Zoloft overdose alone is rarely life-threatening.
Zoloft is the trade name for the generic drug called sertraline. Zoloft is a selective serotonin re-uptake inhibitor (SSRI)-type antidepressant. Almost 50,000 poison center exposures in the US are attributed to SSRIs, which resulted in 90 major outcomes, and only two deaths [^10]. Reports of SSRI overdose have steadily increased, reflecting the increase in prescriptions for SSRIs.
SSRIs relative lack of toxicity in overdose (Zoloft included) is one of their big advantages over the old-school tricyclic antidepressants. Barbey et al.[^1] specifically investigated serotonin the toxicity of sertraline vs tricyclic antidepressants. He reported that:
SSRI antidepressants are rarely fatal in overdose when taken alone. During the 10 years that SSRI antidepressants have been marketed, there have been remarkably few fatal overdoses reported in the literature or to the AAPCC or FDA involving ingestion only of an SSRI. Moderate overdoses (up to 30 times the common daily dose) are associated with minor or no symptoms, while ingestions of greater amounts typically result in drowsiness, tremor, nausea, and vomiting. At very high doses (> 75 times the common daily dose), more serious adverse events, including seizures, electrocardiogram (ECG) changes, and decreased consciousness may occur. SSRI overdoses in combination with alcohol or other drugs are associated with increased toxicity, and almost all fatalities involving SSRIs have involved coingestion of other substances.
The greatest danger posed by Zoloft overdose is serotonin syndrome. But serotonin syndrome rarely manifests unless two or more serotonergic drugs are combined.
What Constitutes a Zoloft Overdose?
A typical starting dosage of Zoloft is 25 mg, which is titrated up to 50 mg. A study based on data from poison control centers[^7] found that of 42 Zoloft overdose and adverse effect reports, the stated amount ingested ranged from 50 to 8000 mg (mean 1,579 mg). The authors also reported:
- Mean time from ingestion to the onset of overdose symptoms was 3 hours
- 17 of the 40 patients ingested sertraline alone.
- Of these 17 patients, 10 had no signs or symptoms
- The most common overdose symptoms were tremor, lethargy, and nausea
- Less common findings included agitation, confusion, and vomiting
- Treatment included lavage, activated charcoal, and observation
Serotonin Syndrome Cheatsheet
Think you're experiencing serotonin syndrome? Lookout for these signs and symptoms:
- gastroinestinal distress (nausea and vomiting)
- Myoclonus (muscle twitching)
- Hyperreflexia (manifested by clonus), tremor.
Background: What Are SSRIs?
- obsessive-compulsive disorder
- social anxiety disorder
- posttraumatic stress disorder
Zoloft (sertraline) works by inhibiting a protein subunit of the serotonin transporter (SERT). Zoloft elevates serotonin in the synaptic cleft by blocking serotonin reuptake into neurons.
Low levels of serotonin in the nervous system are linked to mood disorders and aggression. Researchers theorize that SSRIs like Zoloft improve mood by (1) increasing neurognesis, (2) normalizing the hypothalamaic-pituitary-adrenal axis, and (3)blunting negative emotional affect.
Zoloft's Side Effect Profile
Any discussion of sertraline overdose should mention the side effects of the drug. Some Zoloft overdose symptoms are an extension of its adverse effects at therapeutic doses..
Common side effects of Zoloft include:
- gastrointestinal (GI) upset
But what are the signs and symptoms of true Zoloft toxicity?
Sertraline (Zoloft) Toxicity
Perhaps some of the most staggering case studies of sertraline toxicity involve pediatric patients.
One case study[^3] describes an 8-year-old girl who was admitted to the emergency department after ingesting 1500 mg of sertraline.
The girl was on a regimen of sertraline and risperidone. Risperidone is an antipsychotic that's sometimes used to augment antidepressants.
Her signs and symptoms included:
- perfuse sweating
- flushing of the skin
- involuntary movements
Her symptoms were managed with several benzodiazepines including diazepam, midazolam, and biperide. However, she was transferred to the pediatric ICU when her state worsened.
The signs and symptoms she exhibited were part of a clinical triad of cognitive, autonomic, and somatic effects seen in serotonin syndrome. Recall that Zoloft is belongs to the class of drugs which blocks the serotonin transporter. Though SSRIs increase serotonin by design, excess serotonin can result in profound and life-threatening cluster of symptoms known as serotonin syndrome.
Consequences of Serotonin Syndrome
Left untreated, serotonin syndrome leads to:
- renal failure
- circulatory shock
Serotonin syndrome is actually a spectrum of signs and symptoms that range from mild to severe. When it is caused as a result of drugs, it is called drug-induced serotonin syndrome. Serotonin syndrome can result from a variety of drug classes, not just SSRIs. Any drug that directly or indirectly increases levels of serotonin in the central nervous system has the potential to cause serotonin syndrome [^5].
Drugs That Can Precipitate Serotonin Syndrome
|Class||Drugs that can induce serotonin syndrome|
|Antidepressants||Monoamine oxidase inhibitors (MAOIs), TCAs, SSRIs, SNRIs, nefazodone, trazodone and atypical antidepressants like mirtazapine.|
|5-HT1 agonists||Triptans (used to treat migraines)|
|Psychedelics||LSD is a potent 5-HT2A-type serotonin agonist; 5-Methoxy-diisopropyltryptamine|
|Opioids||Dextropropoxyphene, tramadol, tapentadol, pethidine (meperidine), fentanyl, pentazocine, buprenorphine, oxycodone, hydrocodone|
|CNS stimulants||MDMA, MDA, methamphetamine, lisdexamfetamine, amphetamine, phentermine, amfepramone (diethylpropion), serotonin releasing agents like hallucinogenic substituted amphetamines, sibutramine, methylphenidate, cocaine|
|Herbs||St John's Wort, Syrian rue, Panax ginseng, Nutmeg, Yohimbe|
|Others||tryptophan, L-Dopa, valproate, buspirone, lithium, linezolid, dextromethorphan, 5-hydroxytryptophan, chlorpheniramine, risperidone, olanzapine, ondansetron, granisetron, metoclopramide, ritonavir, metaxalone|
Another case study[^4] of Zoloft overdose involved a 25-year-old woman who visited the emergency department complaining of muscle swelling and dark urine.
She had a history of depression and frequent, strenuous exercise. Six weeks prior to the visit, her Zoloft dose was increased from 100 mg to 150 mg daily. After blood testing the emergency department discovered sertraline-induced rhabdomyolysis. Rhabdomyolysis results from damage to skeletal muscle, which triggers the release of harmful, nephrotoxic byproducts.
Ultimately, kidney failure is an imminent consequence. Though the biochemical progression of sertraline-induced rhabdomyolysis is unknown, researchers believe sertraline reduces muscle’s time to contract while increasing contraction time.
This case study is interesting because the patient was taking therapeutic doses of sertraline.
How Long Until Zoloft Overdoe Symptoms Manifest?
How rapidly can the associated effects of Zoloft toxicity appear?
The literature suggests a timeframe of several hours. Apart from the triad of cognitive, autonomic, and somatic effects, clinicians should suspect serotonin syndrome if the patient is taking multiple serotonergic drugs. Plasma concentrations of Zoloft peak after 4 to 8 hours.
Zoloft's elimination half-life is around 26 hours. Hence, a daily dose is necessary to maintain therapeutic levels in the body. Compared to other antidepressants, experts consider Zoloft well-tolerated with a favorable side effect profile. Zoloft overdose is quite rare, mild, and short-lived.
Mild Zoloft Toxicity
Up to this point, only the most life-threatening and lethal effects of Zoloft overdose were discussed. What are the effects of mild Zoloft toxicity?
- irregular muscle activity
- confusion/mild agitation
Unless the clinician increases the dose of Zoloft, the patient’s signs and symptoms will most likely disappear in time, or at the very least continue to present mildly. Clinicians often experiment with prescribing the correct dose of Zoloft until the patients meet a happy medium of effectiveness and safety. Symptoms of Zoloft overdose in mild to moderate cases often resolve on their own.
Severe Zoloft Toxicity
Severe overdose symptoms require immediate medical attention.
One of the common effects of severe Zoloft toxicity is hyperthermia or an abnormally high body temperature. Left uncontrolled, hyperthermia can progress to seizures and death.
Serotonin syndrome is managed with benzodiazepines and less commonly serotonin antagonists. Chlorpromazine is an antipsychotic that is also a serotonin antagonist. Cyproheptadine, an antihistamine, is another drug used to reverse Zoloft toxicity. However, it must be combined with generous amounts of intravenous fluid therapy to reduce the risk of hypotension.
In one particular study[^8], researchers showed that single dose activated charcoal (SDAC) had a promising effect on patients exhibiting signs of Zoloft toxicity. Activated charcoal has the unique property of adsorbing, or binding to, substances inside the GI tract. Among 28 patients, researchers showed that SDAC, when given up to 1.5 to 4 hours after overdose, was able to increase the clearance of Zoloft by a factor of 1.9. SDAC also decreased Zoloft’s maximum plasma concentrations. SDAC's ability to hasten Zoloft elimination form the body and limit its toxicity is promising.
How Common Is Zoloft Overdose?
The prevalence of Zoloft toxicity is low. Pfizer succeeded in securing FDA approval for sertraline in 1991, and the drug has been on the market for over 20 years.
Researchers are still learning new things about Zoloft's drug interactions and pharmacodynamics.
SSRI-type antidepressants like Zoloft can interact with up to one thousand different drugs. Ten percent of these interactions are serious and can precipitate serotonin syndrome.
Research has made strides with useful clinical tools like the Hunter Serotonin Toxicity Criteria[^9]. The toxicity criteria are a simple, targeted flowchart that helps clinicians identify serotonin toxicity secondary to drug overdose.
[^1]: Barbey JT, Roose SP. SSRI safety in overdose. J Clin Psychiatry. 1998;59 Suppl 15:42-8.
[^2]: Young SN, Leyton M. The role of serotonin in human mood and social interaction. Insight from altered tryptophan levels. Pharmacol Biochem Behav. 2002;71(4):857-65.
[^3]: Grenha J, Garrido A, Brito H, Oliveira MJ, Santos F. Serotonin syndrome after sertraline overdose in a child: a case report. Case Rep Pediatr. 2013;2013:897902.
[^4]: Snyder M, Kish T. Sertraline-Induced Rhabdomyolysis: A Case Report and Literature Review. Am J Ther. 2016;23(2):e561-5.
[^5]: Bartlett D. Drug-Induced Serotonin Syndrome. Crit Care Nurse. 2017;37(1):49-54.
[^6]: Murdoch D, Mctavish D. Sertraline. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depression and obsessive-compulsive disorder. Drugs. 1992;44(4):604-24.
[^7]: Lau GT, Horowitz BZ. Sertraline overdose. Acad Emerg Med. 1996;3(2):132-6.
[^8]: Cooper JM, Duffull SB, Saiao AS, Isbister GK. The pharmacokinetics of sertraline in overdose and the effect of activated charcoal. Br J Clin Pharmacol. 2015;79(2):307-15.
[^9]: Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96(9):635-42.
[^10]: Bronstein AC, Spyker DA, Cantilena LR, Rumack BH, Dart RC. 2011 Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 29th Annual Report. Clin Toxicol (Phila). 2012;50(10):911-1164.