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

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Presentation on theme: "Antimanic-Mood Stabilizers: Lithium & Anticonvulsants Cesar A. Soutullo, M.D. UC-3 Psychopharm Lectures."— Presentation transcript:

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

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

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

5 Mood Stabilizers LithiumLithium AnticonvulsantsAnticonvulsants –Valproic Acid [Depakote] –Carbamazepine [Tegretol] –New Anticonvulsants (?): Lamotrigine [Lamictal]Lamotrigine [Lamictal] Topiramate [Topamax]Topiramate [Topamax] Gabapentin [Neurontin]Gabapentin [Neurontin] AntipsychoticsAntipsychotics –Classic (Haloperidol) –Novel (Clozapine, Olanzapine)

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

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

8 Lithium: Pharmacology Not liver metabolized. Kidney excretedNot liver metabolized. Kidney excreted Not protein boundNot protein bound 70-80% reabsorb prox Tubule, Na comp:  Na (dehydr, thiazide diuret)  Li level70-80% reabsorb prox Tubule, Na comp:  Na (dehydr, thiazide diuret)  Li level Excretion related to GFR:  elder  pregExcretion related to GFR:  elder  preg Half-life 24 hrs (HS), steady state 5 daysHalf-life 24 hrs (HS), steady state 5 days Peak Levels 2 hrs, SR 4-4.5Peak Levels 2 hrs, SR –fast release: N/V, slow rel: diarrhea

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

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

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

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

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

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

15 Valproate Increases GABA levelsIncreases GABA levels Effects 2nd Messenger, Prot-Kinase-CEffects 2nd Messenger, Prot-Kinase-C % Protein bound80-95 % Protein bound Liver Metabolized p450 (inhibitor)Liver Metabolized p450 (inhibitor) Half life 8-17 hrsHalf life 8-17 hrs

16 VPA: Common Side Effects GI distressGI distress SedationSedation Liver transaminase elevationLiver transaminase elevation TremorTremor Hair lossHair loss Weight gain-increased appetiteWeight gain-increased appetite Thrombocitopenia (eldersThrombocitopenia (elders) Teratogenic: neural tube, cranio-facial

17 VPA: Less Common SE NeutropeniaNeutropenia Coagulopathies,  platelet FunctionCoagulopathies,  platelet Function endocrine abnormalitiesendocrine abnormalities –Amenorrhea, policystic ovary? –Hypothyroidism –Hypocortisolemia

18 VPA: Rare Dangerous SE Idiosincratic Hepatic FailureIdiosincratic 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 PancreatitisAcute Hemorrhagic Pancreatitis Bone Marrow SupressionBone Marrow Supression

19 VPA: Interactions Prot-bound drugs (ASA, phenobarb, CBZ, warfarin, digoxin)  free-VPAProt-bound drugs (ASA, phenobarb, CBZ, warfarin, digoxin)  free-VPA VPA (p450)  levels of liver-metab drugs:VPA (p450)  levels of liver-metab drugs: –TCAs, CBZ, phenobarb, phenitoin, lamotrig CBZ(p450 inducer)  VPA levelsCBZ(p450 inducer)  VPA levels p450 inhibitors (fluoxetine)  VPA levelsp450 inhibitors (fluoxetine)  VPA levels

20 VPA Use Baseline: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 hypomLoad 20 mg/kg/day, lower outpt hypom –add a ZERO to wt in pounds: 150+0=1,500 mg/d Level (check in 1-5 days)Level (check in 1-5 days) Monitor LFT, CBCMonitor LFT, CBC

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

22 CBZ: Side Effects Less cognitive probl than LiLess cognitive probl than Li Less Wt gain, hair loss, tremor than VPALess Wt gain, hair loss, tremor than VPA Neuro: Diplopia,blurr vision, fatigue/sedNeuro: Diplopia,blurr vision, fatigue/sed GI: Naus/diarr, Dry mouthGI: Naus/diarr, Dry mouth Leukopenia, thrombocitopenia, rashLeukopenia, thrombocitopenia, rash  LFT  LFT Agranulocytosis (, Liver fail, pancreatitis, Stevens-Johnson (exfol skin), neuroteratogenicAgranulocytosis (, 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 contraceptivesp450 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 levelsp450 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, ferritinBaseline: Medical Hx, CBC+diff,LFT, Renal, TFT, HCG, ferritin Start low:Start low: – mg/day, –  mg every several days, bid (occasionally qd) Follow CBC, LFTFollow CBC, LFT –clinical monitoring more effective than labs

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


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