Selective serotonin reuptake inhibitors (SSRI) are widely prescribed medications
SSRI have a high therapeutic to toxicity ratio and are associated with less toxicity than tricyclic antidepressants (TCA)
Anorexia Nervosa
Bulimia
Depression (see Depression, [[Depression]]): most depressants prescribed in the US are SSRI’s
Obsessive-Compulsive Disorder
Panic Disorder
Social Phobia
Agents
Citalopram (Celexa) (see Citalopram, [[Citalopram]])
Highly selective presynaptic SSRI: minimal effects on norepinephrine and serotonin reuptake
Bicyclic phthalane derivative
Terminal half-life: 35 hours
The drug is hepatically metabolized, but has less effect on the cytochrome P450 enzyme system than other SSRI
Although didesmethylcitalopram is only a minor metabolite (<10%) in human studies, it has been implicated in the cardiac toxicity of citalopram
Escitalopram (Lexapro) (see Escitalopram, [[Escitalopram]])
Fluoxetine (Prozac) (see Fluoxetine, [[Fluoxetine]])
Fluvoxamine (Luvox) (see Fluvoxamine, [[Fluvoxamine]])
Paroxetine (Paxil) (see Paroxetine, [[Paroxetine]])
Sertraline (Zoloft) (see Sertraline, [[Sertraline]])
Vortioxetine (Brintellix) (see Vortioxetine, [[Vortioxetine]])
Pharmacology
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 Physiology
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
Serotonin Metabolism
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
Sleep-Wake Cycles
Mood
Thermoregulation
Appetite
Pain Perception
Sexual Function
Serotonin Projections to Brainstem and Medulla
Muscle Tone
Precipitants of Excess Serotonergic Activity
Large Doses or Combinations of Serotonergic Agents: may occur in overdoses
Direct 5HT Receptor Stimulation
Buspirone (Buspar)
Carbamazepine (Tegretol)
Lithium
Lysergic Acid Diethylamide (LSD)
Mescaline-containing cacti (peyote, etc)
Triptans (Sumitriptan, etc)
Direct 5HT Release from Stored Vesicles
3,4 methylenedioxymethamphetamine (MDMA, Ecstasy)
Amphetamines
Cocaine
Codeine
Dextromethorphan
Levodopa
MAO Inhibitors: methylene blue, etc
Pentazocine (Talwin)
Reserpine
Increased Availability of 5HT Precursors
L-Tryptophan
Decreased 5HT Reuptake
Amphetamines
Carbamazepine (Tegretol)
Cocaine
Dextromethorphan
Hypericum Species (St. John’s Wort)
Linezolid
Meperidine (Demerol)
Methadone
Nefazodone
Selective Serotinin Reuptake Inhibitors (SSRI)
Tramadol (Ultram)
Trazodone (Desyrel)
Tricyclic Antidepressants (TCA)
Venlafaxine (Effexor)
Decreased 5HT Degradation
Hypericum Species (St. John’s Wort)
MAO Inhibitors
Other
Methylphenidate (Ritalin)
Ginseng
S-Adenosyl-Methionine
Adverse Effects
Gastrointestinal Adverse Effects
Increased Risk of Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]])
Epidemiology
Physiology: possibly related to their effects on platelet serotonin
Epidemiology: no clear association with the development of adult pulmonary hypertension
Maternal use may result in persistent pulmonary hypertension of the neonate
Use of SSRI’s is associated with worse prognosis in those with established pulmonary hypertension
Toxicologic Adverse Effects
SSRI Intoxication/Serotonin Syndrome (see Serotonin Syndrome, [[Serotonin Syndrome]])
Epidemiology
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
References
Citalopram in the treatment of depression and other potential uses in psychiatry. Pharmacotherapy. 1999;19:675-689.
QTc interval prolongation associated with citalopram overdose: a case report and literature review. Clin Neuropharmacol. 2001;24:158-162.
Citalopram overdose–review of cases treated in Swedish hospitals. J Toxicol Clin Toxicol. 1997;35:237-240.
Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol. 2004;42:277-285.
Cardiotoxicity and late onset seizures with citalopram overdose. J Emerg Med. 2003;25:163-166.
Speculations on difference between tricyclic and selective serotonin reuptake inhibitor antidepressants on their cardiac effects. Is there any? Curr Med Chem. 1999;6:469-480.
Mechanism of reversal of toxic effects of amitriptyline on cardiac Purkinje fibers by sodium bicarbonate. J Pharmacol Exp Ther. 1984;231:387-394.
Reversal of citalopram-induced junctional bradycardia with intravenous sodium bicarbonate. Pharmacotherapy. 2005;25:119-12
