Potential Dextromethorphan-Induced Serotonin Syndrome Leading to Homicide and Suicide

Abstract

Limited case reports have been published regarding serotonin syndrome due to the combined effects of supratherapeutic levels of dextromethorphan and selective serotonin reuptake inhibitor. We report a case of an adolescent with postmortem findings suggestive of a diagnosis of serotonin syndrome-induced psychosis associated with a double homicide and suicide. Postmortem toxicology of the suicide victim was remarkable for elevated serotonergic metabolites of fluoxetine and dextromethorphan in a 14-year-old male.

Introduction

Serotonin syndrome is a collection of autonomic and cholinergic symptoms often caused by drug-induced activation of serotonin receptors (1). The diagnosis is heavily reliant on patient history of drug use and the compatible clinical presentation. The symptoms exist on a spectrum of signs and symptoms including but not limited to altered mental status, increased autonomic activity, and clonus or other neuromuscular abnormalities. We report a case involving an adolescent possibly related to serotonin syndrome, from drug interactions between dextromethorphan and fluoxetine, enhancing the known possibility of dextromethorphan-related psychosis.

Case Report

Law enforcement was notified of a scene with multiple deaths and on responding found three individuals dead from apparent gunshot wounds. The deceased individuals included a white 14-year-old male, his 21-year-old female cousin, and her 22-year-old male boyfriend. The 22-year-old boyfriend was found lying on a couch, suggesting that he had been sleeping, with a single gunshot wound to the forehead of distant range. The other two bodies were found in an adjacent bedroom. The female was lying on the bed with a single contact gunshot wound to her right parietal scalp. She was found naked from the waist down. Partly lying across her body was the 14-year-old male, whose pants had been pulled down to his knees.

Blood consistent with the deceased female’s was found on his hands as well as on his genitalia, suggesting that he had been masturbating following her death. The 14-year-old male had sustained a self-inflicted contact gunshot wound to the left temple with extensive hemorrhage.

Six weeks prior to these deaths occurring, the 14-year-old male had been admitted for inpatient evaluation at an adolescent psychiatric facility. Initially he had been evaluated for depression with suicidal ideation and self-harm, with a history of posttraumatic stress disorder and attention-deficit/hyperactivity disorder. He denied delusions or hallucinations. During the nine days that he was hospitalized, he appeared to be normal, responsive to treatment, and denied any further depression, suicidal thoughts, or intent to harm prior to discharge. No additional incidents were reported following his discharge until the deaths of these three individuals.

Toxicological analysis was performed by NMS labs in Willow Grove, Pennsylvania. Toxicology on the 14-year-old male required using central blood due to inadequate volume remaining in the femoral vessels. His blood demonstrated the presence of tetrahydrocannabinol (THC), and a blood ethanol level of 56 mg/dL. Fluoxetine was present at a level of 200 ng/mL, and norfluoxetine also at 200 ng/mL, measured by gas chromatography-mass spectrometry (GCMS). Dextro/Levo Methorphan levels were obtained by liquid chromatography with tandem mass spectrometry (LC-MS/MS) at a level of 1400 ng/mL.

Discussion

Dextromethorphan is a synthetic analogue of codeine used notably for its antitussive effects (2). It was first approved by the United States Food and Drug Administration (U.S. FDA) in 1958 for antitussive purposes. As a result, it can be found in numerous over-the-counter cough medications (3). Dextromethorphan is metabolized by the CYP2D6 group of isoenzymes, which yields high variation in metabolism between individuals, to produce the active agent dextrorphan (4). Reports of abuse of this drug have been documented in the literature for over 50 years (5-7). Chronic abuse has led to psychosis, with the first such case being reported in 1967 (8, 9). Meanwhile, the first case of addiction to dextromethorphan was reported in 1986 (10), and the first deaths attributed to dextromethorphan overdose were reported in 1988 (11).

Both dextromethorphan and dextrorphan act as N-methyl-D-aspartate (NMDA) antagonist like the drug phencyclidine (PCP). Price reported how a case of deliberate dextromethorphan abuse can present similar to abuse of PCP (12). Cochems et al. similarly reports “As the dextromethorphan dose increases, the resulting impairment can mimic that of a central nervous system depressant and phencyclidine” (13). At doses heavily exceeding the therapeutic dose, individuals may experience euphoria before symptoms of serotonin syndrome (14, 15).

Schwartz et al. note that acute megadoses of dextromethorphan have profound psychological and physiological effects similar to PCP (16). Sharma et al. reports that dextromethorphan may cause psychosis by with its metabolite dextrorphan, and a case of acute psychosis has been induced by patients using just double the manufacturer’s recommended dose (9). A case report by Bachar et al. details the case of a 31-year-old woman with a history substance abuse brought in with signs of serotonin syndrome with enough violence to warrant sedation and intubation following digestion of dextromethorphan-containing “Triple-C” tablets, though the serum concentration of dextromethorphan was unknown (17).

Though the antitussive efficacy is debated in pediatric patients (18, 19), dextromethorphan remains one of the most prescribed antitussive medications for adolescents (20). Abuse of dextromethorphan among teenagers led to a 2010 U.S. FDA panel to consider the scheduling of dextromethorphan, which concluded that dextromethorphan should remain unscheduled (20). The National Institute on Drug Abuse Monitoring the Future Survey estimated the prevalence of abuse among adolescents has decreased among eighth graders to 3.2% from a high of 4.6% in 2020 (21). Meanwhile prevalence for abuse in tenth graders increased from a 2021 low of 2.7% to 3.9%, and prevalence among twelfth graders increased from a 2021 low of 1.7% to 2.4% (21).

Fluoxetine is a commonly prescribed selective serotonin reuptake inhibitor (SSRI) that is metabolized into norfluoxetine as treatment for major depressive disorder (22) and generalized anxiety disorder (23). As a side effect, fluoxetine is a known inhibitor of CYPD6 isozymes that metabolize many pharmaceutical agents, which increases the potential to cause serotonin syndrome when taken in addition to other serotonergic agents (24). Deodhar et al. studied the inhibitory effects of fluoxetine on CYP2D6 and found that inhibition of CYP2D6 increases after 8 days and is associated with significant decreases in the clearance of dextromethorphan. Additional notable findings were inhibition of CYP2D6 lasting long after the first pass of fluoxetine through the liver and continued inhibition long after discontinuation of fluoxetine (25).

Schwartz et al. report two cases of serotonin syndrome precipitated by the use of SSRIs and dextromethorphan and observes that few case reports on the ingestion of dextromethorphan have been published. In the first case, a 20-year-old male with a blood dextromethorphan concentration of 950 ng/mL showed signs of fever, clonus, and incomprehensible speech which fully recovered after treatment. The second case involved a 6-year-old who presented with a blood dextromethorphan level of 2820 ng/mL with irritability, fever, tachycardia, tachypnea, clonus, and hypertension but recovered within 15 hours (26). Another case by Navarro et al. documents the presentation of serotonin syndrome in a 22-year-old male being treated for bipolar disorder with fluoxetine and lithium presenting to the emergency room after ingesting 900 mL of cough syrup containing dextromethorphan for euphoric purposes, which had not precipitated serotonin syndrome prior to his treatment for bipolar disorder (27).

Our case is consistent with the pharmacological conditions leading to these documented cases of serotonin syndrome, which may have caused the altered mental status in conjunction with the PCP-like effects related to dextromethorphan intoxication. We hypothesize that the erratic sexual, homicidal, and ultimate suicide presented by this case may be explained by the mechanism of an SSRI (fluoxetine) both causing elevated dextromethorphan levels via CYP2D6 inhibition and triggering the serotonin syndrome.

There are potential limitations to determining the precise mechanisms involved in this case. One of these is for a case of this nature is the possible genotypic variation in addition to inhibition of CYP2D6 via fluoxetine makes accurate determination of the actual ingested dosage of dextromethorphan difficult. This difficulty was illustrated in a case report by Bailey et al. which found a dextromethorphan level almost 100-fold higher than expected after a therapeutic dose (28). In addition, Bailey et al. has noted postmortem drug redistribution of dextromethorphan after death of 6 +/- 5-fold in rat studies (29).

Another possible limitation is distinguishing between dextromethorphan and levomethorphan due to their similar structures. Although levomethorphan is a methylated prodrug of levorphanol, a schedule II narcotic with the trade name Levo-Dromoran, there are no known commercial pharmaceuticals on the market in the United States, and its use is therefore highly unlikely.

A final limitation to the case is that we did not confirm the CYP2D6 metabolism profile of the decedent. While it is possible for the decedent to be a slow metabolizer, Bailey et al. cites that 5% to 10% of white North Americans have genetically poor CYP2D6 metabolism (29). Given the presence of fluoxetine and its known CYP2D6 inhibitory mechanism, it is more plausible that dextromethorphan’s effects were amplified by fluoxetine which precipitated a potential psychosis regardless of the decedent’s genetic CYP2D6 enzyme metabolism type.

Conclusion

Serotonin syndrome is a condition precipitated by a serotonergic agent activating both serotonergic and cholinergic receptors and presents with altered mental status that can lead to violence. Abuse of the antitussive agent dextromethorphan has become widespread among adolescents and has been reported to have the potential for causing psychosis. We hypothesize that the combination of dextromethorphan abuse in a 14-year-old receiving the SSRI Fluoxetine as a possible explanation for a case of double homicide, erratic sexual behavior, and subsequent suicide. As such, providers should reconsider prescribing fluoxetine or other SSRIs to adolescents with potential for substance abuse. Our case is one of the only reported cases of potential serotonin syndrome precipitated by an over-the-counter agent with an SSRI that resulted in both homicide and suicide by an adolescent.

Authors

Matthew M. Pavelka, B.S.Chem, Indiana University School of Medicine-Terre Haute

Roles : B, C, D, E

Roland Kohr, MD, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine

Roles : A, C, D, E