Posted by Shawn. T. on September 12, 2002, at 6:49:07
In reply to Re: Mirtazapine with Tianeptine, posted by cybercafe on September 12, 2002, at 0:53:29
> hmm.... does mirtazepine inhibit the serotonin uptake transporter? .... if so.. by what means? and how does tianeptine potentiate it's actions... and what would happen if they both tried to do the same thing at once, on a molecular level ?
Mirtazapine antagonizes alpha-2 adrenergic heteroreceptors on serotonergic neurons. This results in an inhibition of the K+ current evoked release of serotonin by neurons in the dorsal raphe nucleus (where the majority of serotonin neurons reside in the brain). An alternate pathway to enhanced serotonergic activity is through the activation of alpha-1 adrenoceptors mediating serotonin cell firing. These receptors will be indirectly activated as a result of the enhanced noradrenaline release caused by mirtazapine's antagonism of alpha-2 autoreceptors.
See De Boer et al. (1994) for verification.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7912194&dopt=AbstractThe combination of tianeptine and mirtazapine could be looked at from a few different directions, the REM augmentation idea is one. On the topic of a shared activity at the molecular level, they could hypothetically interact at the level of K+ current evoked release of serotonin. A similar situation takes place in a drug free individual as serotonin auto and heteroreceptors are affected through various pathways (in addition to positive affectors such as alpha-1 adrenoceptors).
Whitton et al. (1991) have shown that in the hippocampus, tianeptine reduces the K+ evoked rise in extracellular serotonin. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=2046875&dopt=Abstract
Now considering that tianeptine may reduce extracellular serotonin in some brain areas via K+ currents while mirtazapine could increase extracellular serotonin levels, the two drugs would potentially offset each other in a fashion similar to the effect seen when mixing tianeptine and the SSRI citalopram (Celexa). Thus, tianeptine might be seen as a way to "fine-tune" extracellular serotonin levels for a person taking mirtazapine. Ideally, the CNS should maintain a relative balance between low and high serotonin levels while a person is awake (serotonin levels drop during sleep). Low extracellular serotonin levels are generally associated with depression and high levels are generally associated with anxiety, this might be seen as a spectrum from low alertness to a high level of alertness.
If tianeptine's effectiveness is correlated with levels of REM sleep, then combining it with a drug shown to improve REM sleep should result in added efficacy. See Schittecatte et al. (2002) (note that metirzapine, not mirtazapine is the selective alpha-2 antagonist, although mirtazapine has this quality among others)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11850045&dopt=AbstractFor information on metirzapine's action on REM sleep, see Ruigt et al. 1999
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2373128&dopt=AbstractFor information on 5-HT2 receptor involvement in mirtazapine's actions on sleep, see Thase (2000)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10926055&dopt=AbstractCarley and Radulovacki (1999) have shown that 5-HT3 receptor antagonism may play a role in mirtazapine's effects upon REM related sleap apnea
http://ajrccm.atsjournals.org/cgi/content/full/160/6/1824My personal speculation (e.g. lacking any concrete scientific evidence) on tianeptine's direct mechanism of action is that it binds to the low-affinity 5-HT-moduline binding site on 5-HT1B/1D receptors. This would imply that tianeptine prevents binding of 5-HT-moduline to its high-affinity binding site. Also implied is that tianeptine is a 5-HT-moduline antagonist as described by Plantefol et al. (1999)
http://www.jneurochem.org/cgi/content/full/73/6/2617?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=%225-ht-moduline%22&searchid=1031829084064_183&stored_search=&FIRSTINDEX=&fdate=1/1/1965&tdate=8/31/2002&journalcode=jneurochemI'll have to check into this idea some more; it seems to have some evidence in its favor.
Shawn
poster:Shawn. T.
thread:119452
URL: http://www.dr-bob.org/babble/20020906/msgs/119613.html