ANXLETY 2:56-57 (1996) EFFICACY OF CLOMIPIN REFERENCES OBSESSIVE-COMPULSIVE 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. 0 1996 WILEY-LISS, INC. Potter WZ, Rapoport J L (1994) Changes in cerebrospinal fluid neurochemistry during treatment of obsessive-compulsive disorder with clomipramine. Arch Gen Psychiatry 51:794803. Arya DK (1994) Extrapyramidal symptoms with selective serotonin reuptake inhibitors. Br J Psychiatry 165:728-733. Baldessarini RJ, Marsh E (1990) Fluoxetine and side effects. Arch Gen Psychiatry 47:191-192. Barr LC, Goodman WK, Price LH, McDougle CJ, Charney DS (1 992) The serotonin hypothesis of obsessive compulsive disorder: Implications of pharmacologic challenge studies. J Clin Psychiatry 53[4, Suppl]:17-28. Bertilsson L, Asberg M (1984) Amine metabolites in the cerebrospinal fluid as a measure of central neurotransmitter function: Methodological aspects. Adv Biochem Psychopharmacol39:27-34. Bowers MB (1 973) 5-Hydroxyindoleacetic acid (SH I M ) and homovanillic acid (HVA) following probenecid in acute psychotic patients treated with phenothiazines. Psychopharmacologia 28:309-318. De Bellis MD, Geracioti T D , Altemus M, Kling MA (1993) Cerebrospinal fluid monoamine metabolites in fluoxetine-treated patients with major depression and in healthy volunteers. Biol Psychiatry 33:636-641. 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. Greist J H (1990) Treatment of obsessive compulsive disorder: Psychotherapies, drugs, and other somatic treatment. J Clin Psychiatry 51[8, Suppl]:44-50. Greist JH, Jefferson JW, Kobak KA, Katzelnick DJ, Serlin RC (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. Insel T R (1992) Toward a neuroanatomy of obsessive-compulsive disorder. Arch Gen Psychiatry 49:739-744. Martuza RL, Chiocca EA, Jenike MA, Giriunas IE, Ballantine HT (1990) Stereotactic radiofrequency thermal cingulotomy for obsessive compulsive disorder. J Neuropsychiatry 2:33 1-336. McDougle CJ, Goodman WK, Leckman JF, Lee NC, Heninger GR, Price L H (1994) Haloperidol addition in fluvoxamine-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 5 1:302-308. Modell JG, Mountz JM, Curtis GC, Greden J F (1989) Neurophysiologic dysfunction in basal ganglia/limbic striatal and 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. Piccinelli M, Pini S, Bellantuono C, Wilkinson G (1995) Efficacy of drug treatment in obsessive-compulsive disorder: A meta-analytic review. Br J Psychiatry 166:424-443. Rauch SL, Jenike MA, Alpert NM, Baer L, Breiter HCR, Savage 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. Risby ED, Hsiao JK, Sunderland T, Agren H, Rudorfer Mv, Potter F7 WZ (1987) The effects of antidepressants on the cerebrospinal fluid homovanillic acid/S-hydroxyindoleaceticacid ratio. Clin Pharmacol Ther 42:547-554. Stein DJ, Spadaccini E, Hollander E (1995) Meta-analysis of pharmacotherapy trials for obsessive-compulsive disorder. Int Clin Psychopharmacol 1O:ll-18. Thomas DR, Nelson DR, Johnson AM (1987) Biochemical effects of the antidepressant paroxetine, a specific 5-hydroxyuyptamine uptake inhibitor. Psychopharmacology 93: 193-200. Wise RA (1982) Hypotheses of neuroleptic action: Levels of progress. Behav Brain Sci 5:78-82.