Clomipramine obsessive-compulsive disorder

The Food and Drug Administration (FDA) has approved clomipramine for the treatment of obsessive-compulsive disorder. Clomipramine is also used in the United States, Europe, Canada, England, and, indeed, most of the world as an antidepressant. In six random-assignment, double-blind studies, this agent was equal in efficacy to standard tricyclics, with a side-effect profile comparable with other TCAs ( Table 7-6). 

Imipramine Mixed and variable blockade of NET and SERT Like SNRIs plus significant blockade of autonomic nervous system and histamine receptors Major depression not responsive to other drugs chronic pain disorders incontinence obsessive-compulsive disorder (clomipramine) Long half-lives CYP substrates active metabolites Toxicity Anticholinergic, G.-blocking effects, sedation, weight gain, arrhythmias, and seizures in overdose Interactions CYP inducers and inhibitors... 

Obsessive-compulsive disorder + + ++ (Clomipramine) Addition of antipsydiotics... 

Clomipramine is considered to be the most powerful antidepressant ever made. This dihydrodibenzazepine TCA, with actions on both the NE and 5-HT transporters, was the last of the major TCAs to come to market. Initially, the U.S. FDA regarded it as another me-too drug, and accordingly, they did not license it. Subsequently, however, it was licensed for the treatment of obsessive-compulsive disorders. Clomipramine differs from imipramine only by the addition of a 3-chloro group (Fig. 21.15). 

The efficacy of clomipramine relative to the other TCAs in the treatment of obsessive-compulsive disorder may be related to its potency in blocking 5-HT reuptake at the presynaptic neuronal membrane, suggesting a dysregulation of 5-HT for the pathogenesis of obsessive-compulsive disorder. Clomipramine appears to decrease the turnover of 5-HT in the CNS, probably because of a decrease in the release and/or synthesis of 5-HT. 

SSRIs are well tolerated. Adverse effects for compounds in this class include nervousness, tremor, dizziness, headache, insomnia, sexual dysfunction, nausea, and diarrhea. In addition, the tricycHc antidepressant clomipramine (33), which is a potent nonselective serotonin reuptake inhibitor, is approved for treatment of obsessive—compulsive disorder. 

Doxepin [1668-19-5] (38), unlike other commercially available tricyclics, has an oxygen atom in the bridge between the two aromatic rings. It is marketed as a cis—trans mixture (1 5) of isomers, both of which are active. This close relative of amitriptyline (33) has both sedative and anxiolytic properties associated with its antidepressant profile. Maprotiline [10262-69-8] (39) and amoxapine [14028-44-5] (40) are pharmacologically, although not chemically, similar to the tricycHc secondary amines. Clomipramine [303-49-1] (41) has similar pharmacological and antidepressant efficacy. However, clomipramine is approved by the U.S. FDA only for the treatment of obsessive—compulsive disorder. Representative brands of tricycHc antidepressants marketed in the United States are Hsted in Table 2. 

TCAs primarily work by blocking the reuptake of norepinephrine, although they block serotonin reuptake as well. The lone exception is clomipramine (Anafranil), which preferentially blocks serotonin reuptake. It is this unique characteristic that makes clomipramine the only TCA that effectively treats obsessive-compulsive disorder (OCD). 

Zohar and Insel have suggested that the s)nnptoms of obsessive-compulsive disorder are due to supersensitive 5-HTi-type receptors and that the function of SSRIs such as clomipramine, fluoxetine and the non-selective 5-HT antagonist metergoline owe their efficacy to their ability to reduce the activity of these receptors. 

Clomipramine Only for treatment of Obsessive-Compulsive Disorder (OCD). 

Clomipramine (Anafranil) also a member of the tricyclic family, possesses similar pharmacology and antidepressant efficacy. This agent, however, has Food and Drug (FDA) approval only for use in the treatment of obsessive-compulsive disorder and is not included in this discussion of antidepressant drugs. 

DeVeaugh-Geiss, J., Moroz, G., Biederman, J., Cantwell, D., Fontaine, R., Greist, J.H., Reichler, R., Katz, R., and Landau, P. (1992) Clomipramine hydrochloride in childhood and adolescent obsessive-compulsive disorder—a multicenter trial. / Am Acad Child Adolesc Psychiatry 31 45 9. 

Clomipramine Tertiary Same as imipramine (above) 28 7 5.4 0.2 Obsessive-compulsive disorder, age 12+ years... 

Flament, M.F, Rapoport, J.L., Berg, C.J., Sceery, W., Kilts, C., Mells-trom, B., and Linnoila, M. (1985) Clomipramine treatment of childhood obsessive-compulsive disorder. A double-blind controlled study. Arch Gen Psychiatry 42 977—983. 

Leonard, H.L., Swedo, S.E., Rapaport, J.L., et al. (1989) Treatment of obsessive-compulsive disorder with clomipramine and desipra-mine in children and adolescents a double-blind crossover comparison. Arch Gen Psychiatry 46 1088-1092. 

FIGURE 39.2 Treatment algorithm for pediatric obsessive-compulsive disorder (OCD). In adjusting cognitive behavior therapy (CBT), increase frequency or intensity, or alter the setting or format, e.g., have it be home based or day treatment. CMI, clomipramine DMI, desipramine NT, nortriptyline SSRI, selective serotonin reuptake inhibitor (fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram). 

Altemus, M., Swedo, S., Leonard, H., Richter, D., Rubinow, D., Potter, W., and Rapoport, J. (1994) Changes in cerebrospinal fluid neurochemistry during treatment of obsessive-compulsive disorder with clomipramine. Arch Gen Psychiatry 51 794-803. 

Figueroa, Y., Rosenberg, D., Birmaher, B., and Keshavan, M. (1998) Combination treatment with clomipramine and selective serotonin reuptake inhibitors for obsessive-compulsive disorder in children and adolescents. / Child Adolesc Psychopharmacol 8 61-67. 

Simeon, J. and Thatte, S. (1990) Treatment of adolescent obsessive-compulsive disorder with clomipramine-fluoxetine combination. Psychopharmacol Bull 26 285—290. 

Note. BROF = brofaromine CIT = citalopram CLO = clomipramine CT = cognitive therapy Dx = diagnosis EXP = exposure in vivo FLU = fluvoxamine FLUOX = fluoxetine GAD = generalized anxiety disorder 5-HTP = 5-hydrox3rtryptophan IMl = imipramine MAP = maprotiline OCD = obsessive-compulsive disorder PAR = paroxetine PD = panic disorder PLA = placebo PPM = psychological panic management RIT = ritanserin ... 

Aulde J The use of lithium bromide in combination with solution of potassium citrate. Medical Bulletin [Philadelphia) 9 35-39, 69-72, 228-233, 1887 Austin LS, Lydiard RB, Ballenger JC, et al Dopamine blocking activity of clomipramine in patients with obsessive-compulsive disorder. Biol Psychiatry 30 225-232, 1991... 

Baer L, Jenike MA, Black DW, et al Effect of Axis 11 diagnoses on treatment outcome with clomipramine in 55 patients with obsessive compulsive disorder. Arch Gen Psychiatry 49 862-866, 1992... 

Cox BJ, Swinson RP, Morrison B, Lee PS Clomipramine, fluoxetine and behavior therapy in the treatment of obsessive-compulsive disorder a meta-analysis. J Behav Ther Exp Psychiatry 24 2, 149-153, 1993a... 

Faedda GL, Baldessarini RJ, Tohen M, et al Episode sequence in bipolar disorder and response to lithium treatment. Am J Psychiatry 148 1237-1239, 1991 Falkenburg T, Mohammed AK, Henriksson B, et al Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment. Neurosci Lett 138 153-156, 1992 Fallon BA, Campeas R, Schneier FR, et al Open trial of intravenous clomipramine in five treatment-refractory patients with obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci 4 70-75, 1992... 

Haresh H, Aizenberg D, Munitz H Trazodone in clomipramine-resistant obsessive-compulsive disorder. Clin Neuropharmacol 13 322-328, 1990 Harrington MA, Zhong P, Garlow SJ, et al Molecular biology of serotonin receptors. 

Joyce D, Hurwitz HMB Avoidance behaviour in the rat after 5-hydroxytryptophan (5-HTP) administration. Psychopharmacologia 5 424-430, 1964 Joyce EM The neurochemistry of Korsakoff s syndrome, in Cognitive Neurochemistry. Edited by Stahl SM, Iversen SD, Goodman EC. Oxford, England, Oxford Science Publications, 1987, pp 327-345 Judd EK, Chua P, Lynch C, et al Eenfluramine augmentation of clomipramine treatment of obsessive compulsive disorder. Aust N Z J Psychiatry 25 412-414, 1991 Judge R, Steiner M The long-term efficacy and safety of paroxetine in panic disorder. 

McTavish D, Benfield P Clomipramine an overview of its pharmacological properties and a review of its therapeutic use in obsessive compulsive disorder and panic disorder. Drugs 39 136-153, 1990... 

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