5.3 Psychiatric Pharmacotherapy

5.3 Psychiatric Pharmacotherapy

Psychiatric pharmacotherapy represents a significant portion of the Board Certified Pharmacotherapy Specialist (BCPS) exam blueprint. Clinicians must possess deep expertise in patient-specific selection, monitoring, adverse effect management, and key drug-drug and drug-food interactions.

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1. Major Depressive Disorder (MDD)

First-Line Antidepressants (SSRIs and SNRIs)

Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) are established as first-line pharmacotherapy for MDD due to their favorable tolerability profile compared to older agents.

Agents and Mechanisms

• SSRIs: Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline. They selectively inhibit the presynaptic serotonin transporter (SERT), increasing synaptic serotonin concentrations.
• SNRIs: Venlafaxine, Desvenlafaxine, Duloxetine, Levomilnacipran. They inhibit both SERT and the norepinephrine transporter (NET). At lower doses (e.g., < 150 mg/day of venlafaxine), these agents primarily inhibit SERT, with NET inhibition occurring at higher doses.

Clinical Monitoring and Key Adverse Effects

• Sexual Dysfunction: Extremely common (up to 40-70% of patients) and a major driver of non-adherence. Manifests as decreased libido, anorgasmia, or delayed ejaculation. Management includes dose reduction, switching to an agent with fewer sexual side effects (e.g., bupropion, mirtazapine), or adding sildenafil.
• Hyponatremia and SIADH: Older adults (≥ 65 years) are at a disproportionate risk. The mechanism involves drug-induced release of antidiuretic hormone (ADH), leading to water retention and dilutional hyponatremia. Monitor serum sodium at baseline and within the first 1-2 weeks of initiation, particularly if the patient is also taking diuretics.
• QTc Prolongation: Most pronounced with citalopram and escitalopram. The FDA mandates a maximum citalopram dose of 40 mg/day in adults, and 20 mg/day in patients who are:
  • Older than 60 years.
  • Hepatic impairment.
  • Poor CYP2C19 metabolizers.
  • Taking CYP2C19 inhibitors (e.g., cimetidine, omeprazole).
• Discontinuation Syndrome: Caused by abrupt withdrawal of serotonergic agents. It is characterized by the mnemonic FINISH:
  • Flu-like symptoms (lethargy, fatigue, headache, achiness, sweating).
  • Insomnia (with vivid dreams or nightmares).
  • Nausea (sometimes vomiting).
  • Imbalance (dizziness, vertigo, lightheadedness).
  • Sensory disturbances ("brain zaps," burning, tingling, electric shock-like sensations).
  • Hyperactivity (anxiety, irritability, agitation).
  • Half-life correlation: Short half-life agents without active metabolites (e.g., paroxetine, venlafaxine) carry the highest risk. Fluoxetine carries the lowest risk due to the extremely long half-life of its active metabolite, norfluoxetine ($t_{1/2} \approx 7-15$ days), which creates a self-tapering effect.
• Suicide Risk Black Box Warning (BBW): Antidepressants increase the risk of suicidal thoughts and behaviors in children, adolescents, and young adults (aged 18–24) during initial treatment (typically the first 1-2 months) and following dose adjustments. Close clinical monitoring for worsening depression, suicidality, or unusual changes in behavior is required.

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Tricyclic Antidepressants (TCAs) and Monoamine Oxidase Inhibitors (MAOIs)

These older agents are generally reserved for treatment-resistant cases due to severe toxicity profiles and dietary or drug interactions.

Tricyclic Antidepressants (TCAs)

TCAs (e.g., Amitriptyline, Nortriptyline, Imipramine, Desipramine) inhibit SERT and NET but also block histamine-1 (H1), alpha-1 adrenergic, and muscarinic acetylcholine receptors.

• Anticholinergic Profile: Leads to dry mouth, blurred vision, urinary retention, constipation, and cognitive impairment/delirium (especially in older adults). Tertiary amines (amitriptyline, imipramine) have a significantly higher anticholinergic burden than secondary amines (nortriptyline, desipramine).
• Cardiotoxicity: TCAs block cardiac sodium channels, causing QRS widening, QTc prolongation, and potentially fatal arrhythmias (torsades de pointes, ventricular tachycardia). A QRS duration > 100 ms on ECG in a suspected TCA overdose is a critical indicator of toxicity, treated immediately with sodium bicarbonate to alkalinize the blood and increase sodium concentration, thereby displacing the TCA from sodium channels.
• Other Side Effects: Orthostatic hypotension (alpha-1 blockade) and sedation/weight gain (H1 blockade).

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs (e.g., Phenelzine, Tranylcypromine, Isocarboxazid, Selegiline) inhibit the monoamine oxidase enzyme, preventing the breakdown of serotonin, norepinephrine, and dopamine.

• Tyramine Dietary Restrictions: Traditional MAOIs (except low-dose transdermal selegiline, 6 mg/24 hr) require a strict tyramine-restricted diet. Consuming tyramine-rich foods (aged cheeses, air-dried or cured meats, draft beers, red wine, soy sauce, sauerkraut) leads to a hypertensive crisis. Tyramine is normally degraded by gastrointestinal MAO-A. When MAO-A is inhibited, systemic tyramine enters the circulation and acts as an indirect sympathomimetic, displacing massive amounts of norepinephrine from storage vesicles.
• Drug-Drug Interactions: Concomitant use with sympathomimetics (e.g., pseudoephedrine, phenylephrine, stimulants) can cause a hypertensive crisis. Concomitant use with other serotonergic agents (SSRIs, SNRIs, triptans, tramadol, linezolid, dextromethorphan) can precipitate Serotonin Syndrome.
• Strict Washout Periods:
  • When switching from an MAOI to another antidepressant (or vice versa), a minimum 14-day washout period is required to allow for the synthesis of new MAO enzymes.
  • When switching from fluoxetine to an MAOI, a 5-week (35 days) washout period is mandatory due to the extremely prolonged half-life of fluoxetine and norfluoxetine.

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Atypical Antidepressants

Bupropion (Norepinephrine-Dopamine Reuptake Inhibitor - NDRI)

• Clinical Advantages: Does not affect serotonin; therefore, it is associated with a negligible risk of sexual dysfunction and is weight-neutral or promotes weight loss.
• Contraindications:
  1. Seizure Disorders: Bupropion dose-dependently lowers the seizure threshold.
  2. Bulimia or Anorexia Nervosa: Patients with active or historical eating disorders have a highly elevated risk of seizures when taking bupropion due to electrolyte shifts.
  3. Abrupt Withdrawal of Alcohol, Benzodiazepines, or Sedatives: Increases seizure susceptibility.

Mirtazapine (Alpha-2 Adrenergic Antagonist)

• Mechanism: Antagonizes central presynaptic alpha-2 auto- and hetero-receptors, increasing the release of serotonin and norepinephrine. It also antagonizes 5-HT2 and 5-HT3 receptors, and exhibits high affinity for histamine H1 receptors.
• Dosing-Dependent Side Effect Profile:
  • At lower doses (7.5 mg to 15 mg daily), antihistaminic activity dominates, causing severe sedation and significant appetite stimulation/weight gain.
  • At higher doses (30 mg to 45 mg daily), increased noradrenergic transmission offsets some of the antihistaminic sedation, making the drug less sedating (though weight gain risks persist).

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2. Serotonin Syndrome vs. Neuroleptic Malignant Syndrome (NMS)

Serotonin Syndrome (SS) and Neuroleptic Malignant Syndrome (NMS) are critical, life-threatening pharmacotherapy emergencies. Differentiating them is vital for rapid intervention.

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3. Schizophrenia and Antipsychotic Pharmacotherapy

First-Generation Antipsychotics (FGAs) vs. Second-Generation Antipsychotics (SGAs)

• First-Generation Antipsychotics (Typical): (e.g., Haloperidol, Fluphenazine, Chlorpromazine). Act primarily as high-affinity dopamine D2 receptor antagonists. They are highly effective against positive symptoms (hallucinations, delusions) but carry a high risk of extrapyramidal symptoms (EPS) and hyperprolactinemia. High-potency agents (e.g., haloperidol) have high EPS risk but lower sedative/anticholinergic/hypotensive risks. Low-potency agents (e.g., chlorpromazine) have lower EPS risk but higher antihistaminic (sedation), anticholinergic, and alpha-1 blocking (orthostasis) properties.
• Second-Generation Antipsychotics (Atypical): (e.g., Clozapine, Olanzapine, Risperidone, Quetiapine, Aripiprazole, Ziprasidone, Lurasidone). Act as serotonin-dopamine antagonists (blocking 5-HT2A and D2 receptors) or partial D2 agonists (aripiprazole, brexpiprazole, cariprazine). They have a lower risk of EPS and tardive dyskinesia but a significantly higher propensity to cause metabolic syndrome.

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SGA Metabolic Syndrome Risks and ADA/APA Monitoring

The risk of metabolic syndrome (weight gain, dyslipidemia, hyperglycemia/type 2 diabetes, and hypertension) varies widely among SGAs.

Risk Stratification

• Highest Risk: Clozapine, Olanzapine.
• Moderate Risk: Quetiapine, Risperidone, Paliperidone.
• Lowest Risk: Aripiprazole, Ziprasidone (requires taking with ≥ 500 kcal food), Lurasidone (requires taking with ≥ 350 kcal food), Asenapine, Cariprazine.

ADA/APA Monitoring Protocol

Clinicians must follow the consensus guidelines from the American Diabetes Association (ADA) and American Psychiatric Association (APA) to monitor metabolic parameters:

Note: More frequent monitoring is indicated if the patient experiences significant weight gain (> 5% of baseline body weight) or demonstrates abnormal laboratory values.

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Clozapine: Boxed Warnings and REMS Protocol

Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia (defined as failing ≥ 2 adequate trials of other antipsychotics), but its use is tightly restricted.

Severe Boxed Warnings

1. Severe Neutropenia (Agranulocytosis): Can lead to life-threatening infections.
2. Orthostatic Hypotension, Bradycardia, Syncope: Highest risk during initial titration; requires slow dose escalation.
3. Seizures: Dose-dependent risk; concentrations > 350 ng/mL increase risk.
4. Myocarditis and Cardiomyopathy: Often presents within the first 4-8 weeks. Monitor for unexplained tachycardia, dyspnea, or chest pain.
5. Dementia-Related Psychosis: Increased risk of death in elderly patients.

Absolute Neutrophil Count (ANC) REMS Monitoring Protocol

Dispensing clozapine requires enrollment in the Clozapine REMS registry. Absolute Neutrophil Count (ANC) must be monitored regularly. ANC is calculated as: $\text{ANC} = \text{WBC} \times (\% \text{Neutrophils} + \% \text{Bands}) / 100$

Monitoring Frequency Schedules (General Population)

• Baseline: Must have a documented ANC $\ge 1500/\mu\text{L}$ prior to initiation.
• Weekly (Weeks 1 to 26): Every week for the first 6 months of treatment.
• Biweekly (Weeks 27 to 52): Every 2 weeks for the second 6 months of treatment.
• Monthly (Week 53 and thereafter): Every 4 weeks for the duration of treatment.

Warning Thresholds and Clinical Management (General Population)

• Normal (ANC $\ge 1500/\mu\text{L}$): Continue routine monitoring.
• Mild Neutropenia (ANC $1000 - 1499/\mu\text{L}$):
  • Action: Continue clozapine therapy.
  • Monitoring: Increase monitoring frequency to 3 times weekly until ANC $\ge 1500/\mu\text{L}$.
• Moderate Neutropenia (ANC $500 - 999/\mu\text{L}$):
  • Action: Interrupt clozapine therapy.
  • Monitoring: Monitor ANC daily until ANC $\ge 1000/\mu\text{L}$. Once ANC returns to $\ge 1000/\mu\text{L}$, resume clozapine and monitor ANC 3 times weekly until $\ge 1500/\mu\text{L}$, then return to baseline schedule.
• Severe Neutropenia (ANC $< 500/\mu\text{L}$):
  • Action: Discontinue clozapine permanently (re-challenge is contraindicated unless benefits clearly outweigh risks, requiring hematology consultation).
  • Monitoring: Monitor ANC daily until $\ge 1000/\mu\text{L}$ and confirm resolution of any signs of infection.
• Note: For patients with documented Benign Ethnic Neutropenia (BEN), the baseline threshold is $\ge 1000/\mu\text{L}$, and management thresholds are adjusted accordingly (e.g., severe neutropenia is defined as ANC $< 500/\mu\text{L}$).

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Antipsychotic-Induced Extrapyramidal Symptoms (EPS) Management

D2 blockade in the nigrostriatal pathway leads to various movement disorders.

1. Acute Dystonia

• Presentation: Painful, spasmodic contraction of muscle groups (e.g., torticollis [neck twist], oculogyric crisis [eyes rolling upward], trismus [lockjaw]). Typically occurs within hours to days of initiating or escalating a D2 antagonist (highest risk with high-potency FGAs in young males).
• Management:
  • First-line: Anticholinergic therapy. Benztropine 1-2 mg or Diphenhydramine 50 mg administered IV or IM for rapid relief.
  • Maintain oral anticholinergics for 1-2 weeks to prevent recurrence.

2. Akathisia

• Presentation: An intense subjective feeling of inner restlessness and anxiety, coupled with objective motor hyperactivity (e.g., pacing, shifting weight, inability to sit still). Typically develops within days to weeks.
• Management:
  • First-line: Lipophilic beta-blockers, specifically Propranolol 30–120 mg/day (in divided doses).
  • Alternatives/Adjuncts: Benzodiazepines (e.g., Lorazepam 1-2 mg/day).
  • Clinical note: Anticholinergic drugs are generally ineffective for akathisia.

3. Parkinsonism

• Presentation: Bradykinesia, cogwheel rigidity, resting tremor (pill-rolling), masked facies, and shuffling gait. Typically develops within weeks to months.
• Management:
  • First-line: Oral anticholinergic agents (e.g., Benztropine 1-6 mg/day in divided doses, or Trihexyphenidyl).
  • Alternative: Amantadine 100-300 mg/day (a weak NMDA antagonist and dopamine agonist). Amantadine is preferred in older adults to avoid anticholinergic side effects (e.g., worsening cognition, constipation, urinary retention).

4. Tardive Dyskinesia (TD)

• Presentation: Involuntary, repetitive, purposeless movements, particularly of the lower face, tongue, and extremities (e.g., lip-smacking, tongue protrusion, grimacing, rapid blinking, choreiform limb movements). Typically occurs after months to years of cumulative D2 blockade. Can be irreversible.
• Management:
  • Prevention: Use the lowest effective dose of antipsychotic; transition to an SGA (especially Clozapine or Quetiapine) if TD develops.
  • First-line FDA-approved treatments: Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors (e.g., Valbenazine, Deutetrabenazine).

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4. Bipolar Disorder

Lithium Pharmacotherapy

Lithium remains a gold standard mood stabilizer for bipolar I disorder (specifically classic mania and suicide prevention), but has a highly complex pharmacokinetic and monitoring profile.

Therapeutic Drug Monitoring (TDM)

Lithium has an extremely narrow therapeutic index. Blood samples must be drawn as a 12-hour trough (12 hours after the last dose, at steady state, typically after 5 days of consistent dosing).

• Acute Mania Target: 0.8 to 1.2 mEq/L
• Maintenance Target: 0.6 to 1.0 mEq/L (up to 1.2 mEq/L in highly symptomatic patients)

Renal Clearance Dynamics

Lithium is a monovalent cation that is 100% renally cleared and is not metabolized. In the kidneys, lithium is filtered at the glomerulus. In the proximal tubule, the kidneys handle lithium identically to sodium, reabsorbing approximately 80% of it. Consequently, any state that increases proximal tubule sodium reabsorption (e.g., hyponatremia, dehydration, volume depletion) will cause a corresponding increase in lithium reabsorption, precipitating toxicity.

Critical Drug-Drug Interactions (The "Big Three")

1. Thiazide Diuretics: Consistently increase lithium levels by 25-50%. Thiazides block sodium reabsorption in the distal convoluted tubule. The resulting sodium depletion prompts the proximal tubule to compensate by aggressively reabsorbing sodium—and lithium—leading to accumulation.
2. NSAIDs: Increase lithium levels (typically by 20-40%). NSAIDs inhibit renal prostaglandins, which decreases renal blood flow and reduces glomerular filtration rate (GFR). Furthermore, prostaglandin inhibition increases sodium and lithium reabsorption.
   • Exceptions: Aspirin and Sulindac have negligible effects on renal prostaglandins and are preferred if an NSAID or analgesic is required.
3. ACE Inhibitors and ARBs: Increase lithium levels (frequently causing severe, delayed toxicity). They block angiotensin II, leading to efferent arteriole vasodilation, which alters intraglomerular pressure and promotes proximal tubule sodium/lithium retention.
4. Volume Depletion/Dehydration: Vomiting, diarrhea, excessive sweating, febrile illness, or a low-sodium diet will decrease sodium volume and trigger renal sodium/lithium retention, causing rapid lithium toxicity.

Lithium Toxicity

• Mild-Moderate Toxicity (1.5 - 2.0 mEq/L): Coarse hand tremor (differentiated from benign fine tremor), persistent nausea/vomiting, severe diarrhea, muscle weakness, slurred speech, ataxia, drowsiness.
• Severe Toxicity (> 2.0 mEq/L): Impaired consciousness, seizures, cardiac arrhythmias, QRS prolongation, stupor, coma, and death.
  • Treatment of Toxicity: Discontinue lithium. Aggressive hydration with normal saline ($0.9%$ NaCl) is the cornerstone of therapy to promote osmotic excretion of lithium.
  • Hemodialysis: Indicated for:
    • Lithium level $> 4.0\text{ mEq/L}$ (regardless of clinical status).
    • Lithium level $> 2.5\text{ mEq/L}$ in patients with severe symptoms (seizures, altered mental status, hemodynamically unstable) or significant renal impairment.

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Alternative Mood Stabilizers

Divalproex Sodium / Valproic Acid

• Therapeutic Range: 50 to 125 mcg/mL (trough, drawn prior to morning dose).
• Monitoring Parameters:
  • Liver Function Tests (LFTs) due to BBW for fatal hepatotoxicity (highest risk in children < 2 years and patients with mitochondrial disorders).
  • Complete Blood Count (CBC) with platelets due to BBW for thrombocytopenia (dose-dependent).
  • Ammonia levels: Monitor if the patient presents with unexplained lethargy, confusion, or cognitive changes, as valproate can cause hyperammonemic encephalopathy (even with normal LFTs).
  • Lipase/Amylase: Monitor if abdominal pain occurs, due to BBW for life-threatening pancreatitis.
• Teratogenicity: Highly teratogenic, causing neural tube defects (spina bifida). Avoid in females of childbearing potential unless alternative therapies are ineffective or tolerated poorly.

Carbamazepine

• Therapeutic Range: 4 to 12 mcg/mL.
• Pharmacokinetics: A potent inducer of hepatic enzymes (CYP3A4, CYP1A2, CYP2C9/19) and a notorious auto-inducer. It induces its own metabolism, shortening its half-life from ~30 hours initially to ~15 hours after 2-4 weeks of therapy. Trough levels must be monitored periodically, and dose increases are commonly required after the first few weeks.
• HLA-B*1502 Genetic Screening: Mandatory by the FDA for patients of Asian descent prior to initiating carbamazepine. The presence of the HLA-B*1502 allele is strongly associated with the development of life-threatening cutaneous reactions, including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN).

Lamotrigine

• Indication: Approved for the maintenance treatment of Bipolar I disorder to delay the time to occurrence of depressive episodes. It is not effective for acute mania.
• Titration Schedule: Must be titrated extremely slowly over at least 6 weeks to minimize the risk of serious rash, including SJS/TEN.
• Drug-Interaction Adjusted Titration Schedules:

Important: If a patient discontinues lamotrigine for more than 5 half-lives (approximately 3 to 5 days), the titration schedule must be restarted from Week 1 to avoid SJS/TEN.

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5. Anxiety Disorders

First-Line Antidepressants (SSRIs and SNRIs)

SSRIs and SNRIs are preferred long-term treatments for Generalized Anxiety Disorder (GAD), Panic Disorder, and Social Anxiety Disorder.

• Slow Titration Principle: Patients with anxiety disorders are hyper-sensitive to the stimulatory effects of serotonergic/noradrenergic activation. Initiating therapy at standard antidepressant doses can cause an acute, transient spike in anxiety, panic attacks, and agitation ("activation syndrome").
• Clinical Pearl: Always initiate anxiety pharmacotherapy at half the typical starting dose used for MDD (e.g., Escitalopram 5 mg daily, Sertraline 25 mg daily, or Venlafaxine XR 37.5 mg daily) and titrate slowly over several weeks.

Buspirone

• Mechanism: A partial agonist at the serotonin 5-HT1A receptor. It does not affect GABA receptors.
• Clinical Advantages: Lacks abuse potential, does not cause physical dependence or withdrawal, and does not cause significant sedation, motor impairment, or cognitive dysfunction.
• Dosing Consistency: Has a high first-pass metabolism that is heavily influenced by food. Patients must take buspirone consistently either always with food or always without food to maintain stable systemic exposure.
• Delayed Onset: Requires 2 to 4 weeks (and up to 6 weeks) of continuous daily administration for therapeutic onset. It is completely ineffective as a PRN (as-needed) medication.

Benzodiazepines

• Role in Therapy: Limited to short-term, adjunctive use during the initiation phase of SSRIs/SNRIs, or for acute, severe anxiety/panic episodes.
• Risks: Development of tolerance (requiring higher doses), physical dependence, addiction, and a severe withdrawal syndrome (characterized by rebound anxiety, tremors, sweating, and life-threatening seizures upon abrupt discontinuation).
• Beers Criteria and Older Adults: The American Geriatrics Society (AGS) Beers Criteria recommends avoiding all benzodiazepines in older adults (aged $\ge 65$), regardless of the half-life. Older adults have decreased hepatic clearance, increased sensitivity to GABA-mediated CNS effects, and an elevated risk of:
  • Cognitive impairment and delirium.
  • Falls and hip fractures (due to ataxia and muscle relaxation).
  • Motor vehicle accidents.
• Preferred Agents in Hepatic Impairment / Elderly (if unavoidable): Use the LOT agents: Lorazepam, Oxazepam, Temazepam. These agents undergo direct conjugation (Phase II glucuronidation) to inactive metabolites, bypass Phase I oxidation (CYP450 pathway), and do not accumulate in patients with reduced hepatic function or advanced age.