Serotonin Syndrome: Prophylactic Treatment With Cyproheptadine

Serotonin Syndrome:

Prophylactic Treatment With Cyproheptadine

O. Greg Deardorff, PharmD, BCPPa,b,c,d,*; Talha Khan, PharmDd; Gaurav Kulkarni, MDe; Richard Doisy, MDa; and Colleen Loehr, MDa,c

ABSTRACT

Despite the numerous advantages of linezolid therapy, one disadvantage continuing to hinder its use is the risk of serotonin syndrome when coadministered with other serotonergic agents. Developing a better understanding of serotonin syndrome is essential for the prevention and management of this potentially life-threatening condition. This report describes a patient with schizophrenia, depression, and severe, acute osteomyelitis. The patient was taking multiple serotonergic agents and required the use of linezolid without the possibility of a sufficient washout period. The severity of the patient’s condition in conjunction with increased risk for serotonin syndrome warranted prophylactic treatment with cyproheptadine. The complex pathophysiology of prophylactic treatment of serotonin syndrome with cyproheptadine is worthy of discussion.

Prim Care Companion CNS Disord 2016;18(4):doi:10.4088/PCC.16br01966

© Copyright 2016 Physicians Postgraduate Press, Inc.

aFulton State Hospital, Fulton, Missouri

bUniversity of Missouri-Kansas City School of Pharmacy, Kansas City

cUniversity of Missouri-Columbia School of Medicine, Columbia

dSaint Louis College of Pharmacy, St Louis

eCompass Health, Inc, Columbia, Missouri

*Corresponding author: O. Greg Deardorff, PharmD, BCPP, Fulton State Hospital, 600 East 5th St, Fulton, MO 65251 ([email protected]).

Serotonin syndrome is a rare but potentially fatal condition precipitated by the use of drugs with serotonergic activity. Serotonin syndrome usually occurs when serotonergic agents are combined but can occur with monotherapy at therapeutic or supratherapeutic doses.1,2 Excessive serotonergic activity leads to overstimulation of central and peripheral serotonin receptors, specifically the 5-hydroxytryptamine 2A (5-HT2A) and 5-HT1A receptors.1 Recent evidence3 suggests that mild cases of serotonin syndrome are mediated by 5-HT1A activation resulting in low body temperatures, while severe cases are mediated by 5-HT2A activation resulting in hyperthermia. Clinical presentation is characterized by mental status changes, autonomic instability, and neuromuscular abnormalities.1,2 In the clinical setting, patients should be assessed for serotonin syndrome after starting a serotonergic medication or after a dose increase. The recommended criteria for diagnosis is the Hunter Serotonin Toxicity Criteria (HSTC),4 which includes the use of at least 1 serotonergic agent with 1 of the following stipulations: tremor with hyperreflexia, spontaneous clonus, ocular clonus with diaphoresis or agitation, inducible clonus with diaphoresis or agitation, or the presence of muscle rigidity with a temperature > 38°C (> 100.4°F) with inducible or ocular clonus.2 Other methods used to diagnose serotonin syndrome include the Sternbach criteria5 and the Boyer and Shannon algorithm.6 The Sternbach criteria is nonspecific and is now typically used as an assessment tool in helping diagnose serotonin syndrome. On the other hand, the Boyer and Shannon algorithm utilizes the HSTC, creating a simplified approach for clinicians to use readily in the assessment and diagnosis of serotonin syndrome.6 The symptom severity of serotonin syndrome varies and can range from mild to life-threatening. In animal experimental models, most signs and symptoms of the syndrome were reversed by administration of 5-HT2A antagonists.7

Patients presenting with moderate to severe symptoms should be treated immediately in an effort to prevent serious complications including rhabdomyolysis, myoglobinuria, seizures, metabolic acidosis, renal failure, acute respiratory distress syndrome, respiratory failure, diffuse intravascular clotting, coma, and even death.2 The respective management and treatment should take into account the pharmacokinetics of the insulting agent(s), as this will dictate the duration and intensity of treatment. Due to a lack of available evidence, management of serotonin syndrome may vary among clinicians; however, the key to proper management is discontinuing all agents that have serotonergic activity, while providing supportive care as needed. Treatment with benzodiazepines should be considered for seizure prophylaxis and sedation. In severe, life-threatening cases, additional sedation, intubation, and paralysis may be necessary.2

• The most effective approach to prevent serotonin syndrome is avoiding concomitant use of serotonergic agents when possible.
• Cyproheptadine may be a viable option for serotonin syndrome prophylaxis in high-risk patients who warrant immediate treatment with a serotonergic agent without sufficient time for a washout period.
• Cyproheptadine, a relatively benign agent with minimal drug interactions, may be an effective treatment option for certain patients with psychiatric disorders.

Cyproheptadine, a potent histamine (H1) and 5-HT2A receptor antagonist, is a widely used antidote for serotonin syndrome. An in vivo study using [18F] setoperone positron emission tomography scans demonstrated that treatment with cyproheptadine 4 mg or 6 mg 3 times daily blocked 85% and 95% of 5-HT2A receptors in the prefrontal cortex, respectively.8 While no clinical trial has been performed to validate cyproheptadine’s efficacy for the prevention of serotonin syndrome, several case reports and case series have shown clinical improvement in patients with serotonin syndrome.

Linezolid, a broad-spectrum antimicrobial agent, is a monoamine oxidase inhibitor (MAOI) that increases the risk of developing serotonin syndrome when concomitantly administered with other serotonergic agents.9,10 In 2011, the US Food and Drug Administration (FDA) issued a warning against the concomitant use of these agents, and in instances where the use of linezolid is warranted, advised an appropriate washout period of serotonergic agents prior to initiation of linezolid therapy. This interaction has prevented many patients from receiving treatment with linezolid. We report the case of a patient receiving long-term therapy with fluoxetine and carbamazepine who required treatment with linezolid for osteomyelitis. This combination resulted in the prophylactic administration of cyproheptadine for the prevention of serotonin syndrome.

CASE REPORT

Mr A, a 39-year-old white male resident of a long-term psychiatric facility, developed osteomyelitis secondary to cervical spinal cord surgery. His past medical history was remarkable for schizophrenia, depression, hypercholesterolemia, seizure disorder, and deep vein thrombosis. The medication regimen included carbamazepine 700 mg twice daily, fluoxetine 20 mg daily, gabapentin 400 mg 3 times daily, topiramate 50 mg twice daily, vancomycin 15 mg/kg daily, and warfarin 5 mg daily.

Following surgery, Mr A returned to the psychiatric facility with a central line in place for administration of vancomycin. After careful consideration, the treatment team determined there was a significant health and safety risk in continuing management of a central line in the setting of warfarin anticoagulation. Moreover, due to his level of disability from the psychiatric illness, there was concern that the central line could be removed by Mr A. With concomitant warfarin therapy, the risk of potential life-threatening bleeding could not be overlooked. The decision was made to remove the central line, discontinue vancomycin therapy, and initiate oral treatment with linezolid 600 mg twice daily. However, this decision was made cautiously, keeping in mind the increased risk of developing serotonin syndrome. The decision to continue carbamazepine 700 mg twice daily for treatment of seizures, while discontinuing long-term treatment of fluoxetine 20 mg daily for depression, compounded this risk further due to fluoxetine’s long half-life and an insufficient washout period.11

Cyproheptadine 2 mg twice daily was initiated along with linezolid 600 mg twice daily on the day preceding discontinuation of fluoxetine. In addition, appropriate and diligent monitoring was initiated; the physicians, nurses, and pharmacists assessed for serotonin syndrome daily per HSTC as described previously.2,4 Mr A continued carbamazepine 700 mg twice daily despite the contraindication of concomitant use with a MAOI, such as linezolid. The infection resolved after approximately 1 month of this medication regimen, while no report of serotonin syndrome or worsening of Mr A’s psychiatric illness occurred. Although we cannot be certain of what complications would have arisen without prophylactic treatment, the absence of serotonin syndrome may be attributed to the prophylactic use of cyproheptadine. After discontinuation of linezolid and cyproheptadine therapy, fluoxetine was restarted 12 days later with no complications.

LITERATURE REVIEW

This case illustrates the need for clinicians to understand the pathophysiology behind the development of serotonin syndrome in order to promote more appropriate management strategies. Our patient was started on linezolid without an appropriate washout period for fluoxetine, which increased the risk for developing serotonin syndrome. There are 7 serotonin receptors (5-HT1 to 5-HT7) with 14 serotonin receptor subtypes.4,12,13 In serotonin syndrome, serotonergic activity exhibits concentration-dependent actions at postsynaptic 5-HT2A receptors.4,12-14 Therefore, cyproheptadine, a potent 5-HT2A receptor antagonist, has been widely accepted as an antidote for serotonin syndrome. Although 5-HT1A receptors have been speculated to play a substantial role in the development of serotonin syndrome, 5-HT1A antagonists have been ineffective or have worsened symptoms in patients with serotonin syndrome.8,15,16

Since the introduction of linezolid, at least 17 published case reports17 describe the occurrence of serotonin syndrome in patients coadministered linezolid and other serotonergic agents. A retrospective study18 at the Mayo Clinic evaluated patients who were prescribed concomitant linezolid and serotonergic agents or had received concomitant treatment within the past 14 days. Of the 72 patients in the study who met inclusion criteria, 4 patients met clinical criteria for serotonin syndrome according to the Sternbach criteria and the Boyer and Shannon algorithm. In these patients, symptoms generally subsided within 5 days after discontinuation of at least 1 of the serotonergic agents. This finding illustrates the notion that although serotonin syndrome is rare, it is well documented and is a potential complication that should not be overlooked.

Additionally, cyproheptadine is widely used as an antidote for serotonin syndrome because of its relatively benign adverse effect profile and its efficacy as demonstrated by a small number of case reports and case series. In a case series19 of 5 patients with mild to moderate manifestations of serotonin syndrome, 4 patients had a complete response 1 to 2 hours after administration of cyproheptadine 8 mg. One patient who had a partial response only received 1 dose of cyproheptadine 4 mg, which was considered a subtherapeutic dose. In all 5 cases, no adverse events were reported from the use of cyproheptadine.19

Furthermore, in a retrospective study20 of 12 reports of serotonin syndrome, 7 patients were administered cyproheptadine 8 mg 3 times daily. In these 7 patients, response to therapy was noted in 1 to 3 days, with complete response in 5 to 14 days. No side effects were reported from patients receiving cyproheptadine therapy. Patients were followed for at least 2 months with no signs or symptoms of serotonin syndrome.

Likewise, another case report21 describes a 30-year-old man with a social history significant for drug abuse who developed a temperature of 40°C (104°F) and was empirically treated with linezolid and piperacillin-tazobactam. Following initiation of dual antimicrobial therapy, the patient’s high-grade fever did not subside, and additional symptoms of altered mental status and tremors manifested. Linezolid was discontinued in the patient, while cyproheptadine 4 mg 3 times daily was initiated. Symptom improvement was seen within 48 hours.

An additional case report22 discusses a 60-year-old woman who presented to the emergency department unconscious secondary to an increase in her paroxetine dose. The patient was ultimately diagnosed with serotonin syndrome predicated by a recently increased dose of paroxetine. She was given supportive care and treated with cyproheptadine 8 mg 3 times daily. The patient regained consciousness shortly after administration of cyproheptadine and remained symptom-free at 3-month follow-up.22

Similarly, another case report23 details a 26-year-old woman treated with a MAOI, isocarboxazid 50 mg daily, for 8 weeks with no improvement in her depression. She was tapered off the medication over a 3-day period and took a single dose of sertraline 100 mg on the third day. Approximately 2 hours after her dose, the patient started experiencing restlessness and twitching of her legs. She was taken to the emergency department where she was diagnosed with serotonin syndrome. She was treated intravenously with diazepam 5 mg and propranolol 1 mg with little to no effect. The patient was then administered cyproheptadine 4 mg, and within 30 minutes her symptoms began to improve. The patient’s symptoms completely resolved within 30 minutes after a second dose of cyproheptadine 4 mg was administered.23

Lastly, a case report24 details the instance of an 8-year-old girl who presented with serotonin syndrome after ingestion of 1,500 mg of sertraline. She was treated with midazolam, propranolol, and cyproheptadine. Her dose of cyproheptadine was 0.25 mg/kg/d administered every 2 hours until symptoms improved. She remained on cyproheptadine for 5 days due to the severity of her condition. At discharge, she had no neurologic sequelae, and at follow-up 2 years later, she was reevaluated and found to have no neurologic deficit resulting from her overdose.24

While cyproheptadine may be beneficial in the treatment or prevention of serotonin syndrome, some clinicians fear the use of a serotonin antagonist may exacerbate the symptoms of a patient’s psychiatric disorder. Interestingly, a small number of studies have demonstrated a therapeutic effect in patients with schizophrenia, major depressive disorder, posttraumatic stress disorder (PTSD)-associated nightmares, and neuropsychiatric adverse effects of efavirenz-based antiretroviral therapy (ART) regimens.7,25-30

A study by Olarte-Sסnchez et al26 compared clozapine to cyproheptadine, suggesting cyproheptadine exerts antagonistic effects on H1 and 5-HT2A receptors similar to clozapine. Cyproheptadine may have a therapeutic role in the treatment of cognitive and negative symptoms of schizophrenia, especially when used with typical antipsychotics as adjunctive therapy to achieve a 5-HT2A/dopamine 2 (D2) binding affinity ratio similar to atypical antipsychotics.27,28 Evidence31 suggests the combination of 5-HT2A and D2 receptor antagonism of atypical antipsychotics on the mesolimbic dopamine pathway improves efficacy against positive symptoms of schizophrenia. In addition, the 5-HT2A receptor antagonism of atypical antipsychotics in the nigrostriatal and tuberoinfundibular dopamine pathways disinhibits dopamine release resulting in a lower incidence of extrapyramidal side effects and hyperprolactinemia.31 In major depressive disorder, 5-HT2A receptor antagonists facilitate activity at 5-HT1A autoreceptors leading to receptor desensitization and subsequent antidepressant effects.27,32 A decline in 5-HT1A heteroreceptors and up-regulation of 5-HT1A autoreceptors have been implicated in the pathophysiology of depression.27,32 The 5-HT2A receptor antagonism of atypical antipsychotics is thought to play a key role in augmenting the therapeutic effect of antidepressant agents.27

While the antidepressant effects of cyproheptadine have been inconsistent in clinical studies, findings have supported a therapeutic effect in a subset of patients with depression.33,34 It has been estimated that 40%-50% of patients with major depression have elevated cortisol levels similar to that of Cushing disease.25 The therapeutic benefit reported with the use of cyproheptadine for the treatment of Cushing disease may explain the antidepressant effect demonstrated in low-dose dexamethasone nonsuppressors with depression.25,33,34 For patients with anorexia nervosa, depression is a commonly encountered problem that has been linked to dexamethasone resistance.34 In nonbulimic anorectic patients, cyproheptadine has been successfully used as an antidepressant promoting weight gain and reducing cortisol levels.34 However, therapeutic effects have not been observed in bulimic anorectic patients presumably due to impaired weight gain.34

Individuals with PTSD often suffer with sleep disturbances that warrant treatment with pharmacotherapy. Cyproheptadine has been a successful treatment for some patients with PTSD-associated nightmares.29 However, it is important to note that this is a level C recommendation supported by a limited number of studies with low-grade data.29

Another patient population that has demonstrated therapeutic effects with cyproheptadine treatment are HIV-positive patients receiving efavirenz-based ART regimens.30 A clinical trial by Dabaghzadeh et al30 found cyproheptadine to be an effective treatment option for the prevention of ART-induced neuropsychiatric adverse effects (anxiety, depression, hallucinations, aggressive behaviors, poor impulse control, poor rapport, emotional withdrawal, active social avoidance, suicidal ideation). The lack of significant drug interactions is also important in this patient population since interactions between antiretroviral and psychotropic medications limit treatment options.35 Additional research in this area may provide more effective treatment options for a subset of patients and guide the development of future treatments. As we predicted, our patient did not experience an exacerbation of symptoms associated with mood, agitation, or psychosis.

DISCUSSION

This case illustrates a treatment approach for patients who are taking serotonergic agents, which makes the use of linezolid unsafe during infections in this patient population. Since linezolid has an inhibitory effect on monoamine oxidases, it can increase the risk of serotonin syndrome in patients receiving serotonergic therapy. Our patient was on long-term therapy with carbamazepine and fluoxetine, 2 serotonergic agents that are contraindicated with concomitant use of linezolid.

The FDA recommends a 5-week washout period for fluoxetine prior to the administration of linezolid due to the increased risk for development of serotonin syndrome. The recommended washout period accounts for the long half-life of fluoxetine (1-3 days after acute administration; 4-6 days after chronic administration) and its active metabolite, norfluoxetine (4-16 days after acute and chronic administration).36 In patients with hepatic impairment, a lower or less frequent dose is advised due to the decreased clearance of fluoxetine and norfluoxetine, which prolongs the half-life to 7.6 and 12 days, respectfully.36 Hepatic impairment was not present in our patient, but an active, acute infection did prevent the possibility of a 5-week washout period. Thus, cyproheptadine 2 mg twice daily was administered prophylactically for 1 month—a dose considered relatively low for the treatment of serotonin syndrome.

Of particular interest in this case, serotonin syndrome did not develop per HSTC despite continuing treatment with carbamazepine while initiating linezolid 1 day after the discontinuation of fluoxetine. While the treatment of serotonin syndrome focuses on the management of hyperthermia and muscle rigidity, there are limited data regarding the use of cyproheptadine as an antidote.37 It should also be noted that although the case reports and case series reviewed in this article show marked improvement in the symptomatology of serotonin syndrome, the risk of publication bias cannot be overlooked. In addition, some patients may not be able to take cyproheptadine tablets orally. In these instances, cyproheptadine is available as oral syrup or the tablets may be crushed and administered via a nasogastric tube.5

CONCLUSION

This case report illustrates the importance of understanding serotonin syndrome, as it may hinder the use of linezolid and other antimicrobials with similar serotonergic potential. Typically, the most current approach to prevent serotonin syndrome is to avoid concomitant use of serotonergic agents. However, this approach is not always viable or realistic in clinical practice. While the incidence of serotonin syndrome is on the rise and the list of serotonergic agents grows, it is of benefit to explore the role of prophylactic treatment.37 On the basis of the substantial impact of 5-HT2A receptor agonism in the development of serotonin syndrome, cyproheptadine may be an ideal medication to use prophylactically in high-risk patients when an appropriate washout period is not feasible.

Submitted: April 15, 2016; accepted July 20, 2016.

Published online: August 25, 2016.

Drug names: carbamazepine (Tegretol, Epitol, and others), clozapine (Clozaril, FazaClo, and others), dexamethasone (Maxidex, Ozurdex), diazepam (Valium and others), efavirenz (Sustiva and others), fluoxetine (Prozac and others), gabapentin (Neurontin, Gralise, and others), isocarboxazid (Marplan), linezolid (Zyvox and others), paroxetine (Paxil, Pexeva, and others), piperacillin-tazobactam (Zosyn and others), propranolol (Inderal and others), sertraline (Zoloft and others), topiramate (Topamax and others), warfarin (Coumadin, Jantoven, and others).

Potential conflicts of interest: None.

Funding/support: None.

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