bipolar disorder
DESCRIPTION
Pathways. Bipolar Disorder. from Jamison KEY: H= Asylum or psychiatric hospital; S= Suicide; SA = Suicide Attempt - PowerPoint PPT PresentationTRANSCRIPT
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