PsychoTropical Research - Dr Ken Gillman, Serotonin Syndrome, Mirtazapine, Dual Action Drugs. Antidepressants - Nefazodone.

PsychoTropicalResearch, serotonin and serotonin syndrome research.

Antidepressants - Nefazodone

Antidepressants - Nefazodone

Date Created: 26/01/1998   Last Modified: 22/04/2003   Last Checked: 23/04/2003

Introduction

Nefazodone (Serzone) is a 'non SSRI' closely related to trazodone. It claims to be an antidepressant. It blocks post synaptic 5-HT2A receptors but has insignificant serotonin reuptake inhibitor activity. So far experience suggests that it is not a satisfactory or effective antidepressant. As of 2003 it is being progressively withdrawn from various markets.

I'd forget it; for GPs it is unlikely to be worth devoting the time needed to learn about it and its problems and disadvantages.

I am not being wise after the event; I espoused this view in the original version of this note in 1998.

But read on: the lessons that may be learnt from reviewing failed drugs like this are valuable.

Now, in 2003, it is being withdrawn from some European markets (liver toxicity is cited as the reason): that may be because doctors have greatly reduced their use of it, and its not much of an earner. Liver toxicity may be no worse than some other antidepressants still being used. If it was a highly effective drug, with a different effectiveness profile, then it might well be appropriate to continue using it.

Nefazodone is a recent different 'non SSRI' antidepressant closely related to trazodone. It claims to be an antidepressant. The clinical trial evidence supporting its efficacy in major ('endogenous') depressive illness is poor; as it is for many antidepressant drugs. It blocks post synaptic 5-HT2A receptors (see 'receptor affinities') and may have some weak (clinically insignificant) serotonin reuptake inhibitor activity. It is thought to increase serotonergic activity. Whether that is to a useful extent remains doubtful, and from my analysis of the evidence, unlikely. So far experience suggests that it is not a satisfactory or effective antidepressant.

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

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

  1. It's 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 significant CYP450 3A4 inhibitors). That is another undesirable characteristic.
  3. Plasma levels of both nefazodone and it's metabolites show great inter-individual variation making dosage adjustment more difficult and therapeutic drug monitoring desirable (but it is generally unavailable).
  4. Nefazodone has another undesirable property-- that of 'non-linear' pharmacokinetics. Nefazodone and its two main metabolites are significant 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 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 (and now more-- see above).

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 (small) 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.

Nefazodone is metabolised (inter alia) into an anxio-genic metabolite called 'm-CPP' and this may cause problems. m-CPP is itself further broken down by CYP4502D6 and may accumulate in slow metabolisers.

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, this indicates 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 toxicity (serotonin syndrome) in over-dose by themselves, or if mixed with monoamine oxidase inhibitors. Indeed trazodone is used as a hypnotic in combination with MAOIs without apparent problems. All other SRIs used in humans are likely to cause life-threatening serotonin syndrome if mixed with monoamine oxidase inhibitors.

The general hypothesis relating to serotonin toxicity and how it may provide an index of the serotonergic activity of particular drugs in clinical doses in human useage is set out in detail in the Oxford University Press book chapter on serotonin toxicity I have co-authored with Assoc Prof Ian Whyte and in a published letter in J Clin Psych (Gillman, 2003).