Antidepressant & Antipsychotic Selection

Antidepressant & Antipsychotic Selection

Master antidepressant and antipsychotic selection with free flashcards and evidence-based protocols. This lesson covers medication selection algorithms, safety monitoring parameters, and high-yield drug interactions—essential concepts for NAPLEX success and safe psychiatric practice.

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🧠 Welcome to Psychiatric Medication Selection

Psychiatric pharmacotherapy requires careful consideration of efficacy, safety profiles, drug interactions, and patient-specific factors. This lesson focuses on the systematic approach to selecting antidepressants and antipsychotics while minimizing adverse effects and maximizing therapeutic outcomes.

Why This Matters for NAPLEX:

• High-frequency topic on the exam
• Requires integration of pharmacology, pathophysiology, and patient assessment
• Safety monitoring is heavily tested
• Drug interactions are a common pitfall

💡 Pro Tip: The NAPLEX emphasizes safety first—always consider contraindications, monitoring parameters, and drug interactions before efficacy.

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📊 Core Concepts: Antidepressant Selection

First-Line Antidepressants: SSRIs and SNRIs

Selective Serotonin Reuptake Inhibitors (SSRIs) are typically first-line due to favorable safety profiles and tolerability.

Drug	Key Features	Important Considerations
Sertraline	• Broad FDA indications • Minimal drug interactions • Linear kinetics	• Safe in cardiac disease • Mild GI side effects • Pregnancy Category C
Escitalopram	• Most selective SSRI • Rapid onset • Well-tolerated	• QT prolongation at >20 mg • Avoid in long QT syndrome • Lower max dose in elderly (10 mg)
Fluoxetine	• Longest half-life (4-6 days) • Active metabolite (norfluoxetine) • Less withdrawal	• Strong CYP2D6 inhibitor • 5-week washout for MAOIs • May cause activation/insomnia
Paroxetine	• Most anticholinergic • Sedating • Short half-life	• Pregnancy Category D • Highest discontinuation syndrome • Weight gain • Strong CYP2D6 inhibitor
Citalopram	• Minimal P450 effects • Predictable dosing	• QT prolongation risk • Max dose: 40 mg (20 mg if >60 yo) • ECG if cardiac risk factors

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) add noradrenergic activity:

Drug	Unique Features	Clinical Pearls
Venlafaxine	• Dose-dependent mechanism • Low: SSRI activity • High: SNRI activity	• Monitor BP (especially >150 mg/day) • Effective for GAD, social anxiety • Must taper to avoid discontinuation
Duloxetine	• FDA approved for neuropathic pain • Balanced 5-HT/NE reuptake	• Avoid in hepatic impairment • Monitor LFTs • Useful for diabetic neuropathy + depression
Desvenlafaxine	• Active metabolite of venlafaxine • No dose titration needed • Renal elimination	• Dose adjust in renal impairment • Less BP elevation than venlafaxine • Fixed dosing (50 mg)

🧠 Mnemonic - SSRI Side Effects: SSCARED

• Serotonin syndrome risk
• Sexual dysfunction (60-70%)
• CNS effects (headache, insomnia)
• Activation/anxiety initially
• Restlessness/akathisia
• Electrolyte (SIADH/hyponatremia)
• Discontinuation syndrome

Alternative Antidepressants

Class/Drug	Mechanism	Best For	Key Safety Issues
Bupropion (NDRI)	Dopamine & norepinephrine reuptake inhibition	• SSRI sexual dysfunction • Smoking cessation • Seasonal affective disorder • ADHD + depression	⚠️ Lowers seizure threshold • Contraindicated: seizure disorder, eating disorders, abrupt alcohol/benzo withdrawal • No sexual dysfunction • No weight gain
Mirtazapine (Tetracyclic)	α2-antagonist, 5-HT2/5-HT3 antagonist	• Depression with insomnia • Poor appetite/weight loss • Nausea	• Sedation (inverse dose-related) • Weight gain (H1 antagonism) • Increased appetite • Monitor CBC (rare agranulocytosis)
Trazodone (SARI)	5-HT2A antagonist, weak SSRI	• Insomnia (25-100 mg HS) • Depression with insomnia	⚠️ Priapism (rare but serious) • Orthostatic hypotension • Sedation (α1-blockade) • Use low doses for sleep
Vilazodone/Vortioxetine	SSRI + 5-HT receptor modulation	• Depression with cognitive symptoms • Less sexual dysfunction	• Take with food (vilazodone) • Nausea common initially • More expensive than generics

MAOIs: Last-Line But High-Yield for NAPLEX

Monoamine Oxidase Inhibitors require extensive dietary restrictions but are effective for treatment-resistant depression.

MAOI	Type	Notes
Phenelzine	Non-selective, irreversible	• Most evidence for atypical depression • Requires strict dietary adherence
Tranylcypromine	Non-selective, irreversible	• Amphetamine-like structure • May cause insomnia • Faster onset than phenelzine
Selegiline patch	MAO-B selective (at low doses)	• 6 mg patch: no dietary restrictions • ≥9 mg: dietary restrictions apply • Application site reactions

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🎯 Antidepressant Selection Algorithm

┌─────────────────────────────────────────────────────────────┐
│           MAJOR DEPRESSIVE DISORDER TREATMENT               │
└─────────────────────────────────────────────────────────────┘
                            │
                            ▼
            ┌───────────────────────────────┐
            │  Patient Assessment           │
            │  • Symptom profile            │
            │  • Comorbidities              │
            │  • Prior treatments           │
            │  • Drug interactions          │
            │  • Pregnancy status           │
            └───────────┬───────────────────┘
                        │
        ┌───────────────┼───────────────┐
        ▼               ▼               ▼
┌───────────────┐ ┌──────────────┐ ┌─────────────────┐
│ FIRST-LINE    │ │ SPECIAL      │ │ AVOID           │
│ • SSRI        │ │ SITUATIONS   │ │ • MAOIs (1st)   │
│ • SNRI        │ │              │ │ • TCAs (1st)    │
│               │ │              │ │                 │
│ Consider:     │ │              │ │                 │
│ Sertraline    │ │              │ │                 │
│ Escitalopram  │ │              │ │                 │
└───────┬───────┘ └──────┬───────┘ └─────────────────┘
        │                │
        │                ▼
        │    ┌──────────────────────────────────┐
        │    │ Insomnia? → Mirtazapine         │
        │    │ Sexual dysfunction? → Bupropion  │
        │    │ Neuropathic pain? → Duloxetine  │
        │    │ Smoking cessation? → Bupropion  │
        │    │ Atypical features? → SNRI/MAOI  │
        │    └──────────────────────────────────┘
        │
        ▼
┌─────────────────────────────────────────┐
│  Trial for 4-8 weeks at therapeutic dose│
└─────────────┬───────────────────────────┘
              │
      ┌───────┴────────┐
      ▼                ▼
  ✅ Response    ❌ Non-response/Intolerance
      │                │
      ▼                ▼
  Continue      Switch or Augment
  6-12 months   • Different class
                • Add bupropion
                • Add mirtazapine
                • Add atypical antipsychotic

💡 Clinical Pearl: Allow adequate trial duration (4-8 weeks) and therapeutic dosing before declaring treatment failure. Many patients are under-dosed or switched too early.

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🧬 Core Concepts: Antipsychotic Selection

First-Generation Antipsychotics (FGAs/Typicals)

Mechanism: D2 dopamine receptor antagonism in all pathways

Potency	Examples	Key Features	Side Effect Profile
High Potency	• Haloperidol • Fluphenazine • Perphenazine	• Low doses effective • Less sedation • Less anticholinergic • Long-acting injectable available	⚠️ HIGH EPS risk • Akathisia • Dystonia • Parkinsonism • Tardive dyskinesia (long-term)
Low Potency	• Chlorpromazine • Thioridazine	• Higher doses needed • More sedating • More anticholinergic	⚠️ HIGH metabolic/cardiovascular risk • Orthostatic hypotension • Sedation • Weight gain • QT prolongation • Anticholinergic effects

🧠 Mnemonic - High vs Low Potency: "High and Nervous, Low and Slow"

• High potency: More EPS (nervous system effects)
• Low potency: More sedation/metabolic effects (slow/tired)

Second-Generation Antipsychotics (SGAs/Atypicals)

Mechanism: D2 + 5-HT2A antagonism (and various other receptor activities)

Drug	Unique Features	Advantages	Key Adverse Effects
Risperidone	• Dose-dependent D2 blockade • Active metabolite (9-OH) • Long-acting injectable available	• Effective for positive symptoms • Less expensive • Pediatric approvals	⚠️ Dose-related EPS (>6 mg/day) • Hyperprolactinemia (highest risk) • Orthostatic hypotension • Weight gain (moderate)
Olanzapine	• Broad receptor binding • Very effective • Multiple formulations	• Excellent efficacy • IM available (agitation) • Low EPS • Minimal prolactin effects	⚠️ HIGHEST metabolic risk • Weight gain (7-10 kg average) • Diabetes risk • Dyslipidemia • Sedation
Quetiapine	• Weak D2 binding • Active metabolite (norquetiapine) • XR formulation available	• Low EPS risk • FDA approved for bipolar depression • Useful for sleep (low doses) • Minimal prolactin elevation	• Sedation (H1 antagonism) • Weight gain (moderate-high) • Metabolic effects • Orthostatic hypotension • Cataracts (monitor in long-term)
Aripiprazole	• D2 partial agonist • Long half-life (75 hrs) • LAI formulations • Active metabolite	• LOWEST metabolic risk • Weight neutral • No prolactin elevation • No sedation • Once-monthly injection available	⚠️ Akathisia (20-25%) • Activation/insomnia • Nausea initially • May worsen agitation initially
Ziprasidone	• 5-HT/NE reuptake inhibition • BID dosing • Take with food (↑absorption)	• Weight neutral • Low metabolic risk • May improve depressive symptoms	⚠️ QTc prolongation • Must take with ≥500 cal meal • Moderate EPS • Activation/anxiety
Lurasidone	• Take with food (≥350 cal) • Renal/hepatic dose adjustment • Once daily	• Weight neutral • Low metabolic risk • FDA approved for bipolar depression • Low sedation	• Akathisia • Nausea • Must take with food • More expensive
Clozapine	• GOLD STANDARD for treatment-resistant schizophrenia • Weak D2 binding • Requires REMS program	• Most effective antipsychotic • Reduces suicide risk • Lowest EPS • No tardive dyskinesia • No prolactin elevation	⚠️ AGRANULOCYTOSIS (1-2%) • Requires weekly → biweekly ANC monitoring • Seizures (dose-related, 5%) • Myocarditis • Severe constipation • Hypersalivation • Highest metabolic risk • Sedation

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🎯 Antipsychotic Selection Algorithm

┌──────────────────────────────────────────────────────────┐
│              SCHIZOPHRENIA TREATMENT                     │
└──────────────────────────────────────────────────────────┘
                         │
                         ▼
        ┌────────────────────────────────┐
        │   Patient Assessment           │
        │   • First episode vs chronic   │
        │   • Metabolic risk factors     │
        │   • Previous trials/response   │
        │   • Side effect history        │
        │   • Adherence concerns         │
        └────────────┬───────────────────┘
                     │
    ┌────────────────┼────────────────┐
    ▼                ▼                ▼
┌─────────┐    ┌──────────┐    ┌────────────┐
│ FIRST   │    │ SPECIAL  │    │ LAST LINE  │
│ EPISODE │    │ CONCERNS │    │            │
└────┬────┘    └─────┬────┘    └──────┬─────┘
     │               │                 │
     ▼               ▼                 ▼
┌─────────────┐ ┌────────────────┐ ┌──────────┐
│ Prefer SGA  │ │ Metabolic risk?│ │ Clozapine│
│ Lower dose  │ │ → Aripiprazole │ │ (2+ failed│
│ Avoid high  │ │ → Ziprasidone  │ │  trials) │
│ metabolic   │ │ → Lurasidone   │ │          │
│ risk agents │ │                │ │ Requires │
│             │ │ Adherence issue│ │ REMS     │
│             │ │ → LAI (long-   │ │ Weekly → │
│             │ │    acting inj) │ │ Monthly  │
│             │ │                │ │ ANC      │
└─────────────┘ └────────────────┘ └──────────┘

💡 NAPLEX High-Yield: Know which antipsychotics are available as long-acting injectables (LAIs):

• FGAs: Haloperidol decanoate, fluphenazine decanoate (q2-4 weeks)
• SGAs: Risperidone (Risperdal Consta, q2 weeks), Paliperidone (Invega Sustenna/monthly, Trinza/q3 months), Aripiprazole (Abilify Maintena/Aristada, monthly), Olanzapine (Zyprexa Relprevv, q2-4 weeks)

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📋 Examples with Clinical Application

Example 1: SSRI Selection in Cardiac Patient

Case: 68-year-old male with major depression and history of MI 6 months ago. Current medications include aspirin, metoprolol, atorvastatin, lisinopril. No other psychiatric history.

Analysis:

Step	Consideration	Decision
1	First-line for depression	SSRI or SNRI appropriate
2	Cardiac safety	Avoid citalopram/escitalopram (QT risk at higher doses) SNRIs increase BP (avoid venlafaxine)
3	Drug interactions	Metoprolol metabolized by CYP2D6 Avoid strong 2D6 inhibitors (fluoxetine, paroxetine)
4	Best choice	Sertraline - cardiac safe, minimal drug interactions, linear kinetics

Recommendation: Sertraline 50 mg daily, titrate to 100-150 mg as needed. Monitor for GI upset initially. Safe with cardiac medications.

⚠️ Common Mistake: Starting citalopram 40 mg in elderly cardiac patient → QT prolongation risk. Maximum dose is 20 mg in patients >60 years old.

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Example 2: Managing SSRI Sexual Dysfunction

Case: 32-year-old female with good response to escitalopram 20 mg for depression (8 months), but reports decreased libido and anorgasmia. Depression is in remission. She wants to continue medication.

Options:

Strategy	Mechanism	Evidence	Considerations
Switch to bupropion	No serotonergic activity DA/NE reuptake inhibition	⭐⭐⭐ Strong No sexual dysfunction May improve libido	• Risk of relapse when switching • 2-week taper recommended • May cause activation/insomnia
Add bupropion	Dopamine augmentation May counteract 5-HT effects	⭐⭐⭐ Strong Maintains antidepressant effect Improves sexual function	• BEST OPTION • Bupropion XL 150-300 mg AM • No relapse risk • Synergistic antidepressant effect
Add sildenafil PRN	PDE-5 inhibition Increases blood flow	⭐⭐ Moderate Works in males>females Addresses arousal/erectile issues	• Take 1 hour before activity • Doesn't address libido • More effective for arousal than desire
Drug holiday	Temporary SSRI discontinuation	⭐ Weak Not recommended	❌ AVOID • Risk of discontinuation syndrome • Risk of relapse • Not practical long-term

Recommendation: Add bupropion XL 150 mg AM, increase to 300 mg after 1 week. Continue escitalopram 20 mg. Reassess in 4-6 weeks.

💡 Pro Tip: Sexual dysfunction occurs in 60-70% of SSRI/SNRI patients. Always ask about it proactively, as patients often don't volunteer this information due to embarrassment.

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Example 3: First-Episode Psychosis in Young Adult

Case: 19-year-old male college student with first episode of psychosis (auditory hallucinations, paranoid delusions). No substance use confirmed. BMI 22, no medical conditions. Family history of type 2 diabetes (mother).

Selection Priorities:

1. Efficacy - need good symptom control
2. Metabolic profile - young patient, diabetes family history
3. Tolerability - first episode, adherence critical
4. Cognitive effects - college student

Option	Pros	Cons	Rating
Olanzapine	• Excellent efficacy • Low EPS • Evidence in first episode	❌ Highest metabolic risk • 7-10 kg weight gain average • Diabetes risk with family history • Sedation affects academics	⚠️ AVOID (metabolic concerns)
Risperidone	• Good efficacy • Well-studied • Lower cost	⚠️ Dose-related EPS • Hyperprolactinemia • Moderate metabolic effects • Gynecomastia risk in males	⚠️ Consider (watch dose/prolactin)
Aripiprazole	✅ Weight neutral ✅ No metabolic effects ✅ No prolactin elevation ✅ No sedation • Good efficacy	• Akathisia (20-25%) • May cause activation • Longer titration	✅ BEST CHOICE (ideal profile for this patient)
Lurasidone	• Weight neutral • Low metabolic risk • Low sedation	• Must take with food • More expensive • Less long-term data	✅ Good alternative

Recommendation:

• Aripiprazole 5-10 mg daily, titrate to 10-15 mg over 2 weeks
• Monitoring: Weight, waist circumference, fasting glucose, lipids at baseline and every 3 months
• Counsel: May experience restlessness (akathisia) - treatable with dose reduction or propranolol if needed
• Duration: Minimum 1-2 years for first episode, possibly longer

🧠 Clinical Pearl: In first-episode psychosis, metabolic-friendly agents (aripiprazole, lurasidone, ziprasidone) should be strongly favored. Early weight gain predicts long-term metabolic complications and is a major cause of non-adherence in young patients.

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Example 4: Treatment-Resistant Depression

Case: 45-year-old female with MDD, failed adequate trials of:

• Sertraline 200 mg × 8 weeks
• Venlafaxine XR 225 mg × 10 weeks
• Duloxetine 120 mg × 8 weeks

All trials had adequate duration at therapeutic doses. Partial response to each but persistent symptoms (PHQ-9 score remains 15-18).

Augmentation Strategies:

Strategy	Evidence Level	Mechanism	Key Points
Add aripiprazole	⭐⭐⭐⭐ FDA approved Multiple RCTs	D2 partial agonist 5-HT1A agonist 5-HT2A antagonist	• Start 2-5 mg daily • Effective dose: 5-15 mg • Response in 1-2 weeks • Watch for akathisia • Weight neutral
Add quetiapine XR	⭐⭐⭐⭐ FDA approved Strong evidence	Norquetiapine (metabolite): NE reuptake inhibition	• Dose: 150-300 mg HS • Sedating (bedtime dosing) • ⚠️ Weight gain • ⚠️ Metabolic effects
Add bupropion	⭐⭐⭐ Good evidence Common practice	DA/NE reuptake inhibition Complements serotonergic agents	• Bupropion XL 150-300 mg • May improve energy/motivation • No metabolic effects • Addresses sexual dysfunction
Add lithium	⭐⭐⭐ Strong evidence Oldest augmentation	Enhances serotonin transmission	• Target level: 0.6-0.8 mEq/L • Requires monitoring (level, TSH, Cr) • Narrow therapeutic index • Drug interactions
Switch to MAOI	⭐⭐⭐ Effective for TRD	Increases all monoamines	• Requires 2-week washout • Dietary restrictions • Reserve for refractory cases • Consider after 2-3 failed trials

Recommendation for this patient: Add aripiprazole 5 mg daily, increase to 10 mg after 1 week. Continue current duloxetine. This provides:

• ✅ FDA-approved indication
• ✅ Rapid onset (1-2 weeks vs 4-6 weeks for other strategies)
• ✅ Favorable metabolic profile
• ✅ Can stay on current effective SNRI

Alternative if sedation/sleep is an issue: Add quetiapine XR 150 mg HS, increase to 300 mg after 3-4 days.

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⚠️ Common Mistakes in Psychiatric Medication Selection

Mistake #1: Not Considering Drug Interactions

Scenario: Prescribing fluoxetine to patient on tamoxifen for breast cancer.

Why it's wrong:

• Fluoxetine is a strong CYP2D6 inhibitor
• Tamoxifen is a prodrug requiring 2D6 conversion to active endoxifen
• Result: ⚠️ Reduced tamoxifen efficacy → increased cancer recurrence risk

Correct approach: Use antidepressants with minimal 2D6 inhibition:

• ✅ Venlafaxine
• ✅ Citalopram/escitalopram
• ✅ Sertraline (weak inhibition at low doses)

💡 NAPLEX Tip: Strong CYP2D6 inhibitors = "FPP" - Fluoxetine, Paroxetine, buproPion

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Mistake #2: Inadequate Trial Duration/Dose

Scenario: Switching antidepressants after 2 weeks at starting dose because "it's not working."

Why it's wrong:

• Antidepressants require 4-8 weeks at therapeutic dose for full effect
• Partial response at 2-4 weeks often predicts eventual response
• Premature switching → prolonged suffering, polypharmacy

Correct approach:

Week	Action	Expected Response
1-2	Start at initial dose Assess tolerability	Side effects appear Minimal therapeutic effect
3-4	Titrate to therapeutic dose	Side effects diminish Early improvement (energy, sleep)
4-6	Maintain therapeutic dose	Mood improvement begins Partial response
6-8	Assess full response	Maximum benefit achieved Decision point: continue, increase, or switch

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Mistake #3: Ignoring Metabolic Monitoring with Antipsychotics

Scenario: Patient on olanzapine for 6 months, no metabolic monitoring done.

Why it's wrong:

• SGAs (especially olanzapine, clozapine, quetiapine) cause significant metabolic effects
• Weight gain, diabetes, dyslipidemia develop insidiously
• Cardiovascular disease is leading cause of death in schizophrenia patients

Required monitoring schedule:

Parameter	Baseline	Month 1	Month 2	Month 3	Quarterly	Annually
Weight/BMI	✅	✅	✅	✅	✅	✅
Waist circumference	✅					✅
Blood pressure	✅			✅	✅	✅
Fasting glucose	✅			✅	✅	✅
Fasting lipids	✅			✅	✅	✅

Action thresholds:

• Weight gain >5% baseline → Consider switching to metabolic-neutral agent
• Fasting glucose >100 mg/dL → Lifestyle intervention, consider metformin
• Fasting glucose >126 mg/dL → Diagnose diabetes, treat appropriately
• LDL >130 mg/dL → Consider statin therapy

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Mistake #4: Using QT-Prolonging Combinations

Scenario: Patient on citalopram 60 mg + haloperidol + methadone

Why it's wrong:

• All three agents prolong QT interval
• Additive effect → risk of Torsades de Pointes (potentially fatal arrhythmia)
• Citalopram 60 mg exceeds maximum dose (40 mg)

High-risk QT-prolonging psychiatric medications:

Correct approach:

• Reduce citalopram to ≤40 mg (≤20 mg if >60 yo)
• Consider switching to sertraline (no QT effect)
• Obtain baseline and follow-up ECG
• Check electrolytes

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Mistake #5: Abrupt Discontinuation of Antidepressants

Scenario: Patient stops paroxetine 40 mg abruptly after 6 months of treatment.

Result: Severe discontinuation syndrome within 24-48 hours:

• Dizziness, vertigo
• "Brain zaps" (electric shock sensations)
• Flu-like symptoms (fatigue, myalgia, chills)
• Insomnia, vivid dreams
• Nausea
• Irritability, anxiety
• Crying spells

Why paroxetine is worst:

• Shortest half-life among SSRIs (~21 hours)
• No active metabolites
• Strong anticholinergic rebound

Risk ranking for discontinuation syndrome:

1. Highest risk: Paroxetine, venlafaxine (short half-life, no active metabolites)
2. Moderate risk: Sertraline, citalopram, escitalopram, duloxetine
3. Low risk: Fluoxetine (long half-life + active metabolite), bupropion

Proper taper schedule:

Original Dose	Week 1-2	Week 3-4	Week 5-6	Week 7+
Paroxetine 40 mg	30 mg	20 mg	10 mg	Discontinue
Venlafaxine 225 mg	150 mg	75 mg	37.5 mg	Discontinue

💡 Exception: Fluoxetine can often be stopped without taper due to long half-life (4-6 days) and active metabolite norfluoxetine (4-16 days).

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🎯 Key Takeaways

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📚 Further Study

1. American Psychiatric Association - Practice Guidelines for Major Depressive Disorder
   https://www.psychiatry.org/psychiatrists/practice/clinical-practice-guidelines

2. NAPLEX Competency Statements (Psychiatric Disorders Section)
   https://nabp.pharmacy/programs/naplex/

3. Stahl's Essential Psychopharmacology Online - Antidepressants and Antipsychotics
   https://stahlonline.cambridge.org/

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🎯 You've completed Antidepressant & Antipsychotic Selection! You now have the framework to systematically choose psychiatric medications based on efficacy, safety, and patient-specific factors. Remember: NAPLEX emphasizes safety monitoring and drug interactions - master these and you'll excel!

Next Steps:

• Review flashcards daily using spaced repetition
• Practice case-based questions
• Create your own clinical scenarios
• Master monitoring parameters for high-risk agents

Good luck on your NAPLEX journey! 💊🧠