Serotonin Syndrome From the Complex Drug Interactions of Second-Generation Antipsychotics in Older Patients: Case Report and Literature Review

To the Editor: Serotonin syndrome is a state caused by an excess of serotonergic activity in the nervous system that may occur with the use of serotonergic medications. Symptoms vary widely, ranging from mild to severe, and from altered mental status, autonomic instability, and neuromuscular hyperactivity, potentially to death.1 Widespread prescription of serotonergic agents, especially antidepressants, to older adults has become a clinical concern. In a recent study,2 researchers found that one-fourth of elderly patients taking antidepressants developed serotonin syndrome, whereas at least two-thirds of these patients showed potentially life-threatening symptoms. Ingestion of multiple drugs increases the risk of serotonin syndrome. It is primarily triggered when taking selective serotonin reuptake inhibitors (SSRIs) in combination with other medications or drugs that also increase serotonin levels, such as second-generation antipsychotics. Older adult patients may be at higher risk because of the presence of drug–drug interactions from polypharmacy, as well as pharmacokinetic changes associated with the aging process. As the aging society gradually becomes a global trend, the impact of polypharmacy in elderly patients should be of greater concern and researched more extensively. The objective of this study was to present a case of serotonin syndrome in an older adult man who demonstrated a clear association between complex interactions from the prescribing cascade of multiple antipsychotics and antidepressants and to review the related literature on this topic. All aspects of data collection received ethical approval from the Institutional Review Board (IRB) of the Chang Gung Memorial Hospital. CASE REPORT A 67-year-old man presented to the ER intoxicated after alcohol consumption and with a history of chronic heavy drinking for more than 30 years. According to his statement, he consumed 600–1200 mL daily of traditional rice wine (alcohol volume 22%). Depressed mood, delusional jealousy, and auditory hallucinations had developed a few years ago. He had been admitted once previously for alcohol use disorder and alcohol-induced psychosis, and oral low-dose naltrexone regimen was introduced 2 months ago. For the present admission, he was brought to the hospital by his wife for violent behavior in the context of morbid jealousy. The patient was medically cleared upon admission (temperature = 36–36.5°C, heart rate = 98–104 beats per minute, blood pressure = 114–135 mm Hg/63–71 mm Hg, respiratory rate = 20, and blood oxygen saturation level = 95%–99%). Hemogram and urine toxicology were unremarkable. Before presentation, his psychiatrist had placed him on naltrexone 50 mg, paroxetine 10 mg, and quetiapine 75 mg in total daily. After admission, lorazepam 1 mg 4 times daily was given initially to prevent alcohol withdrawal. His medications from the outpatient department remained, including quetiapine 25 mg twice daily and once before bed for agitation and behavioral disturbance; paroxetine 20 mg daily for depressed mood and naltrexone. Lorazepam was gradually tapered down within the initial 2 weeks of hospitalization because no obvious alcohol withdrawal symptoms were noticed or reported. Quetiapine was titrated up slowly to 175 mg in total daily for unimproved agitation and elated mood observed. Morbid jealousy was reported frequently. He presented with agitation, impulsivity, and high risk of violence associated with the mentioned delusional jealousy thoughts. Thus, risperidone was cross titrated from quetiapine for higher potency. Risperidone was increased to 2 mg daily maximum. The patient responded well to risperidone, with less delusional jealousy reported. However, fever up to 38°C was noticed a few days later, without specific findings on laboratory data, which was resolved with hydration. During the fourth week of hospitalization, obvious extrapyramidal symptoms were noticed because the patient showed rigidity, unsteady gait, and unstable posture, regardless of less psychosis and agitation observed. Risperidone was then immediately decreased to 1 mg daily, and biperiden was prescribed. Quetiapine continued to be tapered down to 100 mg in total daily, whereas paroxetine 10 mg was taken down completely, for medication reconciliation and for the fact that the patient complained of dizziness. By the end of the fourth week, fever episodes above 38°C with dysautonomia (increase in heart rate and blood pressure) were brought to our attention. Laboratory data showed elevated C-reactive protein (78.85 mg/dL) and leukocytosis (14,200/μL). However, the foci could not be properly identified. Meanwhile, muscle stiffness, involuntary movement (muscle twitching in 4 limbs for 5–15 seconds with irregular intervals from minutes to hours), dystonia, and hyperreflexia were also examined. The patient was in altered mental status, with disorientation, agitation, and reversed circadian rhythm. Computed tomography of the brain was done, and results were unremarkable. Psychotropic medications were all withheld for unstable physical status and suspected neuroleptic malignant syndrome or serotonin syndrome. Amantadine 50 mg twice daily was tried for a few days temporarily, which showed no improvement in his condition. Three days later, the rigidity only slightly improved, whereas laboratory data showed surging C-reactive protein (165.36 mg/dL), elevated myoglobin (121.5 ng/mL), and creatine phosphokinase (577 IU/L). No seizure activity was captured on electroencephalogram. Abdominal computed tomography was performed to rule out intra-abdominal infection, given his history of hepatic cell carcinoma. The patient's status gradually improved a week after discontinuing antipsychotics. The patient was observed to have better spirits, less muscle stiffness, and less disorientation. Fever subsided and his vital signs remained stable. Laboratory data showed improvement as well (C-reactive protein = 39.70 mg/dL, creatine phosphokinase = 165 IU/L). Over the following weeks, his symptoms resolved, he regained mobility through physical therapy and returned to his baseline mental status. Delusional jealousy reemerged, but no behavioral disturbance was noticed. As a result, he was once again placed on risperidone regimen, but titrations were low and slow. He returned to his home with his wife, with residual psychosis that could be managed through regular outpatient visits, once he was stabilized on risperidone 0.25 mg daily. DISCUSSION The features of serotonin toxicity were first described half a century ago,3 when several studies reported similar symptoms from the use of serotonergic medications. In the 1990s, Sterbach reviewed and analyzed 12 of 38 published cases and developed the concept of “serotonin syndrome,” proposing a diagnostic criterion under the prerequisite of using a “known” serotonergic agent.4 To date, no single test confirms a diagnosis of serotonin syndrome. It is diagnosed on the basis of clinical findings. Laboratory abnormalities are nonspecific but may include elevated creatine phosphokinase and leukocytosis. The current widely used Hunter Serotonin Toxicity Criteria5 was developed in 2003, by Dunkley et al and requires any of the following symptoms in the setting of serotonergic agent use: spontaneous clonus, clonus induced by sudden dorsiflexion of the ankle plus agitation or diaphoresis, ocular clonus (slow continuous lateral eye movements) plus agitation or diaphoresis, tremor plus hyperreflexia, or hypertonia plus temperature above 38°C plus ocular clonus or inducible clonus, with better sensitivity and specificity than those of Sterbach criteria. By virtue of presenting myoclonus, hyperreflexia, hyperthermia, confusion, and agitation, our patient met the Hunter Serotonin Toxicity Criteria for serotonin syndrome. However, it was still necessary to rule out other possibilities, such as infection, metabolic disorder, substance intoxication, or withdrawal. A single therapeutic dose of an SSRI has been reported to cause serotonin syndrome.6 Ingestion of multiple drugs that affect the serotonergic system appears to further increase the risk of serotonin syndrome. A large number of drug–drug combinations have been associated with serotonin syndrome, including concomitant use with monoamine oxidase inhibitors, tricyclic antidepressants, SSRIs, opiate analgesics, and recreational drugs and herbal products. It is primarily triggered when taking SSRIs in combination with another medication or drug that also increases serotonin levels, most often with combinations of 2 antidepressants. Atypical antipsychotic medications have also been implicated.7–11 In the present case, the patient was taking 2 second-generation antipsychotics in combination with the SSRI paroxetine when the symptoms of serotonin syndrome were first noticed. No single receptor was identified as the direct cause of the development of serotonin syndrome, although some animal models suggest that agonism of serotonin receptor subtype 1A (5-HT1A) and 5-HT2A receptors may be responsible for the condition.12–14 Quetiapine and risperidone are both atypical antipsychotic agents that exhibit serotonergic receptor 5-HT2A antagonism. In the comparison of atypical antipsychotic medication on the serotonergic systems, risperidone has higher risk due to higher receptor potency on 5-HT2A receptors, whereas quetiapine has the lowest risk among these drugs.15,16 In addition, many second-generation antipsychotics, including quetiapine, have also been shown to be 5‐HT1A agonists.17,18 There is evidence that antagonism of 5-HT2A may cause selective activation of 5-HT1A, which may in turn increase the sensitivity of this receptor to serotonin.14,19 A synergistic effect between second-generation antipsychotics and SSRIs was found in a recent study analyzing the US Food and Drug Administration Adverse Event Reporting System.18 Concomitant administration of additional serotonergic medications may increase the risk of serotonin syndrome, such as with second-generation antipsychotics. In combination, the above mechanisms may increase serotonin levels and receptor sensitivity to serotonin or magnify the effects of SSRIs. Even a slight change of dose in these medications, such as risperidone and quetiapine in the present case, may potentially cause serotonin syndrome. The present case may demonstrate the cumulative effect of prescribing several serotonergic agents. An increase in quetiapine or risperidone strengthens the hypothesis of 5-HT2A and 5-HT1A receptor mediation, causing serotonin syndrome when used concomitantly with paroxetine. The syndrome is more commonly reported among elderly patients. In a recent study,2 Erken et al found that 25.2% (60 out of 238 participants) of elderly patients taking antidepressants resulted in serotonin syndrome, and at least two-thirds (68.3%) of these patients showed potentially life-threatening symptoms. Women were twice as likely as men to have serotonin syndrome, with the most common diagnostic findings in these patients being tremor and hyperreflexia.20 Management of serotonin syndrome mainly involves supportive care and discontinuing serotonergic drugs for mild cases without unstable hemodynamics, and treatment with benzodiazepines can be used for agitation. Sedation, hydration, and intubation are performed in severe cases.17,21 In the present case, the patient's symptoms gradually improved and resolved in 1 week after all antipsychotics were discontinued. Caution is warranted, especially among elderly patients, when prescribing serotonergic agents. Effort should be made to avoid unnecessary polypharmacy and the prescribing cascade in this group of patients. Although the use of second-generation antipsychotics or antidepressants alone has lower risk of serotonin syndrome, clinicians must heighten awareness of complex drug interactions between serotonergic drugs that work by different mechanisms. Early detection of symptoms in older patients using antidepressants is also crucial. Serotonin syndrome can progress quickly, severely and even fatally, if not swiftly identified and appropriately treated. Further areas of research should include the mechanism of 5-HT2A/5-HT1A interaction and serotonin levels with second-generation antipsychotics to better clarify their association with serotonin syndrome. In addition, further investigation of the pathophysiology in pharmacokinetic changes of serotonergic systems with aging should be performed. Confirmation of these mechanisms may help to reduce the risk of serotonin syndrome in older adults.