Mood Stabilizers Bipolar Disorder (Etiology) Monoamines (NA, DA) Mania Drugs Monoamine activity Exacerbate mania Mood

od Stabilizing Agents Lithium Anticonvulsants y Sodium valproate y Carbamazepine y Lamotrigine y Gabapentin y Topiramate Antipsychotics y Olanzepine y Risperidone Benzodiazepines y Clonazepam y Lorazepam Others y Calcium channel blockers y Antidepressants Alternative Treatment ECT Consider when y Other therapies failed y Seriously ill, unable to take medication y Suicidal y Pregnant Natural products Long chain, unsaturated omega-3 fatty acids (fish oils) (DHA, linoleic acids) Choice of Regimen Presentation Mild-mod Mania Mixed episode

Depression Monoamine activity Relieve mania

Mod-severe Mania Mixed episode Mod-severe depressive episode

Preferred Strategy Lithium BDZ VPA Atypical antipsychotics Lithium Lamotrigine Lithium Lamotrigine + Antidepressants

Alternative Strategy CBZ Lamotrigine +/- BDZ CBZ VPA CBZ VPA

Lithium Lithium (Li ) Share same property as Na+ (handled by body as Na+) y Na+ loading enhance Li+ excretion y Na+ depletion promotes Li+ retention Mood stabilizer 1st line y Acute mania y Prophylaxis Bipolar I, Bipolar II Other Uses y Adjunct, alternative to antidepressants (in severe recurrent depression) y Bulimia y Aggressive behaviour Response is all-or-none phenomenon MOA (Unknown)(3 Theories) Effects on Electrolytes, Ion transport Replace Na+ in supporting single AP (but not pumped out by Na+/K+ ATPase) Unable to maintain membrane potential Effects on Neurotransmitters Inhibits release of NA, DA (antimanic effect) Enhance 5HT release Choline uptake into nerve terminals (Ach) nd Effects on 2 messengers In manic states, enhance stimulation of adrenergic, dopaminergic receptors Action Modes Affect actions of ADH polyuria TSH hypothyroidism (subclinical) Pharmacokinetics Therapeutic index Therapeutic drug monitoring Day 5, 12h after last dose Monitoring 2-4 monthly Discontinuation gradually y Abrupt withdrawal lead to mania y CBZ, VPA may be added while Li+ is gradually discontinued Preparations Salt 2 Carbonate (CO3 ) (available in Msia) y y Citrate as inert vehicles Different salt has different bioavailability (200mg LiCO3 = 509mg Li citrate) Adverse Reactions Therapeutic Level Fine tremors Polyuria, polydipsia Nausea Dysphoria ( reaction time)
+

Lithium Interactions Li+ retention ( Toxicity risk) Li+ excretion Hyponatremia Hypernatremia, Saline Sodium bicarbonate y dehydration Acetazolamide y vomiting Theophylline, aminophylline y diarrhoea Triamterene Thiazides (Na+ depletion) Drugs that promote renal excretion of ACE inhibitors Li+ are of little use in toxicity when NSAIDs kidney is unable to function y indomethacin y ibuprofen Coadministration ( Neurotoxicity risk) Haloperidol Phenothiazines CBZ Li+ and ECT interaction Memory impairment Delirium (Li+ should be discontinued before ECT) Precautions Maintain adequate fluid intake (avoid dehydration, alcohol) Avoid dietary changes (change Na+ levels) Not to change different brand (bioavailability) Treatment is for long term (do not stop once feeling well)

Toxic Levels Coarse hand tremor Diarrhoea, vomiting Drowsiness, muscle weakness Neurological damages y Mental confusion y Hyperreflexia y Dysarthria Seizures, coma, death

Nephrogenic diabetes insipidus Renal tubular damage Hypothyroidism Cardiac arrhythmia Sexual dysfunction Allergic reactions dermatitis, vasculitis, acneiform Weight Teratogenicity (Ebstein anomaly) (avoid 1st trimester) Management of Li+ Toxicity Mild Moderate Hydration Normal saline infusion Na+ loading Investigations before Li+ therapy Creatinine clearance (CrCl), RFT ECG (> 40y/o) Thyroid function test (TFT) FBC (Li+ causes leucocytosis)

Severe Haemodialysis

Sodium Valproate (VPA) MOA Membrane excitability (block voltage gated Na+ channel) GABA content in brain Clinical Uses 1st line of treatment (besides Li+) Antimanic effect equivalent to Li+ during early weeks of treatment Efficacious in Li+ resistant manic (mixed episode, mania with psychosis) Combined with Li+ in refractory cases Efficacy Mania (best) Bipolar maintenance (less well) Bipolar depression (least well) Pharmacokinetics Oral (rapid, complete absorption) Highly protein bound (90%) Adverse Effects Transient GIT effects y Gastritis y Nausea y Vomiting CNS effects y Sedation y Tremor y Memory y Motor impairment Alopecia, curling of hair Hepatotoxicity Teratogenicity (spina bifida) Drug Interactions Inhibits drugs metabolized by y CYP2C9 (phenytoin, phenobarbital) y UGT (lamotrigine, lorazepam) Displaces drugs bound to albumin (phenytoin)

Carbamazepine (CBZ) MOA Membrane excitability (block voltage gated Na+ channel) Glutamate release Efficacy Bipolar maintenance (best) Bipolar depression (less well) Mania (least well) Pharmacokinetics Good oral absorption (rate of absorption varies) Protein bound (75%) Adverse Effects CNS ataxia, nystagmus, dysarthria, vertigo GIT nausea Idiosyncratic blood dyscrasia aplastic anaemia, agranulocytosis Hypersensitivity reactions skin rash H2O retention hyponatraemia Drug Interactions Metabolism of other drugs (enzyme inducer) y Phenytoin y OCP y Warfarin y Corticosteroids y Haloperidol Metabolism inhibited by y Erythromycin y Cimetidine y Isoniazid y Fluoxatine VPA level (VPA accelerate metabolism of CBZ to metabolite)

Lamotrigine MOA Membrane excitability (block voltage gated Na+ channel) Glutamate release Efficacy Bipolar maintenance (best) Bipolar depression (less well) Mania (least well)