Pharmacology of Antidepressants

Introduction/Overview

Major depressive disorder represents a significant global health burden, characterized by persistent low mood, anhedonia, and a constellation of cognitive and somatic symptoms. The pharmacological management of this condition, along with other mood and anxiety disorders, relies primarily on antidepressant medications. These agents modulate central nervous system neurotransmission, primarily targeting monoamine pathways, to alleviate symptoms and restore functional capacity. The evolution of antidepressant pharmacotherapy from the early tricyclic compounds to contemporary selective agents reflects an ongoing effort to enhance efficacy while minimizing adverse effect profiles. Understanding the pharmacology of these drugs is fundamental for rational therapeutic decision-making in clinical practice.

The clinical relevance of antidepressant pharmacology extends beyond the treatment of major depression. These medications are employed across a spectrum of psychiatric and, in some cases, non-psychiatric conditions, including anxiety disorders, chronic pain syndromes, and certain sleep disorders. Their widespread use necessitates a thorough comprehension of their mechanisms, kinetic profiles, and potential for interactions. The selection of an appropriate antidepressant involves a careful balance between anticipated therapeutic benefit and the risk of adverse effects, guided by patient-specific factors such as age, comorbidities, and concomitant medications.

Learning Objectives

• Classify major antidepressant drugs based on their primary mechanism of action and chemical structure.
• Explain the detailed pharmacodynamic mechanisms, including receptor interactions and downstream cellular effects, that underlie the therapeutic and adverse effects of different antidepressant classes.
• Compare and contrast the pharmacokinetic properties, including absorption, distribution, metabolism, and elimination, of key antidepressant agents.
• Evaluate the approved clinical indications, common off-label uses, major adverse effect profiles, and significant drug interactions for each major class of antidepressants.
• Apply knowledge of special population considerations, including use in pregnancy, lactation, pediatrics, geriatrics, and organ impairment, to guide safe and effective antidepressant prescribing.

Classification

Antidepressants are systematically classified according to their primary neurochemical mechanism of action. This classification provides a framework for understanding their pharmacological profiles, therapeutic applications, and adverse effect spectra. A secondary classification based on chemical structure is also relevant, particularly for older drug classes.

Mechanism-Based Classification

• Selective Serotonin Reuptake Inhibitors (SSRIs): Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline.
• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Desvenlafaxine, duloxetine, levomilnacipran, venlafaxine.
• Tricyclic Antidepressants (TCAs): Amitriptyline, clomipramine, desipramine, imipramine, nortriptyline.
• Monoamine Oxidase Inhibitors (MAOIs): Phenelzine, tranylcypromine, selegiline (transdermal), isocarboxazid.
• Atypical Antidepressants: This heterogeneous group includes agents with unique mechanisms.
  • Serotonin antagonist and reuptake inhibitors (SARIs): Trazodone, nefazodone.
  • Norepinephrine-dopamine reuptake inhibitor (NDRI): Bupropion.
  • Serotonin modulator and stimulator (SMS): Vortioxetine.
  • Melatonergic agonist and selective serotonin antagonist (MASS): Agomelatine.
  • Multimodal agents: Mirtazapine (a presynaptic α₂-adrenergic antagonist and serotonin receptor antagonist).

Chemical Classification

Chemical classification is most pertinent to the TCAs and MAOIs. TCAs share a core three-ring (tricyclic) chemical structure, with variations in side chains influencing their relative potency for norepinephrine versus serotonin reuptake inhibition and their anticholinergic and sedative properties. MAOIs are classified as hydrazines (phenelzine, isocarboxazid) or non-hydrazines (tranylcypromine, selegiline). SSRIs and SNRIs are more appropriately defined by their pharmacodynamic targets rather than a unifying chemical structure, though they often share structural features that confer selectivity for monoamine transporters.

Mechanism of Action

The primary mechanism of action for most conventional antidepressants involves the acute enhancement of monoaminergic neurotransmission in the synaptic cleft. The monoamine hypothesis of depression, while an oversimplification of a complex neurobiological process, provides a foundational model. It posits that depression is associated with a functional deficiency of serotonin (5-HT), norepinephrine (NE), and possibly dopamine (DA) in key brain circuits. Antidepressants act to increase the availability of these neurotransmitters. However, a critical temporal disconnect exists: while reuptake inhibition or enzyme blockade occurs within hours of administration, clinical antidepressant effects typically require several weeks to manifest. This latency suggests that acute neurochemical changes initiate a cascade of downstream neuroadaptive processes responsible for the therapeutic effect.

Pharmacodynamics of Major Classes

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs exert their primary effect by selectively and potently blocking the serotonin transporter (SERT) on presynaptic neurons. This inhibition prevents the reuptake of serotonin from the synaptic cleft, leading to an increased concentration and prolonged action of serotonin on pre- and postsynaptic receptors. Their selectivity for SERT over the norepinephrine transporter (NET) is high, which largely accounts for their different adverse effect profile compared to TCAs. The acute increase in synaptic serotonin activates various serotonin receptor subtypes (e.g., 5-HT_1A, 5-HT_2A, 5-HT₃), which is implicated in both therapeutic and adverse effects. Chronic administration leads to adaptive changes, including desensitization of somatodendritic 5-HT_1A autoreceptors, which may enhance serotonergic neurotransmission more robustly.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

SNRIs inhibit both SERT and NET with varying degrees of potency and ratio. For example, venlafaxine at lower doses primarily inhibits SERT, with significant NET inhibition emerging at higher doses (>150 mg/day). Duloxetine exhibits relatively balanced reuptake inhibition. By augmenting both serotonin and norepinephrine signaling, SNRIs may influence a broader range of symptoms, particularly those related to energy, motivation, and certain pain pathways. The dual mechanism is thought to underlie their efficacy in conditions like neuropathic pain and fibromyalgia.

Tricyclic Antidepressants (TCAs)

TCAs are potent inhibitors of both SERT and NET, with individual agents showing relative selectivity (e.g., clomipramine is more serotonergic, desipramine is more noradrenergic). However, their clinical use is significantly limited by their antagonistic activity at other receptor systems, which are responsible for many of their adverse effects. These include:

• Muscarinic acetylcholine receptors: Causes anticholinergic effects (dry mouth, blurred vision, constipation, urinary retention, cognitive impairment).
• Histamine H₁ receptors: Mediates sedative effects and weight gain.
• α₁-Adrenergic receptors: Contributes to orthostatic hypotension and dizziness.

Their mechanism also involves downstream adaptations, including downregulation of β-adrenergic receptors and sensitization of adenylate cyclase systems following chronic administration.

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs produce their effect by irreversibly (or reversibly, in the case of moclobemide, not available in all regions) inhibiting the enzyme monoamine oxidase. MAO exists in two isoforms: MAO-A, which preferentially deaminates serotonin, norepinephrine, and tyramine; and MAO-B, which prefers phenylethylamine and dopamine. Traditional MAOIs (phenelzine, tranylcypromine) are non-selective and irreversible. Inhibition of MAO-A in central neurons leads to an accumulation of monoamines in the presynaptic cytoplasm and, consequently, increased synaptic release. The irreversible nature of the inhibition means that enzyme activity is only restored through the synthesis of new enzyme, leading to a long duration of action. The inhibition of intestinal and hepatic MAO-A is responsible for the potentially lethal hypertensive crisis (“cheese reaction”) upon ingestion of tyramine-rich foods.

Atypical Antidepressants

The mechanisms of atypical agents are diverse:

• Bupropion: A weak inhibitor of neuronal reuptake of norepinephrine and dopamine, with minimal effect on serotonin. Its active metabolites contribute to its effects. It also acts as a non-competitive antagonist at nicotinic acetylcholine receptors.
• Mirtazapine: Acts as an antagonist at central presynaptic α₂-adrenergic autoreceptors and heteroreceptors. Blockade of autoreceptors increases norepinephrine release, while blockade of heteroreceptors on serotonergic neurons enhances serotonin release. It is also a potent antagonist of postsynaptic 5-HT₂ and 5-HT₃ receptors and histamine H₁ receptors.
• Trazodone: Primarily acts as an antagonist at 5-HT_2A receptors and a serotonin reuptake inhibitor. Its metabolite, m-chlorophenylpiperazine (mCPP), is a serotonin receptor agonist. Strong α₁-adrenergic blockade and histamine H₁ blockade are also notable.
• Vortioxetine: Has a multimodal mechanism: it is a serotonin reuptake inhibitor, a partial agonist at 5-HT_1A receptors, an antagonist at 5-HT₃ receptors, and an agonist at 5-HT_1B receptors. This profile is proposed to enhance cognitive function and reduce certain serotonergic side effects.
• Agomelatine: Acts as an agonist at melatonin MT₁ and MT₂ receptors and as an antagonist at 5-HT_2C receptors. This combination is believed to resynchronize circadian rhythms and enhance dopaminergic and noradrenergic tone in the frontal cortex.

Downstream Neuroadaptive Mechanisms

The therapeutic delay associated with antidepressants is attributed to slow adaptive changes in signal transduction and gene expression. Chronic administration of most antidepressants has been associated with:

• Increased expression of brain-derived neurotrophic factor (BDNF) and activation of its receptor, TrkB, particularly in the hippocampus and prefrontal cortex, promoting neuronal plasticity and resilience.
• Modulation of the hypothalamic-pituitary-adrenal (HPA) axis, often leading to a reduction in cortisol secretion.
• Alterations in the activity of intracellular second messenger systems, such as cyclic AMP and protein kinase A pathways.
• Changes in neurogenesis, particularly in the dentate gyrus of the hippocampus.

These downstream effects are increasingly considered central to the recovery of neural circuitry implicated in mood regulation.

Pharmacokinetics

The pharmacokinetic properties of antidepressants significantly influence their dosing regimens, potential for interactions, and suitability for specific patient populations. Considerable inter-individual variability exists due to genetic polymorphisms in metabolic enzymes.

Absorption and Distribution

Most antidepressants are well absorbed after oral administration, although food may delay the rate but not the extent of absorption for some agents. They are generally lipophilic, facilitating widespread distribution throughout the body and penetration across the blood-brain barrier. Volume of distribution is typically large (often >10 L/kg), indicating extensive tissue binding. Plasma protein binding is frequently high (>80-90%), particularly for agents like duloxetine and sertraline. This can be a source of protein-binding displacement interactions, though the clinical significance of such displacement is often limited due to compensatory increases in drug clearance.

Metabolism

Hepatic metabolism via the cytochrome P450 (CYP) system is the principal route of biotransformation for the vast majority of antidepressants. This makes them both substrates and, in many cases, inhibitors or inducers of specific CYP isoenzymes, forming the basis for numerous drug-drug interactions.

• CYP2D6: Metabolizes many TCAs, fluoxetine, paroxetine, duloxetine, and venlafaxine. Paroxetine and fluoxetine are potent CYP2D6 inhibitors.
• CYP2C19: Involved in the metabolism of citalopram, escitalopram, sertraline, and amitriptyline. Fluoxetine, fluvoxamine, and omeprazole are notable inhibitors.
• CYP3A4: Metabolizes nefazodone, trazodone, mirtazapine, citalopram, and sertraline. Nefazodone and fluvoxamine are inhibitors.
• CYP1A2: Metabolizes agomelatine, duloxetine, and fluvoxamine. Fluvoxamine is a very potent CYP1A2 inhibitor.

Many antidepressants undergo Phase II conjugation (glucuronidation) as a secondary metabolic pathway. Some agents, like venlafaxine and desvenlafaxine, have active metabolites (O-desmethylvenlafaxine) that contribute to their pharmacological effect.

Elimination and Half-Life

Elimination occurs primarily via renal excretion of metabolites, with a minor fraction excreted unchanged. Half-life (t_1/2) varies widely across and within classes:

• Long t_1/2: Fluoxetine (1-4 days for parent drug; 7-15 days for its active metabolite norfluoxetine), allowing for once-daily dosing and a slower onset of withdrawal symptoms upon discontinuation.
• Intermediate t_1/2 (15-30 hours): Sertraline, citalopram, escitalopram, paroxetine, venlafaxine (extended-release), duloxetine. Typically dosed once daily.
• Short t_1/2 (<12 hours): Immediate-release venlafaxine, some TCAs (imipramine), bupropion (immediate-release). Often require multiple daily doses to maintain stable plasma concentrations.

Steady-state concentration (C_ss) is reached after approximately 4-5 half-lives. For drugs with long half-lives, this may take several weeks. The relationship between plasma concentration and therapeutic effect is established for some TCAs (e.g., nortriptyline has a defined therapeutic window) but is less clear for most SSRIs and SNRIs, where dosage is generally titrated to clinical response and tolerability.

Therapeutic Uses/Clinical Applications

While developed for major depressive disorder, the therapeutic applications of antidepressants have expanded significantly based on clinical trial evidence and clinical experience.

Approved Indications

• Major Depressive Disorder (MDD): The core indication for all antidepressant classes. Efficacy among different classes for acute treatment is generally comparable, though individual patient response varies. Selection is guided by side effect profile, comorbidities, and patient history.
• Anxiety Disorders: SSRIs and SNRIs are first-line pharmacological treatments for generalized anxiety disorder (GAD), panic disorder, social anxiety disorder (SAD), and post-traumatic stress disorder (PTSD). Their anxiolytic effect often requires similar timeframes as their antidepressant effect.
• Obsessive-Compulsive Disorder (OCD): SSRIs (particularly fluoxetine, fluvoxamine, paroxetine, sertraline) and the TCA clomipramine are approved, typically requiring higher doses than used for MDD.
• Chronic Pain Conditions: Certain antidepressants, particularly TCAs (amitriptyline, nortriptyline) and SNRIs (duloxetine, venlafaxine), are effective in neuropathic pain (e.g., diabetic neuropathy, postherpetic neuralgia), fibromyalgia (duloxetine, milnacipran), and chronic musculoskeletal pain. Their analgesic mechanism is independent of their effect on mood and involves modulation of descending pain inhibitory pathways in the spinal cord.
• Other Psychiatric Indications: Bupropion is approved for smoking cessation and seasonal affective disorder. Fluoxetine is approved for bulimia nervosa and premenstrual dysphoric disorder (PMDD).

Common Off-Label Uses

• Insomnia: Low-dose trazodone and mirtazapine are frequently used for sleep initiation due to their sedating properties via H₁ receptor blockade.
• Migraine Prophylaxis: TCAs (amitriptyline) and some SNRIs (venlafaxine) may be used.
• Stress Urinary Incontinence: Duloxetine is used in some regions, though not universally approved, due to its effects on the Onuf’s nucleus in the spinal cord.
• Attention-Deficit/Hyperactivity Disorder (ADHD): Bupropion may be considered as an alternative to stimulants in certain cases.
• Hot Flashes: Certain SSRIs (paroxetine) and SNRIs (venlafaxine) are used to manage vasomotor symptoms in menopause, particularly when hormone therapy is contraindicated.

Adverse Effects

Adverse effects are a major determinant of medication adherence and selection. They are often an extension of the drug’s primary or secondary pharmacological actions and tend to be dose-dependent and time-dependent, with some effects attenuating over weeks.

Common Side Effects by Class

SSRIs and SNRIs

• Gastrointestinal: Nausea, diarrhea, anorexia (early, may improve). SNRIs, particularly duloxetine, may cause more nausea.
• Central Nervous System: Headache, insomnia (or somnolence, e.g., with paroxetine), dizziness, agitation, akathisia (inner restlessness).
• Sexual Dysfunction: Very common (≈30-50%): decreased libido, delayed orgasm, anorgasmia, erectile dysfunction. May persist.
• Other: Sweating, yawning. SNRIs may increase blood pressure (dose-dependent, more with venlafaxine) and heart rate.

Tricyclic Antidepressants

• Anticholinergic: Dry mouth, blurred vision, constipation, urinary retention, tachycardia, cognitive clouding.
• Antihistaminic (Sedative): Drowsiness, weight gain.
• Cardiovascular: Orthostatic hypotension (α₁-blockade), conduction delays (QRS/QTc prolongation), tachycardia, arrhythmias in overdose.

MAOIs

• Orthostatic Hypotension: Common, especially early in treatment.
• Weight Gain.
• Sexual Dysfunction.
• Insomnia (with tranylcypromine).
• Peripheral Edema.

Atypical Agents

• Bupropion: Insomnia, dry mouth, headache, tremor; minimal weight gain or sexual dysfunction. Seizure risk is dose-dependent (increased at doses >450 mg/day).
• Mirtazapine: Pronounced sedation, increased appetite/weight gain (H₁ blockade), dizziness.
• Trazodone: Sedation, orthostatic hypotension, priapism (a rare but serious medical emergency requiring prompt treatment).
• Vortioxetine: Nausea (common), diarrhea, constipation.

Serious/Rare Adverse Reactions and Black Box Warnings

Several serious adverse effects carry regulatory warnings.

• Suicidality (Black Box Warning): Antidepressants may increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (≤24 years) during initial treatment (first few months) or dose changes. Close monitoring is mandatory. This risk must be balanced against the significant risk of untreated depression.
• Serotonin Syndrome: A potentially life-threatening condition resulting from excessive serotonergic activity. Symptoms range from tremor and hyperreflexia to hyperthermia, autonomic instability, and delirium. Risk is highest with combinations of serotonergic drugs (e.g., MAOI + SSRI, SSRI + tramadol, SSRI + linezolid).
• Activation of Mania/Hypomania: Can occur in patients with bipolar disorder misdiagnosed as unipolar depression. A careful assessment of personal and family history of bipolarity is required before initiation.
• QTc Prolongation: Associated with higher doses of citalopram (>40 mg/day, >20 mg/day in elderly/hepatic impairment) and some TCAs. Can predispose to torsades de pointes.
• Hepatotoxicity: Associated with nefazodone (rare, but risk of liver failure led to its near withdrawal) and, less commonly, duloxetine and agomelatine.
• Hypertensive Crisis (MAOIs): Can occur with ingestion of tyramine-rich foods (aged cheeses, cured meats, some beers, fermented products) or sympathomimetic drugs due to peripheral accumulation of norepinephrine.
• Withdrawal/Discontinuation Syndrome: Particularly common with agents with short half-lives and high potency (paroxetine, venlafaxine). Symptoms include dizziness, paresthesias (“brain zaps”), nausea, anxiety, and irritability. Tapering is recommended for most antidepressants.

Drug Interactions

Antidepressants are implicated in numerous pharmacokinetic and pharmacodynamic interactions, largely due to their metabolism by and effects on CYP enzymes and their potentiation of monoaminergic systems.

Major Pharmacokinetic Interactions

• Inhibition of Metabolism:
  • Paroxetine/Fluoxetine (CYP2D6 inhibitors): Can increase levels of TCAs, some antipsychotics (risperidone), certain beta-blockers (metoprolol), and codeine (reducing its activation to morphine).
  • Fluvoxamine (CYP1A2/3A4 inhibitor): Can markedly increase levels of theophylline, clozapine, olanzapine, and caffeine.
  • Bupropion (CYP2D6 inhibitor): Can increase levels of drugs metabolized by this pathway.
• Induction of Metabolism: St. John’s Wort (an herbal antidepressant) is a potent inducer of CYP3A4 and P-glycoprotein, reducing plasma concentrations of many drugs, including cyclosporine, warfarin, and oral contraceptives.
• Competition for Metabolism: Two drugs metabolized by the same enzyme (e.g., paroxetine and tamoxifen, where paroxetine inhibits the activation of tamoxifen) can lead to therapeutic failure or toxicity.

Major Pharmacodynamic Interactions

• Serotonin Syndrome Risk: Concomitant use with other serotonergic agents: other antidepressants (especially MAOIs), tramadol, fentanyl, lithium, triptans, linezolid, methylene blue, and illicit drugs (MDMA, cocaine). A minimum 14-day washout period is required between stopping an SSRI/SNRI and starting an MAOI (5 weeks for fluoxetine due to its long t_1/2).
• Increased Bleeding Risk: SSRIs/SNRIs inhibit platelet serotonin uptake, impairing platelet aggregation. This effect is potentiated by concomitant use of anticoagulants (warfarin, DOACs), antiplatelets (aspirin, clopidogrel), and NSAIDs, increasing the risk of gastrointestinal and other bleeds.
• Hypertensive Crisis with MAOIs: Interaction with sympathomimetics (decongestants like pseudoephedrine, stimulants), certain anesthetics, and tyramine-containing foods.
• Potentiation of CNS Depression: Additive sedation with alcohol, benzodiazepines, opioids, and other sedating medications.
• Cardiovascular Effects: TCAs can potentiate the effects of other QTc-prolonging drugs (antiarrhythmics, some antipsychotics) and may antagonize the effects of antihypertensives like clonidine.

Contraindications

• MAOIs: Absolute contraindication with concurrent use of other serotonergic antidepressants, sympathomimetics, meperidine, and certain other opioids. Relative contraindications include pheochromocytoma and cerebrovascular disease.
• Bupropion: Contraindicated in patients with a seizure disorder, eating disorders (bulimia or anorexia nervosa), or those undergoing abrupt discontinuation of alcohol or sedatives.
• TCAs: Generally contraindicated in the acute recovery phase following myocardial infarction, in patients with certain conduction abnormalities, and in narrow-angle glaucoma.
• SSRIs/SNRIs: Caution is advised but not absolute contraindication with concomitant use of strong CYP inhibitors or inducers, or in patients with uncontrolled hypertension (SNRIs).

Special Considerations

Pregnancy and Lactation

The decision to use antidepressants during pregnancy involves weighing the risks of fetal medication exposure against the risks of untreated maternal depression. No antidepressant is considered completely risk-free.

• SSRIs: Generally considered first-line if pharmacotherapy is required. Paroxetine is associated with a small increased risk of cardiac malformations (particularly when used in the first trimester) and is often avoided. Third-trimester use of any SSRI/SNRI may be associated with a self-limited neonatal adaptation syndrome (respiratory distress, jitteriness, weak cry, feeding difficulty) and, rarely, persistent pulmonary hypertension of the newborn (PPHN).
• TCAs: Nortriptyline and desipramine have lower anticholinergic burden and may be alternatives, though neonatal withdrawal symptoms are possible.
• Bupropion: Data are more limited; some studies suggest a possible small increase in cardiovascular malformations.
• Lactation: Most antidepressants are excreted in breast milk in low concentrations. Sertraline, paroxetine, and nortriptyline have relatively lower infant exposure levels and are often preferred. Monitoring the infant for sedation, irritability, or feeding changes is advised.

Pediatric and Geriatric Considerations

Pediatrics: SSRIs (fluoxetine, escitalopram) are the primary pharmacological option for moderate-to-severe pediatric depression and anxiety, with strict adherence to black box warning monitoring requirements. Starting doses are lower, and titration is slower. Paroxetine is generally not recommended due to lack of efficacy and greater discontinuation symptoms.

Geriatrics: Age-related pharmacokinetic and pharmacodynamic changes necessitate caution. Reduced hepatic metabolism and renal clearance may lead to higher plasma levels. Increased sensitivity to anticholinergic effects (cognitive impairment, delirium, constipation, urinary retention), orthostatic hypotension (risk of falls), and hyponatremia (due to SIADH, especially with SSRIs) is common. Lower starting doses (often 50% of adult dose) and slow titration are standard. SSRIs (except paroxetine, due to anticholinergic properties) and SNRIs are often preferred over TCAs. Mirtazapine at low doses may be useful for depression with comorbid insomnia and anorexia.

Renal and Hepatic Impairment

Renal Impairment: For drugs primarily excreted renally as active compounds or metabolites (e.g., venlafaxine, desvenlafaxine, duloxetine), dose reduction is recommended in moderate-to-severe impairment. Duloxetine is not recommended in end-stage renal disease. TCAs and most SSRIs require caution but less specific adjustment; monitoring for increased adverse effects is key.

Hepatic Impairment: Dose reduction is necessary for most antidepressants due to reduced first-pass metabolism and clearance. For some drugs (e.g., citalopram, escitalopram, agomelatine), use is contraindicated in severe hepatic impairment. Agents with a high hepatic extraction ratio (e.g., TCAs, trazodone) will have significantly increased bioavailability in cirrhosis. Starting with a low dose and titrating slowly is imperative.

Summary/Key Points

• Antidepressants are primarily classified by their mechanism of action: SSRIs, SNRIs, TCAs, MAOIs, and atypical agents. Their therapeutic effect is mediated by acute enhancement of monoaminergic transmission, followed by slower neuroadaptive changes involving neurotrophic factors and neural plasticity.
• SSRIs and SNRIs are first-line agents due to their more favorable tolerability and safety profile compared to TCAs and MAOIs. TCAs are limited by significant anticholinergic, antihistaminic, and cardiovascular adverse effects. MAOIs require strict dietary and medication restrictions.
• Pharmacokinetics are characterized by good oral absorption, high protein binding, extensive hepatic metabolism via CYP enzymes (leading to numerous drug interactions), and renal elimination of metabolites. Half-lives vary, influencing dosing frequency and discontinuation syndrome risk.
• Therapeutic applications extend beyond major depression to include anxiety disorders, OCD, chronic pain conditions, and other indications. Off-label uses are common, such as low-dose trazodone for insomnia.
• Adverse effects are often mechanism-based: GI upset and sexual dysfunction with SSRIs/SNRIs; anticholinergic effects and sedation with TCAs; hypertensive crisis with MAOIs. All antidepressants carry a black box warning for increased suicidality risk in young patients.
• Major drug interactions are common, both pharmacokinetic (via CYP inhibition/induction) and pharmacodynamic (serotonin syndrome, bleeding risk). Careful review of concomitant medications is essential.
• Special population management requires tailored approaches: cautious use in pregnancy/lactation with agent-specific risk profiles; lower starting doses and vigilant monitoring in geriatric patients; and dose adjustments in renal and hepatic impairment.

Clinical Pearls

• Start low, go slow, but aim for an adequate therapeutic dose. An insufficient trial is a common cause of perceived treatment failure.
• Inform patients about the typical 2-4 week latency for onset of therapeutic effects and the likelihood of transient side effects that often improve with time.
• Always assess for bipolar disorder before initiating treatment to avoid precipitating a manic episode.
• Do not abruptly discontinue antidepressants, especially paroxetine and venlafaxine; implement a gradual taper over weeks to months to minimize discontinuation symptoms.
• When switching between antidepressants, particularly to or from an MAOI, adhere to appropriate washout periods to prevent serotonin syndrome.
• In treatment-resistant depression, strategies include dose optimization, switching to a different class, or augmentation with a second agent (e.g., atypical antipsychotics, lithium).

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