Mood Stabilizers & Anticonvulsant Pharmacology – Comprehensive Exam Notes

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Brexanolone (Zulresso)
- Positive allosteric modulator of GABA$A$ receptor; may also act on 5-HT$3$ (serotonin) receptors.
- Rapid antidepressant effect (similar to ketamine): improvement within $2\text{–}3\,\text{days}$ in responders.
- Unclear long-term efficacy.
- Schedule IV controlled substance; available only via national registry.
- Drawbacks:
- Requires continuous IV infusion over $60$ h with gradual dose increase (hospitalization needed to monitor sedation/syncope).
- High cost: $\approx \$34{,}000$ per single dose + facility fees; usually not covered by insurance.

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Lithium – Historical & Chemical Facts

First shown effective for mania by John F. J. Cade (early 1950 s).
FDA approvals: acute mania (1970); maintenance therapy (1974).
Elemental details: monovalent alkali metal (Group IA). Occurs naturally as $^6\text{Li}$ ( $7.42\%$ ) and $^7\text{Li}$ ( $92.58\%$ ) — $^7\text{Li}$ useful for MRS imaging.
Conversion: $300\,\text{mg Li} \equiv 1{,}597\,\text{mg Li}<em>2\text{CO}</em>3$ .
U.S. lithium sourced mainly from dry-lake brines in Chile & Argentina.

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Pharmacokinetics of Lithium

Rapid, complete oral absorption.
$t_{\max}$ : $1\text{–}1.5\,\text{h}$ (standard); $4\text{–}4.5\,\text{h}$ (SR/CR).
No protein binding; no metabolism; renal excretion.
Initial plasma $t_{1/2}$ $\approx 1.3\,\text{days}$ ; after >1\,\text{yr} therapy $\approx 2.4\,\text{days}$ .
Elimination $t_{1/2}$ : $18\text{–}24\,\text{h}$ in young adults; ↓ in children, ↑ in elderly.
Equilibrium after $5\text{–}7\,\text{days}$ regular dosing.
↑ Clearance in obesity; ↓ with renal insufficiency; pregnancy ↑ excretion but postpartum ↓.
Concentrates in thyroid & kidney > serum.
Theories of action: altered ion transport, neurotransmission, signal transduction, second-messenger modulation.

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Lithium – Indications (Bipolar I)

Acute mania: ~ $80\%$ response; onset $1\text{–}3\,\text{weeks}$ → start benzodiazepine, DRA, SDA, or valproate for first weeks.
Poorer response in mixed/dysphoric mania, rapid cycling, SUD, organicity.
Bipolar depression: useful solo or as add-on; augmentation with valproate/carbamazepine common.
- Check for lithium-induced hypothyroidism, SUD, non-adherence.
- Strategies: raise serum to $1.0\text{–}1.2\,\text{mEq/L}$ ; add valproate/carbamazepine; add liothyronine $25\,\mu\text{g/day}$ ; consider antidepressant or ECT.
Maintenance: markedly ↓ frequency, severity, duration of episodes; better mania prophylaxis than depression.
- Indications after 1st episode (esp. adolescents, family history, high suicide risk, no precipitant, poor support).
- Reduces suicide six- to seven-fold.
- Lower plasma levels often sufficient; taper slowly if discontinuing.

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MDD: add-on lithium ( $300\,\text{mg TID}$ ) converts $50\text{–}60\%$ of antidepressant non-responders.
Schizoaffective / Schizophrenia: augmentation with SDA/DRA when mood prominent or treatment-resistant; occasional monotherapy if antipsychotics contraindicated.
Anti-aggression: useful in schizophrenia, prison inmates, conduct disorder, ID, self-mutilation.
Tables 21-25 & 21-26 list wide psychiatric & non-psychiatric off-label uses (epilepsy, headache, movement disorders, endocrinologic, dermatologic, GI, respiratory, etc.).

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Highlighted off-label psychiatric areas (evidence variable): rapid-cycling BP, cyclothymia, OCD, PTSD, ADHD, EDs, impulse-control, personality disorders, PMDD, sexual disorders.
Non-psychiatric (unapproved): neurologic pain, hematologic neutropenia, thyroid cancers, SIADH, dermatologic conditions, GI ulcers, asthma, CF, etc.

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Lithium – Adverse-Effect Overview

> $80\%$ experience AEs.
Monitoring critical (blood levels, patient education).
Changes in Na$^+$/water alter levels: high Na$^+$ ↓ Li$^+$; low Na$^+$ ↑ Li$^+$; dehydration ↑ toxicity.
Table 21-27 lists major AEs:
- Neurologic: benign cognitive dulling, tremor; toxic signs (coarse tremor, ataxia, seizures).
- Endocrine: goiter, hypothyroid, hyperparathyroid.
- Cardiac: T-wave changes, SND.
- Renal: concentrating defect → polyuria (NDI), ↓ GFR, microcysts.
- Derm: acne, psoriasis, alopecia.
- GI: N/V/D.
- Metabolic: weight gain, edema.

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Cardiac

ECG: diffuse slowing, widened spectrum, arrhythmias; can unmask Brugada syndrome → ask FHx sudden death < $45$ .

GI

Nausea, vomiting, diarrhea → give with food, split doses; lithium citrate least diarrheagenic; manage with loperamide, bismuth, diphenoxylate.

Weight

From carb metabolism change, hypothyroid, edema, sugary drinks.

Tremor

$8\text{–}12\,\text{Hz}$ postural; treat by dose division, SR form, ↓ caffeine, propranolol $30\text{–}120\,\text{mg}$ , primidone $50\text{–}250\,\text{mg}$ , correct hypokalemia.

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Cognitive & Neuro effects

Dysphoria, slowed RT, memory issues; rule out depression, thyroid, hyperCa$^{2+}$, meds.
Rare: parkinsonism, neuropathy, BIH, MG-like, seizure risk ↑.

Renal

Polyuria (> $3\,\text{L/day}$ ) via ADH antagonism.
- Assess with 24-h Cr clearance; manage fluids, lowest dose, once-daily dosing, add diuretic (amiloride, spironolactone, triamterene, HCTZ) but halve Li dose & delay diuretic $5$ days.
Long-term: interstitial fibrosis, microcysts (MRI), nephrotic syndrome.

Thyroid

$5\%$ goiter, $7\text{–}10\%$ hypothyroid (women > men).
50 % lab abnormalities (TRH, ↑ TSH).
Treat with levothyroxine; check TSH $q6\text{–}12\,\text{mo}$ .

Cardiac again

T-wave flatten/invert; sinus dysrhythmia, heart block; contraindicated in sick-sinus.

Dermatologic

Acneiform, psoriasis worsening; monitor if on tetracycline.

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Lithium Toxicity

Early: coarse tremor, dysarthria, ataxia, GI upset, arrhythmia.
Levels:
1. Mild $1.5\text{–}2.0\,\text{mEq/L}$ → GI, ataxia.
2. Moderate $2.0\text{–}2.5\,\text{mEq/L}$ → neuro signs, EEG changes, syncope.
3. Severe >2.5\,\text{mEq/L} → seizures, renal failure, death.
Management (Table 21-29): stop drug, vitals, labs, gastric lavage/Kayexalate/GoLYTELY, hemodialysis if >4.0\,\text{mEq/L}.
Post-dialysis rebound → repeat dialysis.
Adolescents: similar levels but acne/weight issues.
Elderly: start low, go slow.
Pregnancy: avoid 1st trimester (Ebstein anomaly risk $1/1000$ ).
- Use lowest dose; monitor closely ante/post-partum; breastfeeding usually avoided.

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Drug Interactions (Table 21-30)

↑ Li levels/toxicity: thiazides, K-sparing diuretics, ACEIs (not AT1 blockers), most NSAIDs (except aspirin, sulindac), metronidazole, Ca-channel blockers (neurotoxicity).
↓ Li: osmotic & loop diuretics, xanthines (caffeine), carbonic anhydrase inhibitors.
Synergistic neurotoxicity: high-dose DRAs, carbamazepine, valproate, lamotrigine, clonazepam.
ECT: stop Li $2$ days before to prevent delirium.

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Dosing & Monitoring

Pre-workup: creatinine (±24-h Cr clearance), electrolytes, TSH/T3/T4, CBC, ECG, pregnancy test.
Starting: $300\,\text{mg}$ regular-release TID (elderly = $300\,\text{mg}$ QD–BID).
Usual: $900\text{–}1{,}200\,\text{mg/day}$ → $0.6\text{–}1.0\,\text{mEq/L}$ ; $1{,}200\text{–}1{,}800$ mg → $0.8\text{–}1.2$ mEq/L.
Mania target $1.0\text{–}1.2$ ; maintenance $0.4\text{–}0.8$ mEq/L.
Draw levels 12 h post-dose, steady state after $5\,\text{days}$ .
Labs $q2\text{–}6\,\text{mo}$ ; ECG yearly.
Treat patient, not lab: some need > $1.2$ , some fine < $0.4$ .
Patient education essentials (Table 21-31): dosing adherence, 12-h blood draw rule, OTC interactions, stable diet/fluids, recognize toxicity.

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Valproate (Depakene/Depakote)

Simple branched-chain carboxylic acid; dissociates to valproate ion.
Formulations: valproic acid (caps/syrup), divalproex sodium (delayed-release tablet & sprinkle), sodium valproate IV, ER tablets.
PK: complete absorption; $t_{1/2}=10\text{–}16\,\text{h}$ ; high protein binding saturates > $50\text{–}100\,\mu\text{g/mL}$ .
Metab: hepatic glucuronidation & β-oxidation.
Mechanisms: ↑ GABA, modulate Na$^+$ channels, affect neuropeptides.

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Indications

Epilepsy (partial & absence), migraine prophylaxis.
Bipolar I:
- Acute mania: $\approx 66\%$ response; effective levels $50\text{–}125\,\mu\text{g/mL}$ ; rapid oral loading $20\text{–}30\,\text{mg/kg}$ achieves target day 1.
- Bipolar depression: mild benefit, esp. agitation; used as add-on to prevent switch.
- Prophylaxis: equal or better tolerance vs lithium; esp. rapid cycling, dysphoric/mixed, comorbid SUD/panic.
Schizoaffective / schizophrenia: accelerates antipsychotic response; monotherapy weak.
Other: alcohol withdrawal, PTSD, BPD aggression, dementia agitation (evidence weak).

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Warnings (Table 21-32)

Hepatotoxicity: idiosyncratic, greatest risk < $3$ yrs, polytherapy, neuro disorders; adult psych risk low (0.85/100k).
Pancreatitis: rare, mostly within 6 mo.
Hyperammonemia: esp. with carbamazepine; treat L-carnitine.
Teratogenicity: neural tube defect $1\text{–}4\%$ ; ↓ IQ, ↑ autism risk; use folate $1\text{–}4\,\text{mg}$ .
Elderly somnolence; thrombocytopenia > $110$ (women) $/$ $135$ (men) µg/mL.

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Common AEs (Table 21-33)

GI: irritation, nausea, vomiting, diarrhea.
Neuro: sedation, tremor, ataxia, dysarthria.
Weight gain, hair loss.
Uncommon: persistent LFT ↑, hyponatremia.
Rare: fatal hepatitis, pancreatitis, thrombocytopenia, agranulocytosis, edema, encephalopathy, respiratory muscle weakness.

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Drug Interactions (Table 21-34)

Lithium: ↑ tremor.
DRAs: ↑ sedation, EPS.
Lamotrigine: valproate doubles lamotrigine → rash risk (SJS/TEN).
↑ levels of: carbamazepine epoxide, diazepam, tricyclics, phenobarbital.
↓ levels of: phenytoin (free ↑ though), desipramine.
Valproate levels ↓ by carbamazepine; ↑ by amitriptyline, fluoxetine, guanfacine.
Watch anticoagulants (protein binding displacement).

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Monitoring (Table 21-35)

Baseline: LFTs, CBC/platelets; ± amylase/coag if needed; pregnancy test.
Repeat LFTs & CBC at 1 mo; then $q6\text{–}24\,\text{mo}$ .
Mild LFT ↑ < $3×$ ULN → monitor; > $3×$ or sx → dose ↓ or stop.
Therapeutic range $50\text{–}125\,\mu\text{g/mL}$ ; typical $1{,}200\text{–}1,500\,\text{mg/day}$ .
Loading mania: $20\text{–}30\,\text{mg/kg/day}$ oral/IV ((Depacon)).

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Forms (Table 21-36)

Depacon IV $100\,\text{mg/mL}$ (peak 1 h).
Depakene syrup/caps $250\,\text{mg}$ (peak 1–2 h).
Depakote DR tabs 125/250/500 (peak 3–8 h).
Depakote sprinkle 125 mg beads (earlier onset).
Depakote ER 250/500 (peak 4–17 h) — allows QD dosing.

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Lamotrigine

Folate-antagonist derived; approved 2003 for maintenance BP I.
Best at preventing depression (“stabilizes from below”); modest acute bipolar depression effect; not acute mania.
PK: 98 % bioavailability; $t_{1/2}=25\,\text{h}$ but varies 6-fold with co-meds.
55 % protein-bound; urinary excretion of inactive metabolites.
MOA: blocks voltage Na$^+$ channels → ↓ glutamate/aspartate; mild Ca$^{2+}$ effects; ↑ serotonin (reuptake block); weak 5-HT$_3$ block.

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Indications

Maintenance BP, esp. delay depressive episode; rapid-cycling utility; BPD (borderline) & pain anecdotal.

Adverse

Generally well-tolerated; no weight gain/metabolic issues.
Common: dizziness, ataxia, somnolence, vision blur, headache, nausea, cognitive/back pain.
Rash: 8 % benign; risk SJS/TEN 0.08–0.13 % adults, higher in <16 yrs.
- Risk ↑ with rapid titration, high start dose, valproate co-admin.
- Any rash → stop immediately; if >4 days missed, restart titration from scratch.

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Drug Interactions & Dosing

Valproate doubles lamotrigine; lamotrigine ↓ valproate 25 %.
Carbamazepine, phenytoin, phenobarbital ↓ lamotrigine 40–50 %.
Sertraline modest ↑.
Dosing (Table 21-37):
- Mono: 25 mg QD (weeks 1–2) → 50 mg QD (3–4) → 100–200 mg QD (≥5).
- + Carbamazepine: 50 → 100 → 200–400 mg.
- + Valproate: 25 mg every other day → 25 mg QD → 50–100 mg QD (max 100).
Usual target 100–200 mg QD; split BID if needed.

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Carbamazepine (Tegretol, Equetro)

Tricyclic-like; approved for trigeminal neuralgia 1968, epilepsy 1974, acute mania (Equetro XR) 2002.
PK: slow variable absorption; food ↑; $t_{1/2}=18\text{–}54\,\text{h}$ initially, ↓ to $\approx 12\,\text{h}$ after 3–5 wks (auto-induction via CYP3A4).
Active metabolite: 10,11-epoxide.
MOA: voltage-dependent Na$^+$ channel block → ↓ Ca$^{2+}$ influx, ↓ NMDA current, adenosine A1 antagonism, catecholamine potentiation.

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Indications

Acute mania (50–70 % respond in 2–3 wks); good for lithium-non-responders (dysphoric, rapid-cycling).
Maintenance: bipolar II, schizoaffective, dysphoric mania.
Acute depression (selected refractory cases).
Other: alcohol withdrawal adjunct, PTSD paroxysms, impulsive aggression, agitation in schizophrenia/schizoaffective.

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AEs (Table 21-38)

Dose-related: diplopia, vertigo, GI upset, ataxia, performance impairment.
Idiosyncratic: agranulocytosis, aplastic anemia (1/125,000), SJS/TEN, hepatic failure, rash, pancreatitis.
Hematology: benign leukopenia 1–2 %; monitor CBC at 3,6,9,12 mo.
Hepatitis/cholestasis: watch LFT; > $3×$ ULN + sx → stop.
Derm: 10–15 % benign rash; severe rashes stop drug.
Hyponatremia via SIADH-like effect; monitor elderly.
Cardiac: conduction slowing; caution pre-existing disease.

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Interactions (Table 21-39)

Strong CYP3A4 inducer → ↓ OCPs, many psych meds.
Serum ↑ from: cimetidine, erythromycin, diltiazem, azoles, grapefruit juice, valproate (epoxide ↑).
Serum ↓ from: carbamazepine auto-induction, phenytoin, phenobarb, rifampin.
Avoid with MAOIs; need 2-wk washout.

Monitoring & Dosing

Pre-labs: CBC, LFT, electrolytes, ECG (>40 yrs).
Target dose ~ $1{,}200\,\text{mg/day}$ ; XR preferred (Carbatrol/Equetro).
Anticonvulsant therapeutic range $4\text{–}12\,\mu\text{g/mL}$ ; aim ≥4 before deeming non-response.
Benign leukopenia: can add lithium to ↑ WBC.
Patient guide (Table 21-40): titrate slowly, watch rash, hematologic warning signs, contraception, avoid in pregnancy (spina bifida 0.5 %).

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Oxcarbazepine (Trileptal)

Carbamazepine analog; not proven in controlled mania trials.
PK: rapid absorption; parent $t_{1/2}=2\,\text{h}$ ; active monohydroxy derivative $9\,\text{h}$ ; no auto-induction.
AEs: sedation, nausea, cognitive issues, diplopia, tremor; much less blood dyscrasia risk; rash lower but cross-react 25–30 % if allergic to carbamazepine.
Hyponatremia $3\text{–}5\%$ → check Na early.
Dose bipolar (empiric): 900–1,200 mg/day (divided BID).
CYP3A4/5 inducer; inhibits CYP2C19; reduce OCP efficacy.

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Other Anticonvulsants

Gabapentin: ↑ GABA, ↓ glutamate; used for insomnia, anxiety, neuropathic pain.
- Dosing: start 300 mg → titrate to 1,200–2,400 mg (max 4,800).
- AEs: somnolence, ataxia; minimal interactions.
Topiramate: GABAergic; weight loss, migraine, binge eating, PTSD; not effective acute mania.
- AEs: paresthesia, cognitive dulling, nephrolithiasis (1.5 %); encourage fluids.
- Dose: titrate 25 mg weekly → 75–150 mg QHS (max 400).
Tiagabine: GAT-1 inhibitor; risks seizures/status if misused; limited psych use (GAD, insomnia).
Levetiracetam: unclear MOA; anxiolytic/mania adjunct; AEs behavioral (irritability, hallucination).
Zonisamide: Na$^+$ block & carbonic anhydrase inhibition; weight loss; risk rash, nephrolithiasis.
Pregabalin: similar to gabapentin; approved for neuropathic pain, fibromyalgia, GAD; AEs dizziness, edema; renal dosing.
Phenytoin: Na$^+$ block; antimanic evidence but nonlinear PK, gingival hyperplasia, hematologic risk; therapeutic $10\text{–}20\,\mu\text{g/mL}$ .

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Calcium Channel Blockers (CCBs)

Rationale: L-type Ca$^{2+}$ channel genes linked to BP, schizophrenia, MDD, ADHD, autism.
Agents: nifedipine, nimodipine, isradipine, amlodipine, nicardipine, nisoldipine, nitrendipine, verapamil, diltiazem.
PK: oral absorption complete; first-pass metabolism; half-lives range $1\text{–}2$ h (nimodipine) to $30\text{–}50$ h (amlodipine).

Clinical Use

Bipolar maintenance: nimodipine & verapamil show benefit; nimodipine for ultradian cycling.
Verapamil prevents antidepressant-induced mania.
Not antidepressant; may blunt AD response.
Other: MAOI hypertensive crisis (nifedipine sublingual); potential in Tourette, Huntington, panic, IED, TD.

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AEs & Interactions

Vasodilatory: dizziness, headache, tachycardia, edema.
Verapamil/diltiazem: hypotension, bradycardia, AV block; monitor vitals & ECG.
Contra with β-blockers, digoxin, other antihypertensives without specialist input.
Verapamil ↑ levels of carbamazepine, digoxin (CYP3A4).
Combined with lithium → neurotoxicity/deaths.

Dosing Examples

Verapamil: start 40 mg TID → up to 120 mg TID (SR versions exist).
Nifedipine: 10 mg QID → max 120 mg/day.
Nimodipine: 60 mg q4h (acute), up to 360 mg/day.
Isradipine: 2.5 mg BID → max 20 mg.
Amlodipine: 5 mg QHS → max 10–15 mg.

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Overall Practical Pearls

Choose mood stabilizer based on episode polarity, cycling pattern, comorbidities, tolerability, reproductive status.
Lithium remains gold standard for classic mania & suicide prevention but monitor closely.
Valproate preferred for rapid cycling, dysphoric mania, comorbid SUD, children/elderly (but teratogenic).
Lamotrigine valuable for depressive prophylaxis; watch rash.
Carbamazepine useful for lithium non-responders; consider interactions & monitoring.
Oxcarbazepine, topiramate, gabapentin, others serve adjunct or specific niche (weight, pain, anxiety).
Brexanolone offers rapid antidepressant effect in PPD but has access & cost barriers.
Calcium channel blockers & older anticonvulsants may help refractory cases but require cardiac or metabolic vigilance.