This blog is a way of sharing the information and resources that have helped me to recover my son Roo from an Autism Spectrum Disorder. What I have learned is to view our symptoms as the results of underlying biological cause, which can be identified and healed. I say "our symptoms" because I also have a neuro-immune disorder called Myalgic Encephalomyelitis.

And, of course, I am not a doctor (although I have been known to impersonate one while doing imaginative play with my son)- this is just our story and information that has been helpful or interesting to us. I hope it is helpful and interesting to you!

Saturday, April 13, 2019

Serotonin Syndrome (aka Serotonin Toxicity or Serotonin Storm)

What is Serotonin Syndrome?

Serotonin Syndrome is a condition that occurs when levels of serotonin, a neurotransmitter, rise too high and specific serotonin receptors are overstimulated.  Symptoms can be mild and often begin with headache, shaking and tremors, racing heart, nausea, feeling too hot, and mild anxiety and confusion.  Progressive symptoms can include diarrhea, vomiting, and other digestive system symptoms; hyperthermia, clonus, hyperreflexia, and an increase in anxiety, OCD, and panic.  In some cases it can progress to life-threatening symptoms including seizures, cardiac symptoms, heart attack, severe hyperthermia, coma, and death.  In mild cases treatment is usually limited to removal of the causative medication(s).  In more serious cases the serotonin antagonist medications cyproheptadine or chlorpromazine can be used to rapidly reduce the level of serotonin in the body.  Moderate to severe cases are a medical emergency and require emergency medical treatment.  This syndrome is rarely recognized (or even known about) by most doctors and other medical personal including EMTs/paramedics and ER doctors and nurses (even specialists).  Those who are aware of it often have an oversimplified understanding of it's potential causes and presentations and are likely unaware of the few acute treatments available.

Serotonin is one of the mediators released from mast cells during a mast cell reaction and is therefore something that mast cell patients should be aware of, as the potential for serotonin toxicity seems to be a situation even less recognized than that caused by drug interactions.  Additionally, the majority of serotonin in the body is in the digestive tract (about 80-90%) and blood platelets (about 10%) so disorders involving those two systems seem to also be risk factors (I will elaborate on these interactions in another post).  Acute Serotonin Storm resulting from the combination of SSRIs and MAOIs does seem to the most widely recognized case and is (in my experience) the most effective way to get a doctor or other medical provider to realize what you're talking about (the only way that I have successfully gotten doctors to take my serotonin sensitivity seriously is to tell them that I have genetics that mimic the situation in which a person is taking both an SSRI and an MAOI).  Genetic mutations involving enzymes that play a role in regulating serotonin levels in the body also seem to be significant in at least some patients, including myself (more on that in another post as well).

More information about serotonin syndrome...  (emphasis added)

Overview of serotonin syndrome.
"SS commonly occurs after the use of serotonergic agents alone or in combination with monoamine oxidase inhibitors. SS classically consists of a triad of signs and symptoms broadly characterized as alteration of mental status, abnormalities of neuromuscular tone, and autonomic hyperactivity.  However, all 3 triads of SS may not occur simultaneously. Clinical manifestations are diverse and nonspecific, which may lead to misdiagnosis. SS can range in severity from mild to life-threatening. Most cases of SS are mild and resolve with prompt recognition and supportive care. Management of SS involves withdrawal of the offending agent(s), aggressive supportive care to treat hyperthermia and autonomic dysfunction, and occasionally the administration of serotonin antagonists--cyproheptadine or chlorpromazine. Patients with moderate and severe cases of SS require inpatient hospitalization."

Serotonin syndrome: a complex but easily avoidable condition.
"Serotonin syndrome is a potentially life-threatening adverse drug reaction caused by excessive serotonergic agonism in central and peripheral nervous system serotonergic receptors. Symptoms are characterized by a triad of neuron-excitatory features, which include (a) neuromuscular hyperactivity -- tremor, clonus, myoclonus, hyperreflexia and, in advanced stages, pyramidal rigidity; (b) autonomic hyperactivity -- diaphoresis, fever, tachycardia and tachypnea; (c) altered mental status -- agitation, excitement and, in advanced stages, confusion. It arises when pharmacological agents increase serotonin neurotransmission at postsynaptic 5-hydroxytryptamine 1A and 5-hydroxytryptamine 2A receptors through increased serotonin synthesis, decreased serotonin metabolism, increased serotonin release, inhibition of serotonin reuptake or direct agonism of the serotonin receptors. The etiology is often the result of therapeutic drug use, intentional overdosing of serotonergic agents or complex interactions between drugs that directly or indirectly modulate the serotonin system. Due to the increasing availability of agents with serotonergic activity, physicians need to more aware of serotonin syndrome. "

The Serotonin Syndrome

Understanding the symptoms...

Tachypnea is a form of rapid breathing similar to hyperventilation, but differs in that it involves rapid shallow breathing whereas hyperventilation (at least in some medical references) refers to rapid deeper breathing and seems to be associated only with mental health disorders such as anxiety and panic, according to many medical sources.

In this video two physical therapists explain what clonus is and how to recognize it.  It is a form of involuntary tremor that is essentially part of a reflex that the body can't control due to an injury or disorder.  It can be limited to a few repetitions of a movement (such as the ankle moving up and down) or can become continuous.

The Many Presentations/Manifestations of Serotonin Syndrome

Headache as a presenting feature in patients with serotonin syndrome: a case series.

Serotonin syndrome in patients with headache disorders.
"Various serotonergic drugs are used in different headache disorders. Therefore, a possibility of developing SS exists in patients with headache. Herein, we are reporting two patients with headache disorders who developed SS.Case 1: a 49-year-old man had a 6-year history of episodic cluster headache (CH). However, he had never been diagnosed with CH before reporting to us. He had been receiving amitriptyline, tramadol/acetaminophen combination and flunarizine. Lithium was started for CH. He developed features consistent with SS. The patient responded to cyprohepatdine. Case 2: a 36-year-old chronic migraineur was on amitriptyline. Addition of sodium valproate led to the development of new features that fulfilled the criteria of SS. The patient responded to cyprohepatdine.  As SS may be fatal, there is a need to increase awareness about SS in physicians treating patients with headache."

Serotonin syndrome presenting as surgical emergency: A report of two cases.

Psychiatric Emergencies for Clinicians: Emergency Department Management of Serotonin Syndrome

Generalized Itching and Lower-Extremity Spasticity in a Patient with Intrathecal Baclofen Pump

Serotonin syndrome presenting as hypotonic coma and apnea: potentially fatal complications of selective serotonin receptor inhibitor therapy.

Diagnosis and Management of Serotonin Syndrome

Prevention, Diagnosis, and Management of Serotonin Syndrome

Recognition and treatment of serotonin syndrome

"Numerous clinical features were associated with serotonin toxicity, but only clonus (inducible, spontaneous or ocular), agitation, diaphoresis, tremor and hyperreflexia were needed for accurate prediction of serotonin toxicity as diagnosed by a clinical toxicologist. Although the learning dataset did not include patients with life-threatening serotonin toxicity, hypertonicity and maximum temperature 38 degrees C were universal in such patients; these features were therefore added. Using these seven clinical features, decision rules (the Hunter Serotonin Toxicity Criteria) were developed. These new criteria were simpler, more sensitive (84% vs. 75%) and more specific (97% vs. 96%) than Sternbach's criteria....  These redefined criteria for serotonin toxicity should be more sensitive to serotonin toxicity and less likely to yield false positives."

Serotonin toxicity: a practical approach to diagnosis and treatment.  
"Excess serotonin in the central nervous system leads to a condition commonly referred to as the serotonin syndrome, but better described as a spectrum of toxicity - serotonin toxicity. Serotonin toxicity is characterized by neuromuscular excitation (clonus, hyperreflexia, myoclonus, rigidity), autonomic stimulation (hyperthermia, tachycardia, diaphoresis, tremor, flushing) and changed mental state (anxiety, agitation, confusion). Serotonin toxicity can be: mild (serotonergic features that may or may not concern the patient); moderate (toxicity which causes significant distress and deserves treatment, but is not life-threatening); or severe (a medical emergency characterized by rapid onset of severe hyperthermia, muscle rigidity and multiple organ failure). Diagnosis of serotonin toxicity is often made on the basis of the presence of at least three of Sternbach's 10 clinical features. However, these features have very low specificity. The Hunter Serotonin Toxicity Criteria use a smaller, more specific set of clinical features for diagnosis, including clonus, which has been found to be more specific to serotonin toxicity. There are several drug mechanisms that cause excess serotonin, but severe serotonin toxicity only occurs with combinations of drugs acting at different sites, most commonly including a monoamine oxidase inhibitor and a serotonin reuptake inhibitor. Less severe toxicity occurs with other combinations, overdoses and even single-drug therapy in susceptible individuals. Treatment should focus on cessation of the serotonergic medication and supportive care. Some antiserotonergic agents have been used in clinical practice, but the preferred agent, dose and indications are not well defined."

Prevention, recognition, and management of serotonin syndrome.

Controversies in Serotonin Syndrome Diagnosis and Management: A Review.

Risks, Use and Management of Serotonergic Drugs

"We describe six patients diagnosed with serotonin syndrome after exposure to drugs with serotonergic activity. Drug interactions occurred as a result of a combination of tricyclic antidepressants, selective serotonin reuptake inhibitors, selective noradrenaline reuptake inhibitors or monoamine oxidase inhibitors. Management included supportive care and the use of non-specific serotonin antagonists (cyproheptadine, benzodiazepines and chlorpromazine). All patients made uneventful recoveries."

Serotonin syndrome resulting from coadministration of tramadol, venlafaxine, and mirtazapine.
"SS is a potentially fatal iatrogenic complication of serotonergic polypharmacy. Considered idiopathic in presentation, it typically appears after initiation or dose escalation of the offending agent to a regimen including other serotonergic agents. All drugs that directly or indirectly increase central serotonin neurotransmission at postsynaptic 5-HT(1A) and 5-HT(2A) receptors can produce SS. Individual vulnerability appears to play a role in the development of SS. It is likely that the activation of 5-HT(1A) receptors by mirtazapine, the combined serotonin reuptake inhibition by venlafaxine and tramadol, as well as possible serotonin release by tramadol, contributed to the development of SS in this case."

eComment: Serotonin syndrome: pharmacogenomics and treatment

Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.

[Serotonin syndrome and pain medication : What is relevant for practice?].
"Opioids with serotonergic effects include the phenylpiperidine series opioids fentanyl, methadone, meperidine and tramadol and the morphine analogues oxycodone and codeine. In combination with certain serotonergic drugs, e.g. antidepressants, they can provoke serotonin syndrome. In patients with such combinations, special attention should be paid to clinical signs of serotonergic hyperactivity. Higher risk combinations (e.g. monoamine oxidase inhibitors with tramadol) must be avoided. Treatment with serotonergic agents must be stopped in moderate or severe serotonin syndrome. Patients with a severe serotonin syndrome require symptomatic intensive care and specifically a pharmacological antagonism with cyproheptadine or chlorpromazine."

Serotonin syndrome induced by fluvoxamine and oxycodone.
"A 70-year-old woman developed severe serotonergic features, including confusion, nausea, fever, clonus, hyperreflexia, hypertonia, shivering, and tachycardia, following the addition of oxycodone 40 mg twice daily to fluvoxamine 200 mg/day, easily fulfilling diagnostic criteria for serotonin syndrome. Discontinuation of the offending drugs resulted in resolution of her symptoms over 48 hours, and no other cause of the syndrome was identified."

Treatment of the serotonin syndrome with cyproheptadine
"All patients were administered cyproheptadine (4–8 mg orally) for serotonergic signs. Three had complete resolution of signs within 2 h of administration. Another two had a residual tremor or hyperreflexia following the first dose, which resolved following a repeat dose. There were no adverse outcomes from cyproheptadine use. The role of specific serotonin receptor antagonists such as cyproheptadine in the treatment of the serotonin syndrome remains to be delineated. Its use should be considered an adjunct to supportive care. Currently, it is unknown whether cyproheptadine modifies patient outcome."

"Chlorpromazine is in the typical antipsychotic class. Its mechanism of action is not entirely clear but believed to be related to its ability as a dopamine antagonist. It also has anti-serotonergic and antihistaminergic properties."