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Antimanic-Mood Stabilizers: Lithium & Anticonvulsants

Antimanic-Mood Stabilizers: Lithium & Anticonvulsants. Cesar A. Soutullo, M.D. UC-3 Psychopharm Lectures. Bipolar Disorder (Manic-Depressive Illness). Mania: 1 wk of (hypomania 4 days) Elevated, Expansive, Irritable Mood +3 (4): inflated self-esteem or Grandiosity

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Antimanic-Mood Stabilizers: Lithium & Anticonvulsants

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  1. Antimanic-Mood Stabilizers:Lithium & Anticonvulsants Cesar A. Soutullo, M.D. UC-3 Psychopharm Lectures

  2. Bipolar Disorder (Manic-Depressive Illness) • Mania: 1 wk of (hypomania 4 days) • Elevated, Expansive, Irritable Mood +3 (4): • inflated self-esteem or Grandiosity •  need for sleep (rested with <3hrs) •  talkative • Flight of ideas, racing thoughts • Distractibility •  goal-directed activity / psychomotor agit. •  pleasurable activ. w painful consequence (spending, sex, investments)

  3. Bipolar Disorder • Depressive episode: 2 wks (5 Total Sx) • Depressed (Irritable in kids) • Anhedonia •  /  appetite •  /  sleep • psychomotor agitation /retardation • Fatigue /  energy • worthless / guilt •  concentration / indecisive • suicidal ideation

  4. Bipolar Disorder • BP-I: Mania (with/without Depr) • M or M-D • BP-II: Depression and hypomania • D-m • Cyclothymia: m-d • Mixed episode: M + D (same time) • Rapid cycling: 4 or more episodes / yr.

  5. Mood Stabilizers • Lithium • Anticonvulsants • Valproic Acid [Depakote] • Carbamazepine [Tegretol] • New Anticonvulsants (?): • Lamotrigine [Lamictal] • Topiramate [Topamax] • Gabapentin [Neurontin] • Antipsychotics • Classic (Haloperidol) • Novel (Clozapine, Olanzapine)

  6. Lithium: History • Used since mid-XIX: gout, diabetes... • For BP since 1960’s, FDA ‘74 • Effective Antimanic, mood stab, BP depr. • If Discontinued relapse near 100% 2 yr • Therapeutic Levels: 0.6-1.5 mEq/ml • 0.3-0.8 in elderly • Same levels for prophylaxis • Narrow therapeutic index

  7. Lithium: Molecular Biology[Moore, McNamara, Trevor-Young, Manji] • RecepGProtcAMPInosCREBDNA • Inositol: • CaStabilize Membr: Firing vpa • Activ Prot-Kinase-C (Tamoxifen PKc inhib) vpa • MARKS binds to calmoduline inside Memb. vpa • CREB Phosphorilation vpa • Activ DNA Neuroprotec Prots (BCL-2) vpa • NAA: marker of neuronal viability in Grey Matter • Neuroprotective-Neuronal Regeneration • VPA GRPF78 protect from malformed prots, buffers Ca • Prots cytoskeletal re-structuring

  8. Lithium: Pharmacology • Not liver metabolized. Kidney excreted • Not protein bound • 70-80% reabsorb prox Tubule, Na comp: Na (dehydr, thiazide diuret) Li level • Excretion related to GFR:elder preg • Half-life 24 hrs (HS), steady state 5 days • Peak Levels 2 hrs, SR 4-4.5 • fast release: N/V, slow rel: diarrhea

  9. Predictors: Good Li Response • Past Li response (personal or family) • Euphoric, pure (classic) mania • Sequence Mania-Depr-Euthymia • No psychosis • No Rapid Cycling

  10. Predictors: Poor Li Response[Good response to anticonvulsants] • Mixed mania (adolescents) • Irritable mania • Secondary mania (geriatric) • Psychotic Sx • Rapid Cycling • Depression-Mania-Euthymia • Comorbid substance abuse

  11. Lithium: Common Side Effects • GI distress: upper LiCO3, lower GI SR. • Polyuria / polydipsia • Sedation-lethargy • Cognitive (memory, concentr, slow) • Wt. Gain • Poor coordination, tremor • Skin (worse acne)

  12. Lithium: Serious SE • Renal • nephrogenic diabetes insipidus • tubular interstitial nephritis • Hypothyroidism • Psoriasis (onset or worsening) • Cardiac: EKG flat T, SA dysfx, tachicardia • Li Tox. N/V/D, delirium, ataxia, stupor • Tx dyalisis if >3.0, correct fluid-electrolites

  13. Li: Interactions & Use • Li levels: • diuretics, • NSAIDs (ASA, sulindac OK) • ACE-inhibitors • Starting: • Baseline Renal, TFT, HCG, EKG >40yo, UA, weight, medical Hx • 300-600 mg/day divided doses • Levels in 5 days • Increase 300-900 mg/day q 5-7 days

  14. Valproate [Depakote] • FDA Sz ‘78, BP ‘96 • Effective antimanic, BP depression • Therapeutic effect 2 d. level 50-125 mg/l • oral loading 20-30 mg/kg/day • Elderly & hypomania responde to lower? • Mixed, rapid cycling, schizoaffective • Closed had injury, EEG abnormality

  15. Valproate • Increases GABA levels • Effects 2nd Messenger, Prot-Kinase-C • 80-95 % Protein bound • Liver Metabolized p450 (inhibitor) • Half life 8-17 hrs

  16. VPA: Common Side Effects • GI distress • Sedation • Liver transaminase elevation • Tremor • Hair loss • Weight gain-increased appetite • Thrombocitopenia (elders) • Teratogenic: neural tube, cranio-facial

  17. VPA: Less Common SE • Neutropenia • Coagulopathies, platelet Function • endocrine abnormalities • Amenorrhea, policystic ovary? • Hypothyroidism • Hypocortisolemia

  18. VPA: Rare Dangerous SE • Idiosincratic Hepatic Failure • lethargy, anorexia, N/V, jaund, bleed, edema • Risk: <2 y.o., many anticonvuls, Dev. Delay • Remote risk in >10yo psychiatric patients • Acute Hemorrhagic Pancreatitis • Bone Marrow Supression

  19. VPA: Interactions • Prot-bound drugs (ASA, phenobarb, CBZ, warfarin, digoxin) free-VPA • VPA (p450) levels of liver-metab drugs: • TCAs, CBZ, phenobarb, phenitoin, lamotrig • CBZ(p450 inducer) VPA levels • p450 inhibitors (fluoxetine) VPA levels

  20. VPA Use • Baseline: • Medical Hx, CBC-diff, LFT (LDH, SGOT, SGPT, bili, Alk. Phos, GGT), HCG, PT,PTT if bleeding abnorm, amylase? • Warn about hepatic, pancreatic, hematologic, teratogenic risks • Load 20 mg/kg/day, lower outpt hypom • add a ZERO to wt in pounds: 150+0=1,500 mg/d • Level 50-120 (check in 1-5 days) • Monitor LFT, CBC

  21. Carbamazepine [Tegretol] • FDA Trig Neuralg ‘68, TLE ‘74 • Effective antimanic, Tx-refract Depr • Onset 2 wks, antidepr 4-6 wk • Ther. Levels: 4-12 or 15 mg/L • Half life decreases to 12-17 hrs • p450 liver induction

  22. CBZ: Side Effects • Less cognitive probl than Li • Less Wt gain, hair loss, tremor than VPA • Neuro: Diplopia,blurr vision, fatigue/sed • GI: Naus/diarr, Dry mouth • Leukopenia, thrombocitopenia, rash • LFT • Agranulocytosis (, Liver fail, pancreatitis, Stevens-Johnson (exfol skin), neuroteratogenic

  23. CBZ: Interactions (Many) • p450 induction, CBZlevels of: CBZ, VPA, lamotrig, TCAs, prednisone, theophiline, warfarin, benzos, & oral contraceptives • p450 inhibitors: acetazolamide, Ca-channe blockers [diltiazem & verapamil, but not nifedipine], danazol, erythromycin, fluoxetine, isoniazid, VPA all CBZ levels

  24. CBZ: Use • Baseline: Medical Hx, CBC+diff,LFT, Renal, TFT, HCG, ferritin • Start low: • 100-400 mg/day, • 100-200 mg every several days, bid (occasionally qd) • Follow CBC, LFT • clinical monitoring more effective than labs

  25. Future Mood Stabilizers? • Novel Antipsychotics • Olanzapine: effective (2 DBPC trials) • Quetiapine? • New Anticonvulsants • Lamotrigine: ?Effective BP & depr, 10%rash, levels by CBZ, by VPA • Topiramate: wt loss, 1.5% renal stones • Gabapentin: effective?? (open reports, add-on) • Tiagabine, Vigabatril Ca • Others: • Ca-channel blockers • Tamoxifen Prot Kinase-C inhibitor

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