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1 Bipolar Disorder Pathways
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2 from Jamison KEY: 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)
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DIAGNOSIS
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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.
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Manic Episode Symptoms: 1. Inflated self-esteem or grandiosity 2. Decreased need for sleep 3. Pressured speech or more talkative than usual 4. Flight of ideas or racing thoughts 5. Distractibility 6. Psychomotor agitation or increase in goal- directed activity 7. Hedonistic interests
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Hypomanic Episode Similarities with Manic Episode = Same symptoms Differences = Length of time Impairment not as severe
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Hypomanic Episode Similarities with Manic Episode = Same symptoms Differences = Length of time Impairment not as severe
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Major Depressive Episode Symptoms: 1. Depressed mood (in children can be irritable) 2. Diminished interest in activities 3. Significant weight loss or gain 4. Insomnia or hypersomnia 5. Psychomotor agitation or retardation 6. Fatigue/loss of energy 7. Feelings of worthlessness/inappropriate guilt 8. Diminished ability to think or concentrate/indecisiveness 9. Suicidal ideation or suicide attempt
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Mixed Episode Both Manic and Major Depressive Episode criteria are met nearly every day for a least a one week period.
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Subtypes Bipolar 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
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EPIDEMIOLOGY
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Prevalence Estimated between 3-6% Subsyndromal bipolar disorder Equal distribution across gender variables Average age @ onset = 20 years old
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Course Initial cycle typically major depressive episode Recovery Relapse Rapid Cycling Rapid cycling=4 episodes/year Ultrarapid cycling=5-364 episodes/year Ultradian cycling=>365 episodes/year
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Age at Onset Pediatric, prepubertal, or early adolescent (prior to age 12) Adolescent (12 - 18 years) Adult onset (+ 18 years)
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IMPAIRMENTS
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Comorbidity Attention Deficit Hyperactivity Disorder (ADHD) Between 60-80%
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Criteria Comparison Bipolar Disorder (mania) 1. More talkative than usual, or pressure to keep talking 2. Distractibility 3. Increase in goal directed activity or psychomotor agitationADHD Often talks excessively Is often easily distracted by extraneous stimuli Is often “on the go” or often acts as if “driven by a motor” Differentiation= elated mood, grandiosity, decreased need for sleep, hypersexuality, and irritable mood.
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Comorbidity (cont.) Oppositional Defiant Disorder (ODD) & Conduct Disorder (CD) 70-75% Substance Abuse 40-50% Anxiety Disorders 35-40%
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Suicidal Behaviors Prevalence of suicide attempts 40-45% Age of first attempt Multiple attempts Severity of attempts Suicidal ideation
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Cognitive Deficits Executive Functions Attention Memory Sensory-Motor Integration Nonverbal Problem-Solving Academic Deficits Mathematics
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Psychosocial Deficits Relationships Peers Family members Recognition and Regulation of Emotion Social Problem-Solving Self-Esteem Impulse Control
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TREATMENT APPROACHES
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Psychopharmacological DEPRESSION Mood Stabilizers Anti-Obsessional Anti-Depressant Atypical AntipsychoticsMANIA Mood Stabillizers Aypical Antipsychotics Anti-Anxiety
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Lithium: Pharmacology Not liver metabolized. Kidney excreted Not liver metabolized. Kidney excreted Not protein bound Not protein bound 70-80% reabsorb prox Tubule, Na comp: Na (dehydr, thiazide diuret) Li level 70-80% reabsorb prox Tubule, Na comp: Na (dehydr, thiazide diuret) Li level Excretion related to GFR: elder preg Excretion related to GFR: elder preg Half-life 24 hrs (HS), steady state 5 days Half-life 24 hrs (HS), steady state 5 days Peak Levels 2 hrs, SR 4-4.5 Peak Levels 2 hrs, SR 4-4.5 – fast release: N/V, slow rel: diarrhea
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Predictors: 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-Euthymia Sequence Mania-Depr-Euthymia No psychosis No psychosis No Rapid Cycling No Rapid Cycling
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Predictors: Poor Li Response [Good response to anticonvulsants] Mixed mania (adolescents) Mixed mania (adolescents) Irritable mania Irritable mania Secondary mania (geriatric) Secondary mania (geriatric) Psychotic Sx Psychotic Sx Rapid Cycling Rapid Cycling Depression-Mania-Euthymia Depression-Mania-Euthymia Comorbid substance abuse Comorbid substance abuse
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Lithium: Common Side Effects GI distress: upper LiCO3, lower GI SR. GI distress: upper LiCO3, lower GI SR. Polyuria / polydipsia Polyuria / polydipsia Sedation-lethargy Sedation-lethargy Cognitive (memory, concentr, slow) Cognitive (memory, concentr, slow) Wt. Gain Wt. Gain Poor coordination, tremor Poor coordination, tremor Skin (worse acne) Skin (worse acne)
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Lithium: Serious SE Renal Renal – nephrogenic diabetes insipidus – tubular interstitial nephritis Hypothyroidism Hypothyroidism Psoriasis (onset or worsening) Psoriasis (onset or worsening) Cardiac: EKG flat T, SA dysfx, tachicardia Cardiac: EKG flat T, SA dysfx, tachicardia Li Tox. N/V/D, delirium, ataxia, stupor Li Tox. N/V/D, delirium, ataxia, stupor – Tx dyalisis if >3.0, correct fluid-electrolites
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Li: Interactions & Use Li levels: Li levels: diuretics, diuretics, NSAIDs (ASA OK) NSAIDs (ASA OK) ACE-inhibitors ACE-inhibitors Starting: Starting: – Baseline Renal, TFT, HCG, EKG, UA, weight, medical Hx – 300-600 mg/day divided doses – Levels in 5 days – Increase 300-900 mg/day q 5-7 days
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Valproate FDA Sz ‘78, BP ‘96 FDA Sz ‘78, BP ‘96 Effective antimanic, BP depression Effective antimanic, BP depression Therapeutic effect 2 d. level 50-125 mg/l Therapeutic effect 2 d. level 50-125 mg/l – oral loading 20-30 mg/kg/day Elderly & hypomania responde to lower? Elderly & hypomania responde to lower? Mixed, rapid cycling, schizoaffective Mixed, rapid cycling, schizoaffective
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Valproate FDA Sz ‘78, BP ‘96 FDA Sz ‘78, BP ‘96 Effective antimanic, BP depression Effective antimanic, BP depression Therapeutic effect 2 d. level 50-125 mg/l Therapeutic effect 2 d. level 50-125 mg/l – oral loading 20-30 mg/kg/day Elderly & hypomania responde to lower? Elderly & hypomania responde to lower? Mixed, rapid cycling, schizoaffective Mixed, rapid cycling, schizoaffective
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Valproate Increases GABA levels Increases GABA levels Effects 2nd Messenger, Prot-Kinase-C Effects 2nd Messenger, Prot-Kinase-C 80-95 % Protein bound 80-95 % Protein bound Liver Metabolized p450 (inhibitor) Liver Metabolized p450 (inhibitor) Half life 8-17 hrs Half life 8-17 hrs
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VPA: Common Side Effects GI distress GI distress Sedation Sedation Liver transaminase elevation Liver transaminase elevation Tremor Tremor Hair loss Hair loss Weight gain-increased appetite Weight gain-increased appetite Thrombocitopenia (elders Thrombocitopenia (elders) Teratogenic: neural tube, cranio-facial
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VPA: Less Common SE Neutropenia Neutropenia Coagulopathies, platelet Function Coagulopathies, platelet Function endocrine abnormalities endocrine abnormalities – Amenorrhea, policystic ovary? – Hypothyroidism – Hypocortisolemia
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VPA: Rare Dangerous SE Idiosincratic Hepatic Failure Idiosincratic Hepatic Failure – lethargy, anorexia, N/V, bleed, edema – Risk: <2 yo, many anticonvuls, Dev. Delay – Remote risk in >10yo psychiatric patients Acute Hemorrhagic Pancreatitis Acute Hemorrhagic Pancreatitis Bone Marrow Supression Bone Marrow Supression
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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 hypom Load 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, CBC Monitor LFT, CBC
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Carbamazepine Effective antimanic, Tx-refract Depr Onset 2 wks, antidepr 4-6 wk Onset 2 wks, antidepr 4-6 wk Ther. Levels: 4-12 or 15 mg/L Ther. Levels: 4-12 or 15 mg/L Half life decreases to 12-17 hrs Half life decreases to 12-17 hrs – p450 liver induction
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CBZ: Side Effects Less cognitive probl than Li Less cognitive probl than Li Less Wt gain, hair loss, tremor than VPA Less Wt gain, hair loss, tremor than VPA Neuro: Diplopia,blurr vision, fatigue/sed Neuro: Diplopia,blurr vision, fatigue/sed GI: Naus/diarr, Dry mouth GI: Naus/diarr, Dry mouth Leukopenia, thrombocitopenia, rash Leukopenia, thrombocitopenia, rash LFT Agranulocytosis (, Liver fail, pancreatitis, Stevens-Johnson (exfol skin), neuroteratogenic Agranulocytosis (, Liver fail, pancreatitis, Stevens-Johnson (exfol skin), neuroteratogenic
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CBZ: Interactions (Many) p450 induction, CBZ levels of: CBZ, VPA, lamotrig, TCAs, prednisone, theophiline, warfarin, benzos, & oral contraceptives 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 p450 inhibitors: acetazolamide, Ca- channe blockers [diltiazem & verapamil, but not nifedipine], danazol, erythromycin, fluoxetine, isoniazid, VPA all CBZ levels
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CBZ: Use Baseline: Medical Hx, CBC+diff,LFT, Renal, TFT, HCG, ferritin Baseline: Medical Hx, CBC+diff,LFT, Renal, TFT, HCG, ferritin Start low: Start low: – 100-400 mg/day, 100-200 mg every several days, bid (occasionally qd) Follow CBC, LFT Follow CBC, LFT – clinical monitoring more effective than labs
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Therapy Psychoeducation Family Interventions Cognitive-Behavioral Therapy RAINBOW Program Interpersonal and Social Rhythm Therapy Schema-focused Therapy
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Biological mechanisms Macro Micro
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MACRO Which parts of the brain are relevant to BP
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▲ 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)
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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
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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
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neurodevelopment BP begins in late adolescence BP is progressive
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pruning Increased brain volumes in prefrontal and parahippocampal cortices
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Red → frontal Black → parietal Purple → termporal Occipital → green
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MICRO Which molecular cascades are relevant to BD ?
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Wnt IP GSK3
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Wnt IP GSK3
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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
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Wnt IP GSK3
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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
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Wnt IP GSK3
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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
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Oxidative stress
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