Title: Bipolar Disorder
1Bipolar Disorder
2from Jamison KEYH 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)
3DIAGNOSIS
4DSM-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.
5Manic Episode
- Symptoms
- Inflated self-esteem or grandiosity
- Decreased need for sleep
- Pressured speech or more talkative than usual
- Flight of ideas or racing thoughts
- Distractibility
- Psychomotor agitation or increase in
goal-directed activity - Hedonistic interests
6Hypomanic Episode
- Similarities with Manic Episode
- Same symptoms
- Differences
- Length of time
- Impairment not as severe
7Hypomanic Episode
- Similarities with Manic Episode
- Same symptoms
- Differences
- Length of time
- Impairment not as severe
8Major Depressive Episode
- Symptoms
- Depressed mood (in children can be irritable)
- Diminished interest in activities
- Significant weight loss or gain
- Insomnia or hypersomnia
- Psychomotor agitation or retardation
- Fatigue/loss of energy
- Feelings of worthlessness/inappropriate guilt
- Diminished ability to think or concentrate/indecis
iveness - Suicidal ideation or suicide attempt
9Mixed Episode
- Both Manic and Major Depressive Episode
criteria are met nearly every day for a least a
one week period.
10Subtypes
- 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
11EPIDEMIOLOGY
12Prevalence
- Estimated between 3-6
- Subsyndromal bipolar disorder
- Equal distribution across gender variables
- Average age _at_ onset 20 years old
13Course
- Initial cycle typically major depressive episode
- Recovery
- Relapse
- Rapid Cycling
- Rapid cycling4 episodes/year
- Ultrarapid cycling5-364 episodes/year
- Ultradian cyclinggt365 episodes/year
14Age at Onset
- Pediatric, prepubertal, or early adolescent
(prior to age 12) - Adolescent (12 - 18 years)
- Adult onset ( 18 years)
15IMPAIRMENTS
16Comorbidity
- Attention Deficit Hyperactivity Disorder (ADHD)
- Between 60-80
17Criteria Comparison
- Bipolar Disorder (mania)
- More talkative than usual, or pressure to keep
talking - Distractibility
- Increase in goal directed activity or psychomotor
agitation
- ADHD
- 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.
18Comorbidity(cont.)
- Oppositional Defiant Disorder (ODD) Conduct
Disorder (CD) - 70-75
- Substance Abuse
- 40-50
- Anxiety Disorders
- 35-40
19Suicidal Behaviors
- Prevalence of suicide attempts
- 40-45
- Age of first attempt
- Multiple attempts
- Severity of attempts
- Suicidal ideation
20Cognitive Deficits
- Executive Functions
- Attention
- Memory
- Sensory-Motor Integration
- Nonverbal Problem-Solving
- Academic Deficits
- Mathematics
21Psychosocial Deficits
- Relationships
- Peers
- Family members
- Recognition and Regulation of Emotion
- Social Problem-Solving
- Self-Esteem
- Impulse Control
22TREATMENT APPROACHES
23Psychopharmacological
- DEPRESSION
- Mood Stabilizers
- Anti-Obsessional
- Anti-Depressant
- Atypical Antipsychotics
- MANIA
- Mood Stabillizers
- Aypical Antipsychotics
- Anti-Anxiety
24Lithium Pharmacology
- Not liver metabolized. Kidney excreted
- Not protein bound
- 70-80 reabsorb prox Tubule, Na comp ?Na
(dehydr, thiazide diuret) ?Li level - Excretion related to GFR?elder ?preg
- Half-life 24 hrs (HS), steady state 5 days
- Peak Levels 2 hrs, SR 4-4.5
- fast release N/V, slow rel diarrhea
25Predictors Good Li Response
- Past Li response (personal or family)
- Euphoric, pure (classic) mania
- Sequence Mania-Depr-Euthymia
- No psychosis
- No Rapid Cycling
26Predictors Poor Li ResponseGood response to
anticonvulsants
- Mixed mania (adolescents)
- Irritable mania
- Secondary mania (geriatric)
- Psychotic Sx
- Rapid Cycling
- Depression-Mania-Euthymia
- Comorbid substance abuse
27Lithium Common Side Effects
- GI distress upper LiCO3, lower GI SR.
- Polyuria / polydipsia
- Sedation-lethargy
- Cognitive (memory, concentr, slow)
- Wt. Gain
- Poor coordination, tremor
- Skin (worse acne)
28Lithium Serious SE
- Renal
- nephrogenic diabetes insipidus
- tubular interstitial nephritis
- Hypothyroidism
- Psoriasis (onset or worsening)
- Cardiac EKG flat T, SA dysfx, tachicardia
- Li Tox. N/V/D, delirium, ataxia, stupor
- Tx dyalisis if gt3.0, correct fluid-electrolites
29Li Interactions Use
- ?Li levels
- diuretics,
- NSAIDs (ASA OK)
- ACE-inhibitors
- 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
30Valproate
- FDA Sz 78, BP 96
- Effective antimanic, BP depression
- Therapeutic effect 2 d. level 50-125 mg/l
- oral loading 20-30 mg/kg/day
- Elderly hypomania responde to lower?
- Mixed, rapid cycling, schizoaffective
31Valproate
- FDA Sz 78, BP 96
- Effective antimanic, BP depression
- Therapeutic effect 2 d. level 50-125 mg/l
- oral loading 20-30 mg/kg/day
- Elderly hypomania responde to lower?
- Mixed, rapid cycling, schizoaffective
32Valproate
- Increases GABA levels
- Effects 2nd Messenger, Prot-Kinase-C
- 80-95 Protein bound
- Liver Metabolized p450 (inhibitor)
- Half life 8-17 hrs
33VPA Common Side Effects
- GI distress
- Sedation
- Liver transaminase elevation
- Tremor
- Hair loss
- Weight gain-increased appetite
- Thrombocitopenia (elders)
- Teratogenic neural tube, cranio-facial
34VPA Less Common SE
- Neutropenia
- Coagulopathies, ?platelet Function
- endocrine abnormalities
- Amenorrhea, policystic ovary?
- Hypothyroidism
- Hypocortisolemia
35VPA Rare Dangerous SE
- Idiosincratic Hepatic Failure
- lethargy, anorexia, N/V, bleed, edema
- Risk lt2 yo, many anticonvuls, Dev. Delay
- Remote risk in gt10yo psychiatric patients
- Acute Hemorrhagic Pancreatitis
- Bone Marrow Supression
36VPA Use
- 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
- Level 50-120 (check in 1-5 days)
- Monitor LFT, CBC
37Carbamazepine
- Effective antimanic, Tx-refract Depr
- Onset 2 wks, antidepr 4-6 wk
- Ther. Levels 4-12 or 15 mg/L
- Half life decreases to 12-17 hrs
- p450 liver induction
38CBZ Side Effects
- Less cognitive probl than Li
- Less Wt gain, hair loss, tremor than VPA
- Neuro Diplopia,blurr vision, fatigue/sed
- GI Naus/diarr, Dry mouth
- Leukopenia, thrombocitopenia, rash
- ?LFT
- Agranulocytosis (, Liver fail, pancreatitis,
Stevens-Johnson (exfol skin), neuroteratogenic
39CBZ Interactions (Many)
- 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
40CBZ Use
- Baseline Medical Hx, CBCdiff,LFT, Renal, TFT,
HCG, ferritin - Start low
- 100-400 mg/day,
- ?100-200 mg every several days, bid (occasionally
qd) - Follow CBC, LFT
- clinical monitoring more effective than labs
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42Therapy
- Psychoeducation
- Family Interventions
- Cognitive-Behavioral Therapy
- RAINBOW Program
- Interpersonal and Social Rhythm Therapy
- Schema-focused Therapy
43Biological mechanisms
44MACRO
- Which parts of the brain are relevant to BP
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48? 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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51Key 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
52limits
- 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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54neurodevelopment
- BP begins in late adolescence
- BP is progressive
55pruning
- Increased brain volumes in prefrontal and
parahippocampal cortices
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58Red ? frontal Black ? parietal Purple ?
termporal Occipital ? green
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60MICRO
- Which molecular cascades are relevant to BD ?
61 62 63- 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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65 66- 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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68 69- 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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72Oxidative stress