Clomipramine antidepressant effect

Danish University Antidepressant Group Paroxetine a selective serotonin reuptake inhibitor showing better tolerance but weaker antidepressant effect profile in comparison with clomipramine a controlled multicentre study. J Affect Disord 18 289-299, 1990... 

The use of antidepressants outside the treatment of MDD tends to require specific agents. For example, the TCAs and SNRIs appear to be useful in the treatment of pain conditions, but other antidepressant classes appear to be far less effective. SSRIs and the highly serotonergic TCA, clomipramine, are effective in the treatment of OCD, but noradrenergic antidepressants have not proved to be as helpful for this condition. Bupropion and nortriptyline have usefulness in the treatment of smoking cessation, but SSRIs have not been proven useful. Thus, outside the treatment of depression, the choice of antidepressant is primarily dependent on the known benefit of a particular antidepressant or class for a particular indication. 

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... 

Kelly MW, Myers CW. Clomipramine a tricyclic antidepressant effective in obsessive compulsive disorder. DICP 1990 24(7-8) 739-44. 

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. 

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. 

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

All TCAs are either secondary- or tertiary-amines of a dibenzazepine nucleus (Fig. 20.3), and they all inhibit neuronal reuptake of noradrenaline and/or 5-HT but are much less potent as dopamine reuptake blockers. A common claim is that secondary amines (e.g. desipramine) are preferential inhibitors of noradrenaline uptake whereas the tertiary derivatives (e.g. imipramine, doxepin and amitryptyline) preferentially inhibit 5-HT uptake. However, when Richelson and Pfenning (1984) actually compared the effects of a wide range of antidepressants on the synaptosomal uptake of [ H]monoamines in vitro, and compared their A s, instead of merely ranking /C50S collected from different studies, they found that tertiary- and secondary-substituted compounds were equi-potent inhibitors of [ H]noradrenaline uptake. Moreover, all the TCAs turned out to be more potent inhibitors of [ H]noradrenaline than of [ H]5-HT uptake. Tertiary amines are even less convincing inhibitors of 5-HT reuptake in vivo, because any such action is diminished by their metabolism to secondary amines (e.g. imipramine to desipramine amitriptyline to nortriptyline). Only clomipramine retains any appreciable 5-HT uptake blocking activity in vivo with (an unimpressive) five-fold selectivity for 5-HT versus noradrenaline. 

The tricyclic antidepressant clomipramine also has been studied for PMDD. In placebo-controlled trials, both continuous daily dosing and luteal phase administration proved effective.17 Compared with the SSRIs, however, clomipramine has a less desirable side-effect profile with low tolerability. 

If treatment with an SSRI or another antidepressant such as clomipramine is not successful, hormonal treatment with a GnRH agonist, such as leuprolide, maybe considered. The use of leuprolide improves premenstrual emotional symptoms as well as some physical symptoms such as bloating and breast tenderness. Cost, the need for intramuscular administration, and the side effects of hypoestrogenism (e.g., vaginal dryness and hot flashes) limit its use. 

Until the introduction of selective serotonin reuptake inhibitors (SSRIs) in the 1980s, tricyclic antidepressants were the most widely used drugs. The therapeutic effect of amitriptyline and imipramine are related to their ability to inhibit the presynaptic reuptake of both NA and 5-HT. They are referred to as non-selective reuptake inhibitors, whereas many of the other tricyclics are more selective thus, clomipramine is a selective reuptake inhibitor for 5-HT and desipramine and nortriptyline are selective... 

In addition to this serious diet-drug interaction, irreversible MAOIs also potentiate the effects of sympathomimetic drugs like ephedrine found in over-the-counter cold remedies and recreational stimulants like amphetamine. The MAOIs also interact with drugs that increase synaptic concentrations of 5-HT, such as the tricyclic antidepressant clomipramine and the herbal SSRI antidepressant St John s wort (Hypericum spp.). The resulting serotonin syndrome is characterised by hyperthermia and muscle rigidity. While devoid of these side effects the reversible MAO-A inhibitor moclobemide has yet to establish itself as a first-line alternative to the SSRIs. 

The most effective treatment for cataplexy is the tricyclic antidepressants, fluoxetine, or venlafaxine. Imipramine, protriptyline, clomipramine, fluoxetine, and nortriptyline are effective in about 80% of patients. 

Tricyclic drugs have, as the name implies, a three-ring structure, and interfere with reuptake of norepinephrine and/or serotonin into axon terminals. Tricyclic drugs include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), and nortriptyline (Pamelor, Aventil). Tricyclics have the occasional but unfortunate cardiovascular side effects of arrhythmia and postural hypotension. Newer, nontricyclic antidepressants have been developed that are collectively referred to as SSRIs. These have a potent and selective action on serotonin, and lack the cardiovascular side effects of the tricyclics. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). A fifth SSRI, citalopram (Celexa) has been used in Europe and has recently been approved in the United States. Venlafaxine (Effexor) blocks reuptake of norepinephrine and serotonin, while bupropion (Wellbutrin) acts on both dopamine and norepinephrine. 

The traditional scheme is complicated by the fact that some antidepressants exhibit characteristics of more than one class. For example, clomipramine, a tricyclic antidepressant (TCA) with side effects and toxicity similar to other TCAs, works more like the selective serotonin reuptake inhibitors (SSRls). Similarly, venlafaxine and duloxetine, which are usually grouped with the atypical antidepressants, have a side effect and safety profile comparable to the SSRls. Although a classihcation system based on mechanism of action offers some advantage (see Table 3.7), even this scheme is limited by the fact that antidepressants that work in the same way may have widely divergent side effect and safety profiles. In the following discussion, the traditional classification system is adopted. Although fraught with problems and inconsistencies. 

Tricyclic Antidepressants (TCAs). The TCAs, particularly imipramine (Tofranil), were also discovered soon after their introduction to be effective in the treatment of panic attacks. Imipramine, the best-studied TCA in the treatment of panic disorder, is most often helpful at daily doses of 150-250 mg, though it must be started at 10-25 mg, usually at bedtime, and gradually increased over 2-4 weeks. Although they are not as well studied, many clinicians prefer to use the secondary amine TCAs, desipramine (Norpramin) and nortriptyline (Pamelor), because they have milder side effects than imipramine. Clomipramine (Anafranil), though probably the TCA with the greatest side effect burden, is often said to be most effective in patients with refractory disease. 

Tricyciic Antidepressants (TCAs). There has been surprisingly little study of TCAs in the treatment of social anxiety disorder. Early trials with imipramine and clomipramine suggested they might be beneficial however, subsequent controlled studies indicate that TCAs are no more effective than placebo. Consequently, they are not used to treat social anxiety disorder. 

Serotonin-Boosting Antidepressants. Antidepressants that enhance serotonin activity in the brain have also been studied in ADHD. In particular, fluoxetine (Prozac) and the serotonin-selective TCA clomipramine (Anafranil) have been the most extensively evaluated, with mixed success. They provide some benefit for aggression and impulsivity but don t significantly improve the poor attention of ADHD. As a result, the SSRls and other serotonin-boosting antidepressants do not appear to be effective first-line treatments for ADHD. Conversely, depressed patients without ADHD often show improvements in symptoms of concentration and attention when treated with a SSRI. Although SSRls are not widely used in the treatment of ADHD, they may be worthy of consideration in ADHD patients whose impulsivity is not controlled by stimulants alone. Those with comorbid conduct disorder or ODD who are prone to agitation and at times violent outbursts may be helped by the addition of a SSRI. 

Changing a patient from one MAOI to another, or to a TCA, requires a "wash-out" period of at least 2 weeks to avoid the possibility of a drug interaction. There is evidence to suggest that a combination of an MAOI with clomipramine is more likely to produce serious adverse effects than occurs with other TCAs. Regarding the newer non-tricyclic antidepressants, it is recommended that a "wash-out" period of at least 5 weeks be given before a patient on fluoxetine is given an MAOI this is due to the very long half-life of the main fluoxetine metabolite norfluoxetine. 

This group includes compounds with actions on a range of neurotransmitter systems. Their antidepressant efficacy is mediated by reuptake inhibition of serotonin and noradrenaline, although side-effects such as sedation may also be useful. Their use in anxiety disorders is supported by a long history of clinical experience and a reasonable evidence base from controlled trials. Studies support the use of clomipramine (a potent serotonin reuptake inhibitor) in panic disorder and OCD (Lecrubier et al. 1997 Clomipramine Collaborative Study Group 1991), of imipramine in panic disorder and GAD (Cross-National Collaborative Panic Study 1992 Rickels et al. 1993), and of amitriptyline in PTSD (Davidson et al. 1993a). No controlled studies support the use of TCAs in social anxiety disorder. 

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