Antidepressants

Definition and Overview

Antidepressants are pharmacologic agents primarily used in the management of major depressive disorder (MDD), anxiety disorders, and several other psychiatric and neurologic conditions

They exert their therapeutic effects by modulating neurotransmitter systems within the central nervous system, chiefly serotonin, norepinephrine, and dopamine

Antidepressants are not habit-forming but often require weeks to achieve full clinical effect, and sudden discontinuation may result in withdrawal symptoms

Main Classes of Antidepressants

1. Selective Serotonin Reuptake Inhibitors (SSRIs)

Fluoxetine

Sertraline

Paroxetine

Citalopram

Escitalopram

Fluvoxamine

Block presynaptic serotonin reuptake, increasing serotonin availability in synaptic clefts

2. Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs)

Venlafaxine

Duloxetine

Desvenlafaxine

Milnacipran

Levomilnacipran

Inhibit reuptake of both serotonin and norepinephrine

3. Tricyclic Antidepressants (TCAs)

Amitriptyline

Nortriptyline

Imipramine

Clomipramine

Desipramine

Block reuptake of norepinephrine and serotonin, with additional antihistaminic and anticholinergic effects

4. Monoamine Oxidase Inhibitors (MAOIs)

Phenelzine

Tranylcypromine

Isocarboxazid

Selegiline (transdermal)

Inhibit the enzyme monoamine oxidase, preventing breakdown of serotonin, norepinephrine, and dopamine

5. Atypical Antidepressants

Bupropion: norepinephrine–dopamine reuptake inhibitor

Mirtazapine: presynaptic α₂ antagonist, increases norepinephrine and serotonin release

Trazodone: serotonin antagonist and reuptake inhibitor

Vortioxetine: serotonin modulator and stimulator

Vilazodone: serotonin reuptake inhibitor and partial 5HT1A agonist

6. Other Agents

Agomelatine: melatonin receptor agonist and serotonin receptor antagonist

Reboxetine: selective norepinephrine reuptake inhibitor

Mechanism of Action

All antidepressants aim to increase the concentration or prolong the action of neurotransmitters associated with mood regulation

SSRIs and SNRIs inhibit reuptake pumps

TCAs block reuptake but also interact with histamine and acetylcholine receptors

MAOIs inhibit enzymatic degradation of monoamines

Atypicals have various mechanisms, often combining reuptake inhibition with receptor modulation

Therapeutic Indications

Psychiatric Conditions

Major depressive disorder

Generalized anxiety disorder

Panic disorder

Social anxiety disorder

Obsessive-compulsive disorder

Post-traumatic stress disorder

Bipolar depression (in combination with mood stabilizers)

Premenstrual dysphoric disorder

Seasonal affective disorder

Bulimia nervosa (fluoxetine)

Neurologic and Pain Syndromes

Neuropathic pain (TCAs, SNRIs)

Fibromyalgia (duloxetine, milnacipran)

Migraine prophylaxis (amitriptyline)

Insomnia (low-dose trazodone, mirtazapine)

Smoking cessation (bupropion)

Attention-deficit hyperactivity disorder (bupropion)

Off-label Uses

Irritable bowel syndrome

Urinary incontinence (imipramine)

Hot flashes in menopause (paroxetine)

Tinnitus

Chronic fatigue syndrome

Dosage and Administration

Start low and titrate slowly to minimize side effects

SSRIs and SNRIs: once daily dosing, typically in the morning or evening

TCAs: usually at bedtime due to sedating properties

MAOIs: divided dosing, strict dietary restrictions

Atypicals: specific dosing varies

Dose adjustment may be needed in hepatic or renal impairment

Avoid abrupt discontinuation; tapering is advised

Example Initial Doses

Fluoxetine: 20 mg daily

Sertraline: 50 mg daily

Paroxetine: 20 mg daily

Venlafaxine XR: 37.5–75 mg daily

Duloxetine: 30–60 mg daily

Amitriptyline: 25–50 mg at bedtime

Bupropion SR: 150 mg once daily

Mirtazapine: 15 mg at bedtime

Trazodone: 50–150 mg at bedtime

Onset and Duration of Action

Onset: 2–4 weeks for mood improvement

Full therapeutic effect: 6–8 weeks

Some early benefit may be observed in sleep, anxiety, or appetite

Continuation therapy: at least 6–9 months for first depressive episode

Maintenance: several years or lifelong in recurrent or chronic depression

Pharmacokinetics

SSRIs and SNRIs: hepatic metabolism, primarily via CYP450 enzymes

Half-life varies: fluoxetine has a long half-life, allowing weekly dosing for maintenance

Renal clearance important for SNRIs and some TCAs

Food may or may not affect absorption, depending on agent

Adverse Effects

SSRIs

Nausea, diarrhea

Sexual dysfunction (delayed ejaculation, anorgasmia)

Insomnia or somnolence

Headache, tremor

Weight gain (long-term use)

Anxiety or agitation in early treatment

Hyponatremia (SIADH) in elderly

Increased bleeding risk (especially with NSAIDs, aspirin)

SNRIs

Similar to SSRIs

May increase blood pressure (especially venlafaxine)

Sweating, dizziness

Urinary hesitation

TCAs

Sedation

Orthostatic hypotension

Weight gain

Anticholinergic effects: dry mouth, constipation, urinary retention, blurred vision

Cardiotoxicity in overdose: QRS widening, arrhythmias

Cognitive impairment in elderly

MAOIs

Postural hypotension

Weight gain

Sexual dysfunction

Hypertensive crisis with tyramine-rich foods

Serotonin syndrome if combined with other serotonergic agents

Sleep disturbance

Atypical Antidepressants

Bupropion: insomnia, dry mouth, agitation, seizure risk at high doses

Mirtazapine: sedation, increased appetite, weight gain

Trazodone: sedation, dizziness, priapism (rare)

Vortioxetine: nausea, constipation, less sexual dysfunction

Vilazodone: GI upset, insomnia

Serious Risks

Suicidal ideation: black box warning in children, adolescents, and young adults

Serotonin syndrome: especially with combinations or overdose

Discontinuation syndrome: flu-like symptoms, insomnia, imbalance, sensory disturbances, hyperarousal

Mania induction in bipolar disorder

Hyponatremia

Prolonged QT interval (citalopram, TCA overdose)

Hepatotoxicity (nefazodone, duloxetine in rare cases)

Contraindications

Known hypersensitivity

Concurrent MAOI use (risk of serotonin syndrome)

History of seizure disorder (caution with bupropion)

Recent myocardial infarction (TCA contraindicated)

Severe liver dysfunction

Glaucoma (TCAs can exacerbate angle-closure glaucoma)

Pregnancy and lactation: some agents contraindicated or used with caution

Precautions

Taper slowly to prevent withdrawal

Screen for bipolar disorder before initiating antidepressants

Avoid alcohol and CNS depressants

Monitor weight, sexual function, and mood regularly

Use caution in elderly (anticholinergic and fall risk)

Drug selection should consider comorbidities and patient preference

Drug Interactions

Serotonergic Agents

Increased risk of serotonin syndrome: triptans, linezolid, tramadol, lithium, other antidepressants

CYP450 Interactions

Fluoxetine, paroxetine: potent CYP2D6 inhibitors

Fluvoxamine: strong CYP1A2 inhibitor

Bupropion: CYP2B6 substrate

Carbamazepine: induces CYP3A4, reduces antidepressant levels

Bleeding Risk

SSRIs + NSAIDs or anticoagulants increase risk of GI bleeding

QT Prolongation

Citalopram, escitalopram, and TCAs may prolong QT

Avoid combinations with other QT-prolonging drugs

Alcohol and Sedatives

Additive CNS depression, particularly with TCAs, trazodone, mirtazapine

Tyramine-rich Foods

Contraindicated with MAOIs due to hypertensive crisis risk

Monitoring Parameters

Symptom reduction using validated scales (PHQ-9, HAM-D)

Suicidal thoughts or behavior

Blood pressure (SNRIs, TCAs)

Weight and metabolic parameters

Liver function (duloxetine, nefazodone)

Sodium levels in elderly

ECG if patient has cardiac history or uses high-dose TCAs

Use in Pregnancy and Lactation

SSRIs considered safest, particularly sertraline

Paroxetine discouraged due to fetal cardiac risks

TCAs and bupropion may be used if benefit outweighs risk

Breastfeeding: sertraline and nortriptyline have low transfer into breast milk

Withdrawal and Discontinuation Syndrome

Occurs with abrupt cessation, especially of agents with short half-life (paroxetine, venlafaxine)

Symptoms: dizziness, nausea, flu-like symptoms, irritability, vivid dreams

Tapering over weeks reduces risk

Augmentation Strategies

Used in partial responders

Add lithium, atypical antipsychotics (aripiprazole, quetiapine)

Thyroid hormone (T3)

Psychotherapy combined with pharmacotherapy enhances response

Examples of Brand Names

Prozac (fluoxetine)

Zoloft (sertraline)

Paxil (paroxetine)

Celexa (citalopram)

Lexapro (escitalopram)

Cymbalta (duloxetine)

Effexor XR (venlafaxine)

Wellbutrin (bupropion)

Remeron (mirtazapine)

Elavil (amitriptyline)

Anafranil (clomipramine)

Nardil (phenelzine)

Parnate (tranylcypromine)

Clinical Notes

SSRIs are first-line for depression and anxiety due to tolerability and safety

SNRIs are preferred when pain or fatigue coexist

TCAs effective but limited by side effects and overdose risk

MAOIs reserved for treatment-resistant depression

Bupropion is activating, weight-neutral, and helpful in smoking cessation

Mirtazapine is sedating and ideal in underweight or insomniac patients

Combination or augmentation strategies may be used in refractory cases

Pharmacogenetic testing may help guide drug selection in certain scenarios