Antidepressants and Serotonin Syndrome

Cyclic Antidepressants

(TCAs)

Take 6 hours for full absorption, metabolized by hepatic excretion

Convulsions, Cardiac Collapse, Coma

QRS prolonged, negative inotropy, hypotension from vasodilation

EKG

Rightward axis=TCA on board

Terminal R in aVR, S in I/aVL and QRS width >100=toxicity

rightward terminal deviation of QRS 40 mSec effective screen for toxicity (N Engl J Med 1985 Aug 22;313(8):474-9 and  Am J Cardio 1986 May 1;57(13):1154-9)

If the R wave in aVR is 3 mm or more, then worry,” Dr. Harris advised. Another useful indicator of increased risk is an R/S ratio of 0.7 or more F in the aVR lead, he added. The treatment for these ECG changes is sodium bicarbonate. It is given as an initial bolus of 1-2 mEq/kg followed by a constant infusion of 100-150 mEq per liter of 5% dextrose run at maintenance. The goal in a patient with a wide QRS or tall R wave is to keep the pH at 7.5-7.55. The mechanisms of benefit involve alkalinization to override the TCA’s myocardial sodium channel blockade and boost protein binding so the drug doesn’t cause additional problems, along with an increase in the extracellular sodium channel concentration to improve the cross-channel gradient. The sodium bicarbonate can be stopped once the patient’s QRS interval shrinks to less than 100 milliseconds. Sodium bicarbonate is usually effective. When it’s not, the second-line options are hypertonic saline, lidocaine, and/or magnesium sulfate. Class IA, IC, and III antiarrhythmic agents are contraindicated in TCA overdoses. Calcium channel blockers and beta blockers are poor choices because they will exacerbate hypotension.

Serial ECG recordings should be examined for the presence of QRS prolongation (>100 ms), QTc prolongation (>430 ms) and R/S ratio >0.7 in lead aVR. These changes identify patients at high risk of developing complications following TCA overdose (From GEMNET EMJ 2011)

• Epinephrine may be superior to norepinephrine for treating refractory hypotension and preventing arrhythmias (Grade D).
• It is not unreasonable to administer 10 mg intravenous glucagon to treat life-threatening hypotension or arrhythmias refractory to other measures (Grade D).
• Magnesium sulphate may be considered for the treatment of TCA-induced dysrhythmias when other treatments have been unsuccessful (Grade D).
• Lipid emulsion may be considered for treatment of life-threatening toxicity following TCA overdose that is refractory to other measures (Grade D).

• Phenytoin should be avoided in patients with TCA overdose (Grade D).
• Benzodiazepines should be used to control seizures following TCA overdose (Grade E).

• Following TCA overdose, asymptomatic stable patients with no significant ECG abnormalities 6 h after ingestion may be safely discharged (Grade B).

(From GEMNET EMJ 2011)

From S. Smith:

2. In 49 patients with known TCA overdose, a maximum limb lead QRS duration greater than 100 ms was 100% sensitive for detecting patients who will seize, and seizure is a harbinger of cardiovascular collapse.  At this cutoff of 100 ms, however, the specificity was not perfect.  Of 11 patients with an initial QRS duration of 100-119 ms, 2 (18%) had seizures, and of 22 with an initial QRS duration of 100-139 ms, 4 (18%) had seizures.  Of 14 with initial QRS of 140 ms or longer, 8 (56%) had seizures.  No patient with a QRS of less than 160 ms had ventricular dysrhythmias.
2a.  In an unselected population with suspicion of overdose, a minimally wide QRS (less than 110 ms) will be much less specific; furthermore, it is likely that frequent serial ECGs, by detecting an increasing QRS duration, will detect those at risk of toxicity.  On the other hand, administration of bicarbonate, the antidote, is relatively safe compared with a seizure.  If the diagnosis is unclear, narrowing of a widened QRS on ECG following sodium bicarbonate administration (1-2meq/kg) adds further support that pharmacologic sodium blockade is present.

a.   Blockade of cardiac fast sodium channels (leads to wide QRS, R-wave in aVR, R’ wave in V1, Brugada pattern ECG, ventricular dysrhythmias.)  Sodium channel blockade in the CNS leads to seizures.

e.  Antagonism of histamine (H1) receptors (may contribute to sedation)

h.  Exaggeration of therapeutic effect of inhibiting central norepinephrine re-uptake (increase risk of seizures)

Effects

Fast Sodium Channel Blockade (Quinidine like effect)

Alpha Blockade

ACh Effects

Norepi and Serotonin reuptake blockade

Antihistamine effects

GABA antagonism

patients who do not have the minor symptoms (tachycardia, altered mental status, dry skin, ileus) early, will not have the major symptoms later (seizure, dysrhythmias)

Aggressive Airway, Consider intubation and hyperventilation

IV, OG Lavage and AC if <2 hours,

Bicarb until pH >7.55.  2 meq/kg then add 4 amps to 1 liter d5w and titrate.  Do 12 lead immediately after bolus to see if QRS narrows.

Phenobarb, propofol or Versed Drip if seizures, DO NOT USE DILANTIN

Must treat seizures aggressively as the resultant acidosis will worsen cardiac toxicity.

Consider Norepinephrine if refractory hypotension

No physostigmine

TCAs are the only drug which have had the 6 hour observation rule actually verified, the others we just assume it to be true.

if signs of toxicity, place on bicarb drip at 200 cc/hr (3 amps in 1 L) and admit to monitored bed for 24 hours of drip

Consider hypertonic saline in resistant cases; 1 case report (Annals EM 42:1, 2003)

SSRIs

Prozac lasts 4 days, others 1

Do not give MAOIs for 2-5 weeks

Not dialyzable

Normal overdose is benign.  Any of the SSRIs in very high doses can give seizures or QT prolongations.

Citolopram

(Celexa)-seizure as toxicity, also QT prolongation.  Use bicarb (JEM Aug, 2003)

Q6. Describe the managment of this patient with a citalopram overdose. (from Life in the fast lane)

Using the “Resus-RSI-DEAD” approach:

• Resuscitation, supportive care and monitoring -Assess and support ABC’s.Seizures and agitation – treat with titrated benzodiazepines. If increasing anxiety, sweating, tremor, tachycardia and mydriasis occurs pre-emptively treat with IV diazepam 5mg every 2-5 minutes until gentle sedation is achieved, as these features may herald the onset of seizures.Serotonin syndrome – features of serotonin toxicity respond well to titrated benzodiazepines. Other pharmacologic treatment options include cyproheptadine, chlorpromazine and olanzepine. Consider intubation and neuromuscular paralysis if marked rigidity, PaCO2 is rising, CK is rising or hyperthermia (T>39.5 C) is present.Torsades de pointes (TdP) – treat with oxygen, magnesium chloride 10 mmol IV, correct hypokalemia, and consider overdrive transcutaneous pacing (HR 120/min) or treatment with either isoprenaline, adrenaline or dopamine. If the patient is pulseless then DC cardioversion (~200J biphasic) and CPR is indicated.
• Risk assessment – See Q2.
• Investigations -Screening tests – ECG at presentation, glucose, paracetamol level.Serial 12-lead ECGs – continuous ECG monitoring is performed for at least 13 hours if >1000 mg citalopram is ingested (8 hours if between 600mg and 1000mg is ingested). If QTc is <450ms on a 12-lead ECG at the end of this period ECG monitoring may be ceased.
• Decontamination -50g activated charcoal can be administered to alert and cooperative patients who have ingested >600mg of citalopram. NB. Activated charcoal is not indicated for other SSRIs that do not cause QT prolongation – as outcomes are good with supportive care only).
• Enhanced elimination and antidotes – Nil.
• Disposition -The patient requires cardiac monitoring for a minimum of 13 hours, and may be discharged at this time (following psychiatric clearance) if she is asymptomatic with a QTc <450 ms.If features of serotonin toxicity are present supportive care in a ward environment for 12 to 24 hours is typically required until they resolve. Severe serotonin toxicity requires ICU level care.

From Twin Cities Tox Blog:

usually see citalopram as Celexa in tablets containing 10 mg, 20 mg, or 40 mg.  It peaks in the blood stream at roughly 5.5 hrs during therapeutic use, but potentially longer in the context of overdose.  The elimination takes on the order of a full day.  Similar to venlafaxine, it’s metabolized in the CYP450 system, but this time it’s 3A4 and 2C19 rather than 2D6.  Remember, that means that some people can be much slower in metabolizing than others, and the metabolism can be inhibited or induced by other drugs and some foods.

There is some literature describing QTc prolongation long enough to have caused dysrythmias, and it can be quite profound.  The seizures are the main concern, because the serum peak would lead us to believe that they should come within the first 6 or 8 hours.  This is not the case.  The seizures can be quite delayed; they can even occur out as far as 16-20 hours from ingestion (Carson and Kristin described a case in J Emerg Med in 2003 where the seizures occurred 13 hours post-ingestion with the medics on the way to Regions).

doses as low as 280 mg causing seizures (by the way, escitalopram appears to be much safer, both in similar dosing to citalopram and unknown dosing from all-comers).  Sams recs for: long term observation, I use a relatively arbitrary number of 400mg as a screening tool, because observing those above that line will catch a vast majority of the potential bad outcomes, and the only seizures described in the literature below that dose were short and self-limited with no negative long term effects.  When I say long term observation, I’m talking about 18 hours (you can make it a full day to be conservative and also because that makes things pretty easy, usually).  For shorter term observation, I send overdoses less than 100 mg home or to psych, and between 100 and 400 mg if they have no symptoms and no QTc prolongation at 8 hrs then they’re good.  The data on kids is scarce, and I would (pediatricians will hate this) treat them like little adults.  If 400mg is my number for adults, then I have to arrive at about 5 mg/kg for kids (now you have just one number to remember for venlafaxine and citalopram….how convenient).

What to do?

1) Serotonin syndrome – Again, keep them cool, hydrated, and safe.  IV fluid and benzodiazempines remain the easiest and still best treatments available.  Some drugs marketed for treatment are available and don’t affect morbidity or mortality at all (cyproheptadine).

2) Seizures – The above treatment for the serotonin syndrome is convenient, because most of the seizures that occur with citalopram should be benzo-responsive.  My first three lines of treatment would be benzo, benzo, and benzo.  My next line would be propofol if I had to intubate, and potentially phenobarb whether I had to intubate or not.  I would avoid phenytoin or phosphenytoin at mostly because of classic teaching of avoidance due to the sodium channel blocking actions of it (this theory applies generally to tox-induced seizures).  I don’t know where to fit levetiracetam (Keppra) into the mix yet.

3) Cardiac effects – For the QTc prolongation make sure the serum K+ is at least 4, and if not give KCl.  Give Mg, 2 gm IV, if QTc is greater than 500ms (totally arbitrary without proven benefit, but standard and easy to remember).  IV fluid will be first line for hypotension.  For torsades (which you’re trying to prevent with the QTc stuff above) do the right thing.  Mg fast, etc.  You have to already know torsades, right?

-Sam

Escitalopram

. Would the risk assessment and management plan change if the patient ingested escitalopram instead of citalopram?

Escitalopram is the S-enantiomer of citalopram. It is a more potent inhibitor of the serotonin transporter and is probably responsible for most of the SSRI effect in racemic citalopram. Clinical experience in escitalopram overdose has been relatively limited, although a series of 79 cases was recently published (van Gorp et al, 2009) .

Overall, it appears reasonable to manage escitalopram overdose in a similar way to citalopram. The major manifestations of escitalopram overdose are serotonin toxicity, QT prolongation, and bradycardia. The risk of cardiac arrhythmias according to QT intervals appear similar to that with citalopram. Of note, no cases of seizures or life-threatening dysrhythmias were reported in van Gorp et al’s case series of escitalopram overdose (note that the maximum dose ingested was only 560 mg).

serotonin toxicity, qt prolongation, and bradycardia are escitalopram OD effects (Ann Emerg Med 2009;54:404)

Others

Trazadone-more commonly has hypotension from alpha block, Priapism

Venlafaxine (Effexor)

seizures and tachycardia, need at least 6 hours of observation

From Twin Cities Tox Blog

What’s venlafaxine?  Venlafaxine potentiates neurotransmitter release and acts as a non-specific neurotransmitter reuptake inhibitor as well.  This helps differentiate its mode of action from the SSRIs because it also inhibits the reuptake of norepinephrine and dopamine.  You will almost always see it marketed as Effexor XR, the extended release version.  It’s well-absorbed orally, and the XR version peaks in the blood stream at therapeutic doses at roughly 5.5 hrs after ingestion.  The kicker is that this will be pushed out longer in overdose, and additionally the main active metabolite, O-desmethylvenlafaxine, doesn’t peak for 9 hrs post-ingestion even at therapeutic dosing.  The drug is metabolized in the CYP450 system (2D6 for you true tox nerds out there), so like other CYP-modified drugs there will be some variance from the above serum peak times depending on whether the patient is a fast or slow metabolizer.

Possible clinical effects?  The literature laundry list of bad possible clinical outcomes caused by venlafaxine has grown to almost ridiculous proportions in the last few years.  Like other neurotransmitter reuptake inhibitors, serotonin syndrome along with hyperthermia/altered mental status/agitation is very possible.  Seizures are not uncommon.  Slightly less common are devastating cardiac complications.  These can include QRS and QTc (remember that these are from sodium and channel blockade, respectively) prolongation leading to dysrhythmias, generalized cardiac function depression and hypotension, and even Takotsubo (come on, we went over that just a couple weeks ago in conference).  There seems to be a propensity towards pharmacobezoar formation in the larger overdoses, with potential for aspiration, and bowel ischemia along with the badness already discussed.  An oddball from a recent report is eosinophilic pneumonia following an overdose.

Who to worry about?  First of all, lets talk Old School Regular Effexor vs XR.  If the patient took the non-ER version, if they’re not symptomatic and they’re out 8 hours out from the ingestion, they’re good to be sent to psych at that point.  If they took the XR version and it’s a concerning amount for you, then the patient just bought 24 hours of medicine observation prior to their definitive psych care.  Now, let’s hash out what’s a bad overdose in terms of amount (I’m assuming XR formulation for all of the discussion that follows).  For kids your cutoff is 5 mg/kg.  If you’re positive the kid got into less than that, send them home with reassurance.  If they potentially got more than that, they are now going to be observed for 24 hours by a pediatrician as an inpatient.  That 5 mg/kg is not hard to get to.  Let’s say you’ve got a 15 kg kid, that’s only 75mg.  A lot of prescribed users are taking 150mg tabs.  You do the math. For adults I want you to keep 500 mg in mind.  That is a little conservative, but it’s easy to remember and will make things even easier once you have to remember the dosing stuff for citalopram that I’ll go over in the next couple of days.  Seizures are common once patients get over 1 gm, and cardiac depressant effects, along with dysrhythmias, are common once you get over a few grams.  Of note, seizures have been documented in neonates recently born to mothers with therapeutic serum levels.  Again, that 500 mg to 1 gm beginning trouble zone is easy to get to, because that might mean only 4 tablets.

What to do?

1) Serotonin syndrome – Basically, keep them cool, hydrated, and safe.  IV fluid and benzodiazempines remain the easiest and still best treatments available.  Some drugs marketed for treatment are available and don’t affect morbidity or mortality at all (cyproheptadine).

2) Seizures – The above treatment for the serotonin syndrome is convenient, because most of the seizures that occur with venlafaxine should be benzo-responsive.  My first three lines of treatment would be benzo, benzo, and benzo.  My next line would be propofol if I had to intubate, and potentially phenobarb whether I had to intubate or not.  I would avoid phenytoin or phosphenytoin at mostly because of classic teaching of avoidance due to the sodium channel blocking actions of it (remember, venlafaxine does that already and you don’t need more of it).  I don’t know where to fit levetiracetam (Keppra) into the mix yet.

3) Cardiac effects – Use sodium bicarb for the QRS prolongation.  How much?  As much as it takes.  Start with 2 amps bolus (100meq) to see if you get a response.  If you do you can either pay close attention and rebolus when you need to or start an isotonic drip.  If you get no effect then do the bous again to make sure.  For the QTc prolongation make sure the serum K+ is at least 4, and if not give KCl.  Give Mg, 2 gm IV, if QTc is greater than 500ms (totally arbitrary without proven benefit, but standard and easy to remember).  IV fluid will be first line for hypotension.  If that doesn’t work, then you need to sort out if you’re dealing with peripheral vasodilation of cardiac dysfunction.  Too often peripheral vasopressors are thrown at hypotensive patients that have cardiac dysfunction, which may make them worse.  If you have sorted this out, and it is a peripheral problem, then consider norepi.  If you have cardiac dysfunction then you can try a number of things, without much literature to back you up.  My first line would be calcium and high dose insulin.  We don’t know yet if intralipid rescue therapy will work for this overdose, but it might.  Despite a demonstrated low lipid solubility, I know of a couple of successful “lipid saves” in the context of venlafaxine overdoses.

That’s a lot of info.  Very important stuff though.  I would say the primary pitfalls in the ED in managing these patients is underestimating how sick they might get, not observing them long enough, and not adequately managing the potential cardiac complications.

-Sam

Maprotiline-manage similar to TCAs except this agent has a higher incidence of seizures and arrhythmias.

Observe for 6 hours, Admit celexa overdoses for 24 hours.

Serotonin Syndrome (SS)

excellent review

and this one

Increase in dose or a new agent

Agitation, Ataxia, diaphoresis, diarrhea, hyperreflexia, hyperthermia, mental status, myoclonus, shivering, can have tremor

Serotonin Syndrome: Pearls The serotonin syndrome (SS) results from excess serotonin in the brain stem, and to a lesser extent the spinal cord.  Patients with SS present with varying degrees of neuromuscular manifestations (e.g.  tremor, rigidity, nystagmus), neurobehavioral manifestations (confusion, agitation, seizures), and autonomic nervous system dysfunction (diaphoresis, hyperthermia, tachycardia).  The following pearls are important to keep in mind when dealing with the SS:

a) Classically SS occurs when a second agent capable of increasing serotonin levels, such as MAO inhibitors, is taken together with a serotonin re-uptake inhibitor (SSRI).  Examples of SSRIs include fluoxetine (Prozac) and sertraline (Zoloft).  SS can result from a single dose of seritonergic drug as long as 5 weeks after cessation of a long term MAO inhibitor.  Be aware, however, that SS is being increasingly reported as an idiosyncratic reaction to a single dose of a medication, and in an overdose situations.  Therefore, since the diagnosis of SS is a clinical one, do not exclude it simply because the classic history of drug interaction is not present.

b) Dextromethorphan, a common ingredient in cough medications, has SSRI properties and has been implicated in the serotonin syndrome in patients already taking a seritonergic medication.

c) MDMA (“ecstasy”), now a common drug of abuse, induces increased serotonin release and prevents its reuptake.  Thus, it may also contribute to the serotonin syndrome.

Treatment is generally supportive.

Active cooling

Benzos for rigidity

Cyproheptadine (Periactin) – an infrequently used antihistamine with antiseritonergic properties – has been repeatedly shown to ameliorate the symptoms of SS.  The dose is 4-8 mg, which can be repeated every 1 to 4 hours to a maximum of 32 mg.  The pediatric dose is 0.25mg/kg/d with a maximum of daily dose of 12 mg.  This has been shown to result in dramatic improvement in as little as 30 minutes. U Maryland Tox Info Sheet

Consider Neuroleptic Malignant Syndrome in the differential diagnosis of SS.

MAOI

Nardil, Parnate, Matulane, Eldepryl

Psych Meds-Phenolzine, tranylcypromine

Parkinson’s-selegiline

ABX- forazolidone, procarbazine

Not dialyzable

Blocks reuptake and causes eventual depletion of NorEpi

MAO overdose

Latent Phase (6-12 hours)

Excitatory

CV collapse c bradycardia

Secondary Complications

Sympathetic Storm

Treat Hypertension c Sodium Nitroprusside or Phentolamine

Hypotension needs norepi not dopamine as this relies on synaptic release of catecholamines

MAO/food interaction (tyramine)

Normally metabolized by liver, but MAO blocks this, causing amines that are not broken down.  Usually seen in first few hours.

MAO/Drug interaction

Seizures, coma, muscular rigidity. Especially ephedrine and phenylpropanolamine

Phenelzine -leads to long term peripheral neuropathy secondary to B6 deficiency

Others

Buproprion (Wellbutrin, Zyban)

monocyclic antidepressant

Noradrenergic or dopaminergic effects

can cause intractable Seizures and tachycardia

can cause prolonged QRS, prolonged QTc, N/V, hallucinations and agitiation

if patient has taken sustained release, consider whole bowel irrigation

seizures have been reported up to 14 hours after ingestion

> 1.5 has been associated with ventricular conduction disturbances

(JEM 2004;27(2):147)

must observe at least 24 hours (AJEM Volume 27, Issue 8, October 2009, Pages 911-915)

from twincities tox blog:

What’s bupropion?  The drug functions in a sort of similar fashion to venlafaxine, in that it inhibits the reuptake of all three of the main biogenic neuroamines (dopamine, norepinephrine, and serotonin), although more weakly than venlafaxine does.  You will most commonly see bupropion overdoses in the form of Wellbutrin SR or XL, in doses of 75 mg to 300 mg, depending on the formulation.   The SR version peaks in the bloodstream at roughly 3 hours from ingestion, and the XL version peaks at about 5 hours.  In terms of the elimination half life, just remember that it’s roughly a full day.  The SR version is meant to be taken every 12-24 hours, while the XL version is a qday med.  The metabolism of the drug is by the CYP450 system, similar to venlafaxine and citalopram (in this case it’s 2B6).

Possible clinical effects? QTc prolongation and seizures.  I’m not going to belabor these points, because I have the previous few days.  The big deal is that this is another one where delayed onset seizures can occur.

Who to worry about? The doses are not as well established for this one.  There have been fatalities associated with 5-9 gm ingestion in adults and greater than 40mg/kg in kids.  I would say that anything over 2 gms in an adult or 25 mg/kg in a kid would be concerning enough to watch.

What to do?

1) Serotonin syndrome – serotonin syndrome stuff

2) Seizures – same as venlafaxine and citalopram

3) Cardiac effects – QTc stuff, K+, Mg, treat torsades if it happens, whatever.

4) Observation – watch XL for a full day if greater than a couple gm ingestion or if QTc prolongation or Sz occur.

Meprobamate

cardiac toxicity are unknown [ 2]. Accumulation of meprobamate in the myocardium has been suggested by Kintz et al. [ 23], who reported in autopsies that meprobamate concentration in cardiomyocytes was three times higher than in blood. However, the effect of this accumulation is unknown. A direct lesion of cardiomyocytes is unlikely, and most cases of cardiac failure in our study were quickly reversible in approx. 24 h. On the other hand, we found that troponin Ic, measured in blood 24 h after the admission of eight patients with meprobamate poisoning and cardiac failure, was in the normal range. Finally, we did not observe QRS prolongation, thereby precluding a membrane stabilizing effect of meprobamate. A few limitations of our study should be noted. First, the main criterion used to select our patients was hypotension, which does not automatically mean shock. However, hypotension was associated with increased metabolic acidosis, suggesting a certain degree of tissue hypoperfusion. Second, echocardiography was not performed in patients without hypotension and, in eight cases, was performed when inotropic drug infusion had already started. Therefore one could argue that the incidence of cardiac dysfunction related to meprobamate poisoning was underestimated. Finally, in most patients blood volume expansion was performed before admission to our intensive care unit, precluding elimination of any hypovolemia at baseline. In conclusion, hypotension at admission occurs in about 40% of cases of meprobamate self-poisoning and is especially related to cardiac failure. The therapeutic consequences are important since these results suggest frequent inotropic drug infusion. The mechanisms of cardiac toxicity remain largely unknown and no predictive factor could be isolated. Intensive Care Medicine 2005;31(11)

Seroquel abuse b/c anxiolytic/sedative effects.  Pt’s reportedly use it to blunt the anxiety and insomnia of crack cocaine or in prison to substitute for heroin. Bupropion is crushed and snorted. Gabapentin is snorted to block the irritative effects on the nares from bupropion snorting. (Am J Emerg Med 2006;24(1):137)