Serotonin toxicity

Furthermore, and we haven t reported it yet, PCPA would also be expected to block the serotonergic depletion. It does nothing to the serotonin toxicity. So you are right, it is somewhat of a mystery as to what is going on. 

Isbister, G.K and Buckley, N.A. (2005) The pathophysiology of serotonin toxicity in animals and humans implications for diagnosis and treatment. Clinical Neuropharmacology, 28, 205—214. 

Excess serotonin in the central nervous system leads to a condition commonly referred to as the serotonin syndrome. There are several drug mechanisms that can cause serotonin toxicity. Serotonin toxicity can be a medical emergency characterised by rapid onset of severe hyperthermia, muscle rigidity and multiple organ failure. 

Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity a practical approach to diagnosis and treatment. Med J Aust2007 187(6) 361-5. 

The most common reason for the underutilization of MAOIs is the potential for serious consequences of MAOI drug-food and drug-drug interactions. Combined MAOI treatment with (1) foods or medications involved in monoamine synthesis (2) monoamines themselves or (3) other sympathomimetics routinely found in over-the-counter medications can result in hy-peradrenergic crises or serotonin toxicity (Blackwell, 1991). 

Gillman PK A review of serotonin toxicity data Implications for the mechanisms of antidepressant drug action. Biol Psychiatry 2006 59(11) 1046. [PMID 16460699]... 

Lawrence KR et al Serotonin toxicity associated with the use of linezolid A review of postmarketing data. Clin Infect Dis 2006 42 1578. [PMID 16652315]... 

Isbister GK, Hackett LP, Dawson AH, Whyte IM, Smith AJ. Moclobemide poisoning toxicokinetics and occurrence of serotonin toxicity. Br J Clin Pharmacol 2003 56 441-50. 

A 45-year-old man had definite symptoms of serotonin toxicity (hypomania, myoclonus, sweating, and shivering), first when taking a low therapeutic dose of citalopram (20 mg/day) and then with low-dose sertraline (25 mg/day) he was also taking zolpidem (17). 

The authors speculated that the combination of zolpidem with an SSRI might have predisposed to the serotonin syndrome. It is also possible that some people (for example poor metabolizers) are idiosyncratically vulnerable to serotonin toxicity at low doses of SSRIs. 

Of 93 cases of neonatal symptoms associated with the use of SSRIs in mothers around the time of delivery 64 were associated with paroxetine but reactions were also reported in infants whose mothers had taken citalopram, fluoxetine, and sertraline (87). It is unclear from these data whether paroxetine is actually most likely to provoke the neonatal syndrome, but in adults its use is associated with more severe withdrawal reactions than other SSRIs. It should also be noted that it is not clear whether the syndrome described in neonates is due to SSRI withdrawal or a form of serotonin toxicity. 

Concentrations of nefazodone and its metabolites can be increased by fluoxetine and paroxetine (SEDA-20, 9). Combinations of serotonin agents produce serotonin toxicity, and a case of serotonin syndrome occurred when nefazodone (200 mg/day) was combined with fluoxetine (40 mg/day) in a 50-year-old man (109). The toxic symptoms settled 3 days after withdrawal of both antidepressants. 

The serotonin syndrome can present with hypomanic features, and the clinical picture and rapid onset in this case suggested that the addition of sibutramine to citalopram provoked serotonin toxicity. Sibutramine blocks the reuptake of serotonin, dopamine, and noradrenaline. Whether the serotonin toxicity seen here resulted purely from the combined effects of both citalopram and sibutramine in blocking serotonin re-uptake is unclear. It is possible, for example, that potentiation of dopamine and noradrenaline activity by sibutramine might also have been involved. 

Drugs used in the treatment of acute migraine, such as sumatriptan and rizatriptan, are 5-HTiB/iD-receptor agonists and could theoretically interact pharmacodynami-cally with SSRIs to cause serotonin toxicity. Triptans are metabolized mainly by monoamine oxidase, which makes pharmacokinetic interactions with SSRIs unlikely. Although case series have suggested that sumatriptan can be safely combined with SSRIs (SEDA-22, 14), there are occasional reports of toxicity. 

Caution has been advocated when SSRIs such as fluoxetine are combined with the triptans that are used to treat acute episodes of migraine (SEDA-24,16). There are case reports of symptoms suggestive of serotonin toxicity when fluoxetine has been combined with sumatriptan, perhaps because the SSRI can potentiate the 5-HT1B/iD agonist effects of the triptan (SEDA-22,14). 

The effect of fluoxetine 60 mg/day for 8 days on the pharmacokinetics of almotriptan has been studied in 14 healthy volunteers (43). Fluoxetine produced a significant increase in the peak concentration of almotriptan, but the AUC was not altered. These results suggest that CYP2D6 plays a minor role in the metabolism of almotriptan. The combined treatment was reported to be well tolerated, but this does not exclude the possibility of occasional cases of serotonin toxicity in some individuals. 

Linezolid inhibits monoamine oxidase activity and has been reported to cause serotonin toxicity in combination with paroxetine. While some patients have apparently taken the combination of linezolid and an SSRI safely, this report suggests that patients taking combined treatment should be monitored for serotonin toxicity. 

The authors proposed that in this case erythromycin had inhibited sertraline metabolism by inhibiting CYP3A. This could have led to increased concentrations of sertraline and signs of serotonin toxicity. Unfortunately sertraline concentrations were not measured to confirm this suggestion. 

There have been previous reports of serotonin toxicity when venlafaxine was combined with therapeutic doses of conventional MAO inhibitors (SEDA 20, 21). The serotonin syndrome has been reported in four patients who were switched from the MAO inhibitor phenelzine to venlafaxine (83). In two of the subjects, the 14-day washout period recommended when switching from phenelzine to other antidepressant drugs had elapsed. 

These cases suggest that even after the recommended 2-week washout from MAO inhibitors, venlafaxine can provoke serotonin toxicity in some patients. In principle it should be possible to switch from one conventional MAO inhibitor to another without a washout period. However, there have been reports that patients who switched from phenelzine to tranylcypromine had hypertensive reactions, with disastrous consequences (84). Whenever possible, a 2-week washout period when switching MAO inhibitors or when introducing serotonin re-uptake inhibitors seems advisable. 

This suggests that even after the recommended 2-week washout from MAO inhibitors, venlafaxine can provoke serotonin toxicity in some patients. 

The combination of stimulants and SSRIs is not uncommon in clinical practice, but reports of serotonin toxicity are unusual, perhaps because drugs such as dexamfetamine and methylphenidate predominantly release dopamine and noradrenaline rather than serotonin. However, psychostimulants do cause some degree of serotonin release, which might have been sufficient to cause serotonin toxicity in this case. 

Prior FH, Isbister GK, Dawson AH, Whyte IM. Serotonin toxicity with therapeutic doses of dexamphetamine and venlafaxine. Med J Aust 2002 176(5) 240-1. 

LITHIUM SSRIs Lithium may enhance the pharmacologic effects of SSRIs and potentiate the risk of serotonin syndrome. Excessive somnolence has been reported with fluvoxamine. However, there are reports of both T and l plasma concentrations of lithium. There are reports of lithium toxicity and of serotonergic effects Lithium is a direct stimulant of 5-HT receptors, while SSRIs i the reuptake of 5- HT these are considered to t the effects of serotonin in the brain. Seizures are a neurotoxic effect of lithium and could occur even with plasma lithium concentrations within the normal range. SSRIs and lithium may have additive effects to cause seizures Be aware of the possibility of serotonin syndrome. Also need to monitor lithium levels with appropriate dose adjustments during co-administration > For signs and symptoms of serotonin toxicity, see Clinical Features of Some Adverse Drug Interactions, Serotonin toxicity and serotonin syndrome... 

LITHIUM OTHER-VENLAFAXINE Possible risk of serotonin syndrome Additive effect Be aware of the possibility of serotonin syndrome. Also need to monitor lithium levels with appropriate dose adjustments during co-administration >- For signs and symptoms of serotonin toxicity, see Clinical Features of Some Adverse Drug Interactions, Serotonin toxicity and serotonin syndrome... 

---