Selective Serotonin Reuptake Inhibitor Toxicity

Selective serotonin reuptake inhibitors (SSRIs), widely prescribed medications for the treatment of depression, obsessive-compulsive disorder, bulimia, anorexia nervosa, panic disorder, anxiety, and social phobia, have a high therapeutic to toxicity ratio. However, although they are associated with less toxicity than tricyclic antidepressants (TCAs), they are often involved in co-ingestions that can precipitate the potentially lethal serotonin syndrome (SS). (See Etiology.) 

SS represents a constellation of signs and symptoms that manifest in the neuromuscular, autonomic nervous, and gastrointestinal systems, in which concentrations of serotonin receptors are highest. SS represents the most severe end of a spectrum of serotonin excess and is characterized by mental status changes, neuromuscular hyperactivity, and autonomic instability. (See Prognosis and Presentation.) ^{[1, 2]}

The majority of antidepressants prescribed in the United States are from the SSRI family. ^{[3, 4]} 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. (See Etiology.)

SS is often caused by combinations of SSRIs with other proserotonergic agents, including:

• Monoamine oxidase inhibitors (MAOIs)

• TCAs

• Trazodone (Desyrel)

• Serotonin-norepinephrine reuptake inhibitors (SNRIs)

• Norepinephrine-dopamine reuptake inhibitors

• Lithium

• Opioids

• 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 an 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 is a tetracyclic drug that blocks serotonin reuptake and also has an antagonistic effect at the serotonin 5HT₂ receptor site.

Bupropion (Wellbutrin), a norepinephrine-dopamine reuptake inhibitor classified as neither an SSRI nor a TCA, is another commonly prescribed antidepressant that can precipitate SS; it 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.

Numerous reports have described SS precipitated by combination of serotonergic drugs with the antimicrobial agent linezolid, which exhibits monoamine oxidase (MAO)-type effects. ^[5]

Pharmacokinetics

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

Hence, addition of serotonergic medications to a patient's regimen must not occur until 2 to 3 weeks after discontinuation of an SSRI. Some recommend a 5-week "wash-out" period for fluoxetine prior to initiation of an MAOI. (See Treatment.) ^{[7, 8]}

Complications

Complications of SSRI toxicity can include the following:

• Seizures

• Arrhythmia

• Rhabdomyolysis

• Disseminated intravascular coagulation

• Acute renal failure

• Respiratory failure

Serotonin, or 5-hydroxytryptamine (5HT), is a neurotransmitter found in the central and peripheral nervous system. Serotonin is produced in the brainstem’s raphe nuclei 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 it is locally metabolized by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid. Systemic metabolism is through MFOs of the liver.

Inhibition of particular MFOs by other medications or plant materials (eg, grapefruit) may cause increased drug effect from decreased metabolism. ^[6]

SS is most often caused by simultaneous ingestion of 2 or more proserotonergic medications, which may be associated with therapeutic error, idiopathic response, or intentional overdose. ^{[9, 10]}

A recently increased dose of a chronic medication or a new addition to an extensive medication regimen is an important component of the history that may provide the diagnosis. Use of over-the-counter medications or dietary supplements in addition to prescribed serotonergic medications is also an important etiology.

Seven distinct 5HT receptors, which can be further divided into specific subtypes, exist and produce a wide variety of physiologic effects. This diverse activity gives rise to the multiple signs and symptoms of serotonin toxicity. ^{[11, 12]}

Mechanisms of serotonin increase

Excess serotonergic activity can be precipitated through any of the following mechanisms ^[13] :

• Direct 5HT-receptor stimulation - Buspirone (BuSpar), triptans (Imitrex, Amerge, Zomig, others), lithium, carbamazepine (Tegretol), lysergic acid diethylamide (LSD), 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

Receptor locations and symptoms

Large dosages or combinations of any of the drugs in the above lists can produce serotonin toxicity or SS. The physiologic manifestations of SS are largely due to stimulation of 5HT_1a and 5HT₂ receptors, with the symptoms of serotonin toxicity arising from the specific location of the 5HT receptors in the body. ^[8]

For example, 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. Seizures are rare in SSRI overdose, with the exception of citalopram, which has an increased risk of inducing seizures in both adults and children. ^{[14, 15]}

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. Dose-dependent QT prolongation has been reported with citalopram (Celexa). ^{[15, 16]} Because of the risk for QT prolongation, revised prescribing information was announced in August 2011. ^[17] Citalopram is contraindicated in individuals with congenital long QT syndrome, and the dose should not exceed 40mg daily. ^[18]

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. ^[19]

Occurrence in the United States

Data from the 2013 Annual Report of the American Association of Poison Control Centers' National Poison Data System (AAPCC-NPDS) revealed approximately 2.2 million toxic exposures and 2,113 fatalities. ^[20] Antidepressants were involved in 4.2% of all exposures, ranking 5th for the most frequently cited substance class. SSRIs were mentioned in 2.2% of all exposures, accounting for 47,336 cases.

Of SSRI exposures without co-ingestion, 50% did not develop any signs or symptoms and 32% had a minor, self-limiting reaction. Moderate effects necessitating treatement were present in 17% of exposures, while 1% had a major, life-threatening effect and 0.05% resulted in death. ^[20]

Age-related demographics

Based on data from identifiable cases, 41% of SSRI exposures occurred in persons 20 years or older with rates comparable in children 5 years or younger (25%) and in teenagers aged 13 to 19 years (28%). The majority of SSRI exposures were unintentional (51%), while 45% were intentional and 4% were due to adverse reactions from prescribed use.

Side effects from SSRIs are not age specific, however elderly persons may be more susceptible by taking a wide variety of medications that alter cytochrome P-450 MFO metabolism.

Most cases fully resolve without residual deficits if supportive care has been provided. The prognosis is generally favorable. Most fatalities occur within the first 24 hours. Patients who remain asymptomatic for 6-8 hours after ingestion are unlikely to require further treatment.

AAPCC-NPDS 2013 data showed that of 2,113 fatalities attributed to toxic exposures, SSRIs were present in 92 of these cases, while only 6 deaths were attributable to SSRI exposure without co-ingestion. SSRIs have a wide therapeutic index, with most fatalaties resulting from co-ingestion of other substances. ^[20]

All patients started on SSRIs by psychiatrists or primary care physicians should be educated about symptoms of serotonin toxicity and SS.

Patients should be counseled about potential interactions among any medications they take—including over-the-counter medications (particularly dextromethorphan-containing cold remedies), illicit drugs (especially amphetamines, MDMA, cocaine, and mescaline), and herbal dietary supplements/nutraceuticals (eg, St. John's wort, ginseng, and S-adenosyl-methionine)—that might affect the patient's tissue concentrations of serotonin.