PsychoTropicalResearch, serotonin and serotonin syndrome research.
Antidepressants - Reboxetine
Antidepressants - Reboxetine
Date Created: 20/09/1999 Last Modified: 25/04/2003 Last Checked: 25/04/2003
Reboxetine is a specific noradrenaline reuptake inhibitor (NRI) and has no affinity for those receptors that cause problems (and, perhaps, some benefits) for tricyclic antidepressants: viz-- A1, H1, M1-6 (muscarinic) etc. It has less of these side effects, especially it does not cause postural hypotension or memory impairment which, with the TCAs, is mediated by their blockade of A1 and muscarinic receptors (see 'receptor affinities').
It looks like Reboxetine may be a significant new antidepressant drug. If you have read my comments on many other new antidepressants you will appreciate that is a more consequential statement than it might at first appear.
Reboxetine is well absorbed and absorption is unaffected by food. The (plasma) half-life is about 13 hours and the central nervous system activity is, presumably, rather longer: thus it appears suitable for once daily administration. Excretion is largely renal after oxidation and hydroxylation probably via 3A4 and the dose may need to be lower in patients with severe renal impairment. It does not seem to adversely affect any cytochrome P450 enzymes and thus, similar to citalopram and sertraline, is likely to be free from significant interactions (at least through major metabolic pathways of the cytochrome P450 enzymes).
Reboxetine is a drug that may be particularly useful in combination with an SSRI like sertraline; such a combination would be expected to emulate the ‘serotonin and noradrenalin’ reuptake (SNRI) effect that may be responsible for the putative superior effect of clomipramine, and venlafaxine (which may not be an NRI, only an SRI) as well as milnacipran and duloxetine (which may after much delay be marketed- althought it too may not be a true NRI in humans). Animal research supports this idea, see Harkin below.
It is perhaps helpful to put reboxetine in context; it is likely to be most similar to the most noradrenergic of the tricyclic antidepressants (see receptor affinities); this is because most of the tricyclic antidepressants (TCAs) probably work mainly as noradrenalin reuptake inhibitors (NRIs). Of the tricyclic antidepressants, only clomipramine is sufficiently potent as a serotonin reuptake inhibitor to a) treat obsessive compulsive disorder and b) to induce serotonin syndrome at usual doses (see serotonin syndrome). The most potent noradrenalin reuptake inhibitors of the TCAs, in descending order of potency are: desipramine, lofepramine and nortriptyline.
A common misconception, and one that is still repeated in supposedly authoritative texts, is that tricyclic antidepressants are unsafe if combined with MAOIs; that is only true for those that are significant serotonin reuptake inhibitors (viz clomipramine and imipramine), since most TCAs are not serotonin reuptake inhibitors they are safe with MAOIs. The above comments are not intended to suggest that there is much evidence that this combination is useful. However certain properties of some 'TCAs' can be utilised to good effect when combined with MAOIs eg the potent sedative effect of a small (10-20 mg) of doxepin.
The above recapitulation helps in understanding this interesting paradox:-- that MAOIs are actually safer when combined with drugs like reboxetine that act as noradrenalin reuptake inhibitors. This is because the hypertension resulting from ingestion of tyramine (the 'cheese effect') depends on tyramine being able to enter the pre-synaptic nerve. That process is enabled by the noradrenalin reuptake mechanism ("transporter") and that is itself blocked by those antidepressant drugs which act through noradrenalin reuptake inhibition. ie reboxetine and TCAs.
With reboxetine the absence of sedative properties (no H1 blockade) may mean that some patients will need something else to improve their sleep. Indeed, a decade of experience with sertraline + either desipramine (very little H1 sedative effect) or nortriptyline (mild but useful H1 sedative effect) suggests that the sertraline, in the morning, + nortriptyline, in the evening, combination is usually the most satisfactory because it usually helps sleep well without causing a daytime sedative effect. My 12 months experience of sertraline + reboxetine shows, as anticipated, similar limitations as sertraline + desipramine did.
Reboxetine may have a different antidepressant effect profile to SSRIs; more news of this as the evidence accumulates. In brief, the advent of this drug is (re)focussing attention on the old idea that specific neurotransmitter pathways mediate different aspects of the illness. This is an idea whose time may have come, and in my view none too soon. See 'Diagnostic criteria -- alternative concepts'.
Nearly ten years ago in "Plus ça change, plus c'est la même chose" I opined that we might find ourselves discovering that specificity was not the holy grail. "The wheel is come full circle", or so it seems. I mean that it is begining to appear as if drugs that are specific, either as serotonin reuptake inhibitors, noradrenalin reuptake inhibitors (NRIs) or as serotonin and noradrenalin reuptake inhibitors (SNRI) are not as potent as amitryptiline or clomipramine. That serves to remind us that our current presumptions about how antidepressants work may well appear somewhat unscientific and naive to future observers.
Exactly how useful reboxetine will turn out to be, when used on its own, is yet to become clear: but I am confident that it augments the efficacy of sertraline in a similar manner, and to a similar degree, to nortriptyline. The optimal choice depends on other effects such as sleep pattern, weight, blood pressure and other illnesses the patient may have.
Despite total lack of anti-muscarinic activity the noradrenergic activity may make it liable to aggravate benign prostatic hypertrophy, constipation, and narrow angle glaucoma. Indeed it even causes urinary retention or difficulty in females.
Remember that either increased noradrenalin, or decreased acetylcholine, activity may precipitate these problems.
All text ©Dr Ken Gillman MRC Psych - PsychoTropical Research®
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