Many noncyclic antidepressants with different mechanisms of action are available. Selective serotonin reuptake inhibitors (SSRIs) include fluoxetine, sertraline, citalopram, escitalopram, paroxetine, and fluvoxamine. Serotonin-norepinephrine reuptake inhibitors (SNRIs) include venlafaxine, desvenlafaxine, duloxetine, milnacipran, and levomilnacipran. Serotonin antagonist and reuptake inhibitors (SARIs) include trazodone and nefazadone. Serotonin partial agonist and reuptake inhibitors (SPARIs) include vilazodone and vortioxetine. Others include norepinephrine-dopamine reuptake inhibitors (NDRIs) like bupropion and the tetracyclic antidepressant mirtazapine. Bupropion is also marketed for smoking cessation. In overdose these drugs are generally less toxic than the tricyclic antidepressants and the monoamine oxidase (MAO) inhibitors; however, serious effects, such as seizures, hypotension, cardiac arrhythmias, and serotonin syndrome, occasionally occur. Usual doses, pharmacologic mechanisms, and types of toxicity of various noncyclic and tricyclic antidepressants are described in Table II-8.

1. SSRIs inhibit serotonin reuptake transporters resulting in increased stimulation of serotonin receptors in the brain. SNRIs inhibit both serotonin and nor­epinephrine reuptake transporters and also increase stimulation of CNS nor­epinephrine receptor. SARIs and SPARIs also increase the effective amount of serotonin in the CNS. Bupropion is a stimulant that can also cause seizures, presumably related to inhibition of reuptake of dopamine and norepinephrine, and cardiac toxicity possibly due to effects on gap junctions that can appear similar to sodium channel blockade.
2. Trazodone and others can produce peripheral alpha-adrenergic blockade, which can result in orthostatic hypotension and priapism.
3. Serotonin reuptake inhibitors, such as fluoxetine, citalopram, sertraline, paroxetine, fluvoxamine, venlafaxine, and trazodone, may interact with each other, with chronic use of an MAO inhibitor, or with dextromethorphan to produce the “serotonin syndrome” (see below).
4. None of the drugs in this group has significant anticholinergic effects.
5. Pharmacokinetics. These drugs have large volumes of distribution (Vd = 12-88 L/kg), except for trazodone (Vd = 1.3 L/kg). Most are eliminated via hepatic metabolism (see also Table II-63). Fluoxetine, paroxetine, and bupropion are potent inhibitors of the drug-metabolizing cytochrome P450 enzyme CYP2D6, which leads to many potential drug interactions. Absorption may be delayed with extended-release formulations.

The noncyclic antidepressants generally have a wide therapeutic index, with doses in excess of 10 times the usual therapeutic dose tolerated without serious toxicity. Bupropion can cause seizures in some patients even in therapeutic doses, particularly in people with a history of seizure disorders.

1. Central nervous system. The usual presentation after SSRI overdose includes ataxia, sedation, and coma. The syndrome of inappropriate ADH and movement disorders can occur even at therapeutic doses. Respiratory depression may occur, especially with co-ingestion of alcohol or other drugs. These agents, particularly bupropion, can cause restlessness, anxiety, and agitation. Tremor and seizures are common with bupropion but occur occasionally after overdose with SSRIs, particularly citalopram and escitalopram, as well as the SNRIs venlafaxine and duloxetine.
2. Cardiovascular effects are usually not life-threatening, although trazodone can cause hypotension and orthostatic hypotension, bupropion and SNRIs can cause sinus tachycardia and hypertension, and citalopram and escitalopram can cause sinus bradycardia with hypotension. Citalopram and escitalopram toxicity can be delayed up to 24 hours after exposure.
   1. Severe cardiotoxicity, including QRS-interval prolongation, hypotension, and cardiac arrest, has been reported with overdoses involving bupropion, citalopram, escitalopram and venlafaxine.
   2. Venlafaxine and citalopram also cause QT-interval prolongation, and the FDA has recommended a maximal daily citalopram dose of 40 mg to minimize the risk of torsade de pointes.
3. Serotonin syndrome is characterized by a triad of clinical features: neuromuscular hyperactivity (hyperreflexia, spontaneous or induced clonus, ocular clonus, rigidity, tremor); autonomic instability (tachycardia, hypertension, diaphoresis, hyperthermia, mydriasis); and mental status changes (agitation, anxiety, confusion).
   1. This reaction may be seen when a patient taking an MAO inhibitor ingests a serotonin uptake blocker. Because of the long duration of effects of MAO inhibitors and most of the serotonin uptake blockers, this reaction can occur up to several days to weeks after either treatment regimen has been discontinued.
   2. The syndrome has also been described in patients taking an overdose of a single SSRI or SNRI, an SSRI with meperidine, tramadol, tricyclic antidepressants, fentanyl, amphetamines, and derivatives (eg, methylenedioxymethamphetamine [MDMA]), dextromethorphan, linezolid, lithium, St. John's wort, or combinations of various SSRIs and/or SNRIs. The FDA has issued a warning about the risk for serotonin syndrome from the combination of triptans with SSRIs, but causation is still uncertain.

Antidepressant overdose should be suspected in patients with a history of depression who develop lethargy, arrythmia, serotonin syndrome, coma, or seizures.

1. Specific levels. Blood and urine assays are not routinely available and are not useful for emergency management. These drugs are not likely to appear on a rapid “drugs of abuse” screen, and they may or may not appear on comprehensive toxicology screening, depending on the laboratory.
2. Other useful laboratory studies include electrolytes, glucose, creatinine, creatine kinase (CK), arterial blood gases or pulse oximetry, cardiac troponin, and ECG monitoring.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if needed. Administer supplemental oxygen.
   2. Treat coma, QRS-interval prolongation, QT prolongation or arrhythmias, hypotension, hypertension, and seizures if they occur.
   3. For mild serotonin syndrome, benzodiazepines can be used for control of agitation and tremor. Severe serotonin syndrome with hyperthermia requires hospitalization and aggressive cooling measures, which often include neuromuscular paralysis and endotracheal intubation.
   4. Because of the potential for delayed onset of seizures or cardiotoxicity, observe patients for 24 hours after citalopram, escitalopram, or sustained-release bupropion or venlafaxine overdose.
2. Specific drugs and antidotes. In patients with serotonin syndrome, case reports suggest benefit with cyproheptadine, 12 mg orally, followed by 4 mg every hour for 3-4 doses. Other agents such as chlorpromazine, 25-50 mg IV, have also been used.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Gastric lavage is typically not necessary after small-to-moderate ingestions.
4. Enhanced elimination. In general, owing to extensive protein binding and large volumes of distribution, dialysis, hemoperfusion, and peritoneal dialysis are not effective.