Bipolar d/o/Mania
in
Late Life
Robert Kelly, MD
Assistant Professor of Psychiatry
Weill Cornell Medical College
White Plains, New York
Lecture available at www.robertkelly.us
Financial Conflicts of Interest
As faculty of Weill Cornell Medical College we are
committed to providing transparency for any and all
external relationships prior to giving an academic
presentation.
I do not have an interest in any commercial products
or services—Robert Kelly, MD
Outline
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Introduction
Bipolar Disorders in The Elderly
Differential Diagnosis
Management
Famous People with “Bipolar
Disorder”
Other “Bipolars”
The list goes on…..
Honore de Balzac, writer
Charles Baudelaire, poet
Ludwig von Beethoven, composer
Marlon Brando, actor
Albert Camus, writer
Truman Capote, writer
Jim Carrey, actor and comedian
Ray Charles, R&B performer
Frederic Chopin, composer
Kurt Cobain, rock star
Rodney Dangerfield, comedian
Theodore Dostoevski, writer
Larry Flynt, magazine publisher
Michel Foucault, writer, philosopher
Paul Gascoigne, athlete (soccer)
Paul Gauguin, artist
Bill Wilson, co-founder of Alcoholics
Anonymous
Ernest Hemingway, writer
Robin Williams, Actor
Audrey Hepburn, actress
Sir Anthony Hopkins, actor
Victor Hugo, author
Andrew Jackson, U.S. President
Kay Redfield Jamison, psychologist,
writer
Elton John, musician, composer
Franz Kafka, writer
Jessica Lange, actor
Robert E. Lee, U.S. general
John Lennon, musician
Courtney Love, musician
Imelda Marcos, Philippine dictator's
wife
Claude Monet, artist
Marilyn Monroe, actor
Boris Yeltsin, former President,
Russia
Virginia Woolf, writer
Celebrity Meltdown, Psychology Today, December 1999, pp. 46-49,70,78
Bipolar Disorder in The Elderly
By DSM-IV
• Type I –the subtype most studied in the
aged.
• Type II- hypomania; seen in ambulatory
populations; little data.
Rapid cycling—no systematic study in
elders.
Bipolar Spectrum Disorders
• Bipolar I – History of mania
• Bipolar II – History of hypomania and
major depressive episodes
• Cyclothymia



Hyperthymic temperament
Secondary mania – to other illnesses or drugs
Antidepressant-induced mania and hypomania
= DSM-IV categories
DSM-IV™. Washington, DC: American Psychiatric Association; 1994:317-391.
Akiskal HS. J Clin Psychopharmacol. 1996;16(2 suppl 1):4S-14S.
Mood Disorder Criteria
Distress or Impairment
Clinically Significant
“Abnormal”
Involves Mood
Elevated
Expansive
Irritable
Depressed
Manic Episode
Elevated, Expansive, or Irritable
DIGFAST
Distractibility
Involvement in pleasurable, risky activities
Grandiosity
Flight of Ideas
Activity Increase
Sleep not needed
Talkative (pressured speech)
One Week
Not Mixed Episode
Not Substance- or Treatment-Induced
Not General Medical Condition
Marked Impairment
Hypomanic Episode
Elevated, Expansive, or Irritable
DIGFAST
Distractibility
Involvement in pleasurable, risky activities
Grandiosity
Flight of Ideas
Activity Increase
Sleep not needed
Talkative (pressured speech)
Four Days
Unequivocal, Observable Change
Not Substance- or Treatment-Induced
Not General Medical Condition
NOT Marked Impairment
Major Depressive Episode
Depressed Mood or Anhedonia
Mood + SIGECAPS (most sx)
Two Weeks
Not Mixed Episode
Not Substance-Induced
Not General Medical Condition
Not Bereavement
Clinically Significant Distress or Impairment
Mixed Episode
Manic and Major Depressive Episode
One Week
Not Substance- or Treatment-Induced
Not General Medical Condition
Marked Impairment
Mood Disorders, DSM-IV
Mood Disorder Due to a General Medical Condition
Substance-Induced Mood Disorder
Adjustment Disorders
Depressive Disorders
Major Depressive Disorder
Dysthymic Disorder
Depressive Disorder NOS
Bipolar Disorders
Bipolar I Disorder
Bipolar II Disorder
Cyclothymic Disorder
Bipolar Disorder NOS
Schizoaffective Disorder
Depressive Type
Bipolar Type
Mood Disorder NOS
Mood Disorder Due to a General Medical Condition
Prominent and Persistent
Depressed Mood or Anhedonia
Elated, Expansive, or Irritable
Evidence
Direct Physiological Consequence
Not Due to Other Mental Disorder
Not During Delirium
Clinically Significant Distress or Impairment
Substance-Induced Mood Disorder
Prominent and Persistent
Depressed Mood or Anhedonia
Elated, Expansive, or Irritable
Evidence
Temporal--intoxication or withdrawal
Etiologically Related
Not Due to Other Mental Disorder
Not During Delirium
Clinically Significant Distress or Impairment
Bipolar I Disorder
Manic or Mixed Episode
Major Depressive Episode
Not Schizoaffective Disorder
Not Superimposed on Psychotic Disorder
Clinically Distress or Impairment
Bipolar II Disorder
Hypomanic Episode
Major Depressive Episode
Never Manic or Mixed Episode
Not Schizoaffective Disorder
Not Superimposed on Psychotic Disorder
Clinically Distress or Impairment
Schizoaffective Disorder
Mood Episode + Schizophrenia Criterion A
Mood, not anhedonia
Bipolar or depressive types
Schizophrenia-like period
Two weeks
No prominent mood symptoms
Delusions or hallucinations
Mood Episode “Substantial” Portion
40% or more
Not Substance-Induced
Not General Medical Condition
Lifetime Prevalence
Bipolar Disorders
Bipolar I Disorder (0.4-1.6%)
First manic/mixed episode very late in life
Bipolar II Disorder (0.5% ??)
Cyclothymic Disorder (0.4-1%)
Bipolar Disorder NOS
Symptom Domains of Bipolar Disorder
Manic Mood
and Behavior
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Euphoria
Grandiosity
Pressured speech
Impulsivity
Excessive libido
Recklessness
Social intrusiveness
Diminished need for sleep
Psychotic Symptoms
Delusions
Hallucinations
Dysphoric or Negative
Mood and Behavior
Bipolar
Disorder
Depression
Anxiety
Irritability
Hostility
Violence or suicide
Cognitive
Symptoms
Racing thoughts
Distractibility
Disorganization
Inattentiveness
Goodwin FK, Jamison KR. Manic-Depressive Illness. New York, NY: Oxford University Press; 1990:85-125.
Differential Diagnosis of Mania
• The differential diagnosis of manic and mixed
states in late life is broad and includes:
delirium, dementia, schizophrenia, bipolar
(BP) disorders, schizoaffective disorder- BP
type, drug intoxication, and mood disorder
due to medical disorders or treatments.
• Lack of detection and misdiagnosis are likely
Additional Heterogeneity
• BP elders have a broad range of clinical
features, prior illness course, treatment
history, comorbidity, functional status,
psychosocial circumstances, and
outcomes.
• The heterogeneity includes additional ageassociated factors.
Neurobiology of bipolar disorder
• Meta-analysis of MRI Brain Morphometry
Studies in Adults With Bipolar Disorder 26
studies comprising 404 patients
• Compared volumetric brain measurements of
patients with bipolar disorder with controls
• Patients with bipolar disorder had enlarged
right lateral ventricles compared with controls
• Findings suggest that bipolar disorder is more
likely to be associated with right-sided cerebral
pathology
McDonald C, et al. Biol Psychiatry. 2004;56:411-417.
Mania and acute brain lesions
• Stroke and other focal brain
disease
– especially right
orbitofrontal and
basotemporal areas
Brooks et al Am J Psychiatry
2005
Mania in Neurological Disorders
• Associations with other neurological disorders
– Huntington’s Disease
– Multiple sclerosis
– Alzheimer’s disease—Confabulation versus
Grandiosity
Starkstein et al 1991; Shulman 1997
Bipolar Disorder and the Brain
• New theory from Autopsy studies – mitochondrial
malfunction
• Mitochondria – vital organelle for energy production
• Depletion of Mitochondria in autopsied bipolar brains;
mutant mitochondrial DNA – two suspect genes
Kato, University of Tokyo 2000
• Decreased expression of genes that coded for
mitochondrial proteins in hippocampus of bipolar
patients
Christine Konradi Harvard and McLean
Hospital, Archives of General Psychiatry 2004
Neurobiology of mania
• Less studied than that of major depression
• Current hypothesis posits deficient serotonergic
neurotransmission as a pathophysiological cause of
both depression and mania
• In mania, neurotransmission may be related to GABA
deficits
• Without usual GABA functioning, unopposed relative
increases in NE and DA activity may underlie the
development and progression of mania
• Hypothesis supported by efficacy of GABA agents in
the treatment of mania
Neurotransmitters and mania
• Several neurotransmitters
involved (SE, NE, Dopamine,
? Cortisol)
• Increase dopamine
transmission from the
substantia nigra to the
neostriatum
increased
sensory stimuli and
movement.
• Dopamine activity in the other
two pathways, from the
ventral tegmentum and the
tubero-infundibular, remains
unchanged in mania
Berns and Nemeroff 2003
Secondary Mania
• Antidepressant Associated Mania
• Neurological disorders with mania as
initial clinical presentation
• Delirium (medications, drugs, infections,
other…)
Antidepressant Associated
Mania
• Controversial nature; can occur in elders
• SSRIs involve less risk than TCAs?
• Avoided by use of mood stabilizers
• Can occur with ECT
Bittman and Young 1991
Treatment
•
•
•
•
Multidisciplinary approach +++
Medications
Psychotherapies
Psychosocial interventions
Psychopharmacotherapy
• Mood stabilizers
• Atypicals
• Others
APA Practice Guidelines for Bipolar
Disorder: First-Line Treatments
• Manic/mixed episodes
– Severe cases: combination therapy
(lithium/divalproex + antipsychotic)
– Mild to moderate cases: monotherapy
(lithium, divalproex, or atypical antipsychotic)
• Depressed episode
– Lithium or lamotrigine monotherapy
– Severe cases may require combination therapy
• Maintenance: lithium, divalproex, or other agents
(reasonable to continue same agent used to achieve
remission)
American Psychiatric Association. Am J Psychiatry. 2002;159(4 suppl):1-50.
Mania and FDA
• Currently FDA approved
• lithium (Eskalith or Lithobid),divalproex sodium
(Depakote), carbamazepine (Tegretol),
• olanzapine (Zyprexa), risperidone (Risperdal),
quetiapine (Seroquel), ziprasidone (Geodon),
aripiprazole (Abilify)
• At least one adequate well controlled study with
positive data: haloperidol (Haldol)
NAMI website 2007
Mood Stabilizers: Lithium
Theory: Urea is related to mania, so urea
salts may have a calming effect–John
Cade, 1940’s
Finding: Lithium urate made guinea pigs
lethargic, but careful controls revealed that
this appeared to be due to due to lithium
rather than urea.
New hypothesis: Lithium may be useful in
treating the manic phase of bipolar disorder
Finding: Lithium effective for Bipolar
Disorder.
Mood Stabilizers: Lithium
•
•
•
•
For BP since 1960’s, FDA ‘74
Effective Antimanic, mood stab, BP depr.
If Discontinued relapse near 100% 2 yr
Therapeutic Levels: 0.6-1.5 mEq/ml
– 0.3-0.8 in elderly
– Same levels for prophylaxis
– Narrow therapeutic index
Mood Stabilizers: Lithium
STRENGTHS
•
•
•
•
“Gold standard”
(for classic mania)
Established efficacy in
maintenance therapy
Efficacy in augmenting
antidepressants
Suicide prevention
WEAKNESSES
•
•
•
•
•
Less effective in rapid
cycling and (?) mixed states
Limited efficacy against
depression?
Slow onset of action
Need for plasma-level
monitoring
Low therapeutic index
American Psychiatric Association. Am J Psychiatry. 2002;159(4 suppl):1-50.
Carney SM, Goodwin GM. Acta Psychiatr Scand Suppl. 2005;426:7-12.
Nolen WA, Bloemkolk D. Neuropsychobiology. 2002;42 suppl 1:11-17.
Swann AC, et al. Arch Gen Psychiatry. 1997;54:37-42.
Goodwin GM, et al. J Clin Psychiatry. 2004;65:432-441.
Mood Stabilizers: Divalproex
STRENGTHS
•
•
•
•
•
Effective against mania
Superior to lithium in mixed
states
Useful in comorbid
substance abuse
Can be started at a
therapeutic dose
Less cognitive dysfunction
than lithium?
WEAKNESSES
•
•
•
•
•
•
•
•
Limited efficacy against
depression?
Weight gain and hair loss
Teratogenesis
Thrombocytopenia
Polycystic ovary syndrome
Pancreatitis
Need for plasma-level
monitoring
Long-term efficacy not clearly
established
American Psychiatric Association. Am J Psychiatry. 2002;159(4 suppl):1-50.
Albanese MJ, et al. J Clin Psychiatry. 2000;61:916-921.
Gyulai L, et al. Neuropsychopharmacology.;180:23-32.
2003;28:1374-1382.
Hirsch E, et al. Acta Neurol Scand Suppl. 2003 Stoll AL, et al. J Clin Psychiatry. 1996;57:356359.
Polifka JE, Friedman JM. CMAJ. 2002;167:265-273.
Mood Stabilizers: Carbamazepine
WEAKNESSES
STRENGTHS
•
•
•
Effective against mania
Useful with comorbid
substance abuse
Relatively little weight gain
•
•
•
•
Limited efficacy against
depression?
Complex pharmacokinetics
(many drug-drug interactions)
Lowers steroidal contraceptive
blood levels
Hyponatremia, agranulocytosis,
Stevens-Johnson syndrome
American Psychiatric Association. Am J Psychiatry. 2002;159(4 suppl):1-50.
Weisler RH, et al. J Clin Psychiatry. 2005;66:323-330.
Goldberg JF, et al. J Clin Psychiatry. 1999;60:733-740.
Goldberg JF, Citrome L. Postgrad Med. 2005;117:25-26, 29-32, 35-36.
Wilbur K, Ensom MH. Clin Pharmacokinet. 2000;38:355-365.
Extended-Release Carbamazepine:
Efficacy in 239 Hospitalized Manic or Mixed Episode
Patients
0
-2
YMRS Scores
Baseline
PBO = 27.93
CBZ = 28.46
-4
-6
-8
-10
End Point
PBO = 20.82
CBZ = 13.38
-12
-14
-16
-8.0
*
0
Mean Change in HAM-D
Score (LOCF)
Mean Change in YMRS
Score (LOCF)
Reduction in YMRS
Total Scores
Reduction in HAM-D
Total Scores
-1
-1.5
End Point
PBO = 8.47
CBZ = 6.88
-2
-2.5
-3
PBO (n=115)
HAM-D Scores
Baseline
PBO = 9.45
CBZ = 9.60
-0.5
-1.7
†
CBZ (n=120)
*P <.0001; †P <.01.
CBZ = carbamazepine; HAM-D = Hamilton Rating Scale for Depression; LOCF = last observation
carried forward; PBO = placebo; YMRS = Young Mania Rating Scale.
Weisler RH, et al. J Clin Psychiatry. 2005;66:323-330.
Mood Stabilizers: Lamotrigine
STRENGTHS
• Effective as depression
prophylaxis and
(to a lesser extent)
as mania prophylaxis
• Little cognitive
dysfunction
• Generally well tolerated,
little or no adverse effect
on weight
WEAKNESSES
• Acute antidepressant
effect less established
• Very slow titration rate
• Drug interactions
(eg, valproate,
carbamazepine, OCs)
• Rash, Stevens-Johnson
syndrome
American Psychiatric Association. Am J Psychiatry. 2002;159(4 suppl):1-50.
Goodwin GM, et al. J Clin Psychiatry. 2004;65:432-441.
Goldberg JF, Burdick KE. J Clin Psychiatry. 2001;62(suppl 14):27-33.
Bowden CL, et al. Drug Saf. 2004;27:173-184.
Sabers A, et al. Neurology. 2003;61:570-571.
Lithium vs Carbamazepine
• 2.5-year study; N = 171 patients with bipolar disorder
• Lithium statistically superior to carbamazepine in
“classical” euphoric bipolar I disorder, but less well
tolerated
• Carbamazepine better than lithium for moodincongruent, atypical, non classical bipolar disorder
• Patient satisfaction statistically higher in
carbamazepine group
Kleindienst N, Greil W. Neuropsychobiology. 2000;42(suppl 1):2-10.
Atypical Antipsychotics
for Bipolar Mania
• Recommended both as monotherapy and as
combination therapy with a mood stabilizer1-3
• Base selection on4
–
–
–
–
1.
2.
3.
4.
Efficacy
Onset of action
Safety and tolerability profile
Individual patient factors: history, characteristics,
prior response
American Psychiatric Association. Am J Psychiatry. 2002;159(4 suppl):1-50.
Suppes T, et al. J Clin Psychiatry. 2005;66:870-886.
Yatham LN, et al. Bipolar Disord. 2005;7(suppl 3):5-69.
Keck PE Jr. J Clin Psychiatry. 2005;66(suppl 3):5-11.
TIMA Treatment Algorithm for
Acute Hypomanic/Manic/Mixed Episodes
in Patients With Bipolar I Disorder
Stage 1
Euphoric
Mixed
1A: Li, VPA, ARP, QTP, RIS, ZIP
1A: VPA, ARP, RIS, ZIP
1B: OLZ or CBZ
Monotherapy
Nonresponse:
Try Alternate
Monotherapy
Response
1B: OLZ or CBZ
Response
CONT
Partial Response
Partial Response
ARP = aripiprazole; CBZ = carbamazepine; CONT = continuation; Li = lithium; OLZ = olanzapine;
QTP = quetiapine; RIS = risperidone; TIMA = Texas Implementation of Medication Algorithms;
VPA = valproate; ZIP = ziprasidone.
Adapted with permission from Suppes T, et al. J Clin Psychiatry. 2005;66:870-886.
Nonresponse:
Try Alternate
Monotherapy
TIMA Treatment Algorithm for
Acute Hypomanic/Manic/Mixed Episodes
in Patients With Bipolar I Disorder cont.
Stage 2
Li, VPA, AAP
Choose 2 (not 2 AAPs, not ARP or CLOZ)
Two-Drug Combination
Response
CONT
Partial Response
or Nonresponse
Stage 3
Li, VPA, AAPs, CBZ, OXC, TAP
Choose 2 (not 2 AAPs, not CLOZ)
Two-Drug Combination
Response
Partial Response
or Nonresponse
Stage 4
CONT
ECT or Add CLOZ or
Li + [VPA or CBZ or OXC] + AAP
AAP = atypical antipsychotic; ARP = aripiprazole; CBZ = carbamazepine; CLOZ = clozapine;
CONT = continuation; ECT = electroconvulsive therapy; Li = lithium; OXC = oxcarbazepine;
TAP = typical antipsychotic; TIMA = Texas Implementation of Medication Algorithms; VPA = valproate.
Adapted with permission from Suppes T, et al. J Clin Psychiatry. 2005;66:870-886.
Risks Associated With Antidepressant
Use in Bipolar Depression
• Antidepressant monotherapy (eg,
TCAs, MAOIs, SSRIs, SNRIs) are
associated with risk of
– Mania induction
– Cycle acceleration
• SSRIs and bupropion may be
relatively safer with regard to these
risks than TCAs
El-Mallakh RS, Karippot A. Psychiatr Serv. 2002;53:580-584.
Wehr TA, Goodwin FK. Am J Psychiatry. 1987;144:1403-1411.
Vieta E, et al. J Clin Psychiatry. 2002;63:508-512.
ECT
ECT
ECT
• Effective in manic and mixed episodes, and in
BP depression
• Can be used in pharmacologically refractory or
intolerant patients, and in severe cases
• Clinicians have often used bilateral electrode
placement in younger manic/mixed patients;
efficacy of high dose unilateral ECT awaits
study in elders
• Many clinicians avoid using lithium during ECT
Psychotherapies
•
•
•
•
Family-focused
Interpersonal and social rhythm
Cognitive-behavioral
Life goals program
Psychosocial Interventions Goals
• Improve medication adherence
• Medicationminimize side effects, complexity,
cost Reduce recurrences
• Improve psychosocial functioning
• Improve occupational functioning
• Improve quality of life Education
• Availability and support
Continuation and Maintenance Treatment
• Psychoeducation and social support are especially
important in long-term management.
• Continuation treatment--mood stabilizers usually
maintained at stable doses for > 6 mo.
• Maintenance pharmacotherapy
– Indications and optimal conditions poorly defined in
the elderly;
– Prolonged exposure to antidepressants should be
avoided if feasible; the same is true of antipsychotic
cotherapy.