HyperCKemia and rhabdomyolysis in the neuroleptic malignant and serotonin syndromes: A literature review.

Neuroleptic malignant syndrome and serotonin syndrome are two syndromes whose molecular bases remain poorly understood. The phenotypes of both syndromes overlap with other syndromes that have a clear genetic background, in particular RYR1-related malignant hyperthermia. Through a literature review, performed according to the PRISMA guidelines, we aimed to report the clinical features of both syndromes, and the results of genetic testing performed. 10 case series and 99 case reports were included, comprising 134 patients. A male predominance of 58% was found. The median age was 35 (range 4-84) years. Eight patients experienced recurrent episodes of rhabdomyolysis. Genetic analysis was performed in eleven patients (8%), revealing four RYR1 variants, three likely benign (p.Asp849Asn, p.Arg4645Gln, p.Arg4645Gln) and one variant of uncertain significance (p.Ala612Thr). This review underlines that a subset of patients with neuroleptic malignant syndrome and serotonin syndrome develop recurrent episodes of rhabdomyolysis. This recurrent pattern suggests a possible underlying (genetic) susceptibility. However, the genetic background of neuroleptic malignant syndrome and serotonin syndrome has only been investigated to a very limited degree so far. The increasing availability of next generation sequencing offers an opportunity to identify potentially associated genetic backgrounds, especially in patients with recurrent episodes or a positive family history.

Citalopram overdose and severe serotonin syndrome in an intermediate metabolizing patient.

INTRODUCTION: Citalopram is a selective serotonin reuptake inhibitor used for treatment of depression. Metabolism is primarily through CYP3A4 and CYP2C19; activity of the latter can vary depending on genetics. Although rare after single agent exposure, large citalopram ingestions can lead to serotonin syndrome. We report a case of citalopram overdose in an intermediate CYP2C19 metabolizer complicated by severe serotonin syndrome. CASE DETAILS: A 25-year-old female presented after intentional citalopram overdose with seizures, tachycardia, persistent neuromuscular findings, and severe hyperthermia requiring aggressive sedation and cooling. Protracted symptoms required critical care services throughout a 14 day hospital stay despite traditional treatment of serotonin syndrome. Pharmacogenomic studies revealed intermediate CYP2C19 metabolism which reduces citalopram inactivation and may cause increased levels and toxicity. DISCUSSION: In the majority of serotonin syndrome cases, symptoms resolve rapidly after treatment initiation and discontinuation of the offending agents. Severe cases are typically associated with ingestion of multiple serotonergic agents. Our patient had severe toxicity after single agent ingestion. Pharmacogenetic testing identified abnormal CYP2C19 activity and previous cases have associated enzyme dysfunction and citalopram toxicity. CONCLUSION: Citalopram overdose may be associated with severe serotonin syndrome and further investigation is warranted to understand the impact of enzyme genotype on toxicity.

The Serotonin Syndrome: From Molecular Mechanisms to Clinical Practice.

The serotonin syndrome is a medication-induced condition resulting from serotonergic hyperactivity, usually involving antidepressant medications. As the number of patients experiencing medically-treated major depressive disorder increases, so does the population at risk for experiencing serotonin syndrome. Excessive synaptic stimulation of 5-HT2A receptors results in autonomic and neuromuscular aberrations with potentially life-threatening consequences. In this review, we will outline the molecular basis of the disease and describe how pharmacologic agents that are in common clinical use can interfere with normal serotonergic pathways to result in a potentially fatal outcome. Given that serotonin syndrome can imitate other clinical conditions, an understanding of the molecular context of this condition is essential for its detection and in order to prevent rapid clinical deterioration.

5-HT1A receptor agonist 8-OH-DPAT induces serotonergic behaviors in mice via interaction between PKCδ and p47phox.

Serotonin syndrome is an adverse reaction due to increased serotonin (5-hydroxytryptophan: 5-HT) concentrations in the central nervous system (CNS). The full 5-HT1A receptor (5-HT1AR) agonist (±)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) has been recognized to elicit traditional serotonergic behaviors. Treatment with 8-OH-DPAT selectively increased PKCδ expression out of PKC isoforms and 5-HT turnover rate in the hypothalamus of wild-type mice. Treatment with 8-OH-DPAT resulted in oxidative burdens, co-immunoprecipitation of 5-HT1AR and PKCδ, and phosphorylation and membrane translocation of p47phox. Importantly, p47phox also interacted with 5-HT1AR or PKCδ in the presence of 8-OH-DPAT. Consistently, the interaction and oxidative burdens were attenuated by 5-HT1AR antagonism (i.e., WAY100635), PKCδ inhibition (i.e., rottlerin and genetic depletion of PKCδ), or NADPH oxidase/p47phox inhibition (i.e., apocynin and genetic depletion of p47phox). However, WAY100635, apocynin, or rottlerin did not exhibit any additive effects against the protective effect by inhibition of PKCδ or p47phox. Furthermore, apocynin, rottlerin, or WAY100635 also significantly protected from pro-inflammatory/pro-apoptotic changes induced by 8-OH-DPAT. Therefore, we suggest that 8-OH-DPAT-induced serotonergic behaviors requires oxidative stress, pro-inflammatory, and pro-apoptotic changes, that PKCδ or p47phox mediates the serotonergic behaviors induced by 8-OH-DPAT, and that the inhibition of PKCδ-dependent p47phox activation is critical for protecting against serotonergic behaviors.

Rapid In Situ Hybridization using Oligonucleotide Probes on Paraformaldehyde-prefixed Brain of Rats with Serotonin Syndrome.

3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) toxicity may cause region-specific changes in serotonergic mRNA expression due to acute serotonin (5-hydroxytryptamine; 5-HT) syndrome. This hypothesis can be tested using in situ hybridization to detect the serotonin 5-HT2A receptor gene htr2a. In the past, such procedures, utilizing radioactive riboprobe, were difficult because of the complicated workflow that needs several days to perform and the added difficulty that the technique required the use of fresh frozen tissues maintained in an RNase-free environment. Recently, the development of short oligonucleotide probes has simplified in situ hybridization procedures and allowed the use of paraformaldehyde-prefixed brain sections, which are more widely available in laboratories. Here, we describe a detailed protocol using non-radioactive oligonucleotide probes on the prefixed brain tissues. Hybridization probes used for this study include dapB (a bacterial gene coding for dihydrodipicolinate reductase), ppiB (a housekeeping gene coding for peptidylprolyl isomerase B), and htr2a (a serotonin gene coding for 5-HT2A receptors). This method is relatively simply, cheap, reproducible and requires less than two days to complete.

Pharmacogenetic workup of perioperative serotonin syndrome.

Serotonin syndrome is gaining attention in perioperative and chronic pain settings due to the growing prevalence of multimodal therapies that increase serotonin levels and thereby heighten patient risk. A patient's genetic make-up may further increase the risk of serotonin syndrome. A case of serotonin syndrome on emergence after general anesthesia is presented. A subsequent cytochrome P4502D6 genetic test result suggested a potential alteration in metabolism. For this patient, who was taking combination antidepressant medications and receiving common perioperative medicines, additive pharmacodynamic effects converged with a pharmacogenetic predisposition, resulting in serotonin syndrome.

Avoiding serotonin syndrome: the nature of the interaction between tramadol and selective serotonin reuptake inhibitors.

OBJECTIVE: To investigate the nature of the interaction between selective serotonin reuptake inhibitors (SSRIs) and tramadol to mitigate or avoid serotonin syndrome. DATA SOURCES: PubMed, Ovid MEDLINE, and International Pharmaceutical Abstracts from January 1990 to August 2012 were searched. Key words used were tramadol, antidepressive agents, antidepressants, drug interactions, selective serotonin uptake inhibitors, and serotonin syndrome. STUDY SELECTION AND DATA EXTRACTION: Only English-language studies were included. No randomized controlled trials were identified. Review articles, case reports, and 1 case series that identified the scope of interaction between tramadol and SSRIs were evaluated. Review articles evaluating the role of pharmacogenetics in the use of tramadol, SSRIs, and serotonin syndrome were also reviewed. DATA SYNTHESIS: Published documentation describing the interaction between tramadol and SSRIs and its relevance to serotonin syndrome is limited to a few case reports and 1 case series. While both tramadol and SSRIs increase the amount of serotonin in the brain, the interaction is much more complicated. Tramadol is metabolized through CYP2D6 enzymes and all SSRIs are inhibitors of these enzymes. Inhibitors of CYP2D6 can increase the concentration of tramadol in the blood and thus increase its effects on serotonin in the brain, contributing to the development of serotonin syndrome. CYP2D6 poor metabolizers are at a greater risk of serotonin syndrome and an inadequate analgesic effect. CONCLUSIONS: Coadministration of tramadol and SSRIs has caused serotonin syndrome. An attempt should be made to identify individuals who are poor metabolizers of CYP2D6 and avoid this combination in those patients. When SSRIs and tramadol must be used in combination, it is critical that patients be aware of the signs and symptoms of serotonin syndrome, should they occur.

Myoclonus after dextromethorphan administration in peritoneal dialysis.

OBJECTIVE: To report a case of myoclonus that developed after administration of dextromethorphan. CASE SUMMARY: A 64-year-old man was diagnosed with chronic renal failure due to diabetic nephropathy. The patient started on peritoneal dialysis 6 months before he was hospitalized. Two days before hospitalization, he developed cough and sputum and he visited an outpatient clinic, where dextromethorphan was prescribed. After taking a total of 30 mg of dextromethorphan, the patient developed myoclonus, tremor, agitation, slurred speech, and diaphoresis, which continued after he stopped taking the prescribed medicine. He visited an emergency department and was hospitalized for examination and treatment of myoclonus. DISCUSSION: As the patient's dialysis schedule was adequate, these symptoms were likely not due to uremia. The blood concentration of dextromethorphan (2.68 ng/mL) 60 hours after the 30-mg dose was higher than expected, and the blood concentration of dextrorphan, a metabolite, was lower than expected. We suspected that myoclonus was due to dextromethorphan-related symptoms induced by CYP2D6, which primarily metabolizes dextromethorphan. We analyzed the CYP2D6 gene for polymorphisms and identified CYP2D6 (*)1/(*)10. The patient had been taking metoprolol 40 mg/day for 2 years. The blood concentration of metoprolol 6 hours after administration was 13 ng/mL, which suggests that it was metabolized normally. Metoprolol has another metabolic pathway, via CYP2C19, and this may have led to its lack of accumulation. Moreover, metoprolol may have bound to active CYP2D6. Thus, affinity for CYP2D6, protein-binding rate, and lipid solubility may influence these drug interactions. Total scores for the Adverse Drug Reaction (ADR) probability scale and the Drug Interaction Probability Scale (DIPS) were 9 (highly probable) and 3 (possible), respectively. CONCLUSIONS: Myoclonus and other symptoms in this patient may have been caused by a prolonged high concentration of dextromethorphan due to CYP2D6 polymorphisms and drug interactions.

Early dysfunction of central 5-HT system in a murine model of bovine spongiform encephalopathy.

The hypothesis of an early vulnerability of the serotonergic system to prion infection was investigated in a murine model of bovine spongiform encephalopathy (BSE). Behavioral tests targeted to 5-HT functions were performed in the course of infection to evaluate circadian activity, anxiety-like behavior, pain sensitivity and the 5-HT syndrome. The first behavioral change was a decrease in nocturnal activity detected at 30% of incubation time. Further behavioral alterations including nocturnal hyperactivity, reduced anxiety, hyperalgesia and exaggerated 5-HT syndrome were observed at 60%-70% of incubation time, before the onset of clinical signs. The same tests performed in 5-HT-depleted mice and in prion protein-deficient mice revealed behavioral abnormalities similar in many aspects to those of BSE-infected mice. Histological and biochemical analysis showed alterations of the serotonergic system in BSE-infected and prion protein-deficient mice. These results indicate that BSE infection affects the homeostasis of serotonergic neurons and suggest that the disruption of prion protein normal function contributes to the early pathological changes in our mouse model of BSE. A similar process may occur in the human variant Creutzfeldt-Jacob disease, as suggested by the early symptoms of alterations in mood, sleep and pain sensitivity.

Perspectives on genetic animal models of serotonin toxicity.

Serotonin syndrome, or serotonin toxicity, is a serious disorder attributable to exaggerated serotonergic function in the brain, most commonly after antidepressant overdose or after combining several psychotropic medications. Similar condition (serotonin syndrome-like behavior) can be evoked in animals experimentally, following administration of serotonergic drugs. In addition to pharmacological stimulation, some genetic and other factors may contribute to serotonin toxicity, prompting the need for new experimental genetic models relevant to this disorder. Here we discuss current problems and perspectives regarding genetic animal models of serotonin-related syndromes, and outline the potential utility of these models in experimental neurochemistry and clinical research.

Hypolocomotion, anxiety and serotonin syndrome-like behavior contribute to the complex phenotype of serotonin transporter knockout mice.

Although mice with a targeted disruption of the serotonin transporter (SERT) have been studied extensively using various tests, their complex behavioral phenotype is not yet fully understood. Here we assess in detail the behavior of adult female SERT wild type (+/+), heterozygous (+/-) and knockout (-/-) mice on an isogenic C57BL/6J background subjected to a battery of behavioral paradigms. Overall, there were no differences in the ability to find food or a novel object, nest-building, self-grooming and its sequencing, and horizontal rod balancing, indicating unimpaired sensory functions, motor co-ordination and behavioral sequencing. In contrast, there were striking reductions in exploration and activity in novelty-based tests (novel object, sticky label and open field tests), accompanied by pronounced thigmotaxis, suggesting that combined hypolocomotion and anxiety (rather than purely anxiety) influence the SERT -/- behavioral phenotype. Social interaction behaviors were also markedly reduced. In addition, SERT -/- mice tended to move close to the ground, frequently displayed spontaneous Straub tail, tics, tremor and backward gait - a phenotype generally consistent with 'serotonin syndrome'-like behavior. In line with replicated evidence of much enhanced serotonin availability in SERT -/- mice, this serotonin syndrome-like state may represent a third factor contributing to their behavioral profile. An understanding of the emerging complexity of SERT -/- mouse behavior is crucial for a detailed dissection of their phenotype and for developing further neurobehavioral models using these mice.

Life-threatening serotonin syndrome in a patient with chronic heart failure and CYP2D6*1/*5.

We report a case of serotonin syndrome that occurred in a patient with chronic heart failure associated with a panic disorder. The 39-year-old Japanese man had been treated with paroxetine at 20 mg/d for 1 1/2 years. He presented with rhabdomyolysis, renal failure, fulminant liver failure, cardiac conduction disturbance, and disseminated intravascular coagulation, as well as conventional symptoms of serotonin syndrome including alterations in cognition (disorientation, confusion) and behavior (restlessness), autonomic nervous system dysfunction (fever, shivering), and abnormal neuromuscular activity (ataxia, hyperreflexia, myoclonus). All medications prescribed before hospital admission were discontinued. After 24 hours of continuous venovenous hemofiltration, diuresis resumed and renal and liver function improved rapidly. Disorientation, restlessness, hyperreflexia, and myoclonus abated slowly over the next 72 hours. The patient's anxiety subsided more slowly, and he recovered completely 1 week later. The plasma concentration of paroxetine was elevated far above the upper limit of the therapeutic range. The patient had cytochrome P-450 (CYP) 2D6*1/*5, a heterozygosity of an inactivated allele of CYP2D6, which metabolizes paroxetine. The patient was determined to be an intermediate metabolizer who was potentially vulnerable to paroxetine, a major inhibitor of CYP2D6. Heart failure is often accompanied by psychiatric disorders. A wide range of drugs commonly prescribed for these conditions, including beta-blockers, antiarrhythmics, and antidepressants, are metabolized by CYP2D6. Genetic screening for CYP2D6 in patients with these conditions may prevent life-threatening drug intoxication.

Some physiological manifestations of the activity of the gene controlling the predisposition to pendulum-like movements in rats.

The physiological actions of the gene controlling the predisposition to stereotypic hyperkinesia in the form of pendulum-like movements (PM) and, probably, a form of spontaneous nystagmus in rats with albinism are manifest as a number of behavioral characteristics (total motor activity, emotionality, startle reflex intensity, sensitivity to serotonin 5-HT2 receptors as assessed in terms of the intensity of head twitching, and predisposition to cataleptic responses). A number of parameters showed differences between hybrids of gray handling-tolerant rats and carriers of the PM gene on the one hand, and between gray rats and animals not carrying the PM gene on the other. Some behavioral characteristics of rats with PM were closer to those of Wistar rats than to those of rats without PM. This, as well as the high frequency of PM in Wistar rats, indicates that the gene responsible for the manifestations of PM is not pathological, but controls a variety of adaptive features of the nervous system. The interaction between PM and the predisposition to catalepsy is biphasic in nature and is described by a curve in the form of an inverted U.