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Serzone: Does it even work?

Posted by dhldn on December 16, 2001, at 11:14:55

Nefazodone is a recent different 'non SSRI' drug closely related to trazodone. It claims to be an antidepressant. It blocks the post synaptic 5-HT2A receptors (see 'receptor affinities') and may have some weak (probably clinically insignificant) serotonin reuptake inhibitor activity. It is thought to increase serotonergic activity. Whether that is to a useful extent remains questionable and from my analysis of the evidence unlikely.

The problems and difficulties caused by this drug mean that careful consideration will frequently relegate it to a priority insufficiently high to warrant its use in primary care.

So far experience suggests that it is not a satisfactory antidepressant.

It is a relatively troublesome drug. Indeed it serves as a good illustration of the pharmacological points to assess when considering a new drug.

1 Its half-life of 1.5 - 4 hours is inconveniently short. Multiple daily dosing is required; at least twice daily, maybe three or even four times. The preferred range for half-life is 12-36 hours. That allows once daily dosing without to long a time to steady state, which would create a longer time lag before optimum improvement.

2 It has not one, but several, active metabolites about which little is known (but two of them are potent 3A4 inhibitors). This is an undesirable characteristic.

3 Plasma levels of both nefazodone and it's metabolites show very great inter-individual variation making dosage adjustment difficult and therapeutic drug monitoring desirable (but it is unavailable).

4 Nefazodone has another undesirable property-- that of 'non-linear' pharmacokinetics. Nefazodone and its two main metabolites are potent inhibitors of cytochrome P450 3A4; so it blocks its own metabolism (via cytochrome P450 3A4) and thus the blood level goes up out of proportion to the dose increase. This makes dose adjustment more tricky and may increase the chance withdrawal effects.

5 It retains significant alpha 1 blocking activity (like the tricyclic antidepressants) and thus has the side effect of postural hypotension.

6 Interactions with drugs metabolised by 3A4 do occur and are clinically significant, eg benzodiazepines, anti-histamines, TCAs and ergotamine (risk of serious toxicity).

7 It requires titration over a period of time.

Like some other new drugs, my view is that there is insufficient evidence of its effectiveness for the long term treatment of major depression compared to the best of the old TCAs (and sertraline).

It is too early to claim it is safer, either in over-dose or for rare serious side effects. Indeed there have recently been three cases of severe liver damage reported in association with nefazodone (see 'new').

In my opinion there is no more reason why this drug should act as an antidepressant than, say, cyproheptadine which also blocks the post synaptic 2A receptors. My experience and interpretation of the evidence leads me to the view that this drug (like its progenitor, trazodone) is not a useful antidepressant.

Trazodone, which is very similar indeed to nefazodone, has been around for over twenty years. It has never gained much of a reputation as an antidepressant; it is perhaps best thought of as an interesting non-benzodiazepine hypnotic with the advantage of having a low fatal toxicity index. There seems little reason to suppose that nefazodone will be much different; indeed since whatever place there may be for such a drug is already taken up by trazodone (in most countries) there may not be an 'ecological niche' for nefazodone and I would not be surprised if it were taken off the market.

Nefazodone is metabolised (inter alia) into an anxio-genic metabolite called 'm-CPP' and this may cause problems in a rather curious way (see cytochrome P450 enzymes interactions; 'curiouser and curiouser')

Note-- it is unlikely that nefazodone works as a clinically effective serotonin reuptake inhibitor at all.

As an inevitable consequence of their mode of action all serotonin reuptake inhibitors reduce platelet serotonin content. This is because platelets themselves do not produce serotonin, they take it up from the plasma. To do this they use the same uptake mechanism as do pre-synaptic neurons. If serotonin reuptake is blocked then platelets become greatly depleted of serotonin.

Neither trazodone nor nefazodone significantly reduce platelet serotonin in humans, ergo, they probably do not act as serotonin reuptake inhibitors. Further evidence that neither trazodone nor nefazodone are capable of significantly increasing brain 5-HT is that they do not cause serotonin syndrome if mixed with monoamine oxidase inhibitors. All other SRIs used in humans are likely to cause life-threatening serotonin syndrome if mixed with monoamine oxidase inhibitors.

***** Click 'view references' to go to the references screen where you can also see the associated notes / abstract summary.

Dr Ken Gillman MRC Psych

PsychoTropical Research




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