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Bipolar Disorder C. Kye, M.D., B.C.
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Modern Scientific Psychiatric Dx and Rx
• Kraepelin: 1st - early 20th century - founder
• Dx based on: Sxs, FHx, Illness Course
• Manic-Depression vs Dementia Praecox
• Psychopharmacology (FDA approval): add Rx response to Dx
• Chlorpromazine (Smith-Kline) 1954, Haloperidol (Jannsen)
1967
• Imipramine (Novartis) 1957, Amitriptyline (Smith-Kline) 1963
• Lithium: acute mania 1970, mania prophylaxis 1975
• Research Diagnostic Criteria: 24 Dxs, JAMA Psychiatry
06/1978
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DSM (Diagnostic & Statistical Manual)
• Official U.S. psychiatric Dx system
• 1st iteration DSM-III - 1980 - approx 250 Dxs
• 3rd major iteration DSM-5 - 2013 - approx 300 Dxs
• Dx design: collection of Sxs “fuzzy” boundaries
• No use of FHx, illness course, response to Rx
• No Validity with Some Reliability
• “Dictionary” not a “Bible
• Caveat: hardest patients exist at Dx boundaries
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DSM-5 Manic Episode Depressive Episode
Gateway
Criteria
• Mood: Elevated, Expansive
or Irritable
AND
• Increased goal-directed
activity or Increased energy
• Mood: Depressed or
Irritable (pediatric only)
OR
• Anhedonia
Secondary
Criteria
3 Criteria
(4 if mood only irritable)
• Distractibilty
• Psychomotor agitation
• Decreased sleep
• Grandiosity
• Pleasurable and dangerous
behaviors
• Pressured speech
• Racing thoughts
3 criteria
(4 if only 1 gateway criteria)
• Distractibilty
• Psychomotor agitation or
retardation
• Insomnia, hypersomnia
• Worthlessnes, guilt
• Weight loss/gain (>5%)
• Fatigue
• Suicidal ideation
Mixed Episode qualifier - 3 non-overlapping mood Sxs
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Depression Mixed Mania
Mood Disorder Diagnoses:
Categorical (DSM-5)
or
Dimensional (Mixed States)
Depression Mania
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DSM-5
Major Depressive
Episode:
Mixed Qualifier
BRIDGE:
Bipolar Disorders:
Improving Dx,
Guidance and
Education
JAMA Psychiatry
08/11
BRIDGE-II-MIX:
Research-based DX
criteria for
depressive MiXed
episodeS
(RBDC-MXS )
J Clin Psychiatry
03/2015
meets criteria for a DSM Major Depressive Episode
• addition of 3 non-
over-lapping manic
episode criteria Sxs
• Gateway mania
criteria requirement
from both to either
• Duration reduced
from 4 day to 1 day
• Antidepressant
induced mania
exclusion eliminated
• 3 of 14 criteria from
DSM Manic episode
plus:
• Mood lability
• Impulsivity
• Aggression
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BRIDGE Study - Mixed Depression
5635 DSM major depressive episode patients
47% met the Bipolarity specifier criteria or “Mixed Episode”
Heritability - FHx - Kraepelin
Borderline Personality Disorder - mood lability
Substance Use Disorder - impulsivity
Treatment Emergent Mania - Rx response - Kraeplin
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BRIDGE-II-MIX: DSM-5 Major Depressive Episode - N 2,811
RDBC incr MXS - Sx distribution - relation to DSM - STAR*D
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Mixed Depression
• Sxs
• emotional/ mood lability
• irritability
• More chronicity, more episodes, earlier onset
• Comorbidity: more substance dependence, more borderline
personality disorder
• FHx: bipolar
• Rx
• Traditional antidepressant - ineffective, possibly
worsening
• Low dose antipsychotics, mood stabilizers
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• Cerebral Cortical Topology
and Bioenergetics
• Cerebral Glycolytic Index
• Bullmore E, Sporns O
• Nature Rev Neuroscience
05/2012
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Amy Arnsten
JAACAP 2012
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Glial-Neuron Ratio: (Human 1.65-1) (Gorilla 1.2-1)
Sherwood CC - PNAS 09/12/06
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Mood Disorders
& Sub-genual
Prefrontal Cortex
Drevets W: Nature 97, CNS Spectrum 08
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15
Mood Disorder Sleep EEG:
• Decreased SWS
• Unipolar and Bipolar
Neurotrophic Effects of Sleep
• Slow Wave Sleep: relieves sleep pressure - state/trait decrease in mood DO
• Few % variation in gene expression in brain with circadian rhythm
• Increased transcription of anabolic gene products during sleep
• Increased transcription of catabolic gene products during wake
• Chronic insomnia associated with decreased cerebral cortex grey matter
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Circadian rhythms relative to desired sleep-wake times Glickman G: Neuroscience & Biobehavioral Review, 2010
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Clock Gene Exon 19 deletion Mania Model Roybal K: PNAS USA 2007
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Bipolar DO Rx: FDA-approved
FDA-Approved
Bipolar Rx Mania Depression Maintenance
Dopamine 2
Receptor
Blocker
Old generation: without Serotonin 2R block
New generation: with Serotonin 2R block
5HT-2aR block: decreased risk of EPS and TD
5HT-2cR block: increased risk of metabolic syndrome
Mood Stabilizer
Depakote,
Lithium (pediatric),
Equetro
Lamictal,
Lithium
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“Hot Cognition” - high limbic tone
Arnsten A, NRN 2009
Stress and EF
Effects of stress
exposure on
performance of
cognitive tasks:
• impaired
complex, flexible
thinking (lPFC).
• improved
simpler and/or
well-rehearsed
tasks (basal
ganglia).
Arnsten A. NRN,
06-09
20
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“Cool Cognition” - low limbic tone
Arnsten A. NRN 2009
21
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Long-term Antipsychotic Treatment and Brain Volumes:
A Longitudinal Study of First-Episode Schizophrenia
• Nancy C. Andreasen, JAMA-Psychiatry 02/2011
• 211 patients - ave 3 f/u MRI - ave 7.2 yr f/u
929 mg CPZ 392 mg CPZ 112 mg CPZ
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Effect of Chronic Antipsychotic Exposure on Astrocyte and
Oligodendrocyte Numbers in Parietal Cortex Macaque Monkeys
Lewis DA, Biol Psychiatry 2008
18 experimentally naïve, adult male macaque monkeys three
groups (n 6 monkeys/group)
haloperidol, olanzapine, or sham for 17–27 months to steady
state, trough, therapeutic plasma levels of haloperidol and
olanzapine of 1.5 and 15 ng/mL
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Schizophrenic pts acutely Rx with Haldol 2mg/day at 2 wks
Dopamine 2 Receptor Occupancy (PET scan - raclopride)
Kapur S - Amer J Psychiatry - 07/1996
N 7
Age Range 20-37 yrs
D2R Occupancy Mean 67%
D2R Occupancy Range 53-74%
Psychosis Cleared 5 of 7 subjects
Dopamine 2 Receptor Occupancy: associated effects
• 80% block - extrapyramidal symptoms
• 65% block - antipsychotic effect
• Shitij Kapur McGill - PET Raclopride
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First Episode Psychosis Patients
Incidence of Tardive Dyskinesia
on Haloperidol low-dose at 1 year
Oosthuizen P - J Clin Psychiatry - 09/2003
First 4 wks - Haldol 1mg/day -
in 1/2 of subjects psychosis cleared -
in no subjects significant extra-pyramidal side effects
+ Tardive Dyskinesia - Tardive Dyskinesia
N 7 subjects 50 subjects
Age 37+9 yrs 27+8 yrs
Dose 2.8+1.6 mg 1.4+0.7 mg
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Systematic Treatment Enhancement Program
for Bipolar Disorder (STEP-BD)
• Design: 4361 participants - 1999-2005
• Major findings regarding bipolar depression
• Presentation: without manic Sxs: 31%
• Recurrence risk 1 yr: 1/2 depression, 1/4 manic/mixed
• Recurrence predictor: #1 - residual mood elevation
• Rx - Lamotrigine: 1/4 response rate
• Rx - antidepressants: no response rate
• Limitations - mood instability and impulsivity not assessed
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TCA-TEM in Rapidly Cycling Bipolar
Goodwin F: JAMA-Psychiatry 1987
N 10,
inpatient,
prospective
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Reticular Activating System
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Hippocratic Psychopharmacology for Bipolar Disorder
Ghaemi N - Psychiatry 06/2006
Psych med sales (IMS 2010) - drug class (rank, billion $):
Antipsychotics (#5 - 16B$), Antidepressants (#7 - 12B$), ADHD
(#12 - 7B$), Antiepileptics (#18 - 6B$)
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• Clock Gene KO Models Li Efficacy - figure Coyle J: PNAS 2007
• GSK-3 activity in neocortical cells is inhibited by lithium but not
carbamazepine or valproic acid - Bipolar Disorders - 06/2005
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• Valproic Acid is a Histone Deacetylase Inhibitor
• Synergistic Neuroprotective Effects of Lithium and Valproic Acid or
Other Histone Deacetylase Inhibitors in Neurons: Roles of Glycogen
Synthase Kinase-3 Inhibition - NIMH - J Neurosci. 03/05/08
Ott M - 2015
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DAB staining - AQP2 collecting ducts apical - Mag 400x
Kalita-DeCroft et al - Nephrology - in press
Control Li - 1 mos Li - 6 mos Li - Amiloride
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Li - 6mos
Li -
Amiloride
Li -
1 mos
Control
• rat kidney cortex collagen - DeCroft. Nephrology, in press
• Kessing JAMA P 12/15 - Denmark (1.5 M), Li Rx (26731)
• CKD HR: BPD - 2; Li > 5yrs - 3.5
• Li > 5yrs end stage CKD -1
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Treatment Resistant Depression - Electrical Interventions
• ECT - response of 2 in 3 patients
• TMS - sham-controlled - NNT 1 in 7
Sarah Hollingsworth Lisanby
NIH Director - Division of Translational Research
SOBP 2015
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Ontogeny of
Amygdalar Reactivity
to Empty Threat
(Fearful Faces) Hare TA. BP 2008
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Ventral
Striatal
&
PFC
Ontogen
y Casey BJ:
Neuron
2010
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Cohort Effect: Menarche. Dahl R: NYAS, 2004
Finland: 16.5 y.o. -> 13.5 y.o.
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Ontogeny of Fronto-Limbic Connectivity Casey BJ: Neuron, 2011
PFC regulatory tone & Subcortical limbic/emotional tone relationship.
Left-shift or phase-advance of puberty’s onset/increased limbic reactivity difficulties.
Temporally unchanged onset of PFC’s maturation/regulatory control of limbic reactivity.
cohort effect “left shift”
Blue: “cool” cognitive tone
Purple: “hot” emotional tone
Red: puberty phase advance
Casey BJ: Neuron, 2010.
additional adolescent duration,
i.e. difficulty with “hot
cognition”
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Psychiatric Disorders - Age of Onset
National Comorbidity Survey - Replication Keshevan M, Giedd J: NRN, 2008
39