a n t (p < 0.004). To assess the degree of association in the dupficate ~ u r e s of Ka and B ~ within the six individuals, the intraclass con'e!ation was computed for each of two measures from the variance component estimates of the model. For Ka, the intraclass correlation was not estimable as different from zero; however, for B ~ a large intraclass correlation of 0.89 was observed, indicating the reproducibility wi~in individuals of the B ~ values across the two timepoints. We determined platelet 3H-IMI binding sites in the platelets o b r ~ l from 24 ~ tients with OCD at me end of a 4-week drug-free baseline period and 23 normal con¢ol subjects. The demogaphic and clinical characteristics of the OCD patients are shown in Table 1. The average age of onset for major symptoms that interfered with ~nctioning was 22 _ 5 years and the duration of illness was 16 -- 12 years. The average tonal Y-BOCS at baseline was 25 _4- 4 and the average LOI symp~m score was 32

470

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BIOL PSY~IATRY 1991;30:467-474

Table !. Clinical and Demographic Characteristics (Mean --. SD) of OCD Patients Demographic data Number of Patients Sex Age (yr) Age of onset (yr) Duration of illness (yr)

24 13F, IIM 39 4. 13 22 4. 5 16 4. 12

Scale Yale-Brown Obsessive--Compulsive ~ n g Leyton Obsession~ Symptom Score Leyton Obsessional Resistance Score Leyton Obsessioani Interference Score SCL-90-(X~ Hamilton Depressive Rating

25-.4 32 --.6 41 + 16 52 - 16 2.4 4- 0.6 9-*-3

-+ 6. The average LOI resistance score at ~ l i n e was 41 _+ 16 and the average LOI interference score was 52 _+ 16. T'ne average SCL 90-OC was 2.4 _+ 0.6 and the HDRS score was 9 _+ 3. The Bmax 3H'IMI binding sites in the platelets obtained from OCD patients were lower than those of normal controls but the difference was not significant (t -- 1.35, p = 0.18) (Table 2). The Kd (rim) of 3 H - ~ binding in the platelets of OCD patients was not significantly different from normal control subjects (Table 2). No significant correlation was observed between the Bin=, and age. We then examined the correlation between the Bm~ and various clinical measures. No significant correlation was observed Bm,~ and severity of OCD symptoms as measured by the YBOCS, SCL-90-OC, the LOI symptom scale, the LOI resistance scale, or the LOI interference scale. We then examined the gender differences in patients and normal control subjects. The B,,=, (fmol/mg protein) for 11 male patients was 818 +_ 289 and for 13 female patients was 783 _+ 346, which was not significantly different. We also observed that Bin=, (984 - 318) for 13 female controls was not significantly different from Bm~ (858 -+ 147) for 10 male normal controls. The Bm~ was lower in female patients than controls but the difference was not significant. No significant correlation was observed between the HDRS scores and the baseline B , ~ values. To examine if those OCD p~ient~ with symptoms of depression (higher HDRS scores) had lower Be= values, we compared the Bmax (881 -+- 371) values of 11 patients with high HDRS scores (11.5 _ 1.6) with Bma~ (728 -+ 253) of 13 patients with low HDRS (6.9 _'_+ 2.1) and observed no significant differences between the two groups. During the 1G-week drug trial, 11 patients (4 men, 7 women) received clomipra-

Table 2. [3H]-ImipramineBinding Sites in the Platelets Obtained from Patients with OCD and Normal Controlsa SErlax

Group

N

Age

(fnml/mgprotein)

Ka (nmol/L)

Normal controls OCD patients

23 24

36 _+ !0 39 "*" 13

929 "4- 261 816 -4- 308

0.73 "- 0.61 0.89 _+ 0.55

°Values are expressed as mean -,- SD.

Platelet ~H-Imilramine Binding in OCD

mine and 13 patients (7 men, 6 women) received placebo. We compared ~ b a s e l ~ Bm~, value of the drug group (761 + 252) with the ~ | i n e B ~ value of ~ p | ~ group (830 + 367) and observed no significant differences. We also e x ~ i ~ relationship between baseline B ~ , and clinical improvement between the p|a~e~ the drag group. The average percentage of improve~nt for the ~ D rating s c ~ s w ~ determined at the end of the 3-month ciomipra_mine ~ . For the YBOCS, the average decrease was 41 _+ 31 and for the SCL-90-OC the LOI symptom score, ~ ~ LO| interference score, the decreases were 44 +_ 3 | , 31 ± 33, and 48 *_ 32, respectively° No significant correlation was observed between the baseline B ~ , v~ue ~ post|rearmen| change scores on the Y-BOCS, SCL-90-OC, -*.heLOI symptom score, ~ LO~ interference score. The baseline B ~ for the five pat/ents wLo improve most on Y-BOCS change score (67%) was compared with t ~ B ~ for the five who improved the least (16%). These B,~, values (834 +_ 230, 706 ± 305) were also ~ significantly different from each other.

Discussion Imipramine binding sites have been related to and are probably a part of the ser~onin transporter complex (Davis 1984). Because ~ g s such as fluoxetine and c l o m i w ~ n e , which are potent blockers of serotonin reupmke, have been f o u ~ to be effective in treatment of OCD (Ananth et al 1979; Zak et al 1988; Kim ar~ Dysken |988), it may be inferred that OCD is associated with an abnormalRy of serotonin reupt~e. To test this suggestion, imipramine binding sites in plategets have been studied by s e v e n investigators in patients with OCD. In the present study, we found no si~ficant differences in the platelet 3H-IMI B ~ between patients with ~ O and a o ~ controls. These results are similar to those reported by Insel et al (1985) and Black et al (1990), who also found no significant differences in platelet 3H-IMI B ~ between ~ patients ar~ n o ~ controls. A mere-analysis, using the method of Hedges and O ~ m (1985), of the stu&es of Insel et al (1985), Black et al ( I ~ ) , and the present study i~icated no overall differences between OCD patients and nemaal controls, and ~ test for homoge~Ry is nonsignificant (X2 = 3, df = 2, NS). The results of the three studies are ~ r e f o r e not different from each other. Weizmm'1 et al (1986) r e p o ~ a si~ficant ~crease in imipramine binding sites in both adult and adolescent OCT)patients as compared with normal me|a-analysis, the Hedges test of homogeneity (Hedges and O ~ 1985) ~ c a t e d that the Weizman study had different results from the other three studies (X2 = 14.7, df = 4, p = 0.005). No significant differences in the gd was o ~ r v e d between OCD patients and normd] controls by us and other investigators ([nsel et al I985; Weizman et al |986; Black et al 1990). These discrepancies observed in the 8 , ~ may be attributed to (l) the nature of the OCD patients studied by each group, for example, heterogeneity, severity of OCD, presence or absence or severity of depression, and so on, (2) the differences in the methodology for measuring imipramine binding sites, (3) effects of previous e x ~ u r e to psychotropic drugs and lack of adequate washout period, and (4) the small sample size. Imiprami~e binding sites in the platelets of depressed patients have been studied by various investigators, and although many studies observed decreased ~ p ~ e binding sites in the platelets of depressed patients, some have reported no dffferehces (Bfi-

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Icy et al 1980; Paul et al 1981; Mellemp et al 1982). It is therefore possible that the decreased imipramine binding sites observed by Weizman et al (1986) may be related to the presence of some depressed patients or to the severity of depression in the patient population studied by Weizman et al (1986). However, both the Weizman et al (1986) and the present study excluded patients with severe depression. Moreover, in our study we observed that the mean B , ~ in the high HDRS group was not significantly different from the mean Bm=~, in the low HDRS group, suggesting that imipramine binding sites in our study are not related to the presence or severity of depression in the C(?D group. Because we and u ~ r groups of investigators (Black et al 1990; Weizman et al 1986) did not find any correlation between severity of OCD symptoms and imipramipe binding sites, it is also unlikely that the differences in the results reported by the various investigators may be related to the differences in the severity of OCD symFtoms. The dis,,repancies in the results observed by various groups of investigators, may, however, be related to the clinical heterogeneity of the patients, it is possible that OCD patients represent more than one clinically homogeneous diagnostic group. Further studies on the clinical characteristics and IMI binding of the patients on a larger scale n, oy be warranted to address this issue. Another possibility is that the differences may be related to the biochemical methodology used by various groups. Large variations in the B,,~ of ~H-IMI binding sites, ranging from 300 to 1500 fmol/mg protein, have been reported (Tang and Morris 1985). Our Bma, falls right in the middle of the range reported in the literature and is similar to that observed by Black et al (1990). It is possible but unlikely that the differences may be related to the biochemical methodology. The possibility that the inadequate drug washout period may account for the observed discrepancies should not be dismissed, however. Treatment with antidepressant drugs has been shown to decrease imipramine binding in the brain (Pokier et al 1984; Mellelmp and Plenge 1986), and this decrease appears to persist for up to 4 weeks after withdrawal of treatment. Our patients were drug free at least for a period of 4 weeks, and information on the drug-free washout period from other reports is unclear, especially in the Weizman et al study (1986). The possibility that inadequate drug-free washout period might account for decreased imipramine binding sites cannot therefore he ruled out. A seasonal variation in imipramine binding sites has also been reported by some, but not other investigators (Egrise et al 1983; Whitaker et al 1984; Galzin et ai 1986). Where~ Wei_zman et al (i986) controlled for seasonal changes, as they studied most of the patients during a 34 month period, we did not control for seasonal variation, however, the controls and the OCD patients were studied during the same period; hence, seaso:aal variations are unlikely to account for the differences in our findings as compared with Weizman :.t al (1986). Neither we nor other investigators (Black et al 1990; lnsel et al 1985; Weizman et al 1986) found any correlation between severity of OCD symptoms and ~H-IMI binding sites. The severity of OCD symptoms as measured by Y-BOCS scores were similar to that reported by Black et al (1990). It is therefore also unlikely that the changes may be related to the severity of OCD symptoms. lmipramine binding sites represent only a part of the serotonin uptake system. Our observation of normal imipramine binding sites in platelets of OCD patients, therefore, does not necessarily exclude an abnormality of the serotonin uptake system or abnormalities of the serotonergic system at other sites in patients with OCD. It is possible that serotonergic dysfunction in OCD may occur at the level of receptors, for example, 5-HT2 or 5-HT~A, or at sites distal to receptors. Further studies of imipramine binding sites, with a larger sample size and characterizing clinical subgroups of OCD patients,

Platelet ~Hdmipramine Binding in OCD

B ~ ~¥CHIATRY

473

|~| :][0:46~-o47'4

as well as investigations of other serotonergic mechanisms, may be needed to furt_lxr clarify and/or support the ser~tonin hypothesis of O C D

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