Antidepressants

Mechanism of Action

Antidepressants target specific neurotransmitter systems to modulate mood and behavior. Most antidepressants are believed to increase serotonin, norepinephrine, or both in the synapse; however, newer agents also target glutamatergic and GABAergic pathways. The mechanisms by which antidepressants increase these neurotransmitters vary; many antidepressants inhibit their reuptake into presynaptic nerve terminals.[9]

Selective Serotonin Reuptake Inhibitors

• The reuptake of 5-hydroxytryptamine (5-HT, serotonin) into presynaptic terminals is mediated by the serotonin transporter. Neuronal uptake is the primary mechanism by which 5-HT neurotransmission is terminated. Selective Serotonin Reuptake Inhibitors (SSRIs) block serotonin reuptake, thereby enhancing and prolonging serotonergic neurotransmission. With continuous administration of SSRIs, cyclic adenosine monophosphate signaling, phosphorylation of nuclear transcription factors, expression of trophic factors such as brain-derived neurotrophic factor (BDNF), and neurogenesis increase.[10]
• SSRIs are first-line pharmacologic agents for the treatment of depression.[11]

Serotonin and Norepinephrine Reuptake Inhibitors

• Serotonin and norepinephrine reuptake inhibitors (SNRIs) block serotonin and norepinephrine reuptake into the synapse, thereby increasing stimulation of postsynaptic receptors. SNRIs differ in their affinity for the serotonin and norepinephrine transporters.
• In contrast to other selective SNRIs such as duloxetine, venlafaxine, and desvenlafaxine, milnacipran and levomilnacipran have higher selectivity for inhibiting norepinephrine reuptake than serotonin reuptake.[12][13]

Atypical Antidepressants

• Atypical antidepressants have various mechanisms of action.
• Bupropion, for example, works by inhibiting the reuptake of dopamine and norepinephrine at the presynaptic cleft.[14]
• Agomelatine acts as an agonist at the melatonin MT1 and MT2 receptors. Agomelatine also antagonizes serotonergic 5-HT2C receptors, promoting dopamine and norepinephrine release.[15] 
• Mirtazapine works by blocking alpha-2 adrenergic receptors on the cell bodies and nerve terminals, promoting the release of norepinephrine into the synapse. Furthermore, mirtazapine antagonizes the 5-HT receptor, which has been shown to increase norepinephrine and dopamine concentrations in the cerebral cortex.[9]

Serotonin Modulators

• Serotonin modulators such as vilazodone inhibit the presynaptic reuptake of serotonin. Vilazodone is also a partial agonist at the postsynaptic serotonin 5-HT1A receptor. 
• Trazodone acts upon postsynaptic serotonin 5-HT2A and 5-HT2C receptors and weakly inhibits presynaptic serotonin reuptake. In addition, trazodone blocks postsynaptic alpha-adrenergic and histamine receptors.
• Nefazodone antagonizes postsynaptic serotonin 5-HT2A receptors and inhibits presynaptic serotonin and norepinephrine reuptake; these actions increase serotonergic transmission at 5-HT1A receptors.[14]
• Vortioxetine inhibits serotonin reuptake and modulates multiple serotonin receptors, acting as a 5-HT1A receptor agonist, a 5-HT1B receptor partial agonist, and an antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors.

Tricyclic Antidepressants

• TCAs, such as amitriptyline, inhibit the reuptake of norepinephrine and serotonin into presynaptic neurons. Amitriptyline also has high affinity for muscarinic M1 and histamine H1 receptors. TCA can therefore cause sedation and anticholinergic adverse effects.[16]

Monoamine Oxidase Inhibitors

• Monoamine oxidase inhibitors (MAOIs) inhibit monoamine oxidase, the enzyme responsible for catabolizing serotonin, norepinephrine, and dopamine. MAOIs were the first antidepressants discovered. MAOIs are not considered first-line therapy for depression because of their adverse effects and drug-drug interactions.[17] 

N-Methyl-D-Aspartate Antagonists

• Dysregulation in glutamatergic neurotransmission is implicated in the pathophysiology of depression. Clinical research has recognized alterations in glutamate and GABA activity. Glutamate is an excitatory neurotransmitter that binds to N-methyl-D-aspartate (NMDA) receptors. Consequently, NMDA receptor antagonists have emerged as effective treatments for certain forms of depression.
• Esketamine, the S-enantiomer of racemic ketamine, is a nonselective, noncompetitive NMDA antagonist indicated for TRD.[18]
• Dextromethorphan is an uncompetitive NMDA receptor antagonist and opioid sigma receptor agonist. Bupropion, as discussed above, works by inhibiting the uptake of dopamine and norepinephrine. The fixed-dose combination of dextromethorphan-bupropion has a rapid onset of action (approximately 1 week) in patients with MDD.[3][19]

Brain-Derived Neurotrophic Factor Hypothesis

• The initial increase in synaptic serotonin levels eventually leads to increased levels of neuroprotective proteins such as BDNF. BDNF concentrations in depression normalize in response to pharmacological treatment. An increase in BDNF level and enhanced neuroplasticity leads to the remission of depression.[20]

Selective Serotonin 1A (5-HT1A) Receptor Agonist

• Gepirone acts as a selective partial agonist at postsynaptic and presynaptic 5-HT1A receptors. Presynaptic autoreceptor agonism initially reduces serotonin neuronal firing before autoreceptor desensitization with chronic use, whereas postsynaptic agonism mediates antidepressant effects. Unlike SSRIs, gepirone does not inhibit serotonin reuptake, which may contribute to its more favorable sexual adverse-effect profile. Gepirone is metabolized primarily by cytochrome P450 (CYP) 3A4.[4]

Gamma-Aminobutyric Acid Type A Receptor–Positive Allosteric Modulator

• Zuranolone is a synthetic neuroactive steroid analog of allopregnanolone, a metabolite of progesterone. Zuranolone acts as a positive allosteric modulator of synaptic and extrasynaptic GABA-A receptors, augmenting inhibitory neurotransmission. This mechanism is distinct from all existing antidepressant classes. The postpartum decline in allopregnanolone is hypothesized to contribute to PPD, providing the mechanistic rationale for zuranolone use in this indication.[5]
• Brexanolone, an IV formulation of allopregnanolone, also acts as a positive allosteric modulator of synaptic and extrasynaptic GABA-A receptors and is approved for postpartum depression.

Administration

Commercially available antidepressants are available in various dosage forms, including oral tablets, extended-release tablets, oral suspensions, and transdermal patches. Studies have evaluated alternative routes of administration, including inhalation, intranasal, sublingual, and rectal delivery. Among these approaches, intranasal esketamine has demonstrated clinical success.[21] According to the manufacturer's prescribing information, the usual starting and maintenance doses for commonly used antidepressants are listed below. Total daily oral doses may need to be administered in 2 or 3 equal doses per day, depending on the specific antidepressant and patient comorbidities. 

Selective Serotonin Reuptake Inhibitors

• Citalopram: The starting dose is 20 mg daily, and the usual maintenance dose is 20 to 40 mg daily.
• Escitalopram: The starting dose is 5 to 10 mg daily, and the usual maintenance dose is 10 to 20 mg daily.
• Paroxetine: The starting dose is 20 mg daily, and the usual maintenance dose is 20 to 40 mg daily.
• Sertraline: The starting dose is 50 mg daily, and the usual maintenance dose is 100 to 200 mg daily.
• Fluoxetine: The starting dose is 20 mg daily, and the usual maintenance dose is 20 to 60 mg daily.
• Fluvoxamine: The starting dose is 50 mg daily, and the usual maintenance dose is 50 to 200 mg daily.

Serotonin and Norepinephrine Reuptake Inhibitors

• Venlafaxine: The starting dose is 75 mg daily, and the usual maintenance dose is 225 to 375 mg daily, depending on formulation.
• Desvenlafaxine: The starting dose is 25 to 50 mg daily, and the usual maintenance dose is 50 mg daily.
• Duloxetine: The starting dose is 30 mg daily, and the usual maintenance dose is 60 mg daily.
• Milnacipran: The starting dose is 12.5 mg daily, and the usual maintenance dose is 100 mg daily.
• Levomilnacipran: The starting dose is 20 mg daily, and the usual maintenance dose is 40 to 120 mg daily.

Atypical Antidepressants

• Bupropion: The starting dose is 150 mg daily, and the usual maintenance dose is 300 mg daily.
• Mirtazapine: The starting dose is 15 mg daily, and the usual maintenance dose is 15 to 45 mg daily. 

Serotonin Modulators

• Nefazodone: The starting dose is 200 mg daily, and the usual maintenance dose is 200 to 600 mg daily.
• Trazodone: The starting dose is 150 mg daily, and the usual maintenance dose is 200 to 400 mg daily.       
• Vortioxetine: The starting dose is 10 mg daily, and the usual maintenance dose is 20 mg daily.
• Vilazodone: The starting dose is 10 mg orally once daily with food for 7 days, followed by 20 mg once daily for 7 days. The usual maintenance dose is 20 to 40 mg once daily with food.

Tricyclic Antidepressants

• Amitriptyline: The starting dose is 25 to 50 mg daily, and the usual maintenance dose is 100 to 200 mg daily.
• Nortriptyline: The starting dose is 25 mg daily, and the usual maintenance dose is 50 to 150 mg daily. 
• Imipramine: The starting dose is 75 mg daily, and the usual maintenance dose is 150 mg daily.
• Clomipramine (off-label use): The starting dose is 25 mg daily, and the usual maintenance dose is 100 to 250 mg daily.
• Desipramine: The starting dose is 25 to 50 mg daily, and the usual maintenance dose is 100 to 300 mg daily.

Monoamine Oxidase Inhibitors

• Isocarboxazid: The starting dose is 20 mg daily, and the usual maintenance dose is 20 to 60 mg daily.     
• Phenelzine: The starting dose is 45 mg daily, and the usual maintenance dose is 60 to 90 mg daily.
• Selegiline transdermal patch: The starting dose is 6 mg/24 hours, and the usual maintenance dose is 6 to 12 mg/24 hours.

N-Methyl-D-Aspartate Antagonists

• Esketamine (nasal spray): During the induction phase (weeks 1-4), the dose is 56 or 84 mg twice weekly. During the maintenance phase (weeks 5-8), the dose is 56 or 84 mg once weekly. Dosing should be individualized (with the least frequent dosing) according to the clinical response.
• Dextromethorphan/bupropion(extended-release tablets): The starting dose is 45 mg dextromethorphan/105 mg bupropion once daily in the morning. After 3 days, increase the dose to the maximum recommended dose of 1 tablet twice daily, with doses separated by at least 8 hours. Do not exceed 2 doses in a 24-hour period.[3]

Serotonin 1A Receptor Agonist

• Gepirone (Exxua): The starting dose is 18.2 mg orally once daily in the morning. Titrate to 36.3 mg once daily on day 4; may increase to 54.5 mg once daily after day 7; may further increase to a maximum of 72.6 mg once daily after an additional 7 days. Extended-release tablets should not be crushed, split, or chewed. Food has no clinically significant effect on absorption. Dose reduction is required when coadministered with strong CYP3A4 inhibitors.[4]

Neuroactive Steroids

• Zuranolone (Zurzuvae): The recommended dose for postpartum depression is 50 mg orally once daily at bedtime for 14 days, taken with a high-fat meal to ensure adequate absorption. A second treatment course may be considered if needed. Patients should avoid driving or operating heavy machinery for at least 12 hours after each dose because of the risk of central nervous system (CNS) depression. Zuranolone is a Schedule IV controlled substance and is not currently approved for MDD.[5]
• Brexanolone (Zulresso): The recommended regimen is a continuous IV infusion over 60 hours in a certified healthcare facility under a REMS program. The infusion is titrated according to the manufacturer's prescribing information, with a maximum infusion rate of 90 mcg/kg/h.

Switching Antidepressants

• A washout period of 2 to 5 half-lives (most frequently 2–5 days) between cessation of the previous drug and the introduction of a new drug is the safest switching strategy from the point of view of drug interactions.[22]

Treatment-Resistant Depression

• According to the FDA and the European Medicines Agency (EMA), patients are considered to have TRD when their MDD fails to respond sufficiently to 2 or more consecutive antidepressants during a single depressive episode.[23] Patients with TRD may require augmentation with another antidepressant or atypical antipsychotic agent. 

Psychotherapy

• The combination of pharmacotherapy and psychotherapy is more effective than pharmacotherapy alone.[24]

Adverse Effects

The most common adverse effects of antidepressants include sexual dysfunction, drowsiness, weight gain, insomnia, anxiety, dizziness, headache, dry mouth, blurred vision, nausea, rash, and tremor. Patients may also experience asthenia and malaise while on antidepressant therapy. Clinicians should also monitor for hyperprolactinemia, syndrome of inappropriate antidiuretic hormone, and hyponatremia in patients receiving antidepressants.[25] Although antidepressants share several common adverse effects, each medication and drug class has a distinct adverse effect profile influenced by its pharmacologic properties, receptor-binding characteristics, and mechanism of action. The adverse effects listed below represent common class–associated effects and are not intended to provide a comprehensive list for every individual agent.

Selective Serotonin Reuptake Inhibitors

• Sexual dysfunction
• Headache
• QTc prolongation (particularly with citalopram and escitalopram) [26]

Serotonin and Norepinephrine Reuptake Inhibitors

• Hypertension (particularly venlafaxine)
• Headache
• Diaphoresis
• Increased markers for bone resorption with long-term use [27]

 Atypical Antidepressants

• Agomelatine: Hepatotoxicity
• Mirtazapine: Sedation, weight gain [28]
• Bupropion: Tremor and risk of dose-dependent seizures [29]

 Serotonin Modulators

• Nefazodone: Hepatotoxicity (acute hepatitis with cholestasis and variable degrees of centrilobular necrosis) [30]
• Vilazodone: Diarrhea
• Vortioxetine: Nausea 
• Trazodone: Sedation, priapism [31][32]

Tricyclic Antidepressants

• Dry mouth
• Urinary retention
• Constipation
• QRS prolongation
• Seizures
• Orthostatic hypotension [33]

Monoamine Oxidase Inhibitors

• Potential for serotonin syndrome [34]
• Sexual dysfunction
• Hypertensive crisis with tyramine-containing foods or interacting medications

 Esketamine

• Increased blood pressure
• Potential for misuse or abuse, dissociative or perceptual changes, and sedation [35]

Dextromethorphan/Bupropion

• Dizziness, headache, somnolence, and dry mouth [3]

Serotonin 1A Receptor Agonists

• Gepirone has a favorable adverse effect profile compared to SSRIs and SNRIs. Because it does not inhibit serotonin reuptake, sexual dysfunction is significantly less common—a meaningful advantage for patients who have discontinued SSRIs due to this side effect. Common adverse effects include dizziness, nausea, and somnolence. Weight gain has not been associated with gepirone. Concomitant use of strong CYP3A4 inhibitors may significantly increase plasma concentrations, requiring dose reduction.[4]

Neuroactive Steroids

• Zuranolone most commonly causes somnolence, dizziness, headache, nausea, diarrhea, and nasopharyngitis. CNS depression is the primary safety concern; patients must avoid driving or operating heavy machinery for at least 12 hours after each dose and should not combine zuranolone with alcohol or other CNS depressants. As a Schedule IV controlled substance, zuranolone has the potential for abuse and dependence. Use during pregnancy is not recommended.[5]
• Brexanolone commonly causes sedation, dizziness, dry mouth, flushing, and loss of consciousness. Because of the risk of excessive sedation and sudden loss of consciousness, administration is restricted through a REMS program.

Contraindications

Contraindications and precautions vary considerably among antidepressant classes and individual agents. Clinically important contraindications and major safety considerations are listed below.

• Antidepressants should be used cautiously in patients with known hypersensitivities and in those taking other psychotropic medications.
• SSRIs and SNRIs, for example, should not be taken with other MAOIs, TCAs, and other psychotropics because of the risk of serotonin syndrome, which can lead to severe neuromuscular and autonomic symptoms. Caution is also warranted when combining serotonergic antidepressants with other medications that increase serotonin activity.[36]
• TCAs can provide another good example of relative contraindications in antidepressant therapy. Clinicians should be mindful when prescribing TCAs to individuals with cardiovascular disease. TCAs have been shown to cause orthostatic hypotension. Additionally, TCAs may lead to heart block in patients with preexisting bundle-branch disease.[37]
• Bupropion is contraindicated in patients with seizure disorders, current or prior diagnoses of bulimia nervosa or anorexia nervosa, and those undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Like other antidepressants, bupropion should not be used in patients taking MAOIs or drugs that can lower the seizure threshold.[38]
• Liver injury due to previous treatment is a contraindication to nefazodone therapy.[30]
• Esketamine is contraindicated in aneurysmal vascular disease (including the thoracic and abdominal aorta, intracranial, and peripheral arterial vessels) and arteriovenous malformations, according to the product labeling.
• Dextromethorphan/bupropion is contraindicated in patients with a seizure disorder, bulimia/anorexia nervosa, and concomitant use with MAOIs or within 14 days of discontinuing treatment with dextromethorphan/bupropion.[39][40][41]
• Gepirone is contraindicated with concurrent use of strong CYP3A4 inhibitors due to the risk of significantly elevated plasma concentrations. Gepirone should not be used concurrently with MAOIs; an appropriate washout period is required when switching between gepirone and an MAOI. Gepirone is not approved for pediatric patients, and its safety during pregnancy and lactation has not been established.[4]
• Zuranolone is not recommended during pregnancy and is currently approved by the FDA only for postpartum depression; the MDD indication received a Complete Response Letter requesting additional data. Concomitant use of strong CYP3A4 inducers is expected to significantly reduce zuranolone exposure. Concurrent use with alcohol or other CNS depressants should be avoided due to additive CNS depression.[5]

FDA Boxed Warning

Suicidal thoughts and behaviors: Antidepressants increase the risk of suicidal thoughts and behavior in pediatric and young adult patients. Closely monitor all antidepressant-treated patients for clinical worsening and the emergence of suicidal thoughts and behaviors.[42]

Monitoring

Therapeutic Drug Monitoring

• Therapeutic drug monitoring (TDM) is most useful for antidepressants with established therapeutic concentration ranges, particularly TCAs (eg, nortriptyline, imipramine, desipramine). TDM may also assist in evaluating medication adherence, drug interactions, adverse effects, or inadequate therapeutic response.
• TDM may also be helpful in patients who are refractory to treatment, experience adverse effects, or have a history of nonadherence. TDM is expensive, so clinicians must weigh the benefits against the cost of the study.[38]

Psychiatric Assessment 

• Various clinical rating scales can assist in monitoring a patient’s symptoms and assessing therapeutic response.
• Patient Health Questionnaire-9 (PHQ-9).[43]
• Hamilton Depression Rating Scale (HDRS-17).
• Montgomery-Åsberg Depression Rating Scale (MADRS).[44]
• In addition, monitoring for suicidal ideation is of paramount importance.
• Clinicians should monitor symptom severity, treatment adherence, adverse drug reactions, suicidal ideation, psychiatric comorbidities, and relevant medical conditions throughout therapy. Additional monitoring may be required for specific antidepressants, including blood pressure with SNRIs and esketamine, liver function with agomelatine, and plasma drug concentrations with selected TCAs.
• Clinicians should also assess the response to therapy and consider augmentation or switching antidepressants in patients with an inadequate response.

Toxicity

The toxicity of antidepressants varies substantially among and within drug classes. Antidepressants are commonly involved in intentional self-poisoning, making overdose toxicity an important consideration when selecting therapy for patients at increased risk of suicide. Older TCAs generally have a higher toxicity profile in overdose than newer antidepressants, particularly SSRIs.[45] Researchers have evaluated antidepressant toxicity using measures such as the fatal toxicity index, which compares self-poisoning mortality rates with prescription rates, and the case fatality index, which compares fatal and nonfatal self-poisoning episodes. These data may help inform treatment decisions in patients with elevated suicide risk.[45]

According to literature reviews, overdose toxicity is greatest with TCAs and MAOIs, followed by venlafaxine, bupropion, and mirtazapine, whereas SSRIs generally have the lowest toxicity in overdose. Among the SSRIs, citalopram appears to be associated with a greater risk of cardiotoxicity and fatal outcomes in overdose, while fluvoxamine has also been associated with higher case fatality rates than several other SSRIs.[46]

Selective Serotonin Reuptake Inhibitor Poisoning

Clinical features:

• CNS: Drowsiness, tremor
• Cardiovascular system: QRS widening and QTc interval prolongation (especially with citalopram and escitalopram)
• Potential serotonin syndrome: Hyperthermia, hypertonia, hyperreflexia, and clonus

Management:

• Secure airway, breathing, and circulation; intubate as clinically indicated
• Treat prolonged QRS intervals with sodium bicarbonate
• Prolonged QTc leading to torsades: Administer magnesium sulfate 2 g IV
• Treat seizures with benzodiazepines (eg, lorazepam 1-2 mg IV) as needed
• SSRIs are relatively safe, although serotonin syndrome is common in overdose. The exception is citalopram, which is significantly associated with QTc prolongation.[47]

Serotonin and Norepinephrine Reuptake Inhibitor Poisoning

Clinical features:

• Tachycardia
• Hypertension
• Electrocardiogram changes (eg, prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia
• Changes in the level of consciousness (ranging from somnolence to coma)
• Mydriasis
• Serotonin syndrome
• Seizures (especially with venlafaxine overdose)
• Rhabdomyolysis
• Death  

Management:

• In case of acute overdose with SNRI, the clinician should ensure an adequate airway, breathing, and circulation.
• For serotonin syndrome, specific treatment (such as with cyproheptadine may be considered).
• Treat prolonged QRS intervals with sodium bicarbonate.
• Prolonged QTc leading to torsades- Administer magnesium sulfate 2 g IV.
• Consider extracorporeal life support/extracorporeal membrane oxygenation (ECLS/ECMO) in severe poisoning with venlafaxine.[48]

Atypical Antidepressant Poisoning

Bupropion:

• Clinical features
  • Tachycardia
  • Agitation
  • Hallucinations
  • Hypertension
  • Seizures [49]

•  Management
  • Ensure adequate airway, oxygenation, and ventilation.
  • Provide continuous cardiac monitoring and observe for delayed seizures for the first 48 hours post-ingestion following a significant overdose, particularly with extended-release formulations.
  • Administer IV benzodiazepine for seizures.[50][51]

Mirtazapine:

• Clinical features
  • Disorientation
  • Drowsiness
  • Tachycardia
  • Impaired memory
  • Bradyarrhythmias [52]

•  Management
  • Ensure adequate airway, oxygenation, and ventilation.
  • Monitor cardiac rhythm and vital signs.
  • Treat arrhythmias according to Advanced Cardiovascular Life Support (ACLS) and Pediatric Advanced Life Support (PALS) protocols.

Serotonin Modulators Poisoning

Trazodone:

• Clinical features
  • Arrhythmias: QT prolongation and ventricular arrhythmias; hypotension
  • Respiratory arrest
  • Coma
  • Priapism [53]

•  Management
  • Treatment should be symptomatic and supportive in the case of hypotension or excessive sedation.
  • Priapism requires urgent urologic evaluation. 
  • In patients with ischemic priapism, administer an intracavernosal injection of phenylephrine.[54]

Vilazodone:

• Clinical features
  • Drowsiness
  • Vomiting
  • Tachycardia
  • Serotonin syndrome (altered mental status, autonomic instability, and neuromuscular abnormalities) [55]

•  Management
  • Ensure adequate airway, breathing, and circulation. 
  • Serotonin syndrome: Vilazodone has up to 30-fold higher potency for serotonin reuptake inhibition than conventional SSRIs. Consequently, management of serotonin syndrome is the mainstay of therapy.
  • Treatment of serotonin syndrome 
    • Administer benzodiazepines (eg, lorazepam 1-2 mg IV per dose) until the patient is asymptomatic. 
    • Administer IV fluids. 
    • Consider sedation, paralysis, and endotracheal intubation for severe hyperthermia.
    • Administer the antidote cyproheptadine (a 5-HT1A and 5-HT2A receptor antagonist).[56]

Tricyclic Antidepressants Poisoning

Clinical features:

• Anticholinergic: Dilated pupils, absent bowel sounds, constipation, urinary retention
• Cardiac: Tachycardia, hypotension, conduction abnormalities, QRS duration greater than 100 ms
• Neurologic: Sedation, seizures

Management:

• Ensure adequate airway, breathing, and circulation.
• Treat hypotension with IV crystalloid. Administer vasopressors, such as norepinephrine, for refractory hypotension. 
• If the QRS duration exceeds 100 ms, administer IV sodium bicarbonate.
• Administer activated charcoal (1 g/kg) if the patient presents within 2 hours of ingestion; often, charcoal is avoided due to the presence of ileus.
• Administer benzodiazepines (lorazepam 2 mg IV) for seizures. 
• QRS interval greater than 100 ms is a reliable predictor of serious complications.[57]

Monoamine Oxidase Inhibitor Poisoning

Clinical features:

• Serotonin syndrome
• Hypertensive crisis

Management:

• Ensure adequate airway, breathing, and circulation.
• Treat hypertensive crisis with appropriate IV antihypertensive therapy.
• Serotonin syndrome: Administer IV fluids, benzodiazepines, and cyproheptadine.[58]

N-Methyl-D-Aspartate Antagonist (Esketamine) Poisoning

Clinical features:

• Sedation
• Dissociation
• Hypertension
• Ulcerative or interstitial cystitis with long-term misuse
• Embryo-fetal toxicity

Management:

• Ensure adequate airway, breathing, and circulation.
• There is no specific antidote for esketamine overdose. In the case of overdose, clinicians should consider the possibility of multiple drug involvement. Contact a certified poison control center for the most up-to-date information on managing overdosage.

Dextromethorphan/Bupropion Poisoning

Clinical features:

• Seizures
• Serotonin syndrome
• Psychosis [59]

Management:

• Ensure adequate airway, oxygenation, and ventilation.
• There is no specific antidote. Provide supportive care.
• Administer benzodiazepines for seizures.[51]
• Consult a medical toxicologist or a certified poison control center.[60]

Gepirone Poisoning

No specific antidote exists. Limited clinical overdose data are available, given gepirone's recent approval; management is supportive. Co-ingestion with strong CYP3A4 inhibitors or other CNS depressants may amplify toxicity. Expected symptoms based on the known adverse effect profile include dizziness, somnolence, nausea, and vomiting. Poison control consultation is recommended in all suspected overdose cases.[4]

Zuranolone Poisoning

As a GABA-A receptor–positive allosteric modulator, zuranolone overdose is expected to present similarly to benzodiazepine toxicity, with excessive sedation, respiratory depression, and loss of consciousness, particularly when co-ingested with alcohol or other CNS depressants. Management is supportive; the utility of flumazenil has not been established. Intentional misuse should be considered in the differential diagnosis of overdose presentations.[5]

Enhancing Healthcare Team Outcomes

While antidepressants are beneficial in treating depression and other indications, many patients fail to receive adequate treatment. To effectively manage depression, clinicians should employ an interprofessional, team-based approach to detect and diagnose depression, provide patient education, prescribe evidence-based pharmacotherapy, provide close follow-up to promote adherence, identify adverse effects, and assess treatment effectiveness.[61] Studies show that multiple factors contribute to medication adherence among patients receiving antidepressants. Generally, concerns about adverse drug effects were associated with medication adherence.[62] 

Patient comorbidities can also affect adherence to antidepressant medications. In particular, conditions that impair cognitive function can lead to nonadherence.[63] Alcohol or other substance abuse, cardiovascular disease, metabolic disorders, young age, low income, and use of older-generation antidepressants were associated with lower adherence, particularly during the acute phase.[64]

Identifying and addressing these concerns is essential to the management of depression and the appropriate prescribing of antidepressant medications. Several randomized controlled trials support the collaborative care approach in treating depression. The literature suggests that the program should include a depression care manager, a psychiatric consultant, a prescribing physician, and the patient. The depression care manager can manage antidepressant therapy, provide education, and coordinate referrals when necessary. The psychiatric consultant can help optimize treatment strategies for patients who are not achieving the desired response.[65] 

Other healthcare team members who contribute to antidepressant care include pharmacists and nursing staff. Psychiatric specialty nurses are well equipped to recognize treatment failure, counsel patients on medication use, monitor adverse effects, and assess medication adherence. Pharmacists can verify drug selection and dosing, perform medication reconciliation, and identify potential drug interactions. Both pharmacists and nurses should have open access to the prescriber to address concerns promptly.

In an overdose of antidepressants, emergency department physicians should rapidly stabilize the patient by ensuring adequate airway, breathing, and circulation. Patients with cardiac arrhythmias, serotonin syndrome, or seizures may require intensive care unit (ICU) admission under the supervision of a critical care physician. Medical toxicologists should be consulted for severe poisoning. Patients may be receiving more than 1 antidepressant concurrently. Therefore, emergency physicians and triage nurses should identify all drugs involved in the overdose. Deliberate overdose requires consultation with a psychiatrist. As described above, clinicians (MDs, DOs, NPs, PAs), specialists, pharmacists, nurses, and other healthcare professionals are involved in the care of patients receiving antidepressant therapy. When all interprofessional team members function as a cohesive unit, they can maximize treatment efficacy, minimize adverse effects, and improve patient outcomes.

With the approval of newer antidepressant therapies, including gepirone, zuranolone, and esketamine, interprofessional collaboration has become increasingly important. Pharmacists should screen for clinically significant drug interactions, including CYP3A4-mediated interactions with gepirone and zuranolone. Nurses and other healthcare professionals play a key role in reinforcing adherence, monitoring for adverse effects, and educating patients about administration requirements and safety precautions. For patients receiving esketamine, care teams must ensure compliance with the REMS program requirements, including supervised administration and post-dose monitoring for sedation, dissociation, and blood pressure changes. For patients receiving zuranolone, clinicians should counsel patients regarding the 14-day treatment course, the risk of CNS depression, and driving restrictions following each dose.[4][5][2]