Serotonergic Medications Research Articles

Functional Connectivity of the Raphe Nuclei: Link to Tobacco Withdrawal in Smokers.

BackgroundAlthough nicotine alters serotonergic neurochemistry, clinical trials of serotonergic medications for smoking cessation have provided mixed results. Understanding the role of serotonergic dysfunction in tobacco use disorder may advance development of novel pharmacotherapies.MethodsFunctional magnetic resonance imaging was used to measure resting-state functional connectivity of the raphe nuclei as an indicator of serotonergic function. Connectivity of the dorsal and median raphe nuclei was compared between 18 young smokers (briefly abstinent, ~40 minutes post-smoking) and 19 young nonsmokers (16–21 years old); connectivity was also examined in a separate sample of overnight-abstinent smokers (18–25 years old), before and after smoking the first cigarette of the day. Relationships between connectivity of the raphe nuclei with psychological withdrawal and craving were tested in smokers.ResultsConnectivity of the median raphe nucleus with the right hippocampal complex was weaker in smokers than in nonsmokers and was negatively correlated with psychological withdrawal in smokers. In overnight-abstinent smokers, smoking increased connectivity of the median raphe nucleus with the right hippocampal complex, and the increase was positively correlated with the decrease in psychological withdrawal.ConclusionsRelief of withdrawal due to smoking is potentially linked to the serotonergic pathway that includes the median raphe nucleus and hippocampal complex. These results suggest that serotonergic medications may be especially beneficial for smokers who endorse strong psychological withdrawal during abstinence from smoking.

Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.

Drugs may cause serotonin toxicity by a number of different mechanisms including inhibition of serotonin uptake and metabolism, increased serotonin synthesis and release, activation of serotonin receptors, and inhibition of cytochrome P450 oxidases. Some drug interactions involving opioids can increase intrasynaptic levels of serotonin, and opioid analgesic drugs are now recognized as being involved in some cases of serotonin toxicity especially if administered in conjunction with other serotonergic medications including monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants. In March 2016, the FDA issued a Drug Safety Communication concerning the association of the entire class of opioid pain medicines with serotonin toxicity. Reports of the involvement of individual opioids particularly tramadol, tapentadol, meperidine, methadone, oxycodone, fentanyl, and dextromethorphan are reviewed. While relevance to human serotonin toxicity of animal models, including many studies on rat brain synaptosomes, is questionable, important insights have recently been forthcoming from research utilizing 5-HT receptors, serotonin transporter (SERT), and knockout mice. In studies with human SERT-transfected human HEK293 cells, the synthetic opioids tramadol, meperidine, methadone, tapentadol, and dextromethorphan inhibited SERT, but fentanyl and a number of phenanthrenes including morphine and hydromorphone did not. Receptor ligand-binding assays revealed interaction of fentanyl with 5-HT1A receptors and interaction of meperidine, methadone, and fentanyl with 5-HT2A receptors. Although the opioids most often associated with serotonin toxicity in humans inhibit human SERT in vitro, fentanyl and oxycodone are not inhibitory even though their clinical involvement has been reported. This suggests some SERT-independent effects on the serotonin system in vivo. Heightened clinician awareness of the possibility of serotonin toxicity among patients taking opioids and serotonergic antidepressants is called for.

THE ROLE OF ADENYLATE-CYCLASE ACTIVITY IN PLATELETS OF PATIENTS WITH OBSESSIVE-COMPULSIVE DISORDER

Introduction Blood platelets can be considered a reliable peripheral model of presynaptic serotonergic neurons, as they are endowed with a 5-HT reuptake transporter similar to that present in the brain cells (Marazziti et al., 2004). The biological basis of the patophysiology of obsessive-compulsive disorder (OCD) is centered on serotonergic system, although evidences of both dopaminergic and adrenergic systems involvement are consistent (Westenberg et al., 2007). A possible role of second messengers, such as cyclic adenosine monophosphate (cAMP) signaling, in the development of OCD has been recently postulated, although evidences are meager and, in some cases, contradictory (McDougle et al., 1999). The aim of the present study was to explore and to compare the adenylate cyclase (AC) activity either in basal conditions, either after the stimulation by isoprenaline (ISO) in platelets of OCD patients and healthy control subjects. Also, AC activity was measured both in the absence and in the presence of α- and β- adrenoreceptor antagonists. Materials and methods Forty patients (20 men and 20 women, aged between 23 and 34 years; mean±SD: 26.5 ± 4.8) were included in the study. All of them met Diagnostic and Statistic Manual of Mental Disorders 5th edition (DSM-5) criteria for OCD, were not currently depressed, nor had any history of mood disorders or any other comorbid conditions. This group was compared to a similar one, composed by 40 healthy volunteers patients (20 men and 20 women, aged between 21 and 32 years; mean±SD: 24.6 ± 6.3), all of them without familiar or personal history of major psychiatric disorders. The severity of OC symptoms was evaluated by means of the Yale Brown Obsessive-Compulsive Scale (Y-BOCS). Thirty (30) ml of blood were collected from fasting subjects between 8.00-10.00 a.m. to avoid circadian rhythm interference. Results The platelet basal AC activity was similar in OCD patients and healthy subjects. The addition of 10 μM ISO enhanced significantly (p Discussion No difference in the basal AC activity in platelet membranes of healthy subjects and OCD patients was found. The addition of 10 µM ISO to platelet membranes provoked a significant stimulation of the enzyme activity of the same magnitude in the two groups. Our findings suggests that, at our experimental conditions, there is an inhibitory component of ISO effect on platelet AC, due to the agonist interaction with α2 receptors, at its higher concentrations (> 1 μM). These data suggest the presence of a condition of supersensitive β-receptors in platelets of OCD patients that, perhaps, could reflect (or provoke) alterations of the intracellular signaling system mediated by the cAMP and of the related kinases. In conclusion, the results of the present study suggest that abnormal second messenger pathways in OCD may be also related to cathecolamine system disturbances, which might open new therapeutic strategies especially in resistant patients who do not respond to serotonergic medications.

Spontaneously reported adverse drug events related to tapentadol and oxycodone/naloxone in Australia.

The rapid increase in prescribing and use of opioids for noncancer pain has coincided with an increase in opioid-related adverse drug events (ADEs). The objective of our study was to describe ADEs related to tapentadol and oxycodone/naloxone spontaneously reported to the Australian Therapeutic Goods Administration (TGA). Public case detail reports for tapentadol (September 2013-March 2017) and oxycodone/naloxone (April 2011-March 2017) were sourced from the TGA. The total number of public case detail reports for tapentadol were 104 and 249 for oxycodone/naloxone. Demographic characteristics of patients, concomitant medications, causality assessment and outcome were described for each opioid according to the Medical Dictionary for Regulatory Activities (MedDRA) system organ class. The most prevalent ADEs for tapentadol were nervous system disorders (n = 52, 50%), psychiatric (n = 34, 32.7%), gastrointestinal (n = 18, 17.3%), and general disorders and administration site conditions (n = 21, 20.2%). Sixteen (23.2%) of 69 nervous system disorders reaction terms were consistent with serotonin syndrome of which 14 (87.5%) involved documented coadministration with another serotonergic medication. The most prevalent ADEs for oxycodone/naloxone were psychiatric disorders (n = 78, 31.3%), gastrointestinal (n = 73, 29.3%), general disorders and administration site conditions (n = 87, 35%), and nervous system disorders (n = 62, 24.9%). There were 40 (16%) public case detail reports for oxycodone/naloxone with the MedDRA reaction terms 'drug withdrawal syndrome' and 'withdrawal syndrome'. The profiles of spontaneous ADE reports for tapentadol and oxycodone/naloxone are largely consistent with their premarketing randomized controlled studies and profiles of opioids in general. Further research into the risk of serotonin syndrome with tapentadol use is warranted. The ADEs suggest clinicians should be cautious when switching patients to oxycodone/naloxone from other opioids.

Effects of Treadmill Training Combined with Serotonergic Interventions on Spasticity after Contusive Spinal Cord Injury.

Spasticity usually emerges during the course of recovery from spinal cord injury (SCI). While medications and physical rehabilitation are prescribed to alleviate spastic symptoms, the insufficiency of their effects remains an important problem to be addressed. Given the challenges associated with increasing the dose of medication, we hypothesized that a combination therapy with medication and physical rehabilitation can be effective. Therefore, we examined the effects of treadmill training (TMT) along with serotonergic medication using a spastic rat model after contusive injury. Spasticity-strong SCI rats were selected 4 weeks after SCI and received one of the following interventions for 2 weeks: only TMT, TMT with fluoxetine (a selective serotonin re-uptake inhibitor), TMT with cyproheptadine (a 5-HT2 receptor antagonist), only fluoxetine, or only cyproheptadine. We performed the swimming test to quantify the frequency of spastic behaviors. We also evaluated hindlimb locomotor functions every week. At the end of the intervention, we examined the Hoffman reflex from the plantar muscle and the immunoreactivity of the 5-HT2A receptor in spinal cord tissues. While the TMT group and cyproheptadine-treated groups showed decreased spastic behaviors and reduction in spinal hyperreflexia, the fluoxetine-treated group showed the opposite effect, even with TMT. Moreover, TMT suppressed the expression of the 5-HT2A receptor in the lumbar spinal motor neurons, while cyproheptadine treatment did not change it. We did not observe any differences in locomotor functions between the groups. Taken together, our findings indicate that TMT and cyproheptadine significantly alleviated spastic symptoms, but did not show synergistic or additive effects.

Conservative management of severe serotonin syndrome with coma, myoclonus, and crossed-extensor reflex complicated by hepatic encephalopathy

ABSTRACTSerotonin syndrome (SS) is an underrecognized and potentially fatal disorder that occurs secondary to combinational use or overdose of a single serotonergic medication. The presentation may be complicated by hepatic encephalopathy in cirrhotic patients, which may also affect metabolism of these serotonergic agents. The authors report a rare case of severe SS complicated by hepatic encephalopathy secondary to cirrhosis in a 52-year-old woman after an increase in her home dosage of fluoxetine and addition of other psychiatric medications.

When the drugs don't work: treatment-resistant schizophrenia, serotonin and serendipity.

Treatment-resistant schizophrenia is a serious clinical problem. We adopt a systems-level approach positing a greater role for cognitive control mechanisms in the development of psychotic symptoms and illustrate the clinical application of this via a case report of treatment-resistant patients treated successfully with adjunct pro-cognitive serotonergic medication.

Serotonin Syndrome Complicating Treatment of Ifosfamide Neurotoxicity With Methylene Blue.

Methylene blue is a widely used treatment for ifosfamide neurotoxicity. We present a case of severe encephalopathy complicating ifosfamide-based therapy for recurrent retroperitoneal leiomyosarcoma. After treatment with methylene blue, the patient experienced clinical decompensation and was diagnosed with serotonin syndrome based on a constellation of clinical findings. Withdrawal of methylene blue and other serotonergic medications led to clinical stabilization and ultimately neurological recovery. Our case highlights the challenge of diagnosing serotonin syndrome in the face of preexisting ifosfamide neurotoxicity, as there is significant clinical overlap between these 2 syndromes. Practitioners must remain vigilant of this potential life-threatening complication in this vulnerable population.

Increased postpartum haemorrhage, the possible relation with serotonergic and other psychopharmacological drugs: a matched cohort study

BackgroundPostpartum haemorrhage is a major obstetric risk worldwide. Therefore risk factors need to be investigated to control for this serious complication. A recent systematic review and meta-analysis revealed that the use of both serotonergic and non-serotonergic antidepressants in pregnancy are associated with a higher risk of postpartum haemorrhage. However, use of antidepressants in pregnancy is often necessary because untreated depression in pregnancy is associated with adverse maternal and neonatal outcome, such as postpartum depression, preterm birth and dysmaturity. Therefore it is of utmost importance to unravel the possible association between postpartum haemorrhage and the use of serotonergic and other psychopharmacological medication during pregnancy.MethodsWe performed a matched cohort observational study consecutively including all pregnant women using serotonergic medication (n = 578) or other psychopharmacological medication (n = 50) visiting two teaching hospitals in Amsterdam between 2010 and 2014. The incidence of postpartum haemorrhage in women using serotonergic medication or other psychopharmacological medication was compared with the incidence of postpartum haemorrhage in 641,364 pregnant women not using psychiatric medication selected from the database of the Netherlands Perinatal Registry foundation (Perined). Matching took place 1:5 for nine factors, i.e., parity, maternal age, ethnicity, socioeconomic status, macrosomia, gestational duration, history of postpartum haemorrhage, labour induction and hypertensive disorder.ResultsPostpartum haemorrhage occurred in 9.7% of the women using serotonergic medication. In the matched controls this was 6.6% (p = 0.01). The adjusted odds ratio (aOR) before matching was 1.6 (95% CI 1.2–2.1) and after matching 1.5 (95% CI 1.1–2.1). Among the women using other psychopharmacological medication, the incidence of postpartum haemorrhage before matching was 12.0% versus 6.1% (p = 0.08) with OR 2.1 (95% CI 0.9–4.9), and after matching 12.1% versus 4.4% (p = 0.03) with aOR of 3.3 (95% CI 1.1–9.8).ConclusionsPregnant women using serotonergic medication have an increased risk of postpartum haemorrhage, but this high risk is also seen in pregnant women using other psychopharmacological medication. We suggest that this higher risk of postpartum haemorrhage could not only be explained by serotonin, but also by other mechanisms. An additional explanation could be the underlying psychiatric disorder.

Retrospective review of serotonergic medication tolerability in patients with neuroendocrine tumors with biochemically proven carcinoid syndrome.

Patients with carcinoid tumors frequently could benefit from the pharmacologic treatment of depression and anxiety. However, many prescribers avoid serotonergic medications due to the theoretical risk of exacerbating carcinoid syndrome. The authors conducted a retrospective chart review of patients with carcinoid tumors and elevated serotonin levels (as measured by 24-hour urine 5-hydroxyindoleacetic acid [5-HIAA]) at Dana-Farber/Brigham and Women's Cancer Center who initiated treatment with serotonergic antidepressants after a carcinoid diagnosis from 2003 to 2016. Each medication regimen was categorized based on the presence of adverse interactions as defined by clinical worsening of symptoms of carcinoid syndrome in the absence of progressive disease that temporally correlated with a serotonergic medication trial. A total of 73 serotonergic regimens received by 52 patients were included in the primary analysis. Among these medication trials, 8.2% of the regimens (6 regimens) were categorized as being associated with a likely adverse interaction, 61.6% of the regimens (45 regimens) were categorized as having no adverse reaction, 9.6% of the regimens (7 regimens) were categorized as an unlikely adverse reaction, and 20.6% of the regimens (15 regimens) were categorized as unknown. It is interesting to note that none of the 73 trials resulted in a carcinoid crisis requiring emergency care or hospitalization. Only 3 patients discontinued serotonergic medications due to worsening carcinoid syndrome. Serotonergic medications appear to be a safe option for the treatment of depressive and anxiety symptoms in the majority of patients with neuroendocrine tumors and carcinoid syndrome. In the current study, <10% of patients developed a combination of flushing, diarrhea, and bloating after the initiation of serotonergic medications. Clinicians can begin with low doses, monitor these symptoms, and reduce the dose or discontinue the medication if necessary. Cancer 2017;123:2735-42. © 2017 American Cancer Society.

Famotidine-induced reversal of meperidine-related serotonin syndrome: a case report.

Serotonin syndrome is an unexpected fatal adverse event related to serotonergic medication. This case report is the first report describing the possible treatment effect of famotidine on serotonin syndrome. Furthermore, this is the first case report of serotonin syndrome induced by meperidine alone in a patient with no previous history suggesting a susceptibility to serotonin syndrome. A 70-year-old male with no recent history of serotonergic drug use presented with severe serotonin syndrome following ureteroscopy, possibly due to postoperative meperidine administration. The patient's symptoms included hypertension, tachycardia, tachypnea, hyperthermia, myoclonus, diaphoresis, retching, nausea, agitation, and semicoma mentality with no pupillary light reflex. Symptoms began to subside immediately after the administration of intravenous famotidine for prevention of aspiration pneumonia, with mental and neurological symptoms showing improvement initially, followed by autonomic symptoms. This case report suggests that the histamine type 2 receptor antagonist famotidine may be an effective emergency treatment for serotonin syndrome.

Serotonergic medication enhances the association between suicide and sunshine

BackgroundAn association between suicide and sunshine has been reported. The effect of sunshine on hormones and neurotransmitters such as serotonin has been hypothesized to exert a possible triggering effect on susceptible individuals. The aim of this study is to examine if there is an association between sunshine and suicide, adjusting for season, and if such an association differs between individuals on different antidepressants. MethodsBy using Swedish Registers and the Swedish Meteorological and Hydrological Institute we obtained information, including forensic data on antidepressive medication for 12,448 suicides and data on monthly sunshine duration. The association between monthly suicide and sunshine hours was examined with Poisson regression analyses while stratifying for sex and age and controlling for time trend and season. These analyses were repeated in different groups of antidepressant treatment. ResultsWe found a significantly increased suicide risk with increasing sunshine in both men and women. This finding disappeared when we adjusted for season. Among both men and women treated with selective serotonin reuptake inhibitors (SSRIs) there was a positive association between sunshine and suicide even after adjustment for season and time trend for suicide. Pair comparisons showed that the sunshine–suicide association was stronger among men treated with SSRIs compared to other antidepressant medications or no medication at all. LimitationsOther meteorological factors were not controlled (i.e. temperature) for in the analyses. ConclusionsThere is an enhanced association between sunshine and suicide among those with SSRI medication, even after adjusting for season. This may have interesting theoretical and clinical implications.

Variation in the Serotonin Transporter Gene and Alcoholism: Risk and Response to Pharmacotherapy.

SLC6A4, the gene encoding the serotonin transporter protein (5-HTT), has been extensively examined as a risk factor for alcohol dependence (AD). More recently, variability in the transporter gene was identified to be a potential moderator of treatment response to serotonergic medications such as ondansetron and sertraline. There is an insertion-deletion polymorphism in the promoter region (5-HTTLPR) of the SLC6A4, with the most common alleles being a 14-repeat short (S) allele and a 16-repeat long (L) allele. The S allele has often been associated with AD. By contrast, the L allele has been associated with pharmacological responsiveness in some individuals with AD. Differences in clinical phenotype may determine the utility of the 5-HTTLPR polymorphism as a moderator of pharmacological interventions for AD. We review the AD typology and disease onset in the context of pharmacogenetic and genomic studies that examine the utility of 5-HTTLPR in improving treatment outcomes.

Successful treatment of paroxysmal tonic upgaze with low dose Gravol ®

Background: We present a case of paroxysmal tonic upgaze (PTU) of infancy treated with a daily low dose of Gravol ® to improve symptoms. Method: Case report Results: A one year-old boy presented with episodes of sustained conjugate upgaze that persisted for 30 to 45 minutes, varied in severity, and occurred with increasing frequency over the past two months. The episodes were worse when fatigued and were relieved by sleep. Pregnancy, delivery, and development were normal. Neurological examination between episodes was normal, as were EEG, brain MRI, and blood analysis. CSF neurotransmitter analysis showed serotonin and dopamine metabolites at lower levels of normal. The patient was diagnosed with paroxysmal tonic upgaze of infancy and was treated with 12.5 mg of Gravol ® daily with complete cessation of episodes. Conclusions: Paroxysmal tonic upgaze (PTU) of infancy is a disorder seen in infants where the eyes are forcibly deviated upwards for minutes to hours at a time. PTU often resolves spontaneously over several months, however episodes are extremely debilitating. Currently, treatments with levodopa have been tried with some success. Via its anticholinergic effects, Gravol may be a novel therapeutic option for PTU, negating the need to use serotonergic medications.

Tramadol overdose causes seizures and respiratory depression but serotonin toxicity appears unlikely

Context. Tramadol is a commonly used centrally acting analgesic associated with seizures and suspected to cause serotonin toxicity in overdose. Objective. This study sought to investigate the effects of tramadol overdose, and included evaluation for serotonin toxicity based on the Hunter Serotonin Toxicity Criteria where the seven clinical features of spontaneous clonus, inducible clonus, ocular clonus, agitation, diaphoresis, tremor and hyperreflexia are examined for in all patients taking serotonergic medications; seizures and central nervous system depression. Materials and methods. This was an observational cases series based on a retrospective review of tramadol overdoses (> 400 mg) admitted to a tertiary toxicology unit from November 2000 to June 2013. Demographic details, information on ingestion (dose and co-ingestants), clinical effects, complications (seizures, serotonin toxicity and cardiovascular effects) and intensive care unit (ICU) admission were extracted from a clinical database. Results. There were 71 cases of tramadol overdose (median age: 41 years, range: 17–69 years; and median ingested dose: 1000 mg, interquartile range [IQR]: 800–2000 mg). Seizures were dose related and occurred in 8 patients, one of them co-ingested a benzodiazepine compared with 16 patients without seizures. There were no cases of serotonin toxicity meeting the Hunter Serotonin Toxicity Criteria. Tachycardia occurred in 27 and mild hypertension occurred in 32. The Glasgow Coma Score was < 15 in 29 and < 9 in 5 patients; three co-ingested tricyclic antidepressants and two tramadol alone (3000 mg and 900 mg). Respiratory depression occurred in 13, median dose: 2500 (IQR: 1600–3000) mg which was significantly different (p = 0.003) to patients without respiratory depression, median dose: 1000 (IQR: 750–1475) mg. Eight patients were admitted to ICU, five due to co-ingestant toxicity and three for respiratory depression. Discussion. Tramadol overdose was associated with a significant risk of seizures and respiratory depression in more severe cases, both which appear to be related to the ingested dose. There were no cases of serotonin toxicity, while opioid-like effects and adrenergic effects were prominent. Conclusion. Tramadol overdose is associated with seizures and respiratory depression, but is unlikely to cause serotonin toxicity.

Serotonin Syndrome and Opioids—What’s the Deal?

There are myriad (that’s fancy talk for a lot) of medications that can precipitate serotonin syndrome (SS) or serotonin toxicity. Meperidine arguably received the most publicity through the Libby Zion case, which led to regulation of resident physician duty hours. 1 Lerner B.H. A case that shook medicine. Washington Post. November 28, 2006; (Available at:) (Accessed February 8, 2014)http://www.washingtonpost.com/wp-dyn/content/article/2006/11/24/AR2006112400985.html Google Scholar Although serotonergic medications obviously play a role in SS, which opioids, aside from meperidine, have been associated with SS? And, given the frequency of pain medication administration in the emergency department, which opioids, if any, are presumably safe to use?

Opioids induced serotonin toxicity? Think again.

Sir, In a recently published article, ‘Cardiac arrest from tramadol and fentanyl combination’ by Nair and Chandy,[1] the authors concluded this case to be the first ever report of serotonin toxicity due to the co-administration of fentanyl and tramadol. We argue against this diagnosis as the patient did not fall into the diagnostic criteria of serotonin syndrome. The diagnosis of serotonin toxicity remains clinical one, and no laboratory test confirms the same. It is a syndrome characterised by a triad of neuroexcitatory features (neuromuscular hyperactivity, tremor, clonus, hyper-reflexia, pyramidal rigidity), autonomic hyperactivity (diaphoresis, fever, tachycardia, tachypnoea), and altered mental status (agitation, excitement, confusion).[2] According to another commonly used ‘Hunter's Serotonin Toxicity Criteria’, at least one out of the following five clinical feature is required for the diagnosis of serotonin syndrome: Spontaneous clonus; inducible clonus with agitation or diaphoresis; ocular clonus with agitation or diaphoresis; tremors and hyper-reflexia; hypertonia, temperature above 38°C, and ocular or inducible clonus.[3] The patient in discussion had only agitation without any clonus, hyper-reflexia, or hyperthermia. Occurrence of ventricular tachycardia and subsequent fibrillation remain unexplained using any of the diagnostic criteria's of serotonin toxicity. The same review article[3] as quoted by the authors clearly mentions that both fentanyl and tramadol are weak serotonin reuptake inhibitors (SRIs) and rarely precipitate dose-dependent serotonin toxicity in conjunction with serotonergic medications and that too only if large doses of fentanyl or tramadol are used or in susceptible individuals.[3] The patient in discussion was not on any serotonergic medications and authors had injected only 0.83 μg/kg of fentanyl and over 1 mg/kg of tramadol. They deferred injecting additional doses of fentanyl with the fear of developing chest wall rigidity, which did not appear by that time. Wooden chest syndrome usually occurs at much higher doses of fentanyl (12–15 μg/kg in an adult), or when the drug is injected at a rapid rate.[4] Lack of classical clinical presentation, the absence of administration of large doses of opioids and drug interaction with SRIs, makes the diagnosis of serotonin syndrome unlikely.

Cardiac arrest from tramadol and fentanyl combination.

Sir, Tramadol is a centrally acting atypical opioid analgesic commonly used in the treatment of moderate to severe pain. It has a low affinity to μ opioid receptors and also inhibits the reuptake of serotonin and norepinephrine. Fentanyl is a potent, synthetic opioid with a rapid onset of action and strong affinity to μ receptor. Both the drugs are considered to have a high safety profile and used widely in anaesthesia. Fentanyl and tramadol impair presynaptic reuptake of serotonin and in combination with other serotonergic medications can cause serotonin syndrome. We report a case where premedication with the two drugs in therapeutic doses led to serotonin syndrome with severe life-threatening cardiac arrhythmia. A 43-year-old male American Society of Anaesthesiologists physical status1 patient, with radicular pain was scheduled for C5–6 anterior cervical discectomy. He was on gabapentin 150 mg tid and ibuprofen 200 mg bid for pain relief since 1 month. Preanaesthetic evaluation had been insignificant, and and so was the examination prior to shifting into the theatre. After connecting standard monitors and preoxygenation, intravenous (i.v.) fentanyl 50 μg (0.83 μg/kg, in dilution of 1 ml = 50 μg) was administered. Patient was agitating, and pain was thought to be the cause of his agitation. For the fear of developing chest wall, rigidity another agent was considered instead of higher doses of fentanyl. I.v. tramadol 75 mg (1.25 mg/kg, in dilution of 1 ml = 20 mg) was administered slowly over 2–3 min. Immediately a supraventricular rhythm (SVT) with a rate of 180/min and ventricular ectopics were noted on the monitor. It soon deteriorated to ventricular tachycardia (VT) and then into ventricular fibrillation (VF). Cardiopulmonary resuscitation (CPR) was initiated, and airway was secured with endotracheal intubation. Defibrillation with biphasic mode (200 J) was administered thrice during the CPR cycle without sustained sinus rhythm. Injection amiodarone 300 mg bolus was administered after 3rd shock after which sustained sinus rhythm was achieved. After initiating maintenance amiodarone infusion (0.5 mg/kg/h for 24 h) and vasoactive support (noradrenaline and adrenaline infusion at 20 mcg/min) patient was shifted to the intensive care unit (ICU). In the ICU, ventilation was continued for a day with midazolam and morphine for sedation and analgesia. A bedside echocardiogram revealed a good cardiac contractility and output. Induced hypothermia at 34°C was maintained for the day. The next day vasoactive drugs were weaned off, and the patient was awake and successfully extubated. Amiodarone was changed to oral mode of administration and patient was discharged to the ward on 2nd day. The combination of tramadol and fentanyl for premedication is seldom used. The combination has improved tolerance for awake endotracheal intubation[1] and has reduced the incidence of supraventricular arrhythmia in patients undergoing pulmonary resection.[2] Fentanyl associated fatalities have been primarily due to respiratory depression as even low concentrations lead to it.[3] Life-threatening central nervous system (CNS) and cardiac complications are generally found after tramadol ingestion at high doses with unintentional or intentional suicidal attempts. Ahmadi et al., after analysing the cases of tramadol intoxication found mortality rate of 0.97%. Most of the cases have been reported in conjunction with other drugs such as CNS depressants.[4] However, Shadnia et al., reported two fatalities with tramadol intoxication without any co-ingestions.[5] In therapeutic doses, both tramadol and fentanyl have been implicated in serotonin toxicity though tramadol is more notorious for severe toxicity.[6] Serotonin toxicity is marked by the triad of neuromuscular excitation, autonomic stimulation and changes in mental state. Based on the clinical profile we suspected serotonin syndrome to be causative for the complication in our patient. The features of toxicity from drug combination develop rapidly after onset of effective blood levels of the second drug. The autonomic features such as tachycardia and tachypnea are not usually severe.[6] In our patient, the administration of i.v. fentanyl initiated the toxicity features (agitation) which became more pronounced with tramadol dose. However, the cardiac signs erstwhile considered not to be of serious consequence, in our patient caused near fatal arrhythmia. The rhythm quickly transformed from SVT to VT and then to VF [Figure 1]. No role of use of gabapentin preoperatively in this peroperative drug interaction between fentanyl and tramadol could be explained. Figure 1 Electrocardiogram tracing of the rhythm during cardiopulmonary resuscitation To our knowledge and belief, this is the first report of serotonin toxicity with tramadol and fentanyl combination, in therapeutic doses without any other serotonergic medication. The inability to monitor serum drug level has been a limitation, but the absence of any other drug administered prior to fentanyl and tramadol effectively establishes the aetiology. This case report highlights the dangers of combining two drugs with potential of serotonin toxicity and the severity of cardiac complication that can even be near fatal.

Neurobiology of Kleptomania: an overview

Kleptomania is a psychiatric manifestation frequently encountered in neurological conditions, especially Parkinson’s disease. This disorder has traditionally been considered to be a part of the obsessive compulsive spectrum disorder, but recently the focus has shifted to possible associations with addiction disorders. There are no FDA approved medications for the treatment of kleptomania. While serotonergic medications form the mainstay treatment, questions have been raised regarding their effectiveness, especially with reports emerging about these medications paradoxically inducing kleptomania. Keeping these points in perspective, a short review of literature was performed about the neurobiology of kleptomania, and a treatment algorithm is suggested based on the findings. DOI: http://dx.doi.org/10.4038/sljpsyc.v5i2.7305 SL J Psychiatry 2014; 5(2) 2-4

Self-injury in autism spectrum disorder: An effect of serotonin transporter gene promoter variants

Self-injurious behavior in autism spectrum disorder (ASD) has been associated with lower whole blood serotonin levels and the role of serotonin transporter gene promoter region (5HTTLPR) polymorphisms is of interest because of their effects on transporter functioning. This study examined the association between self-injurious behavior in ASD and allelic frequencies of 5HTTLPR. Sixty-four children and adolescents with ASD who were not taking serotonergic medication at the time of the assessment were included in the analysis. Self-injury was assessed using the Autism Diagnostic Interview-Revised (ADI-R) and whole blood serotonin levels were measured using high-pressure liquid chromatography (HPLC) with fluorometic detection. DNA was extracted from saliva and PCR amplified with fluorescent primers. Self-injury significantly increased with the number of La alleles of the 5HTTLPR and decreased with the number of Lg alleles. Self-injury in ASD may be associated with a specific genotype of the serotonin transporter gene promoter region. Future studies should continue to explore subgroups to clarify the underlying clinical and genetic heterogeneity in ASD.