1

Bipolar Disorder

Pathways

2

from JamisonKEY:H= Asylum or psychiatric hospital; S= Suicide; SA = Suicide Attempt

Writers Hans Christian Andersen, Honore de Balzac, James Barrie, William Faulkner (H), F. Scott Fitzgerald (H), Ernest Hemingway (H, S), Hermann Hesse (H, SA), Henrik Ibsen, Henry James, William James, Samuel Clemens (Mark Twain), Joseph Conrad (SA), Charles Dickens, Isak Dinesen (SA), Ralph Waldo Emerson, Herman Melville, Eugene O'Neill (H, SA), Mary Shelley, Robert Louis Stevenson, Leo Tolstoy, Tennessee Williams (H), Mary Wollstonecraft (SA), Virginia Woolf (H, S)

Composers Hector Berlioz (SA), Anton Bruckner (H), George Frederic Handel, Gustav Holst, Charles Ives, Gustav Mahler, Modest Mussorgsky, Sergey Rachmaninoff, Giocchino Rossini, Robert Schumann (H, SA), Alexander Scriabin, Peter Tchaikovsky

Nonclassical composers and musicians Irving Berlin (H), Noel Coward, Stephen Foster, Charles Mingus (H), Charles Parker (H, SA), Cole Porter (H)

Poets William Blake, Robert Burns, George Gordon, Lord Byron, Samuel Taylor Coleridge, Hart Crane (S) , Emily Dickinson, T.S. Eliot (H), Oliver Goldsmith, Gerard Manley Hopkins, Victor Hugo, Samuel Johnson, John Keats, Vachel Lindsay (S), James Russell Lowell, Robert Lowell (H), Edna St. Vincent Millay (H), Boris Pasternak (H), Sylvia Plath (H, S), Edgar Allan Poe (SA), Ezra Pound (H), Anne Sexton (H, S), Percy Bysshe Shelley (SA), Alfred, Lord Tennyson, Dylan Thomas, Walt Whitman

Artists Richard Dadd (H), Thomas Eakins, Paul Gauguin (SA), Vincent van Gogh (H, S), Ernst Ludwig Kirchner (H, S), Edward Lear, Michelangelo, Edvard Meunch (H), Georgia O'Keeffe (H), George Romney, Dante Gabriel Rossetti (SA)

DIAGNOSIS

DSM-IV-TR

Five types of episodes

Four subtypes Four severity levels Three course

specifiers

American Psychiatric Association. (2000). Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition-Text Revision. Washington, DC: Author.

Manic Episode

Symptoms:1. Inflated self-esteem or grandiosity2. Decreased need for sleep 3. Pressured speech or more talkative than

usual4. Flight of ideas or racing thoughts5. Distractibility6. Psychomotor agitation or increase in

goal-directed activity7. Hedonistic interests

Hypomanic Episode

Similarities with Manic Episode = Same symptoms

Differences = Length of timeImpairment not as severe

Hypomanic Episode

Similarities with Manic Episode = Same symptoms

Differences = Length of timeImpairment not as severe

Major Depressive Episode

Symptoms:1. Depressed mood (in children can be irritable)2. Diminished interest in activities3. Significant weight loss or gain4. Insomnia or hypersomnia5. Psychomotor agitation or retardation6. Fatigue/loss of energy7. Feelings of worthlessness/inappropriate guilt8. Diminished ability to think or

concentrate/indecisiveness9. Suicidal ideation or suicide attempt

Mixed Episode

Both Manic and Major Depressive Episode criteria are met nearly every day for a least a one week period.

SubtypesBipolar Disorder I = more classic form;

clear episodes of depression & mania

Bipolar Disorder II = presents with less intense and often unrecognized manic phases

Cyclothymia = chronic moods of hypomania & depression, often evolves into a more serious type

Bipolar Disorder Not Otherwise Specified (NOS) = largest group of individuals

EPIDEMIOLOGY

Prevalence

Estimated between 3-6%Subsyndromal bipolar disorderEqual distribution across gender

variablesAverage age @ onset = 20 years old

Course

Initial cycle typically major depressive episode

RecoveryRelapseRapid Cycling

Rapid cycling=4 episodes/yearUltrarapid cycling=5-364 episodes/yearUltradian cycling=>365 episodes/year

Age at Onset

Pediatric, prepubertal, or early adolescent (prior to age 12)

Adolescent (12 - 18 years)Adult onset (+ 18 years)

IMPAIRMENTS

Comorbidity

Attention Deficit Hyperactivity Disorder (ADHD)Between 60-80%

Criteria Comparison

Bipolar Disorder (mania)1. More talkative

than usual, or pressure to keep talking

2. Distractibility3. Increase in goal

directed activity or psychomotor agitation

ADHDADHD1.1. Often talks Often talks

excessivelyexcessively2.2. Is often easily Is often easily

distracted by distracted by extraneous stimuliextraneous stimuli

3.3. Is often “on the Is often “on the go” or often acts go” or often acts as if “driven by a as if “driven by a motor”motor”

Differentiation= elated mood, grandiosity, decreased need for sleep, hypersexuality, and irritable mood.

Comorbidity(cont.)

Oppositional Defiant Disorder (ODD) & Conduct Disorder (CD)70-75%

Substance Abuse40-50%

Anxiety Disorders35-40%

Suicidal Behaviors

Prevalence of suicide attempts40-45%

Age of first attemptMultiple attemptsSeverity of attemptsSuicidal ideation

Cognitive Deficits

Executive FunctionsAttentionMemorySensory-Motor IntegrationNonverbal Problem-SolvingAcademic Deficits

Mathematics

Psychosocial Deficits

Relationships PeersFamily members

Recognition and Regulation of EmotionSocial Problem-SolvingSelf-Esteem Impulse Control

TREATMENT APPROACHES

Psychopharmacological

DEPRESSIONMood Stabilizers

Anti-Obsessional

Anti-Depressant

Atypical Antipsychotics

MANIAMANIA Mood StabillizersMood Stabillizers

Aypical AntipsychoticsAypical Antipsychotics

Anti-AnxietyAnti-Anxiety

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 [Good response to anticonvulsants]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, tachicardiaCardiac: EKG flat T, SA dysfx, tachicardia• 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 OK)NSAIDs (ASA OK)• ACE-inhibitorsACE-inhibitors

• Starting:Starting:– Baseline Renal, TFT, HCG, EKG, UA, weight, Baseline Renal, TFT, HCG, EKG, UA, weight,

medical Hx 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 Valproate

• 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

Valproate Valproate

• 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

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, bleed, edemalethargy, anorexia, N/V, bleed, edema– Risk: <2 yo, many anticonvuls, Dev. DelayRisk: <2 yo, 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 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• Level 50-120 (check in 1-5 days)Level 50-120 (check in 1-5 days)• Monitor LFT, CBCMonitor LFT, CBC

CarbamazepineCarbamazepine

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, levels of: CBZ, VPA, lamotrig, TCAs, prednisone, VPA, lamotrig, TCAs, prednisone, theophiline, warfarin, benzos, & oral theophiline, warfarin, benzos, & oral contraceptivescontraceptives

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

Therapy

PsychoeducationFamily InterventionsCognitive-Behavioral TherapyRAINBOW Program Interpersonal and Social Rhythm TherapySchema-focused Therapy

Biological mechanisms

Macro Micro

MACRO

Which parts of the brain are relevant to BP

▲ volumes

amygdala ↑ at later phases of the disease (drugs ?)

(Strakowski, 2012) ↓ at the first episode (Bitter, 2011)

VPC and striatum ↓ volume inversely correlated with age (Blumberg,

2006; Sanches, 2009)

Key points

Subtle abnormalities in the brains of BP

Preservation of total cerebral volume with regional grey and white matter changes in

prefrontal, midline and limbic networks

limits

Findings are not consitent Medications Illness duration Sample sizes

Img studies do not test the “activity” per se but a ▲ of the activity in ≠ experimental conditions

neurodevelopment

BP begins in late adolescence BP is progressive

pruning

Increased brain volumes in prefrontal and parahippocampal cortices

Red → frontalBlack → parietalPurple → termporalOccipital → green

MICRO

Which molecular cascades are relevant to BD ?

Wnt IP GSK3

Wnt IP GSK3

Axon guidance, planar cell position

A network of proteins: signals from receptors to DNA expression

Controls beta-catenin (turns on the expression of genes):

Wnt: ▲ phosphorylation of beta-catenin → ▲ degradation

Ø Wnt → ↑ gene expression

Wnt IP GSK3

Inositol phosphates are a group of mono- to polyphosphorylated inositols.

They act as second messangers for cell growth, apoptosis, cell migration, endocytosis, and cell differentiation

Wnt IP GSK3

GSK3 is a widely influential enzyme that is capable of phosphorylating, and thereby regulating, over forty known substrates.

serotonergic, dopaminergic, cholinergic, and glutamatergic systems control the activity of GSK3

neural plasticity, neurogenesis, gene expression, and the ability of neurons to respond to stressful, potentially lethal, conditions are modulated by GSK3

Oxidative stress