Anxiolytics clomipramine

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. 

Ultrasonic vocalizations are emitted by rat pups (under the age of 14 days) when they are isolated from their mother, and are thought to reflect anxiety. This measure has proven sensitive to both anxiolytic and anxiogenic manipulation of GABA neurotransmission. However, the early developmental window used is problematic, in that chronic drug administration probably results in a variety of compensatory changes not seen in adulthood, and may alter development of relevant brain systems. Indeed, in contrast to the clinical situation, the antidepressant clomipramine has acute, but not chronic, anxiolytic efficacy in this model. 

Imipramine, a TCA, was the first pharmacological agent noted to treat panic disorder (Klein 1964). Other TCAs, notably clomipramine, have also been found to have significant anxiolytic properties (den Boer et al. 1990 Modigh 1992). Studies of ethnic differences in the pharmacokinetics of the TCAs in... 

The efficacy of TCAs, principally impramine, has also been tested as treatment of separation anxiety and school phobia. Four placebo-controlled studies involving 140 children have been conducted (153, 158, 159 and 160). Whereas early studies were positive, subsequent reports were not. Gittelman-Klein and Klein ( 161) demonstrated a significant benefit over placebo from 6 weeks of treatment with imipramine (mean dose = 159 mg per day) in 45 children with school phobia. A subsequent study using lower amounts of clomipramine (40 to 75 mg per day) was negative but the doses used make interpretation difficult. Also, because of its tolerability and safety profile, clomipramine is generally not used as an anxiolytic agent in children or adolescents. 

By the 1970s and early 1980s it was recognized that certain tricyclic antidepressants and monoamine oxidase (MAO) inhibitors were effective in treating panic disorder and one tricyclic antidepressant (clomipramine) was effective in treating obsessive-compulsive disorder. Thus, there began to be recognized that some antidepressants overlapped with anxiolytics for the treatment of anxiety disorder sub-types or for mixtures of anxiety and depression (Fig. 8—8). However, either anxiolytics... 

Benzo derivatives are well known (Figure 4) and some are the basis of important therapeutic agents such as the tricyclic antidepressant clomipramine 3 and the anxiolytic agent diazepam 4. In these molecules the seven-membered rings act as extremely good scaffolds that allow a wide variety of substituent variation and exploration of conformational space during the discovery phase of drug development. 

UGTs are responsible for the metabolism of many anxiolytics, antidepressants, mood stabilizers and antipsychotics. Inhibition of the metabolism of carbamazepine by valproic acid in part results from an effect on UGTs. Amitriptyline and clomipramine decrease the metabolism of morphine by affecting UGTs. 

It will be noted (Table 12-17) that these four first-generation TCAs are tertiary amines. Their clinical activity was initially described as neuroleptic (mood elevating). They also exhibited a degree of anxiolytic effects and reduced agitation in animals and humans. The introduction of clomipramine (2-chloroimipramine) (1990) offered the psychiatrist the first drug effectively to treat obsessive-compulsive disorders of the type serious enough to interfere with social or occupational functions. 

Indalpine is a non-tricyclic antidepressant with a serotonin selective profile. It is 6-7 times more potent than fluoxetine and clomipramine in inhibiting serotonin reuptake m vitro in rat brain synaptosomes. Statistically significant clinical effects within one week of onset of treatment have been reported. An anxiolytic effect may accompany the antidepressant effect. Indalpine appears devoid of anticholinergic and cardiovascular side effects and does not promote weight gain or affect appetite. 

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