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Efficacy of clomipramine in obsessive-compulsive disorder.

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2:56-57 (1996)
DISORDERAltemus M, Swedo SE, Leonard HL, Richter D, Rubinow DR,
Robert H. Howland
Received for publication May 27, 1995; accepted June 6, 1995.
s e v e n l recently published meta-analyses comparing clomipramine
to other serotonin reuptake inhibitors (SRIs) in obsessive-compulsive
disorder (OCD) suggest that clomipramine may have superior efficacy
(Greist et al., 1995; Piccinelli et al., 1995; Stein et al., 1995). If true,
there may be a possible explanatim for thisdifference.
Although the efficacy of the SRIs implicates serotonin in
OCD, direct studies have not demonstrated consistent serotonergic abnormalities (Barr et al., 1992). Other research suggests
a possible role for dopamine. Dopamine agonist drugs can induce O C D symptoms (Goodman et al., 1990). Obsessive-compulsive symptoms are highly prevalent in disorders involving
dopamine abnormalities, such as schizophrenia (Hwang and
Opler, 1994) and Tourette’s syndrome (Goodman et al., 1990).
Also, neuroleptics may augment SRIs in some patients with refractory O C D (McDougle et al., 1994).
Functional brain imaging studies of OCD show increased
activity in some prefrontal o r frontal regions (Insel, 1992;
Rauch et al., 1994). Treatment with the SRIs is associated with
decreased activity in some of these regions (Insel, 1992), suggesting that a common feature of effective treatments might be
their ability to decrease or attenuate frontal lobe function
(Hoehn-Saric et al., 1993). This is consistent with the effects of
neurosurgical treatment, which may work by disrupting frontal
and subcortical connections thought to be part of a dysfunctional neuroanatomical circuit in O C D (Model1 et al., 1989;
Martuza et al., 1990). Neuroleptics may inhibit dopamine input
to prefrontal and frontal regions (Wise, 1982) and thus might
work synergistically with the SRIs in some patients. Curiously,
treatment of O C D may be more successful in some patients after neurosurgery (Martuza et al., 1990; Greist, 1990). Such an
effect might be akin to adding a neuroleptic, in that both tend
to decrease frontal lobe function or its input to subcortical regions (Hoehn-Saric et al., 1993).
T h e SRIs can inhibit dopamine function indirectly by enhancing serotonergic transmission (Baldessarini and Marsh,
1990; Arya, 1994). These drugs increase the cerebrospinal fluid
homovanillic acid/S-hydroxyindoleacetic acid ratio (DeBellis et
al., 1993; Altemus et al., 1994). This biochemical effect is similar to that found with neuroleptics (Bowers, 1973), and distinguishes the SRIs from other antidepressants that are ineffective
in O C D (Bertilsson and Asberg, 1984; Risby et al., 1987).
Moreover, clomipramine could inhibit dopamine more strongly
than other SRIs because it has greater affinity for D2 receptors
(Thomas et al., 1987). Hence, clomipramine might be more effective than other SRIs due to synergistic effects on serotonin
uptake and dopamine inhibition. This hypothesis could be
tested by including neurobiological measures (Insel, 1992;
Altemus et al., 1994) in studies comparing the efficacy of
clomipramine and the SRIs in OCD.
Potter WZ, Rapoport J L (1994) Changes in cerebrospinal fluid
neurochemistry during treatment of obsessive-compulsive disorder with clomipramine. Arch Gen Psychiatry 51:794803.
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Barr LC, Goodman WK, Price LH, McDougle CJ, Charney DS
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Goodman WK, McDougle CJ, Price LH, Riddle MA, Pauls DL,
Leckman JF (1990) Beyond the serotonin hypothesis: A role for
dopamine in some forms of obsessive compulsive disorder? J
Clin Psychiatry 51[8, Suppl]:36-43.
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(1995) Efficacy and tolerability of serotonin transport inhibitors
in obsessive-compulsive disorder. Arch Gen Psychiatry 5253-60.
Hoehn-Saric R, McLeod DR, Zimmerli WD, Hipsley PA (1993)
Symptoms and physiologic manifestations in obsessive compulsive patients before and after treatment with clomipramine. J
Clin Psychiatry 54:272-276.
Hwang My, Opler LA (1994) Schizophrenia with obsessive-compulsive features: Assessment and treatment. Psychiat Ann 24:468472.
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disorder. Arch Gen Psychiatry 49:739-744.
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(1990) Stereotactic radiofrequency thermal cingulotomy for obsessive compulsive disorder. J Neuropsychiatry 2:33 1-336.
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GR, Price L H (1994) Haloperidol addition in fluvoxamine-refractory obsessive-compulsive disorder. Arch Gen Psychiatry
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University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
Address reprint requests to Robert H. Howland, M.D., Western
Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh,
PA 15213.
Peer-Reviewed Letter
thalamocortical circuits as a pathogenetic mechanism of obsessive-compulsive disorder. J Neuropsychiatry 1:27-36.
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of drug treatment in obsessive-compulsive disorder: A meta-analytic review. Br J Psychiatry 166:424-443.
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CR, Fischman AJ (1994) Regional cerebral blood flow measured
during symptom provocation in obsessive-compulsive disorder
using oxygen 15-labeled carbon dioxide and positron emission
tomography. Arch Gen Psychiatry 5 1:62-70.
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WZ (1987) The effects of antidepressants on the cerebrospinal
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Clin Psychopharmacol 1O:ll-18.
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efficacy, obsessive, disorder, compulsive, clomipramine
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