Comprehensive Notes – Mood Stabilizers & Related Agents

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Brexanolone (Zulresso)

• Positive allosteric modulator of the GABA(A) receptor (possible action on serotonin $5\text{-HT}3$ )
• Rapid antidepressant response (onset within $2\text{–}3$ days)
• Long-term efficacy unknown
• Schedule IV; distributed only through a national registry
• Drawbacks ↦ continuous IV infusion over $60$ h + mandatory monitoring for excess sedation/syncope; single-dose cost ≈ $\$34{,}000$ (hospitalization not included); rarely covered by insurance

Introduction to Mood-Stabilizers

Lithium – historical background

• Efficacy for acute mania & prophylaxis of bipolar illness discovered (John F. J. Cade, early $1950\text{s}$ )
• FDA approvals: acute mania ( $1970$ ), maintenance ( $1974$ )
• Adjunctive in major depressive disorder (MDD)
• Chemistry: monovalent alkali metal ion $\text{Li}^+$ ; natural isotopes $^6\text{Li}\,(7.42\%)$ & $^7\text{Li}\,(92.58\%)$ (the latter imaged via magnetic-resonance spectroscopy)
• Pharmaceutical conversion: $300\,\text{mg Li} = 1{,}597\,\text{mg Li}2\text{CO}3$
• Major mining sources ↦ Chile & Argentina dry-lake deposits

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Pharmacokinetics of Lithium

• Oral absorption rapid/complete; $t{\max}$ : standard prep $1\text{–}1.5$ h, SR/CR $4\text{–}4.5$ h • No plasma-protein binding, no metabolism; renal excretion only • Plasma $t{1/2}$ initially $1.3$ d → $2.4$ d after > $1$ y therapy
• Elimination $t_{1/2}$ : $18\text{–}24$ h (young adults) ↓ children, ↑ elderly
• Equilibrium after $5\text{–}7$ d of steady dosing
• Factors ↓ renal clearance ↦ renal insufficiency, postpartum period; ↑ clearance ↦ obesity, pregnancy
• Tissue concentrations ↑ in thyroid & kidney relative to serum

Proposed Mechanisms (unknown, multifactorial)

• Altered ion transport; effects on neurotransmitters/peptides
• Modulation of second-messenger & signal-transduction pathways

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Therapeutic Indications – Bipolar I disorder

Acute Mania

• Lithium controls ≈ $80\%$ of classic manic episodes; slower onset $1\text{–}3$ wk
• Add adjunct (benzodiazepine, DRA, SDA, valproate) during titration
• Lower efficacy in mixed/dysphoric mania, rapid cycling, substance abuse comorbidity, organic brain disease

Bipolar Depression

• Effective monotherapy or augmentation for severe MDD
• Strategies for inadequate response ↦ raise lithium level to $1\text{–}1.2\,\text{mEq/L}$ , add valproate/carbamazepine, consider $25\,\mu\text{g}$ liothyronine, antidepressants, or ECT

Maintenance

• Reduces frequency/severity/duration of episodes; greater prophylaxis for mania than depression
• Indications after first manic episode (especially adolescents, family Hx, high suicide risk, poor support, precipitants absent)
• Lithium ↓ suicide incidence $6\text{–}7$ -fold
• Early relapse on maintenance ≠ failure; late loss of efficacy → add valproate/carbamazepine
• Abrupt discontinuation ↑ relapse risk; taper gradually

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Additional Clinical Points

• Relapse risk ↑ with each manic episode; $28\times$ more likely post-discontinuation in responders
• Long-term monotherapy dose may be lower than acute-phase dose
• Lithium also useful for severe cyclothymia
• Discontinue slowly to avoid rebound

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Lithium – Other Psychiatric Uses

• Major depressive disorder (augmentation): $300\,\text{mg}$ $3\,\times/\text{day}$ ; $50\text{–}60\%$ of antidepressant-nonresponders improve, onset days–weeks
• Schizoaffective disorder (mood-prominent) – augmentation with SDAs/DRAs
• Limited utility in schizophrenia monotherapy when antipsychotics contraindicated

Page 6 & 7 (summary combined)

Wide-Ranging Off-Label Uses (variable evidence)

Psychiatric

• Aggression/impulse disorders (conduct disorder, prisoners, intellectual disability)
• Rapid-cycling bipolar II, cyclothymia, PTSD, OCD, eating & personality disorders, Kleine–Levin, PMDD, pathological sexuality, etc.

Non-psychiatric

• Neurologic ↦ epilepsy, cluster & migraine headaches, Ménière, Huntington, Parkinsonian fluctuations, Tourette, neuropathic pain, periodic paralysis
• Hematologic ↦ neutropenia rescue, Felty, adjunct in cancer Tx
• Endocrine ↦ thyrotoxicosis, thyroid cancer adjuvant, SIADH
• Dermatologic ↦ genital herpes, seborrheic dermatitis
• GI/Respiratory ↦ cyclic vomiting, ulcerative colitis, asthma (unsupported)

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Adverse-Effect Spectrum (Table 21-27 highlights)

Neurologic

• Benign cognitive blunting, $8\text{–}12$ Hz postural tremor
• Toxic levels ↦ coarse tremor, ataxia, seizures, coma

Endocrine ↦ goiter, hypothyroidism $7\text{–}10\%$ , hyperparathyroidism

Renal ↦ nephrogenic diabetes insipidus (polyuria > $3\,\text{L/day}$ ), chronic interstitial fibrosis (> $10\,\text{y}$ )

Cardiovascular ↦ benign $T$ -wave flattening, sinus node dysfunction, Brugada unmasking

Dermatologic ↦ acne, psoriasis, alopecia

GI/Metabolic ↦ nausea, diarrhea, weight gain, fluid retention

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Lithium Toxicity

• Risk factors ↦ overdose, renal impairment, low sodium, dehydration, drug interactions (e.g., NSAIDs, thiazides)
• Severity scale
– Mild $1.5\text{–}2.0\,\text{mEq/L}$ ↦ GI upset, ataxia, lethargy
– Moderate $2.0\text{–}2.5\,\text{mEq/L}$ ↦ neuro symptoms, delirium, arrhythmias
– Severe >2.5\,\text{mEq/L} ↦ seizures, renal failure, death
• Management (Table 21-29) ↦ stop lithium, labs, gastric decontamination (Kayexalate, PEG; NOT charcoal), IV fluids, hemodialysis when >4.0\,\text{mEq/L} or severe neuro signs; watch for rebound levels post-dialysis

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Special Populations

• Adolescents ↦ acne/weight gain problematic
• Elderly ↦ start low, slow titration, monitor closely (↓ renal clearance)
• Pregnancy ↦ avoid first trimester (Ebstein anomaly risk $1/1000$ ; teratogenicity $4\text{–}12\%$ ); use lowest effective dose, monitor levels (↑ clearance in pregnancy ↓ postpartum); contraindicated in breast-feeding (infant signs: lethargy, cyanosis)
• Diabetes, dehydration, comorbid illness ↑ toxicity risk

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Drug Interactions (Table 21-30)

• ↑ Lithium (↓ clearance) ↦ thiazide & K(^+)-sparing diuretics, NSAIDs (except aspirin/sulindac), ACEIs, most CCBs, metronidazole
• ↓ Lithium ↦ osmotic/loop diuretics, xanthines, acetazolamide
• Neuro-synergy ↦ antipsychotics, carbamazepine, valproate ↦ ↑ tremor, EPS, rare encephalopathy
• Absolute caution with CCBs & during ECT (hold lithium $\ge 48$ h pre-ECT)

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Dosing & Monitoring Guidelines

• Baseline labs ↦ $\text{SCr}$ , electrolytes, TSH/T(3)/T(4), CBC, ECG, pregnancy test
• Typical starting dose 300\,\text{mg}TID $(elderly$ 300\,\text{mg}QD\text{–}BID)
• Acute mania target level 1.0\text{–}1.2\,\text{mEq/L} $(≈$ 1{,}800\,\text{mg/day} $); maintenance$ 0.4\text{–}0.8\,\text{mEq/L}
• Draw serum 12 $h post-dose, at steady state (day$ 5 $); then$ q2\text{–}6 mo or as clinically indicated
• Treat the patient, not the lab: some need >1.2\,\text{mEq/L}; others maintained <0.4\,\text{mEq/L}

Patient Education Essentials (Table 21-31)

• Adherence, lab schedule, maintain 2\text{–}3\,\text{L} fluids & normal salt, caution with OTC NSAIDs, recognize toxicity signs, avoid abrupt discontinuation

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Valproate (Valproic Acid / Divalproex)

Pharmacology

• Simple branched-chain carboxylic acid; formulations: valproic acid, divalproex sodium (enteric), sprinkle caps, ER tabs, IV sodium valproate
• Absorption rapid/complete; t{\max}4\text{–}5 $h;$ t{1/2}10\text{–}16 h
• Highly protein-bound; binding saturable >50\text{–}100\,\mu\text{g/mL} → ↑ free fraction
• Hepatic metabolism (glucuronidation, \beta $-oxidation); mechanisms: ↑ GABA, modulate Na(^+$ ) channels, neuropeptide effects

Clinical Use in Bipolar I

• Acute mania response $\approx 66\%$ ; therapeutic range $50\text{–}125\,\mu\text{g/mL}$ ; oral loading $20\text{–}30\,\text{mg/kg/day}$ controls symptoms within $5$ d
• Bipolar depression ↦ modest benefit (agitation), mostly adjunct to antidepressant
• Prophylaxis as effective as lithium; superior in rapid cycling, mixed states, comorbid SUD or panic
• Preferred in children & elderly (tolerability)

Black-Box Warnings / Serious Risks (Table 21-32)

• Hepatotoxicity (idiosyncratic, highest < $3$ y; risk $1:118{,}000$ adults)
• Acute pancreatitis
• Teratogenicity ↦ neural-tube defects $1\text{–}4\%$ ; cognitive deficits & ASD risk; women of child-bearing age need folate $1\text{–}4\,\text{mg/day}$
• Hyperammonemic encephalopathy
• Dose-related thrombocytopenia (threshold $\ge110\,\mu\text{g/mL}$ women, $\ge135$ men)

Common Adverse Effects (Table 21-33)

• GI upset (nausea, vomiting, diarrhea) especially early
• Sedation, ataxia, tremor (treat with propranolol/gabapentin)
• Weight gain; alopecia (consider zinc/selenium)
• Benign transaminase ↑ (< $3\times$ ULN)
• Rare: hyponatremia, agranulocytosis, edema, respiratory depression in overdose

Interactions (Table 21-34)

• ↑ Lamotrigine (× $2$ ) → serious rash; ↓ valproate by $25\%$
• ↑ levels of carbamazepine-epoxide, diazepam, phenobarbital, TCAs
• ↓ Phenytoin, desipramine levels; valproate ↓ by carbamazepine
• Additive CNS depression with alcohol, antipsychotics

Monitoring & Dosing

• Baseline LFTs, CBC/platelets; repeat at $1$ mo then $q6\text{–}24$ mo
• Acute loading $20\text{–}30\,\text{mg/kg}$ or start $250\,\text{mg}$ day 1 → $750\,\text{mg}$ day 3; adjust to level $50\text{–}125\,\mu\text{g/mL}$ (typical $1{,}200\text{–}1{,}500\,\text{mg/day}$ )
• Once-daily ER dosing after stabilization

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Lamotrigine

Key Features

• Oral bioavailability $98\%$ ; $t{1/2}$ $25$ h (varies $\times6$ with drug interactions) • Mechanism ↦ blocks voltage-gated Na(^+ $) channels → ↓ glutamate/aspartate; weak 5-HT(3$ ) antagonism

Clinical Profile

• FDA-approved for maintenance in bipolar I (prevents depressive>manic relapses); not for acute mania
• Useful in rapid cycling & bipolar depression (“stabilizes from below”)

Dosing (Table 21-37)

• Monotherapy: $25\,\text{mg}$ daily weeks 1–2 → $50$ mg weeks 3–4 → target $100\text{–}200\,\text{mg/day}$
• With carbamazepine/phenytoin: start $50\,\text{mg}$ ; target $200\text{–}400\,\text{mg}$
• With valproate: $25\,\text{mg}$ every other day → $50\,\text{mg}$ → max $100\,\text{mg}$
• Restart titration if >4 missed days

Adverse Effect Highlight

• Rash $8\%$ (usually benign); severe SJS/TEN rare (≈ $0.1\%$ adults, higher in kids, ↑ risk with rapid titration & valproate)
• Otherwise weight-neutral, non-sedating

Drug Interactions

• ↑ Lamotrigine ↦ valproate, sertraline
• ↓ Lamotrigine ↦ carbamazepine, phenytoin, phenobarbital
• Lamotrigine ↓ valproate $25\%$

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Carbamazepine

Pharmacokinetics/Mechanism

• Slow, erratic absorption; auto-induces CYP3A4 → $t_{1/2}$ drops from $26$ h to $≈12$ h over $3\text{–}5$ wk
• Active $10,11$ -epoxide metabolite
• Blocks voltage-gated Na(^+) channels, ↓ NMDA currents, ↑ catecholamines

Bipolar Uses

• Acute mania response 50\text{–}70\% $within$ 2\text{–}3 wk (good for dysphoric/rapid-cycling)
• Maintenance esp. bipolar II, schizoaffective
• Useful in alcohol withdrawal, impulsive aggression, PTSD paroxysms

Adverse Effects (Table 21-38)

• Dose-related: diplopia, vertigo, GI upset, ataxia
• Idiosyncratic: agranulocytosis (≈1/125{,}000), aplastic anemia, hepatotoxicity, SJS/TEN (esp. HLA-B*1502 genotype in Asians)
• Benign leukopenia in 1\text{–}2\%; monitor CBC
• Hyponatremia/SIADH, rash 10\text{–}15\%
• Teratogenic (spina bifida 0.5\% $; total major malfx$ ≈8\%)

Drug Interactions (Table 21-39)

• Potent CYP3A4 inducer → ↓ levels of OCPs, antipsychotics, many others
• Levels ↑ by CYP3A4 inhibitors (erythro-, clarithro-, ketoconazole, verapamil, grapefruit juice)
• Avoid with MAOIs; caution with lithium (neurotoxicity reports)

Dosing & Labs

• Target 4\text{–}12\,\mu\text{g/mL} (anticonvulsant range)
• Extended-release (Carbatrol/Equetro) 100\text{–}300\,\text{mg} $beads; once- or twice-daily; typical mania dose$ \approx1{,}200\,\text{mg/day}
• Baseline & periodic CBC, LFTs, electrolytes; ECG if >40 y

Oxcarbazepine

• Keto-analog; fewer hematologic rashes but 25\text{–}30\% cross-rash with carbamazepine
• Hyponatremia 3\text{–}5\% $(check Na(^+$ ) early)
• Dose $900\text{–}1{,}200\,\text{mg/day}$ (divided BID)

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Other Anticonvulsants (evidence graded)

Gabapentin

• ↑ GABA, modulates Ca(^{2+} $) channels; useful for insomnia, anxiety, neuropathic pain; dose$ 300\text{–}3{,}600\,\text{mg/day} (TID)

Topiramate

• GABAergic, carbonic-anhydrase inhibition; migraine, weight loss (counteracts psychotropic weight gain), binge eating; start 25\,\text{mg} $↑ weekly; max$ 200\,\text{mg BID}; watch paresthesias, cognitive dulling, kidney stones (hydrate)

Tiagabine

• GABA reuptake inhibitor; limited psych use (GAD/insomnia); risk seizures/status; start 4\,\text{mg} daily ↑ slowly

Levetiracetam

• Mechanism unknown (SV2A binding); off-label mania/anxiety; usual 1\,\text{g/day}; neuro-behavioural effects (irritability)

Zonisamide

• Na(^+)/Ca(^{2+} $) block + CA inhibition; weight-loss adjunct; once-daily dosing (half-life$ 60 h); risk kidney stones, rash

Pregabalin

• α(_2\delta) Ca(^{2+} $) subunit ligand; FDA-approved for neuropathic pain, fibromyalgia; anxiolytic; dose$ 150\text{–}600\,\text{mg/day}; dizziness, edema, weight gain

Phenytoin

• Na(^+) channel blocker; occasional bipolar use; nonlinear kinetics (monitor $10\text{–}20\,\mu\text{g/mL}$ ); side fx: nystagmus, ataxia, gingival hyperplasia, cytopenias, teratogenic

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Calcium Channel Blockers (CCBs) in Mood Disorders

Rationale & Agents

• L-type Ca(^{2+}) channel genes linked to bipolar, schizophrenia, MDD
• Agents: verapamil, nimodipine, nifedipine, isradipine, amlodipine, diltiazem, nicardipine, nisoldipine, nitrendipine

Clinical Use

• Verapamil & nimodipine evidence for maintenance & ultra-rapid cycling; may prevent antidepressant-induced mania
• Dosing examples: verapamil start 40\,\text{mg TID} $(max$ 120\,\text{mg TID} $); nimodipine$ 60\,\text{mg q4h}$$; monitor BP/HR

Adverse Effects

• Vasodilatory ↦ dizziness, headache, edema, tachycardia
• CV conduction block (verapamil/diltiazem), constipation
• Drug interactions: verapamil ↑ carbamazepine, digoxin; avoid with β-blockers, lithium (neurotoxicity/deaths reported)