Serotonin syndrome

Journal o f the American Psychiatric Nurses Association

Psychobiology Perspectives Serotonin Syndrome R. J. Westphal, RN, CS, MSN Editor's note: In this issue, we are pleased to offer

a Psychobiology Perspectives article on a very important subject that has received inconsistent attention in the literature but is of critical consequence to the practice of clinical nursing, especially for those whose patients receive serotonergic agents. Serotonin syndrome is potentially fatal and as such carries with it a very salient set of implications, ranging from the pragmatic to the theoretical. Cutting across these various dimensions is the ethical directive underlying all practice: do no harm. Being knowledgeable about the biological basis for a treatment-bound condition such as serotonin syndrome is essential. Knowing how to identify serotonin syndrome in the clinical setting and intervene in an effective fashion is requisite for safe and sound practice. Toward these ends, this article aims to facilitate your understanding of serotonin syndrome and, we hope, enrich your current understanding of the condition and add value to the knowledge you bring to the practice setting.--Geoffry McEnany, R~, PhD, CS

S

erotonin (5-hydroxytryptamine [5-HT]) has become the focus of considerable attention in this waning decade of the brain. From fluoxetine (Prozac) and trazodone (Desyrel) to fenfluramine/ phentermine (Fen-Phen) and Hypericum perforatum

R. J. Wes~hal is a Commander, Nurse Corps, US Navy, and Head, Psychiatric Technician School, Naval School of Health Sciences, Portsmouth, Virginia. The statements and opinions expressed herein are strictly those of the author and do not represent the official views of the US Navy or Department of Defense. Reprint requests: R.J. Wes~phal, RN,, CS, MSN, 401 Sandy Hill Way, Chesapeake, VA 23322-6405. J Am Psychiatr Nurses Assoc (1999). 5, 97-102. Copyright © 1999 by the American Psychiatric Nurses Association. 1078-3903/99/$8.00 + 0 rune 1999

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(St John's Wort), serotonergic compounds are making news headlines on a regular basis. For many people, these products produce a profound relief from the suffering caused by the symptoms of mental illness. As one of the most important regulatory amines of the body, serotonin works in concert with histamine, epinephrine, norepinephrine, dopamine, and 7-aminobutyric acid to orchestrate human experience within a given environment. The quality of the experience largely depends on the various components of the central nervous system (CNS) functioning in concert in a highly regulated and systematic fashion. Disruption of the delicate balance and relationship between these neurotransmitters plays an important role in specific psychiatric disorders (Anderson, 1998).

As one of the most important regulatory amines of the body, serotonin works in concert with histamine, epinephrine, norepinephrine, dopamine, and yaminobutyric acid to orchestrate human experience within a given environment. Sites rich in serotonin activity include the CNS; hypothalamus, raphe nuclei of the brain stem, and caudate nucleus; and, peripherally, the gastrointestinal tract and blood platelets (deGroot & Chusid, 1988). Two percent of the body's total serotonin is in the CNS (Goth, 1981). Originating in the raphe nuclei, serotonergic neurons branch throughout the brain with high concentrations in the limbic system, basal ganglia, and cerebral cortex (Snyder, 1986). Through these connections, serotonin modulates sleep, appetite, pain sensitivity, temperature, release of pituitary hormones, and mood states (deGroot & Chusid, 1987; Goth, 1981; Kaplan, Sadock, & Grebb, 1994). Peripherally, approximately 8% of total serotonin is in the platelets, where its role is unclear, and 90% is in the intestine, where it plays a role in intestinal motility (Goth, 1981). APNA website: www.apna.org 97

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Journal o f the American Psychiatric Nurses Association

Synthesis]

•

Metabolism

Tryptophan]

•

V~Trans '~"

.

port Pump

(

transport pump to get into the neuron. Once in the serotonin neuron, tryptophan is converted into serotonin by a two-step enzymatic process. Storage vesicles hold the serotonin until a neuronal impulse signals release into the synapse (Kaplan & Sadock, 1996). After the serotonin stimulates postsynaptic receptors, it is released into the synapse as free serotonin. The metabolism of serotonin requires a presynaptic transport pump, as in the case of norepinephrine and dopamine. The serotonin transporter pulls free serotonin from the synapse and pumps it into the presynaptic cell. Serotonin is then converted to an inactive metabolite by monoamine oxidase (MAO). When MAO is inhibited, the amount of free serotonin in the synapse increases (Stahl, 1996).

SEROTONERGIC RECEPTORS

Figure 1. Synthesis and metabolism of serotonin.

KEY NEUROTRANSMITTERS Recognizing that the neurotransmitters serotonin, norepinephrine, and dopamine work in concert is important. Each has a role in the production and activity of the other two. Norepinephrine is most closely associated with learning and memory, mood and affect, reinforcement, sleep-wake cycle regulation, and anxiety. Dopamine is believed to be dysregulated in persons with disorders of thought. Serotonin is involved in the enactment of behaviors and/or symptoms related to the disorders of mood, anxiety, obsessions, and phobias (Kaplan et al., 1994). The imbalance of these neurotransmitters produces the wide variety and clustering of mental illness symptoms. The dynamic interplay of neurotransmitters are the basis for a variety of symptoms--for example, persons who have major depression with psychotic features, as well as those with psychotic disorders with depressed mood.

SEROTONIN SYNTHESIS AND METABOLISM Understanding the synthesis and metabolism of serotonin provides insight about the mechanism of action and side effects of serotonergic agents (Figure 1). Serotonin is converted from tryptophan, an amino acid precursor, in the serotonin neuron, and requires a 98 APNA website: www.apna.org

A key to the development of new antidepressant medications is aggressive research into the subtyping of neurotransmitter receptor sites. The greater the receptor site specificity of a particular medication, the more accurately that medication can be used for treating specific symptoms. As of 1998, seven major types of 5HT receptors have been identified, and each type has additional subtypes (Anderson, 1998; Dubovsky & Thomas, 1995). Receptor sites are subtyped according to molecular or pharmacologic features (Kaplan & Sadock, 1996).

Tricyclic antidepressants are effective in treating about 80% of persons who have symptoms of depression. Stahl (1996) described the location and clinically significant reactions of four key serotonin receptor sites (Table 1). The 5HT1A receptor is found on both presynaptic and postsynaptic membranes. The presynaptic receptors are autoreceptors located on the cell body in the raphe nuclei of the brain stem and regulate the synthesis and release of serotonin through a negative feedback mechanism (Dubovsky & Thomas, 1995; Stahl, 1996). The presynaptic 5HT1A receptor detects the presence of serotonin and decreases the neuronal impulse activity. This down regulation, also called disinhibition, causes an increase in the release of seroVol. 5, No. 3

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tonin and the therapeutic effects in the treatment of depression and anxiety disorders. The postsynaptic 5HTIA receptors are located in the amygdala, hippocampus, hypothalamus, and frontal cortex and function to decrease body temperature and facilitate signal communication with other neurons. Clinically, stimulation of the postsynaptic 5HT1A receptors produces relief from the symptoms of depression, obsession and compulsions, panic, social phobia, and bulimia (Stahl, 1996). 5HTm receptors are located on the terminal end of the presynaptic neuron and function as an autoreceptor. As a terminal autoreceptor, the 5HT1D blocks the release of serotonin into the synapse and produces antimigraine actions (Stahl, 1996). 5HT 2 receptors are critically important in understanding the symptoms of mental illness and the problematic side effects of psychotropic medications. Stimulation of the 5HT2 receptor alters postsynaptic impulses by blocking the expression of neuronal genes producing both therapeutic and iatrogenic effects. Stimulation of 5HT2 receptors causes an increase in anxiety, temperature, hallucinations, psychosis, and panic. Early in treatment, the nerve impulses are no longer inhibited and increase the amount of 5HT to be released into the somatodendritic (receiving branches) autoreceptors of the neuron, thus stimulating 5HT2. Once the somatodendritic sites are activated, a delay occurs before the neuronal impulse signals the release of 5HT from the axon terminal. The increase in 5HT from the axon terminal causes the postsynaptic receptors to down regulate and produce a decrease in the symptoms of panic, depression, obsessive-compulsive disorder (OCD), bulimia, sleep function, and sexual function (Stahl, 1996). The delay in down regulation causes the paradox of panic and anxiety in early treatment and therapeutic effects after several weeks. 5HT3 receptors are found in the gastrointestinal centers of the brain stem and in the alimentary tract itself. Stimulation produces the adverse effects of nausea, decreased appetite, increased gastrointestinal motility, and weight loss (Stahl, 1996). SEROTONERGIC

MEDICATIONS From the late 1950s into the 1980s, the classic antidepressants were the MAO inhibitors (MAOI) and the tricyclic antidepressants (TCA). The MAOIs were the first antidepressants. Use of the MAOIs was limited by the potential for serious adverse effects of hepatotoxicity, 'une 1999

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Table 1. Serotonin Receptor Sites and Associated

Actions Receptor Site 5HT1A Presynaptic and postsynaptic membranes 5HTID Terminal end of the presynaptic

Associated Actions " Antidepressant Anxiolytic Decrease temperature Antimigraine

neuron 5HT 2 Postsynaptic membranes

Increase Anxiety Temperature Hallucinations Psychosis Panic

Decrease Panic Depression OCD Bulimia Sleep Sexual

function 5HT 3 Brain stem, GI centers and alimentary tract

Nausea Decreased appetite Increased G1 motility

Note. GI = gastrointestinal; OCD = obsessive-complusive disorder.

postural hypotension, and the potentially fatal hypertensive crisis caused by the ingestion of foods with high tyramine levels. Tricyclic antidepressants are effective in treating about 80% of persons who have symptoms of depression. Along with antidepressant effects, the TCAs have substantial anticholinergic activity and a quinidine effect on the heart (Goth, 1981). As research uncovered the mechanism of action of these medications, pharmacokinetic refinements were made to maintain treatment efficacy while reducing the severity of adverse effects. Since the late 1980s, the serotonin selective reuptake inhibitors (SSRI) have become the first-line treatment for major depression (Mitchell, 1997). The SSRIs are also being used for the treatment of OCD, eating disorders, panic disorder, phobias, and borderline personality disorder and thus go beyond the specific use as antidepressants (Kaplan et al., 1994). The classic MAOIs are irreversible and nonselectively block the reuptake of both serotonin and norepinephrine. A new class of MAOI is the reversible inhibitor of MAO-A (RIMA). With RIMA drugs, the excessive build-up of norepinephrine that occurs when tyramine is ingested displaces the RIMA and reduces the risk of a hypertensive crisis (Stahl, 1996). Pharmaceutical-grade psychotropic medications are not the only drugs that alter the serotonin system. APNA website: www.apna.org 99

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Food is first and foremost in serotonergic activity and availability. The 5HT precursor tryptophan is commonly found in cheese, milk, poultry, and red wine (Anderson, 1998). The amino acid supplement L-tryptophan was a very popular sleep aid before it was removed from the United States market because of product contamination; it is still widely available outside of the United States. There are recreational and over-the-counter medications with serotonergic activity, such as alcohol, dextromethorphan, diet pills, and Hypericum perforatum (St. John's Wort). Popular street drugs that have serotonergic activity include 3, 4-Methylenedioxymethamphetamine (MDMA), also known as Ecstasy, and lysergic acid diethylamide (LSD) (Brown, Skop, & Mareth, 1996; Demirkiran, Jankovic, & Dean, 1996). Given the wide variety of substances that impacts the serotonin system, nurses need to be aware of the potential for overstimulation.

SEROTONIN SYNDROME Serotonin syndrome (SS) is a potentially life-threatening disorder resulting from overstimulation of serotonergic receptors by drug therapy (Mills, 1997). The syndrome usually occurs shortly after initiating or increasing dosages of an MAOI and a serotonergic agonist (Ivanusa, Demarin, & Hecimovic, 1997; LoCurto, 1997). SS can also appear with treatment intervention with SSRIs alone. In particular, the risk increases when changing medications (Bhatara, Magnus, Paul, & Preskorn, 1998). These agents cause the presynaptic 5HTIA autoreceptor to down regulate, resulting in an increase of serotonin release at the axon. With the increase of serotonin release, the postsynaptic receptors 5HT2 and 5HT3 are stimulated (Stahl, 1996). Whether a person has a therapeutic response or whether SS develops depends on the presence of several risk factors. Brown et al. (1996) proposed a three-component pathophysiologic mechanism for SS that considers inherited, acquired, and iatrogenic risk factors. Some persons may have low endogenous MAO activity resulting from a genetic predisposition or inherited cardiovascular disease. Acquired risk factors include liver disease resulting from alcohol abuse or hepatitis, pulmonary disease, tobacco abuse, and cardiovascular disease. Medications, both prescription and nonprescription, that stimulate serotonin activity or inhibit its breakdown form the iatrogenic factors. Serotonin syndrome symptoms. Sternbach (1991) proposed diagnostic criteria for SS consisting of three elements. First, there is a coincidental addition 100 APNA webs#e: www.apna.org

or increase of a serotonergic agent to an established medication regimen, producing at least three of the following symptoms: agitation, diaphoresis, fever, diarrhea, hyperreflexia, incoordination, mental status changes, myoclonus, shivering, or tremor. Second, other causes have been ruled out, such as substance intoxication or withdrawal, metabolic disorders, or infections. Third, a dopamine receptor antagonist had not been started or increased before the onset of symptoms. Because of the significant overlap of symptoms with neuroleptic malignant syndrome, some researchers argue that SS and neuroleptic malignant syndrome represent a generalized neurotoxic syndrome versus separate syndromes (Fink, 1996). Hegerl et al. (1998) are developing and testing an SS scale based on Sternbach's diagnostic criteria. Case studies show variability in the onset and course of SS. Onset of symptoms can occur within 30 minutes of when an MAOI is one of the iatrogenic factors to 48 hours w h e n changing medications (Molaie, 1997; Weiner, Smythe, & Cisek, 1998). The symptoms of SS are usually of short duration and resolve within hours of either discontinuing the inciting agent or initiating supportive treatment (LoCurto, 1997).

The symptoms of SS are readily amenable to nursing interventions when identified early in the trajectory of the condition. Treatment. Brown et al. (1996) proposed a medical treatment protocol for the management of SS based on a review of the literature and clinical case studies. Once the individual's symptoms have been identified as being consistent with SS, a thorough assessment of all the serotonergic agents the patient may be taking needs to be completed. One should be particularly alert to over-the-counter drugs and nutritional supplements. Next, identifiable contributing agents should be discontinued. When discontinuing medications, the risks of withdrawal symptoms associated with shortacting agents must be weighed against the severity and risks of the SS symptoms. The aggressiveness of treatment will depend on the severity of the symptoms. For mild symptoms, the patient can be sent home with close follow-up and lorazepam, propranolol, or cyproheptadine, a serotonin receptor antagVol. 5, No. 3

Journal of the American Psychiatric Nurses Association

onist, as needed. For moderate to severe symptoms, hospitalization for monitoring and supportive measures is indicated. Supportive measures include the use of cooling blankets, maintaining safety, a n d intravenous hydration. Inadequate symptom improvement will guide the step-by-step use of lorazepam, then propranolol, then cyproheptadine. After the patient is stabilized and the risk of further crisis has passed, serotonergic medications should be reassessed and other risk factors minimized.

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patient safety is at risk because of impaired cognition, 1:1 monitoring and supervision should be provided. Fluid and electrolyte imbalance. Fluid and electrolyte balance is a significant factor in maintaining homeostasis and mental status. The patient should be monitored for signs and symptoms of dehydration and diaphoresis. Intake and output should be monitored, encouraging adequate hydration. If adequate oral hydration cannot be maintained, intravenous hydration should be considered.

NURSING CARE ISSUES Nurses play a critical role in the early assessment of SS and the implementation of supportive measures. The symptoms of SS are readily amenable to nursing interventions when identified early in the trajectory of the condition. Identification and Prevention o f SS. First and foremost is the prevention of SS. Prevention starts with the education of all staff regarding the risk factors, signs, and symptoms of SS. The importance of continued assessment of routine vital signs, especially temperature, should be stressed. Staff should report changes in vital signs, motor activity, and mental status to the prescriber immediately. Prevention also includes patient and family teaching regarding the many sources of serotonergic agents and the early symptoms of SS. The remedies the patient has tried in the past or is currently using to augment the prescribed treatment should be assessed. Hyperthermia. Temperature dysregulation with severe hyperthermia can lead to a potentially fatal cascading effect. If the temperature reaches 37.7°C (100°F), it should be monitored every 1 to 2 hours. If the affected person is agitated or restrained, adequate room ventilation should be ensured, and blankets or full sheet restraints should not be used. The fever should be treated with antipyretic agents or with cooling blankets or a sponge/tepid bath. With children, the elderly, and persons who already experience temperature fluctuations, changes in b o d y temperature may occur rapidly and quickly result in physiologic crisis. Mental status changes. Knowing the patient's baseline symptoms will be very important for monitoring changes in mental status. As with other forms of delirium and transient mental status changes, the nurse will need to make frequent mental status assessments. Reassurance and reality orientation should be provided in an ongoing and supportive manner. If rune 1999

As more serotonergic agents are being used, there is an increased risk for serious and potentially lifethreatening adverse effects.

Incoordination, myoclonus, tremor, rigidity. Impairment of the motor centers produces incoordination, myoclonus (rapid rhythmic movement), tremor, and rigidity. The patient may require assistance with activity of daily living and ambulation. Patient exposure to sudden stimuli that trigger motor responses should be reduced.

SUMMARY As knowledge and understanding of the function of the brain leads to new treatments for mental illness, it also leads to new iatrogenic dilemmas. Through greater neurotransmitter receptor specificity, the new generation of antidepressants has r e d u c e d - - b u t not eliminated--potentially serious adverse effects. Often the full spectrum of adverse effects is not revealed until a medication is being widely used. As more serotonergic agents are being used, there is an increased risk for serious and potentially life-threatening adverse effects. For all psychotropic medication, early recognition of side effects is the key to reducing the risk of significantly adverse events. Nurses play a critical role in symptom management, medication adherence, and adverse effect risk management through client, family, and staff education. REFERENCES Anderson, S. L. (1998). The biological basis of mental illness. In C. A. Glod (Ed.), Contemporarypsychiatric-mental health nursing: The brain-behavior connection (pp. 75-90). Philadelphia: Davis.

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Bhatara, V. S., Magnus, R. D., Paul, K. L., & Preskorn, S. H. (1998). Serotonin syndrome induced by venlafaxine and fluoxetine: A case study in polypharmacy and potential pharmacodynamic and pharmacokinetic mechanisms. Annals of Pharmacotherapy, 32, 432-436. Brown, T. M., Skop, B. P., & Mareth, T. R. (1996). Pathophysiology and management of the serotonin syndrome. The Annals of Pharmocotherapy, £ 527-533. deGroot, J., & Chusid, J. G. (1988). Correlative neuroanatomy (20th ed.). East Norwalk, CT: Appleton & Lange. Demirkiran, M., Jankovic, J., & Dean, J. M. (1996). Ecstasy intoxication: An overlap between serotonin syndrome and neuroleptic malignant syndrome. Clinical Neuropharmacology, 19, 157-164. Dubovsky, S. L., & Thomas, M. (1995). Serotonergic mechanisms a n d current and future psychiatric practice. Journal of Clinical Psychiatry, 56(Suppl. 2), 38-48. Fink, M. (1996). Toxic serotonin syndrome or neuroleptic malignant syndrome? Pharmacopsychiatry, 29, 159-161. Goth, A. (1981). Medicalpharmacology (10th ed.). St. Louis, MO: Mosby. Hegerl, U., Bottlender, R., Gallinat, J., Kuss, H. J., Ackenheil, M., & Moiler, H. J. (1998). The Serotonin Syndrome Scale: First results on validity. European Archives of Psychiatry and Clinical Neuroscience, 248, 96-103.

Ivanusa, Z., Demarin, V., & Hecimovic, H. (1997). Serotonin syndrome. Neuropsychiatry, Neuropsychology, and Behavioral Neurology, 10 (3), 209-212. Kaplan, H., & Sadock, B. (1996). Comprehensivetextbook ofpsychiatry/ 1/7(6th ed.). Baltimore, MD: Williams and Wilkins. Kaplan, H., Sadock, B., & Grebb, J. A. (1994). Synopsis of psychiatry (7th ed.). Baltimore, MD: Williams and Wflkins. LoCurto, M. J. (1997). The serotonin syndrome. Emergency Medicine Clinics of North America, 15, 665-666. Mills, K. C. (1997). Serotonin syndrome: A clinical update. Critical Care Clinics, 13, 763-783. Mitchell, P. B. (1997). Drug interactions of clinical significance with selective serotonin reuptake inhibitors. Drug Safety, 1 7, 390-406. Molaie, M. (1997). Serotonin syndrome presenting with migrainelike stroke. Headache, 37, 519-521. Snyder, S. (1986). Drugs and the brain. New York: Scientific American Books. Sternbach, H. (1991). The serotonin syndrome. AmericanJournal of Psychiatry, 148, 705-713. Stahl, S. M. (1996). Essentialpsychophar, macology. London; Cambridge University Press. Weiner, L. A., Smythe, M., & Cisek, J. (1998). Serotonin syndrome secondary to phenelzine-venlafaxine interaction. Pharmacotherapy, 18, 399-403.

Intent to Submit Journal o f the American Psychiatric Nurses Association Nikki S. Polis, RN, PhD University M a c D o n a l d W o m e n ' s Hospital Mail Stop: MAC 5033 11100 Euclid Ave. Cleveland, O H 44106 If y o u w o u l d like to h a v e a m a n u s c r i p t r e v i e w e d for p o s s i b l e publication, p h o t o c o p y this form a n d s e n d it to the J o u r n a l o f the A m e r i c a n Psychiatric Nurses Association. We'll b e h a p p y to get in t o u c h w i t h y o u a b o u t y o u r article or c o l u m n idea. Q I w o u l d like y o u to c o n s i d e r m y m a n u s c r i p t for p o s s i b l e publication. Subject I will s e n d m y m a n u s c r i p t b y

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