CNS Pharmacotherapy: Antidepressants and Anxiolytics

Master central nervous system pharmacotherapy with free flashcards and spaced repetition practice. This lesson covers antidepressants (SSRIs, SNRIs, TCAs, MAOIs), anxiolytics (benzodiazepines, buspirone), and clinical decision-making for depression and anxiety disorders—essential knowledge for NAPLEX success and safe patient care.

Welcome to CNS Pharmacotherapy

Central nervous system disorders represent some of the most challenging therapeutic areas in pharmacy practice. Unlike cardiovascular or infectious disease treatments where objective markers (blood pressure, culture results) guide therapy, CNS conditions require careful assessment of subjective symptoms, consideration of psychiatric comorbidities, and management of complex drug interactions. 🧠

This lesson builds on your foundational knowledge from previous lessons by introducing psychiatric pharmacotherapy. You'll learn to apply clinical reasoning to select appropriate antidepressants and anxiolytics, adjust dosing for special populations, identify dangerous drug interactions, and counsel patients on medication safety. The NAPLEX expects you to integrate pharmacokinetics, patient-specific factors, and clinical guidelines—not just memorize drug names.

Core Concepts: Understanding Depression and Anxiety Pharmacotherapy

Depression: Pathophysiology and Treatment Approach

Major Depressive Disorder (MDD) affects approximately 20% of adults and results from complex neurotransmitter imbalances, primarily involving serotonin (5-HT), norepinephrine (NE), and dopamine (DA). The monoamine hypothesis suggests that depression results from deficient monoamine neurotransmission in the CNS.

Treatment Timeline ⏰

💡 Clinical Pearl: Patients often discontinue antidepressants prematurely due to side effects appearing before therapeutic benefits. Proper counseling about the 4-6 week onset is critical for adherence!

First-Line Antidepressants: SSRIs and SNRIs

Selective Serotonin Reuptake Inhibitors (SSRIs) are first-line for most patients due to favorable side effect profiles and safety in overdose.

SSRI	Starting Dose	Typical Dose Range	Half-Life	Key Features
Fluoxetine (Prozac)	20 mg daily	20-80 mg	4-6 days (active metabolite: 4-16 days)	Longest half-life; least withdrawal; activating
Sertraline (Zoloft)	50 mg daily	50-200 mg	26 hours	Most GI side effects; dopaminergic at high doses
Paroxetine (Paxil)	20 mg daily	20-50 mg	21 hours	Most anticholinergic; worst withdrawal; sedating
Citalopram (Celexa)	20 mg daily	20-40 mg	35 hours	⚠️ QTc prolongation risk >40 mg; max 20 mg if >60 years
Escitalopram (Lexapro)	10 mg daily	10-20 mg	27-32 hours	S-enantiomer of citalopram; fewer drug interactions

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) provide dual neurotransmitter action and may be more effective for pain-related depression.

SNRI	Starting Dose	Typical Dose Range	Unique Indications
Venlafaxine (Effexor XR)	37.5-75 mg daily	75-225 mg	GAD, social anxiety, panic disorder
Duloxetine (Cymbalta)	30-60 mg daily	60-120 mg	Diabetic neuropathy, fibromyalgia, chronic pain
Desvenlafaxine (Pristiq)	50 mg daily	50 mg (max 100 mg)	Active metabolite of venlafaxine; no dose titration needed

💡 Mechanism Insight: At low doses, venlafaxine primarily inhibits serotonin reuptake (like an SSRI). Norepinephrine reuptake inhibition increases at doses ≥150 mg/day, providing the dual-action benefit.

Second-Line and Atypical Antidepressants

Bupropion (Wellbutrin)

Mechanism: Norepinephrine-dopamine reuptake inhibitor (NDRI)

Unique characteristics:

• ✅ No sexual side effects (unlike SSRIs/SNRIs)
• ✅ Weight neutral or weight loss (helpful in metabolic syndrome)
• ✅ Smoking cessation aid (approved as Zyban)
• ⚠️ Contraindication: Seizure disorder or eating disorder (lowers seizure threshold)
• ⚠️ Activating: May worsen anxiety or insomnia

Dosing:

• Bupropion SR: 150 mg daily → 150 mg twice daily (max 400 mg/day)
• Bupropion XL: 150 mg daily → 300 mg daily (max 450 mg/day)
• Space doses ≥8 hours apart to minimize seizure risk

Mirtazapine (Remeron)

Mechanism: α2-adrenergic antagonist; 5-HT2 and 5-HT3 receptor antagonist

Unique characteristics:

• ✅ Sedating: Excellent for insomnia with depression
• ✅ Appetite stimulant: Useful in elderly or patients with weight loss
• ✅ No sexual side effects
• ⚠️ Weight gain: Antihistamine (H1) activity increases appetite
• 💡 Paradoxical dosing: More sedating at lower doses (15 mg) than higher doses (30-45 mg) due to increased noradrenergic activity at higher doses

Dosing: 15 mg at bedtime → increase to 30-45 mg as tolerated

Trazodone (Desyrel)

Mechanism: Serotonin antagonist and reuptake inhibitor (SARI)

Primary use: Low-dose (25-100 mg) for insomnia (not depression treatment at these doses)

Unique characteristics:

• ✅ Non-habit forming alternative to benzodiazepines for sleep
• ⚠️ Orthostatic hypotension: α1-adrenergic blockade
• ⚠️ Priapism risk (rare but serious): Warn male patients to seek emergency care for prolonged erection

Older Antidepressants: TCAs and MAOIs

Tricyclic Antidepressants (TCAs)

Mechanism: Inhibit reuptake of serotonin and norepinephrine; also block histamine, muscarinic, and α-adrenergic receptors (causing side effects)

TCA	Typical Dose Range	Clinical Use
Amitriptyline	75-150 mg at bedtime	Depression, neuropathic pain, migraine prophylaxis
Nortriptyline	75-150 mg at bedtime	Preferred TCA in elderly (less orthostatic hypotension)
Desipramine	100-200 mg at bedtime	Less sedating/anticholinergic than others

TCA Side Effects ("SLUDGE BAM" for anticholinergic effects):

• Sedation (antihistamine)
• Loss of accommodation (blurred vision)
• Urinary retention
• Dry mouth
• Gastric stasis (constipation)
• Elevated heart rate
• Blocked α-receptors (orthostatic hypotension)
• Arrhythmias (QTc prolongation)
• Mydriasis (dilated pupils)

⚠️ CRITICAL: TCAs are lethal in overdose (as little as 1-week supply) due to cardiac toxicity. Reserved for patients who fail other treatments.

💡 Therapeutic Drug Monitoring: TCAs have narrow therapeutic windows. Monitor serum levels for optimal dosing (e.g., nortriptyline: 50-150 ng/mL).

Monoamine Oxidase Inhibitors (MAOIs)

Mechanism: Irreversibly inhibit MAO-A and MAO-B enzymes, preventing breakdown of serotonin, norepinephrine, and dopamine

Examples: Phenelzine (Nardil), tranylcypromine (Parnate), selegiline patch (Emsam)

Major Concerns:

1. Hypertensive Crisis 🚨

   • Tyramine-rich foods (aged cheese, cured meats, fermented products) accumulate and trigger massive norepinephrine release
   • Symptoms: Severe headache, chest pain, nausea, palpitations, stroke risk
   • Treatment: Phentolamine (α-blocker) or nifedipine

2. Serotonin Syndrome (when combined with other serotonergic agents)

   • Must wait 2 weeks after stopping MAOI before starting SSRI/SNRI
   • Must wait 5 weeks after stopping fluoxetine before starting MAOI (long half-life)

3. Drug Interactions: Avoid meperidine, dextromethorphan, sympathomimetics, SSRIs/SNRIs

Dietary restrictions: Patients must avoid tyramine >6 mg per serving

⚠️ HIGH-TYRAMINE FOODS TO AVOID
┌────────────────────────────────────┐
│ • Aged cheeses (cheddar, blue)    │
│ • Cured/smoked meats (salami)     │
│ • Fermented foods (sauerkraut)    │
│ • Draft beer, red wine             │
│ • Soy sauce, miso                  │
│ • Overripe bananas, avocados       │
│ • Fava beans                       │
└────────────────────────────────────┘

Anxiolytics: Benzodiazepines and Alternatives

Benzodiazepines

Mechanism: Enhance GABA-A receptor activity (allosteric modulation) → neuronal inhibition

Classification by Half-Life:

Duration	Drug	Half-Life	Clinical Use
Short-Acting	Triazolam (Halcion)	1.5-5 hours	Insomnia (short-term)
	Alprazolam (Xanax)	11-15 hours	Panic disorder, GAD (⚠️ high abuse potential)
Intermediate	Lorazepam (Ativan)	12-18 hours	GAD, acute agitation, alcohol withdrawal
	Temazepam (Restoril)	8-22 hours	Insomnia
Long-Acting	Clonazepam (Klonopin)	19-60 hours	Panic disorder, seizures
	Diazepam (Valium)	20-100 hours	GAD, muscle spasms, alcohol withdrawal

Metabolism Considerations:

• Lorazepam, oxazepam, temazepam ("LOT"): Glucuronidation only → preferred in elderly and liver disease
• Most others: CYP450 metabolism → active metabolites → accumulation risk

Benzodiazepine Equivalency (oral dosing for anxiety):

⚠️ Benzodiazepine Withdrawal Syndrome:

Abrupt discontinuation after chronic use (>4 weeks) can cause life-threatening withdrawal:

• Mild: Anxiety, insomnia, tremor, diaphoresis
• Moderate: Tachycardia, hypertension, hyperthermia
• Severe: Seizures, delirium, death

Tapering protocol: Reduce dose by 10-25% every 1-2 weeks depending on duration of use. Consider switching short-acting to long-acting (e.g., alprazolam → clonazepam) for smoother taper.

💡 Clinical Decision: Short-acting benzodiazepines (alprazolam) have higher abuse/dependence risk due to rapid onset and withdrawal symptoms between doses. Long-acting agents (clonazepam, diazepam) provide more stable serum levels.

Buspirone (BuSpar)

Mechanism: 5-HT1A partial agonist (serotonergic anxiolytic)

Characteristics:

• ✅ Non-sedating, non-addictive (not a controlled substance)
• ✅ No withdrawal or tolerance
• ⚠️ Delayed onset: Takes 2-4 weeks for effect (like antidepressants)
• ⚠️ Not effective for acute anxiety or panic attacks
• ⚠️ Does NOT work in patients previously exposed to benzodiazepines (they expect immediate relief)

Dosing: 7.5 mg twice daily → increase by 5 mg every 2-3 days → target 15-30 mg twice daily (max 60 mg/day)

Best for: Generalized anxiety disorder in benzodiazepine-naïve patients willing to wait for gradual onset

Hydroxyzine (Vistaril, Atarax)

Mechanism: First-generation antihistamine (H1-antagonist)

Characteristics:

• ✅ Non-controlled, no abuse potential
• ✅ Rapid onset (unlike buspirone)
• ⚠️ Sedating: Useful for anxiety with insomnia
• ⚠️ Anticholinergic side effects: Dry mouth, constipation, urinary retention
• ⚠️ QTc prolongation at high doses

Dosing: 25-100 mg up to four times daily as needed for anxiety

Best for: Acute, situational anxiety or adjunct to SSRIs during onset period

Clinical Application: Drug Interactions and Contraindications

Serotonin Syndrome 🚨

Definition: Life-threatening excess of serotonin in CNS and peripheral nervous system

Causes: Combining serotonergic medications

• SSRI/SNRI + MAOI (most dangerous)
• SSRI + tramadol, meperidine, fentanyl
• SSRI + linezolid (antibiotic with MAOI activity)
• SSRI + St. John's Wort, triptans (migraine drugs)
• SSRI + methylene blue (surgical dye with MAOI activity)

Serotonin Syndrome Triad:

1. Neuromuscular changes: Clonus (most specific finding), hyperreflexia, myoclonus, rigidity
2. Autonomic instability: Hyperthermia, tachycardia, diaphoresis, mydriasis, diarrhea
3. Mental status changes: Agitation, confusion, delirium

Severity Scale:

SEROTONIN SYNDROME SEVERITY
┌──────────────────────────────────────┐
│ MILD: Tremor, diaphoresis, mydriasis│
│       Tachycardia, mild agitation   │
├──────────────────────────────────────┤
│ MODERATE: ↑↑ temp (>38°C)          │
│          Hyperreflexia, clonus      │
│          Horizontal ocular clonus   │
├──────────────────────────────────────┤
│ SEVERE: T >41.1°C, rigidity         │
│        Altered consciousness        │
│        SEIZURES, rhabdomyolysis     │
│        ⚠️ MEDICAL EMERGENCY          │
└──────────────────────────────────────┘

Treatment:

1. Discontinue all serotonergic agents immediately
2. Supportive care: IV fluids, cooling, benzodiazepines for agitation
3. Severe cases: Cyproheptadine (5-HT2A antagonist), ICU admission

💡 NAPLEX Pearl: The key to diagnosing serotonin syndrome is clonus (involuntary muscle contractions). If a patient on an SSRI develops tremor, sweating, and clonus after starting a new medication, suspect serotonin syndrome!

CYP450 Drug Interactions

Fluoxetine and paroxetine are potent CYP2D6 inhibitors → increase levels of:

• Tamoxifen (breast cancer): Reduced conversion to active metabolite → treatment failure
• Codeine: Reduced conversion to morphine → inadequate analgesia
• β-blockers (metoprolol, carvedilol): Increased levels → bradycardia, hypotension
• Antipsychotics (risperidone, aripiprazole): Increased levels → extrapyramidal symptoms

Fluvoxamine is a potent CYP1A2 inhibitor → avoid with:

• Theophylline: Increased levels → seizures, arrhythmias
• Clozapine: Increased levels → agranulocytosis risk

✅ Safest SSRIs for drug interactions: Citalopram and escitalopram (minimal CYP inhibition)

QTc Prolongation Risk

QTc >500 ms or increase >60 ms from baseline → risk of torsades de pointes (potentially fatal arrhythmia)

Psychiatric medications with QTc risk:

• Citalopram: Max 40 mg daily (20 mg if >60 years, hepatic impairment, or CYP2C19 poor metabolizers)
• Escitalopram: Max 20 mg daily (10 mg in elderly)
• TCAs: All prolong QTc (especially overdose)
• Antipsychotics (not covered in this lesson but important interaction)

⚠️ Avoid combinations: QTc-prolonging antidepressant + diuretic (hypokalemia) + macrolide antibiotic (also prolongs QTc)

Pregnancy and Breastfeeding Considerations

Pregnancy Categories (older system, but still tested):

• Category C (most SSRIs/SNRIs): Animal studies show risk; human data limited
• Category D (paroxetine): Positive evidence of human fetal risk (cardiac malformations)

Current approach: Use sertraline as first-line in pregnancy (most data, appears safest)

⚠️ Third-trimester exposure to SSRIs may cause:

• Neonatal adaptation syndrome: Jitteriness, irritability, poor feeding (self-limited)
• Persistent pulmonary hypertension of newborn (rare but serious)

Balance: Untreated maternal depression poses risks to both mother and fetus. Generally, benefits of treatment outweigh risks.

Breastfeeding: Sertraline and paroxetine preferred (lowest milk transfer)

Examples: Clinical Case Applications

Example 1: First-Episode Depression in Young Adult

Case: 28-year-old male with first episode of major depression. No significant medical history. Reports low energy, anhedonia, difficulty concentrating for 6 weeks. No suicidal ideation. BMI 24, BP 118/72.

Question: Which is the BEST first-line treatment?

Analysis:

• First episode → try SSRI or SNRI first
• Young, healthy → no comorbidities to influence choice
• Need to consider side effect tolerability for long-term adherence

Best choice: Escitalopram 10 mg daily or sertraline 50 mg daily

Rationale:

• Escitalopram: Excellent efficacy, favorable side effects, few drug interactions
• Sertraline: Also excellent choice; slightly more GI side effects but better evidence in diverse populations
• Avoid fluoxetine (very long half-life can complicate switching if needed)
• Avoid paroxetine (worst withdrawal, anticholinergic effects)

Counseling points:

1. "This medication will take 4-6 weeks to show full benefit. Don't stop early!"
2. "You may notice nausea or headache in the first week—these usually improve"
3. "Take with food if you experience stomach upset"
4. "Continue for at least 6-12 months after feeling better to prevent relapse"
5. "Avoid alcohol—it can worsen depression and increase sedation"

Example 2: Depression with Comorbid Insomnia and Weight Loss

Case: 68-year-old female with depression, poor appetite (5 lb weight loss in 2 months), insomnia. History: hypertension (controlled on lisinopril), osteoarthritis. No current psychiatric medications.

Question: Which antidepressant is MOST appropriate?

Best choice: Mirtazapine 15 mg at bedtime

Rationale:

• ✅ Addresses insomnia: Immediate sedative effect (unlike SSRIs which may worsen sleep initially)
• ✅ Stimulates appetite: Helpful for unintentional weight loss
• ✅ Safe in elderly: No anticholinergic effects (unlike TCAs)
• ⚠️ Monitor for excessive sedation (fall risk in elderly)

Alternative consideration: If mirtazapine causes too much sedation, could use trazodone 25-50 mg at bedtime for sleep + SSRI for depression

Counseling points:

1. "Take at bedtime—this will help you sleep"
2. "Your appetite should improve—this is a positive effect given your weight loss"
3. "Get up slowly from lying or sitting to avoid dizziness"
4. "Takes 4-6 weeks for full antidepressant effect, but sleep may improve within days"

Example 3: Depression with Sexual Dysfunction on SSRI

Case: 35-year-old male on sertraline 100 mg daily for 6 months with good response for depression, but now reports erectile dysfunction and decreased libido. This is affecting his relationship and he wants to discontinue the medication.

Question: What is the BEST intervention?

Options:

1. Discontinue sertraline (risk of relapse)
2. Add sildenafil for erectile dysfunction
3. Switch to bupropion
4. Decrease sertraline dose
5. Add buspirone

Best answer: C) Switch to bupropion

Rationale:

• Sexual dysfunction affects 40-65% of patients on SSRIs/SNRIs (often unreported unless asked!)
• Bupropion: NO sexual side effects (mechanism doesn't involve serotonin)
• Switching preserves depression remission while addressing intolerable side effect
• Cross-taper: Start bupropion XL 150 mg daily while gradually reducing sertraline

Other strategies (if bupropion not suitable):

• Mirtazapine (also low sexual side effects)
• "Drug holidays" (skip SSRI for 2 days before sexual activity—NOT recommended due to discontinuation symptoms)
• PDE5 inhibitors (sildenafil) can help erectile dysfunction but don't address libido

Counseling for switch:

1. "We'll overlap medications for 1-2 weeks while transitioning"
2. "Bupropion doesn't cause sexual side effects like sertraline can"
3. "Takes 4-6 weeks to reach full effect—don't stop abruptly"
4. "⚠️ Contact me if you notice increased anxiety or trouble sleeping (bupropion is activating)"

Example 4: Generalized Anxiety Disorder - Acute vs. Long-Term Management

Case: 42-year-old female with new diagnosis of GAD. Symptoms: Excessive worry about work and family, muscle tension, restlessness, difficulty concentrating for 8 months. Significantly impairs functioning. Requests "something that works immediately" because she has an important presentation in 3 days.

Question: What is the BEST treatment strategy?

Optimal approach: Two-phase treatment

Phase 1 (Acute - next 3-4 weeks):

• Lorazepam 0.5-1 mg twice to three times daily as needed for immediate anxiety relief
• Counseling: "This is temporary—only for the next few weeks while the long-term medication starts working"

Phase 2 (Long-term):

• Start immediately: Escitalopram 10 mg daily (or other SSRI)
• SSRIs are first-line for GAD but take 4-6 weeks for full effect
• After 4-6 weeks: Taper and discontinue lorazepam (reduce by 25% weekly)

Why not benzodiazepine monotherapy?

• ⚠️ Tolerance develops (need escalating doses)
• ⚠️ Dependence risk (withdrawal syndrome)
• ⚠️ Cognitive impairment (memory, coordination)
• ⚠️ Increased fall risk (especially elderly)
• ⚠️ Beers Criteria: Avoid in adults ≥65 years

Alternative if patient refuses benzodiazepines: Hydroxyzine 25-50 mg three times daily for acute anxiety + SSRI for long-term

Counseling:

1. "The escitalopram is your long-term treatment—it prevents anxiety but takes 4-6 weeks"
2. "Lorazepam provides quick relief but is only temporary to bridge you until the escitalopram works"
3. "Avoid alcohol with both medications"
4. "Lorazepam may cause drowsiness—don't drive until you know how it affects you"
5. "We'll gradually stop the lorazepam once your anxiety is controlled by the escitalopram"

Common Mistakes and How to Avoid Them

❌ Mistake 1: Stopping Antidepressants Too Soon

Scenario: Patient feels better after 2 months on sertraline and discontinues medication.

Problem: Relapse risk is 50-80% if medication stopped before 6-12 months (first episode) or indefinitely (recurrent episodes).

Prevention:

• Counsel at initiation: "Plan to continue for at least 6-12 months after you feel completely better"
• At follow-up: Reinforce duration even if patient feels well
• Use analogy: "Depression is like pneumonia—you finish the antibiotic course even after fever resolves"

❌ Mistake 2: Not Tapering SSRIs Before Discontinuation

Scenario: Patient abruptly stops paroxetine 40 mg daily.

Problem: SSRI discontinuation syndrome within 1-3 days

• Symptoms: "FINISH" mnemonic
  • Flu-like symptoms (fatigue, myalgia)
  • Insomnia, vivid dreams
  • Nausea, vomiting
  • Imbalance, dizziness, vertigo
  • Sensory disturbances ("brain zaps," paresthesias)
  • Hypersomnolence or hyperarousal

Prevention:

• Taper all antidepressants (except fluoxetine, which self-tapers due to long half-life)
• Reduce by 25% every 1-2 weeks
• Paroxetine and venlafaxine: Highest risk (short half-life, no active metabolites)
• If symptoms occur: Resume previous dose, then taper more slowly

❌ Mistake 3: Using Benzodiazepines as First-Line for Depression

Scenario: Patient with depression and anxiety prescribed alprazolam without antidepressant.

Problem:

• Benzodiazepines do NOT treat depression
• May worsen depression over time
• Creates dependence without addressing underlying disorder

Correct approach:

• SSRIs/SNRIs treat both depression and anxiety
• Use benzodiazepine only as short-term bridge if anxiety is severe

❌ Mistake 4: Combining Contraindicated Serotonergic Agents

Scenario: Patient on fluoxetine 40 mg daily presents with migraine; physician prescribes sumatriptan.

Problem: Both are serotonergic → serotonin syndrome risk

Prevention:

• Screen medication list before adding any serotonergic drug
• Alternatives for migraine in SSRI patients: NSAIDs, antiemetics (not contraindicated)
• If triptan necessary: Use lowest dose, monitor closely, educate patient on symptoms

❌ Mistake 5: Ignoring Hepatic/Renal Dosing Adjustments

Scenario: Patient with CrCl 25 mL/min started on duloxetine 60 mg daily.

Problem: Duloxetine is contraindicated in CrCl <30 mL/min (accumulation of toxic metabolites)

Prevention:

• Always check renal/hepatic dosing before prescribing
• Renally eliminated: Venlafaxine (reduce dose), desvenlafaxine (reduce dose)
• Hepatically metabolized: Most antidepressants (reduce dose in severe liver disease)
• Safest in renal impairment: Mirtazapine, sertraline (no dose adjustment needed for mild-moderate impairment)

❌ Mistake 6: Not Assessing for Bipolar Disorder Before Starting Antidepressants

Scenario: Patient with "depression" started on fluoxetine; develops agitation, insomnia, racing thoughts.

Problem: Antidepressant-induced mania in unrecognized bipolar disorder

Prevention:

• Screen for history of mania/hypomania before starting antidepressant
• Ask: "Have you ever had periods of feeling 'too good' or overly energetic?"
• "Have you ever gone days without sleep and felt fine?"
• "Have you ever been told you were talking too fast or acting impulsively?"
• If positive: Refer to psychiatry; may need mood stabilizer ± antidepressant

Key Takeaways

🧠 NAPLEX Success Strategy: The exam tests clinical decision-making, not just drug names. Practice integrating patient-specific factors (age, comorbidities, drug interactions, pregnancy) with drug selection. When answering questions, think: "What would I do for my patient in this situation?"

📚 Further Study

1. AAFP Clinical Guidelines - Depression Management: https://www.aafp.org/pubs/afp/issues/2016/0915/p442.html (Evidence-based approach to MDD treatment and monitoring)

2. FDA Drug Safety Communication - Citalopram and QTc Prolongation: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-abnormal-heart-rhythms-associated-high-doses-celexa-citalopram (Critical safety information for NAPLEX)

3. American Psychiatric Association - Practice Guideline for Major Depressive Disorder: https://psychiatryonline.org/guidelines (Comprehensive clinical guidance including treatment-resistant depression)