Paroxetine (Paxil) (see Paroxetine, [[Paroxetine]])
Sertraline (Zoloft) (see Sertraline, [[Sertraline]])
Vortioxetine (Brintellix) (see Vortioxetine, [[Vortioxetine]])
SSRI are metabolized in the liver by cytochrome P-450 mixed function oxidase microsomal enzymes
They are highly bound to plasma proteins and have a large volume of distribution
Peak plasma levels: occur in 2-10 hrs
Most SSRI have half-lives of approximately 20-24 hrs
A notable exception is fluoxetine, and its active metabolite, norfluoxetine, which have half-lives of 2-4 days and 8-9 days, respectively
Hence, the addition of serotonergic medications to a patient’s regimen must not occur until 2-3 weeks after discontinuation of an SSRI (some recommend a 5-week “wash-out” period for fluoxetine prior to initiation of an MAO inhibitor)
Serotonin (5-hydroxytryptamine, 5HT) is a central and peripheral nervous system neurotransmitter
Serotonin is synthesized from L-tryptophan in the brainstem raphe nucleus and is stored in presynaptic vesicles -> released by neuronal activation
Excess serotonin is taken back up into presynaptic vesicles by active transport or locally metabolized by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid
Systemic serotonin is metabolized via hepatic mixed function oxidases
Inhibition of particular mixed function oxidases by medications or other substances (grapefruit, etc) -> decreased serotonin metabolism -> increased drug effect
Serotonin Receceptors: there are 7 distinct 5HT receptors (with further specific subtypes), producing a wide variety of physiologic effects
Most central nervous system 5HT receptors are located in the brainstem raphe nuclei
The physiologic manifestations of serotonin syndrome are largely due to stimulation of 5HT1a and 5HT2 receptors
Serotonergic Projections to Thalamus and Cortex
Serotonin Projections to Brainstem and Medulla
Precipitants of Excess Serotonergic Activity
Large Doses or Combinations of Serotonergic Agents: may occur in overdoses
Data from the 2009 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (AAPCC-NPDS) showed 2.4 million total toxic drug exposures in 2009
Antidepressants (SSRIs, TCAs, and atypicals) accounted for 102,792 exposures and 260 deaths and were the sixth most common class of drug associated with fatalities
Seven fatalities were related to ingestion of SSRI alone
Of 260 total antidepressant-related fatalities, SSRI were involved in 42 deaths, mostly in combination with other medications or illicit substances
Atypical antidepressants such as venlafaxine (Effexor) and bupropion (Wellbutrin) were involved in a significant number of fatalities, often in combination with alcohol or other prescription medications
Incidence of reported SSRI ingestions is higher in women than in men
Incidence of death from antidepressant ingestions is higher in men than in women
Incidence of SSRI toxicity is highest in persons aged 19-39 years, the age group with the greatest overall number of intentional ingestions
Side effects from SSRI are not age-specific, but they may occur more in elderly persons who are more likely to be taking several serotonergic agents or other medications that alter mixed function oxidase CYP metabolism
Serotonin toxicity is most likely to develop following the initiation of a new serotonergic medication or the increase in dosage of a previously prescribed SSRI
Symptom onset from SSRI toxicity presents within 2-8 hours after acute ingestion, or it may occur over several days if SS develops from initiation of a new therapy or addition of a second serotonergic agent
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