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Antimanic-Mood Stabilizers: Lithium Anticonvulsants

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) ? talkativeFlight of ideas, racing thoughtsDistractibility? goal-directed activity / psy

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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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