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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 http://pdsp.cwru.edu/pdsp.asp

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.

[21-36]

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.

[51]

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.

[52-57]

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.

[58-61]

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

L-tryptophan

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].

References

1. Jacobs, B.L., An animal behavior model for studying central serotonergic synapses. Life Sciences, 1976. 19(6): p. 777-85.
2. Isbister, G.K. and N.A. Buckley, The Pathophysiology of Serotonin Toxicity in Animals and Humans: Implications for Diagnosis and Treatment. Clinical Neuropharmacology, 2005. 28(5): p. 205-214.
3. Gillman, P.K., Serotonin syndrome: history and risk. Fundamental and Clinical Pharmacology, 1998. 12(5): p. 482-491.
4. Marley, E. and K.M. Wozniak, Clinical and experimental aspects of interactions between amine oxidase inhibitors and amine re-uptake inhibitors. Psychological Medicine, 1983. 13: p. 735-749.
5. Marley, E. and K.M. Wozniak, Interactions between non-selective amine oxidase inhibitors (MAOI) and other antidepressants. Brit J Pharmac, 1983. 78: p. 20p.
6. Marley, E. and K.M. Wozniak, Interactions between relatively selective amine oxidase (MAOI) inhibitors and clomipramine. Brit J Pharmac, 1983. 78: p. 21p.
7. Marley, E. and K.M. Wozniak, Interactions of a non-selective monoamine oxidase inhibitor, phenelzine, with inhibitors of 5-hydroxytryptamine, dopamine or noradrenaline re-uptake. Journal of Psychiatric Research, 1984. 18: p. 173-189.
8. Marley, E. and K.M. Wozniak, Interactions of non-selective monoamine oxidase inhibitors, tranylcypromine and nialamide, with inhibitors of 5-hydroxytryptamine, dopamine and noradrenaline re-uptake. Journal of Psychiatric Research, 1984. 18: p. 191-203.
9. Marley, E. and K.M. Wozniak, Interactions between relatively selective monoamine oxidase inhibitors and an inhibitor of 5-hydroxytryptamine re-uptake, clomipramine. Journal of Psychiatric Research, 1985. 19: p. 597-608.
10. Nisijima, K., et al., Diazepam and chlormethiazole attenuate the development of hyperthermia in an animal model of the serotonin syndrome. Neurochemistry International, 2003. 43(2): p. 155-64.
11. Nisijima, K., et al., Potent serotonin (5-HT)(2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome. Brain Research, 2001. 890(1): p. 23-31.
12. Nisijima, K., T. Yoshino, and T. Ishiguro, Risperidone counteracts lethality in an animal model of the serotonin syndrome. Psychopharmacology (Berl), 2000. 150(1): p. 9-14.
13. Abdel-Fattah, A.F., et al., Central serotonin level-dependent changes in body temperature following administration of tryptophan to pargyline- and harmaline-pretreated rats. Gen Pharmacol, 1997. 28(3): p. 405-9.
14. Dreshfield-Ahmad, L.J., et al., Enhancement in extracellular serotonin levels by 5-hydroxytryptophan loading after administration of WAY 100635 and fluoxetine. Life Sci, 2000. 66(21): p. 2035-41.
15. Deakin, J.F. and A.R. Green, The effects of putative 5-hydroxytryptamine antagonists on the behaviour produced by administration of tranylcypromine and L-tryptophan or tranylcypromine and L-DOPA to rats. Br J Pharmacol, 1978. 64(2): p. 201-9.
16. Sleight, A.J., et al., Relationship between extracellular 5-hydroxytryptamine and behaviour following monoamine oxidase inhibition and L-tryptophan. British Journal of Pharmacology, 1988. 93: p. 303-310.
17. Green, A.R. and M.B. Youdim, Effects of monoamine oxidase inhibition by clorgyline, deprenil or tranylcypromine on 5-hydroxytryptamine concentrations in rat brain and hyperactivity following subsequent tryptophan administration. British Journal of Pharmacology, 1975. 55(3): p. 415-22.
18. Celada, P. and F. Artigas, Monoamine oxidase inhibitors increase preferentially extracellular 5-hydroxytryptamine in the midbrain raphe nuclei. A brain microdialysis study in the awake rat. Naunyn-Schmiedebergs Archives of Pharmacology, 1993. 347(6): p. 583-590.
19. De Ceballos, M.L., et al., Prenatal exposure of rats to antidepressant drugs down-regulates beta-adrenoceptors and 5-HT2 receptors in cerebral cortex. Lack of correlation between 5-HT2 receptors and serotonin-mediated behaviour. Neuropharmacology, 1985. 24(10): p. 947-52.
20. Shioda, K., et al., Extracellular serotonin, dopamine and glutamate levels are elevated in the hypothalamus in a serotonin syndrome animal model induced by tranylcypromine and fluoxetine. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2004. 28(4): p. 633-40.
21. Whyte, I.M., Neuroleptic malignant syndrome., in Medical Toxicology, R.C. Dart, Editor. 2004, Lippincott Williams & Wilkins: Baltimore. p. 101–103.
22. Whyte, I.M., Serotonin Toxicity (Syndrome). in Medical Toxicology, R.C. Dart, Editor. 2004, Lippincott Williams & Wilkins: Baltimore. p. 103–106.
23. Whyte, I.M., Serotonin uptake inhibitors, in Medical Toxicology, R.C. Dart, Editor. 2004, Lippincott Williams & Wilkins: Baltimore. p. 843–851.
24. Gillman, P.K. and I.M. Whyte, Serotonin syndrome, in Adverse Syndromes and Psychiatric Drugs, P. Haddad, S. Dursun, and B. Deakin, Editors. 2004, Oxford University Press: Oxford. p. 37-49.
25. Whyte, I.M., A.H. Dawson, and N.A. Buckley, Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. Quarterly Journal of Medicine, 2003. 96(5): p. 369-74.
26. Isbister, G.K., Comment: combination risperidone and SSRI-induced serotonin syndrome. Annals of Pharmacotherapy, 2003. 37(10): p. 1531-2; author reply 1532-3.
27. Isbister, G.K., et al., Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity. British Journal of Clinical Pharmacology, 2003. 56: p. 441-450.
28. Isbister, G.K. and L.P. Hackett, Nefazodone poisoning: toxicokinetics and toxicodynamics using continuous data collection. Journal of Toxicology. Clinical Toxicology, 2003. 41(2): p. 167-73.
29. Dunkley, E.J.C., et al., Hunter Serotonin Toxicity Criteria: a simple and accurate diagnostic decision rule for serotonin toxicity. Quarterly Journal of Medicine, 2003. 96: p. 635-642.
30. Balit, C.R., C.N. Lynch, and G.K. Isbister, Bupropion poisoning: a case series. Med J Aust, 2003. 178(2): p. 61-3.
31. Whyte, I.M., Introduction: research in clinical toxicology--the value of high quality data. Journal of Toxicology. Clinical Toxicology, 2002. 40(3): p. 211-2.
32. Whyte, I.M., N.A. Buckley, and A.H. Dawson, Data collection in clinical toxicology: are there too many variables? Journal of Toxicology. Clinical Toxicology, 2002. 40(3): p. 223-30.
33. Whyte, I.M. and A.H. Dawson, Redefining the serotonin syndrome. Journal of Toxicology. Clinical Toxicology, 2002. 40: p. 668-669.
34. Buckley, N.A., I.M. Whyte, and A.H. Dawson, Diagnostic data in clinical toxicology--should we use a Bayesian approach? Journal of Toxicology. Clinical Toxicology, 2002. 40(3): p. 213-22.
35. Whyte, I.M. and A.H. Dawson, Relative toxicity of venlafaxine and serotonin specific reuptake inhibitors in overdose. Proceedings of the Australasian Society of Clinical & Experimental Pharmacologists & Toxicologists, 2000. 8: p. 17.
36. Reith, D.M., et al., Clinical features of self-poisoning with monoamine oxidase inhibitors and / or serotonin reuptake inhibitors. Proceedings of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1996. 3( (Abstract)): p. 29.
37. Buckley, N.A. and T.A. Faunce, 'Atypical' antidepressants in overdose: clinical considerations with respect to safety. Drug Safety, 2003. 26: p. 539-551.
38. Bremner, J.D., P. Wingard, and T.A. Walshe, Safety of mirtazapine in overdose. Journal of Clinical Psychiatry, 1998. 59(5): p. 233-5.
39. Goeringer, K.E., L. Raymon, and B.K. Logan, Postmortem forensic toxicology of trazodone. J Forensic Sci, 2000. 45(4): p. 850-6.
40. Montgomery, S.A., Safety of mirtazapine: a review. International Clinical Psychopharmacology, 1995. 10 Suppl 4: p. 37-45.
41. Lau, G.T. and B.Z. Horowitz, Sertraline overdose. Academic Emergency Medicine, 1996. 3: p. 132-136.
42. Lejoyeux, M., F. Rouillon, and J. Ades, Prospective evaluation of the serotonin syndrome in depressed inpatients treated with clomipramine. Acta Psychiatrica Scandinavica, 1993. 88(5): p. 369-71.
43. Gillman, P.K. and S. Hodgens, Serotonin syndrome following SSRI mono-therapy. Human Psychopharmacology, 1998. 13: p. 525-526.
44. Gillman, P.K., Mirtazapine: unable to induce serotonin toxicity? Clinical Neuropharmacology, 2003. 26: p. 288-289.
45. Gillman, P.K., Moclobemide and the risk of serotonin toxicity (or serotonin syndrome). Central Nervous System Drug Reviews, 2004. 10: p. 83-85.
46. Whyte, I.M., Mirtazapine. personal communication, 2003. Nov 2003.
47. Schaper, E., et al., Suicide with mirtazapine-hardly possible. Journal of Toxicology. Clinical Toxicology, 2002. 40: p. 343-344.
48. Ubogu, E.E. and B. Katirji, Mirtazapine-induced serotonin syndrome. Clinical Neuropharmacology, 2003. 26(2): p. 54-7.
49. Isbister, G.K. and I.M. Whyte, Adverse reactions to mirtazapine are unlikely to be serotonin toxicity. Clinical Neuropharmacology, 2003. 26: p. 287-288.
50. Ubogu, E.E. and B. Katirji, Adverse reactions to mirtazapine are unlikely to be serotonin toxicity and Mirtazapine: unable to induce serotonin toxicity? Clinical Neuropharmacology, 2003. 26(2): p. 289-290.
51. Hernandez, J.L., et al., Severe serotonin syndrome induced by mirtazapine monotherapy. Annals of Pharmacotherapy, 2002. 36(4): p. 641-3.
52. Demers, J.C. and M. Malone, Serotonin syndrome induced by fluvoxamine and mirtazapine. Annals of Pharmacotherapy, 2001. 35(10): p. 1217-20.
53. Kaneda, Y., T. Ohmori, and H. Okabe, Possible mild serotonin syndrome related to co-prescription of tandospirone and trazodone. Gen Hosp Psychiatry, 2001. 23(2): p. 98-101.
54. McDaniel, W.W., Serotonin syndrome: early management with cyproheptadine. Annals of Pharmacotherapy, 2001. 35(7-8): p. 870-3.
55. Dimellis, D., Serotonin syndrome produced by a combination of venlafaxine and mirtazapine. World Journal of Biological Psychiatry, 2002. 3(3): p. 167.
56. Benazzi, F., Serotonin syndrome with mirtazapine-fluoxetine combination. International Journal of Geriatric Psychiatry, 1998. 13: p. 495-6.
57. Isbister, G.K., A.H. Dawson, and I.M. Whyte, Comment: serotonin syndrome induced by fluvoxamine and mirtazapine. Annals of Pharmacotherapy, 2001. 35(12): p. 1674-5.
58. Hilton, S.E., H. Maradit, and H.J. Moller, Serotonin syndrome and drug combinations: focus on MAOI and RIMA. European Archives of Psychiatry and Clinical Neuroscience, 1997. 247(3): p. 113-119.
59. Sternbach, H., The serotonin syndrome. American Journal of Psychiatry, 1991. 148: p. 705-713.
60. Radomski, J.W., et al., An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria. Medical Hypotheses, 2000. 55(3): p. 218-224.
61. Lane, R. and D. Baldwin, Selective serotonin reuptake inhibitor-induced serotonin syndrome: Review. Journal of Clinical Psychopharmacology, 1997. 17: p. 208-221.
62. Gillman, P.K., A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action. Biological Psychiatry, 2006: p. [In press].
63. Gillman, P.K., A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status. Human Psychopharmacology: Clinical and Experimental, 2005. 20: p. 1-9.
64. Oates, J.A. and A. Sjoerdsma, Neurologic effects of tryptophan in patients receiving a monoamine oxidase inhibitor. Neurology, 1960. 10: p. 1076-1078.
65. Sandyk, R., L-tryptophan in neuropsychiatric disorders: a review. Int J Neurosci, 1992. 67(1-4): p. 127-44.
66. Price, L.H., D.S. Charney, and G.R. Heninger, Effects of tranylcypromine treatment on neuroendocrine, behavioral, and autonomic responses to tryptophan in depressed patients. Life Sci, 1985. 37(9): p. 809-18.
67. Levy, A.B., P. Bucher, and N. Votolato, Myoclonus, hyperreflexia and diaphoresis in patients on phenelzine-tryptophan combination treatment. Can J Psychiatry, 1985. 30(6): p. 434-6.
68. Brotman, A.W. and J.F. Rosenbaum, MAOI plus tryptophan: a cause of serotonin syndrome? Massachutsetts General Hospital Newsletter: Biological Therapies in Psychiatry, 1984. 7: p. 45-46.
69. Baloh, R.W., J. Dietz, and J.W. Spooner, Myoclonus and ocular oscillations induced by L-tryptophan. Annals of Neurology, 1982. 11: p. 95-97.
70. d'Elia, G., L. Hanson, and H. Raotma, L-tryptophan and 5-hydroxytryptophan in the treatment of depression. A review. Acta Psychiatr Scand, 1978. 57(3): p. 239-52.
71. Chadwick, D., et al., 5-hydroxytryptophan-induced myoclonus in guinea pigs. A physiological and pharmacological investigations. J Neurol Sci, 1978. 35(1): p. 157-65.
72. Ayuso Gutierrez, J.L. and J.J. Alino, Tryptophan and an MAOI (nialamide) in the treatment of depression. A double-blind study. Int Pharmacopsychiatry, 1971. 6(2): p. 92-7.
73. Curzon, G., et al., The biochemical, behavioral and neurologic effects of high L-tryptophan intake in the rhesus monkey. Neurology, 1963. 12: p. 431-438.
74. Coppen, A., D. Shaw, and J. Farrell, Potentiation of the antidepressant effect of a monoamine-oxidase inhibitor by tryptophan. Lancet, 1963. 1: p. 79–81.
75. Thomas, J.M. and E.H. Rubin, Case report of a toxic reaction from a combination of tryptophan and phenelzine. American Journal of Psychiatry, 1984. 141: p. 281-283.
76. Gwaltney-Brant, S.M., J.C. Albretsen, and S.A. Khan, 5-Hydroxytryptophan toxicosis in dogs: 21 cases (1989-1999). J Am Vet Med Assoc, 2000. 216(12): p. 1937-40.
77. Young, S.N., Use of tryptophan in combination with other antidepressant treatments: a review. Journal of Psychiatry & Neuroscience, 1991. 16(5): p. 241-246.
78. Hodge, J., J. Oates, and A. Sjoerdsma, Reduction of the central effectrs of tryptophan by a decarboxylase inhibitor. Clinical Pharmacology and Therapeutics, 1964. 5: p. 149-155.
79. Smith, B. and D.J. Prockop, Central-nervous-system effects of injestion of L-tryptophan by normal subjects. New England Journal of Medicine, 1962. 267: p. 1338-1341.
80. Salter, M., et al., The effects of an inhibitor of tryptophan 2,3-dioxygenase and a combined inhibitor of tryptophan 2,3-dioxygenase and 5-HT reuptake in the rat. Neuropharmacology, 1995. 34(2): p. 217-27.
81. Botting, R., et al., Modification by monoamine oxidase inhibitors of the analgesic, hypothermic and toxic actions of morphine and pethidine in mice. J Pharm Pharmacol, 1978. 30(1): p. 36-40.
82. Grahame-Smith, D.G., Studies in vivo on the relationship between brain tryptophan, brain 5-HT synthesis and hyperactivity in rats treated with a monoamine oxidase inhibitor and L-tryptophan. Journal of Neurochemistry, 1971. 18: p. 1053-1066.