Are there any interactions between mirtazapine and melatonin?/nBackground: The question relates to

Fråga: Are there any interactions between mirtazapine and melatonin? Background: The question relates to a 69-year-old woman with previous alcohol abuse, and who has been suffering from insomnia for many years. There is no diagnosis of depression. Treatment with various sedatives and hypnotics has been unsuccessful. The patient is currently taking Propavan (propiomazine), 50 mg, in the evening, but with no significant effect on sleep. Her psychiatrist will now introduce Remeron (mirtazapine), 7.5 mg, every evening, and possibly withdraw propiomazine. There have been discussions about combining mirtazapine and melatonin. The patient used melatonin for a limited period of time a few years ago, and the impression was that melatonin to some extent improved her sleep.

Sammanfattning: The sedative properties of mirtazapine are dependent on antihistamine effects and possibly 5HT2-antagonism. Alpha2-blocking effects can possibly play a role by stimulating melatonin release. Although mirtazapine might be useful in a patient with chronic insomnia when other pharmacological strategies have failed, the documentation is very limited. Mirtazapin and melatonin are not expected to interact pharmacokinetically but the clinical effects of this combination are very difficult to predict.

Svar: Mirtazapine is a novel antidepressant with a potent antagonistic action on presynaptic alpha2-adrenergic receptors, as well as postsynaptic 5HT2- and 5HT3-receptors. This leads to an overall increase in noradrenergic- and 5HT1-receptor mediated serotonergic activity (1). Moreover, mirtazapine is a powerful antihistamine (H1-blocker) as a prominent sedative effect. This, together with 5HT2-antagonism (which has also been suggested to promote sleep), explain why mirtazapine has been tested in the treatment of insomnia. However, the documentation of positive effects is very limited (1, 2), especially during long-term treatment.

Mirtazapine is metabolised by the hepatic cytochrome P450 system, mainly by CYP3A4 that catalyses an N-demethylation reaction (1, 4). Another minor pathway involves a CYP2D6-dependent 8-hydroxylation of mirtazapine. Of relevance to the discussion below, mirtazapine was found to be only a very weak inhibitor of CYP1A2 (4).

Melatonin has received considerable attention recently, in particular concerning its ability to promote sleep and the possibility to use exogenous melatonin for this purpose. Endogenous melatonin is synthesised in the pineal gland from tryptophan and serotonin, and exhibits an endocrine type of action. Melatonin not only regulates sleep and circadian rhythm, but possibly also mood, reproduction and immune responses (5, 6). The release of melatonin is controlled by noradrenergic stimulation, which in turn is activated by darkness and inhibited by light.

The effect of supra-physiological doses of melatonin is poorly documented and restricted to short-term positive effects on jet lag and in blind people with a circadian rhythm of more than 24h (6, 7). Due to this limited documentation and that long-term effects of exogenous melatonin are essentially unknown, the Medical Products Agency has strongly recommended great caution with prescribing melatonin (7).

Pharmacological doses of melatonin vary between 0.5-75 mg daily, where the lowest dose gives plasma concentrations similar to peak physiological concentrations of approximately 100-200 pM (6, 7). Melatonin is subject to metabolism in the liver, where a 6-hydroxy-metabolite is formed, followed by conjugation reactions (5).

It was recently described that 6-hydroxylation of melatonin is catalysed by CYP1A2 (8). Therefore, inhibition of CYP1A2 by the SSRI-agent fluvoxamine, leads to a significant increase in plasma levels of melatonin. In contrast, citalopram, an SSRI-agent that inhibits CYP2C19, has no effect on melatonin (8). It follows that therapeutic doses of mirtazapine, being only a very weak CYP1A2-inihibitor (4) are not expected to interact with melatonin metabolism.

It is more difficult to assess possible interactions at the pharmacodynamic level between melatonin and mirtazapine. Despite an extensive literature search, no documentation was found on this combination. However, it was reported that medetomidine, an alpha2-adrenoreceptor agonist, suppressed night-time melatonin levels in rat pineal glands, and that this effect could be counteracted by an alpha2-antagonist, atipamezole (9). This is of interest considering the potent alpha2-inhibition mediated by mirtazapine, and might suggest that mirtazapine could increase endogenous night-time melatonin and thereby promote sleep.

Another report describes that the common beta-blockers propranolol and atenolol caused a decrease in melatonin release. However, in the same report, carvedilol, a non-selective beta-blocker and alpha1-blocker, did not cause any decrease of melatonin, indicating that alpha1-receptor antagonism might play a role in counteracting the effect of beta-blockers (10).

Summarising these data, it appears that some agents interacting with either alpha- or beta-adrenergic receptors, have a potential to influence the release of endogenous melatonin from the pineal gland. However, it is important to keep in mind that these interactions might not be relevant to the situation when mirtazapine is combined with exogenous melatonin.