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Dual action antidepressant drugs: the claims, an independent analysis

Claims concerning dual serotonin and noradrenaline reuptake inhibitor (SNRI) action for antidepressant drugs have been prominent in the literature and sales approach for a few years. This essay is an analysis of the human cloned receptor data (HCR), and tyramine pressor response (TYR30) data, for relevant older tricyclic antidepressants, and the newer drugs (duloxetine venlafaxine, milnacipran and sibutramine). It does not provide support for some claims being made: indeed, it contradicts the claims concerning SNRI properties for both duloxetine and venlafaxine.

I have been using treatments that produce dual SNRI actions for many years and have little doubt that they are of superior effectiveness compared to other currently available antidepressants. The evidence and opinion supporting that position is getting better and stronger gradually, see other PUN notes and references (1-5).

Dual action strategies possible in the past have been Clomipramine (the superiority of which was strongly supported by the DUAG studies (6-8)), and since the early 1990s, combinations like sertraline + nortriptyline (and the MAOI tranylcypromine).

There is one particular disadvantage of using a single drug that supposedly has dual action on both serotonin and noradrenaline reuptake, i.e. a so-called SNRI: it is that the ratio of the potency for effecting these two systems is fixed, and not ideal because most such drugs affect one pathway much more than the other. A useful way of picturing this is to think of a four-wheel drive vehicle. The recently introduced SNRIs, such as venlafaxine and duloxetine, can be compared to 4WD vehicles that put 90% of their power to the ground through one set of wheels, and only 10% through the other; that is fixed and cannot be varied to suit different conditions. That is clearly a sub-standard system and no one would now buy a four-wheel-drive vehicle that did not have intelligent control systems that varied the power to each wheel, depending on the traction available. This analogy makes it clear that using two different drugs (to achieve SNRI) allows the dose of each one to be varied according to the characteristics and severity of the illness, in a way which is definitely more flexible, and probably more effective, than a single drug with a fixed ratio of effects. The second problem with a single drug possessing dual effects is that of the relative potency of these two effects. It is logical to assume that the potencies for each pathway need to be similar, or else there would be a potentially excessive effect on one pathway and an inadequate effect on the other. How similar is similar? Until evidence to the contrary is available it is logical to assume that a ratio close to a 1:1 is better. Reference to the table indicates that few of the new drugs come anywhere near this figure, but, on paper, the old TCAs do. But that is only part of the story.

There is substantive evidence that clinical effectiveness, at least for serotonin pathways, requires a drug with low single figure SRI potency, i.e. a Ki of 1 or less (9). If the same applies to noradrenaline reuptake, which on present evidence would have to be considered a reasonable proposition, then it is evident that the newer drugs may not be sufficiently potent to produce optimal effects (see table).

If it is not possible to obtain therapeutic levels of clomipramine without unacceptable side-effects, then this suggests the next best strategy for achieving effective dual action would be to use two different drugs at the same time (e.g. sertraline + (nortriptyline, or desipramine, or reboxetine)). This strategy is simple and safe providing a few basics about drug interactions are taken into account (see CYP450 notes).

Human cloned receptor (HCR) data

relating to ‘dual action’ Reuptake inhibitor affinities Ki nM (compiled by Dr Gillman Jan 2006)

Drug	TYR30	NA	5-HT	NA/5-HT
SSRIs (for comparison)		>1000	0.1-20	~ 1:1000
Amitriptyline	N/A	19 - 102	2.8 - 36	~1:1.5
Nortriptyline	+++	1.8-21	15-280
Clomipramine	N/A	54	0.14-0.3	~2:1
Desmethylclomipramine*	+++	<1*	-
Imipramine	N/A	20 - 142	1.3 - 20	~1:2
Desipramine	+++	0.63 – 8.6	22 -180
Duloxetine**	0/+	7.5-20	0.8-3.7	~10:1
Venlafaxine**	0/+	1,420–6,300	7.5-145	~200:1
Sibutramine	-	No HCR data	No HCR data
Milnacipran**	-	151-200	68-123	~1.7:1

What affinity at the noradrenaline transporter (NAT) (i.e. potency as an noradrenaline reuptake inhibitor (NRI)) constitutes a clinically useful effect on the NAT? The pressor response to tyramine, the ‘TYR30’ test, provides an in vivo index of peripheral NRI potency. The first direct comparison between the posited SNRI, venlafaxine, and a TCA, desipramine has only just been done (10). If academics were more on the ball it would have been done long ago.

The TYR30 is greatly potentiated by MAOIs, but is also evident when tyramine is administered intravenously in their absence. Tyramine utilises, and requires, the NAT to enter the pre-synaptic terminal, where it then releases noradrenaline (NA). Noradrenaline reuptake inhibitors (NRIs) inhibit tyramine uptake and thus lessen or abolish the response, potent NRIs (reboxetine, desipramine and nortriptyline block this response completely (11,12) ).

The effect of tricyclic antidepressants (TCAs) on the TYR30 is proportional to their relative NRI potency, only affinities of nortriptyline, or greater, are associated with marked attenuation. Duloxetine and venlafaxine have little or no effect on TYR30 even at super high doses. There are no known data for sibutramine or milnacipran. Duloxetine, at 60 mg daily attenuates TYR30 very slightly (13), even at 240 mg per day it is still weak (14). Chalon et al found no effect at 80 mg (15). Venlafaxine only marginally lessens the pressor response at the usual maximum dose of 375 mg daily (16,17). A complete set of data comparing all the TCAs etc under the same conditions would be revealing, but the present evidence indicates that drugs with an NRI potency less than nortriptyline are sub-optimally effective. Dothiepin (dosulepine), doxepin, mianserin and mirtazapine (6-aza-mianserin) are weak NRIs and have no effect on TYR30 (18-20).

There is no special evidence suggesting the cerebral drug levels are much different between drugs, so the provisional supposition that the central effects mirror the TYR30 data seems reasonable.

Discussion

In my opinion the two telling bits of data are the SRI potency difference between imipramine and clomipramine and the TYR30 difference between nortriptyline and desipramine when compared to duloxetine and venlafaxine. It is well established that clomipramine is the only tricyclic antidepressant (TCA) effective for obsessive compulsive disorder (and cataplexy) and that imipramine and amitriptyline are ineffective. It is unlikely that this is accounted for by anything other than their differing SRI potency, e.g. 5-HT2A affinity (see also ). Furthermore, we also know that there is a congruent difference in the ability of amitriptyline / imipramine / clomipramine to precipitate serotonin toxicity. The above receptor affinity data clearly indicates that (at least for TCAs) potencies of less than one (i.e. Ki < 1 nM) are required for clinical effectiveness. It is therefore reasonable to suggest that in designing a dual action strategy it would be ideal to aim for those kinds of potencies in both pathways. Neither venlafaxine nor duloxetine come anywhere near that. Clomipramine definitely does, combinations like sertraline + nortriptyline, or sertraline + reboxetine very probably do.

But who is going to advertise or promote such a combination? It is appropriate to continue to regard clomipramine as the gold standard antidepressant reference compound because the newer ‘dual action’ drugs just do not measure up. But combinations may achieve the same result with less side effects. In my opinion, and extensive experience (well in excess of 1,000 patients), sertraline + nortriptyline probably works a bit better than sertraline + reboxetine (a highly selective NRI), so maybe 5-HT2A receptors, or some other property of TCAs, does make a difference.

It is possible that adding an atypical neuroleptic for the treatment of refractory depression may be emulating the 5-HT2A antagonism that is missing with selective serotonin reuptake inhibitors (SSRIs). Which brings us back ‘full circle’ to clomipramine!

As Alphonse Karr neatly reiterated a couple of centuries ago ‘Plus ça change, plus c'est la même chose’ (21).

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


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