Bipolar Disorder C. Kye, M.D., B.C.

ckyemd@mac.com

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

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

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

Depression Mixed Mania

Mood Disorder Diagnoses:

Categorical (DSM-5)

or

Dimensional (Mixed States)

Depression Mania

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

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

BRIDGE-II-MIX: DSM-5 Major Depressive Episode - N 2,811

RDBC incr MXS - Sx distribution - relation to DSM - STAR*D

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

• Cerebral Cortical Topology

and Bioenergetics

• Cerebral Glycolytic Index

• Bullmore E, Sporns O

• Nature Rev Neuroscience

05/2012

Amy Arnsten

JAACAP 2012

Glial-Neuron Ratio: (Human 1.65-1) (Gorilla 1.2-1)

Sherwood CC - PNAS 09/12/06

Mood Disorders

& Sub-genual

Prefrontal Cortex

Drevets W: Nature 97, CNS Spectrum 08

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

Circadian rhythms relative to desired sleep-wake times Glickman G: Neuroscience & Biobehavioral Review, 2010

Clock Gene Exon 19 deletion Mania Model Roybal K: PNAS USA 2007

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

“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

“Cool Cognition” - low limbic tone

Arnsten A. NRN 2009

21

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

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

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

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

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

TCA-TEM in Rapidly Cycling Bipolar

Goodwin F: JAMA-Psychiatry 1987

N 10,

inpatient,

prospective

Reticular Activating System

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$), Antiepileptics (#18 - 6B$)

• 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

• 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

DAB staining - AQP2 collecting ducts apical - Mag 400x

Kalita-DeCroft et al - Nephrology - in press

Control Li - 1 mos Li - 6 mos Li - Amiloride

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

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

Ontogeny of

Amygdalar Reactivity

to Empty Threat

(Fearful Faces) Hare TA. BP 2008

Ventral

Striatal

&

PFC

Ontogen

y Casey BJ:

Neuron

2010

Cohort Effect: Menarche. Dahl R: NYAS, 2004

Finland: 16.5 y.o. -> 13.5 y.o.

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”

Psychiatric Disorders - Age of Onset

National Comorbidity Survey - Replication Keshevan M, Giedd J: NRN, 2008

39