Serotonin, or 5-hydroxytryptamine (5-HT), is a chemical neurotransmitter in the central and peripheral nervous systems that was discovered in 1940s. ¹ O ne of the most widely studied chemical messengers , serotonin influences many physiologic functions in humans, including regulation of mood, sleep-wake cycle, appetite suppression, memory, emesis, breathing, cognition, blood coagulation, libido, and many other functions. ² In 1992, Insel and colleagues first document ed the toxic symptoms produced from too much serotonin in the central and peripheral nervous systems , naming it serotonin syndrome. ^3,4

Serotonin Syndrome

Experts in the fields of psychiatry, pharmacy, and toxicology refer to these symptoms as serotonin toxicity, because the symptoms result from the toxic effects of too much serotonin.^5-9 The term toxicity instead of syndrome “clarifies that it is a form of poisoning, just as lithium toxicity is a form of poisoning.”⁶ Therefore, serotonin toxicity (ST) can develop with administration of any serotonin-enhancing medication, including therapeutic use, polypharmacy, or accidental/intentional drug overdose.

The incidence of ST has increased over the past decade.^5,6,10,11 Several reasons explain this increase: (1) ST mirrors the increase in depression in the US populations^10,12,13; (2) There has been an increase in off-label antidepressant prescribing by both primary care and mental health providers^14-16; (3) the increased use of illicit drugs¹³; (4) an increase in suicide attempts with antidepressants¹⁷; and (5) increased use of opioids for pain management, including both prescription and illicit use.^11,14 This paper reviews the potential lethal combinations of commonly prescribed medications used to treat both veteran and nonveteran patients and includes the latest information on offending medications; a presentation of symptoms from in utero to adult; diagnostic criteria; and recommended treatments.

The Veterans Health Administration (VHA) and non-VHA health care providers can play a key role in identifying and preventing serotonin syndrome/ST by keeping abreast of the latest updates of potentially lethal drug combinations. Commonly prescribed medications with the potential for a reaction include antidepressants, anxiolytics, pain medications, antinausea medications, herbal medications, and over-the-counter (OTC) medications, such as cough suppressants. Patients may be at increased risk for ST due to the growth of polypharmacy management of comorbidities.

Antidepressants

Over the past decade, antidepressant use has increased substantially in the US,United Kingdom, and Canada.¹⁴ Also the types of antidepressants prescribed has changed and been replaced with the newer agents. The selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) have replaced the older tricyclics (TCAs) and monoamine oxidase inhibitors (MAOIs) as first-line treatments for depression due to their improved comparative efficacy, reduced mortality following overdose, adverse effects (AEs) that are more tolerable for most patients, and the SSRIs have no anticholinergic properties (except paroxetine) (Table 1).¹⁸

In 2017 the National Institute of Mental Health reported that about 17 million adults and 3 million adolescents (aged 11-18 years) experienced at least 1 episode of major depression.¹⁹ About 40% of US veterans will experience depression, which is 3 times higher than the rate of the general US population.¹² A random sampling survey conducted of about 17,000 active-duty service members by the US Department of Defense (DoD) from November 2015 to April 2016 revealed 9.4% reported depression.²⁰ Antidepressant usage in the US and among veterans continues to increase.^12,16 In 2018, the list of top US prescribed drugs, included sertraline (14th), citalopram (21st), trazodone (24th), and escitalopram (26th).²¹ Antidepressant prescribing in the US increased 18% from 2012 to 2017.²² This trend also continues within the military with a 40% increase of antidepressant use in the past decade.¹⁶

One reason for the increase in antidepressant use is off-label prescribing.^14,23 A sampling of about 2 billion psychiatric outpatient visits in a western portion of the US found 12.9% of the prescriptions filled were off-label.¹⁵ In Minnesota, off-label prescribing of antidepressants was found to contribute to an increase in drug interactions in elderly nursing home residents.²⁴ An investigation by the Military Times of the military community revealed off-label prescribing occurs not only with antidepressant medications, but also with anticonvulsants, antipsychotics, anti-anxiety drugs, and antiepileptic medications.¹⁴

A case report that brought ST to the forefront occurred in the 1980s and involved a college student.²⁵ She was initially diagnosed with the flu. Her symptoms progressed over a 24-hour period despite treatment, leading to seizures, hyperthermia, generalized clonus, muscle rigidity, respiratory failure, and death because of unrecognized ST. Her combination of serotonin-elevating drugs included meperidine, phenelzine, chlorpheniramine, and haldol. On autopsy, there were traces of cocaine found in some of her tissue samples.

Pathophysiology

Tryptophan is a precursor of serotonin and must be ingested from foods, including meats, dairy, fruits, and seeds. About 90% of all serotonin is made in the gastrointestinal epithelium and is the major component of the brain-gut axis.²⁶ Serotonin cannot cross the blood-brain barrier; therefore, it is synthesized and stored in presynaptic terminals around the midline of the brainstem.^1,26 Transport of serotonin is provided by serotonin transporter (SERT).^1,26,27 Once released, serotonin can either stimulate postsynaptic neuron receptors or is taken up into the presynaptic terminals for reuse. SSRI antidepressants, such as citalopram and paroxetine inhibit the reuptake of serotonin by binding to 2 different sites on the SERT thus allowing more available serotonin to be accessible to other neurons.²⁷ There are 7 families of serotonin receptors, 5-HT1 to 5-HT7 and at least 15 mammalian subtypes.^28,29 The majority of these receptors have been implicated in depression or depressive-like behavior as evidenced by the efficacy of increasing extracellular serotonin for the treatment of depression with SSRIs, SNRIs, TCAs, and MAOIs.²⁹ Three of the most studied receptors include 5-HT_IA,5-HT_1B,and 5-HT_2A.

Etiology

Most serotonin-induced drug fatalities occur when combining serotonergic drugs that work through different pathways (Table 2).³⁰ The most toxic combination of serotonin-enhancing drugs includes MAOIs taken with SSRIs or SNRIs, or a combination of 2 MAOIs.^5-9

Other potentially lethal combinations may includepolypharmacy with antidepressants, pain medications, OTC medications, and illicit drugs. Linezolid, a new synthetic antimicrobial, is considered to be a weak MAOI. Therefore, prescribing it with other serotonin-elevating agents has been reported to precipitate ST.¹⁸

Most cases of ST do not require hospitalization and can be managed by stopping the medication or decreasing the dose. Therapeutic doses of a single drug are highly unlikely to cause toxicity, although there have been reported cases of patients who are sensitive or more susceptible and develop symptoms after administration of a single agent and/or a dosage increase.

Delayed ST reactions have occurred because of a prolonged half-life of a drug, iron deficiency anemia, and coingestion of shorter acting serotonin antagonists.³¹ Most antidepressants have a short half-life (< 24 hours)except for fluoxetine. A decrease in iron may contribute to ST because iron is needed to process serotonin from tryptophan. An example of 2 shorter-acting serotonin antagonists include cyproheptadine and olanzapine. Cyproheptadine is used in the treatment of ST, and olanzapine is an antipsychotic.

Symptoms

Symptoms of ST range from mild to severe and include a combination of neuromuscular, autonomic, and mental status changes (Table 3).^5,10 Mild symptoms of ST can start within 1 to 2 hours after ingesting a medication that increases serotonin to a toxic state unless the drug has a long half-life (eg, fluoxetine). Sometimes mild symptoms of ST can be difficult to distinguish from common drug AEs, flu symptoms, or viruses. Patients taking therapeutic doses of SSRIs can experience serotonin symptoms, such as lower limb hyperreflexia or a few beats of ankle clonus without being toxic. One thing to remember is that not all patients will start with mild symptoms and may present in moderate or severe distress.

Moderate-to-severe ST symptoms require hospitalization, usually in the intensive care unit (ICU). At this stage, clonus progresses from the lower extremities to the upper body and becomes more generalized. Ocular clonus can be continuous, intermittent, or have a ping pong effect (short cycle, periodic, alternating lateral gaze).

Severe ST is life threatening and leads to multiorgan failure within hours if not treated. The patient is intubated to assist with breathing and sedated because excess agitation and muscular tremors can increase temperature, which is already elevated by the time the symptoms reach the severe state. Of note, hyperthermia is due to a noninfectious elevation of body temperature from hypertonicity, agitation, and muscle rigidity.A true core temperature > 105.8°F causes irreversible cell damage, cerebral injury, and death.^32,33 The patient can develop seizures and a coma. Multiorgan failure occurs, including rhabdomyolysis, myoglobinuria, renal failure, metabolic acidosis, acute respiratory distress, and disseminated intravascular coagulation.

Diagnosis

The diagnosis of ST is clinical and based on a history of ingesting serotonin-elevating medications and physical findings as per Hunter Serotonin Toxicity Criteria³⁴ (Table 4). An in-depth history needs to include previous and current prescriptions, indications of the prescriptions (eg, therapeutic, increase in dosage, suicide intent), OTC medications, and illicit drug use. Early recognition of symptoms, identification of serotonergic medications, and appropriate resuscitative measures lead to more successful outcomes. A serotonin drug level is ineffective and does not correlate with the dosage since serotonin does not cross the blood-brain barrier.

The type of drug determines the length and response of the episode. The drug(s) elimination half-lives need to be calculated along with the pharmacokinetic or pharmacodynamics; agonist, antagonist, reuptake inhibitor, etc. Many drugs have half-lives of < 24 hours; therefore, reducing or eliminating the offending drug(s) will result in a steady reduction of symptoms.Exceptions include medications with a longer activity, such as the irreversible MAOIs (eg, phenelzine, isocarboxazid) and drugs with a longer half-life, such as fluoxetine. These types of medications may have been stopped weeks earlier and may prolong reduction of symptoms.

When initiating or increasing SSRIs or SNRIs, there are common nontoxic AEs that are not consistent with ST, including anxiety, restlessness, and irritability that may last for 2 weeks. The difference in toxic vs nontoxic reactions are the timing and rapid progression of symptoms. The toxic symptoms will start within hours of ingesting the offending agents(s) and progress rapidly to severe symptoms within 24 hours. Therefore, it is imperative to review AEs with the patient and or caregiver, so they may act as their own advocate and seek immediate assistance.

Differentials

There are symptoms specific to ST that can be used to differentiate it from other conditions. These include hyperthermia, bilateral symmetric clonus (inducible, spontaneous, ocular), and hyperreflexia.These criteria form the basis for Hunter criteria.

Differential diagnoses to consider include neuroleptic malignant syndrome; antidepressant initiation AEs; antidepressant discontinuation syndrome; malignant hyperthermia; anticholinergic toxicity; meningitis/encephalitis; sepsis; drug overdose; alcohol/benzodiazepine withdrawal; and preeclampsia. Neuroleptic malignant syndrome (NMS) is the disorder most often misdiagnosed as ST.Key elements that distinguish ST from NMS include the timing of the clinical course (NMS develops over days to weeks); the medications ingested (NMS from dopaminergic drugs); and the symptoms of NMS (bradyreflexia, bradykinesia, bradyphrenia, and no clonus).According to Gillman, serotonin toxicity is a manifestation of toxicity that is predictable and common with specific drug combinations, while NMS is a “rare idiosyncratic reaction to essentially normal doses and very rarely occurs after overdoses.”³⁵ Preeclampsia is a pregnancy complication that can mimic ST with symptoms of hypertension, clonus, and hyperreflexia. It has been estimated to complicate 2% to 8% of pregnancies and remains a principle cause of maternal and fetal morbidity and mortality.^36,37

Treatment

Mild-to-moderate symptoms usually resolve on their own 1 to 3 days after decreasing or stopping the offending drug. The timing will depend on the half-life or active metabolites of the drug. Treatment is largely supportive and may require treatment for control of agitation with benzodiazepines and IV fluids for dehydration/hypotension.¹⁴ In cases not responding to supportive care, treatment with oral cyproheptadine is recommended.¹⁴

There are other medications that have been used in treatment such as olanzapine, chlorpromazine, propranolol, bromocriptine, dantrolene, droperidol, and haloperidol, but their efficacy is unproven and not recommended.¹⁰ Chlorpromazine can cause hypotension and increase hyperthermia. Propranolol has a long duration of action, may cause a prolonged hypotension, and can mask tachycardia that can be used to monitor the effectiveness of treatment.¹⁰ Bromocriptine is a serotonin agonist and may exacerbate symptoms. Dantrolene has no effect on survival in animal models.¹⁰ Droperidol and haloperidol can worsen hyperthermia by inhibiting sweating.³⁸

Mechanical ventilation should be considered especially if muscle rigidity progresses and depressed respiratory function occurs. If the temperature starts to rise, immediate sedation, paralysis, mechanical ventilation, and cyproheptadine are administered.The overall goal is prevention of hyperthermia, which leads to multiorgan failure. A core temperature of ≥ 104°F is associated with neurologic cell death, and recovery is minimal.³² Consultation with an experienced toxicologist is strongly recommended.Antipyretics should not be used, because elevated temperature is centrally mediated from muscle rigidity. If presentation occurs within 1 hour, activated charcoal can be used for detoxification of potentially lethal amounts.

Warning Label Controversies

In 2006, the US Food and Drug Administration (FDA) issued an advisory warning against concurrently using a tryptan antimigraine drug and serotonin-mediated medications.³⁹ In 2018, a research team conducted a 14-year retrospective analysis on 20,000 patients who were coprescribed a tryptan drug with SSRIs or SNRIs.⁴⁰ The study reported that the risk of ST was rare and suggested that the FDA reconsider their advisory. There are several other controversial medications with a ST FDA warning label due to their mechanisms of action and inaccurate case reports.⁴¹

Human Poisonings

Consistent with the 2017 American Association of Poison Control Centers Toxic Exposure report, antidepressants continue to be in the top 5 substance classes most frequently involved in human exposures.⁴² Most accidental ingestions of antidepressants occur in toddlers, whereas intentional ingestions are usually done by adolesents.⁴³ Over the past 10 years, antidepressants are the No. 1 fastest growing category of human exposures in all age groups.⁴²

ST in the Pediatric Population

ST in the pediatric population mirrors that in adults.Differences include the inability of the child to report symptoms, lack of clinician awareness, and reluctance of adolescents to disclose recreational drug use.Management is the same as for adults, including discontinuing the offending drug, supportive care, adequate sedation, oxygen, IV fluids, and continuous cardiac monitoring. Sedation is weight based for benzodiazepines. Mild-to-moderate reactions require admission for observation. Severe reactions require admission to the ICU.

There have been at least 4 published case reports of children aged < 6 years with moderate-to-severe ST secondary to acute vilazodone ingestion.⁴⁴ The dosages included 5.5 to 37 mg/kg. All 4 patients had altered mental status, seizures, hyperthermia, mild clonus, tachycardia, and hypertension. They all survived with intensive care treatment, including intubation, sedation, cyproheptadine in 2 cases, activated charcoal and IV lorazepam in the other cases.

Direk and colleagues reported a case of a 12-year-old girl who was brought to the emergency department by her stepmother for seizurelike activity and was diagnosed with epilepsy and status epilepticus.⁴⁵ In the pediatric ICU she developed tachycardia, fever, agitation, dilated pupils, tremors, increased deep tendon reflexes, spontaneous clonus, and horizontal ocular movements. A detailed clinical history was retaken and revealed that the child had been prescribed risperidone 1 week before by the psychiatric clinic due to behavioral problems, including stealing money, lying, and running away from home and school. On further investigation, the stepmother was taking clomipramine and discovered 9 missing pills.

Pregnancy and Lactation

The American College of Obstetricians and Gynecologists recommends that clinicians screen patients at least once during the perinatal period for depression and anxiety symptoms, using a standardized, validated tool and complete a full assessment of mood and emotional well-being during the postpartum, including screening for postpartum depression and anxiety with a validated instrument.⁴⁶ Treatment with antidepressants is controversial. “Current evidence is generally reassuring and indicates that the absolute risks of negative infant outcomes are small except for PNAS [poor neonatal adaptation syndrome], which largely appears to be self-limited.”⁴⁷ Antidepressants cross the human placenta and fetal blood-brain barrier.⁴⁸ Several cases of infant toxicity from SSRIs have been reported with citalopram and escitalopram.^49,50 Symptoms included severe muscle rigidity, lethargy, tachycardia, QTc prolongation, altered consciousness, hypertonia, and seizures at birth. These mothers had taken an SSRI during pregnancy.

Conclusions

This article highlights some of the latest information on ST. Increased awareness of all clinicians and their patients may help decrease unnecessary comorbidities and death. Early identification of ST symptoms will increase the chances for survival, because of the rapid progression of symptoms within 24 hours. Most fatal reactions occur when combining MAOIs with SSRIs, SNRIs, or another MAOI. Overdose with an SSRI does not progress to the severe symptoms unless combined with another serotonin-elevating medication.

Education of all patients who are prescribed antidepressants must include awareness of the potential for serotonergic drug interactions, particularly from OTC medications, herbal medications, and illicit drugs. The diagnosis of ST is based on clinical findings and there must be a history of ingesting serotonin-elevating drug(s). Hunter Serotonin Toxicity Criteria is the gold standard for diagnosing symptoms along with consulting a toxicologist. Prevention of ST includes informed clinicians, patient education, careful prescribing and monitoring, and avoidance of multidrug regimens.

Serotonin, or 5-hydroxytryptamine (5-HT), is a chemical neurotransmitter in the central and peripheral nervous systems that was discovered in 1940s. ¹ O ne of the most widely studied chemical messengers , serotonin influences many physiologic functions in humans, including regulation of mood, sleep-wake cycle, appetite suppression, memory, emesis, breathing, cognition, blood coagulation, libido, and many other functions. ² In 1992, Insel and colleagues first document ed the toxic symptoms produced from too much serotonin in the central and peripheral nervous systems , naming it serotonin syndrome. ^3,4

Serotonin Syndrome

Experts in the fields of psychiatry, pharmacy, and toxicology refer to these symptoms as serotonin toxicity, because the symptoms result from the toxic effects of too much serotonin.^5-9 The term toxicity instead of syndrome “clarifies that it is a form of poisoning, just as lithium toxicity is a form of poisoning.”⁶ Therefore, serotonin toxicity (ST) can develop with administration of any serotonin-enhancing medication, including therapeutic use, polypharmacy, or accidental/intentional drug overdose.

The incidence of ST has increased over the past decade.^5,6,10,11 Several reasons explain this increase: (1) ST mirrors the increase in depression in the US populations^10,12,13; (2) There has been an increase in off-label antidepressant prescribing by both primary care and mental health providers^14-16; (3) the increased use of illicit drugs¹³; (4) an increase in suicide attempts with antidepressants¹⁷; and (5) increased use of opioids for pain management, including both prescription and illicit use.^11,14 This paper reviews the potential lethal combinations of commonly prescribed medications used to treat both veteran and nonveteran patients and includes the latest information on offending medications; a presentation of symptoms from in utero to adult; diagnostic criteria; and recommended treatments.

The Veterans Health Administration (VHA) and non-VHA health care providers can play a key role in identifying and preventing serotonin syndrome/ST by keeping abreast of the latest updates of potentially lethal drug combinations. Commonly prescribed medications with the potential for a reaction include antidepressants, anxiolytics, pain medications, antinausea medications, herbal medications, and over-the-counter (OTC) medications, such as cough suppressants. Patients may be at increased risk for ST due to the growth of polypharmacy management of comorbidities.

Antidepressants

Over the past decade, antidepressant use has increased substantially in the US,United Kingdom, and Canada.¹⁴ Also the types of antidepressants prescribed has changed and been replaced with the newer agents. The selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) have replaced the older tricyclics (TCAs) and monoamine oxidase inhibitors (MAOIs) as first-line treatments for depression due to their improved comparative efficacy, reduced mortality following overdose, adverse effects (AEs) that are more tolerable for most patients, and the SSRIs have no anticholinergic properties (except paroxetine) (Table 1).¹⁸

In 2017 the National Institute of Mental Health reported that about 17 million adults and 3 million adolescents (aged 11-18 years) experienced at least 1 episode of major depression.¹⁹ About 40% of US veterans will experience depression, which is 3 times higher than the rate of the general US population.¹² A random sampling survey conducted of about 17,000 active-duty service members by the US Department of Defense (DoD) from November 2015 to April 2016 revealed 9.4% reported depression.²⁰ Antidepressant usage in the US and among veterans continues to increase.^12,16 In 2018, the list of top US prescribed drugs, included sertraline (14th), citalopram (21st), trazodone (24th), and escitalopram (26th).²¹ Antidepressant prescribing in the US increased 18% from 2012 to 2017.²² This trend also continues within the military with a 40% increase of antidepressant use in the past decade.¹⁶

One reason for the increase in antidepressant use is off-label prescribing.^14,23 A sampling of about 2 billion psychiatric outpatient visits in a western portion of the US found 12.9% of the prescriptions filled were off-label.¹⁵ In Minnesota, off-label prescribing of antidepressants was found to contribute to an increase in drug interactions in elderly nursing home residents.²⁴ An investigation by the Military Times of the military community revealed off-label prescribing occurs not only with antidepressant medications, but also with anticonvulsants, antipsychotics, anti-anxiety drugs, and antiepileptic medications.¹⁴

A case report that brought ST to the forefront occurred in the 1980s and involved a college student.²⁵ She was initially diagnosed with the flu. Her symptoms progressed over a 24-hour period despite treatment, leading to seizures, hyperthermia, generalized clonus, muscle rigidity, respiratory failure, and death because of unrecognized ST. Her combination of serotonin-elevating drugs included meperidine, phenelzine, chlorpheniramine, and haldol. On autopsy, there were traces of cocaine found in some of her tissue samples.

Pathophysiology

Tryptophan is a precursor of serotonin and must be ingested from foods, including meats, dairy, fruits, and seeds. About 90% of all serotonin is made in the gastrointestinal epithelium and is the major component of the brain-gut axis.²⁶ Serotonin cannot cross the blood-brain barrier; therefore, it is synthesized and stored in presynaptic terminals around the midline of the brainstem.^1,26 Transport of serotonin is provided by serotonin transporter (SERT).^1,26,27 Once released, serotonin can either stimulate postsynaptic neuron receptors or is taken up into the presynaptic terminals for reuse. SSRI antidepressants, such as citalopram and paroxetine inhibit the reuptake of serotonin by binding to 2 different sites on the SERT thus allowing more available serotonin to be accessible to other neurons.²⁷ There are 7 families of serotonin receptors, 5-HT1 to 5-HT7 and at least 15 mammalian subtypes.^28,29 The majority of these receptors have been implicated in depression or depressive-like behavior as evidenced by the efficacy of increasing extracellular serotonin for the treatment of depression with SSRIs, SNRIs, TCAs, and MAOIs.²⁹ Three of the most studied receptors include 5-HT_IA,5-HT_1B,and 5-HT_2A.

Etiology

Most serotonin-induced drug fatalities occur when combining serotonergic drugs that work through different pathways (Table 2).³⁰ The most toxic combination of serotonin-enhancing drugs includes MAOIs taken with SSRIs or SNRIs, or a combination of 2 MAOIs.^5-9

Other potentially lethal combinations may includepolypharmacy with antidepressants, pain medications, OTC medications, and illicit drugs. Linezolid, a new synthetic antimicrobial, is considered to be a weak MAOI. Therefore, prescribing it with other serotonin-elevating agents has been reported to precipitate ST.¹⁸

Most cases of ST do not require hospitalization and can be managed by stopping the medication or decreasing the dose. Therapeutic doses of a single drug are highly unlikely to cause toxicity, although there have been reported cases of patients who are sensitive or more susceptible and develop symptoms after administration of a single agent and/or a dosage increase.

Delayed ST reactions have occurred because of a prolonged half-life of a drug, iron deficiency anemia, and coingestion of shorter acting serotonin antagonists.³¹ Most antidepressants have a short half-life (< 24 hours)except for fluoxetine. A decrease in iron may contribute to ST because iron is needed to process serotonin from tryptophan. An example of 2 shorter-acting serotonin antagonists include cyproheptadine and olanzapine. Cyproheptadine is used in the treatment of ST, and olanzapine is an antipsychotic.

Symptoms

Symptoms of ST range from mild to severe and include a combination of neuromuscular, autonomic, and mental status changes (Table 3).^5,10 Mild symptoms of ST can start within 1 to 2 hours after ingesting a medication that increases serotonin to a toxic state unless the drug has a long half-life (eg, fluoxetine). Sometimes mild symptoms of ST can be difficult to distinguish from common drug AEs, flu symptoms, or viruses. Patients taking therapeutic doses of SSRIs can experience serotonin symptoms, such as lower limb hyperreflexia or a few beats of ankle clonus without being toxic. One thing to remember is that not all patients will start with mild symptoms and may present in moderate or severe distress.

Moderate-to-severe ST symptoms require hospitalization, usually in the intensive care unit (ICU). At this stage, clonus progresses from the lower extremities to the upper body and becomes more generalized. Ocular clonus can be continuous, intermittent, or have a ping pong effect (short cycle, periodic, alternating lateral gaze).

Severe ST is life threatening and leads to multiorgan failure within hours if not treated. The patient is intubated to assist with breathing and sedated because excess agitation and muscular tremors can increase temperature, which is already elevated by the time the symptoms reach the severe state. Of note, hyperthermia is due to a noninfectious elevation of body temperature from hypertonicity, agitation, and muscle rigidity.A true core temperature > 105.8°F causes irreversible cell damage, cerebral injury, and death.^32,33 The patient can develop seizures and a coma. Multiorgan failure occurs, including rhabdomyolysis, myoglobinuria, renal failure, metabolic acidosis, acute respiratory distress, and disseminated intravascular coagulation.

Diagnosis

The diagnosis of ST is clinical and based on a history of ingesting serotonin-elevating medications and physical findings as per Hunter Serotonin Toxicity Criteria³⁴ (Table 4). An in-depth history needs to include previous and current prescriptions, indications of the prescriptions (eg, therapeutic, increase in dosage, suicide intent), OTC medications, and illicit drug use. Early recognition of symptoms, identification of serotonergic medications, and appropriate resuscitative measures lead to more successful outcomes. A serotonin drug level is ineffective and does not correlate with the dosage since serotonin does not cross the blood-brain barrier.

The type of drug determines the length and response of the episode. The drug(s) elimination half-lives need to be calculated along with the pharmacokinetic or pharmacodynamics; agonist, antagonist, reuptake inhibitor, etc. Many drugs have half-lives of < 24 hours; therefore, reducing or eliminating the offending drug(s) will result in a steady reduction of symptoms.Exceptions include medications with a longer activity, such as the irreversible MAOIs (eg, phenelzine, isocarboxazid) and drugs with a longer half-life, such as fluoxetine. These types of medications may have been stopped weeks earlier and may prolong reduction of symptoms.

When initiating or increasing SSRIs or SNRIs, there are common nontoxic AEs that are not consistent with ST, including anxiety, restlessness, and irritability that may last for 2 weeks. The difference in toxic vs nontoxic reactions are the timing and rapid progression of symptoms. The toxic symptoms will start within hours of ingesting the offending agents(s) and progress rapidly to severe symptoms within 24 hours. Therefore, it is imperative to review AEs with the patient and or caregiver, so they may act as their own advocate and seek immediate assistance.

Differentials

There are symptoms specific to ST that can be used to differentiate it from other conditions. These include hyperthermia, bilateral symmetric clonus (inducible, spontaneous, ocular), and hyperreflexia.These criteria form the basis for Hunter criteria.

Differential diagnoses to consider include neuroleptic malignant syndrome; antidepressant initiation AEs; antidepressant discontinuation syndrome; malignant hyperthermia; anticholinergic toxicity; meningitis/encephalitis; sepsis; drug overdose; alcohol/benzodiazepine withdrawal; and preeclampsia. Neuroleptic malignant syndrome (NMS) is the disorder most often misdiagnosed as ST.Key elements that distinguish ST from NMS include the timing of the clinical course (NMS develops over days to weeks); the medications ingested (NMS from dopaminergic drugs); and the symptoms of NMS (bradyreflexia, bradykinesia, bradyphrenia, and no clonus).According to Gillman, serotonin toxicity is a manifestation of toxicity that is predictable and common with specific drug combinations, while NMS is a “rare idiosyncratic reaction to essentially normal doses and very rarely occurs after overdoses.”³⁵ Preeclampsia is a pregnancy complication that can mimic ST with symptoms of hypertension, clonus, and hyperreflexia. It has been estimated to complicate 2% to 8% of pregnancies and remains a principle cause of maternal and fetal morbidity and mortality.^36,37

Treatment

Mild-to-moderate symptoms usually resolve on their own 1 to 3 days after decreasing or stopping the offending drug. The timing will depend on the half-life or active metabolites of the drug. Treatment is largely supportive and may require treatment for control of agitation with benzodiazepines and IV fluids for dehydration/hypotension.¹⁴ In cases not responding to supportive care, treatment with oral cyproheptadine is recommended.¹⁴

There are other medications that have been used in treatment such as olanzapine, chlorpromazine, propranolol, bromocriptine, dantrolene, droperidol, and haloperidol, but their efficacy is unproven and not recommended.¹⁰ Chlorpromazine can cause hypotension and increase hyperthermia. Propranolol has a long duration of action, may cause a prolonged hypotension, and can mask tachycardia that can be used to monitor the effectiveness of treatment.¹⁰ Bromocriptine is a serotonin agonist and may exacerbate symptoms. Dantrolene has no effect on survival in animal models.¹⁰ Droperidol and haloperidol can worsen hyperthermia by inhibiting sweating.³⁸

Mechanical ventilation should be considered especially if muscle rigidity progresses and depressed respiratory function occurs. If the temperature starts to rise, immediate sedation, paralysis, mechanical ventilation, and cyproheptadine are administered.The overall goal is prevention of hyperthermia, which leads to multiorgan failure. A core temperature of ≥ 104°F is associated with neurologic cell death, and recovery is minimal.³² Consultation with an experienced toxicologist is strongly recommended.Antipyretics should not be used, because elevated temperature is centrally mediated from muscle rigidity. If presentation occurs within 1 hour, activated charcoal can be used for detoxification of potentially lethal amounts.

Warning Label Controversies

In 2006, the US Food and Drug Administration (FDA) issued an advisory warning against concurrently using a tryptan antimigraine drug and serotonin-mediated medications.³⁹ In 2018, a research team conducted a 14-year retrospective analysis on 20,000 patients who were coprescribed a tryptan drug with SSRIs or SNRIs.⁴⁰ The study reported that the risk of ST was rare and suggested that the FDA reconsider their advisory. There are several other controversial medications with a ST FDA warning label due to their mechanisms of action and inaccurate case reports.⁴¹

Human Poisonings

Consistent with the 2017 American Association of Poison Control Centers Toxic Exposure report, antidepressants continue to be in the top 5 substance classes most frequently involved in human exposures.⁴² Most accidental ingestions of antidepressants occur in toddlers, whereas intentional ingestions are usually done by adolesents.⁴³ Over the past 10 years, antidepressants are the No. 1 fastest growing category of human exposures in all age groups.⁴²

ST in the Pediatric Population

ST in the pediatric population mirrors that in adults.Differences include the inability of the child to report symptoms, lack of clinician awareness, and reluctance of adolescents to disclose recreational drug use.Management is the same as for adults, including discontinuing the offending drug, supportive care, adequate sedation, oxygen, IV fluids, and continuous cardiac monitoring. Sedation is weight based for benzodiazepines. Mild-to-moderate reactions require admission for observation. Severe reactions require admission to the ICU.

There have been at least 4 published case reports of children aged < 6 years with moderate-to-severe ST secondary to acute vilazodone ingestion.⁴⁴ The dosages included 5.5 to 37 mg/kg. All 4 patients had altered mental status, seizures, hyperthermia, mild clonus, tachycardia, and hypertension. They all survived with intensive care treatment, including intubation, sedation, cyproheptadine in 2 cases, activated charcoal and IV lorazepam in the other cases.

Direk and colleagues reported a case of a 12-year-old girl who was brought to the emergency department by her stepmother for seizurelike activity and was diagnosed with epilepsy and status epilepticus.⁴⁵ In the pediatric ICU she developed tachycardia, fever, agitation, dilated pupils, tremors, increased deep tendon reflexes, spontaneous clonus, and horizontal ocular movements. A detailed clinical history was retaken and revealed that the child had been prescribed risperidone 1 week before by the psychiatric clinic due to behavioral problems, including stealing money, lying, and running away from home and school. On further investigation, the stepmother was taking clomipramine and discovered 9 missing pills.

Pregnancy and Lactation

The American College of Obstetricians and Gynecologists recommends that clinicians screen patients at least once during the perinatal period for depression and anxiety symptoms, using a standardized, validated tool and complete a full assessment of mood and emotional well-being during the postpartum, including screening for postpartum depression and anxiety with a validated instrument.⁴⁶ Treatment with antidepressants is controversial. “Current evidence is generally reassuring and indicates that the absolute risks of negative infant outcomes are small except for PNAS [poor neonatal adaptation syndrome], which largely appears to be self-limited.”⁴⁷ Antidepressants cross the human placenta and fetal blood-brain barrier.⁴⁸ Several cases of infant toxicity from SSRIs have been reported with citalopram and escitalopram.^49,50 Symptoms included severe muscle rigidity, lethargy, tachycardia, QTc prolongation, altered consciousness, hypertonia, and seizures at birth. These mothers had taken an SSRI during pregnancy.

Conclusions

This article highlights some of the latest information on ST. Increased awareness of all clinicians and their patients may help decrease unnecessary comorbidities and death. Early identification of ST symptoms will increase the chances for survival, because of the rapid progression of symptoms within 24 hours. Most fatal reactions occur when combining MAOIs with SSRIs, SNRIs, or another MAOI. Overdose with an SSRI does not progress to the severe symptoms unless combined with another serotonin-elevating medication.

Education of all patients who are prescribed antidepressants must include awareness of the potential for serotonergic drug interactions, particularly from OTC medications, herbal medications, and illicit drugs. The diagnosis of ST is based on clinical findings and there must be a history of ingesting serotonin-elevating drug(s). Hunter Serotonin Toxicity Criteria is the gold standard for diagnosing symptoms along with consulting a toxicologist. Prevention of ST includes informed clinicians, patient education, careful prescribing and monitoring, and avoidance of multidrug regimens.

Serotonin, or 5-hydroxytryptamine (5-HT), is a chemical neurotransmitter in the central and peripheral nervous systems that was discovered in 1940s. ¹ O ne of the most widely studied chemical messengers , serotonin influences many physiologic functions in humans, including regulation of mood, sleep-wake cycle, appetite suppression, memory, emesis, breathing, cognition, blood coagulation, libido, and many other functions. ² In 1992, Insel and colleagues first document ed the toxic symptoms produced from too much serotonin in the central and peripheral nervous systems , naming it serotonin syndrome. ^3,4

Serotonin Syndrome

Experts in the fields of psychiatry, pharmacy, and toxicology refer to these symptoms as serotonin toxicity, because the symptoms result from the toxic effects of too much serotonin.^5-9 The term toxicity instead of syndrome “clarifies that it is a form of poisoning, just as lithium toxicity is a form of poisoning.”⁶ Therefore, serotonin toxicity (ST) can develop with administration of any serotonin-enhancing medication, including therapeutic use, polypharmacy, or accidental/intentional drug overdose.

The incidence of ST has increased over the past decade.^5,6,10,11 Several reasons explain this increase: (1) ST mirrors the increase in depression in the US populations^10,12,13; (2) There has been an increase in off-label antidepressant prescribing by both primary care and mental health providers^14-16; (3) the increased use of illicit drugs¹³; (4) an increase in suicide attempts with antidepressants¹⁷; and (5) increased use of opioids for pain management, including both prescription and illicit use.^11,14 This paper reviews the potential lethal combinations of commonly prescribed medications used to treat both veteran and nonveteran patients and includes the latest information on offending medications; a presentation of symptoms from in utero to adult; diagnostic criteria; and recommended treatments.

The Veterans Health Administration (VHA) and non-VHA health care providers can play a key role in identifying and preventing serotonin syndrome/ST by keeping abreast of the latest updates of potentially lethal drug combinations. Commonly prescribed medications with the potential for a reaction include antidepressants, anxiolytics, pain medications, antinausea medications, herbal medications, and over-the-counter (OTC) medications, such as cough suppressants. Patients may be at increased risk for ST due to the growth of polypharmacy management of comorbidities.

Antidepressants

Over the past decade, antidepressant use has increased substantially in the US,United Kingdom, and Canada.¹⁴ Also the types of antidepressants prescribed has changed and been replaced with the newer agents. The selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) have replaced the older tricyclics (TCAs) and monoamine oxidase inhibitors (MAOIs) as first-line treatments for depression due to their improved comparative efficacy, reduced mortality following overdose, adverse effects (AEs) that are more tolerable for most patients, and the SSRIs have no anticholinergic properties (except paroxetine) (Table 1).¹⁸

In 2017 the National Institute of Mental Health reported that about 17 million adults and 3 million adolescents (aged 11-18 years) experienced at least 1 episode of major depression.¹⁹ About 40% of US veterans will experience depression, which is 3 times higher than the rate of the general US population.¹² A random sampling survey conducted of about 17,000 active-duty service members by the US Department of Defense (DoD) from November 2015 to April 2016 revealed 9.4% reported depression.²⁰ Antidepressant usage in the US and among veterans continues to increase.^12,16 In 2018, the list of top US prescribed drugs, included sertraline (14th), citalopram (21st), trazodone (24th), and escitalopram (26th).²¹ Antidepressant prescribing in the US increased 18% from 2012 to 2017.²² This trend also continues within the military with a 40% increase of antidepressant use in the past decade.¹⁶

One reason for the increase in antidepressant use is off-label prescribing.^14,23 A sampling of about 2 billion psychiatric outpatient visits in a western portion of the US found 12.9% of the prescriptions filled were off-label.¹⁵ In Minnesota, off-label prescribing of antidepressants was found to contribute to an increase in drug interactions in elderly nursing home residents.²⁴ An investigation by the Military Times of the military community revealed off-label prescribing occurs not only with antidepressant medications, but also with anticonvulsants, antipsychotics, anti-anxiety drugs, and antiepileptic medications.¹⁴

A case report that brought ST to the forefront occurred in the 1980s and involved a college student.²⁵ She was initially diagnosed with the flu. Her symptoms progressed over a 24-hour period despite treatment, leading to seizures, hyperthermia, generalized clonus, muscle rigidity, respiratory failure, and death because of unrecognized ST. Her combination of serotonin-elevating drugs included meperidine, phenelzine, chlorpheniramine, and haldol. On autopsy, there were traces of cocaine found in some of her tissue samples.

Pathophysiology

Tryptophan is a precursor of serotonin and must be ingested from foods, including meats, dairy, fruits, and seeds. About 90% of all serotonin is made in the gastrointestinal epithelium and is the major component of the brain-gut axis.²⁶ Serotonin cannot cross the blood-brain barrier; therefore, it is synthesized and stored in presynaptic terminals around the midline of the brainstem.^1,26 Transport of serotonin is provided by serotonin transporter (SERT).^1,26,27 Once released, serotonin can either stimulate postsynaptic neuron receptors or is taken up into the presynaptic terminals for reuse. SSRI antidepressants, such as citalopram and paroxetine inhibit the reuptake of serotonin by binding to 2 different sites on the SERT thus allowing more available serotonin to be accessible to other neurons.²⁷ There are 7 families of serotonin receptors, 5-HT1 to 5-HT7 and at least 15 mammalian subtypes.^28,29 The majority of these receptors have been implicated in depression or depressive-like behavior as evidenced by the efficacy of increasing extracellular serotonin for the treatment of depression with SSRIs, SNRIs, TCAs, and MAOIs.²⁹ Three of the most studied receptors include 5-HT_IA,5-HT_1B,and 5-HT_2A.

Etiology

Most serotonin-induced drug fatalities occur when combining serotonergic drugs that work through different pathways (Table 2).³⁰ The most toxic combination of serotonin-enhancing drugs includes MAOIs taken with SSRIs or SNRIs, or a combination of 2 MAOIs.^5-9

Other potentially lethal combinations may includepolypharmacy with antidepressants, pain medications, OTC medications, and illicit drugs. Linezolid, a new synthetic antimicrobial, is considered to be a weak MAOI. Therefore, prescribing it with other serotonin-elevating agents has been reported to precipitate ST.¹⁸

Most cases of ST do not require hospitalization and can be managed by stopping the medication or decreasing the dose. Therapeutic doses of a single drug are highly unlikely to cause toxicity, although there have been reported cases of patients who are sensitive or more susceptible and develop symptoms after administration of a single agent and/or a dosage increase.

Delayed ST reactions have occurred because of a prolonged half-life of a drug, iron deficiency anemia, and coingestion of shorter acting serotonin antagonists.³¹ Most antidepressants have a short half-life (< 24 hours)except for fluoxetine. A decrease in iron may contribute to ST because iron is needed to process serotonin from tryptophan. An example of 2 shorter-acting serotonin antagonists include cyproheptadine and olanzapine. Cyproheptadine is used in the treatment of ST, and olanzapine is an antipsychotic.

Symptoms

Symptoms of ST range from mild to severe and include a combination of neuromuscular, autonomic, and mental status changes (Table 3).^5,10 Mild symptoms of ST can start within 1 to 2 hours after ingesting a medication that increases serotonin to a toxic state unless the drug has a long half-life (eg, fluoxetine). Sometimes mild symptoms of ST can be difficult to distinguish from common drug AEs, flu symptoms, or viruses. Patients taking therapeutic doses of SSRIs can experience serotonin symptoms, such as lower limb hyperreflexia or a few beats of ankle clonus without being toxic. One thing to remember is that not all patients will start with mild symptoms and may present in moderate or severe distress.

Moderate-to-severe ST symptoms require hospitalization, usually in the intensive care unit (ICU). At this stage, clonus progresses from the lower extremities to the upper body and becomes more generalized. Ocular clonus can be continuous, intermittent, or have a ping pong effect (short cycle, periodic, alternating lateral gaze).

Severe ST is life threatening and leads to multiorgan failure within hours if not treated. The patient is intubated to assist with breathing and sedated because excess agitation and muscular tremors can increase temperature, which is already elevated by the time the symptoms reach the severe state. Of note, hyperthermia is due to a noninfectious elevation of body temperature from hypertonicity, agitation, and muscle rigidity.A true core temperature > 105.8°F causes irreversible cell damage, cerebral injury, and death.^32,33 The patient can develop seizures and a coma. Multiorgan failure occurs, including rhabdomyolysis, myoglobinuria, renal failure, metabolic acidosis, acute respiratory distress, and disseminated intravascular coagulation.

Diagnosis

The diagnosis of ST is clinical and based on a history of ingesting serotonin-elevating medications and physical findings as per Hunter Serotonin Toxicity Criteria³⁴ (Table 4). An in-depth history needs to include previous and current prescriptions, indications of the prescriptions (eg, therapeutic, increase in dosage, suicide intent), OTC medications, and illicit drug use. Early recognition of symptoms, identification of serotonergic medications, and appropriate resuscitative measures lead to more successful outcomes. A serotonin drug level is ineffective and does not correlate with the dosage since serotonin does not cross the blood-brain barrier.

The type of drug determines the length and response of the episode. The drug(s) elimination half-lives need to be calculated along with the pharmacokinetic or pharmacodynamics; agonist, antagonist, reuptake inhibitor, etc. Many drugs have half-lives of < 24 hours; therefore, reducing or eliminating the offending drug(s) will result in a steady reduction of symptoms.Exceptions include medications with a longer activity, such as the irreversible MAOIs (eg, phenelzine, isocarboxazid) and drugs with a longer half-life, such as fluoxetine. These types of medications may have been stopped weeks earlier and may prolong reduction of symptoms.

When initiating or increasing SSRIs or SNRIs, there are common nontoxic AEs that are not consistent with ST, including anxiety, restlessness, and irritability that may last for 2 weeks. The difference in toxic vs nontoxic reactions are the timing and rapid progression of symptoms. The toxic symptoms will start within hours of ingesting the offending agents(s) and progress rapidly to severe symptoms within 24 hours. Therefore, it is imperative to review AEs with the patient and or caregiver, so they may act as their own advocate and seek immediate assistance.

Differentials

There are symptoms specific to ST that can be used to differentiate it from other conditions. These include hyperthermia, bilateral symmetric clonus (inducible, spontaneous, ocular), and hyperreflexia.These criteria form the basis for Hunter criteria.

Differential diagnoses to consider include neuroleptic malignant syndrome; antidepressant initiation AEs; antidepressant discontinuation syndrome; malignant hyperthermia; anticholinergic toxicity; meningitis/encephalitis; sepsis; drug overdose; alcohol/benzodiazepine withdrawal; and preeclampsia. Neuroleptic malignant syndrome (NMS) is the disorder most often misdiagnosed as ST.Key elements that distinguish ST from NMS include the timing of the clinical course (NMS develops over days to weeks); the medications ingested (NMS from dopaminergic drugs); and the symptoms of NMS (bradyreflexia, bradykinesia, bradyphrenia, and no clonus).According to Gillman, serotonin toxicity is a manifestation of toxicity that is predictable and common with specific drug combinations, while NMS is a “rare idiosyncratic reaction to essentially normal doses and very rarely occurs after overdoses.”³⁵ Preeclampsia is a pregnancy complication that can mimic ST with symptoms of hypertension, clonus, and hyperreflexia. It has been estimated to complicate 2% to 8% of pregnancies and remains a principle cause of maternal and fetal morbidity and mortality.^36,37

Treatment

Mild-to-moderate symptoms usually resolve on their own 1 to 3 days after decreasing or stopping the offending drug. The timing will depend on the half-life or active metabolites of the drug. Treatment is largely supportive and may require treatment for control of agitation with benzodiazepines and IV fluids for dehydration/hypotension.¹⁴ In cases not responding to supportive care, treatment with oral cyproheptadine is recommended.¹⁴

There are other medications that have been used in treatment such as olanzapine, chlorpromazine, propranolol, bromocriptine, dantrolene, droperidol, and haloperidol, but their efficacy is unproven and not recommended.¹⁰ Chlorpromazine can cause hypotension and increase hyperthermia. Propranolol has a long duration of action, may cause a prolonged hypotension, and can mask tachycardia that can be used to monitor the effectiveness of treatment.¹⁰ Bromocriptine is a serotonin agonist and may exacerbate symptoms. Dantrolene has no effect on survival in animal models.¹⁰ Droperidol and haloperidol can worsen hyperthermia by inhibiting sweating.³⁸

Mechanical ventilation should be considered especially if muscle rigidity progresses and depressed respiratory function occurs. If the temperature starts to rise, immediate sedation, paralysis, mechanical ventilation, and cyproheptadine are administered.The overall goal is prevention of hyperthermia, which leads to multiorgan failure. A core temperature of ≥ 104°F is associated with neurologic cell death, and recovery is minimal.³² Consultation with an experienced toxicologist is strongly recommended.Antipyretics should not be used, because elevated temperature is centrally mediated from muscle rigidity. If presentation occurs within 1 hour, activated charcoal can be used for detoxification of potentially lethal amounts.

Warning Label Controversies

In 2006, the US Food and Drug Administration (FDA) issued an advisory warning against concurrently using a tryptan antimigraine drug and serotonin-mediated medications.³⁹ In 2018, a research team conducted a 14-year retrospective analysis on 20,000 patients who were coprescribed a tryptan drug with SSRIs or SNRIs.⁴⁰ The study reported that the risk of ST was rare and suggested that the FDA reconsider their advisory. There are several other controversial medications with a ST FDA warning label due to their mechanisms of action and inaccurate case reports.⁴¹

Human Poisonings

Consistent with the 2017 American Association of Poison Control Centers Toxic Exposure report, antidepressants continue to be in the top 5 substance classes most frequently involved in human exposures.⁴² Most accidental ingestions of antidepressants occur in toddlers, whereas intentional ingestions are usually done by adolesents.⁴³ Over the past 10 years, antidepressants are the No. 1 fastest growing category of human exposures in all age groups.⁴²

ST in the Pediatric Population

ST in the pediatric population mirrors that in adults.Differences include the inability of the child to report symptoms, lack of clinician awareness, and reluctance of adolescents to disclose recreational drug use.Management is the same as for adults, including discontinuing the offending drug, supportive care, adequate sedation, oxygen, IV fluids, and continuous cardiac monitoring. Sedation is weight based for benzodiazepines. Mild-to-moderate reactions require admission for observation. Severe reactions require admission to the ICU.

There have been at least 4 published case reports of children aged < 6 years with moderate-to-severe ST secondary to acute vilazodone ingestion.⁴⁴ The dosages included 5.5 to 37 mg/kg. All 4 patients had altered mental status, seizures, hyperthermia, mild clonus, tachycardia, and hypertension. They all survived with intensive care treatment, including intubation, sedation, cyproheptadine in 2 cases, activated charcoal and IV lorazepam in the other cases.

Direk and colleagues reported a case of a 12-year-old girl who was brought to the emergency department by her stepmother for seizurelike activity and was diagnosed with epilepsy and status epilepticus.⁴⁵ In the pediatric ICU she developed tachycardia, fever, agitation, dilated pupils, tremors, increased deep tendon reflexes, spontaneous clonus, and horizontal ocular movements. A detailed clinical history was retaken and revealed that the child had been prescribed risperidone 1 week before by the psychiatric clinic due to behavioral problems, including stealing money, lying, and running away from home and school. On further investigation, the stepmother was taking clomipramine and discovered 9 missing pills.

Pregnancy and Lactation

The American College of Obstetricians and Gynecologists recommends that clinicians screen patients at least once during the perinatal period for depression and anxiety symptoms, using a standardized, validated tool and complete a full assessment of mood and emotional well-being during the postpartum, including screening for postpartum depression and anxiety with a validated instrument.⁴⁶ Treatment with antidepressants is controversial. “Current evidence is generally reassuring and indicates that the absolute risks of negative infant outcomes are small except for PNAS [poor neonatal adaptation syndrome], which largely appears to be self-limited.”⁴⁷ Antidepressants cross the human placenta and fetal blood-brain barrier.⁴⁸ Several cases of infant toxicity from SSRIs have been reported with citalopram and escitalopram.^49,50 Symptoms included severe muscle rigidity, lethargy, tachycardia, QTc prolongation, altered consciousness, hypertonia, and seizures at birth. These mothers had taken an SSRI during pregnancy.

Conclusions

This article highlights some of the latest information on ST. Increased awareness of all clinicians and their patients may help decrease unnecessary comorbidities and death. Early identification of ST symptoms will increase the chances for survival, because of the rapid progression of symptoms within 24 hours. Most fatal reactions occur when combining MAOIs with SSRIs, SNRIs, or another MAOI. Overdose with an SSRI does not progress to the severe symptoms unless combined with another serotonin-elevating medication.

Education of all patients who are prescribed antidepressants must include awareness of the potential for serotonergic drug interactions, particularly from OTC medications, herbal medications, and illicit drugs. The diagnosis of ST is based on clinical findings and there must be a history of ingesting serotonin-elevating drug(s). Hunter Serotonin Toxicity Criteria is the gold standard for diagnosing symptoms along with consulting a toxicologist. Prevention of ST includes informed clinicians, patient education, careful prescribing and monitoring, and avoidance of multidrug regimens.

Creeping fat in Crohn’s disease is likely caused by microbial translocation from the gut to neighboring mesenteric adipose tissue (MAT), based on a recent study.

This finding may lead to early risk stratification for creeping fat, and nonsurgical interventions, according to principal author Suzanne Devkota, PhD, assistant professor at Cedars-Sinai Medical Center in Los Angeles.

Creeping fat, which is unique to Crohn’s disease, is characterized by hyperplastic MAT that grips areas of intestinal inflammation with invasive “fingerlike projections,” the investigators wrote in Cell. This phenomenon was first described by the eponymous Dr. Crohn in 1932; since then, despite associations with fibrotic strictures that may require surgical resection, underlying mechanisms have remained mysterious and largely unexplored.

That changed during a session of grand rounds at Cedars-Sinai in September 2016; Dr. Devkota was discussing adipose tissue when her surgeon colleague, Phillip Fleshner, MD, asked: “What about creeping fat?”

“Yeah, that’s cool,” Dr. Devkota replied, “but I don’t have access to creeping fat.”

“I see it all the time,” Dr. Fleshner said. “I can get you some.”

And so a partnership was born, allowing Dr. Devkota and colleagues to pursue the translocation hypothesis.

The present report involved tissue samples from 11 patients with Crohn’s disease and 13 patients with ulcerative colitis. Healthy tissue controls were taken from four subjects without inflammatory bowel disease who underwent ileostomy.

Microbial cultivation of Crohn’s disease and healthy patient samples revealed bacteria in the mesenteric tissue of both groups, suggesting that microbial translocation from the gut to MAT “may not be unusual;” however, Crohn’s disease samples were associated with an exclusive consortium of five species: Clostridium innocuum, Erysipeloclostridium ramosum, Parabacteroides distasonis, Clostridium symbiosum, and Bifidobacterium pseudolongum. 

C. innocuum was isolated most frequently; and its unique characteristics increased suspicions that it was the creeping fat culprit.

“Core genomic features of C. innocuum include type IV pili and twitching motility, a preference for lipid-derived metabolic substrates, and multiple genes for lipid catabolism, as well as a functional substrate preference for b-hydroxybutyrate, a byproduct of fatty acid oxidation,” the investigators wrote. “This suggests that C. innocuum is well suited for, and perhaps prefers, a lipid-rich environment and seeks these out when the opportunity arises.”

To observe this opportunism firsthand, the investigators gavaged gnotobiotic mice with C. innocuum. Indeed, these mice demonstrated “dramatic mesenteric adiposity,” compared with controls.

Cotreatment with dextran sulfate sodium (DSS) was unnecessary to induce translocation of C. innocuum, which “suggests that overt inflammation is not a prerequisite for its translocation,” the investigators noted.

The profibrotic potential of C. innocuum was supported by in vitro experiments, in which adipose-derived stem cells and primary fibroblasts from Crohn’s disease MAT were exposed to either C. innocuum lysate or macrophage-conditioned media from C. innocuum–exposed macrophages. While the lysate alone did not alter genes involved in fibrosis and remodeling, the macrophage-conditioned media did, indicating that C. innocuum alters MAT indirectly via macrophage activity.

Although multiple signs suggest that C. innocuum causes creeping fat, Dr. Devkota noted that systematic testing is needed to confirm this likelihood.

“But I do think we’ve honed in on the consortium that is at play,” she said, referring to the five identified species.

According to Dr. Devkota, awareness of these microbes could lead to diagnostic and interventional benefits for patients with Crohn’s disease. For example, gut microbiota profiling could be used to measure levels of C. innocuum in newly diagnosed patients, thereby stratifying risk of creeping fat. And phage therapy, with its high specificity for bacterial species, could be an ideal intervention.

“I’m very eager to hear from the surgeons, and hear what their opinion is, and whether this will affect their treatment or how they approach [creeping fat],” Dr. Devkota said.

Beyond Crohn’s disease, the study findings could inform obesity research, as bacterial DNA has been found in obese adipose tissue, which is characteristically fibrotic.

“There are a lot of gene-expression patterns [in the present study], that are also seen in obesity literature,” Dr. Devkota said.

“Obviously there’s a lifestyle caloric aspect to [obesity],” she added. “I definitely don’t claim that microbes are the end-all and be-all of obesity – I want to make that clear. But it could be possible, and particularly related to abdominal fat. Expanded abdominal fat could be a sign that there’s underlying intestinal inflammation ... that there’s something deeper going on that may be unrelated to a metabolic defect.”

The study was funded by Leona M. and Harry B. Helmsley Charitable Trust and the National Institutes of Health. Dr. Devkota and Dr. Ha are inventors on U.S. patent application #62/679,624.

SOURCE: Ha CWY et al. Cell. 2020 Oct 29. doi: 10.1016/j.cell.2020.09.009.

Creeping fat in Crohn’s disease is likely caused by microbial translocation from the gut to neighboring mesenteric adipose tissue (MAT), based on a recent study.

This finding may lead to early risk stratification for creeping fat, and nonsurgical interventions, according to principal author Suzanne Devkota, PhD, assistant professor at Cedars-Sinai Medical Center in Los Angeles.

Creeping fat, which is unique to Crohn’s disease, is characterized by hyperplastic MAT that grips areas of intestinal inflammation with invasive “fingerlike projections,” the investigators wrote in Cell. This phenomenon was first described by the eponymous Dr. Crohn in 1932; since then, despite associations with fibrotic strictures that may require surgical resection, underlying mechanisms have remained mysterious and largely unexplored.

That changed during a session of grand rounds at Cedars-Sinai in September 2016; Dr. Devkota was discussing adipose tissue when her surgeon colleague, Phillip Fleshner, MD, asked: “What about creeping fat?”

“Yeah, that’s cool,” Dr. Devkota replied, “but I don’t have access to creeping fat.”

“I see it all the time,” Dr. Fleshner said. “I can get you some.”

And so a partnership was born, allowing Dr. Devkota and colleagues to pursue the translocation hypothesis.

The present report involved tissue samples from 11 patients with Crohn’s disease and 13 patients with ulcerative colitis. Healthy tissue controls were taken from four subjects without inflammatory bowel disease who underwent ileostomy.

Microbial cultivation of Crohn’s disease and healthy patient samples revealed bacteria in the mesenteric tissue of both groups, suggesting that microbial translocation from the gut to MAT “may not be unusual;” however, Crohn’s disease samples were associated with an exclusive consortium of five species: Clostridium innocuum, Erysipeloclostridium ramosum, Parabacteroides distasonis, Clostridium symbiosum, and Bifidobacterium pseudolongum. 

C. innocuum was isolated most frequently; and its unique characteristics increased suspicions that it was the creeping fat culprit.

“Core genomic features of C. innocuum include type IV pili and twitching motility, a preference for lipid-derived metabolic substrates, and multiple genes for lipid catabolism, as well as a functional substrate preference for b-hydroxybutyrate, a byproduct of fatty acid oxidation,” the investigators wrote. “This suggests that C. innocuum is well suited for, and perhaps prefers, a lipid-rich environment and seeks these out when the opportunity arises.”

To observe this opportunism firsthand, the investigators gavaged gnotobiotic mice with C. innocuum. Indeed, these mice demonstrated “dramatic mesenteric adiposity,” compared with controls.

Cotreatment with dextran sulfate sodium (DSS) was unnecessary to induce translocation of C. innocuum, which “suggests that overt inflammation is not a prerequisite for its translocation,” the investigators noted.

The profibrotic potential of C. innocuum was supported by in vitro experiments, in which adipose-derived stem cells and primary fibroblasts from Crohn’s disease MAT were exposed to either C. innocuum lysate or macrophage-conditioned media from C. innocuum–exposed macrophages. While the lysate alone did not alter genes involved in fibrosis and remodeling, the macrophage-conditioned media did, indicating that C. innocuum alters MAT indirectly via macrophage activity.

Although multiple signs suggest that C. innocuum causes creeping fat, Dr. Devkota noted that systematic testing is needed to confirm this likelihood.

“But I do think we’ve honed in on the consortium that is at play,” she said, referring to the five identified species.

According to Dr. Devkota, awareness of these microbes could lead to diagnostic and interventional benefits for patients with Crohn’s disease. For example, gut microbiota profiling could be used to measure levels of C. innocuum in newly diagnosed patients, thereby stratifying risk of creeping fat. And phage therapy, with its high specificity for bacterial species, could be an ideal intervention.

“I’m very eager to hear from the surgeons, and hear what their opinion is, and whether this will affect their treatment or how they approach [creeping fat],” Dr. Devkota said.

Beyond Crohn’s disease, the study findings could inform obesity research, as bacterial DNA has been found in obese adipose tissue, which is characteristically fibrotic.

“There are a lot of gene-expression patterns [in the present study], that are also seen in obesity literature,” Dr. Devkota said.

“Obviously there’s a lifestyle caloric aspect to [obesity],” she added. “I definitely don’t claim that microbes are the end-all and be-all of obesity – I want to make that clear. But it could be possible, and particularly related to abdominal fat. Expanded abdominal fat could be a sign that there’s underlying intestinal inflammation ... that there’s something deeper going on that may be unrelated to a metabolic defect.”

The study was funded by Leona M. and Harry B. Helmsley Charitable Trust and the National Institutes of Health. Dr. Devkota and Dr. Ha are inventors on U.S. patent application #62/679,624.

SOURCE: Ha CWY et al. Cell. 2020 Oct 29. doi: 10.1016/j.cell.2020.09.009.

Creeping fat in Crohn’s disease is likely caused by microbial translocation from the gut to neighboring mesenteric adipose tissue (MAT), based on a recent study.

This finding may lead to early risk stratification for creeping fat, and nonsurgical interventions, according to principal author Suzanne Devkota, PhD, assistant professor at Cedars-Sinai Medical Center in Los Angeles.

Creeping fat, which is unique to Crohn’s disease, is characterized by hyperplastic MAT that grips areas of intestinal inflammation with invasive “fingerlike projections,” the investigators wrote in Cell. This phenomenon was first described by the eponymous Dr. Crohn in 1932; since then, despite associations with fibrotic strictures that may require surgical resection, underlying mechanisms have remained mysterious and largely unexplored.

That changed during a session of grand rounds at Cedars-Sinai in September 2016; Dr. Devkota was discussing adipose tissue when her surgeon colleague, Phillip Fleshner, MD, asked: “What about creeping fat?”

“Yeah, that’s cool,” Dr. Devkota replied, “but I don’t have access to creeping fat.”

“I see it all the time,” Dr. Fleshner said. “I can get you some.”

And so a partnership was born, allowing Dr. Devkota and colleagues to pursue the translocation hypothesis.

The present report involved tissue samples from 11 patients with Crohn’s disease and 13 patients with ulcerative colitis. Healthy tissue controls were taken from four subjects without inflammatory bowel disease who underwent ileostomy.

Microbial cultivation of Crohn’s disease and healthy patient samples revealed bacteria in the mesenteric tissue of both groups, suggesting that microbial translocation from the gut to MAT “may not be unusual;” however, Crohn’s disease samples were associated with an exclusive consortium of five species: Clostridium innocuum, Erysipeloclostridium ramosum, Parabacteroides distasonis, Clostridium symbiosum, and Bifidobacterium pseudolongum. 

C. innocuum was isolated most frequently; and its unique characteristics increased suspicions that it was the creeping fat culprit.

“Core genomic features of C. innocuum include type IV pili and twitching motility, a preference for lipid-derived metabolic substrates, and multiple genes for lipid catabolism, as well as a functional substrate preference for b-hydroxybutyrate, a byproduct of fatty acid oxidation,” the investigators wrote. “This suggests that C. innocuum is well suited for, and perhaps prefers, a lipid-rich environment and seeks these out when the opportunity arises.”

To observe this opportunism firsthand, the investigators gavaged gnotobiotic mice with C. innocuum. Indeed, these mice demonstrated “dramatic mesenteric adiposity,” compared with controls.

Cotreatment with dextran sulfate sodium (DSS) was unnecessary to induce translocation of C. innocuum, which “suggests that overt inflammation is not a prerequisite for its translocation,” the investigators noted.

The profibrotic potential of C. innocuum was supported by in vitro experiments, in which adipose-derived stem cells and primary fibroblasts from Crohn’s disease MAT were exposed to either C. innocuum lysate or macrophage-conditioned media from C. innocuum–exposed macrophages. While the lysate alone did not alter genes involved in fibrosis and remodeling, the macrophage-conditioned media did, indicating that C. innocuum alters MAT indirectly via macrophage activity.

Although multiple signs suggest that C. innocuum causes creeping fat, Dr. Devkota noted that systematic testing is needed to confirm this likelihood.

“But I do think we’ve honed in on the consortium that is at play,” she said, referring to the five identified species.

According to Dr. Devkota, awareness of these microbes could lead to diagnostic and interventional benefits for patients with Crohn’s disease. For example, gut microbiota profiling could be used to measure levels of C. innocuum in newly diagnosed patients, thereby stratifying risk of creeping fat. And phage therapy, with its high specificity for bacterial species, could be an ideal intervention.

“I’m very eager to hear from the surgeons, and hear what their opinion is, and whether this will affect their treatment or how they approach [creeping fat],” Dr. Devkota said.

Beyond Crohn’s disease, the study findings could inform obesity research, as bacterial DNA has been found in obese adipose tissue, which is characteristically fibrotic.

“There are a lot of gene-expression patterns [in the present study], that are also seen in obesity literature,” Dr. Devkota said.

“Obviously there’s a lifestyle caloric aspect to [obesity],” she added. “I definitely don’t claim that microbes are the end-all and be-all of obesity – I want to make that clear. But it could be possible, and particularly related to abdominal fat. Expanded abdominal fat could be a sign that there’s underlying intestinal inflammation ... that there’s something deeper going on that may be unrelated to a metabolic defect.”

The study was funded by Leona M. and Harry B. Helmsley Charitable Trust and the National Institutes of Health. Dr. Devkota and Dr. Ha are inventors on U.S. patent application #62/679,624.

SOURCE: Ha CWY et al. Cell. 2020 Oct 29. doi: 10.1016/j.cell.2020.09.009.

The gut-selective alpha₄beta₇ integrin antibody vedolizumab is safe and effective for long-term use in patients with inflammatory bowel disease (IBD), according to data from more than 2,200 patients in the GEMINI LTS trial.

With a median cumulative exposure of approximately 3 years and some patients taking vedolizumab for more than 9 years, the study revealed no new safety concerns and showed that responses were stable over time, reported lead author Edward V. Loftus Jr., MD, of the Mayo Clinic in Rochester, Minn., and colleagues.

“Interim analyses (based on 4 years of follow-up) demonstrated that long-term vedolizumab therapy was well-tolerated and also provided clinical and health-related quality of life (HRQOL) benefits,” the investigators wrote in Alimentary Pharmacology & Therapeutics. “In this final analysis ... we report the final safety outcomes, along with exploratory clinical and HRQOL outcomes.”

The phase 3 trial involved 1,822 patients with IBD from previous phase 2 and 3 trials, plus 421 vedolizumab-naive patients. Out of 2,243 participants in the final analysis, 894 had ulcerative colitis, and 1,349 had Crohn’s disease.

All patients received vedolizumab 300 mg IV every 4 weeks, which the investigators noted is more frequent than the dosing interval of 8 weeks that was approved after the trial was designed.

Median cumulative exposure times among patients with ulcerative colitis and Crohn’s disease were 42.4 months and 31.5 months, respectively. Adverse events of any grade occurred in 93% of patients with ulcerative colitis and 96% of patients with Crohn’s disease, approximately one-third of which were exacerbations of IBD. Serious adverse events occurred in 31% and 41% of patients with ulcerative colitis and Crohn’s disease, respectively. Adverse events led to discontinuation in 15% of ulcerative colitis patients and 17% of those with Crohn’s disease. Of the 10 deaths that occurred during the study period, the investigators categorized 2 of them as drug related (hepatocellular carcinoma and West Nile virus infection–related encephalitis). No increase in the rate of overall malignancies was observed.

Dr. Loftus and colleagues noted that rates of serious infection with vedolizumab treatment were superior to historical long-term data for adalimumab, at 18.0 (ulcerative colitis) and 33.6 (Crohn’s disease) per 1,000 person-years for vedolizumab, compared with 35 (ulcerative colitis) and 67 (Crohn’s disease) per 1,000 person-years for adalimumab, as reported by Colombel and colleagues.

“While these data suggest a decreased risk of systemic infections with vedolizumab, an increased risk of gastrointestinal infections is plausible given the gut-selective mechanism of action and evidence for reduced immune response in the gastrointestinal tract,” the investigators wrote, reporting rates of 34.9 and 39.6 per 1,000 person-years for ulcerative colitis and Crohn’s disease, respectively. Comparative, historical rates for adalimumab were not provided.

In the present trial, clinical response rates, clinical remission rates, and HRQOL estimates remained stable over time. At 400 treatment weeks, clinical remission was maintained in 33% and 28% of patients with ulcerative colitis and Crohn’s disease, respectively.

“[T]he final analysis of GEMINI LTS comprehensively demonstrates that vedolizumab therapy has a safety and tolerability profile suitable for long-term treatment of patients with moderately to severely active ulcerative colitis or Crohn’s disease,” the investigators concluded.

According to Randy Longman, MD, director of the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine and New York-Presbyterian, “The results from the GEMINI LTS trial help to solidify the favorable safety profile of vedolizumab for the treatment of IBD. With large patient numbers and cumulative duration of vedolizumab exposure, these pivotal data convincingly reveal low rates of serious infections, identified no cases of progressive multifocal leukoencephalopathy, and showed no increased risk of malignancy. Arthralgias, or joint pain, was the most common treatment-emergent adverse event, but occurred largely in patients with a history of IBD-associated arthralgia and suggest that these symptoms should be monitored during treatment. Overall, these results provide meaningful reassurance to patients and providers using vedolizumab for the treatment of IBD.”

GEMINI LTS was funded by Takeda. The investigators reported additional relationships with AbbVie, Janssen, Amgen, and others. Dr. Longman reported no conflicts of interest.

SOURCE: Loftus Jr EV et al. AP&T. 2020 Sep 2. doi: 10.1111/apt.16060.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at http://ow.ly/szHz30rdKyx.

The gut-selective alpha₄beta₇ integrin antibody vedolizumab is safe and effective for long-term use in patients with inflammatory bowel disease (IBD), according to data from more than 2,200 patients in the GEMINI LTS trial.

With a median cumulative exposure of approximately 3 years and some patients taking vedolizumab for more than 9 years, the study revealed no new safety concerns and showed that responses were stable over time, reported lead author Edward V. Loftus Jr., MD, of the Mayo Clinic in Rochester, Minn., and colleagues.

“Interim analyses (based on 4 years of follow-up) demonstrated that long-term vedolizumab therapy was well-tolerated and also provided clinical and health-related quality of life (HRQOL) benefits,” the investigators wrote in Alimentary Pharmacology & Therapeutics. “In this final analysis ... we report the final safety outcomes, along with exploratory clinical and HRQOL outcomes.”

The phase 3 trial involved 1,822 patients with IBD from previous phase 2 and 3 trials, plus 421 vedolizumab-naive patients. Out of 2,243 participants in the final analysis, 894 had ulcerative colitis, and 1,349 had Crohn’s disease.

All patients received vedolizumab 300 mg IV every 4 weeks, which the investigators noted is more frequent than the dosing interval of 8 weeks that was approved after the trial was designed.

Median cumulative exposure times among patients with ulcerative colitis and Crohn’s disease were 42.4 months and 31.5 months, respectively. Adverse events of any grade occurred in 93% of patients with ulcerative colitis and 96% of patients with Crohn’s disease, approximately one-third of which were exacerbations of IBD. Serious adverse events occurred in 31% and 41% of patients with ulcerative colitis and Crohn’s disease, respectively. Adverse events led to discontinuation in 15% of ulcerative colitis patients and 17% of those with Crohn’s disease. Of the 10 deaths that occurred during the study period, the investigators categorized 2 of them as drug related (hepatocellular carcinoma and West Nile virus infection–related encephalitis). No increase in the rate of overall malignancies was observed.

Dr. Loftus and colleagues noted that rates of serious infection with vedolizumab treatment were superior to historical long-term data for adalimumab, at 18.0 (ulcerative colitis) and 33.6 (Crohn’s disease) per 1,000 person-years for vedolizumab, compared with 35 (ulcerative colitis) and 67 (Crohn’s disease) per 1,000 person-years for adalimumab, as reported by Colombel and colleagues.

“While these data suggest a decreased risk of systemic infections with vedolizumab, an increased risk of gastrointestinal infections is plausible given the gut-selective mechanism of action and evidence for reduced immune response in the gastrointestinal tract,” the investigators wrote, reporting rates of 34.9 and 39.6 per 1,000 person-years for ulcerative colitis and Crohn’s disease, respectively. Comparative, historical rates for adalimumab were not provided.

In the present trial, clinical response rates, clinical remission rates, and HRQOL estimates remained stable over time. At 400 treatment weeks, clinical remission was maintained in 33% and 28% of patients with ulcerative colitis and Crohn’s disease, respectively.

“[T]he final analysis of GEMINI LTS comprehensively demonstrates that vedolizumab therapy has a safety and tolerability profile suitable for long-term treatment of patients with moderately to severely active ulcerative colitis or Crohn’s disease,” the investigators concluded.

According to Randy Longman, MD, director of the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine and New York-Presbyterian, “The results from the GEMINI LTS trial help to solidify the favorable safety profile of vedolizumab for the treatment of IBD. With large patient numbers and cumulative duration of vedolizumab exposure, these pivotal data convincingly reveal low rates of serious infections, identified no cases of progressive multifocal leukoencephalopathy, and showed no increased risk of malignancy. Arthralgias, or joint pain, was the most common treatment-emergent adverse event, but occurred largely in patients with a history of IBD-associated arthralgia and suggest that these symptoms should be monitored during treatment. Overall, these results provide meaningful reassurance to patients and providers using vedolizumab for the treatment of IBD.”

GEMINI LTS was funded by Takeda. The investigators reported additional relationships with AbbVie, Janssen, Amgen, and others. Dr. Longman reported no conflicts of interest.

SOURCE: Loftus Jr EV et al. AP&T. 2020 Sep 2. doi: 10.1111/apt.16060.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at http://ow.ly/szHz30rdKyx.

The gut-selective alpha₄beta₇ integrin antibody vedolizumab is safe and effective for long-term use in patients with inflammatory bowel disease (IBD), according to data from more than 2,200 patients in the GEMINI LTS trial.

With a median cumulative exposure of approximately 3 years and some patients taking vedolizumab for more than 9 years, the study revealed no new safety concerns and showed that responses were stable over time, reported lead author Edward V. Loftus Jr., MD, of the Mayo Clinic in Rochester, Minn., and colleagues.

“Interim analyses (based on 4 years of follow-up) demonstrated that long-term vedolizumab therapy was well-tolerated and also provided clinical and health-related quality of life (HRQOL) benefits,” the investigators wrote in Alimentary Pharmacology & Therapeutics. “In this final analysis ... we report the final safety outcomes, along with exploratory clinical and HRQOL outcomes.”

The phase 3 trial involved 1,822 patients with IBD from previous phase 2 and 3 trials, plus 421 vedolizumab-naive patients. Out of 2,243 participants in the final analysis, 894 had ulcerative colitis, and 1,349 had Crohn’s disease.

All patients received vedolizumab 300 mg IV every 4 weeks, which the investigators noted is more frequent than the dosing interval of 8 weeks that was approved after the trial was designed.

Median cumulative exposure times among patients with ulcerative colitis and Crohn’s disease were 42.4 months and 31.5 months, respectively. Adverse events of any grade occurred in 93% of patients with ulcerative colitis and 96% of patients with Crohn’s disease, approximately one-third of which were exacerbations of IBD. Serious adverse events occurred in 31% and 41% of patients with ulcerative colitis and Crohn’s disease, respectively. Adverse events led to discontinuation in 15% of ulcerative colitis patients and 17% of those with Crohn’s disease. Of the 10 deaths that occurred during the study period, the investigators categorized 2 of them as drug related (hepatocellular carcinoma and West Nile virus infection–related encephalitis). No increase in the rate of overall malignancies was observed.

Dr. Loftus and colleagues noted that rates of serious infection with vedolizumab treatment were superior to historical long-term data for adalimumab, at 18.0 (ulcerative colitis) and 33.6 (Crohn’s disease) per 1,000 person-years for vedolizumab, compared with 35 (ulcerative colitis) and 67 (Crohn’s disease) per 1,000 person-years for adalimumab, as reported by Colombel and colleagues.

“While these data suggest a decreased risk of systemic infections with vedolizumab, an increased risk of gastrointestinal infections is plausible given the gut-selective mechanism of action and evidence for reduced immune response in the gastrointestinal tract,” the investigators wrote, reporting rates of 34.9 and 39.6 per 1,000 person-years for ulcerative colitis and Crohn’s disease, respectively. Comparative, historical rates for adalimumab were not provided.

In the present trial, clinical response rates, clinical remission rates, and HRQOL estimates remained stable over time. At 400 treatment weeks, clinical remission was maintained in 33% and 28% of patients with ulcerative colitis and Crohn’s disease, respectively.

“[T]he final analysis of GEMINI LTS comprehensively demonstrates that vedolizumab therapy has a safety and tolerability profile suitable for long-term treatment of patients with moderately to severely active ulcerative colitis or Crohn’s disease,” the investigators concluded.

According to Randy Longman, MD, director of the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine and New York-Presbyterian, “The results from the GEMINI LTS trial help to solidify the favorable safety profile of vedolizumab for the treatment of IBD. With large patient numbers and cumulative duration of vedolizumab exposure, these pivotal data convincingly reveal low rates of serious infections, identified no cases of progressive multifocal leukoencephalopathy, and showed no increased risk of malignancy. Arthralgias, or joint pain, was the most common treatment-emergent adverse event, but occurred largely in patients with a history of IBD-associated arthralgia and suggest that these symptoms should be monitored during treatment. Overall, these results provide meaningful reassurance to patients and providers using vedolizumab for the treatment of IBD.”

GEMINI LTS was funded by Takeda. The investigators reported additional relationships with AbbVie, Janssen, Amgen, and others. Dr. Longman reported no conflicts of interest.

SOURCE: Loftus Jr EV et al. AP&T. 2020 Sep 2. doi: 10.1111/apt.16060.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at http://ow.ly/szHz30rdKyx.

The gut-selective alpha₄beta₇ integrin antibody vedolizumab is safe and effective for long-term use in patients with inflammatory bowel disease (IBD), according to data from more than 2,200 patients in the GEMINI LTS trial.

With a median cumulative exposure of approximately 3 years and some patients taking vedolizumab for more than 9 years, the study revealed no new safety concerns and showed that responses were stable over time, reported lead author Edward V. Loftus Jr., MD, of the Mayo Clinic in Rochester, Minn., and colleagues.

“Interim analyses (based on 4 years of follow-up) demonstrated that long-term vedolizumab therapy was well-tolerated and also provided clinical and health-related quality of life (HRQOL) benefits,” the investigators wrote in Alimentary Pharmacology & Therapeutics. “In this final analysis ... we report the final safety outcomes, along with exploratory clinical and HRQOL outcomes.”

The phase 3 trial involved 1,822 patients with IBD from previous phase 2 and 3 trials, plus 421 vedolizumab-naive patients. Out of 2,243 participants in the final analysis, 894 had ulcerative colitis, and 1,349 had Crohn’s disease.

All patients received vedolizumab 300 mg IV every 4 weeks, which the investigators noted is more frequent than the dosing interval of 8 weeks that was approved after the trial was designed.

Median cumulative exposure times among patients with ulcerative colitis and Crohn’s disease were 42.4 months and 31.5 months, respectively. Adverse events of any grade occurred in 93% of patients with ulcerative colitis and 96% of patients with Crohn’s disease, approximately one-third of which were exacerbations of IBD. Serious adverse events occurred in 31% and 41% of patients with ulcerative colitis and Crohn’s disease, respectively. Adverse events led to discontinuation in 15% of ulcerative colitis patients and 17% of those with Crohn’s disease. Of the 10 deaths that occurred during the study period, the investigators categorized 2 of them as drug related (hepatocellular carcinoma and West Nile virus infection–related encephalitis). No increase in the rate of overall malignancies was observed.

Dr. Loftus and colleagues noted that rates of serious infection with vedolizumab treatment were superior to historical long-term data for adalimumab, at 18.0 (ulcerative colitis) and 33.6 (Crohn’s disease) per 1,000 person-years for vedolizumab, compared with 35 (ulcerative colitis) and 67 (Crohn’s disease) per 1,000 person-years for adalimumab, as reported by Colombel and colleagues.

“While these data suggest a decreased risk of systemic infections with vedolizumab, an increased risk of gastrointestinal infections is plausible given the gut-selective mechanism of action and evidence for reduced immune response in the gastrointestinal tract,” the investigators wrote, reporting rates of 34.9 and 39.6 per 1,000 person-years for ulcerative colitis and Crohn’s disease, respectively. Comparative, historical rates for adalimumab were not provided.

In the present trial, clinical response rates, clinical remission rates, and HRQOL estimates remained stable over time. At 400 treatment weeks, clinical remission was maintained in 33% and 28% of patients with ulcerative colitis and Crohn’s disease, respectively.

“[T]he final analysis of GEMINI LTS comprehensively demonstrates that vedolizumab therapy has a safety and tolerability profile suitable for long-term treatment of patients with moderately to severely active ulcerative colitis or Crohn’s disease,” the investigators concluded.

According to Randy Longman, MD, director of the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine and New York-Presbyterian, “The results from the GEMINI LTS trial help to solidify the favorable safety profile of vedolizumab for the treatment of IBD. With large patient numbers and cumulative duration of vedolizumab exposure, these pivotal data convincingly reveal low rates of serious infections, identified no cases of progressive multifocal leukoencephalopathy, and showed no increased risk of malignancy. Arthralgias, or joint pain, was the most common treatment-emergent adverse event, but occurred largely in patients with a history of IBD-associated arthralgia and suggest that these symptoms should be monitored during treatment. Overall, these results provide meaningful reassurance to patients and providers using vedolizumab for the treatment of IBD.”

GEMINI LTS was funded by Takeda. The investigators reported additional relationships with AbbVie, Janssen, Amgen, and others. Dr. Longman reported no conflicts of interest.

SOURCE: Loftus Jr EV et al. AP&T. 2020 Sep 2. doi: 10.1111/apt.16060.

The gut-selective alpha₄beta₇ integrin antibody vedolizumab is safe and effective for long-term use in patients with inflammatory bowel disease (IBD), according to data from more than 2,200 patients in the GEMINI LTS trial.

With a median cumulative exposure of approximately 3 years and some patients taking vedolizumab for more than 9 years, the study revealed no new safety concerns and showed that responses were stable over time, reported lead author Edward V. Loftus Jr., MD, of the Mayo Clinic in Rochester, Minn., and colleagues.

“Interim analyses (based on 4 years of follow-up) demonstrated that long-term vedolizumab therapy was well-tolerated and also provided clinical and health-related quality of life (HRQOL) benefits,” the investigators wrote in Alimentary Pharmacology & Therapeutics. “In this final analysis ... we report the final safety outcomes, along with exploratory clinical and HRQOL outcomes.”

The phase 3 trial involved 1,822 patients with IBD from previous phase 2 and 3 trials, plus 421 vedolizumab-naive patients. Out of 2,243 participants in the final analysis, 894 had ulcerative colitis, and 1,349 had Crohn’s disease.

All patients received vedolizumab 300 mg IV every 4 weeks, which the investigators noted is more frequent than the dosing interval of 8 weeks that was approved after the trial was designed.

Median cumulative exposure times among patients with ulcerative colitis and Crohn’s disease were 42.4 months and 31.5 months, respectively. Adverse events of any grade occurred in 93% of patients with ulcerative colitis and 96% of patients with Crohn’s disease, approximately one-third of which were exacerbations of IBD. Serious adverse events occurred in 31% and 41% of patients with ulcerative colitis and Crohn’s disease, respectively. Adverse events led to discontinuation in 15% of ulcerative colitis patients and 17% of those with Crohn’s disease. Of the 10 deaths that occurred during the study period, the investigators categorized 2 of them as drug related (hepatocellular carcinoma and West Nile virus infection–related encephalitis). No increase in the rate of overall malignancies was observed.

Dr. Loftus and colleagues noted that rates of serious infection with vedolizumab treatment were superior to historical long-term data for adalimumab, at 18.0 (ulcerative colitis) and 33.6 (Crohn’s disease) per 1,000 person-years for vedolizumab, compared with 35 (ulcerative colitis) and 67 (Crohn’s disease) per 1,000 person-years for adalimumab, as reported by Colombel and colleagues.

“While these data suggest a decreased risk of systemic infections with vedolizumab, an increased risk of gastrointestinal infections is plausible given the gut-selective mechanism of action and evidence for reduced immune response in the gastrointestinal tract,” the investigators wrote, reporting rates of 34.9 and 39.6 per 1,000 person-years for ulcerative colitis and Crohn’s disease, respectively. Comparative, historical rates for adalimumab were not provided.

In the present trial, clinical response rates, clinical remission rates, and HRQOL estimates remained stable over time. At 400 treatment weeks, clinical remission was maintained in 33% and 28% of patients with ulcerative colitis and Crohn’s disease, respectively.

“[T]he final analysis of GEMINI LTS comprehensively demonstrates that vedolizumab therapy has a safety and tolerability profile suitable for long-term treatment of patients with moderately to severely active ulcerative colitis or Crohn’s disease,” the investigators concluded.

According to Randy Longman, MD, director of the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine and New York-Presbyterian, “The results from the GEMINI LTS trial help to solidify the favorable safety profile of vedolizumab for the treatment of IBD. With large patient numbers and cumulative duration of vedolizumab exposure, these pivotal data convincingly reveal low rates of serious infections, identified no cases of progressive multifocal leukoencephalopathy, and showed no increased risk of malignancy. Arthralgias, or joint pain, was the most common treatment-emergent adverse event, but occurred largely in patients with a history of IBD-associated arthralgia and suggest that these symptoms should be monitored during treatment. Overall, these results provide meaningful reassurance to patients and providers using vedolizumab for the treatment of IBD.”

GEMINI LTS was funded by Takeda. The investigators reported additional relationships with AbbVie, Janssen, Amgen, and others. Dr. Longman reported no conflicts of interest.

SOURCE: Loftus Jr EV et al. AP&T. 2020 Sep 2. doi: 10.1111/apt.16060.

The gut-selective alpha₄beta₇ integrin antibody vedolizumab is safe and effective for long-term use in patients with inflammatory bowel disease (IBD), according to data from more than 2,200 patients in the GEMINI LTS trial.

With a median cumulative exposure of approximately 3 years and some patients taking vedolizumab for more than 9 years, the study revealed no new safety concerns and showed that responses were stable over time, reported lead author Edward V. Loftus Jr., MD, of the Mayo Clinic in Rochester, Minn., and colleagues.

“Interim analyses (based on 4 years of follow-up) demonstrated that long-term vedolizumab therapy was well-tolerated and also provided clinical and health-related quality of life (HRQOL) benefits,” the investigators wrote in Alimentary Pharmacology & Therapeutics. “In this final analysis ... we report the final safety outcomes, along with exploratory clinical and HRQOL outcomes.”

The phase 3 trial involved 1,822 patients with IBD from previous phase 2 and 3 trials, plus 421 vedolizumab-naive patients. Out of 2,243 participants in the final analysis, 894 had ulcerative colitis, and 1,349 had Crohn’s disease.

All patients received vedolizumab 300 mg IV every 4 weeks, which the investigators noted is more frequent than the dosing interval of 8 weeks that was approved after the trial was designed.

Median cumulative exposure times among patients with ulcerative colitis and Crohn’s disease were 42.4 months and 31.5 months, respectively. Adverse events of any grade occurred in 93% of patients with ulcerative colitis and 96% of patients with Crohn’s disease, approximately one-third of which were exacerbations of IBD. Serious adverse events occurred in 31% and 41% of patients with ulcerative colitis and Crohn’s disease, respectively. Adverse events led to discontinuation in 15% of ulcerative colitis patients and 17% of those with Crohn’s disease. Of the 10 deaths that occurred during the study period, the investigators categorized 2 of them as drug related (hepatocellular carcinoma and West Nile virus infection–related encephalitis). No increase in the rate of overall malignancies was observed.

Dr. Loftus and colleagues noted that rates of serious infection with vedolizumab treatment were superior to historical long-term data for adalimumab, at 18.0 (ulcerative colitis) and 33.6 (Crohn’s disease) per 1,000 person-years for vedolizumab, compared with 35 (ulcerative colitis) and 67 (Crohn’s disease) per 1,000 person-years for adalimumab, as reported by Colombel and colleagues.

“While these data suggest a decreased risk of systemic infections with vedolizumab, an increased risk of gastrointestinal infections is plausible given the gut-selective mechanism of action and evidence for reduced immune response in the gastrointestinal tract,” the investigators wrote, reporting rates of 34.9 and 39.6 per 1,000 person-years for ulcerative colitis and Crohn’s disease, respectively. Comparative, historical rates for adalimumab were not provided.

In the present trial, clinical response rates, clinical remission rates, and HRQOL estimates remained stable over time. At 400 treatment weeks, clinical remission was maintained in 33% and 28% of patients with ulcerative colitis and Crohn’s disease, respectively.

“[T]he final analysis of GEMINI LTS comprehensively demonstrates that vedolizumab therapy has a safety and tolerability profile suitable for long-term treatment of patients with moderately to severely active ulcerative colitis or Crohn’s disease,” the investigators concluded.

According to Randy Longman, MD, director of the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine and New York-Presbyterian, “The results from the GEMINI LTS trial help to solidify the favorable safety profile of vedolizumab for the treatment of IBD. With large patient numbers and cumulative duration of vedolizumab exposure, these pivotal data convincingly reveal low rates of serious infections, identified no cases of progressive multifocal leukoencephalopathy, and showed no increased risk of malignancy. Arthralgias, or joint pain, was the most common treatment-emergent adverse event, but occurred largely in patients with a history of IBD-associated arthralgia and suggest that these symptoms should be monitored during treatment. Overall, these results provide meaningful reassurance to patients and providers using vedolizumab for the treatment of IBD.”

GEMINI LTS was funded by Takeda. The investigators reported additional relationships with AbbVie, Janssen, Amgen, and others. Dr. Longman reported no conflicts of interest.

SOURCE: Loftus Jr EV et al. AP&T. 2020 Sep 2. doi: 10.1111/apt.16060.

In patients with pediatric-onset multiple sclerosis (MS), increased abundance of Blautia stercoris and its variants in the gut is associated with an increased risk of relapse. No broad differences in gut bacterial composition, however, are associated with risk of relapse, according to the investigators. The findings were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Previous research has found an association between Blautia stercoris and disease activity in other immune-mediated diseases such as systemic lupus. Although the current study is the largest in patients with MS that includes data about the microbiome and relapses, its findings require replication, said Mary Horton, a doctoral candidate in epidemiology at the University of California, Berkeley.

Gut microbes digest food, produce vitamins (for example, B12 and K), create a barrier against pathogens, and regulate the immune system, among other tasks. Most current knowledge about the gut microbiome in MS comes from studies of patients with adult-onset MS. In 2016, Tremlett et al. found an increase in Desulfovibrionaceae and a decrease in Lachnospiraceae and Ruminococcaceae in patients with pediatric-onset MS. They also found that a decrease in Fusobacteria was associated with risk of relapse in this population.
 

Advanced analytical methods

Using a larger sample size and newer analytical methods than in the study by Tremlett and colleagues, Ms. Horton’s group sought to determine whether features of the gut microbiome are associated with relapse. From 2014 to 2018, the investigators recruited 53 patients with pediatric-onset MS from the University of California, San Francisco, and six centers in the U.S. Network of Pediatric MS Centers. At baseline, they collected stool samples, blood samples, information about past relapses, medication records, demographics, and environmental factors. At each relapse, the investigators collected information about the patient’s current and past medication use and about relapses that the patient had had since the previous visit.

Ms. Horton and colleagues analyzed the stool samples using 16S rRNA sequencing of the V4 region. They identified amplicon sequence variants (ASVs), which are used to define species of bacteria, with the Divisive Amplicon Denoising Algorithm-2 (DADA2). Taxonomies were assigned using the naive Bayesian classifier method, and the read count was normalized using multiple rarefaction.

The investigators identified ASV clusters using weighted genetic correlation network analysis (WGCNA). To evaluate whether individual ASVs were associated with relapse, they used a Prentice, Williams, and Peterson (PWP) recurrent event model, an extension of the Cox proportional hazards model.
 

The role of methanogenesis

Ms. Horton and colleagues included 53 patients (72% girls) in their study. The population’s mean age was 14.3 years at disease onset and 15.5 years at stool sample collection. About 70% of patients were White, and about 36% were Hispanic. Mean disease duration was 1.3 years, and median Expanded Disability Status Scale score was 1.0.

Approximately 45% of participants had one relapse, and 30% had more than one relapse during the subsequent mean follow-up of 2.5 years. About 91% of patients used a disease-modifying therapy during follow-up.

Gut bacterial abundance was broadly similar between patients who relapsed during the study period and those who did not. Of 270 ASVs included in the analyses, 20 were nominally associated with risk of relapse. Blautia stercoris had the most significant association with relapse risk (hazard ratio, 2.50). Blautia massiliensis also was among the 20 ASVs associated with risk of relapse.

WGCNA identified six ASV clusters. Higher values of one cluster’s eigengene were significantly associated with higher relapse risk (HR, 1.23). The following four ASVs nominally associated with higher relapse risk were in this cluster: Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.

When Ms. Horton and colleagues examined the pathways from these bacterial species, they found 10 that were significantly associated with the risk of relapse. Four of these 10 pathways are involved in methane production, which suggests the involvement of methanogenesis pathways in relapse.

Although the investigators used advanced techniques for genetic and statistical analysis, the study’s sample size is small, Ms. Horton acknowledged. In addition, the conclusions that can be drawn from observational data are limited.

These suggest several avenues for future research. “There is a big question about how the different treatments that people are on when they are experiencing relapses might impact the microbiome,” said Ms. Horton. “Is the microbiome impacting your treatment response, or is it the reverse?” Investigators also could examine why the methane production pathway is overrepresented among people with MS who have relapses. “Which specific archaea might be leading to that increase in methane is a ripe future study question. Just what that means for health is really unknown.”

The National MS Society and the National Institute of Neurological Disorders and Stroke provided funding for the study. Ms. Horton had no disclosures.

[email protected]

SOURCE: Horton M et al. MSVirtual2020, Abstract LB01.05.

In patients with pediatric-onset multiple sclerosis (MS), increased abundance of Blautia stercoris and its variants in the gut is associated with an increased risk of relapse. No broad differences in gut bacterial composition, however, are associated with risk of relapse, according to the investigators. The findings were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Previous research has found an association between Blautia stercoris and disease activity in other immune-mediated diseases such as systemic lupus. Although the current study is the largest in patients with MS that includes data about the microbiome and relapses, its findings require replication, said Mary Horton, a doctoral candidate in epidemiology at the University of California, Berkeley.

Gut microbes digest food, produce vitamins (for example, B12 and K), create a barrier against pathogens, and regulate the immune system, among other tasks. Most current knowledge about the gut microbiome in MS comes from studies of patients with adult-onset MS. In 2016, Tremlett et al. found an increase in Desulfovibrionaceae and a decrease in Lachnospiraceae and Ruminococcaceae in patients with pediatric-onset MS. They also found that a decrease in Fusobacteria was associated with risk of relapse in this population.
 

Advanced analytical methods

Using a larger sample size and newer analytical methods than in the study by Tremlett and colleagues, Ms. Horton’s group sought to determine whether features of the gut microbiome are associated with relapse. From 2014 to 2018, the investigators recruited 53 patients with pediatric-onset MS from the University of California, San Francisco, and six centers in the U.S. Network of Pediatric MS Centers. At baseline, they collected stool samples, blood samples, information about past relapses, medication records, demographics, and environmental factors. At each relapse, the investigators collected information about the patient’s current and past medication use and about relapses that the patient had had since the previous visit.

Ms. Horton and colleagues analyzed the stool samples using 16S rRNA sequencing of the V4 region. They identified amplicon sequence variants (ASVs), which are used to define species of bacteria, with the Divisive Amplicon Denoising Algorithm-2 (DADA2). Taxonomies were assigned using the naive Bayesian classifier method, and the read count was normalized using multiple rarefaction.

The investigators identified ASV clusters using weighted genetic correlation network analysis (WGCNA). To evaluate whether individual ASVs were associated with relapse, they used a Prentice, Williams, and Peterson (PWP) recurrent event model, an extension of the Cox proportional hazards model.
 

The role of methanogenesis

Ms. Horton and colleagues included 53 patients (72% girls) in their study. The population’s mean age was 14.3 years at disease onset and 15.5 years at stool sample collection. About 70% of patients were White, and about 36% were Hispanic. Mean disease duration was 1.3 years, and median Expanded Disability Status Scale score was 1.0.

Approximately 45% of participants had one relapse, and 30% had more than one relapse during the subsequent mean follow-up of 2.5 years. About 91% of patients used a disease-modifying therapy during follow-up.

Gut bacterial abundance was broadly similar between patients who relapsed during the study period and those who did not. Of 270 ASVs included in the analyses, 20 were nominally associated with risk of relapse. Blautia stercoris had the most significant association with relapse risk (hazard ratio, 2.50). Blautia massiliensis also was among the 20 ASVs associated with risk of relapse.

WGCNA identified six ASV clusters. Higher values of one cluster’s eigengene were significantly associated with higher relapse risk (HR, 1.23). The following four ASVs nominally associated with higher relapse risk were in this cluster: Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.

When Ms. Horton and colleagues examined the pathways from these bacterial species, they found 10 that were significantly associated with the risk of relapse. Four of these 10 pathways are involved in methane production, which suggests the involvement of methanogenesis pathways in relapse.

Although the investigators used advanced techniques for genetic and statistical analysis, the study’s sample size is small, Ms. Horton acknowledged. In addition, the conclusions that can be drawn from observational data are limited.

These suggest several avenues for future research. “There is a big question about how the different treatments that people are on when they are experiencing relapses might impact the microbiome,” said Ms. Horton. “Is the microbiome impacting your treatment response, or is it the reverse?” Investigators also could examine why the methane production pathway is overrepresented among people with MS who have relapses. “Which specific archaea might be leading to that increase in methane is a ripe future study question. Just what that means for health is really unknown.”

The National MS Society and the National Institute of Neurological Disorders and Stroke provided funding for the study. Ms. Horton had no disclosures.

[email protected]

SOURCE: Horton M et al. MSVirtual2020, Abstract LB01.05.

In patients with pediatric-onset multiple sclerosis (MS), increased abundance of Blautia stercoris and its variants in the gut is associated with an increased risk of relapse. No broad differences in gut bacterial composition, however, are associated with risk of relapse, according to the investigators. The findings were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Previous research has found an association between Blautia stercoris and disease activity in other immune-mediated diseases such as systemic lupus. Although the current study is the largest in patients with MS that includes data about the microbiome and relapses, its findings require replication, said Mary Horton, a doctoral candidate in epidemiology at the University of California, Berkeley.

Gut microbes digest food, produce vitamins (for example, B12 and K), create a barrier against pathogens, and regulate the immune system, among other tasks. Most current knowledge about the gut microbiome in MS comes from studies of patients with adult-onset MS. In 2016, Tremlett et al. found an increase in Desulfovibrionaceae and a decrease in Lachnospiraceae and Ruminococcaceae in patients with pediatric-onset MS. They also found that a decrease in Fusobacteria was associated with risk of relapse in this population.
 

Advanced analytical methods

Using a larger sample size and newer analytical methods than in the study by Tremlett and colleagues, Ms. Horton’s group sought to determine whether features of the gut microbiome are associated with relapse. From 2014 to 2018, the investigators recruited 53 patients with pediatric-onset MS from the University of California, San Francisco, and six centers in the U.S. Network of Pediatric MS Centers. At baseline, they collected stool samples, blood samples, information about past relapses, medication records, demographics, and environmental factors. At each relapse, the investigators collected information about the patient’s current and past medication use and about relapses that the patient had had since the previous visit.

Ms. Horton and colleagues analyzed the stool samples using 16S rRNA sequencing of the V4 region. They identified amplicon sequence variants (ASVs), which are used to define species of bacteria, with the Divisive Amplicon Denoising Algorithm-2 (DADA2). Taxonomies were assigned using the naive Bayesian classifier method, and the read count was normalized using multiple rarefaction.

The investigators identified ASV clusters using weighted genetic correlation network analysis (WGCNA). To evaluate whether individual ASVs were associated with relapse, they used a Prentice, Williams, and Peterson (PWP) recurrent event model, an extension of the Cox proportional hazards model.
 

The role of methanogenesis

Ms. Horton and colleagues included 53 patients (72% girls) in their study. The population’s mean age was 14.3 years at disease onset and 15.5 years at stool sample collection. About 70% of patients were White, and about 36% were Hispanic. Mean disease duration was 1.3 years, and median Expanded Disability Status Scale score was 1.0.

Approximately 45% of participants had one relapse, and 30% had more than one relapse during the subsequent mean follow-up of 2.5 years. About 91% of patients used a disease-modifying therapy during follow-up.

Gut bacterial abundance was broadly similar between patients who relapsed during the study period and those who did not. Of 270 ASVs included in the analyses, 20 were nominally associated with risk of relapse. Blautia stercoris had the most significant association with relapse risk (hazard ratio, 2.50). Blautia massiliensis also was among the 20 ASVs associated with risk of relapse.

WGCNA identified six ASV clusters. Higher values of one cluster’s eigengene were significantly associated with higher relapse risk (HR, 1.23). The following four ASVs nominally associated with higher relapse risk were in this cluster: Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.

When Ms. Horton and colleagues examined the pathways from these bacterial species, they found 10 that were significantly associated with the risk of relapse. Four of these 10 pathways are involved in methane production, which suggests the involvement of methanogenesis pathways in relapse.

Although the investigators used advanced techniques for genetic and statistical analysis, the study’s sample size is small, Ms. Horton acknowledged. In addition, the conclusions that can be drawn from observational data are limited.

These suggest several avenues for future research. “There is a big question about how the different treatments that people are on when they are experiencing relapses might impact the microbiome,” said Ms. Horton. “Is the microbiome impacting your treatment response, or is it the reverse?” Investigators also could examine why the methane production pathway is overrepresented among people with MS who have relapses. “Which specific archaea might be leading to that increase in methane is a ripe future study question. Just what that means for health is really unknown.”

The National MS Society and the National Institute of Neurological Disorders and Stroke provided funding for the study. Ms. Horton had no disclosures.

[email protected]

SOURCE: Horton M et al. MSVirtual2020, Abstract LB01.05.

A new group of nonhormonal drugs currently in clinical trials shows strong promise for treating menopausal hot flashes as effectively as hormones, researchers told attendees at the virtual North American Menopause Society 2020 Annual Meeting.

“The KNDy [kisspeptin/neurokinin B/dynorphin] neuron manipulation is really exciting and holds great promise for rapid and highly effective amelioration of hot flashes, up to 80%, and improvement in other menopausal symptoms, though we’re still looking at the safety in phase 3 trials,” reported Susan D. Reed, MD, MPH, director of the Women’s Reproductive Health Research Program at the University of Washington, Seattle.

“If we continue to see good safety data, these are going to be the greatest things since sliced bread,” Dr. Reed said in an interview. “I don’t think we’ve seen anything like this in menopause therapeutics in a long time.”

While several nonhormonal drugs are already used to treat vasomotor symptoms in menopausal women with and without breast cancer, none are as effective as hormone treatments.

“For now, the SSRIs, SNRIs [serotonin norepinephrine reuptake inhibitors], and GABAergics are the best frontline nonhormonal options with a moderate effect, and clonidine and oxybutynin are effective, but we see more side effects with these,” Dr. Reed said. She noted the importance of considering patients’ mood, sleep, pain, sexual function, weight gain, overactive bladder, blood pressure, and individual quality of life (QOL) goals in tailoring those therapies.

But women still need more nonhormonal options that are at least as effective as hormonal options, Dr. Reed said. Some women are unable to take hormonal options because they are at risk for blood clots or breast cancer.

“Then there’s preference,” she said. “Sometimes people don’t like the way they feel when they take hormones, or they just don’t want hormones in their body. It’s absolutely critical to have these options available for women.”

Nanette F. Santoro, MD, a professor of ob.gyn. at the University of Colorado at Denver, Aurora, who was not involved in the presentation, said in an interview that physicians may not always realize the extent to which vasomotor symptoms interfere with women’s daily lives.

“They have an eroding effect on QOL that is not appreciated sometimes,” she said. Though hot flashes eventually subside in most women, others may continue to experience them into their 70s, when hormonal therapies can begin causing more harm than benefit.

“It goes underappreciated that, for a proportion of women, hot flashes will never go away, and they’re just as bad [as] when they were in their 50s,” Dr. Santoro said. “They need to be treated, and the nonhormonal treatments do not work for everybody.”
 

Promising KNDy therapeutics

Autopsy studies of postmenopausal women revealed that a complex of neurons in the hypothalamus was “massively hypertrophied” and sits right next to the thermoregulatory center of the brain, Dr. Reed explained.

The complex produces three types of molecules: kisspeptin (a neuropeptide), neurokinin B (a neuropeptide), and dynorphin (a kappa opioid), collectively referred to as the KNDy. The KNDy neural complex is located in the same place as the majority of hormone receptors in the arcuate nucleus, a collection of nerve cells in the hypothalamus.

The current hypothesis is that the KNDy neurons, which communicate with each other, become hyperactivated and cause hot flashes by spilling over to and triggering the thermoregulatory center next door. NKB (kisspeptin and neurokinin B) agonists activate KNDy neurons and dynorphin agonists inactivate KNDy, so the expectation is that NKB antagonists or dynorphin agonists would stop hot flashes.

Indeed, research published in 2015 showed that women taking kappa agonists experienced fewer hot flashes than women in the placebo group. However, no peripherally restricted kappa agonists are currently in clinical trials, so their future as therapeutics is unclear.

Right now, three different NK antagonists are in the pipeline for reducing vasomotor symptoms: MLE 4901 (pavinetant) and ESN364 (fezolinetant) are both NK3R antagonists, and NT-814 is a dual NK1R/NK3R antagonist. All three of these drugs were originally developed to treat schizophrenia.

Phase 2 clinical trials of pavinetant were discontinued in November 2017 by Millendo Therapeutics because 3 of 28 women experienced abnormal liver function, which normalized within 90 days. However, the study had shown an 80% decrease in hot flashes in women taking pavinetant, compared with a 30% decrease in the placebo group.

Fezolinetant, currently in phase 3 trials with Astellas, showed a dose response effect on reproductive hormones in phase 1 studies and a short half-life (4-6 hours) in women. It also showed no concerning side effects.

“There was, in fact, a decrease in the endometrial thickness, a delayed or impeded ovulation and a prolonged cycle duration,” Reed said.

The subsequent phase 2a study showed a reduction of five hot flashes a day (93% decrease), compared with placebo (54% decrease, P <.001) “with an abrupt return to baseline hot flash frequency after cessation,” she said. Improvements also occurred in sleep quality, quality of life, disability, and interference of hot flashes in daily life.

The phase 2b study found no difference in effects between once-daily versus twice-daily doses. However, two severe adverse events occurred: a drug-induced liver injury in one woman and cholelithiasis in another, both on the 60-mg, once-daily dose. Additionally, five women on varying doses had transient increases (above 1000 U/L) in creatinine kinase, though apparently without dose response.

A 52-week, three-arm, phase 3 trial of fezolinetant is currently under way with a goal of enrolling 1,740 participants, and plans to be completed by December 2021. Participants will undergo regular adverse event screening first biweekly, then monthly, with vital signs, blood, and urine monitoring.

Meanwhile, NT-814 from KaNDy Therapeutics, has completed phase 2a and phase 2b trials with phase 3 slated to begin in 2021. Adverse events in phase 1 included sleepiness and headache, and it had a long half-life (about 26 hours) and rapid absorption (an hour).

The phase 2a trial found a reduction of five hot flashes a day, compared with placebo, with main side effects again being sleepiness and headache. No events of abnormal liver function occurred. Phase 2b results have not been published.

So far, existing research suggests that KNDy interventions will involve a single daily oral dose that begins taking effect within 3 days and is fully in effect within 1-2 weeks. The reduction in hot flashes, about five fewer a day, is more effective than any other currently used nonhormonal medications for vasomotor symptoms. SSRIs and SNRIs tend to result in 1.5-2 fewer hot flashes a day, and gabapentin results in about 3 fewer per day. It will take longer-term studies, however, and paying attention to liver concerns for the NK3R antagonists to move into clinic.

“We want to keep our eye on the [luteinizing hormone] because if it decreases too much, it could adversely affect sexual function, and this does appear to be a dose-response finding,” Dr. Reed said. It would also be ideal, she said, to target only the KNDy neurons with NK3 antagonists without effects on the NK3 receptors in the liver.
 

Other nonhormonal options

Oxybutynin is another a nonhormonal agent under investigation for vasomotor symptoms. It’s an anticholinergic that resulted in 80% fewer hot flashes, compared with 30% with placebo in a 2016 trial, but 52% of women complained of dry mouth. A more recent study similarly found high efficacy – a 60%-80% drop in hot flashes, compared with 30% with placebo – but also side effects of dry mouth, difficulty urinating, and abdominal pain.

Finally, Dr. Reed mentioned three other agents under investigation as possible nonhormonal therapeutics, though she has little information about them. They include MT-8554 by Mitsubishi Tanabe; FP-101 by Fervent Pharmaceuticals; and Q-122 by QUE Oncology with Emory University, Atlanta, and the University of Queensland, Brisbane, Australia. 

None of the currently available nonhormonal options provide as high efficacy as hormones, but they do reduce symptoms:

Clonidine is an off-label option some physicians already use as a nonhormonal treatment for vasomotor symptoms, but again, the side effects are problematic: dry mouth, constipation, drowsiness, postural hypotension, and poor sleep.

Paroxetine, at 7.5-10 mg, is the only FDA-approved nonhormonal treatment for vasomotor symptoms, but she listed other off-label options found effective in evidence reviews: gabapentin (100-2,400 mg), venlafaxine (37.5-75 mg), citalopram (10 mg), desvenlafaxine (150 mg), and escitalopram (10 mg).

“I want you to take note of the lower doses in all of these products that are efficacious above those doses that might be used for mood,” Dr. Reed added.

Dr. Reed receives royalties from UpToDate and research funding from Bayer. Dr. Santoro owns stock in MenoGeniX and serves as a consultant or advisor to Ansh Labs, MenoGeniX, and Ogeda/Astellas.

A version of this article originally appeared on Medscape.com.

A new group of nonhormonal drugs currently in clinical trials shows strong promise for treating menopausal hot flashes as effectively as hormones, researchers told attendees at the virtual North American Menopause Society 2020 Annual Meeting.

“The KNDy [kisspeptin/neurokinin B/dynorphin] neuron manipulation is really exciting and holds great promise for rapid and highly effective amelioration of hot flashes, up to 80%, and improvement in other menopausal symptoms, though we’re still looking at the safety in phase 3 trials,” reported Susan D. Reed, MD, MPH, director of the Women’s Reproductive Health Research Program at the University of Washington, Seattle.

“If we continue to see good safety data, these are going to be the greatest things since sliced bread,” Dr. Reed said in an interview. “I don’t think we’ve seen anything like this in menopause therapeutics in a long time.”

While several nonhormonal drugs are already used to treat vasomotor symptoms in menopausal women with and without breast cancer, none are as effective as hormone treatments.

“For now, the SSRIs, SNRIs [serotonin norepinephrine reuptake inhibitors], and GABAergics are the best frontline nonhormonal options with a moderate effect, and clonidine and oxybutynin are effective, but we see more side effects with these,” Dr. Reed said. She noted the importance of considering patients’ mood, sleep, pain, sexual function, weight gain, overactive bladder, blood pressure, and individual quality of life (QOL) goals in tailoring those therapies.

But women still need more nonhormonal options that are at least as effective as hormonal options, Dr. Reed said. Some women are unable to take hormonal options because they are at risk for blood clots or breast cancer.

“Then there’s preference,” she said. “Sometimes people don’t like the way they feel when they take hormones, or they just don’t want hormones in their body. It’s absolutely critical to have these options available for women.”

Nanette F. Santoro, MD, a professor of ob.gyn. at the University of Colorado at Denver, Aurora, who was not involved in the presentation, said in an interview that physicians may not always realize the extent to which vasomotor symptoms interfere with women’s daily lives.

“They have an eroding effect on QOL that is not appreciated sometimes,” she said. Though hot flashes eventually subside in most women, others may continue to experience them into their 70s, when hormonal therapies can begin causing more harm than benefit.

“It goes underappreciated that, for a proportion of women, hot flashes will never go away, and they’re just as bad [as] when they were in their 50s,” Dr. Santoro said. “They need to be treated, and the nonhormonal treatments do not work for everybody.”
 

Promising KNDy therapeutics

Autopsy studies of postmenopausal women revealed that a complex of neurons in the hypothalamus was “massively hypertrophied” and sits right next to the thermoregulatory center of the brain, Dr. Reed explained.

The complex produces three types of molecules: kisspeptin (a neuropeptide), neurokinin B (a neuropeptide), and dynorphin (a kappa opioid), collectively referred to as the KNDy. The KNDy neural complex is located in the same place as the majority of hormone receptors in the arcuate nucleus, a collection of nerve cells in the hypothalamus.

The current hypothesis is that the KNDy neurons, which communicate with each other, become hyperactivated and cause hot flashes by spilling over to and triggering the thermoregulatory center next door. NKB (kisspeptin and neurokinin B) agonists activate KNDy neurons and dynorphin agonists inactivate KNDy, so the expectation is that NKB antagonists or dynorphin agonists would stop hot flashes.

Indeed, research published in 2015 showed that women taking kappa agonists experienced fewer hot flashes than women in the placebo group. However, no peripherally restricted kappa agonists are currently in clinical trials, so their future as therapeutics is unclear.

Right now, three different NK antagonists are in the pipeline for reducing vasomotor symptoms: MLE 4901 (pavinetant) and ESN364 (fezolinetant) are both NK3R antagonists, and NT-814 is a dual NK1R/NK3R antagonist. All three of these drugs were originally developed to treat schizophrenia.

Phase 2 clinical trials of pavinetant were discontinued in November 2017 by Millendo Therapeutics because 3 of 28 women experienced abnormal liver function, which normalized within 90 days. However, the study had shown an 80% decrease in hot flashes in women taking pavinetant, compared with a 30% decrease in the placebo group.

Fezolinetant, currently in phase 3 trials with Astellas, showed a dose response effect on reproductive hormones in phase 1 studies and a short half-life (4-6 hours) in women. It also showed no concerning side effects.

“There was, in fact, a decrease in the endometrial thickness, a delayed or impeded ovulation and a prolonged cycle duration,” Reed said.

The subsequent phase 2a study showed a reduction of five hot flashes a day (93% decrease), compared with placebo (54% decrease, P <.001) “with an abrupt return to baseline hot flash frequency after cessation,” she said. Improvements also occurred in sleep quality, quality of life, disability, and interference of hot flashes in daily life.

The phase 2b study found no difference in effects between once-daily versus twice-daily doses. However, two severe adverse events occurred: a drug-induced liver injury in one woman and cholelithiasis in another, both on the 60-mg, once-daily dose. Additionally, five women on varying doses had transient increases (above 1000 U/L) in creatinine kinase, though apparently without dose response.

A 52-week, three-arm, phase 3 trial of fezolinetant is currently under way with a goal of enrolling 1,740 participants, and plans to be completed by December 2021. Participants will undergo regular adverse event screening first biweekly, then monthly, with vital signs, blood, and urine monitoring.

Meanwhile, NT-814 from KaNDy Therapeutics, has completed phase 2a and phase 2b trials with phase 3 slated to begin in 2021. Adverse events in phase 1 included sleepiness and headache, and it had a long half-life (about 26 hours) and rapid absorption (an hour).

The phase 2a trial found a reduction of five hot flashes a day, compared with placebo, with main side effects again being sleepiness and headache. No events of abnormal liver function occurred. Phase 2b results have not been published.

So far, existing research suggests that KNDy interventions will involve a single daily oral dose that begins taking effect within 3 days and is fully in effect within 1-2 weeks. The reduction in hot flashes, about five fewer a day, is more effective than any other currently used nonhormonal medications for vasomotor symptoms. SSRIs and SNRIs tend to result in 1.5-2 fewer hot flashes a day, and gabapentin results in about 3 fewer per day. It will take longer-term studies, however, and paying attention to liver concerns for the NK3R antagonists to move into clinic.

“We want to keep our eye on the [luteinizing hormone] because if it decreases too much, it could adversely affect sexual function, and this does appear to be a dose-response finding,” Dr. Reed said. It would also be ideal, she said, to target only the KNDy neurons with NK3 antagonists without effects on the NK3 receptors in the liver.
 

Other nonhormonal options

Oxybutynin is another a nonhormonal agent under investigation for vasomotor symptoms. It’s an anticholinergic that resulted in 80% fewer hot flashes, compared with 30% with placebo in a 2016 trial, but 52% of women complained of dry mouth. A more recent study similarly found high efficacy – a 60%-80% drop in hot flashes, compared with 30% with placebo – but also side effects of dry mouth, difficulty urinating, and abdominal pain.

Finally, Dr. Reed mentioned three other agents under investigation as possible nonhormonal therapeutics, though she has little information about them. They include MT-8554 by Mitsubishi Tanabe; FP-101 by Fervent Pharmaceuticals; and Q-122 by QUE Oncology with Emory University, Atlanta, and the University of Queensland, Brisbane, Australia. 

None of the currently available nonhormonal options provide as high efficacy as hormones, but they do reduce symptoms:

Clonidine is an off-label option some physicians already use as a nonhormonal treatment for vasomotor symptoms, but again, the side effects are problematic: dry mouth, constipation, drowsiness, postural hypotension, and poor sleep.

Paroxetine, at 7.5-10 mg, is the only FDA-approved nonhormonal treatment for vasomotor symptoms, but she listed other off-label options found effective in evidence reviews: gabapentin (100-2,400 mg), venlafaxine (37.5-75 mg), citalopram (10 mg), desvenlafaxine (150 mg), and escitalopram (10 mg).

“I want you to take note of the lower doses in all of these products that are efficacious above those doses that might be used for mood,” Dr. Reed added.

Dr. Reed receives royalties from UpToDate and research funding from Bayer. Dr. Santoro owns stock in MenoGeniX and serves as a consultant or advisor to Ansh Labs, MenoGeniX, and Ogeda/Astellas.

A version of this article originally appeared on Medscape.com.

A new group of nonhormonal drugs currently in clinical trials shows strong promise for treating menopausal hot flashes as effectively as hormones, researchers told attendees at the virtual North American Menopause Society 2020 Annual Meeting.

“The KNDy [kisspeptin/neurokinin B/dynorphin] neuron manipulation is really exciting and holds great promise for rapid and highly effective amelioration of hot flashes, up to 80%, and improvement in other menopausal symptoms, though we’re still looking at the safety in phase 3 trials,” reported Susan D. Reed, MD, MPH, director of the Women’s Reproductive Health Research Program at the University of Washington, Seattle.

“If we continue to see good safety data, these are going to be the greatest things since sliced bread,” Dr. Reed said in an interview. “I don’t think we’ve seen anything like this in menopause therapeutics in a long time.”

While several nonhormonal drugs are already used to treat vasomotor symptoms in menopausal women with and without breast cancer, none are as effective as hormone treatments.

“For now, the SSRIs, SNRIs [serotonin norepinephrine reuptake inhibitors], and GABAergics are the best frontline nonhormonal options with a moderate effect, and clonidine and oxybutynin are effective, but we see more side effects with these,” Dr. Reed said. She noted the importance of considering patients’ mood, sleep, pain, sexual function, weight gain, overactive bladder, blood pressure, and individual quality of life (QOL) goals in tailoring those therapies.

But women still need more nonhormonal options that are at least as effective as hormonal options, Dr. Reed said. Some women are unable to take hormonal options because they are at risk for blood clots or breast cancer.

“Then there’s preference,” she said. “Sometimes people don’t like the way they feel when they take hormones, or they just don’t want hormones in their body. It’s absolutely critical to have these options available for women.”

Nanette F. Santoro, MD, a professor of ob.gyn. at the University of Colorado at Denver, Aurora, who was not involved in the presentation, said in an interview that physicians may not always realize the extent to which vasomotor symptoms interfere with women’s daily lives.

“They have an eroding effect on QOL that is not appreciated sometimes,” she said. Though hot flashes eventually subside in most women, others may continue to experience them into their 70s, when hormonal therapies can begin causing more harm than benefit.

“It goes underappreciated that, for a proportion of women, hot flashes will never go away, and they’re just as bad [as] when they were in their 50s,” Dr. Santoro said. “They need to be treated, and the nonhormonal treatments do not work for everybody.”
 

Promising KNDy therapeutics

Autopsy studies of postmenopausal women revealed that a complex of neurons in the hypothalamus was “massively hypertrophied” and sits right next to the thermoregulatory center of the brain, Dr. Reed explained.

The complex produces three types of molecules: kisspeptin (a neuropeptide), neurokinin B (a neuropeptide), and dynorphin (a kappa opioid), collectively referred to as the KNDy. The KNDy neural complex is located in the same place as the majority of hormone receptors in the arcuate nucleus, a collection of nerve cells in the hypothalamus.

The current hypothesis is that the KNDy neurons, which communicate with each other, become hyperactivated and cause hot flashes by spilling over to and triggering the thermoregulatory center next door. NKB (kisspeptin and neurokinin B) agonists activate KNDy neurons and dynorphin agonists inactivate KNDy, so the expectation is that NKB antagonists or dynorphin agonists would stop hot flashes.

Indeed, research published in 2015 showed that women taking kappa agonists experienced fewer hot flashes than women in the placebo group. However, no peripherally restricted kappa agonists are currently in clinical trials, so their future as therapeutics is unclear.

Right now, three different NK antagonists are in the pipeline for reducing vasomotor symptoms: MLE 4901 (pavinetant) and ESN364 (fezolinetant) are both NK3R antagonists, and NT-814 is a dual NK1R/NK3R antagonist. All three of these drugs were originally developed to treat schizophrenia.

Phase 2 clinical trials of pavinetant were discontinued in November 2017 by Millendo Therapeutics because 3 of 28 women experienced abnormal liver function, which normalized within 90 days. However, the study had shown an 80% decrease in hot flashes in women taking pavinetant, compared with a 30% decrease in the placebo group.

Fezolinetant, currently in phase 3 trials with Astellas, showed a dose response effect on reproductive hormones in phase 1 studies and a short half-life (4-6 hours) in women. It also showed no concerning side effects.

“There was, in fact, a decrease in the endometrial thickness, a delayed or impeded ovulation and a prolonged cycle duration,” Reed said.

The subsequent phase 2a study showed a reduction of five hot flashes a day (93% decrease), compared with placebo (54% decrease, P <.001) “with an abrupt return to baseline hot flash frequency after cessation,” she said. Improvements also occurred in sleep quality, quality of life, disability, and interference of hot flashes in daily life.

The phase 2b study found no difference in effects between once-daily versus twice-daily doses. However, two severe adverse events occurred: a drug-induced liver injury in one woman and cholelithiasis in another, both on the 60-mg, once-daily dose. Additionally, five women on varying doses had transient increases (above 1000 U/L) in creatinine kinase, though apparently without dose response.

A 52-week, three-arm, phase 3 trial of fezolinetant is currently under way with a goal of enrolling 1,740 participants, and plans to be completed by December 2021. Participants will undergo regular adverse event screening first biweekly, then monthly, with vital signs, blood, and urine monitoring.

Meanwhile, NT-814 from KaNDy Therapeutics, has completed phase 2a and phase 2b trials with phase 3 slated to begin in 2021. Adverse events in phase 1 included sleepiness and headache, and it had a long half-life (about 26 hours) and rapid absorption (an hour).

The phase 2a trial found a reduction of five hot flashes a day, compared with placebo, with main side effects again being sleepiness and headache. No events of abnormal liver function occurred. Phase 2b results have not been published.

So far, existing research suggests that KNDy interventions will involve a single daily oral dose that begins taking effect within 3 days and is fully in effect within 1-2 weeks. The reduction in hot flashes, about five fewer a day, is more effective than any other currently used nonhormonal medications for vasomotor symptoms. SSRIs and SNRIs tend to result in 1.5-2 fewer hot flashes a day, and gabapentin results in about 3 fewer per day. It will take longer-term studies, however, and paying attention to liver concerns for the NK3R antagonists to move into clinic.

“We want to keep our eye on the [luteinizing hormone] because if it decreases too much, it could adversely affect sexual function, and this does appear to be a dose-response finding,” Dr. Reed said. It would also be ideal, she said, to target only the KNDy neurons with NK3 antagonists without effects on the NK3 receptors in the liver.
 

Other nonhormonal options

Oxybutynin is another a nonhormonal agent under investigation for vasomotor symptoms. It’s an anticholinergic that resulted in 80% fewer hot flashes, compared with 30% with placebo in a 2016 trial, but 52% of women complained of dry mouth. A more recent study similarly found high efficacy – a 60%-80% drop in hot flashes, compared with 30% with placebo – but also side effects of dry mouth, difficulty urinating, and abdominal pain.

Finally, Dr. Reed mentioned three other agents under investigation as possible nonhormonal therapeutics, though she has little information about them. They include MT-8554 by Mitsubishi Tanabe; FP-101 by Fervent Pharmaceuticals; and Q-122 by QUE Oncology with Emory University, Atlanta, and the University of Queensland, Brisbane, Australia. 

None of the currently available nonhormonal options provide as high efficacy as hormones, but they do reduce symptoms:

Clonidine is an off-label option some physicians already use as a nonhormonal treatment for vasomotor symptoms, but again, the side effects are problematic: dry mouth, constipation, drowsiness, postural hypotension, and poor sleep.

Paroxetine, at 7.5-10 mg, is the only FDA-approved nonhormonal treatment for vasomotor symptoms, but she listed other off-label options found effective in evidence reviews: gabapentin (100-2,400 mg), venlafaxine (37.5-75 mg), citalopram (10 mg), desvenlafaxine (150 mg), and escitalopram (10 mg).

“I want you to take note of the lower doses in all of these products that are efficacious above those doses that might be used for mood,” Dr. Reed added.

Dr. Reed receives royalties from UpToDate and research funding from Bayer. Dr. Santoro owns stock in MenoGeniX and serves as a consultant or advisor to Ansh Labs, MenoGeniX, and Ogeda/Astellas.

A version of this article originally appeared on Medscape.com.

Makena should be withdrawn from the market because a postmarketing study did not show clinical benefit, according to a statement released today from the Center for Drug Evaluation and Research at the Food and Drug Administration.

The drug, hydroxyprogesterone caproate injection, was approved in 2011 to reduce the risk of preterm birth in women who with previous spontaneous preterm birth. The FDA approved the medication under an accelerated pathway that required another trial to confirm clinical benefit.

The required postmarketing study “not only failed to demonstrate Makena’s benefit to the neonate, but also failed to substantiate any effect of Makena on the surrogate endpoint of gestational age at delivery that was the basis of the initial approval,” Patrizia Cavazzoni, MD, acting director of the CDER, wrote in a letter to AMAG Pharma USA, which markets Makena. The letter also was sent to other companies developing products that use the drug.

Beyond the lack of efficacy, risks associated with the drug include thromboembolic disorders, allergic reactions, decreased glucose tolerance, and fluid retention. “The risk of exposing treated pregnant women to these harms, in addition to false hopes, costs, and additional healthcare utilization outweighs Makena’s unproven benefit,” Dr. Cavazzoni said.

The letter notifies companies about the opportunity for a hearing on the proposed withdrawal of marketing approval. Makena and its generic equivalents will remain on the market until the manufacturers remove the drugs or the FDA commissioner mandates their removal, the CDER said.

The FDA commissioner ultimately will decide whether to withdraw approval of the drug. An FDA panel previously voted to withdraw the drug from the market in October 2019, and the drug has remained in limbo since.

Health care professionals should discuss “Makena’s benefits, risks, and uncertainties with their patients to decide whether to use Makena while a final decision is being made about the drug’s marketing status,” the CDER announcement said.

A version of this article originally appeared on Medscape.com.

Makena should be withdrawn from the market because a postmarketing study did not show clinical benefit, according to a statement released today from the Center for Drug Evaluation and Research at the Food and Drug Administration.

The drug, hydroxyprogesterone caproate injection, was approved in 2011 to reduce the risk of preterm birth in women who with previous spontaneous preterm birth. The FDA approved the medication under an accelerated pathway that required another trial to confirm clinical benefit.

The required postmarketing study “not only failed to demonstrate Makena’s benefit to the neonate, but also failed to substantiate any effect of Makena on the surrogate endpoint of gestational age at delivery that was the basis of the initial approval,” Patrizia Cavazzoni, MD, acting director of the CDER, wrote in a letter to AMAG Pharma USA, which markets Makena. The letter also was sent to other companies developing products that use the drug.

Beyond the lack of efficacy, risks associated with the drug include thromboembolic disorders, allergic reactions, decreased glucose tolerance, and fluid retention. “The risk of exposing treated pregnant women to these harms, in addition to false hopes, costs, and additional healthcare utilization outweighs Makena’s unproven benefit,” Dr. Cavazzoni said.

The letter notifies companies about the opportunity for a hearing on the proposed withdrawal of marketing approval. Makena and its generic equivalents will remain on the market until the manufacturers remove the drugs or the FDA commissioner mandates their removal, the CDER said.

The FDA commissioner ultimately will decide whether to withdraw approval of the drug. An FDA panel previously voted to withdraw the drug from the market in October 2019, and the drug has remained in limbo since.

Health care professionals should discuss “Makena’s benefits, risks, and uncertainties with their patients to decide whether to use Makena while a final decision is being made about the drug’s marketing status,” the CDER announcement said.

A version of this article originally appeared on Medscape.com.

Makena should be withdrawn from the market because a postmarketing study did not show clinical benefit, according to a statement released today from the Center for Drug Evaluation and Research at the Food and Drug Administration.

The drug, hydroxyprogesterone caproate injection, was approved in 2011 to reduce the risk of preterm birth in women who with previous spontaneous preterm birth. The FDA approved the medication under an accelerated pathway that required another trial to confirm clinical benefit.

The required postmarketing study “not only failed to demonstrate Makena’s benefit to the neonate, but also failed to substantiate any effect of Makena on the surrogate endpoint of gestational age at delivery that was the basis of the initial approval,” Patrizia Cavazzoni, MD, acting director of the CDER, wrote in a letter to AMAG Pharma USA, which markets Makena. The letter also was sent to other companies developing products that use the drug.

Beyond the lack of efficacy, risks associated with the drug include thromboembolic disorders, allergic reactions, decreased glucose tolerance, and fluid retention. “The risk of exposing treated pregnant women to these harms, in addition to false hopes, costs, and additional healthcare utilization outweighs Makena’s unproven benefit,” Dr. Cavazzoni said.

The letter notifies companies about the opportunity for a hearing on the proposed withdrawal of marketing approval. Makena and its generic equivalents will remain on the market until the manufacturers remove the drugs or the FDA commissioner mandates their removal, the CDER said.

The FDA commissioner ultimately will decide whether to withdraw approval of the drug. An FDA panel previously voted to withdraw the drug from the market in October 2019, and the drug has remained in limbo since.

Health care professionals should discuss “Makena’s benefits, risks, and uncertainties with their patients to decide whether to use Makena while a final decision is being made about the drug’s marketing status,” the CDER announcement said.

A version of this article originally appeared on Medscape.com.

The number of heart attack survivors in the United States who experienced repeat attacks within a year decreased between 2008 and 2017, especially among women, yet women’s awareness of their risk of death from heart disease also decreased, according to data from a pair of studies published in Circulation.

Recurrent MI rates drop, but not enough

Although the overall morbidity and mortality from coronary heart disease (CHD) in the United States has been on the decline for decades, CHD remains the leading cause of death and disability in both sexes, wrote Sanne A.E. Peters, PhD, of Imperial College London, and colleagues.

To better assess the rates of recurrent CHD by sex, the researchers reviewed data from 770,408 women and 700,477 men younger than 65 years with commercial health insurance or aged 66 years and older with Medicare who were hospitalized for myocardial infarction between 2008 and 2017. The patients were followed for 1 year for recurrent MIs, recurrent CHD events, heart failure hospitalization, and all-cause mortality.

In the study of recurrent heart disease, the rate of recurrent heart attacks per 1,000 person-years declined from 89.2 to 72.3 in women and from 94.2 to 81.3 in men. In addition, the rate of recurrent heart disease events (defined as either an MI or an artery-opening procedure), dropped per 1,000 person-years from 166.3 to 133.3 in women and from 198.1 to 176.8 in men. The reduction was significantly greater among women compared with men (P < .001 for both recurrent MIs and recurrent CHD events) and the differences by sex were consistent throughout the study period.

However, no significant difference occurred in recurrent MI rates among younger women (aged 21-54 years), or men aged 55-79 years, the researchers noted.

Heart failure rates per 1,000 person-years decreased from 177.4 to 158.1 in women and from 162.9 to 156.1 in men during the study period, and all-cause mortality decreased per 1,000 person-years from 403.2 to 389.5 for women and from 436.1 to 417.9 in men.

Potential contributing factors to the reductions in rates of recurrent events after a heart attack may include improved acute cardiac procedures, in-hospital therapy, and secondary prevention, the researchers noted. In addition, “changes in the type and definition of MI may also have contributed to the decline in recurrent events,” they said. “Also, the introduction and increasing sensitivity of cardiac biomarkers assays, especially cardiac troponin, may have contributed to an increased detection of less severe MIs over time, which, in turn, could have resulted in artifactual reductions in the consequences of MI,” they said.

The study findings were limited by several factors including the use of claims data, lack of information on the severity of heart attacks, and inability to analyze population subgroups, but the results were strengthened by the use of a large, multicultural database.

Despite the decline seen in this study, overall rates of recurrent MI, recurrent CHD events, heart failure hospitalization, and mortality remain high, the researchers said, and the results “highlight the need for interventions to ensure men and women receive guideline recommended treatment to lower the risk for recurrent MI, recurrent CHD, heart failure, and mortality after hospital discharge for MI,” they concluded.

Many women don’t recognize heart disease risk

Although women showed a greater reduction in recurrent MI and recurrent CHD events compared with men, the awareness of heart disease as the No. 1 killer of women has declined, according to a special report from the American Heart Association.

Based on survey data from 2009, 65% of women were aware that heart disease was their leading cause of death (LCOD); by 2019 the number dropped to 44%. The 10-year decline occurred across all races and ethnicities, as well as ages, with the exception of women aged 65 years and older.

The American Heart Association has conducted national surveys since 1997 to monitor awareness of cardiovascular disease among U.S. women. Data from earlier surveys showed increased awareness of heart disease as LCOD and increased awareness of heart attack symptoms between 1997 and 2012, wrote Mary Cushman, MD, of the University of Vermont, Burlington, chair of the writing group for the statement, and colleagues.

Heart disease needs new PR plan

The study of heart disease risk awareness among women was an important update to understand how well the message about women’s risk is getting out, said Martha Gulati, MD, president-elect of the American Society of Preventive Cardiology, in an interview.

The issue remains that heart disease is the No. 1 killer of women, and the decrease in awareness “means we need to amplify our message,” she said.

“I also question whether the symbol of the red dress [for women’s heart disease] is working, and it seems that now is the time to change this symbol,” she emphasized. “I wear a red dress pin on my lab coat and every day someone asks what it means, and no one recognizes it,” she said. “I think ‘Go Red for Women’ is great and part of our outward campaign, but our symbol needs to change to increase the connection and awareness in women,” she said.

What might be a better symbol? Simply, a heart, said Dr. Gulati. But “we need to study whatever is next to really connect with women and make them understand their risk for heart disease,” she added.

“Additionally, we really need to get to minority women,” she said. “We are lagging there, and the survey was conducted in English so it missed many people,” she noted.

Dr. Gulati said she was shocked at how much awareness of heart disease risk has fallen among women, even in those with risk factors such as hypertension, who were 30% less likely to be aware that heart disease remains their leading cause of death. “Younger women as well as very unaware; what this means to me is that our public education efforts need to be amplified,” Dr. Gulati said.

Barriers to educating women about heart disease risk include language and access to affordable screening, Dr. Gulati emphasized. “We need to ensure screening for heart disease is always included as a covered cost for a preventive service,” she said.

“Research needs to be done to identify what works toward educating women about cardiac risk. We need to identify a marketing tool to increase awareness in women. It might be something different for one race versus another,” Dr. Gulati said. “Our messaging needs to improve, but how we improve it needs more than just health care professionals,” she said.
 

Focus on prevention to reduce MI recurrence

“The study regarding recurrent events after MI is important because we really don’t know much about recurrent coronary heart disease after a MI over time,” said Dr. Gulati. These data can be helpful in managing surviving patients and understanding future risk, she said. “But I was surprised to see fewer recurrent events in women, as women still have more heart failure than men even if it has declined with time,” she noted.

Dr. Gulati questioned several aspects of the study and highlighted some of the limitations. “These are claims data, so do they accurately reflect the U.S. population?” she asked. “Remember, this is a study of people who survived a heart attack; those who didn’t survive aren’t included, and that group is more likely to be women, especially women younger than 55 years,” she said.

In addition, Dr. Gulati noted the lack of data on type of heart attack and on treatment adherence or referral to cardiac rehab, as well as lack of data on long-term medication adherence or follow-up care.

Prevention is the key take-home message from both studies, “whether we are talking primary prevention for the heart disease awareness study or secondary prevention for the recurrent heart attack study,” Dr. Gulati said.

The recurrent heart disease study was supported in part by Amgen and the University of Alabama at Birmingham. Lead author Dr. Peters disclosed support from a UK Medical Research Council Skills Development Fellowship with no financial conflicts. Dr. Cushman had no financial conflicts to disclose; several coauthors on the writing committee disclosed relationships with companies including Amarin and Boehringer Ingelheim. Dr. Gulati had no financial conflicts to disclose.
 

SOURCE: Peters SAE et al. Circulation. 2020 Sep 21. doi: 10.1161/CIRCULATIONAHA.120.047065; Cushman M et al. Circulation. 2020 Sep 21. doi: 10.1161/CIR.0000000000000907.

The number of heart attack survivors in the United States who experienced repeat attacks within a year decreased between 2008 and 2017, especially among women, yet women’s awareness of their risk of death from heart disease also decreased, according to data from a pair of studies published in Circulation.

Recurrent MI rates drop, but not enough

Although the overall morbidity and mortality from coronary heart disease (CHD) in the United States has been on the decline for decades, CHD remains the leading cause of death and disability in both sexes, wrote Sanne A.E. Peters, PhD, of Imperial College London, and colleagues.

To better assess the rates of recurrent CHD by sex, the researchers reviewed data from 770,408 women and 700,477 men younger than 65 years with commercial health insurance or aged 66 years and older with Medicare who were hospitalized for myocardial infarction between 2008 and 2017. The patients were followed for 1 year for recurrent MIs, recurrent CHD events, heart failure hospitalization, and all-cause mortality.

In the study of recurrent heart disease, the rate of recurrent heart attacks per 1,000 person-years declined from 89.2 to 72.3 in women and from 94.2 to 81.3 in men. In addition, the rate of recurrent heart disease events (defined as either an MI or an artery-opening procedure), dropped per 1,000 person-years from 166.3 to 133.3 in women and from 198.1 to 176.8 in men. The reduction was significantly greater among women compared with men (P < .001 for both recurrent MIs and recurrent CHD events) and the differences by sex were consistent throughout the study period.

However, no significant difference occurred in recurrent MI rates among younger women (aged 21-54 years), or men aged 55-79 years, the researchers noted.

Heart failure rates per 1,000 person-years decreased from 177.4 to 158.1 in women and from 162.9 to 156.1 in men during the study period, and all-cause mortality decreased per 1,000 person-years from 403.2 to 389.5 for women and from 436.1 to 417.9 in men.

Potential contributing factors to the reductions in rates of recurrent events after a heart attack may include improved acute cardiac procedures, in-hospital therapy, and secondary prevention, the researchers noted. In addition, “changes in the type and definition of MI may also have contributed to the decline in recurrent events,” they said. “Also, the introduction and increasing sensitivity of cardiac biomarkers assays, especially cardiac troponin, may have contributed to an increased detection of less severe MIs over time, which, in turn, could have resulted in artifactual reductions in the consequences of MI,” they said.

The study findings were limited by several factors including the use of claims data, lack of information on the severity of heart attacks, and inability to analyze population subgroups, but the results were strengthened by the use of a large, multicultural database.

Despite the decline seen in this study, overall rates of recurrent MI, recurrent CHD events, heart failure hospitalization, and mortality remain high, the researchers said, and the results “highlight the need for interventions to ensure men and women receive guideline recommended treatment to lower the risk for recurrent MI, recurrent CHD, heart failure, and mortality after hospital discharge for MI,” they concluded.

Many women don’t recognize heart disease risk

Although women showed a greater reduction in recurrent MI and recurrent CHD events compared with men, the awareness of heart disease as the No. 1 killer of women has declined, according to a special report from the American Heart Association.

Based on survey data from 2009, 65% of women were aware that heart disease was their leading cause of death (LCOD); by 2019 the number dropped to 44%. The 10-year decline occurred across all races and ethnicities, as well as ages, with the exception of women aged 65 years and older.

The American Heart Association has conducted national surveys since 1997 to monitor awareness of cardiovascular disease among U.S. women. Data from earlier surveys showed increased awareness of heart disease as LCOD and increased awareness of heart attack symptoms between 1997 and 2012, wrote Mary Cushman, MD, of the University of Vermont, Burlington, chair of the writing group for the statement, and colleagues.

Heart disease needs new PR plan

The study of heart disease risk awareness among women was an important update to understand how well the message about women’s risk is getting out, said Martha Gulati, MD, president-elect of the American Society of Preventive Cardiology, in an interview.

The issue remains that heart disease is the No. 1 killer of women, and the decrease in awareness “means we need to amplify our message,” she said.

“I also question whether the symbol of the red dress [for women’s heart disease] is working, and it seems that now is the time to change this symbol,” she emphasized. “I wear a red dress pin on my lab coat and every day someone asks what it means, and no one recognizes it,” she said. “I think ‘Go Red for Women’ is great and part of our outward campaign, but our symbol needs to change to increase the connection and awareness in women,” she said.

What might be a better symbol? Simply, a heart, said Dr. Gulati. But “we need to study whatever is next to really connect with women and make them understand their risk for heart disease,” she added.

“Additionally, we really need to get to minority women,” she said. “We are lagging there, and the survey was conducted in English so it missed many people,” she noted.

Dr. Gulati said she was shocked at how much awareness of heart disease risk has fallen among women, even in those with risk factors such as hypertension, who were 30% less likely to be aware that heart disease remains their leading cause of death. “Younger women as well as very unaware; what this means to me is that our public education efforts need to be amplified,” Dr. Gulati said.

Barriers to educating women about heart disease risk include language and access to affordable screening, Dr. Gulati emphasized. “We need to ensure screening for heart disease is always included as a covered cost for a preventive service,” she said.

“Research needs to be done to identify what works toward educating women about cardiac risk. We need to identify a marketing tool to increase awareness in women. It might be something different for one race versus another,” Dr. Gulati said. “Our messaging needs to improve, but how we improve it needs more than just health care professionals,” she said.
 

Focus on prevention to reduce MI recurrence

“The study regarding recurrent events after MI is important because we really don’t know much about recurrent coronary heart disease after a MI over time,” said Dr. Gulati. These data can be helpful in managing surviving patients and understanding future risk, she said. “But I was surprised to see fewer recurrent events in women, as women still have more heart failure than men even if it has declined with time,” she noted.

Dr. Gulati questioned several aspects of the study and highlighted some of the limitations. “These are claims data, so do they accurately reflect the U.S. population?” she asked. “Remember, this is a study of people who survived a heart attack; those who didn’t survive aren’t included, and that group is more likely to be women, especially women younger than 55 years,” she said.

In addition, Dr. Gulati noted the lack of data on type of heart attack and on treatment adherence or referral to cardiac rehab, as well as lack of data on long-term medication adherence or follow-up care.

Prevention is the key take-home message from both studies, “whether we are talking primary prevention for the heart disease awareness study or secondary prevention for the recurrent heart attack study,” Dr. Gulati said.

The recurrent heart disease study was supported in part by Amgen and the University of Alabama at Birmingham. Lead author Dr. Peters disclosed support from a UK Medical Research Council Skills Development Fellowship with no financial conflicts. Dr. Cushman had no financial conflicts to disclose; several coauthors on the writing committee disclosed relationships with companies including Amarin and Boehringer Ingelheim. Dr. Gulati had no financial conflicts to disclose.
 

SOURCE: Peters SAE et al. Circulation. 2020 Sep 21. doi: 10.1161/CIRCULATIONAHA.120.047065; Cushman M et al. Circulation. 2020 Sep 21. doi: 10.1161/CIR.0000000000000907.

The number of heart attack survivors in the United States who experienced repeat attacks within a year decreased between 2008 and 2017, especially among women, yet women’s awareness of their risk of death from heart disease also decreased, according to data from a pair of studies published in Circulation.

Recurrent MI rates drop, but not enough

Although the overall morbidity and mortality from coronary heart disease (CHD) in the United States has been on the decline for decades, CHD remains the leading cause of death and disability in both sexes, wrote Sanne A.E. Peters, PhD, of Imperial College London, and colleagues.

To better assess the rates of recurrent CHD by sex, the researchers reviewed data from 770,408 women and 700,477 men younger than 65 years with commercial health insurance or aged 66 years and older with Medicare who were hospitalized for myocardial infarction between 2008 and 2017. The patients were followed for 1 year for recurrent MIs, recurrent CHD events, heart failure hospitalization, and all-cause mortality.

In the study of recurrent heart disease, the rate of recurrent heart attacks per 1,000 person-years declined from 89.2 to 72.3 in women and from 94.2 to 81.3 in men. In addition, the rate of recurrent heart disease events (defined as either an MI or an artery-opening procedure), dropped per 1,000 person-years from 166.3 to 133.3 in women and from 198.1 to 176.8 in men. The reduction was significantly greater among women compared with men (P < .001 for both recurrent MIs and recurrent CHD events) and the differences by sex were consistent throughout the study period.

However, no significant difference occurred in recurrent MI rates among younger women (aged 21-54 years), or men aged 55-79 years, the researchers noted.

Heart failure rates per 1,000 person-years decreased from 177.4 to 158.1 in women and from 162.9 to 156.1 in men during the study period, and all-cause mortality decreased per 1,000 person-years from 403.2 to 389.5 for women and from 436.1 to 417.9 in men.

Potential contributing factors to the reductions in rates of recurrent events after a heart attack may include improved acute cardiac procedures, in-hospital therapy, and secondary prevention, the researchers noted. In addition, “changes in the type and definition of MI may also have contributed to the decline in recurrent events,” they said. “Also, the introduction and increasing sensitivity of cardiac biomarkers assays, especially cardiac troponin, may have contributed to an increased detection of less severe MIs over time, which, in turn, could have resulted in artifactual reductions in the consequences of MI,” they said.

The study findings were limited by several factors including the use of claims data, lack of information on the severity of heart attacks, and inability to analyze population subgroups, but the results were strengthened by the use of a large, multicultural database.

Despite the decline seen in this study, overall rates of recurrent MI, recurrent CHD events, heart failure hospitalization, and mortality remain high, the researchers said, and the results “highlight the need for interventions to ensure men and women receive guideline recommended treatment to lower the risk for recurrent MI, recurrent CHD, heart failure, and mortality after hospital discharge for MI,” they concluded.

Many women don’t recognize heart disease risk

Although women showed a greater reduction in recurrent MI and recurrent CHD events compared with men, the awareness of heart disease as the No. 1 killer of women has declined, according to a special report from the American Heart Association.

Based on survey data from 2009, 65% of women were aware that heart disease was their leading cause of death (LCOD); by 2019 the number dropped to 44%. The 10-year decline occurred across all races and ethnicities, as well as ages, with the exception of women aged 65 years and older.

The American Heart Association has conducted national surveys since 1997 to monitor awareness of cardiovascular disease among U.S. women. Data from earlier surveys showed increased awareness of heart disease as LCOD and increased awareness of heart attack symptoms between 1997 and 2012, wrote Mary Cushman, MD, of the University of Vermont, Burlington, chair of the writing group for the statement, and colleagues.

Heart disease needs new PR plan

The study of heart disease risk awareness among women was an important update to understand how well the message about women’s risk is getting out, said Martha Gulati, MD, president-elect of the American Society of Preventive Cardiology, in an interview.

The issue remains that heart disease is the No. 1 killer of women, and the decrease in awareness “means we need to amplify our message,” she said.

“I also question whether the symbol of the red dress [for women’s heart disease] is working, and it seems that now is the time to change this symbol,” she emphasized. “I wear a red dress pin on my lab coat and every day someone asks what it means, and no one recognizes it,” she said. “I think ‘Go Red for Women’ is great and part of our outward campaign, but our symbol needs to change to increase the connection and awareness in women,” she said.

What might be a better symbol? Simply, a heart, said Dr. Gulati. But “we need to study whatever is next to really connect with women and make them understand their risk for heart disease,” she added.

“Additionally, we really need to get to minority women,” she said. “We are lagging there, and the survey was conducted in English so it missed many people,” she noted.

Dr. Gulati said she was shocked at how much awareness of heart disease risk has fallen among women, even in those with risk factors such as hypertension, who were 30% less likely to be aware that heart disease remains their leading cause of death. “Younger women as well as very unaware; what this means to me is that our public education efforts need to be amplified,” Dr. Gulati said.

Barriers to educating women about heart disease risk include language and access to affordable screening, Dr. Gulati emphasized. “We need to ensure screening for heart disease is always included as a covered cost for a preventive service,” she said.

“Research needs to be done to identify what works toward educating women about cardiac risk. We need to identify a marketing tool to increase awareness in women. It might be something different for one race versus another,” Dr. Gulati said. “Our messaging needs to improve, but how we improve it needs more than just health care professionals,” she said.
 

Focus on prevention to reduce MI recurrence

“The study regarding recurrent events after MI is important because we really don’t know much about recurrent coronary heart disease after a MI over time,” said Dr. Gulati. These data can be helpful in managing surviving patients and understanding future risk, she said. “But I was surprised to see fewer recurrent events in women, as women still have more heart failure than men even if it has declined with time,” she noted.

Dr. Gulati questioned several aspects of the study and highlighted some of the limitations. “These are claims data, so do they accurately reflect the U.S. population?” she asked. “Remember, this is a study of people who survived a heart attack; those who didn’t survive aren’t included, and that group is more likely to be women, especially women younger than 55 years,” she said.

In addition, Dr. Gulati noted the lack of data on type of heart attack and on treatment adherence or referral to cardiac rehab, as well as lack of data on long-term medication adherence or follow-up care.

Prevention is the key take-home message from both studies, “whether we are talking primary prevention for the heart disease awareness study or secondary prevention for the recurrent heart attack study,” Dr. Gulati said.

The recurrent heart disease study was supported in part by Amgen and the University of Alabama at Birmingham. Lead author Dr. Peters disclosed support from a UK Medical Research Council Skills Development Fellowship with no financial conflicts. Dr. Cushman had no financial conflicts to disclose; several coauthors on the writing committee disclosed relationships with companies including Amarin and Boehringer Ingelheim. Dr. Gulati had no financial conflicts to disclose.
 

SOURCE: Peters SAE et al. Circulation. 2020 Sep 21. doi: 10.1161/CIRCULATIONAHA.120.047065; Cushman M et al. Circulation. 2020 Sep 21. doi: 10.1161/CIR.0000000000000907.

I remember New Year’s Day 2020, full of hope and wonderment of what the year would bring. I was coming into the Society of Hospital Medicine as the incoming President, taking the 2020 reins in the organization’s 20th year. It would be a year of transitioning to a new CEO, reinvigorating our membership engagement efforts, and renewing a strategic plan for forward progress into the next decade. It would be a year chock full of travel, speaking engagements, and meetings with thousands of hospitalists around the globe.

What I didn’t know is that we would soon face the grim reality that the long-voiced concern of infectious disease experts and epidemiologists would come true. That our colleagues and friends and families would be infected, hospitalized, and die from this new disease, for which there were no good, effective treatments. That our ability to come together as a nation to implement basic infection control and epidemiologic practices would be fractured, uncoordinated, and ineffective. That within 6 months of the first case on U.S. soil, we would witness 5,270,000 people being infected from the disease, and 167,000 dying from it. And that the stunning toll of the disease would ripple into every nook and cranny of our society, from the economy to the fabric of our families and to the mental and physical health of all of our citizens.

However, what I couldn’t have known on this past New Year’s Day is how incredibly resilient and innovative our hospital medicine society and community would be to not only endure this new way of working and living, but also to find ways to improve upon how we care for all patients, despite COVID-19. What I couldn’t have known is how hospitalists would pivot to new arenas of care settings, including the EDs, ICUs, “COVID units,” and telehealth – flawlessly and seamlessly filling care gaps that would otherwise be catastrophically unfilled.

What I couldn’t have known is how we would be willing to come back into work, day after day, to care for our patients, despite the risks to ourselves and our families. What I couldn’t have known is how hospitalists would come together as a community to network and share knowledge in unprecedented ways, both humbly and proactively – knowing that we would not have all the answers but that we probably had better answers than most. What I couldn’t have known is that the SHM staff would pivot our entire SHM team away from previous “staple” offerings (e.g., live meetings) to virtual learning and network opportunities, which would be attended at rates higher than ever seen before, including live webinars, HMX exchanges, and e-learnings. What I couldn’t have known is that we would figure out, in a matter of weeks, what treatments were and were not effective for our patients and get those treatments to them despite the difficulties. And what I couldn’t have known is how much prouder I would be, more than ever before, to tell people: “I am a hospitalist.”

I took my son to the dentist recently, and when we were just about to leave, the dentist asked: “What do you do for a living?” and I stated: “I am a hospitalist.” He slowly breathed in and replied: “Oh … wow … you have really seen things …” Yes, we have.

So, is 2020 shaping up as expected? Absolutely not! But I am more inspired, humbled, and motivated than ever to proudly serve SHM with more energy and enthusiasm than I would have dreamed on New Year’s Day. And even if we can’t see each other in person (as we so naively planned), through virtual meetings (national, regional, and chapter), webinars, social media, and other listening modes, we will still be able to connect as a community and share ideas and issues as we muddle through the remainder of 2020 and beyond. We need each other more than ever before, and I am so proud to be a part of this SHM family.

Dr. Scheurer is chief quality officer and professor of medicine at the Medical University of South Carolina, Charleston. She is president of SHM.

I remember New Year’s Day 2020, full of hope and wonderment of what the year would bring. I was coming into the Society of Hospital Medicine as the incoming President, taking the 2020 reins in the organization’s 20th year. It would be a year of transitioning to a new CEO, reinvigorating our membership engagement efforts, and renewing a strategic plan for forward progress into the next decade. It would be a year chock full of travel, speaking engagements, and meetings with thousands of hospitalists around the globe.

What I didn’t know is that we would soon face the grim reality that the long-voiced concern of infectious disease experts and epidemiologists would come true. That our colleagues and friends and families would be infected, hospitalized, and die from this new disease, for which there were no good, effective treatments. That our ability to come together as a nation to implement basic infection control and epidemiologic practices would be fractured, uncoordinated, and ineffective. That within 6 months of the first case on U.S. soil, we would witness 5,270,000 people being infected from the disease, and 167,000 dying from it. And that the stunning toll of the disease would ripple into every nook and cranny of our society, from the economy to the fabric of our families and to the mental and physical health of all of our citizens.

However, what I couldn’t have known on this past New Year’s Day is how incredibly resilient and innovative our hospital medicine society and community would be to not only endure this new way of working and living, but also to find ways to improve upon how we care for all patients, despite COVID-19. What I couldn’t have known is how hospitalists would pivot to new arenas of care settings, including the EDs, ICUs, “COVID units,” and telehealth – flawlessly and seamlessly filling care gaps that would otherwise be catastrophically unfilled.

What I couldn’t have known is how we would be willing to come back into work, day after day, to care for our patients, despite the risks to ourselves and our families. What I couldn’t have known is how hospitalists would come together as a community to network and share knowledge in unprecedented ways, both humbly and proactively – knowing that we would not have all the answers but that we probably had better answers than most. What I couldn’t have known is that the SHM staff would pivot our entire SHM team away from previous “staple” offerings (e.g., live meetings) to virtual learning and network opportunities, which would be attended at rates higher than ever seen before, including live webinars, HMX exchanges, and e-learnings. What I couldn’t have known is that we would figure out, in a matter of weeks, what treatments were and were not effective for our patients and get those treatments to them despite the difficulties. And what I couldn’t have known is how much prouder I would be, more than ever before, to tell people: “I am a hospitalist.”

I took my son to the dentist recently, and when we were just about to leave, the dentist asked: “What do you do for a living?” and I stated: “I am a hospitalist.” He slowly breathed in and replied: “Oh … wow … you have really seen things …” Yes, we have.

So, is 2020 shaping up as expected? Absolutely not! But I am more inspired, humbled, and motivated than ever to proudly serve SHM with more energy and enthusiasm than I would have dreamed on New Year’s Day. And even if we can’t see each other in person (as we so naively planned), through virtual meetings (national, regional, and chapter), webinars, social media, and other listening modes, we will still be able to connect as a community and share ideas and issues as we muddle through the remainder of 2020 and beyond. We need each other more than ever before, and I am so proud to be a part of this SHM family.

Dr. Scheurer is chief quality officer and professor of medicine at the Medical University of South Carolina, Charleston. She is president of SHM.

I remember New Year’s Day 2020, full of hope and wonderment of what the year would bring. I was coming into the Society of Hospital Medicine as the incoming President, taking the 2020 reins in the organization’s 20th year. It would be a year of transitioning to a new CEO, reinvigorating our membership engagement efforts, and renewing a strategic plan for forward progress into the next decade. It would be a year chock full of travel, speaking engagements, and meetings with thousands of hospitalists around the globe.

What I didn’t know is that we would soon face the grim reality that the long-voiced concern of infectious disease experts and epidemiologists would come true. That our colleagues and friends and families would be infected, hospitalized, and die from this new disease, for which there were no good, effective treatments. That our ability to come together as a nation to implement basic infection control and epidemiologic practices would be fractured, uncoordinated, and ineffective. That within 6 months of the first case on U.S. soil, we would witness 5,270,000 people being infected from the disease, and 167,000 dying from it. And that the stunning toll of the disease would ripple into every nook and cranny of our society, from the economy to the fabric of our families and to the mental and physical health of all of our citizens.

However, what I couldn’t have known on this past New Year’s Day is how incredibly resilient and innovative our hospital medicine society and community would be to not only endure this new way of working and living, but also to find ways to improve upon how we care for all patients, despite COVID-19. What I couldn’t have known is how hospitalists would pivot to new arenas of care settings, including the EDs, ICUs, “COVID units,” and telehealth – flawlessly and seamlessly filling care gaps that would otherwise be catastrophically unfilled.

What I couldn’t have known is how we would be willing to come back into work, day after day, to care for our patients, despite the risks to ourselves and our families. What I couldn’t have known is how hospitalists would come together as a community to network and share knowledge in unprecedented ways, both humbly and proactively – knowing that we would not have all the answers but that we probably had better answers than most. What I couldn’t have known is that the SHM staff would pivot our entire SHM team away from previous “staple” offerings (e.g., live meetings) to virtual learning and network opportunities, which would be attended at rates higher than ever seen before, including live webinars, HMX exchanges, and e-learnings. What I couldn’t have known is that we would figure out, in a matter of weeks, what treatments were and were not effective for our patients and get those treatments to them despite the difficulties. And what I couldn’t have known is how much prouder I would be, more than ever before, to tell people: “I am a hospitalist.”

I took my son to the dentist recently, and when we were just about to leave, the dentist asked: “What do you do for a living?” and I stated: “I am a hospitalist.” He slowly breathed in and replied: “Oh … wow … you have really seen things …” Yes, we have.

So, is 2020 shaping up as expected? Absolutely not! But I am more inspired, humbled, and motivated than ever to proudly serve SHM with more energy and enthusiasm than I would have dreamed on New Year’s Day. And even if we can’t see each other in person (as we so naively planned), through virtual meetings (national, regional, and chapter), webinars, social media, and other listening modes, we will still be able to connect as a community and share ideas and issues as we muddle through the remainder of 2020 and beyond. We need each other more than ever before, and I am so proud to be a part of this SHM family.

Dr. Scheurer is chief quality officer and professor of medicine at the Medical University of South Carolina, Charleston. She is president of SHM.

In the opinion of Lawrence F. Eichenfield, MD, recent advances in the medical treatment of acne make it “an exciting time” for treating patients with the condition.

During the virtual annual Masters of Aesthetics Symposium, he highlighted the following new acne treatment options:

• Trifarotene cream 0.005% (Aklief). This marks the first new retinoid indicated for acne in several decades. It is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older and has been studied in acne of the face, chest, and back. “It’s nice to have in our armamentarium,” he said.
• Tazarotene lotion 0.045% (Arazlo). The 0.1% formulation of tazarotene is commonly used for acne, but it can cause skin irritation, dryness, and erythema. The new 0.045% formulation was developed in a three-dimensional mesh matrix, with ingredients from an oil-in-water emulsion. “This allows for graduated dosing on the skin without as much irritation,” said Dr. Eichenfield, who is chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego.
• Minocycline 4% topical foam (Amzeeq). This marks the first and only topical minocycline prescription treatment for acne. “Its hydrophobic composition allows for stable and efficient delivery of inherently unstable pharmaceutical ingredients,” he said. “There is no evidence of photosensitivity as you’d expect from a minocycline-based product, and there are low systemic levels compared with oral minocycline.”
• Clascoterone cream 1% (Winlevi). This first-in-class topical androgen receptor inhibitor has been approved for the treatment of acne in patients 12 years and older. It competes with dihydrotestosterone and selectively targets androgen receptors in sebocytes and hair papilla cells. “It has been studied on the face and trunk and has been shown to inhibit sebum production, reduce secretion of inflammatory cytokines, and inhibit inflammatory pathways,” said Dr. Eichenfield, who is also professor of dermatology and pediatrics at the University of California, San Diego.
• From a systemic standpoint, sarecycline, a new tetracycline class antibiotic, has been approved for the treatment of inflammatory lesions of nonnodular moderate to severe acne vulgaris in patients 9 years and older. The once-daily drug can be taken with or without food in a weight-based dose. “This medicine appears to have a narrow spectrum of antibacterial activity compared with other tetracyclines,” he said. “It may have less of a negative effect on gut microbiome than traditional oral antibiotics.”

As for integrating these new options into existing clinical practice, Dr. Eichenfield predicts that the general approach to acne treatment will remain the same. “We’ll have to wait to see where the topical androgens fit into the treatment algorithms,” he said. “Our goal is to minimize scarring, minimize disease, and to modulate the disease course.”

Dr. Eichenfield disclosed that he has been an investigator and/or consultant for Almirall, Cassiopea, Dermata, Foamix, Galderma, L’Oreal, and Ortho Dermatologics.

[email protected]

In the opinion of Lawrence F. Eichenfield, MD, recent advances in the medical treatment of acne make it “an exciting time” for treating patients with the condition.

During the virtual annual Masters of Aesthetics Symposium, he highlighted the following new acne treatment options:

• Trifarotene cream 0.005% (Aklief). This marks the first new retinoid indicated for acne in several decades. It is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older and has been studied in acne of the face, chest, and back. “It’s nice to have in our armamentarium,” he said.
• Tazarotene lotion 0.045% (Arazlo). The 0.1% formulation of tazarotene is commonly used for acne, but it can cause skin irritation, dryness, and erythema. The new 0.045% formulation was developed in a three-dimensional mesh matrix, with ingredients from an oil-in-water emulsion. “This allows for graduated dosing on the skin without as much irritation,” said Dr. Eichenfield, who is chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego.
• Minocycline 4% topical foam (Amzeeq). This marks the first and only topical minocycline prescription treatment for acne. “Its hydrophobic composition allows for stable and efficient delivery of inherently unstable pharmaceutical ingredients,” he said. “There is no evidence of photosensitivity as you’d expect from a minocycline-based product, and there are low systemic levels compared with oral minocycline.”
• Clascoterone cream 1% (Winlevi). This first-in-class topical androgen receptor inhibitor has been approved for the treatment of acne in patients 12 years and older. It competes with dihydrotestosterone and selectively targets androgen receptors in sebocytes and hair papilla cells. “It has been studied on the face and trunk and has been shown to inhibit sebum production, reduce secretion of inflammatory cytokines, and inhibit inflammatory pathways,” said Dr. Eichenfield, who is also professor of dermatology and pediatrics at the University of California, San Diego.
• From a systemic standpoint, sarecycline, a new tetracycline class antibiotic, has been approved for the treatment of inflammatory lesions of nonnodular moderate to severe acne vulgaris in patients 9 years and older. The once-daily drug can be taken with or without food in a weight-based dose. “This medicine appears to have a narrow spectrum of antibacterial activity compared with other tetracyclines,” he said. “It may have less of a negative effect on gut microbiome than traditional oral antibiotics.”

As for integrating these new options into existing clinical practice, Dr. Eichenfield predicts that the general approach to acne treatment will remain the same. “We’ll have to wait to see where the topical androgens fit into the treatment algorithms,” he said. “Our goal is to minimize scarring, minimize disease, and to modulate the disease course.”

Dr. Eichenfield disclosed that he has been an investigator and/or consultant for Almirall, Cassiopea, Dermata, Foamix, Galderma, L’Oreal, and Ortho Dermatologics.

[email protected]

In the opinion of Lawrence F. Eichenfield, MD, recent advances in the medical treatment of acne make it “an exciting time” for treating patients with the condition.

During the virtual annual Masters of Aesthetics Symposium, he highlighted the following new acne treatment options:

• Trifarotene cream 0.005% (Aklief). This marks the first new retinoid indicated for acne in several decades. It is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older and has been studied in acne of the face, chest, and back. “It’s nice to have in our armamentarium,” he said.
• Tazarotene lotion 0.045% (Arazlo). The 0.1% formulation of tazarotene is commonly used for acne, but it can cause skin irritation, dryness, and erythema. The new 0.045% formulation was developed in a three-dimensional mesh matrix, with ingredients from an oil-in-water emulsion. “This allows for graduated dosing on the skin without as much irritation,” said Dr. Eichenfield, who is chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego.
• Minocycline 4% topical foam (Amzeeq). This marks the first and only topical minocycline prescription treatment for acne. “Its hydrophobic composition allows for stable and efficient delivery of inherently unstable pharmaceutical ingredients,” he said. “There is no evidence of photosensitivity as you’d expect from a minocycline-based product, and there are low systemic levels compared with oral minocycline.”
• Clascoterone cream 1% (Winlevi). This first-in-class topical androgen receptor inhibitor has been approved for the treatment of acne in patients 12 years and older. It competes with dihydrotestosterone and selectively targets androgen receptors in sebocytes and hair papilla cells. “It has been studied on the face and trunk and has been shown to inhibit sebum production, reduce secretion of inflammatory cytokines, and inhibit inflammatory pathways,” said Dr. Eichenfield, who is also professor of dermatology and pediatrics at the University of California, San Diego.
• From a systemic standpoint, sarecycline, a new tetracycline class antibiotic, has been approved for the treatment of inflammatory lesions of nonnodular moderate to severe acne vulgaris in patients 9 years and older. The once-daily drug can be taken with or without food in a weight-based dose. “This medicine appears to have a narrow spectrum of antibacterial activity compared with other tetracyclines,” he said. “It may have less of a negative effect on gut microbiome than traditional oral antibiotics.”

As for integrating these new options into existing clinical practice, Dr. Eichenfield predicts that the general approach to acne treatment will remain the same. “We’ll have to wait to see where the topical androgens fit into the treatment algorithms,” he said. “Our goal is to minimize scarring, minimize disease, and to modulate the disease course.”

Dr. Eichenfield disclosed that he has been an investigator and/or consultant for Almirall, Cassiopea, Dermata, Foamix, Galderma, L’Oreal, and Ortho Dermatologics.

[email protected]