Download Bipolar Disorder

Bipolar Disorder
Pathways
1
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),2
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:
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 goaldirected activity
7. Hedonistic interests
1.
Hypomanic Episode

Similarities with Manic Episode =


Same symptoms
Differences =

Length of time
 Impairment not as severe
Hypomanic Episode

Similarities with Manic Episode =


Same symptoms
Differences =

Length of time
 Impairment not as severe
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
Mixed Episode
Both Manic and Major Depressive Episode
criteria are met nearly every day for a least a
one week period.
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
EPIDEMIOLOGY
Prevalence




Estimated between 3-6%
Subsyndromal bipolar disorder
Equal distribution across gender variables
Average age @ onset = 20 years old
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
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.
2.
3.
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.
Comorbidity
(cont.)

Oppositional Defiant Disorder (ODD) &
Conduct Disorder (CD)


Substance Abuse


70-75%
40-50%
Anxiety Disorders

35-40%
Suicidal Behaviors

Prevalence of suicide attempts





40-45%
Age of first attempt
Multiple attempts
Severity of attempts
Suicidal ideation
Cognitive Deficits






Executive Functions
Attention
Memory
Sensory-Motor Integration
Nonverbal Problem-Solving
Academic Deficits

Mathematics
Psychosocial Deficits

Relationships

Peers
 Family members




Recognition and Regulation of Emotion
Social Problem-Solving
Self-Esteem
Impulse Control
TREATMENT
APPROACHES
Psychopharmacological
DEPRESSION

Mood Stabilizers

Anti-Obsessional
MANIA
Mood Stabillizers
Aypical Antipsychotics

Anti-Depressant
Anti-Anxiety

Atypical Antipsychotics
Lithium: 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
Predictors: Good Li Response
•
•
•
•
•
Past Li response (personal or family)
Euphoric, pure (classic) mania
Sequence Mania-Depr-Euthymia
No psychosis
No Rapid Cycling
Predictors: Poor Li Response
[Good response to
anticonvulsants]
•
•
•
•
•
•
•
Mixed mania (adolescents)
Irritable mania
Secondary mania (geriatric)
Psychotic Sx
Rapid Cycling
Depression-Mania-Euthymia
Comorbid substance abuse
Lithium: 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)
Lithium: 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 >3.0, correct fluid-electrolites
Li: 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
Valproate
• 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
Valproate
• 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
Valproate
• Increases GABA levels
• Effects 2nd Messenger, Prot-Kinase-C
• 80-95 % Protein bound
• Liver Metabolized p450 (inhibitor)
• Half life 8-17 hrs
VPA: Common Side Effects
•
•
•
•
•
•
•
•
GI distress
Sedation
Liver transaminase elevation
Tremor
Hair loss
Weight gain-increased appetite
Thrombocitopenia (elders)
Teratogenic: neural tube, cranio-facial
VPA: Less Common SE
• Neutropenia
• Coagulopathies, platelet Function
• endocrine abnormalities
– Amenorrhea, policystic ovary?
– Hypothyroidism
– Hypocortisolemia
VPA: Rare Dangerous SE
• 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
• Bone Marrow Supression
VPA 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
Carbamazepine
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
CBZ: 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
CBZ: Interactions (Many)
• p450 induction, CBZlevels of: CBZ,
VPA, lamotrig, TCAs, prednisone,
theophiline, warfarin, benzos, & oral
contraceptives
• p450 inhibitors: acetazolamide, Cachanne blockers [diltiazem & verapamil,
but not nifedipine], danazol,
erythromycin, fluoxetine, isoniazid, VPA
all CBZ levels
CBZ: Use
• Baseline: Medical Hx, CBC+diff,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
Therapy




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
Psychoeducation
Family Interventions
Cognitive-Behavioral Therapy
RAINBOW Program
Interpersonal and Social Rhythm Therapy
Schema-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 → frontal
Black → parietal
Purple → termporal
Occipital → 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

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