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After reading the article you should be able to:

1. Describe the epidemiology of serotonin syndrome.
2. Describe the signs and symptoms of serotonin syndrome.
3. Compare and contrast the different categories of serotonergic drugs that have been implicated in the development of excessive levels of serotonin and the resulting serotonin syndrome.

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By D. L. MACKENZIE, RN, BA, MS, PhD

D. L. MACKENZIE is a registered nurse specializing in mental health and chemical dependency at WCA Hospital in Jamestown, NY. The author has no financial relationships to disclose. STAFF EDITOR: Martha K. Raymond, RN, BSN.

Violent, dangerously ill, and confused, Jason lay restrained in the emergency room, while his mother described finding him on the floor at home, practically unresponsive. He managed to tell his mother he had argued with his girlfriend, and then, feeling depressed, had gone to his room and taken 20 Seroquel and 50 Zoloft pills.

After treatment for an overdose, Jason was admitted to medical intensive care and diagnosed with serotonin syndrome. The leather restraints protected him and the hospital staff from his violent behavior. During the next 48 hours, Jason was in an agitated delirium marked with muscle rigidity; he repeatedly ripped out his IVs and was unable to sleep. More agitated in bed, he sat vested to a chair.

Treatment included running an IV of normal saline with 20 mEq of potassium chloride at 150 ml/hour. Jason received a bolus of 5 mg of Haldol, 2 mg of Cogentin, and 2 mg of Ativan IM for his violent behavior. Then, he received 2 mg of Haldol IM every two hours as needed, and 1 mg of Ativan IV every hour. He also got 8 mg of Cyproheptadine HCl tablets every six hours. Labwork was unremarkable. A head CT scan showed no abnormalities, and he had no seizures.

Potential cardiac complications from a serotonin overdose include bradycardia, tachycardia, widening of the QRS complex, lengthening of the QT interval or a conduction block.² Cardiac arrhythmia or shock could mean death. Consequently, Jason received serial EKGs and continuous cardiac monitoring. He remained in normal sinus rhythm, with a rate of about 60 beats per minute.

A few days later, a repeat head CT remained negative. Except for rare lucid moments, he remained uncooperative, confused, and restless, and he talked incoherently. Poison Control called regularly to check on the patient, and reported that Jason had taken more pills than originally reported.

By the fifth day, Jason was alert and talking coherently. The IV lines and catheter were removed. He denied having any current medical complaints such as headache, blurry vision, tinnitus, malaise, dyspnea, chest pain, rash, or any GI, GU, or musculoskeletal complaints. Later that day, Jason was transferred to the adolescent inpatient mental health unit for further care and rehabilitation.

During his mental health treatment, Jason admitted that he had been noncompliant with his medications, and that his prescription bottles were nearly full when he took the overdose.

Serotonergic drugs go mainstream

Antidepressants—serotonergic drugs—are the most prescribed medication in the U.S.¹ With the number and availability of antidepressants, misuse is easy. In 2004, the Toxic Exposure Surveillance System reported 48,204 toxic exposures to selective serotonin reuptake inhibitors (SSRIs). Of these, 8,187 patients developed serious symptoms of serotonin syndrome; 103 of these patients died. ³

One report estimated that more than 85% of physicians are unaware of serotonin syndrome as a clinical diagnosis. Mild cases of anxiety, tremor, restlessness, diaphoresis, akathisia, diarrhea, or hypertension may be dismissed by both the doctor and the patient, or attributed to the patient's mental state. In most cases, the symptoms resolve within 24 to 72 hours and are dismissed. Consequently, many cases go unreported, and the incidence of serotonin syndrome is unknown.^4,5

Serotonin syndrome can be induced directly by an intentional overdose in a suicide attempt. It can also occur in patients with impaired hepatic or renal function, who develop longer drug half-life and delayed drug clearance. Drugs prescribed therapeutically may interact inadvertently and cause serotonin syndrome, or it may develop in patients who take more of their medicines to attempt to accelerate their therapy.

Most cases reported involve patients taking two or more serotonergic medications that increase central nervous system (CNS) serotonin levels by different mechanisms, such as an SSRI with monoamine oxidase inhibitors (MAOIs) or a tricyclic antidepressant. As the level of serotonin increases, the serotonergic side effects increase until severely toxic. Nonetheless, serotonin syndrome can result from using a single drug. ^2,6

Neurotransmitter traffic jam

Only about 2% of the body's serotonin is in the CNS, where receptors lie along the brain stem from the midbrain to the medulla. Serotonin functions as a neurotransmitter in the CNS and influences mood, wakefulness, sleep, pain perception, migraines, cognition, appetite, and sexual behavior. It also regulates temperature and modulates motor systems.⁵ Low serotonin levels in the CNS are thought to cause depression.

Peripherally, enterochromaffin cells in the GI tract produce more than 90% of the body's serotonin. It regulates motility, but altered levels can cause nausea, vomiting, and diarrhea. The remaining serotonin is distributed among blood platelets and nerve synapses to modulate smooth muscle function, vasoconstriction, bronchial tree constriction, platelet aggregation, and the inflammatory response.

However, serotonin often serves as a cotransmitter and functions in conjunction with dopamine, gamma-aminobutyric acid (GABA), and norepinephrine to regulate many cerebral functions. Most antidepressant medications work by letting serotonin remain available longer in the synaptic spaces of the nervous system. For example, SSRIs block or inhibit serotonin removal and allow other neurotransmitters through.⁷

A large group of drugs that inhibit serotonin uptake and thereby increase the synaptic concentrations of serotonin include SSRIs, nonspecific serotonin reuptake inhibitors (SNRIs), and tricyclic antidepressants.

Another group of drugs, the MAOIs, inhibit or decrease serotonin metabolism and thereby increase serotonin concentrations in the synaptic cleft. In addition, serotonin receptor agonists stimulate postsynaptic 5-HT receptors and increase serotonergic effects. These include buspirone (Buspar), LSD, lysergic acid, and sumatriptan (Sumatrex).

Some drugs increase stored serotonin release. These include amphetamines, lithium, opioids, cocaine, Ecstasy, methoxy, and reserpine. Furthermore, L-tryptophan increases serotonin synthesis. It's in some dietary supplements and foods that contain tryptophan, such as cheese and wine, and also is in herbal medicines such as St. John's wort and ginseng. Other drug types that may increase serotonergic effects include anticonvulsants, analgesics, antiemetics, and antimigraine medications. Over-the-counter drugs such as Nyquil and cough suppressants that contain dextromethorphan also increase serotonergic effects. Dopamine agonists such those used to treat Parkinson's disease may indirectly increase serotonin activity.^6,7

Vague symptoms mask toxicity

Mental status changes often are the first symptoms reported—confusion, anxiety, restlessness, and agitation. Symptoms can progress rapidly and vary with toxicity levels. Approximately 60% of patients call for help within six hours of taking the offending drug.⁵ Of those admitted to an ICU and requiring mechanical ventilation, an estimated 11% die. ^6,8

Symptoms are considered minor or major, depending on the effects of the excessive amounts of serotonin on three areas: mental status changes, neuromuscular abnormalities, and autonomic nervous system dysfunction.

No specific laboratory tests are available to confirm the diagnosis of serotonin syndrome. Blood levels of serotonin do not correlate with the onset or severity of the diagnosis. Creatine kinase levels may be elevated, and the white cell count may be slightly elevated—however, neither of these is specific to serotonin syndrome. ⁵

Diagnosis typically is made in the presence of three of the major symptoms in a patient taking serotonergic medications, for which there are no other obvious causes—that is, all other explanations for the mental status changes, fever, neuromuscular abnormalities, and loss of coordination have been ruled out. The two most useful symptoms in the diagnosis of serotonin syndrome are hyperreflexia and clonus. A physical exam should focus on assessment of deep tendon reflexes, clonus, muscle rigidity, pupilary size and reactivity, bowel sounds, and the presence or absence of diaphoresis. ^4,5,7

Serotonin syndrome is most commonly confused with heat stroke, poisonings, delirium tremens, neuroleptic malignant syndrome (NMS), or use of cocaine, amphetamines, or LSD. An important distinction to make between NMS and serotonin syndrome is NMS occurs from prolonged exposure to therapeutic doses of neuroleptic agents, and is associated with lead-pipe rigidity; while serotonin syndrome is caused by toxic levels of serotonergic drugs and presents with clonus, hyperreflexia, and dilated pupils. Serotonin syndrome typically is diagnosed after all other potential causes are eliminated.

Avoiding a fatality

Severe cases of serotonin syndrome due to an overdose should be treated immediately with activated charcoal. Prehospital treatment begins with maintaining the airway, providing supplemental oxygen, stabilizing vital signs, cardiac monitoring, and treating seizures.²

All serotonergic medications should be stopped. Most patients with minor symptoms will improve once the drugs are stopped. The symptoms will resolve spontaneously within 24 to 72 hours.

Severe cases require intensive care because the syndrome may be complicated by severe hyperthermia, rhabdomyolysis, disseminated intravascular coagulation, renal failure, cardiac arrhythmias, ARDS, and possible death.⁵

Aggressive supportive care and sedation with benzodiazepines are treatment mainstays. Goals include stabilizing the cardiopulmonary status, correcting autonomic instability, controlling agitation, and decreasing hyperthermia. Intubation and paralysis may be needed because a patient's condition may deteriorate quickly. ⁵

Patients with hypotension and bradycardia may require low doses of sympathetic vasopressor drugs. Hypertension and tachycardia should be treated with nitroprusside or beta-blockers.

Keeping the patient safe while he's delirious and agitated is imperative. Benzodiazepines that treat muscle hyperactivity, rigidity, and seizures will also subdue severe agitation. Chemical sedation is preferred to physical restraints, since these are associated with increased isometric muscle contractions, which may increase lactic acidosis and hyperthermia.⁵

Hyperthermia also is best treated with benzodiazepines, since increased body temperature is due to excessive muscle activity. Antipyretic agents may be ineffective. Aggressive cooling measures such as ice, fans, or possibly a cooling blanket may be necessary. Dantrolene (Dantrium) has been used to manage malignant hyperthermia. The initial dose is 1 mg/kg IVP, repeated as needed to a cumulative dose of 10 mg/kg. If the temperature rises above 41.1° C, paralysis should be induced with vecuronium, followed by intubation and ventilation.⁵

Cyproheptadine (Periactin), a serotonin antagonist that binds serotonin receptors, is a recommended therapy for serotonin syndrome. An initial dose of 12 mg may be given orally and repeated in 2 mg doses every two hours. If there's some improvement, the patient may receive cyproheptadine 8 mg every six hours. Cyproheptadine is available in 4 mg tablets and in a 2-mg/ml syrup. The tablets may be crushed and given via a nasogastric tube. It may take 12 mg to 32 mg of cyproheptadine administered during a 24-hour period to bind 85% to 95% of the serotonin receptors.⁵

Propranolol is a serotonin 5-HT antagonist. However, it's no longer recommended for treatment since it may both lower blood pressure and decrease heart rate, causing shock in unstable patients.

Education is key to prevention

Serotonin syndrome prevention involves awareness of serotonergic drugs' toxic potential. The manufacturer's advice about washout periods should be considered when switching antidepressants. Prescribing physicians and their patients should be educated about possible drug interactions. Where multidrug regimens are required, use of computer-based ordering programs can detect potentially harmful drug interactions. Patients taking antidepressants should be warned of the dangers of taking OTC cold remedies that contain dextromethorphan without consulting their physicians. All patients and their families should be given medication education information, which now is available in most hospitals and from most pharmacies.

Jason recovered from his experience with serotonin syndrome. He had no memory of being in the ICU, having restraints, IVs, a catheter, or around-the-clock care. On the mental health unit, he participated in individual, family, group, and milieu therapy, and he developed a personal safety plan, which he could fall back on when he felt his behavior was out of control. He was discharged on Prozac 20 mg and Ritalin LA 20 mg daily, with follow-up appointments with an outpatient counselor and psychiatrist. 

REFERENCES

1. Cherry, D. K., Woodwell, D. A., & Rechtsteiner, E. A. (2007, June 29). National Ambulatory Medical Care Survey: 2005 Summary. Advance data from vital and health statistics; No. 387. Hyattsville, MD: National Center for Health Statistics. 2007. http://www.cdc.gov/nchs/data/ad/ad387.pdf 

2. Miller, J. (2004). Managing antidepressant overdoses. Emergency Medical Services, 33(10), 113-119.

3. Watson, W. A., Litovitz, T. L., et. al. (2004). Annual Report on the American Association of Poison Control Centers Toxic Exposure Surveillance System. American Association of Poison Control Centers. Retrieved from http://www.poison.org/prevent/documents/TESS%20Annual%20Report%202004.pdf

4. Kent, K. J. & Boyer, E. W. (2006). Serotonin Syndrome. UpToDate.com from http://www.uptodate.com/patients/content/topic.do?print=true&topicKey=ad_tox/12270&view=print

5. Boyer, E. W. & Shannon, M. (2005). The serotonin syndrome. N Eng J M, 352(11), 1112-1120.

6. Selective serotonin reuptake inhibitors. (2006, Dec. 8). MayoClinic.com. http://www.mayoclinic.com/health/ssris/MH00066

7. Bijl, D. (2004). The serotonin syndrome. Neth J M, 62(9), 309-313.

8. Gillman, P. K. (2006). A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action. Biological Psychiatry, 59, 1046-1051.

SEVERAL CATEGORIES OF SEROTONERGIC DRUGS HAVE BEEN IMPLICATED IN THE DEVELOPMENT OF EXCESSIVE LEVELS OF SEROTONIN AND THE RESULTING SEROTONIN SYNDROME.

Inhibit serotonin uptake

Selective serotonin reuptake inhibitors (SSRIs)

• citalopram (Celexa)
• escitalopram (Lexapro)
• fluoxetine (Prozac)
• luvoxamine (Luvox)
• paroxetine (Paxil)
• sertraline (Zoloft)

Nonspecific serotonin reuptake inhibitors (SNRIs)

• bupropion (Wellbutrin)
• clomipramine (Anafranil)
• duloxetine (Cymbalta)
• trazodone (Desyrel)
• venlafaxine (Effexor)

Tricyclic antidepressants

• amitriptyline (Elavil)
• desipramine
• doxepin (Sinequan).
• imipramine (Tofranil)
• nortriptyline (Pamelor)
• protriptyline (Vivactil)
• trimipramine (Surmontil)

Monoamine oxidase inhibitors (MAOIs)

• clorgiline
• isocarboxazid (Marplan)
• phenelzine (Nardil)
• tranylcypromine

Serotonin receptor agonists

• buspirone (Buspar)
• LSD
• lysergic acid
• sumatriptan (Sumatrex)

Increase the release of stored serotonin

• amphetamines
• cocaine
• MDMA (Ecstasy)
• lithium
• methoxy groups
• opioids
• reserpine (Serpalan, Serpasil)

Increase serotonin synthesis

• L-tryptophan containing foods
• herbal medicines such as St. John's wort and ginseng containing L-tryptophan

Increase serotonergic effects

• analgesics
• fentanyl (Duragesic)
• meperidine (Demerol)
• pentazocine (Talwin)
• tramadol (Ultram)
• anticonvulsants
• valproate (Depakote)
• antiemetics
• granisetron (Kytril)
• metoclopramide (Reglan)
• ondansetron (Zofran)
• antimigraine medications
• sumatriptan (Imitrex)
• OTCs
• Nyquil and cough suppressants containing dextromethorphan
• dopamine agonists
• levodopa/carbidopa (Sinemet, Stalevo)
• pergolide (Permax)
• selegiline (Eldepryl)

Sources: 1. Bijl, D. (2004). The serotonin syndrome. Neth J M, 62(9), 309-313.

SYMPTOMS OF SEROTONIN TOXICITY

Mild to moderate serotonin toxicity symptoms

• Restlessness, anxiety, pressured speech
• Agitation
• Insomnia
• Tachycardia
• Tachypnea
• Shivering
• Flushing
• Diaphoresis, though may be febrile
• Hypotension or hypertension
• Mydriasis (dilation of the pupil)
• Diarrhea
• Loss of coordination
• Ataxia
• Akathsia (motor restlessness ranging from feeling inner disquiet to inability to sit quietly or sleep)
• Intermittent tremor, myoclonus (abrupt contractions or twitching of a muscle or a group of muscles in one area of the body), or hyperreflexia

Severe serotonin toxicity symptoms

• Confusion
• Agitated delirium
• Seizures
• Coma
• Hypertension
• Tachycardia that may abruptly deteriorate into shock
• Diaphoresis and hyperthermia associated with muscle hyperactivity
• Hypertonia (excessive skeletal muscle tone or increased resistance to passive stretching)
• Clonus (alternating muscular contraction and relaxation in rapid succession)
• Hyperreflexia
• Rhabdomyolysis and renal impairment
• Disseminated intravascular coagulopathy (DIC)
• In severe cases, patients may die from untreated metabolic acidosis, renal failure, shock, or disseminated intravascular coagulopathy.

Sources: 1. Bijl, D. (2004). The serotonin syndrome. Neth J M, 62(9), 309-313.