Duloxetine: another SNRI myth

by | Last updated Sep 28, 2020 | Published on Mar 29, 2020 | Anti-Depressants, SNRIs

Duloxetine does not have a ‘badge-engineered’ metabolite derivative to extend its patent, unlike Venlafaxine (Effexor, now out of patent), and its patent-extending-metabolite, desvenlafaxine.

This commentary will be short because it is simple to demonstrate that duloxetine has an insubstantive claim to be called an SNRI, nor good evidence to show it is superior — even to sugar tablets, never mind other (S)SRIs*. It is therefore of little interest.

*A quick reminder for those who have not yet delved deeply into this sort of thing: much of this terminology, like specific serotonin reuptake inhibitor (SSRI), or serotonin and noradrenaline reuptake inhibitor (SNRI), has got more to do with marketing and advertising than it has to do with pharmacology. Hence the frequent sarcastic asides that I make relating to these sorts of issues; also the disparaging comments that I make about my colleagues who accepted the drug company stories about these sorts of things with such uncritical and acquiescent naïveté.

It is also appropriate to remind people of the history of this drug: it was synthesized way back, patented in 1990, AD trials, which ‘failed’, started 1993 [1, 2]; those original studies have disappeared from the common ken, presumably because they were unsuccessful — for instance, they were not referred to in the Lancet 21 antidepressant to study. It was finally approved by the FDA in 2004. I remember trying to get some off Lilly to trial it myself sometime in the 1990s, only to be told that they had ceased to develop it as an antidepressant. It then reappeared as a drug to help urinary incontinence [3, 4] in a Japanese trial! Talk about flogging a dead horse!

It then resurfaced in a second attempt to sell it as an antidepressant with the SNRI tag. I wrote to Cipriani after the Lancet study to ask him why they had not included those original studies, but he was too busy to reply (perhaps he did not even know about them). Nobody likes inconvenient facts, and as the Frenchman ‘Bernard Le Bovier de Fontenelle’ said:

If my hands were full of truths I should be careful of opening them’

What he actually said, of course was; ‘Si j’avais la main pleine de vérités, je me garderais de l’ouvrir’.

Some unfavourable comment has been made about various aspects of the duloxetine trials: Maund et al. stated ‘Clinical study reports contained extensive data on major harms that were unavailable in journal articles and in trial registry reports’ [4]. I think we interpret that to mean that they had ‘hidden’ unfavourable data, what a surprise. I have neither the time to expend, nor the interest, to look into this any more deeply, but I am sure if one did one would find all sorts of other ‘problems’ similar to the ones that I, and others, have uncovered and written about concerning various other drugs (cf. mirtazapine).

I think I am going to call this repetitive dishonesty and misrepresentation the Trump syndrome — in other words if you keep deceiving people and telling untruths often enough, people will become inured to it, and just stop noticing it. Only a day or two ago I noted somebody who was keeping count saying that Trump had now told 12,000 untruths since he had taken office.

I suppose we should remind ourselves of Winston Churchill’s great phrase for a lie, ‘terminological inexactitude’ – although perhaps Trump has extended it to ‘interminable terminological inexactitudes’.

A splendid euphemism for a lie. And perhaps we might also remember the statement by Lord Birkenhead, (FE Smith), I think it was, who in a debate was admonished for calling an honourable member a liar. In the apology that was demanded he said:

I called the honourable member a liar it is true and I regret it.

You may place the punctuation where you wish.

Promotion of SNRI drugs

Promoting these so-called SNRI drugs as beneficial and superior for severe or TR depression is founded on poor evidence. The Lancet 21 antidepressant study (which I have criticized elsewhere) is the best recent summary of the trials concerning duloxetine [5] — if you deem using the word ‘best’ is appropriate in association with these kinds of studies. Those studies are not equipped to address the question of whether it might be better for treatment resistant cases, but they do indicate that it has a worse side-effect profile, and a higher treatment dropout-rate, than most comparator drugs.

One good reason for saying that duloxetine fails the test as an SNRI is that it does not block the tyramine pressor response, even at 60 mg per day. I quote Blier et al:

However, the same doses of duloxetine, unlike clomipramine, failed to impede the usual increase in blood pressure that follows a tyramine intravenous infusion, indicating that clomipramine but not duloxetine blocked NE reuptake. At doses tested in a population of healthy volunteers, duloxetine acted as a selective 5-HT reuptake inhibitor, having no clear effect on the NE reuptake process, like venlafaxine [6, 7].

A group of experts looked at the ‘SNRIs-are-superior’ question in 2007 [8] and concluded: ‘Three antidepressants met [their defined] criteria: clomipramine, venlafaxine, and escitalopram’.

The first in that list I agree with but…

Summary

There is great doubt that so-called dual action drugs (SNRIs — venlafaxine, duloxetine) have useful, never mind optimal, dual action properties. I have used combinations to attain an SNRI effect, starting in the 1980s, I am very confident that venlafaxine and duloxetine are not as effective as either clomipramine, or a combination of two different drugs such as sertraline and nortriptyline, largely because neither of the aforementioned drugs are in fact significantly potent NRIs, but for other reasons also.

  • The old TCA, clomipramine, remains the benchmark dual action drug
  • Safe and flexible dual action combinations (of an SSRI with an NRI, e.g. sertraline + nortriptyline) allow better efficacy, more flexibility, and less side effects.
  • The widespread ignorance, ambivalence, and reluctance among psychiatrists, regarding mixing different antidepressant drugs, reflects their lack of pharmacological knowledge: there are various perfectly safe options.
  • Mixing several drugs with different actions is routine practice in the treatment of hypertension, diabetes, heart disease and other conditions. The objection that ‘poly-pharmacy’ is prima facie, bad, is both illogical and mistaken (but it is the inevitable result of lack of knowledge about mechanisms of interactions and potential risks — ignorance breeds fear).
  • When I wrote my first note about this drug, 20 years ago, I was sceptical. Now that more evidence is available, I am more confident in stating that as an ‘SNRI’ duloxetine is an imposter, and that as an SRI it is inferior to various other drugs.
  • Its’ claim to be an SNRI has been gullibly and naïvely accepted by psychiatrists. It has no clinically significant effect on noradrenalin in vivo even at doses of 60 mg per day.

References

1. Fuller, R.W., S.K. Hemrick-Luecke, and H.D. Snoddy, Effects of duloxetine, an antidepressant drug candidate, on concentrations of monoamines and their metabolites in rats and mice. J Pharmacol Exp Ther, 1994. 269(1): p. 132-6.

2. Wong, D.T., et al., LY248686, a new inhibitor of serotonin and norepinephrine uptake. Neuropsychopharmacology, 1993. 8(1): p. 23-33.

3. Anttila, S. and E. Leinonen, Duloxetine Eli Lilly. Curr Opin Investig Drugs, 2002. 3(8): p. 1217-21.

4. Maund, E., et al., Benefits and harms in clinical trials of duloxetine for treatment of major depressive disorder: comparison of clinical study reports, trial registries, and publications. BMJ, 2014. 348: p. g3510.

5. Cipriani, A., T.A. Furukawa, and G. Salanti, Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet, 2018. 391(10128): p. 1357–1366 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32802-7/fulltext.

6. Turcotte, J.E., et al., Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects. Neuropsychopharmacology, 2001. 24(5): p. 511-21.

7. Blier, P., et al., Effects of different doses of venlafaxine on serotonin and norepinephrine reuptake in healthy volunteers. International Journal of Neuropsychopharmacology, 2007. 10(1): p. 41-50.

8. Montgomery, S.A., et al., Which antidepressants have demonstrated superior efficacy? A review of the evidence. Int Clin Psychopharmacol, 2007. 22(6): p. 323-9.

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