Selective Serotonin Reuptake Inhibitor Toxicity 

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed medications for the treatment of depression, obsessive-compulsive disorder, bulimia, anorexia nervosa, panic disorder, and social phobia. The majority of all antidepressants prescribed in the United States are from the SSRI family.^{[1, 2]} Commonly prescribed SSRIs include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), escitalopram (Lexapro), and fluvoxamine (Luvox). SSRI toxicity and other adverse drug reactions can occur with overdose, in combination with other medications, or infrequently at therapeutic doses.

SSRIs have a high therapeutic to toxicity ratio and are associated with less toxicity than tricyclic antidepressants (TCAs). However, they are often involved in co-ingestions that can precipitate the potentially lethal "serotonin syndrome" (SS). SS is characterized by mental status changes, neuromuscular hyperactivity, and autonomic instability.^{[3, 4]} SS is often caused by combinations of SSRIs with other proserotonergic agents, including monoamine oxidase inhibitors (MAOIs), TCAs, trazodone (Desyrel), lithium, opioids, and amphetamine/stimulants, including methylphenidate (Ritalin), 3,4 methylenedioxymethamphetamine (MDMA, Ecstasy), cocaine, and herbal dietary supplements or nutraceuticals (St. John's wort, ginseng, and S-adenosyl-methionine). All of these affect the production, release, or breakdown of serotonin at the presynaptic cleft, thereby increasing its levels and toxicity. Less frequently, SS can be precipitated by overdose of a single SSRI.

Venlafaxine (Effexor) and duloxetine (Cymbalta) are serotonin-norepinephrine reuptake inhibitors (SNRIs) that are also associated with serotonin toxicity, as is the tetracyclic drug mirtazapine (Remeron), an alpha-2 adrenergic heteroreceptor blocking agent that causes increased norepinephrine and serotonin release in addition to blocking serotonin receptors. Trazodone (Desyrel) is a tetracyclic drug that blocks serotonin reuptake and also has an antagonistic effect at the serotonin 5-HT2 receptor site. Wellbutrin (buproprion) is a norepinephrine-dopamine reuptake inhibitor classified as neither an SSRI or TCA but is another commonly prescribed antidepressant that can precipitate a serotonin syndrome and is commonly involved in fatal antidepressant overdoses.

Several opioids are serotonergic and have been associated with SS. These include meperidine (Demerol), tramadol (Ultram), dextromethorphan, and pentazocine. The historically significant Libby Zion medicolegal case involved meperidine, cocaine, and an MAOI and was instrumental in changing the working conditions of postgraduate training programs. In addition, numerous reports have described serotonin syndrome precipitated by combination of serotonergic drugs with the newer antimicrobial agent linezolid, which exhibits monoamine oxidase (MAO) type effects.^[5]

Serotonin, or 5-hydroxytryptamine (5HT), is a neurotransmitter found in both the central and peripheral nervous system. Serotonin is produced in the brainstem raphe nucleus from L-tryptophan and is then stored in presynaptic vesicles. Neuronal activation causes release of 5HT into the synapse. Excess serotonin is taken back up into presynaptic vesicles by an active transport mechanism or locally metabolized by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid. Systemic metabolism is through liver mixed function oxidases (MFOs). Inhibition of particular MFOs, by other medications or plant materials (eg, grapefruit), may cause increased drug effect from decreased metabolism.^[6] Seven distinct 5HT receptors with further specific subtypes exist and produce a wide variety of physiologic effects. This diverse activity gives rise to the multiple signs and symptoms of toxicity.^{[7, 8]}

Excess serotonergic activity can be precipitated through any of the several mechanisms listed below.^[9] Large dosages or combinations of any of these drugs can produce serotonin toxicity or the SS. The physiologic manifestations of serotonin syndrome are largely due to stimulation of 5HT_1a and 5HT₂ receptors.^[10]

• Direct 5HT receptor stimulation - Buspirone (BuSpar), triptans (Imitrex, Amerge, Zomig, others), lithium, carbamazepine (Tegretol), lysergic acid diethylamide (LSD), and mescaline-containing cacti (peyote and others)
• Direct 5HT release from stored vesicles - Amphetamines, MDMA, cocaine, reserpine, levodopa, MAOIs, codeine, dextromethorphan, pentazocine
• Increased availability of 5HT precursors - L-tryptophan
• Decreased 5HT reuptake - SSRIs, trazodone (Desyrel), nefazodone, venlafaxine (Effexor), TCAs, dextromethorphan, tramadol (Ultram), meperidine (Demerol), cocaine, Hypericum species (St. John's wort), amphetamines, carbamazepine (Tegretol), methadone, linezolid
• Decreased 5HT degradation - MAOIs, St. John's wort

Serotonergic projections to the thalamus and cortex result in effects on sleep-wake cycles, mood, thermoregulation, appetite, pain perception, and sexual function. Excess 5-HT in these pathways causes the mental status changes, confusion, agitation, ataxia, and fever associated with SSRI toxicity and SS. Toxicity of descending pathways to the brainstem and medulla results in hyperreflexia, myoclonus, and tremor.

Autonomic nervous system effects include diaphoresis, mydriasis, hypertension, tachycardia, hyperthermia, piloerection, and muscular rigidity.

Cardiovascular effects most commonly include sinus tachycardia, flushing, hypertension, and in rare cases, hypotension. Citalopram (Celexa) was associated with prolonged QTc in one series.^[11] Dose-dependent QT prolongation has been reported with citalopram. Because of the risk for QT prolongation, revised prescribing information was announced in August 2011.^[12] Citalopram is contraindicated in individuals with congenital long QT syndrome and the dose should not exceed 40 mg/d.^[13]

Due to the high levels of serotonin in gastric and intestinal mucosal enterochromaffin cells, the most common minor adverse effects of SSRI therapy are gastrointestinal, eg, abdominal cramping, nausea, and diarrhea. SSRIs have also been shown to moderately increase the risk of upper gastrointestinal bleeding.^[14]

Pharmacokinetics

SSRIs are metabolized in the liver by cytochrome P-450 MFO microsomal enzymes. They are highly bound to plasma proteins and have a large volume of distribution. Peak plasma levels are reached in 2-10 hours. Half-lives are variable, but most SSRIs have half-lives of 20-24 hours.^[6] A notable exception is fluoxetine (Prozac), and its active metabolite, norfluoxetine, which have half-lives of 2-4 days and 8-9 days, respectively. Hence, 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 MAOI).^{[15, 10]}

Frequency

United States

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 exposures in 2009.^[16] 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 SSRIs alone. Of 260 total antidepressant-related fatalities, SSRIs 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.^[16]

Mortality/Morbidity

AAPCC-NPDS 2009 data showed that, of 102,792 adult antidepressant exposures, 7 deaths were attributable to SSRIs alone. Most exposures were classified as causing mild-to-moderate effects. A significant number of deaths involved ingestions of bupropion (Wellbutrin) or venlafaxine (Effexor), often in combination with alcohol or other prescription medications.^[16]

Sex

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.

Age

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 SSRIs 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 MFO CYP metabolism.