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The dose effect relationship

Animal evidence

In my opinion it is crucial to understand and remember, when considering the risks of serotonergic drugs, that serotonin toxicity behaves as would be expected of a synaptic serotonin concentration-related phenomenon. If you do not have a clear understanding of the synergistic effects that drugs working by a different mechanisms are capable of exerting then it is not possible to understand serotonergic interactions or serotonin toxicity. A reasonable knowledge of basic neuronal mechanisms is required to understand why and how different kinds of drugs may interact.

Although there has been debate about which receptors mediate which components of the physiological syndrome (various twitches and movements, see Jacobs [1].) Isbister’s recent and much needed review of the animal research has clarified the picture [2] and agrees with my preliminary analysis in the 1998 review [3]: there is little doubt about how to reduce pathological consequences of hyperpyrexia and deaths related to large elevations of serotonin (>50 times basal levels): and that is by blocking 5-HT2A receptors, not 5-HT1A or DA receptors.

There is a clear dose effect relationship in animal work. Evidence supporting the dose effect relationship accumulated, most notably in a series of papers by Marley and Wozniak (1983-85) [4-9] and has been clearly confirmed more recently by Nisijima’s group [10-12]. All this work shows proportionally greater increases in both 5-HT levels and fatalities resulting from MAOI + paroxetine (the most potent SRI) than with MAOI + fluoxetine (weaker SRI), and least deaths with MAOI + imipramine (weakest SRI) The 5-HT human cloned receptor data below demonstrates a close correlation between these affinity potencies and severity of serotonin toxicity when SRIs are mixed with MAOIs.

Death rates from serotonin toxicity, Marley:--

  • Tranylcypromine + clomipramine: -- 12 of 24 deaths
  • Tranylcypromine + imipramine: -- 5 of 45 deaths.
  • (Clomipramine is a much more potent SRI than imipramine).

Table 1 SRI affinity of antidepressants

See full tables below (from Richelson) and see also PDSP - Database at

Drug Affinity nmol

  • Paroxetine 0.13 Most potent- frequent serotonin toxicity + MAOIs
  • Clomipramine 0.28
  • Sertraline 0.29
  • Fluoxetine 0.81
  • Imipramine 1.4 Intermediate potency- less frequent serotonin toxicity + MAOIs
  • Amitriptyline 4.3 Least potent- no serotonin toxicity + MAOIs

Nisijima’s group has done the most recent work. In their 2003 paper using clorgyline (2mg/kg) + 5-Hydroxytrypophan (100mg/kg) this produced an elevation of brain 5-HT of 1200 fold and all rats died within 90 min of drug administration. This contrasts with their 2004 paper in which they reduced the dose to clorgyline 1.2mg/kg + 5-Hydroxytrypophan 80mg/kg. In this 2nd experiment no rats died before sacrifice at 360 mins post drug administration. Furthermore the degree of elevation of 5-HT was less; 40 fold versus 1200 fold.This demonstrates an unequivocal dose effect relationship.

Also, Deakin gave clorgyline + L-tryptophan with no deaths; brain 5-HT was not measured. It may be inferred from this that Clorgyline + L-tryptophan produces lesser elevations of 5-HT than clorgyline + L-5-Hydroxytrypophan.

In Marley’s experiments greater elevations of brain 5-HT, and higher death rates, occurred with inhibition of MAO-A and MAO-B together than with either individually. Also in Nisijima’s work changes in both dopamine were smaller, and with glutamate much smaller, and may be secondary, or even an epiphenomon.

[4-20]. I have reviewed Marley’s work in more detail [3].

This extensive body of research indicates that whatever drug combinations are used to raise serotonin levels there is a dose effect relationship. This dose effect relationship is almost certainly mediated through the final common pathway of elevated brain serotonin levels and the degree of elevation has an increasingly great effect on body temperature and mortality.

Human evidence

HATS data

In humans the evidence strongly indicates that the severity of serotonergic side effects and serotonin toxicity is dose related and occurs frequently with larger doses of selective serotonin reuptake inhibitors (SSRIs) and more frequently in overdoses. Data substantiating this interpretation comes from the HATS database, which has the considerable virtue of being a large series of consecutive poisonings from a toxicology unit with a defined catchment area. These have been documented and reported by ProfessorIan Whyte and his team who have published in this field and are expert at assessing toxicity in general, and serotonin toxicity in particular.


It is notable that the major observations from HATS are confirmed by the evidence available from other research and sources, even though those may not be as co-ordinated and systematic, and are from widely differing countries and settings.

HATS data vs. other literature

It is unsatisfactory to rely a single source of data to substantiate a hypothesis such as the spectrum concept: that is why a comparison of some key findings of HATS, with other data sources, is relevant. The unique content and nature of the HATS data means that is only possible in part: nevertheless it is clear that the findings from other sources are congruent: there appear to be no substantial discrepancies.

For instance the HATS database quantifies the risk of serotonin toxicity from the following: -

HATS Nefazodone, mirtazapine or mianserin- none, Professor Whyte has informally reviewed cases so far, there are 40+, no signs of any serotonin toxicity or serotonergic symptoms

Neither are these recorded in the toxicology reports in the literature ***. Particularly Schaper’s report of 73 cases- no serotonin toxicity or serotonergic symptoms.

NB mirtazapine is an analogue of mianserin; its structure is 6-aza-mianserin

HATS Moclobemide- almost none

Neither are these recorded in the toxicology reports in the literature.

HATS TCAs (excluding imipramine / clomipramine)- none

HATS Clomipramine- frequent

That is reflected in the other literature

HATS SSRIs: ~15% of over-doses of SSRIs show significant serotonin toxicity, but no deaths in 500+ instances of poisoning. That is also reflected in the other literature.

[3, 25, 27, 28, 30, 37-45].

***Toxicology reports

Systematic data (series of over-doses, total ~ 110 cases) indicates no serotonin toxicity or serotonergic symptoms from mirtazapine over-doses.

[46, 47]

There are several individual cases of mirtazapine alone reported as serotonin syndrome, the Ubogu report did not exhibit the key symptoms of serotonin toxicity and has been criticised in the relevant journal by both myself and Professor Whyte’s group.

[44, 48-50]

The Hernandez report is unusual and was in a 75 year old male with clear evidence of significant cerebral pathology. Since it is well established that a variety of drugs cause unusual reactions in persons with organic brian disease it is not apprpriate to consider this a typical case.


All other reports involve a second drug already known to cause serotonin toxicity, these cannot therefore be used to substantiate the case for mirtazapine’s causal role. The Demers report was critiqued by Isbister.


Other major reviews of human cases of serotonin toxicity have noted the essential observations supporting the spectrum concept of serotonin toxicity, even though these may not have been fully appreciated, or elaborated by the authors.


Two of my recent reviews are relevant to the discussion above and present much of this data more formally [62, 63]


Studies using L-tryptophan, going back to the 1950s, demonstrated unequivocal evidence of a dose effect relationship. The seminal paper of Oates et al in 1960 [64]demonstrated a dose effect relationship; and was also the first to propose the presently accepted mechanism for serotonin toxicity.

Although L-tryptophan is little used my most practitioners now it is instructive to note old observations about it. These may be an example of how understanding serotonin toxicity may provide an insight into the mechanism, and extent to which drugs raise serotonin. By itself L-tryptophan appears to do little for depression or brain 5-HT levels (it probably increases 5-HT about as little as mirtazapine—viz. approx. 50-150% over baseline), but it does help sleep noticeably. When combined with MAOIs it provides modestly improved antidepressant efficacy and, in animal models, greater increases in brain 5-HT than MAOIs alone. Brain 5-HT levels have been little studied, but they do provide sufficient evidence to give confidence that there is likely to be a relationship, both between serotonergic side effects / serotonin toxicity (clonus etc) and improved antidepressant efficacy (see references)[13, 14, 16, 17, 64-82].


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