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Antidepressants - Clomipramine

Date Created: 29/09/2000   Last Modified: 18/05/2002   Last Checked: 21/10/2002

It seems ironic that despite all the new drugs that have arrived in the last decade of the last millennium some of the best evidence for superior efficacy is for the older ones (especially clomipramine and clozapine).

Clomipramine was the first, and for some while the only drug (till fluoxetine 1986), that was effective for obsessive compulsive disorder. This was first noted around 1966, the French take the credit for that. The French also were the first to observe the mood stabilising effect of anti-epileptic drugs as well as the anti-psychotic effect of chlorpromazine, to mention but some of their firsts; funny how infrequently those 'firsts' are referenced and quoted; it is an anglo-centric world. The Brits and others were several (that is being kind) years behind.

It is quite extraordinary to reflect that it took the USA and Australia (where clomipramine was not introduced until 1983) so long to appreciate the superiority of this drug. The implications that has for scientific progress in psychiatry hardly require elaboration and certainly do not reflect credit on the discipline.

Clomipramine is effective for obsessive compulsive disorder almost certainly because it is a potent serotonin reuptake inhibitor, indeed more potent (in vitro) than most of the new serotonin reuptake inhibitors (SSRIs). It is metabolised into desmethyl-clomipramine which, like desipramine (which is desmethyl-imipramine), is a potent noradrenalin reuptake inhibitor.

Since both are present in patients the net effect of clomipramine is that of an 'SNRI', that is a serotonin and noradrenalin reuptake inhibitor.

More recently a new compound, venlafaxine, which may also be an 'SNRI', has been introduced. There is still some doubt about how venlafaxine works and how well it works; it is a weak noradrenalin reuptake inhibitor. Its true status as an SNRI is still uncertain.

There will be many younger practitioners who have never seen an advertisement for clomipramine (or tranylcypromine for that matter) but who may have been made aware of the evidence for the beneficial results consequent upon the blockade of 5-HT2A receptors (as expounded for nefazodone and mirtazapine). However, many are not aware that several of the old TCAs, especially clomipramine, are also just as potent as nefazodone as 5-HT2A blockers (see 'receptor affinities').

Clomipramine has now been available for nearly 40 years; for all that time it has possessed the two properties that are now being promoted to increase the sales of two of the newest, and most expensive, drugs: viz it is both an serotonin and noradrenalin reuptake inhibitor and a 5-HT2A blocker. 'Plus ça change, plus c'est la même chose' as the old saying goes (the more things change the more they are the same).

Clomipramine is quite simply one of the most potent 'broad-spectrum' antidepressants in existence. It deserves to be much more widely used. There is persuasive evidence from well executed work (the 'DUAG' studies-- see below) that clomipramine is a more potent antidepressant and it is also effective for obsessive compulsive disorder, generalised anxiety disorder, phobias and panic attacks, not to mention migraine.

Although all TCAs can have troublesome side effects it is sobering to review the latest evidence which is that there is only a 3% difference in side effect discontinuation rates between TCAs and SSRIs (see Anderson). Paradoxically, for older patients this difference may be even less.

Clomipramine is much less toxic than other TCAs in over-dose and is ten times less liable to cause serotonin syndrome in over-dose than the SSRIs (or venlafaxine). It is ironic that most sources relegate clomipramine to a second or third line choice whereas the new and highly promoted drug, venlafaxine, is now being touted not only for depression but also generalised anxiety disorder. It is ironic because current evidence indicates quite strongly that venlafaxine is not less toxic than many tricyclic antidepressants; preliminary evidence indicates venlafaxine is more toxic than clomipramine; venlafaxine causes serotonin syndrome about ten times more frequently after over-dose than does clomipramine.

Providing the dose of clomipramine is adjusted carefully it is tolerated well by most patients; blood levels are often useful in optimising the dose. However the 'therapeutic range' of blood levels may need to be exceeded sometimes; the dose should be judged according to the patients improvement and side effects, not just the blood levels.

All text ©Dr Ken Gillman MRC Psych - PsychoTropical Research®


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