Serotonergic Responsivity Obsessive-Compulsive: Disorder

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Serotonergic Responsivity in

Obsessive-Compulsive Disorder
Effects of Chronic Clomipramine Treatment
Joseph Zohar, MD; Thomas R. Insel, MD; Rachel C. Zohar-Kadouch, MD; James L. Hill, PhD; Dennis L. Murphy, MD

\s=b\ Clomipramine is a potent serotonin reuptake blocker that tients." This apparent paradox might be resolved if chronic
decreases the symptoms of obsessive-compulsive disorder treatment with serotonin reuptake blockers induces adapt¬
(OCD). To investigate whether clomipramine treatment in OCD ive down-regulation of serotonergic responsiveness in the
affects brain serotonergic responsiveness, metachloro- patients with OCD who benefit from this treatment. This
phenylpiperazine (mCPP), a selective serotonin agonist, and study was designed to investigate this possibility.
placebo were given under double-blind conditions to nine The tricyclic antidepressant clomipramine has been
patients with OCD before and after treatment with clomipra- shown to be a potent inhibitor of serotonin reuptake into
mine. Unlike our previous observations of a marked transient synaptosomes in vitro.18 In preclinical in vivo studies,
increase in obsessional symptoms and anxiety following clomipramine is significantly more potent in inducing the
0.5 mg/kg of mCPP, readministration of mCPP after four serotonin behavioral syndrome in rodents than is imipra¬
months of treatment with clomipramine did not significantly mine, amitriptyline, or desipramine.4 Although several
increase obsessional symptoms and anxiety. Similarly, the other tricyclic antidepressants are potent inhibitors of
hyperthermic effect of mCPP observed before treatment was serotonin reuptake, these generally are metabolized to
eliminated after treatment with clomipramine. These findings desmethyl compounds, with a loss of serotonergic potency.
are consistent with the development of adaptive subsensitivity Clomipramine is unique in that its major metabolite, des-
to the serotonergic agonist mCPP during clomipramine treat- methylclomipramine, retains a high potency for serotonin
ment. A similar alteration in the response to endogenous reuptake inhibition while also acting as a norepinephrine
serotonin may mediate clomipramine's antiobsessional ef- uptake inhibitor.19
fects. To investigate possible changes in brain serotonergic
(Arch Gen Psychiatry 1988;45:167-172) responsivity during clomipramine treatment, the behav¬
ioral, thermal, and endocrine responses to mCPP before
tricyclic antidepressant clomipramine hydro¬ and during clomipramine treatment were compared. We
Thechloride, potent
shown to reduce
a serotonin
reuptake blocker,
obsessive-compulsive (OC) symptoms
has been
in
chose mCPP as the serotonergic probe based in part on
studies indicating that mCPP readily displaces tritiated
serotonin from brain membrane homogenates and is
patients with obsessive-compulsive disorder (OCD).18
Other nontricyclic selective serotonin reuptake blockers, thought to act selectively on serotonin receptor sites.20*21 In
such as zimelidine,910 fluoxetine,1112 and fluvoxamine,13 have preclinical in vivo studies, mCPP leads to biochemical
also been reported to be effective treatments of OCD, a (decreased central serotonin synthesis and turnover20"22),
disorder otherwise refractory to psychopharmacologic in¬ behavioral (decreased food consumption15·23 and decreased
tervention." One might therefore hypothesize that admin¬ locomotion24), hormonal (increased prolactin, cortisol, and
istration of a serotonin agonist to patients with OCD would corticotropin concentrations25'28), and thermal (hyperther-
reduce OC symptoms, at least briefly. However, single-dose mia25) effects, all consistent with serotonin agonist activ¬
treatment with metachlorophenylpiperazine (mCPP), a ity.21 These effects of mCPP are blocked by serotonin
serotonin receptor agonist,1516 was recently observed to antagonists and are responsive to presumed alterations in
increase rather than decrease OC symptoms in these pa- serotonin receptor sensitivity15·25·26,28 but not to alterations
in adrenergic or dopaminergic systems.15*21 Recent investi¬
Accepted for publication July 2, 1987.
From the Laboratory of Clinical Science, National Institute of Mental
gations in human subjects indicate that mCPP produces
hormonal (increased prolactin, cortisol, and corticotropin)
Health, National Institutes of Health Clinical Center, Bethesda, Md.
Reprint requests to Beer-Sheva Mental Health Center, POB 4600, Beer- and temperature (hyperthermia) changes that are con¬
Sheva 84170, Israel (Dr Zohar). sistent with the effects of other serotonin agonists.29·30

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These effects of mCPP in humans are also blocked by
pretreatment with the serotonin receptor antagonist
metergoline.30
SUBJECTS AND METHODS
Patients With OCD
Twelve patients with OCD, six women and six men, who were
referred by local psychiatrists to the National Institute of Mental
mCPP f-mCPP mCPP fmCPP
Health (NIMH) OCD outpatient program and were found by two Before During During
clinicians to meet DSM-IIP1 criteria for OCD,17 were given mCPP Treatment Treatment Treatment Treatment
challenges. The first ten consecutive patients were selected for
chronic clomipramine treatment. One patient, who had excessive
drowsiness in the second week of clomipramine treatment, did not £
o
complete the trial. The final sample therefore included nine o
co
patients with OCD, four men (aged 30 to 41 years; mean±SD,
36.2 ±4.2 years) and five women (aged 25 to 65 years; mean± SD,
38.8±14.0 years). All patients gave voluntary written informed
consent for their participation in the study. a.
Q S
Procedures _ 3_
mCPP
All studies consisted of the oral administration on separate days JmCPP
of mCPP (0.5 mg/kg) or placebo under double-blind, random-
O 1 mCPP
assignment conditions. (For more details on the pretreatment Before During * Before During
Treatment Treatment q Treatment Treatment
procedures see Zohar et al.17) Two days after the pretreatment
study, the patients started receiving 50 mg/d of clomipramine
hydrochloride before bedtime; the dosage was increased in incre¬
ments of 50 mg every other day up to a maximum of 300 mg/d, as Fig 1.—Peak changes (mean ± SEM) from baseline on behavioral
tolerated. The final dosages ranged from 200 to 300 mg/d with a ratings before and after four months of clomipramine treatment.
mean ± SD dosage of 278 ± 34 mg. The patients received clomipra¬ Placebo and metachlorophenylpiperazine (mCPP) were adminis¬
mine for at least 31*2 months (range, 3.5 to 5 months; mean±SD, tered orally under double-masked, random-assignment conditions
4.5±0.5 months) before participating in a second study with to same nine patients with obsessive-compulsive (OC) disorder.
mCPP and placebo carried out exactly as was the pretreatment CPRS-OC-5 indicates Comprehensive Psychiatric Rating Scale-
study. For the mCPP/placebo studies during treatment with Obsessive-Compulsive five-item subscale; other scales are Na¬
clomipramine, the subjects arrived at the clinic after an overnight tional Institute of Mental Health Global scales. Asterisk indicates
fast; the last dose of clomipramine was taken at bedtime the night P<.05, f test of paired data comparing peak change after mCPP
before the study day. To evaluate compliance with the treatment, with peak change after placebo in each subject; plus sign, P<.05,
clomipramine blood levels were measured. Dose and drug adminis¬ test of paired data comparing peak change after mCPP before clo¬
tration as well as behavioral, hormonal, and physiologic monitor¬ mipramine treatment with peak change after mCPP during clo¬
ing were identical to the pretreatment studies. Observer ratings of mipramine treatment in each subject.
obsessions, compulsions, anxiety, and depression1·32 and self-rat¬
ings of side effects and mood33 were done at baseline and 2,3, and 4
hours after either mCPP or placebo administration. Descriptions study was done. The comparison of psychological ratings and
of these scales and their interrater reliabilities are reported thermal response before and during clomipramine treatment was
elsewhere.17 done using "double-delta" differences (ie, subtracting the max¬
imum change following placebo from the maximum change follow¬
Biochemical Methods
ing mCPP), obtaining an estimation of the net mCPP effect. To
Plasma prolactin and cortisol concentrations were measured by assess the effects of clomipramine treatment on baseline behav¬
radioimmunoassay, and mCPP concentrations were measured by ioral ratings, plasma concentrations of prolactin, cortisol, and
high-performance liquid chromatography using methods described mCPP were compared by paired t tests of individual data. Pearson
elsewhere.17 All samples from an individual subject were measured product-moment correlation coefficients were computed between
in duplicate in a single-assay run and were accepted for the final the reduction of OC symptoms and the reduction of behavioral and
analysis if their intra-assay coefficient of variation was less than thermal responses to mCPP. All levels of significance were based
10%. The mean interassay correlation coefficient for pretreatment on two-tailed tests. To indicate variance, SDs are provided unless
samples rerun with samples during treatment was greater than .80 otherwise stated.
for cortisol, prolactin, and mCPP blood concentrations.
RESULTS
Data Analysis OC, Anxiety, and Depressive Symptoms
The study was designed to use each patient as his/her own The mean peak changes in observer rating scores of OC symp¬
control. The central question of the data analysis was focused on toms, anxiety, and depression following mCPP and placebo admin¬
whether clomipramine treatment would alter the response to istration before and during treatment with clomipramine are
mCPP. To test this hypothesis we compared drug effect (mCPP vs shown in Fig 1. During clomipramine treatment, mCPP adminis¬
placebo) before and during treatment separately across several tration led to behavioral changes that were 30% to 70% less than
time points using repeated-measures analysis of variance. A those observed prior to clomipramine treatment, and mCPP was
possible drug effect was assessed for the behavioral, thermal, and no longer associated with a significant increase in either OC
endocrine responses of the patients. Significant differences re¬ symptoms (as measured by Comprehensive Psychiatric Rating
vealed by repeated-measures analysis of variance were further Scale [CPRS1-OC-5 or NIMH Global OC score) or anxiety (as
analyzed with post hoc paired t tests of the peak response for each measured by NIMH Global anxiety score) compared with ratings
patient before and during treatment. Differences in peak re¬ following placebo administration. As reported elsewhere for a
sponses before and during treatment were also analyzed by paired larger patient group,17 mCPP in this subset of nine patients prior to
t tests. treatment evoked a significant increase in OC symptoms (CPRS-
The peak responses were calculated by subtracting the max¬ OC-5, F[l,8] 7.99, P<.02; NIMH Global OC score, F[l,8] 14.76,
= =

imum change following mCPP or placebo administration from the P<.005) and anxiety (NIMH Global anxiety score, F[l,8] 16.46,
=

corresponding baseline measure, providing a measure of the P<.004). On one measure, the NIMH Global anxiety score, the
maximum change corrected for the baseline of the day on which the increase following mCPP administration during clomipramine

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·— mCPP, Pre-Rx
* -- Placebo, Pre-Rx
°— mCPP, Rx
a—
Placebo, Rx

<&&
C _1
c
EÎ 20
¿F g-
<fi¿r Ö ·—·

<r Ç _i

in behavioral (left) and ther¬


•iì
Fig 2.—Peak changes (mean ± SEM) o
CO
mal (right) responses to metachlorophenylpiperazine (mCPP) be¬ ·§ .

re

fore (hatched bars) and during (dotted bars) clomipramine treat¬ ets
et¡D (
<o
10
ment. NIMH indicates National Institute of Mental Health; anxiety: _
re

feels anxious, restless, worried, frightened; depression: feels sad,


depressed, hopeless, worthless; dysphoria: feels irritable, angry,
uncomfortable mentally; activation-euphoria: feels elated, more
talkative, especially energetic, has racing thoughts; altered self-
reality: feels out of touch, mistrustful or suspicious, unreal or oScScP <*^N-
strange, has unusual thoughts, hears voices, sees things others do y* -**^
V^tF <·&_<·}·-
not; functional deficit: has difficulty concentrating and functioning, Time, min
feels slowed down. Asterisk indicates P<.05, paired f test compar¬ \<°
ing peak behavioral changes after mCPP before and duringf Fig 3.—Mean ± SEM prolactin time-response curve (left) and distri¬
clomipramine treatment in same patients; dagger,,P<.05, paired bution of maximal prolactin increment over baseline (right) after
test comparing peak thermal changes after mCPP before and placebo and metachlorophenylpiperazine (mCPP) before and dur¬
during clomipramine treatment in same patients. ing clomipramine treatment (n 9). Pre-Rx indicates before treat¬
=

ment; Rx, during treatment. In figure at right, squares indicate men;


circles, women. There were no significant differences in maximal
prolactin increment over baseline. Asterisk indicates P<.05, post
hoc f test of paired data comparing change after mCPP with change
after placebo either before or during clomipramine treatment.
treatment was significantly less than the increase following mCPP
prior to treatment (P<.05).
Changes in self-ratings of mood following mCPP administration
in patients with OCD before and during treatment with clomipra¬
mine are shown in Fig 2. During clomipramine treatment, mCPP
administration was not associated with significant increases in self-
ratings of anxiety and depression compared with ratings on Physical Side Effects
placebo. Prior to clomipramine treatment, the same dose of mCPP general,
In mCPP was very well tolerated physically by the
administered under the same procedure induced a significant patients with OCD both before and during clomipramine treat¬
increase in anxiety (F[l,8] 12.7, P<.007) and depression
=
ment. Physical side effects, if present at all, were modest and
(F[l,8] 6.4, P<.03). In addition, when the maximum change fol¬
=
included (aside from chills and hot, flushed sensations) very mild to
lowing placebo was subtracted from the maximum change follow¬ mild nausea (four patients before and three during clomipramine
ing mCPP and compared before and during clomipramine treat¬ treatment), light-headedness, and dizziness (two patients before
ment, the net increases in both anxiety (paired t 5.4, P<.03) and
=
and one of these two during treatment). These side effects usually
depression (paired i 4.9, P<.05) were significantly different.
=
began within the first hour and gradually subsided over the next
Qualitatively, only two of the nine patients had recurrence of hour or so. Late-onset headache, ten to 12 hours after mCPP
obsessions that had not been present for several months following administration, occurred in two patients before treatment and did
mCPP administration during clomipramine treatment compared not occur in any patients during clomipramine treatment.
with six of the same nine patients (ie, 22% vs 67%) who had
reported this kind of experience following mCPP administration Plasma Prolactin Levels
before clomipramine treatment. Moreover, none of the patients had The prolactin responses after mCPP before and during
mean
crying spells following mCPP (or placebo) while receiving clo¬ clomipramine treatment are shown in Fig 3. In both conditions the
mipramine treatment; four of the same nine patients had crying effect of mCPP was significantly different from placebo
spells after mCPP (but not following placebo) before clomipramine (F[l,6] 32.99, P<.002), with significant increases (P<.05) at 120,
=

treatment.
The time course of the behavioral symptoms was not different
150, 180, and 210 minutes following mCPP. Treatment with clo¬
mipramine was associated with a marked and significant increase
before and during clomipramine treatment, and the behavioral in baseline prolactin concentrations (mean±SD, 5.6±3.9 µg/L
changes roughly paralleled the time of the peak plasma mCPP [5.6±3.9 ng/mL] before treatment, 14.0±7.8 µg/L
concentration and the peak endocrine response. [14.0±7.8 ng/mL] during treatment, paired i9 5.54, P<.001). =

Thermal Responses However, the ability of mCPP to raise the plasma level of prolactin
was not significantly affected by clomipramine treatment as mea¬
During clomipramine treatment, mCPP administration was not sured by maximal increment over baseline (mean±SD, 12.7±7.6
associated with significant temperature changes CF[1,7] 0.35, =
µg/L [12.7±7.6 ng/mL] before treatment, 14.9±3.5 µg/L
P<.6), while mCPP induced hyperthermia when administered [14.9 ±3.5 ng/mL] after treatment, paired i8 0.81, not significant
=

before clomipramine treatment (F[l,6] 8.00, P<.03) (Fig 2). This


=
[NS]). There was a negligible difference in the mean prolactin
difference in the ability of mCPP to induce temperature changes response before treatment in female (13.1 ±9.24 µg/L
was also expressed by the patients' subjective sensations; following [13.1±9.24 ng/mL], n 5) compared with male (10.4±3.89 µg/L
=

mCPP only one (11%) of the nine patients in the clomipramine- [10.4±3.89 ng/mL], 4) patients with OCD (¿, 0.07, NS) that
= =

treated group reported chills or hot/flushed sensations compared did not change during clomipramine treatment (16.2 ±2.17 µg/L
with six patients (67%) who reported these symptoms before [16.2±2.17 ng/mL] for women, 13.3±4.17 µg/L [13.3±4.17 ng/mL]
treatment. for men).

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mCPP, Pre-Rx

Placebo, Pre-Rx Table 1.—Effects of Clomipramine Treatment on Baseline
·>-·
mCPP, Rx Behavior Scores*
Placebo, Rx
_
550 (20) Baseline Behavior Score,
Mean ± SEM ( = 9)
E A
ID —

A
Before During
o
E
I I 280 (10) Scale
Clomipramine
Treatment
Clomipramine
Treatment
Observer
CPRS-OC-5 4.8 + 0.8 1.9 + 0.7f
« S2 Global OC 5.9 ±0.7 4.0 + 0.4-J:
ra
o E m
ü Global Anxiety 4.5 + 0.3 3.6 + 0.6
re cd
Global Depression 4.4 + 0.5 2.7 ± 0.6t
<e. ~0·
Self-rating
Anxiety 14.4+1.8 10.8±3.5
Time, min Depression 12.9 + 2.8 5.3 ±2.5}.
Fig 4.—Mean SEM cortisol time-response
± (left) and distri¬
curve Dysphoria 5.0 + 1.4 3.0±2.4
bution of maximal cortisol increment over baseline (right) after
Euphoria 2.6 + 0.9 1.8 + 0.7
placebo and metachlorophenylpiperazine (mCPP) before and dur¬ Altered self-reality
ing clomipramine treatment (n 9). Pre-Rx indicates before treat¬
= 0.4 + 0.3 1.2 ±0.8
ment; Rx, during treatment. In figure at right, squares indicate men; Functional deficit 12.0±2.7 7.2 ±1.9
circles, women. There were no significant differences in maximal *CPRS-OC-5 indicates Comprehensive Psychiatric Rating Scale-Ob¬
cortisol increment over baseline. Analysis of variance revealed no
sessive-Compulsive five-item subscale; OC, obsessive-compulsive. Each
significant drug effect (mCPP vs placebo) either before or during scorerepresents the mean ± SEM of two baseline measurements taken in the
clomipramine treatment. morning, one on the metachlorophenylpiperazine study day and one on the
placebo study day.
tP<001, paired ( test of patients with obsessive-compulsive disorder
during clomipramine treatment.
tP<.05, paired f test of patients with obsessive-compulsive disorder
Plasma Cortisol Levels during clomipramine treatment.
Figure 4 summarizes the mean cortisol response after adminis¬
tration of mCPP before and during treatment with clomipramine.
The effect of mCPP tended to be different from placebo both before Table 2.—Peak Plasma Concentration of mCPP* Before and
and during treatment, although the overall mCPP effect did not
reach statistical significance (F[l,8] 5.24, P>.05). Clomipramine
=
During Clomipramine Treatment
treatment did not affect baseline cortisol levels (mean± SD, Before Clomipramine
nmol/L [9.8 ±3.6 During Clomipramine
270 + 100 µg/dL] before treatment; Treatment Treatment
300±120 nmol/L [10.9±4.2 µg/dL] during treatment), and the
mean ± SD maximal cortisol increments over baseline before Peak Plasma Peak Plasma
(170 + 90 nmol/L [6.2±3.3 µg/dL]) and during (180±140 nmol/L mCPP Time mCPP Time
[6.5 ±5.1 µg/dL]) treatment were similar. There were no gender Concen¬ After Concen¬ After
differences in the cortisol response to mCPP either before tration, mCPP tration, mCPP
(150 ±40 nmol/L [5.6 ±1.36 µg/dL] for men, 180 ±120 nmol/L Patient nmol/L Dose, nmol/L Dose,
[6.7±4.22 µg/dL] for women) or during (200±130 nmol/L
No. (ng/mL) min (ng/mL) min
[7.2±4.79 µg/dL] for men, 160±140 nmol/L [5.9±5.2 µg/dL] 239 (47.0) 150 426 (83.8) 90
for women) treatment. 155 (30.4) 210 551 (108.4) 120
Baseline Behavior 231 (45.4) 150 207 (40.6) 150
Ratings
47 (9.2) 180 157 (30.9) 210
Chronic treatment with clomipramine in patients with OCD was
associated with significant mean decreases in OC symptoms and 77 (15.2) 180 156 (30.7) 150
depression (Table 1). All the patients experienced a reduction in 113 (22.2) 210 23 (44.3) 150
their OC symptoms during clomipramine treatment as indicated by 122 (24.0) 150 156 (30.7) 150
measurements on two rating scales (CPRS-OC-5 and NIMH Global
128 (25.1) 150 283 (55.8) 150
OC rating scales). The mean percentage improvement in OC
192 (37.8) 150 284 (55.9) 210
symptoms was 32% with the NIMH Global OC scale and 60% with
the CPRS-OC-5 scale (mean± SD, 47.6% ±19.4%). However, no Total, 145 ±27.5 170 + 8.66 272 ±50.5 160+14.14
correlation was found between the reduction in OC symptoms as mean (28.5 + 5.41) (53.5 + 9.93)
measured by either scale or their mean and the decreased behav¬ ±SEMf
ioral or thermal responses to mCPP during clomipramine treat¬ *mCPP indicates metachlorophenylpiperazine.
ment. Plasma levels of at least 559 nmol/L (176 ng/mL) for fMean±SEM peak plasma mCPP concentrations were significantly
clomipramine and 1380 nmol/L (414 ng/mL) for desmethylclomipra- higher during clomipramine treatment than before treatment (fB 3.21. =

mine were detected in all the subjects. P<.02, paired (test).


Peak Plasma mCPP Concentrations
The mean ±SEM peak plasma mCPP concentration ranged from 130% to 360% of the concentration before treatment,
during treatment with clomipramine (272 ±50.5 nmol/L and only one patient had a slight decrease (10%) in peak mCPP
[53.5 ±9.93 ng/mL]) was almost double that before clomipramine concentration during clomipramine treatment. Interassay reliabil¬
treatment (145 ±27.5 nmol/L [28.5 ±5.41 ng/mL]). There was no ity for plasma mCPP measurements was evaluated by reassaying
significant difference in the mean± SEM time of peak mCPP the plasma samples obtained before clomipramine treatment when
concentration in plasma (160 ±14.1 minutes during treatment, the plasma samples obtained during clomipramine treatment were
170±8.7 minutes before treatment). As shown in Table 2, eight of analyzed. An interassay correlation coefficient of 0.91 was found,
nine patients had increases in peak mCPP concentration that with nearly identical mean values for the two assays (175 ± 73 nmol/L

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[34.3 ±14.3 ng/mL] and 170±74 nmol/L [33.4±14.6 ng/mL], re¬ clinical and clinical studies have shown that the neuroen¬
spectively). docrine effects of mCPP are dose dependent. This in¬
terpretation holds even stronger for the cortisol response to
COMMENT
mCPP before and during clomipramine treatment, as for
cortisol there are no baseline differences before and during
treatment. A third interpretation is that these neuroen¬
Chronic treatment with clomipramine, a potent serotonin docrine effects of mCPP are mediated by a subpopulation of
reuptake inhibitor with therapeutic benefit in patients with serotonin receptors that are not down-regulated by clo¬
OCD, was associated with a decrease in behavioral re¬ mipramine. Different effects of chronic clomipramine ad¬
sponses to the serotonin agonist mCPP. Specifically, during ministration on the serotonergic system are in keeping with
clomipramine treatment, mCPP did not significantly in¬ recent preclinical work with fluoxetine demonstrating re¬
crease OC symptoms, anxiety, or depression. Treatment gional variation of receptor down-regulation across sero¬
with clomipramine was also associated with a loss of the tonin receptor fields (range, 12% to 60%).37
hyperthermic response to mCPP. These findings are con¬ The ability of clomipramine to reduce OC symptoms in
sistent with development of adaptive hyporesponsivity of patients with OCD coupled with the development of sero¬
the serotonergic system in patients with OCD treated tonin hyporesponsivity during clomipramine treatment
chronically with clomipramine. raises the possibility that the therapeutic effects of clo¬
Chronic treatment with clomipramine was also associ¬ mipramine in patients with OCD may be associated with the
ated with a surprising increase (almost doubling) of peak development of serotonergic subsensitivity. Thorén et al38
plasma mCPP levels following administration of the same reported that the clinical response of patients with OCD
mCPP dose to the same patients in an identical protocol. treated with clomipramine was positively correlated
The method used to measure plasma mCPP concentrations, (r= .75) with the decrease in cerebrospinal fluid concentra¬
high-performance liquid chromatography with electro¬ tion of 5-hydroxyindoleacetic acid, the main serotonin me¬
chemical detection, is very specific and stable. The differ¬ tabolite, but not with methoxyhydroxyphenylglycol or ho¬
ence between mCPP concentrations before and during movanillic acid. Recently, Flament et al39 reported that
clomipramine treatment does not appear to be due to assay clinical improvement in children with OCD was signifi¬
variability, as the difference persisted when samples ob¬ cantly correlated (r= .62 to .78) with decreases in platelet
tained before and during treatment were reassayed to¬ serotonin concentration. In the present study, probably due
gether. One possible explanation is that the cholinergic to the small number of patients, we did not find a significant
effects of clomipramine, which decreases intestinal correlation between the amplitude of clinical response and
motility, may increase absorption and thus lead to increased the magnitude of the subsensitivity that developed in
plasma mCPP concentrations. Another explanation is that individual patients, although as a group the patients had
clomipramine interferes with the hepatic metabolism of beneficial clinical responses and reduced serotonergic re¬
mCPP. In any case, the significant increase in plasma sponsivity during clomipramine treatment.
mCPP concentrations should have increased rather than Decreased serotonergic responsivity in patients with
decreased behavioral responses during clomipramine treat¬ OCD who benefited from clomipramine treatment is con¬
ment, as the effects of mCPP have previously been demon¬ sistent with an association between increased serotonergic
strated in preclinical and clinical studies to be dose depend¬ activity and the pathophysiologic characteristics of OCD. If
ent. 26,29·30 A second issue of note is the significant reduction this is so, patients with OCD would be expected to get even
in the baseline levels of OC symptoms and depression worse following administration of serotonin agonists (as

during clomipramine treatment. By using a peak response reported after mCPP administration17) and to improve if
(ie, subtracting the maximum change following mCPP or serotonin hyporesponsivity develops (as it often does dur¬
placebo administration from the corresponding baseline ing chronic clomipramine treatment40). However, if hyper-
measure), we attempted to adjust at least partially for these responsivity of the serotonergic system is associated with
baseline differences. the psychopathologic characteristics of OCD, we might also
Clomipramine treatment was associated with a very expect to see worsening of OCD symptoms during the initial
significant increase in baseline prolactin concentrations. phase of treatment with serotonin reuptake blockers, as
This effect of chronic clomipramine treatment was reported initially these medications increase serotonin content in the
more than ten years ago34 and does not occur during chronic synaptic cleft. A recent reanalysis of daily ratings of
administration of amitriptyline, although the basis for this patients from an earlier inpatient study8 provides prelimi¬
effect of clomipramine has not been studied. Possible expla¬ nary support for the notion that many patients with OCD
nations included sustained serotonergic stimulation of experience exacerbation of their symptoms during the first
prolactin release by clomipramine, a change in sleep cycle, three to five days of clomipramine treatment (J.Z., T.R.I.,
and partial dopamine receptor blockade; the last possibility D.L.M., unpublished findings, 1987).
is not an expected consequence of clomipramine administra¬ In conclusion, clomipramine treatment was associated
tion. with decreased serotonergic responsivity in patients with
An increased prolactin response to mCPP during clo¬ OCD compared with the same patients' responses to the
mipramine treatment might have been expected on the same serotonergic challenge (0.5 mg/kg of mCPP) before
basis of increased blood mCPP levels. Failure to observe treatment. This finding along with the increased respon¬
this increase was probably not due to a "ceiling effect." sivity of patients with OCD to mCPP17 is consistent with the
Based on prolactin response to neuroleptic agents35 and hypothesis that increased rather than decreased
thyroid releasing hormone,36 it appears that prolactin levels serotonergic responsiveness is associated with the psycho-
can go higher than the peak reached after mCPP adminis¬ pathologic characteristics of OCD.
tration during clomipramine treatment. The apparently
equivalent endocrine responses to mCPP during clomipra¬
mine treatment in the face of significantly higher plasma We thank Terry Tolliver, MS, and P. K. Narang, PhD, for measuring
mCPP concentrations may reflect hyporesponsivity of mCPP concentrations, Francis Szele for measuring prolactin and cortisol
prolactin secretion to serotonergic provocation, since pre- concentrations, and Dottie Drake for secretarial assistance.

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