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Re: SSRI + Dexedrine, dangerous bc serotonin syndrome? phidippus

Posted by tom2228 on May 21, 2015, at 13:29:04

In reply to Re: SSRI + Dexedrine, dangerous bc serotonin syndrome? tom2228, posted by phidippus on May 20, 2015, at 6:20:48

> Amitriptyline acts primarily as a serotonin-norepinephrine reuptake inhibitor and does increase the amount of serotonin occupying the synapse. It is no safer than any other antidepressant with reuptake qualities with regards to serotonin syndrome.
> Eric

Clearly you didn't read the source. According to Gillman things are not as simple as you so matter-of-factly state. If what you say is empirical, how do you explain how SRIs like clompiramine and imipramine cannot be combined with an MAOIs without producing SS while other TCAs with SRI properties, including amitriptyline can?

"Clomipramine is effective for obsessive compulsive disorder and has high affinity for the SERT, but it remains uncertain if amitriptyline is significantly serotonergic: it has been regarded as an SNRI by many observers and included in meta-analyses comparing SNRIs with other antidepressants. Highly selective reuptake inhibitors now exist for both the NAT and the SERT and these appear to be effective antidepressants, although it is not yet established that they are as effective as TCAs in severe melancholic and psychotic depressions. ST data elucidate the clinical relevance of HCR data and thereby suggest what degree of potency is clinically meaningful. A detailed explanation and discussion of this is contained in a recent review (Gillman, 2006a), including a discussion of the possible role of 5-HT2A receptors. The SERT affinities of amitriptyline, imipramine and clomipramine have been correlated with their therapeutic profile. ST data and the putative serotonin-mediated disorders, obsessive compulsive disorder (Stein et al., 1995; Fineberg and Gale, 2005) and cataplexy (Bassetti, 1999; Vignatelli et al., 2005), illustrate the differences in the propensity to precipitate serotonin-related changes. These are proportional to the increasing affinity for the SERT of amitriptyline weak, imipramine intermediate, clomipramine potent (Table 3). The most dramatic and serious drug interaction in humans is ST it can rapidly culminate in death from hyperthermia. This occurs predictably when a potent SRI is added to a therapeutic dose of an MAOI. Weakly serotonergic drugs such as l-tryptophan precipitate typical, dose-dependent, but mild, ST symptoms when combined with MAOIs (Oates and Sjoerdsma, 1960). This indicates that even small elevations of serotonin, added to the effects of an MAOI, are sufficient to precipitate clinical features of ST (for a detailed exposition of this argument see Gillman, 2006a). Amitriptyline does not produce ST when added to an MAOI (Gillman, 1998). It may thus be inferred that amitriptyline does not significantly raise serotonin levels in humans. In contrast, clomipramine frequently precipitates severe ST with MAOIs and causes fatalities. This indicates the SERT affinity at which TCAs become effective in raising serotonin; imipramine is intermediate."

Actually, according to Gillman, the potential for SRI drugs to elicit SS is not uniform among drugs with this property:

"The PET study of SERT binding from Meyer et al. (2004) demonstrates comparable SERT antagonism in human striatum (∼80%) from the minimum therapeutic dose of all the SSRIs and venlafaxine. That suggests two probable inferences: first, some other factor, for example, higher tissue levels, does indeed compensate for the low SERT affinity displayed by venlafaxine (Table 4), which is consonant with its relatively higher incidence of ST in overdose (twice that of SSRIs; Whyte et al., 2003). Second, a higher CNS tissue level (of venlafaxine compared to TCAs) is likely to be less than one order of magnitude of difference. If it was more than that, then venlafaxine would exhibit ST at therapeutic doses. This reasoning in turn indicates that the discrepancy between venlafaxine's SRI/NRI potency (approximately 200/1) is too large to enable substantial NRI effects at therapeutic doses, without engendering excessive serotonergic effects. That conclusion is congruent with the TYR30 data reviewed below. Data on ST indicate that the SERT affinity of amitriptyline and other tricyclics of lesser SERT affinity is insufficient to cause meaningful serotonergic effects in humans, whereas clomipramine causes marked and clinically relevant effects. This is in accordance with published reviews, which report ST only with imipramine and clomipramine, as reviewed in detail elsewhere (Gillman, 1998, 2006a). The difference in their affinity for the SERT is the most parsimonious explanation for this crucial difference. Further PET-derived SERT-binding studies, comparing all the TCAs directly under similar conditions, may further elucidate this important issue."

"The increasing evidence that SNRIs like clomipramine may be more effective antidepressants makes it especially important to establish the criteria and evidence for valid claims of SNRI action. Recent evidence from ST studies indicates that amitriptyline does not have clinically significant serotonergic effects and is probably not an SNRI drug (Gillman, 1998, 2006a); so it is probably wrong to include it in meta-analyses of SNRI effects."




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