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

PsychoTropicalResearch, serotonin and serotonin syndrome research.

Antidepressants - mirtazapine

Antidepressants - mirtazapine

Date Created: 26/09/1999   Last Modified: 03/09/2003   Last Checked: 16/09/2003

Mirtazapine ('Avanza' & 'Remeron'), is 6-aza-mianserin. As its chemical name indicates it is an analogue of mianserin (Tolvon). Initial investigation in the early 1980's found little pharmacological difference between mianserin and 6-aza-mianserin (mirtazapine) [1, 2]. Indeed the decision to develop it at all seems brave.

There is significant evidence demonstrating mianserin, the 'parent compound', is not an effective antidepressant at all [3]. Indeed it is not, like almost all effective antidepressants, a re-uptake inhibitor. Its most potent pharmacological action by far is that of histamine H1 receptor blockade. It has fallen out of use over the years to the point where it occupies a fraction of 1% of the antidepressant market (UK figures ~ one million scripts for mianserin vs 50 million for SSRIs and 75 million for TCAs). Some experienced psychopharmacologists consider it to be ineffective; I have not initiated a prescription for it in the last twenty years because I have found it is completely ineffective for the treatment of serious depressive illness; but it's quite a good sedative, because of potent H1 blockade.

Mirtazapine (6-azamianserin) was, because of mianserins (its 'parent' compound) potent H1 blockade, first tested as a sedative between 1982 - 1985 *** [4].

*** we now know mirtazapine is the most potent anti-histamine on the world market, eclipsing even doxepin.

It is of significance and interest to note one of the earliest papers in 1985; the title introduced it as a "new antidepressant" even though there was no evidence at that time of any antidepressant efficacy in humans [4]. The paper actually investigated only its sedative effect. There is nothing quite like promoting the idea you wish people to believe before presenting any facts or evidence.

So, is mirtazapine any better than mianserin? Internationally reputable professors of psychopharmacology have expressed the opinion that it may have useful advantages in:--

  • Speed of onset of activity (especially against anxiety)
  • avorable side effect profile
  • ffectiveness in all types of depression.

On the other hand one has to concede that the same, and other notables almost equally eminent, have made such prognostications about now-long-forgotten and failed drugs on numerous previous occasions.

The claim of faster onset of action has been made many times on minimal evidence and never yet subsequently substantiated. Indeed, the claim of faster onset has been made, more or less vociferously, for most antidepressants that have been introduced over the last 25 years. It is such a hoary old chestnut that the earliest paper making that claim in my possession is now yellow and curled at the edges.

Like mianserin, mirtazapine is a potent H1 blocker (anti-histamine) and thus inevitably causes sedation and weight gain; indeed H1 blockade is the most potent property of both these drugs, mirtazapine being even more potent than mianserin and doxepin (in vitro). Their affinities for other receptors (except alpha 1) are so similar and it is a little hard to see much justification for the supposition that mirtazapine would be much different or any better [1].

Note the established relationship between sedative potency (H1 blockade) and the risks of road traffic accidents; with amitriptyline this risk appears to be increased about fivefold; so with mirtazapine we would expect a similar increased risk. Also, mianserin may be the only drug where that risk of accidents continues without lessening after the first week (as it does with amitriptyline); mirtazapine is likely to be the same [5]. Interactions with benzodiazepines multiply the risk even more. This means it is a drug that may be best avoided in ambulant patients, and those who wish to drive or work.

Mirtazapine does not inhibit monoamine re-uptake at all, either for 5-HT, noradrenaline or dopamine (neither does mianserin, of course). The potency of these effects is clinically insignificant, being thousands of times weaker than nortriptyline, amitriptyline or reboxetine.

Mirtazapine is thought to boost noradrenalin, at least in rats, just a little bit. There is no direct evidence it does so in humans; indeed there is evidence to the contrary, that it does not raise noradrenalin. Mirtazapine does not have a noradrenergic symptom profile when taken in over-dose [6]. If it does not have a noradrenergic symptom profile in over-dose one might wonder if it does anything at all in therapeutic doses.

Mirtazapine is also claimed to boost 5-HT activity, by its blocking action at Alpha 2 adrenergic receptors. There are some slightly fanciful notions of how auto-receptors and hetero-receptors modulate neurotransmission. A2 hetero-receptors are supposed to be located on 5-HT neurons and to act to reduce 5-HT release into the synapse. However, this is probably a mechanism that operates only within the physiological range of neurotransmitter concentrations, so what its relevance is to the (presumably) pathological changes associated with illness constitutes speculation, which has little supporting evidence.

The strongest evidence that these mechanisms operate only in the physiological range of neurotransmitter concentrations is the toxicity profile. This is without question non- serotonergic and probably also non-noradrenergic too.

Mirtazapine is also a post-synaptic receptor blocker at 5-HT2A and 2C receptors (as, incidentally, are many of the old tricyclic antidepressants). Possibly as a result of this 5-HT post-synaptic receptor blockade it causes few sexual side effects. Since many sexual side effects are mediated by 5-HT itself, absence of them could more parsimoniously (simply) be interpreted as evidence that mirtazapine actually has no significant effect on elevating 5-HT levels (also, see below).

It is claimed to give relief from the ubiquitous anxiety symptoms of depression better and sooner than SSRIs, this is convincingly accounted for by its extremely potent sedative (and therefore anxiolytic) H1 blocking (anti-histamine) action. Indeed the first trial in 1985 was as a "pre-med" comparing its sedative / anxiolytic properties to diazepam. Mirtazapine 15 mg was stated to be equal to diazepam 10 mg [4].

Mirtazapine is being promoted as a drug with dual action on both noradrenaline and 5-HT (but by a different mechanism to the so-called SNRIs) and thus boards the "dual action" bandwagon. It has been given the acronym "NaSSA" which stands for "noradrenergic and specific serotonergic antidepressant".

There is very real doubt about mirtazapine's ability to significantly increase 5-HT in humans, whatever its mechanism of action is thought to be.

In my view it almost certainly does not significantly increase 5-HT at all, see below and my published references re this.

Since this "dual action" is claimed to account for its mooted superior effectiveness this question merits critical examination.

Mirtazapine's claim to raise 5-HT levels and thus be different or better rests on insubstantive evidence, the observations below indicate it does not raise 5-HT significantly in humans:--

  1. It does not raise prolactin as do other drugs with significant serotonergic action [7].
  2. It does not cause mydriasis as do other 5-HT1A agonists and all SSRIs [8]
  3. It does not cause
    a) serotonin side effects
    b) serotonin toxicity (serotonin syndrome) either in over-dose by itself
    c) serotonin toxicity if mixed with monoamine oxidase inhibitors (as do all other drugs with significant serotonergic actions) [9, 10]
  4. There is no substantive evidence that it has any beneficial effect in obsessive compulsive disorder.
  5. There is no evidence that it lowers platelet 5-HT (as do all serotonin reuptake inhibitors)
  6. Lack of all typical serotonergic sexual side effects, particularly inhibition of orgasm.

Its place in the treatment of depression will never be clearly established. It is now out of patent. Further trials seem both unlikely and probably unwarranted.

I would suggest that mianserin and mirtazapine, along with nefazodone and trazodone and moclobemide, are eloquent testimony to the insufficient quality of most clinical studies on antidepressants; after all, many clinical trials purportedly "proving" that these drugs are as effective as various comparator drugs continue to be published in what are optimistically (and euphemistically) described as reputable journals.

Hopefully there is a useful lesson to be learnt from all those trials, indeed one that remains as important as ever; the lesson is this, whenever you see the statement 'drug x has been proven to be as effective as ........' then your critical / sceptical warning light might start flashing. Journal editors might consider steering authors away from the unscientific and unjustified use of the word "proven".

One common type of drug trial is one that compares the new drug to an established 'gold standard' reference drug. However, failing to show that the two drugs are different is in no way the same as proving that they are the same (ie of equal efficacy, however great or small that might be).

Think of it like this, if I cannot distinguish between a sparrow and a thrush, this does not prove that sparrows and thrushes are the same; but it does suggest I need new spectacles. There is now extensive evidence indicating clinical trial methodology and practice will benefit from refinement of techniques; clinical trial methodology needs new spectacles.

Remember that effectiveness of antidepressants is assumed using a short term proxy measure of symptoms that may not even be central, or directly related to, the essential pathological changes that are the core of depressive illness. I hope it is clear to those with any training in science, logic and methodology that exclusive use of a short term proxy measure of a chronic illness, with no confirming data or evidence of long term outcome, is both nonsense and nonscience. It is not an appropriate activity for medicine in the third millennium [11].

Remember, there were lots of trials that failed to show mianserin ("father" of mirtazapine) was any less effective than gold standard treatments like amitriptyline. It was therefore stated to be as effective. Yet now, after 25 years of experience, you will be hard-pressed to find many specialist clinicians who still think mianserin is an effective antidepressant. GPs, who issue most of the scripts, have clearly voted on this; mianserin has but a fraction of 1% of the antidepressant market share.

What has this to do with mirtazapine? If we are to benefit from the huge amount of work and research already done then we have the chance of learning from history.

"Progress, far from consisting in change, depends on retentiveness. Those who cannot remember the past are condemned to repeat it."
Santayana, G (1863-1952) The Life of Reason

Learning from history means requiring better quality evidence for the effectiveness of all drugs. The presumption that a drug officially approved for use as an antidepressant is therefore an effective antidepressant is not always justified or valid.

In my opinion this is another drug that stands as a monument to the problems and deficiencies of the entire process by which drugs are researched and brought to the market and then officially approved. It exemplifies the need for longer term studies with larger numbers of patients and with more objective and 'final' outcome measures such as: frequency of suicide, days lost from work, functional capacity and utilization of medical services.

In short, just like its predecessor mianserin, it is my opinion there is insufficient evidence mirtazapine is a useful and effective antidepressant to justify its use in usual clinical practice.

1. de Boer, et al. Neuropharmacology, Neurochemical and autonomic pharmacological profiles of the 6-aza- analogue of mianserin, Org 3770 and its enantiomers 1988. 27: p. 399-408.
2. Sugrue. Eur J Pharmacol, The inability of chronic mianserin to block central alpha 2-adrenoceptors 1980. 68: p. 377-80.
3. Isacsson, et al. Acta Psychiatr Scand, The utilization of antidepressants--a key issue in the prevention of suicide: an analysis of 5281 suicides in Sweden during the period 1992- 1994 1997. 96: p. 94-100.
4. Sorensen, et al. Acta Psychiatr Scand, A double-blind group comparative study using the new anti-depressant Org 3770, placebo and diazepam in patients with expected insomnia and anxiety before elective gynaecological surgery 1985. 71: p. 339-46.
5. Ramaekers. J Clin Psychiatry, Antidepressants and driver impairment: empirical evidence from a standard on-the-road test 2003. 64: p. 20-9.
6. Buckley and Faunce. Drug Saf, 'Atypical' antidepressants in overdose: clinical considerations with respect to safety 2003. 26: p. 539-51.
7. Whale, et al. Psychopharmacology (Berl), Does mirtazapine enhance serotonergic neurotransmission in depressed patients? 2000. 148: p. 325-6.
8. Schmitt, et al. Psychopharmacology (Berl), Modulation of the critical flicker fusion effects of serotonin reuptake inhibitors by concomitant pupillary changes 2002. 160: p. 381-6.
9. Gillman. Clinical Neuropharmacology, Mirtazapine: unable to induce serotonin toxicity? 2003. [in press].
10. Gillman. Journal of Clinical Psychiatry, Amitriptyline: Dual-Action Antidepressant? 2003. 64 [in press].
11. Gillman. British Journal of Psychiatry, Fifty years of poor science 2003.