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.

Linezolid-associated serotonin toxicity after escitalopram discontinuation: concomitant drug considerations.

We report a case of a hospitalised patient who developed probable serotonin toxicity shortly after the initiation of linezolid in whom the selective serotonin reuptake inhibitor (SSRI) escitalopram had been recently discontinued. On day 2 of linezolid administration, the patient reported severe anxiety and was observed to have full body jerking and twitching motions without mental status change. Notably, the patient was concomitantly receiving the antidepressant, trazodone and the benzodiazepine, clonazepam possibly affecting the severity and manifestations of serotonin toxicity. Linezolid was discontinued after 5 days and the patient's symptoms resolved. Serotonin toxicity can present with an array of symptoms and be life threatening if left unrecognised. This report highlights the clinical lessons that discontinuation of an SSRI upon initiation of linezolid does not eliminate the risk of serotonin toxicity and that other concomitant medications may worsen or improve some of the symptoms lending delay and uncertainty to the diagnosis.

[Psychosis, Intoxication or Serotonin Syndrome? - A 20-Year Old Male with Ziprasidone und Sertraline]. / Psychotische Dekompensation, Substanzkonsum oder serotonerges Syndrom?

A young male with schizophrenia, dependence syndrome (multiple drug use) and a severe depressive episode develops a serotonin syndrome with Sertraline and Ziprasidone. Making the correct diagnosis, although potentially challenging, remains vital.

Serotonin Syndrome Following an Uncomplicated Orthopedic Surgery in a Patient With Post-Traumatic Stress Disorder.

Serotonin syndrome (SS) is a potentially life-threatening adverse drug reaction that may occur in patients treated with serotonin agonist medications. Medications responsible for serotonin syndrome include commonly prescribed antidepressants, anxiolytics, analgesics, and antiemetics. Veterans with post-traumatic stress disorder (PTSD) are at risk for polypharmacy with serotoninergic medications, given their psychological comorbidities and service-related musculoskeletal injuries. The perioperative period is a particularly vulnerable time owing to the use of high-dose anxiolytics and antiemetics frequently administered in this period, and places PTSD patients at higher risk of SS. Herein, we present the first case of SS in a young veteran with combat-related PTSD following an uncomplicated L5-S1 revision discectomy that highlights the unique set of clinical challenges and dilemmas faced when treating SS in a patient with severe postsurgical pain. As we are likely to encounter increasing numbers of veterans treated for PTSD who require multiple surgical procedures to treat their service-related injuries, health care providers need to be familiar with prevention, recognition, and the clinical challenges in the management of SS in the postoperative period.

Serotonin syndrome following metaxalone overdose and therapeutic use of a selective serotonin reuptake inhibitor.

UNLABELLED: Metaxalone has only recently been associated with serotonin syndrome. The mechanism of action of this centrally acting muscle relaxant is unknown; however, the observation of serotonin syndrome in patients with metaxalone overdose suggests a role in the serotonergic pathway. CASE REPORT: (Case 1) A 29-year-old woman with overdose of metaxalone presented to the emergency department with altered mental status, seizure-like activity, hyperthermia, rigidity in the lower extremities, myoclonus, and hyperreflexia. Vital signs on arrival include blood pressure of 168/80 mmHg, heart rate of 208 beats per minute (bpm), respirations of 20/min, a temperature of 41.6° C rectally, and room air oxygen saturation of 97%. She was intubated and sedated with benzodiazepines, and actively cooled. Serum paroxetine concentration was 23 (therapeutic range: 20-200) ng/mL, and serum metaxalone concentration was 31 mcg/mL (peak plasma concentrations average 0.9 mcg/mL at 3.3 h following a single oral dose of 400 mg). (Case 2) A 27-year-old man presented to the emergency department with altered mental status, rigidity in his lower extremities, myoclonus, and hyperreflexia. Vital signs on arrival include blood pressure of 158/131 mmHg, heart rate of 126 bpm, respiratory rate of 20 breaths per minute, and temperature of 37.2°C, with oxygen saturation of 98% on room air. His medication list included metaxalone and escitalopram. He was managed aggressively with IV boluses of diazepam, in total 80 mg, in the emergency department. Serum escitalopram concentration was 24 ng/mL with a therapeutic range of 21-64 ng/mL, and serum metaxalone concentration was 58 mcg/mL. CONCLUSION: These two cases suggest that at supratherapeutic concentrations metaxalone has serotonergic effects. Severe serotonin toxicity may result from metaxalone abuse in individuals using a selective serotonin reuptake inhibitor therapeutically.

[The interaction of Rhodiola rosea and antidepressants. A case report]. / Das Zusammenwirken von Rhodiola rosea (Eisenwurz) und Antidepressiva.

OBJECTIVE: Rhodiola rosea (Russian Rhodiola/Golden Root) is a high mountain plant from the arctic regions of Europe and Asia which has the active substance phenylpropanoide. It has sedative, anti-depressive, drive-enhancing and stress-modulated properties stimulating the distribution of dopamine and serotonin; in combination with other drugs, an increase of side effects and risk profile has to be expected. METHODS: A case report is presented in order to illustrate the interaction between Rhodiola rosea and antidepressants. RESULTS: We report the case of a 68-year-old female patient with recurrent moderate depressive disorder with somatic syndrome (ICD-10 F33.11) who developed vegetative syndrome, restlessness feeling and trembling since she began to ingest Rhodiola rosea in addition to paroxetine. CONCLUSIONS: Prescribing Rhodiola rosea with paroxetine, pharmacokinetic and -dynamic interactions have to be assumed. The symptoms of the patient can be interpreted as a serotonergic syndrome. Because of its different effects, the plant is widely used. An increase of clinical relevant risks should be considered in the add-on treatments.

Ecstasy use and serotonin syndrome: a neglected danger to adolescents and young adults prescribed selective serotonin reuptake inhibitors.

BACKGROUND: At present, there are scarce clinical and basic lab data concerning the risk of acute serotonin toxicity from selective serotonin reuptake inhibitors (SSRIs) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) co-administration. The health care community can strongly benefit from efforts to address the high risks associated with serotonin syndrome from this specific drug combination. OBJECTIVE: The aim of this work is to review the risk of serotonin syndrome in adolescents and young adults prescribed with SSRIs and are concurrently using ecstasy. DATA SOURCES: An electronic search of the major behavioral science bibliographic databases (Pubmed, PsycINFO, Medline) was conducted to retrieve peer-reviewed articles, which detail the clinical characteristics, biological mechanisms and social implications of SSRIs, MDMA, and their potential synergism in causing serotonin syndrome in the pediatric and young adult population. Search terms included "serotonin syndrome", "ecstasy", "MDMA", "pediatric", and "SSRI". Additional references were incorporated from the bibliographies of these retrieved articles. RESULTS: MDMA, in combination with the widely-prescribed SSRI antidepressant class, can lead to rapid, synergistic rise of serotonin (5-HT) concentration in the central nervous system, leading to the acute medical emergency known as serotonin syndrome. This review addresses such complication through an exploration of the theoretical mechanisms and clinical manifestations of this life-threatening pharmacological interaction. CONCLUSION: The increasing incidences of recreational ecstasy use and SSRI pharmacotherapy among multiple psychiatric disorders in the adolescent population have made this an overlooked yet increasingly relevant danger, which poses a threat to public health. This can be curbed through further research, as well as greater health care provision and attention from a regulatory body owing.

Decynium-22 enhances SSRI-induced antidepressant-like effects in mice: uncovering novel targets to treat depression.

Mood disorders cause much suffering and lost productivity worldwide, compounded by the fact that many patients are not effectively treated by currently available medications. The most commonly prescribed antidepressant drugs are the selective serotonin (5-HT) reuptake inhibitors (SSRIs), which act by blocking the high-affinity 5-HT transporter (SERT). The increase in extracellular 5-HT produced by SSRIs is thought to be critical to initiate downstream events needed for therapeutic effects. A potential explanation for their limited therapeutic efficacy is the recently characterized presence of low-affinity, high-capacity transporters for 5-HT in brain [i.e., organic cation transporters (OCTs) and plasma membrane monoamine transporter], which may limit the ability of SSRIs to increase extracellular 5-HT. Decynium-22 (D-22) is a blocker of these transporters, and using this compound we uncovered a significant role for OCTs in 5-HT uptake in mice genetically modified to have reduced or no SERT expression (Baganz et al., 2008). This raised the possibility that pharmacological inactivation of D-22-sensitive transporters might enhance the neurochemical and behavioral effects of SSRIs. Here we show that in wild-type mice D-22 enhances the effects of the SSRI fluvoxamine to inhibit 5-HT clearance and to produce antidepressant-like activity. This antidepressant-like activity of D-22 was attenuated in OCT3 KO mice, whereas the effect of D-22 to inhibit 5-HT clearance in the CA3 region of hippocampus persisted. Our findings point to OCT3, as well as other D-22-sensitive transporters, as novel targets for new antidepressant drugs with improved therapeutic potential.

On categorizing gestational, birth, and neonatal complications following late pregnancy exposure to antidepressants: the prenatal antidepressant exposure syndrome.

INTRODUCTION: Late in utero exposure to antidepressants has been suspected of adversely impacting pregnancy outcome and compromising neonatal adaptation. Hence, the necessity exists to analyze published information on antidepressant use during late pregnancy to individuate potential recurrent patterns of iatrogenic complications. METHODS: Computerized searches on MEDLINE, PsycINFO, ENBASE, and Cochrane Library through February 10, 2010 were performed for selecting literature information and investigating the safety of antidepressants when used during late pregnancy. RESULTS: Antidepressant treatment during late pregnancy may increase the rates of poor pregnancy outcome and neonatal withdrawal/toxic reactions. CONCLUSIONS: Because both gestational complications and neonatal adverse events acknowledge the same etiology, the author suggests including such iatrogenic events under the definition of prenatal antidepressant exposure syndrome, in order to increase clinicians' awareness about the spectrum of risks which may concern the mother-infant pair when antidepressant treatment is deemed indispensable during late pregnancy.

Linezolid interaction with serotonin reuptake inhibitors: report of two cases and incidence assessment.

BACKGROUND: Prompted by the advent of potentially life-threatening neuromuscular symptoms following initiation of linezolid therapy in two patients receiving treatment with a serotonin reuptake inhibitor antidepressant, an evaluation was conducted to determine the incidence and characteristics of symptomatic serotonin toxicity among hospitalized patients receiving combined treatment with these medications. METHODS: Patients admitted between January 1, 2006 and August 30, 2008 who received linezolid concurrently with citalopram or escitalopram were identified and their medical records were examined. Patients were judged to have serotonin toxicity if their records contained documentation of clinical evidence adequate to fulfill requisites of the Hunter Serotonin Toxicity Criteria. Severity of serotonin-related symptoms was graded according to previously established criteria. RESULTS: During the period of observation, 24 patients received concurrent treatment with linezolid and citalopram or escitalopram. Of these, one patient (4%) treated with citalopram met evidentiary requirements for diagnosis of serotonin toxicity. The severity of symptoms in this patient was graded as mild. No evidence of serious harm related to a possible drug interaction was identified. CONCLUSIONS: Severe symptoms associated with serotonin toxicity were shown to be uncommon in patients receiving linezolid and selected serotonin reuptake inhibitors. Nonetheless, serious interaction-related toxicity has been observed at our institution and reported in detail by others. Accordingly, concurrent use of these medications is categorized as contraindicated. Alternative antimicrobial therapy should be instituted in most cases. If no suitable alternative is available, recipient patients should be hospitalized for expectant observation and rigorous monitoring.

Citalopram neuropharmacological challenge in alcohol-dependent patients and controls: pharmacogenetic, endocrine and psychobehavioral results.

AIM: Alcoholism has been associated with long-lasting alterations in LHPA (limbic-hypothalamus-pituitary-adrenal) axis function, related to a dysfunction of the serotonergic neurotransmission. Functional polymorphisms of the serotonin system were previously reported to have significant influence on serotonin-induced neuroendocrine response. The aim of the study is to investigate in a double-blind, placebo-controlled approach, whether citalopram (a selective serotonin reuptake inhibitor, SSRI) would affect LHPA axis function as measured with ACTH (adrenocorticotrophic hormone) levels representing endocrine responsivity in 11 alcohol-dependent individuals compared to 12 controls. Furthermore we wanted to know whether functional polymorphisms (5-HTTLPR and 5HT2C Ser23Cys), have any influence on this responsivity. PATIENTS AND METHODS: Alcohol-dependent inpatients aged 36.45+/-7.7 years who were detoxified, without comorbid psychiatric/medical disorders or concurrent psychotropic medications, and 12 age-matched healthy controls aged 32.50+/-6.4 years were enrolled. Subjects also reported their subjective experiences like anxiety, craving and intoxication using visual analogue scales (VAS), side-effects were assessed by the serotonin syndrome scale (SSS). Measurements were taken at 8 timepoints at 30 mins interval, from -2 (60 mins pre-application) to +6 (180 mins post-application). Patients had a mean duration of illness of 8.91+/-3.4 years, consumed a mean of 326.36+/-220.8 g alcohol/day whereas control subjects consumed a mean of 32.50+/-41.4 g alcohol/day. A 0.4 mg citalopram/kg body weight dose was administered intravenously to patients (31.96+/-4.45 mg), and to controls (34.22+/-7.65 mg). RESULTS: ACTH levels were higher for both groups in the verum compared to placebo administrations across timepoints. 5HT2C Ser23 alleles effected significantly higher ACTH responses under placebo administration but attenuated the responses under citalopram administration. Considering both groups together, no influence of 5-HTTLPR alleles was found on ACTH levels in either group under either regimen. While citalopram administration did not reduce craving in alcohol-dependent patients, it increased anxiety in patients and controls compared to placebo administration. CONCLUSION: Despite the small differences in endocrine and subjective responses between alcoholic patients and controls, the effect of SSRI on endocrine response with respect to 5HT2C functional alleles deserves further investigation in larger samples to clarify whether this genetic variant constitutes a potential risk factor for changes in neuroendocrine functioning and subsequent psychiatric disorders.

Receptor mediation of exaggerated responses to serotonin-enhancing drugs in serotonin transporter (SERT)-deficient mice.

Administration of serotonin-enhancing drugs induces a distinctive behavioral syndrome in rodents. We previously reported that mice with a targeted disruption of the serotonin transporter (SERT) display some of these behaviors spontaneously, in the absence of drug. In the current studies, we assessed the drug-induced serotonin syndrome in SERT wildtype (+/+), heterozygous (+/-) and knockout (-/-) mice. In SERT -/- mice, the monoamine oxidase inhibitor (MAOI) tranylcypromine (1mg/kg) or the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP; 80 mg/kg) led to markedly exaggerated serotonin syndrome behaviors relative to SERT +/+ mice, with an intermediate phenotype in SERT +/- mice. SERT +/+ mice developed significant serotonin syndrome behaviors only with the combination of the MAO-A/B inhibitor tranylcypromine (0.5 or 1 mg/kg) or the MAO-A-selective inhibitor clorgyline (1.2 mg/kg) plus 5-HTP. In evaluations of underlying mechanisms, pretreatment with the Htr1a receptor antagonist WAY 100635 (1 mg/kg), but not the Htr7 antagonist SB 269970 (3 mg/kg) or the Htr2a antagonist MDL 11,939 (5 mg/kg), markedly decreased the exaggerated 5-HTP-induced behaviors in SERT -/- mice. Subsequent experiments showed that the Htr1a agonist 8-OH-DPAT (1 or 2 mg/kg) elicited serotonin syndrome behaviors in a dose-dependent manner, blocked by WAY 100635 (1 mg/kg), in mice of all three genotypes, confirming the role of Htr1a receptors. The current data document markedly enhanced behavioral sensitivity to serotonin-enhancing drugs in SERT-deficient mice. These studies also show that the exaggerated behavioral responses observed in SERT +/- and -/- mice are mediated by postsynaptic Htr1a receptors, and suggest intact postsynaptic Htr1a function in SERT -/- mice.

Reversal of haloperidol-induced tardive vacuous chewing movements and supersensitive somatodendritic serotonergic response by buspirone in rats.

Tardive dyskinesia (TD), a syndrome of involuntary hyperkinesias in the orofacial region that develops in patients chronically treated with neuroleptic agents is a major limitation of the therapy. Rats chronically treated with haloperidol exhibit vacuous chewing movements (VCMs) with the twitching of facial musculature and tongue protrusion. The syndrome is widely used as an animal model of TD. Evidence suggests a role of 5-hydroxytryptamine (5-HT; serotonin)-1A receptors in the pathogenesis and treatment of TD because repeated administration of haloperidol resulted in an increase in the effectiveness of 5-HT-1A receptors while drugs with agonist activity at 5-HT-1A receptors could attenuate haloperidol-induced VCMs. The present study was designed to test the hypothesis that a decrease in the responsiveness of somatodendritic 5-HT-1A receptors by the coadministration of buspirone could reverse the induction of VCMs and supersensitivity at 5-HT-1A receptors by haloperidol. Rats treated with haloperidol at a dose of 1 mg/kg twice a day for 2 weeks displayed VCMs with twitching of facial musculature that increased in a time dependent manner as the treatment continued to 5 weeks. Coadministration of buspirone attenuated haloperidol-induced VCMs after 2 weeks and completely prevented it after 5 weeks. The intensity of 8-hydroxy-2-di (n-propylamino) tetralin (8-OH-DPAT)-induced locomotion was greater in saline+haloperidol injected animals but not in buspirone+haloperidol injected animals. 8-OH-DPAT-induced decreases of 5-HT metabolism were greater in saline+haloperidol injected animals but not in buspirone+haloperidol injected animals. It is suggested that an impaired somatodendritic 5-HT-1A receptor dependent response is a major contributing factor in the pathophysiology of TD and a normalization of the somatodendritic response by drugs may help extending therapeutics in schizophrenia.

Treatment of acute mania with ambient air anionization: variants of climactic heat stress and serotonin syndrome.

High concentrations of ambient anions (O2-) were used to augment treatment for 20 acutely manic male patients. Anions were produced by an anion generator in a sealed room. A double-blind crossover design was used, and responses were evaluated with the Brief Psychiatric Rating Scale by 2 blinded raters. This produced a significant antimanic effect: total rating scores declined with anion treatment. Presham and postsham total scores for these 5 were 31.3 and 31.6, respectively. Pretreatment and posttreatment total scores were 31.6 and 26.3, respectively. Previous research indicates a role for serotonin in producing this antimanic effect.

Serotonin syndrome in a case of depression with various somatic symptoms: the difficulty in differential diagnosis.

A 65-year-old female patient with major depressive disorder suffered from clonus, shivering and impaired visual acuity after 20 mg/day of paroxetine administration. The symptoms were initially regarded as further manifestations of her somatic symptoms of depression, and paroxetine was increased to 30 mg/day resulting in frequent clonus, increased shivering, serious dysarthria, ongoing impairment in visual acuity and agitation. These symptoms subsided upon paroxetine discontinuation. Ten mg/day of paroxetine rechallenge provoked dysarthria, tremor and headache, but these symptoms improved again upon paroxetine discontinuation. These findings indicate that the patient's symptoms were not somatic in origin but were in fact the symptoms of serotonin syndrome. In conclusion, the present case suggests the difficulty in diagnosing serotonin syndrome in a patient with somatic symptoms.