Materiały źródłowe

• #1 Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6734608/

  Serotonin syndrome (SS) (also referred to as serotonin toxicity) is a potentially life-threatening drug-induced toxidrome associated with increased serotonergic activity in both the peripheral (PNS) and central nervous systems (CNS). […] It is characterised by a dose-relevant spectrum of clinical findings related to the level of free serotonin (5-hydroxytryptamine [5-HT]), or 5-HT receptor activation (predominantly the 5-HT1A and 5-HT2A subtypes), which include neuromuscular abnormalities, autonomic hyperactivity, and mental state changes. […] The combination of a monoamine oxidase inhibitor (MAOI), in particular MAO-A inhibitors that preferentially inhibit the metabolism of 5-HT, with serotonergic drugs is especially dangerous, and may lead to the most severe form of the syndrome, and occasionally death.

• #2

  https://journalofmedula.com/index.php/medula/article/view/186

  Serotonin (SS) syndrome (also referred to as serotonin toxicity) is a potentially life-threatening drug-induced toxidrome associated with increased serotonergic activity in the peripheral (PNS) and central nervous system (CNS). […] It is characterized by a dose-relevant spectrum of clinical findings associated with levels of free serotonin (5-hydroxytryptamine [5-HT]), or activation of 5-HT receptors (especially the 5-HT1A and 5-HT2A subtypes), which include neuromuscular disorders, autonomic hyperactivity, and altered mental states. […] Although many drugs have been implicated in serotonin syndrome, life-threatening cases generally occur only when a monoamine oxidase inhibitor is combined with a selective serotonin re-uptake inhibitor. or non-selective. […] In this review, the pathophysiology, clinical features, drugs involved and diagnosis of serotonin syndrome are discussed. […] The Serotonin Syndrome: From Molecular Mechanisms to Clinical Practice.

• #3 Cyprohepta-doubts? Determining the Role of Cyproheptadine in Serotonin Syndrome | Poison Control | University of Utah Health

  https://poisoncontrol.utah.edu/news/2024/08/cyprohepta-doubts-determining-role-of-cyproheptadine-serotonin-syndrome

  Serotonin syndrome (or serotonin toxicity) is caused by a substantial increase in synaptic serotonin (5-HT), resulting in mild manifestations such as akathisia, increased gastrointestinal activity, and tremors, to more severe and life-threatening presentations such as sustained muscular hypertonicity, hyperthermia, seizures, and hallucinations. […] There are 14 5-HT receptor subtypes that have been identified thus far; however, overstimulation of 5-HT1A and/or 5-HT2A receptors are associated with development of serotonin syndrome. The most severe manifestations (rigidity, hyperthermia, hallucinations) are mediated by 5-HT2A receptors. […] Both 5-HT1A and 5-HT2A have different affinities for serotonin and comodulate each others activity, making it difficult to generate a succinct pathophysiologic model.

• #4 Serotonin syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Serotonin_syndrome

  Serotonin syndrome is typically caused by the use of two or more serotonergic medications or drugs. […] It is a predictable consequence of excess serotonin on the central nervous system. […] The syndrome is caused by increased serotonin in the CNS. […] It was originally suspected that agonism of 5-HT1A receptors in central grey nuclei and the medulla oblongata was responsible for the development of the syndrome. […] Further study has determined that overstimulation of primarily the 5-HT2A receptors appears to contribute substantially to the condition. […] Additionally, noradrenergic CNS hyperactivity may play a role as CNS norepinephrine concentrations are increased in SS and levels appear to correlate with the clinical outcome. […] Serotonin toxicity is more pronounced following supra-therapeutic doses and overdoses, and they merge in a continuum with the toxic effects of overdose.

• #5 Serotonin Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482377/

  Serotonin syndrome results when a clinical manifestation results from modification to the serotonergic transmission system. […] The imbalance is usually seen within 24 hours of either the intake of a new serotonergic agent, dose change of a prior serotonergic agent, or any other change impacting the metabolism of prior serotonergic homeostasis. […] Serotonin syndrome may occur as a consequence of therapeutic medication use, illicit drug use, or intentional overdose. […] Multiple substances may precipitate serotonin toxicity by a variety of mechanisms. […] Broadly, these can be considered by the following categories: 1) increased serotonin synthesis, 2) inhibiting serotonin metabolism or breakdown, 3) increased exocytosis of serotonin from presynaptic neurons, 4) increased activation of postsynaptic serotonin receptors, 5) antagonism of 5-HT2A receptors, 6) inhibiting serotonin reuptake from the synaptic cleft.

• #5 Serotonin Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482377/

  Although the use of a single agent precipitates many cases of serotonin syndrome, drug interactions can perpetuate risk and potentially increase the severity of serotonin syndrome. […] When serotonin syndrome is present, excessive stimulation of 5-HT receptors leads to pathological changes in the affected target organs. […] The etiology of serotonin syndrome results from cellular toxicity of excess target post-synaptic 5-HT stimulation.

• #6 Serotonin syndrome (serotonin toxicity) – UpToDate

  https://www.uptodate.com/contents/serotonin-syndrome-serotonin-toxicity/print

  The diagnosis of serotonin syndrome is made solely on clinical grounds. Therefore, a detailed history and thorough physical and neurologic examinations are essential. […] Serotonin syndrome encompasses a spectrum of disease where the intensity of clinical findings is thought to reflect the degree of serotonergic activity. […] The majority of cases of serotonin syndrome present within 24 hours, and most within six hours, of a change in dose or initiation of a drug. […] The Hunter Criteria are the most accurate diagnostic criteria; a patient must have the presence of a serotonergic agent and meet one of the following conditions: spontaneous clonus, inducible clonus plus agitation or diaphoresis, ocular clonus plus agitation or diaphoresis, tremor plus hyperreflexia, hypertonia plus temperature above 38°C plus ocular clonus or inducible clonus. […] Serotonin syndrome is typically not a diagnosis of exclusion if the Hunter Criteria are met.

• #6 Serotonin syndrome (serotonin toxicity) – UpToDate

  https://www.uptodate.com/contents/serotonin-syndrome-serotonin-toxicity/print

  Serotonin syndrome, also referred to as serotonin toxicity, is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system. It is seen with therapeutic medication use, inadvertent interactions between drugs, and intentional self-poisoning. […] Serotonin syndrome may involve a spectrum of clinical findings, which often include mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. […] Stimulation of the postsynaptic 5-HT1A and 5-HT2A receptors has been implicated in serotonin syndrome, but no single receptor is solely responsible. […] Serotonin syndrome may result from any combination of drugs that has the net effect of increasing serotonergic neurotransmission. […] Episodes of serotonin syndrome involving a monoamine oxidase inhibitor (MAOI) may be more severe and more often lead to adverse outcomes, including death.

• #7 Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6734608/

  This review describes our current understanding of the pathophysiology, clinical presentation and management of SS, and summarises some of the drugs and interactions that may precipitate the condition. […] The cells of the raphe nuclei located in the midline of brainstem (from the midbrain to the medulla) are the source of neuronal 5-HT in the CNS. […] The initial and rate-limiting step in the biosynthesis of 5-HT, the decarboxylation and hydroxylation of the essential amino acid tryptophan, is catalysed by TPH. […] Serotonin syndrome can result from agonism (either from increased concentrations of 5-HT or medications that act directly as receptor agonists), and/or antagonism, of varying combinations of the 5-HT receptor subtypes. […] The classical view, mainly supported by evidence from animal studies (with few studies in humans), is that the life-threatening effects of SS, in particular, severe hypertonicity and hyperthermia, are primarily mediated by the activation of 5-HT2A receptors at higher serotonin concentrations. […] Taken together, these observations are consistent with the hypothesis that SS is a dose-dependent spectrum of adverse effects mediated by a combination of elevation of endogenous intrasynaptic or extrasynaptic serotonins and direct or indirect activation of 5-HT receptors.

• #8 Serotonin syndrome – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/serotonin-syndrome/symptoms-causes/syc-20354758

  Serotonin syndrome is a serious drug reaction. It is caused by medications that build up high levels of serotonin in the body. […] Excessive accumulation of serotonin in the body creates the symptoms of serotonin syndrome. […] Although it’s possible that taking just one drug that increases serotonin levels can cause serotonin syndrome in some people, this condition occurs most often when people combine certain medications. […] For example, serotonin syndrome may occur if you take an antidepressant with a migraine medication. It may also occur if you take an antidepressant with an opioid pain medication. […] Another cause of serotonin syndrome is intentional overdose of antidepressant medications. […] A number of over-the-counter and prescription drugs may be associated with serotonin syndrome, especially antidepressants. Illicit drugs and dietary supplements also may be associated with the condition. […] Serotonin plays a role in regulating the digestive process, blood flow and breathing.

• #9 Detecting and Managing Serotonin Syndrome – Psychiatry Advisor

  https://www.psychiatryadvisor.com/features/detecting-and-managing-serotonin-syndrome/

  Central serotonin, which is present in the midline raphe nuclei of the brainstem, functions to inhibit excitatory transmission. It also plays an important role in modulating wakefulness, attention, mood, affective and sexual behaviors, appetite, thermoregulation, motor tone, migraine, emesis, nociception, and aggression.

• #9 Detecting and Managing Serotonin Syndrome – Psychiatry Advisor

  https://www.psychiatryadvisor.com/features/detecting-and-managing-serotonin-syndrome/

  Serotonin syndrome is caused by drugs that either affect serotonin metabolism or act as direct serotonin receptor agonists, or both, and takes place in the setting of excess stimulation of central and peripheral serotonin receptors. […] Drugs that can cause serotonin syndrome do so by inhibiting serotonin reuptake, increasing serotonin synthesis, decreasing serotonin metabolism, increasing serotonin release, or activating serotonergic receptors. […] The inhibition of cytochrome P450 enzymes by SSRIs can result in the accumulation of certain serotonergic drugs that are usually metabolized by these enzymes, leading to an exacerbation loop in which the SSRI inhibits the metabolism of a certain drug, which in turn increases serotonergic activity. […] Serotonin plays an essential and far-reaching role in multiple systems and acts both peripherally and centrally. Peripheral serotonin is produced primarily in the gastrointestinal tract and is responsible for stimulating vasoconstriction, uterine contraction, bronchoconstriction, gastrointestinal motility, and platelet aggregation.

• #10 August 26, 2022: What are the pathophysiology and clinical manifestations of Serotonin Syndrome? (and welcome to the Question of the Week) | Tennessee Poison Center | FREE 24/7 Poison Help Hotline 800.222.1222

  https://www.vumc.org/poison-control/toxicology-question-week/august-26-2022-what-are-pathophysiology-and-clinical-manifestations

  Serotonin syndrome (SS) is caused by increased intra-synaptic serotonin (5-hydroxytyrptamine or 5-HT) in the Central nervous system (CNS). […] Drugs that cause 5-HT toxicity either increase pre-synaptic 5-HT by increasing the production and inhibiting the metabolism of 5-HT OR they amplify serotonergic effects by increasing 5-HT release into the synapse and inhibiting uptake from the synapse. […] It is important to make the diagnosis of SS in a setting where there is a clear serotonergic pathophysiological mechanism. […] Clinically, there is a spectrum (from mild to severe) of toxicity related to increasing CNS serotonin concentrations.

• #11 Prevention, Diagnosis, and Management of Serotonin Syndrome | AAFP

  https://www.aafp.org/pubs/afp/issues/2010/0501/p1139.html

  Serotonin syndrome is a potentially life-threatening condition caused by excessive serotonergic activity in the nervous system. It is characterized by mental status changes, autonomic instability, and neuromuscular hyperactivity. […] Serotonin syndrome is a potentially life-threatening set of symptoms caused by serotonin toxicity, and usually involves a combination of drugs that increase serotonergic transmission. […] Potential mechanisms of serotonin syndrome include increased serotonin synthesis or release; reduced serotonin uptake or metabolism; and direct serotonin receptor activation. […] Serotonin syndrome can occur with any increase in serotonergic neurotransmission. The majority of cases are iatrogenic from synergistic medication use, although cases of intentional self-poisoning with serotonergic agents also occur. […] Another mechanism for development of serotonin syndrome is the addition of drugs that inhibit the cytochrome P450 2D6 and/or 3A4 (CYP3A4) isoenzymes to therapeutic regimens of selective serotonin reuptake inhibitors (SSRIs).

• #12 The Serotonin Syndrome: From Molecular Mechanisms to Clinical Practice

  https://www.mdpi.com/1422-0067/20/9/2288

  The serotonin syndrome is a medication-induced condition resulting from serotonergic hyperactivity, usually involving antidepressant medications. […] Excessive synaptic stimulation of 5-HT2A receptors results in autonomic and neuromuscular aberrations with potentially life-threatening consequences. […] The exact pathophysiologic mechanism for SS has been difficult to elucidate, partially due to the multitude of known serotonin receptors classes and subtypes. […] Although serotonin is the primary ligand for all of these receptors, only the stimulation of certain receptor subtypes leads to SS. […] The most common cause of SS is polypharmacy causing (1) inhibition of serotonin uptake, (2) decreased serotonin metabolism, (3) increased serotonin synthesis, (4) increased serotonin release, and/or (5) activation of serotonergic receptors.

• #12 The Serotonin Syndrome: From Molecular Mechanisms to Clinical Practice

  https://www.mdpi.com/1422-0067/20/9/2288

  Given the centrality of serotonin excess in precipitating the disease, the term ‘serotonin toxicity’ has been advocated by some in lieu of ‘serotonin syndrome,’ in order to more accurately describe the disease pathophysiology. […] The combination of an MAOI with an SSRI, and SNRI or another MAOI is the most dangerous combination and the most likely to result in SS. […] Increased production of serotonin (through an overabundance of the precursor molecule L-tryptophan) as well as decreased metabolism of serotonin (by the administration of MAOI), may each cause receptor overstimulation and SS. […] The role of genetic polymorphisms affecting the 5-HT2A receptor is the focus of current research in neuropsychiatric disorders. […] It appears that certain individuals with known polymorphisms at the T102C site of the 5-HT2A receptor gene may be predisposed to developing SS. […] Individual variations in serotonin metabolism by CYPs have also been proposed to contribute to SS susceptibility. […] SERT proteins are critical to the termination of synaptic serotonergic activity.

• #13 Serotonin syndrome – EMCrit Project

  https://emcrit.org/ibcc/serotonin/

  There are seven classes of serotonin (5-HT) receptors: 5-HT-1 through 5-HT-7. There are further subdivisions within classes (e.g., 5-HT-1a through 5-HT-1f). […] Based on animal models, 5-HT-2a receptors seem to be involved in the more dangerous symptoms of serotonin syndrome (e.g., hyperthermia and increased muscle tone). Alternatively, 5-HT-1a receptors may contribute to some of the milder symptoms, such as anxiety and hyperactivity. […] Ondansetron triggers serotonin syndrome despite the fact that it blocks 5-HT-3 receptors. This might be explained because due to blockade of 5-HT-3 receptors, there may be more serotonin available to stimulate 5-HT1a and 5-HT2a receptors. […] Serotonin syndrome can occur for a variety of reasons: (1) Overdose of a serotonergic medication (e.g., SSRI or illicits). Serotonin syndrome occurs in ~15% of SSRI overdoses.

• #13 Serotonin syndrome – EMCrit Project

  https://emcrit.org/ibcc/serotonin/

  (2) Inadvertent interaction between several serotonergic medications: 2a) Addition of drugs which are directly serotonergic. 2b) Addition of drugs which cause drug-drug interactions, increasing the levels of other serotonergic medications (i.e. the new medication doesn’t necessarily need to directly affect serotonin signaling). […] (3) Renal dysfunction may cause accumulation of serotonergic medications (e.g., sertraline). […] In practice, most episodes of serotonin syndrome result from multiple drugs interacting together. When in doubt, enter the whole medication list into a program such as the Medscape drug interaction program; this may reveal unexpected interactions. […] Two mechanisms may explain efficacy in serotonin syndrome: (1) Dexmedetomidine stimulates alpha-2C receptors in the striatum, thereby modulating serotonin levels. It appears that alpha-2 receptors located on serotonergic terminal axons may inhibit serotonin release.

• #14 Serotonin syndrome: a spectrum of toxicity | BJPsych Advances | Cambridge Core

  https://www.cambridge.org/core/journals/bjpsych-advances/article/serotonin-syndrome-a-spectrum-of-toxicity/BB07FCAF5DC69DF5FFC0AEB113147A9E

  There appears to be a sequential stimulatory effect in the presence of excess serotonin, which corresponds roughly to the spectrum of increasing toxicity. This may be observed clinically when the more abundant 5-HT1A receptors are stimulated at lower levels, accounting for some of the less severe symptoms, including, initially, hypothermia. Overstimulation of 5-HT2A receptors occurs at much higher serotonin concentrations; this subtype is now generally considered to be the mediator of the more severe, toxic aspects of serotonin syndrome, with marked pyrexia and neuromuscular hyperactivity. Not only is there a complex interplay between these two receptors, but also very high serotonin levels potentiate glutamatergic, noradrenergic and dopaminergic pathways, with progression to extreme toxic states; such toxicity may be precipitated subsequent to the ingestion of cocaine or 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy).

• #14 Serotonin syndrome: a spectrum of toxicity | BJPsych Advances | Cambridge Core

  https://www.cambridge.org/core/journals/bjpsych-advances/article/serotonin-syndrome-a-spectrum-of-toxicity/BB07FCAF5DC69DF5FFC0AEB113147A9E

  There is support for the theory that a particular concentration of serotonin is a prerequisite for the development of serotonin syndrome. However, there is considerable inter-individual variation and this variability has its basis in genetic factors, which include polymorphisms of CYP2D6, SERT or the serotonin receptors themselves.

• #14 Serotonin syndrome: a spectrum of toxicity | BJPsych Advances | Cambridge Core

  https://www.cambridge.org/core/journals/bjpsych-advances/article/serotonin-syndrome-a-spectrum-of-toxicity/BB07FCAF5DC69DF5FFC0AEB113147A9E

  Serotonin syndrome, variously described as serotonin toxicity or serotonin toxidrome, is often an iatrogenic adverse drug reaction. In this article serotonin syndrome refers to the broad spectrum of clinical presentations in humans secondary to a relative or absolute increase in serotonin levels in the central and peripheral nervous system. […] Presynaptic neurons in the raphe nuclei, largely restricted to the basal plate of the pons and medulla, synthesise and release serotonin. The serotonin transporter (SERT) located on these cells plays a major role in reabsorption of much of this; some of this intrasynaptic serotonin also binds to autoreceptors, triggering a negative feedback loop, thus modulating its own release. Serotonergic medications through different mechanisms act on various steps of this process: SSRIs block the action of SERT, thereby increasing the available serotonin in the synaptic space by limiting the recycling process. Increased serotonin neurotransmission results, mainly at postsynaptic 5-HT1A and 5-HT2A receptors; currently both these subtypes, as well as peripheral and central serotonin, are implicated in the wide range of symptoms and signs in serotonin syndrome.

• #15 Methylene Blue and the Risk of Serotonin Toxicity – Anesthesia Patient Safety Foundation

  https://www.apsf.org/article/methylene-blue-and-the-risk-of-serotonin-toxicity/

  Methylene blue is administered intravenously by anesthesia providers for a variety of clinical uses and may be used with increasing frequency as an intraoperative urologic marker dye due to an indefinite nationwide shortage of indigo carmine. It is a potent monoamine oxidase (MAO) inhibitor, and in combination with other serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs), MB can produce serotonin toxicity in the perioperative period. […] Serotonin toxicity is a result of inappropriately high levels of synaptic serotonin and its severity directly relates to the concentration of serotonin (5-HT) in the synaptic spaces in nervous tissue. Both serotonin releasers like methamphetamine and serotonin reuptake inhibitors (SRIs) have the potential to induce severe serotonin toxicity when administered with MAO inhibitors. Selective and non-selective serotonin reuptake inhibitors increase serotonin by preventing its clearance from the intraneuronal synaptic space. MAO inhibitors prevent intraneuronal metabolism of serotonin, leading to increased release of serotonin from neurons. SRIs by themselves, even if taken in overdose, do not usually precipitate the severe form of serotonin toxicity. However, normal therapeutic SRI doses along with even a single dose of an MAOI like methylene blue may lead to serotonin toxicity as a result of the combination of increased 5-HT release and reduced synaptic 5-HT clearance.

• #16 Serotonin syndrome | MedLink Neurology

  https://www.medlink.com/articles/serotonin-syndrome-1

  The mechanism underlying serotonin syndrome following interaction between a MAO inhibitor and a serotonin reuptake inhibitor is that MAO can no longer perform its function of degrading serotonin. […] The recreational drug ecstasy stimulates the release and inhibits the reuptake of serotonin. […] Central 5-hydroxytryptamine 1A receptor is not the only receptor subtype that is involved in the etiology of serotonin syndrome. […] The appearance of the most severe serotonin syndrome symptoms may be related to the agonism of these receptors, as its stimulation can cause platelet aggregation, bronchoconstriction, vasoconstriction (and consequent hypertension), and behavioral cognitive changes characteristic of this syndrome. […] Other factors that may contribute are the endogenous as well as iatrogenic deficits in the peripheral 5-hydroxytryptamine metabolism, the activation of several 5-hydroxytryptamine subtypes, and a stimulus for the release of 5-hydroxytryptamine.

• #16 Serotonin syndrome | MedLink Neurology

  https://www.medlink.com/articles/serotonin-syndrome-1

  A patient’s genetic profile can amplify exposure risk, as many serotonergic drugs are metabolized by CYP450 enzymes and functions of these enzymes may be altered polymorphisms. […] Predisposing factors for the development of serotonin syndrome are as follows: inherited disorders, low endogenous MAO inhibitor activity, decreased metabolism of serotonergic drugs, cardiovascular diseases: hypertension and hyperlipidemia, pharmacogenetic factors. […] Acquired diseases include liver diseases: hepatitis, pulmonary disease, cardiovascular disease.

• #17 SSRIs and Serotonin Syndrome

  https://www.uspharmacist.com/article/ssris-and-serotonin-syndrome

  Serotonin syndrome is a potentially life-threatening adverse drug reaction resulting from excess serotonergic activity. It is characterized by mental, autonomic, and neuromuscular changes attributed largely to changes in serotonin sensitivity (receptor hyperstimulation) in the central and peripheral nervous systems. […] Hyperstimulation of the postsynaptic serotonin receptors remains poorly understood. However, increased serotonin production via serotonin precursors, inhibition of serotonin metabolism (monoamine oxidase inhibitors [MAOIs]), increased serotonin release, stimulation of serotonin receptors, and SSRIs all play a role in the mechanisms of serotonin syndrome. […] Increasing the dose of L-tryptophan will proportionally increase the amount of serotonin synthesis, resulting in an overload of serotonin vesicles, which will then flood the synaptic cleft. The excess serotonin released results in hypersensitivity of the postsynaptic serotonin receptors, eliciting symptoms of serotonin syndrome. […] SSRIs obstruct the reuptake of serotonin by blocking the presynaptic neuron receptors. An SSRI overload therefore increases the concentration of serotonin in the synaptic cleft, resulting in inhibition of the negative feedback system of serotonin and thus in symptoms of serotonin syndrome.

• #18 Drug-Induced Serotonin Syndrome

  https://www.uspharmacist.com/article/drug-induced-serotonin-syndrome

  A potentially lethal condition, serotonin syndrome (SS) is caused most often when certain antidepressant agents are taken concurrently with other drugs that modulate synaptic serotonin levels. […] SS may occur when central and peripheral serotonin receptors are overstimulated through the action of antidepressant medications or drugs of abuse. […] Mechanisms that cause SS include increased serotonin production, inhibition of serotonin reuptake, inhibition of serotonin metabolism, increased serotonin release, and stimulation of serotonin receptors. […] Certain drugs may affect serotonin levels through more than one mechanism. […] One substance that increases serotonin production is the dietary supplement L-tryptophan. This serotonin precursor has been implicated in SS. […] Drugs that inhibit serotonin reuptake include chlorpheniramine; cyclobenzaprine; dextromethorphan (e.g., Robitussin DM); meperidine; methadone; pentazocine; sibutramine; SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine); St. John’s wort; tramadol; trazodone; and tricyclic antidepressants (e.g., clomipramine, imipramine).

• #18 Drug-Induced Serotonin Syndrome

  https://www.uspharmacist.com/article/drug-induced-serotonin-syndrome

  This category includes isocarboxazid, linezolid, methylene blue, phenelzine, selegiline, and tranylcypromine. […] Some drugs that increase serotonin release are dextromethorphan, meperidine, methadone, methylenedioxymethamphetamine (also known as MDMA or ecstasy), and mirtazapine. […] Drugs that stimulate serotonin receptors include buspirone; dihydroergotamine; lithium; lysergic acid diethylamide (LSD); meperidine; metoclopramide; and triptans (e.g, sumatriptan).

• #19 Experimental Serotonin Syndrome: Effects of GABA-ergic Medications and 5-HT2-Antagonists | IntechOpen

  https://www.intechopen.com/chapters/75335

  Experimental studies in animal models of serotonin syndrome have shown that other neurotransmitters such as noradrenaline (NA), N-methyl-D-aspartate (NMDA), gamma-aminobutyric acid (GABA) and dopamine may also play a role in the development of serotonin syndrome but their role is not fully understood. […] It is shown that in serotonin syndrome CNS serotonin levels increase between 40 and 140 times. At the same time, dopamine levels are increased 10 to 44 times. […] Other studies indicate overactivation of the noradrenergic system with a rise in NA levels up to 15.9 times in serotonin syndrome, but the cause remains unknown. […] The degree of NA increase may be related to the prognosis of serotonin syndrome, although it is not fully understood. […] The analysis of Haberzettl et al. showed that the most common autonomic dysregulation manifestation observed in rats with serotonin syndrome is the change in the body temperature. The hyperthermic reaction observed is thought to be mainly related to the activation of 5-HT2A receptors.

• #19 Experimental Serotonin Syndrome: Effects of GABA-ergic Medications and 5-HT2-Antagonists | IntechOpen

  https://www.intechopen.com/chapters/75335

  In summary pretreatment with diazepam (5 mg/kg i.p.), sodium valproate (300 mg/kg i.p.), and vigabatrin (300 mg/kg i.p.) decreased hyperthermia in different experimental models of the serotonin syndrome. These results suggest involvement of interactions between GABA-ergic and serotonergic systems in the processes of thermoregulation. […] From all data reported thus far, it can be concluded that 5-HT2 receptors and the GABA system are strongly involved in the development of hyperthermia in serotonin syndrome and the mortality associated with it.

• #20 Recognition and Management of Serotonin Toxidrome in the Emergency Department—Case Based Review

  https://www.mdpi.com/2075-4426/12/12/2069

  Serotonin syndrome (SS) is a clinical toxidrome with high variability in clinical practice. It develops due to increased serotonin levels in the central nervous system. […] Serotonin syndrome (SS) is the result of increased serotonin levels in the central nervous system. […] Increased levels of serotonin in the CNS represent the foundation for SS development. SS is the result of serotonin over-stimulation through drug agonism, antagonism or a combination of both, which may develop after an overdose of this medication. […] Multiple pathophysiological pathways are probable in our case. The use of serotonin receptor agonists, namely 5-HT1A, and serotonin reuptake inhibitors as chronic treatment led to increased levels of serotonin the CNS. The superimposed overdose with an atypical antipsychotic, with an affinity for 5-HT2A/2C, 5-HT3 and 5-HT6 receptors, escalated serotonin concentrations and precipitated the clinical syndrome.

• #21 Changes in Intensity of Serotonin Syndrome Caused by Adverse Interaction between Monoamine Oxidase Inhibitors and Serotonin Reuptake Blockers | Neuropsychopharmacology

  https://www.nature.com/articles/npp201449

  Drug interaction between inhibitors of monoamine oxidase (MAOIs) and selective serotonin (5-hydroxytryptamine, 5-HT) reuptake (SSRIs) induces serotonin syndrome, which is usually mild but occasionally severe in intensity. […] However, little is known about neural mechanisms responsible for the syndrome induction and intensification. In this study, we hypothesized that the syndrome induction and intensity utilize two different but inter-related mechanisms. Serotonin syndrome is elicited by excessive 5-HT in the brain (presynaptic mechanism), whereas syndrome intensity is attributed to neural circuits involving 5-HT2A and NMDA receptors (postsynaptic mechanism). […] The syndrome induction is dependent on 5HT levels accumulated extracellularly. […] The syndrome intensification depends on the responsivity of postsynaptic 5-HT2A receptors.

• #21 Changes in Intensity of Serotonin Syndrome Caused by Adverse Interaction between Monoamine Oxidase Inhibitors and Serotonin Reuptake Blockers | Neuropsychopharmacology

  https://www.nature.com/articles/npp201449

  Therefore, we concluded that pretreatments of MAOI pharmacologically alter the activity of postsynaptic circuits, which is responsible for changes in syndrome intensity. […] Our data suggest that the 5-HT2A receptor upregulation may be the main mechanism underlying the intensified response to excessive 5-HT. This is in line with the general framework demonstrating that 5-HT2A receptors are the key mediator for the development of severe and malignant syndrome. […] Thus, it is likely that the syndrome induction and subsequently the syndrome intensity involve two different sets of neural mechanisms. Accordingly, the syndrome can be induced or initiated when 5-HT efflux in response to 5-HT-promoting drugs exceeds a tolerable limit in the brain (presynaptic mechanisms). In contrast, the syndrome intensity may be mild, moderate, or severe, depending on responsivity of postsynaptic 5-HT2A and NMDA receptors in neural circuits (postsynaptic mechanism).

• #22 A New Look at Serotonin Syndrome Risk Stratification | Wolters Kluwer

  https://www.wolterskluwer.com/en/expert-insights/a-new-look-at-serotonin-syndrome-risk-stratification

  Serotonin syndrome or serotonin toxicity (SS/ST) is a potentially life-threatening condition that results from excessive serotonergic stimulation within the central nervous system. […] What is important for clinicians to recognize, is that SS/ST is not an idiopathic drug reaction. Rather, it is a predictable consequence of excessive serotonergic stimulation most commonly caused by medications. […] Many drugs possess an ability to enhance central serotonergic activity. This occurs via several known mechanisms including: Inhibition of serotonin reuptake, Increased release of stored serotonin, Decreased serotonin metabolism, Direct serotonin receptor stimulation. […] The concomitant use of two or more of these agents, or use of a single agent at high or supratherapeutic doses, will increase the risk for the development of SS/ST.

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