PsychoTropical Research - Dr Ken Gillman, Serotonin Syndrome, Mirtazapine, Dual Action Drugs. Serotonin toxicity: Symptoms.

PsychoTropicalResearch, serotonin and serotonin syndrome research.

Serotonin toxicity: Symptoms

Serotonin toxicity: Symptoms

Date Created:    Last Modified:    Last Checked: Jan 2006

There is a spectrum of severity going from ‘serotonergic’ side effects to what is arbitrarily called ‘serotonin syndrome’ (SS). The evidence for this 'spectrum' model for understanding serotonin syndrome is reviewed in my published papers.

The most frequent side effects of selective serotonin reuptake inhibitors in therapuetic doses alone are, in approximate descending order of frequency of occurrence:-

Inhibition of orgasm (M and F), nausea, drowsiness, insomnia, loose stools, tremor, nervousness, sweating, fatigue, dizziness.

Other serotonergic symptoms may occur with ‘monotherapy’ including:-
myoclonus (especially nocturnal), diaphoresis, teeth chattering, shivering, chills, over confidence / aggressiveness and impaired concentration and thinking.

More severe symptoms that are characteristic of more sever serotonin syndrome are usually of rapid onset (ie hours) and after the increase, or addition of, a second serotonergic drug (most commonly an MAOI combined with an SRI).

The key symptoms of serotonin syndrome are:--

  1. Mental state:- excitement, hypomania, confusion
  2. Hyperactivity, restlessness
  3. Clonus and myoclonus (including ocular oscillations)
  4. Hyperreflexia / hypertonia
  5. diaphoresis, flushing and hyperthermia (>39 c).

Increasingly severe ‘side effects’ usually precede and accompany the above especially:- nausea, drowsiness, insomnia, loose stools, tremor, sweating, shivering, confusion.

The symptoms that probably distinguish serotonergic toxicity from other drug induce toxicities are clonus and hyperreflexia.

Associate Professor Ian Whyte and his toxicology group in Newcastle (Australia) www.hypertox.com have a longstanding interest in collecting prospective data on serotonin syndrome and have adopted the treatment with chlorpromazine (for severe cases) that emerged as the best option from my review of serotonin syndrome treatment in 1998. They continue to evaluate the symptoms and treatment. Their data is insufficiently recognised or quoted. It is the best quality prospective data available from anyone in the world; I therefore summarise some of their published conclusions briefly here.

They have done a logistic regression of the signs present in patients needing pharmacological treatment for drug toxicity in hospital. Five signs: clonus (inducible /spontaneous/ocular), flushing, tremor/shivering, nystagmus and fever explained 85% of the variance within the model.
Weighting was Clonus-3, flushing-2, Tremor/shivering-2 Nystagmus-1, Fever-1.

They suggest the clinical characteristics that appear to be predictive of poor outcome include fever and spontaneous clonus.

In summarising their view of the spectrum concept Ian Whyte has stated; "Thus, while it is unclear that "serotonin syndrome" exists as a specific entity, it is clear that there is a constellation of signs associated with serotonergic excess and that these features are those of a primarily neuroexcitatory nature with changes in mental status (agitation, restlessness, confusion, hypomania), motor system (myoclonus or clonus [inducible, spontaneous or ocular], tremor or shivering, hyperreflexia, hypertonia, rigidity) and the autonomic system (diaphoresis, tachycardia, flushing, mydriasis). And re the distinction of serotonin syndrome vs neuroleptic malignant syndrome, "a full physical examination and clinical assessment makes it almost impossible to confuse the two diagnoses".

Gillman, P.K., Serotonin Syndrome: History and Risk. Fundamental and Clinical Pharmacology, 1998. 12(5): p. 482-491. [Review]

Gillman, P.K., The serotonin syndrome and its treatment. Journal of Psychopharmacology, 1999. 13(1): p. 100-9. [Review]

Gillman, P.K., Serotonin syndrome: clomipramine too soon after moclobemide. International Clinical Psychopharmacology, 1997. 12: p. 339-342. [Review]

Gillman, P.K. and S. Hodgens, Serotonin syndrome following SSRI mono-therapy. Human Psychopharmacology, 1998. 13: p. 525-526.

Gillman, P.K., Comments on "Serotonin syndrome during treatment with paroxetine and risperidone". J Clin Psychopharmacol, 2001. 21(3): p. 344-5.