Antimanic-Mood Stabilizers:Antimanic-Mood Stabilizers:Lithium & AnticonvulsantsLithium & Anticonvulsants

Cesar A. Soutullo, M.D.Cesar A. Soutullo, M.D.

UC-3 Psychopharm LecturesUC-3 Psychopharm Lectures

Bipolar Disorder Bipolar Disorder (Manic-Depressive Illness)(Manic-Depressive Illness)

• Mania: 1 wk of (hypomania 4 days)Mania: 1 wk of (hypomania 4 days)– Elevated, Expansive, Irritable MoodElevated, Expansive, Irritable Mood +3 (4): +3 (4):

• inflated self-esteem or Grandiosityinflated self-esteem or Grandiosity need for sleep (rested with <3hrs) need for sleep (rested with <3hrs) talkativetalkative

• 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 pleasurable activ. w painful consequence

(spending, sex, investments)(spending, sex, investments)

Bipolar Disorder Bipolar Disorder

• Depressive episode: 2 wks (5 Total Sx)Depressive episode: 2 wks (5 Total Sx)• DepressedDepressed (Irritable in kids) (Irritable in kids)• AnhedoniaAnhedonia / / appetite appetite / / sleep sleep• psychomotor agitation /retardationpsychomotor agitation /retardation• Fatigue / Fatigue / energy energy• worthless / guiltworthless / guilt concentration / indecisiveconcentration / indecisive• suicidal ideationsuicidal ideation

Bipolar DisorderBipolar Disorder

• BP-I: Mania (with/without Depr)BP-I: Mania (with/without Depr)– M or M-D M or M-D

• BP-II: Depression and hypomaniaBP-II: Depression and hypomania– D-mD-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.

Mood StabilizersMood Stabilizers• LithiumLithium

• AnticonvulsantsAnticonvulsants– Valproic Acid [Depakote]Valproic Acid [Depakote]– Carbamazepine [Tegretol]Carbamazepine [Tegretol]– New Anticonvulsants (?):New Anticonvulsants (?):

• Lamotrigine [Lamictal]Lamotrigine [Lamictal]• Topiramate [Topamax]Topiramate [Topamax]• Gabapentin [Neurontin]Gabapentin [Neurontin]

• AntipsychoticsAntipsychotics– Classic (Haloperidol)Classic (Haloperidol)– Novel (Clozapine, Olanzapine)Novel (Clozapine, Olanzapine)

Lithium: HistoryLithium: 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: 0.6-1.5 mEq/mlTherapeutic Levels: 0.6-1.5 mEq/ml– 0.3-0.8 in elderly0.3-0.8 in elderly– Same levels for prophylaxisSame levels for prophylaxis– Narrow therapeutic indexNarrow therapeutic index

Lithium: Molecular BiologyLithium: Molecular Biology[Moore, McNamara, Trevor-Young, Manji][Moore, McNamara, Trevor-Young, Manji]

• RecepRecepGProtGProtcAMPcAMPInosInosCREBCREBDNADNAInositol:Inositol:

CaCaStabilize Membr: Stabilize Membr: Firing Firing vpavpa Activ Prot-Kinase-C (Tamoxifen PKc inhib) Activ Prot-Kinase-C (Tamoxifen PKc inhib) vpavpa

• MARKS binds to calmoduline inside Memb. MARKS binds to calmoduline inside Memb. vpavpa

CREB Phosphorilation CREB Phosphorilation vpavpa

Activ DNA Neuroprotec Prots (BCL-2) Activ DNA Neuroprotec Prots (BCL-2) vpavpa NAA: marker of neuronal viability in Grey MatterNAA: marker of neuronal viability in Grey Matter

• Neuroprotective-Neuronal RegenerationNeuroprotective-Neuronal Regeneration• VPAVPA GRPF78 protect from malformed prots, buffers Ca GRPF78 protect from malformed prots, buffers Ca

Prots cytoskeletal re-structuring Prots cytoskeletal re-structuring

Lithium: PharmacologyLithium: Pharmacology

• Not liver metabolized. Kidney excretedNot liver metabolized. Kidney excreted• Not protein boundNot protein bound• 70-80% reabsorb prox Tubule, Na comp: 70-80% reabsorb prox Tubule, Na comp:

Na (dehydr, thiazide diuret) Na (dehydr, thiazide diuret) Li levelLi level• Excretion related to GFR:Excretion related to GFR:elder elder pregpreg• 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 4-4.5

– fast release: N/V, slow rel: diarrheafast release: N/V, slow rel: diarrhea

Predictors: Good Li ResponsePredictors: Good Li Response

• Past Li response (personal or family)Past Li response (personal or family)

• Euphoric, pure (classic) mania Euphoric, pure (classic) mania

• Sequence Mania-Depr-EuthymiaSequence Mania-Depr-Euthymia

• No psychosisNo psychosis

• No Rapid CyclingNo Rapid Cycling

Predictors: Poor Li ResponsePredictors: Poor Li Response[Good response to anticonvulsants][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

Lithium: Common Side EffectsLithium: 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)

Lithium: Serious SELithium: Serious SE• Renal Renal

– nephrogenic diabetes insipidusnephrogenic diabetes insipidus– tubular interstitial nephritistubular interstitial nephritis

• HypothyroidismHypothyroidism

• Psoriasis (onset or worsening)Psoriasis (onset or worsening)

• Cardiac: EKG flat T, SA dysfx, Cardiac: EKG flat T, SA dysfx, tachicardiatachicardia

• Li ToxLi Tox. N/V/D, delirium, ataxia, stupor. N/V/D, delirium, ataxia, stupor– Tx dyalisis if >3.0, correct fluid-electrolitesTx dyalisis if >3.0, correct fluid-electrolites

Li: Interactions & UseLi: Interactions & UseLi 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, Baseline Renal, TFT, HCG, EKG >40yo, UA,

weight, medical Hx weight, medical Hx – 300-600 mg/day divided doses300-600 mg/day divided doses– Levels in 5 daysLevels in 5 days– Increase 300-900 mg/day q 5-7 daysIncrease 300-900 mg/day q 5-7 days

Valproate [Depakote]Valproate [Depakote]

• FDA Sz ‘78, BP ‘96FDA Sz ‘78, BP ‘96

• Effective antimanic, BP depressionEffective antimanic, BP depression

• Therapeutic effect 2 d. level 50-125 mg/lTherapeutic effect 2 d. level 50-125 mg/l– oral loading 20-30 mg/kg/dayoral loading 20-30 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

ValproateValproate

• Increases GABA levelsIncreases GABA levels

• Effects 2nd Messenger, Prot-Kinase-CEffects 2nd Messenger, Prot-Kinase-C

• 80-95 % Protein bound80-95 % Protein bound

• Liver Metabolized p450 (inhibitor)Liver Metabolized p450 (inhibitor)

• Half life 8-17 hrsHalf life 8-17 hrs

VPA: Common Side EffectsVPA: 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

VPA: Less Common SEVPA: Less Common SE

• NeutropeniaNeutropenia

• Coagulopathies, Coagulopathies, platelet Functionplatelet Function

• endocrine abnormalitiesendocrine abnormalities– Amenorrhea, policystic ovary?Amenorrhea, policystic ovary?– HypothyroidismHypothyroidism– HypocortisolemiaHypocortisolemia

VPA: Rare Dangerous SEVPA: Rare Dangerous SE

• Idiosincratic Hepatic FailureIdiosincratic Hepatic Failure– lethargy, anorexia, N/V, jaund, bleed, edemalethargy, anorexia, N/V, jaund, bleed, edema– Risk: <2 y.o., many anticonvuls, Dev. DelayRisk: <2 y.o., many anticonvuls, Dev. Delay– Remote risk in >10yo psychiatric patientsRemote risk in >10yo psychiatric patients

• Acute Hemorrhagic PancreatitisAcute Hemorrhagic Pancreatitis

• Bone Marrow SupressionBone Marrow Supression

VPA: InteractionsVPA: Interactions

• Prot-bound drugs (ASA, phenobarb, CBZ, Prot-bound drugs (ASA, phenobarb, CBZ, warfarin, digoxin) warfarin, digoxin) free-VPAfree-VPA

• VPA (p450) VPA (p450) levels of liver-metab drugs:levels of liver-metab drugs:– TCAs, CBZ, phenobarb, phenitoin, lamotrigTCAs, CBZ, phenobarb, phenitoin, lamotrig

• CBZ(p450 inducer) CBZ(p450 inducer) VPA levelsVPA levels

• p450 inhibitors (fluoxetine) p450 inhibitors (fluoxetine) VPA levelsVPA levels

VPA UseVPA Use• Baseline:Baseline:

– Medical Hx, CBC-diff, LFT (LDH, SGOT, Medical Hx, CBC-diff, LFT (LDH, SGOT, SGPT, bili, Alk. Phos, GGT), HCG, PT,PTT if SGPT, bili, Alk. Phos, GGT), HCG, PT,PTT if bleeding abnorm, amylase?bleeding abnorm, amylase?

– Warn about hepatic, pancreatic, hematologic, Warn about hepatic, pancreatic, hematologic, teratogenic risksteratogenic 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 add a ZERO to wt in pounds: 150+0=1,500

mg/dmg/d

• Level 50-120 (check in 1-5 days)Level 50-120 (check in 1-5 days)• Monitor LFT, CBCMonitor LFT, CBC

Carbamazepine [Tegretol]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 12-17 hrsHalf life decreases to 12-17 hrs– p450 liver inductionp450 liver induction

CBZ: Side EffectsCBZ: 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, rashLFTLFT• Agranulocytosis (, Liver fail, pancreatitis, Agranulocytosis (, Liver fail, pancreatitis,

Stevens-JohnsonStevens-Johnson (exfol skin), (exfol skin), neuroteratogenicneuroteratogenic

CBZ: Interactions (Many)CBZ: Interactions (Many)

• p450 induction, CBZp450 induction, CBZlevels of: CBZ, VPA, levels of: CBZ, VPA, lamotrig, TCAs, prednisone, theophiline, lamotrig, TCAs, prednisone, theophiline, warfarin, benzos, & oral contraceptiveswarfarin, benzos, & oral contraceptives

• p450 inhibitorsp450 inhibitors: acetazolamide, Ca-channe : acetazolamide, Ca-channe blockers [diltiazem & verapamil, but not blockers [diltiazem & verapamil, but not nifedipine], danazol, erythromycin, nifedipine], danazol, erythromycin, fluoxetine, isoniazid, VPA all fluoxetine, isoniazid, VPA all CBZ levelsCBZ levels

CBZ: UseCBZ: Use

• Baseline: Medical Hx, CBC+diff,LFT, Baseline: Medical Hx, CBC+diff,LFT, Renal, TFT, HCG, ferritinRenal, TFT, HCG, ferritin

• Start low:Start low:– 100-400 mg/day, 100-400 mg/day, 100-200 mg every several days, bid 100-200 mg every several days, bid

(occasionally qd)(occasionally qd)

• Follow CBC, LFTFollow CBC, LFT– clinical monitoring more effective than labsclinical monitoring more effective than labs

Future Mood Stabilizers?Future Mood Stabilizers?• Novel AntipsychoticsNovel Antipsychotics

– Olanzapine: effective (2 DBPC trials)Olanzapine: effective (2 DBPC trials)– Quetiapine?Quetiapine?

• New AnticonvulsantsNew Anticonvulsants• Lamotrigine: ?Effective BP & depr, 10%rash, levels Lamotrigine: ?Effective BP & depr, 10%rash, levels

by CBZ, by CBZ, by VPAby 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