Clomipramine

Abstract

During the 20 years that have elapsed since clomipramine (chlorimipramine) was first marketed, it has become well established in the treatment of depressive illness, particularly treatment-resistant depression. However, in addition to its role as an antidepressant, attention is being focussed on the use of clomipramine in 2 other areas of psychiatry: obsessive compulsive disorder and panic disorder. Short term clinical trials have shown that clomipramine is generally more effective than amitriptyline, imipramine, desipramine, nortriptyline or clorgiline in reducing obsessive compulsive symptoms. Clomipramine appears to produce some short term benefit with exposure therapy in patients with obsessive compulsive disorder. However, the efficacy of the drug after long term follow-up has not been fully investigated. The antiobsessional efficacy of clomipramine appears to be independent of its antidepressant activity. In patients with panic disorder with or without agoraphobia (DSM-HIR), clomipramine reduces the frequency and severity of panic attacks within 7 to 21 days of beginning treatment and efficacy is maintained for at least 12 months. Clomipramine is more effective than imipramine, the generally accepted standard treatment for patients with panic disorder after 2 weeks’ treatment, but after 6 or 10 weeks both drugs are similarly effective. Other double-blind studies have shown that clomipramine is more effective than placebo and at least as effective as fluvoxamine and oxitriptan (5-hydroxytryptophan) in reducing panic attacks and associated anxiety. Adverse effects associated with clomipramine treatment are mild to moderate in nature and are predominantly a result of the drug’s anticholinergic activity. The incidence of seizures is dose related, occurring in 0.48% of all patients receiving clomipramine ≤ 250 mg/day and 2.1% of patients receiving ≥ 300 mg/day. In conclusion, the available data indicate that clomipramine is a worthwhile addition to the limited treatments available for obsessive compulsive disorder and panic disorder, two psychiatric disorders which have previously been difficult to manage pharmacologically. Clomipramine is a potent inhibitor of serotonin (5-hydroxytryptamine) reuptake in vitro. In vivo administration of the drug markedly reduces serotonin and 5-hydroxyin-doleacetic acid levels in cerebrospinal fluid and platelets from patients with depression or obsessive compulsive disorder. Receptor binding studies have shown that clomipramine has affinity for central dopamine-D₂, histamine-H₁, and α₁-adrenergic receptors, but the relevance of these findings to the pharmacological profile of the drug remains to be clarified. Clomipramine also has anticholinergic activity in vitro and in vivo and increases plasma prolactin levels in depressed patients. These effects may be responsible for some of the adverse effects associated with clomipramine treatment. Oral clomipramine is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations of 41 to 81 μg/L are reached within 2 to 4 hours of a single oral 1 mg/ kg dose in healthy volunteers. Steady-state plasma clomipramine concentrations of 20 to 275 μg/L were achieved within 7 to 14 days of oral clomipramine 100 to 200 mg/day in patients with depression or obsessive compulsive disorder. Steady-state plasma demethylclomipramine concentrations are generally higher, but reached later, than those of the parent drug. Most studies in patients with depression or obsessive compulsive disorder have failed to show a relationship between plasma clomipramine or demethyl-clomipramine concentrations and clinical response, but in 1 study an optimal therapeutic response was reported in patients with obsessive compulsive disorder with a plasma clomipramine concentration of 100 to 250 μg/L. Clomipramine is 98% bound to plasma protein and, because of its highly lipophilic nature, the drug would be expected to have a large volume of distribution. Only 1 to 3% of an oral or intravenous clomipramine dose is excreted unchanged. About 60% is excreted as urinary metabolites and about 30% is excreted via faeces. Demethylation is the major metabolic pathway but hydroxylation and N-oxidation also occur. Clomipramine undergoes extensive first-pass hepatic elimination after oral administration. Mean plasma elimination half-lives for clomipramine are 20 to 26 hours in healthy volunteers and 34 to 36 hours in depressed patients. Demethylclomipramine has an elimination half-life of 50 hours in depressed patients. Double-blind studies spanning 5 to 16 weeks have shown the superiority of oral clomipramine in daily doses of 50 to 300 mg/day over placebo in reducing obsessive and compulsive symptoms. In one study, about three-quarters of children, previously unresponsive to other drug therapies, showed at least 25% improvement on the Obsessive Compulsive Rating scale. Similarly, in adult patients a superior effect over placebo was evident after 3 weeks of treatment and this persisted for up to 16 weeks. Data from 2 large multicentre studies have shown a mean improvement of 40 to 45% in obsessive compulsive symptoms after 10 weeks compared with 4 to 5% in patients administered placebo. Several studies have shown that clomipramine has a more pronounced effect on obsessive compulsive symptoms than desipramine, imipramine, amitriptyline, nortriptyline, or clorgiline. Generally, the superiority of clomipramine is evident 3 to 6 weeks after initiation of treatment and withdrawal of clomipramine treatment results in relapse within 3 days. Clomipramine reduced depressive symptoms occurring secondary to obsessive compulsive disorder to a greater extent than other antidepressants but in most comparative studies no significant correlation was seen between the antiobsessional and anti-depressant effects of clomipramine or between improvement in obsessive compulsive symptoms and initial severity of depression. The antiobsessional effect of clomipramine therefore appears independent of its antidepressant activity. Clomipramine appears to produce some short term benefit with exposure therapy in patients with obsessive compulsive disorder. However, the short term benefit of clomipramine was not apparent following change of exposure therapy in the longer term. In the treatment of panic disorder with or without agoraphobia (DSM-IIIR), non-comparative studies have shown that clomipramine resolves panic attacks in at least 75% of patients after 7 to 21 days of treatment and efficacy is maintained for at least 12 months. Clomipramine was as effective as imipramine after 6 to 10 weeks but, unlike imipramine, the efficacy of clomipramine was evident after only 2 weeks of treatment. Clomipramine was also comparable to fluvoxamine and superior to placebo and oxitriptan (5-hydroxytryptophan) in reducing anxiety symptoms, and had a superior effect on reducing associated depression in these patients. Most of the adverse effects associated with clomipramine treatment are extensions of its pharmacological properties, particularly its anticholinergic effects. The most frequently reported adverse effects associated with clomipramine therapy as reported in clinical studies up to 1988 are anticholinergic effects (43%), central nervous system effects (25%), gastrointestinal effects (10.5%), sexual dysfunction (8%), tremor (6%), cardiovascular effects (3%), and sleep disturbances (1.5%). The adverse effect profile in patients with obsessive compulsive disorder follows a similar pattern: in a study of 150 patients, the most common adverse effects were dry mouth (53%), excessive sweating (19%) and constipation (20%). The incidence of clomipramine-induced seizures appears to be dose-related: seizures were reported in 0.48% of patients (n=2514) treated with a maximum dose of 250 mg/ day and in 2.1% of patients (n=472) treated with 300 mg/day or above. Clomipramine has a lower fatal toxicity index (defined as deaths per million prescriptions) after overdose than other tricyclic antidepressants. The incidence of overdose with clomipramine has not been reported, but fatalities have occurred. For the treatment of obsessive compulsive disorder oral clomipramine administration should start at 25mg 2 or 3 times daily, before titrating up to a maximum of 250 mg/ day. The usual maintenance dosage is 50 to 100 mg/day. Parenteral clomipramine should be administered as a 25 to 50 mg/day intramuscular dose or a 50 to 75mg infusion. Maintenance therapy with oral clomipramine can be substituted once clinical improvement has been achieved. In patients with panic disorder or agoraphobia with panic attacks, a low initial dosage (10 mg/day) is recommended. This should be increased gradually until an effective dosage (generally 50 to 100 mg/day) is achieved. The maintenance dosage is usually 25 mg/day or less.