Diagnosis and Treatment of

Bipolar Disorder
in the Elderly
Ralph Kupka MD, PhD

Professor of Psychiatry / Bipolar Disorders

VU University Medical Center
Amsterdam, The Netherlands
ECNP School of Old Age Neuropsychopharmacology / April 2015

Disclosure
April 2015
Ralph Kupka, MD, PhD
I have an interest in relation with one or more organisations that could be perceived as a
possible conflict of interest in the context of the subject of this presentation.
The relationships are summarised below:
Interest

Name of organisation

Grant

Astra-Zeneca, Stanley Medical Research Institute, NWO

Other involvement

Honoraria for lectures on symposia sponsored by AstraZeneca,

Bristol-Myers Squibb, Eli Lilly, Janssen, Lundbeck

Bipolar disorder in the elderly

Diagnosis and treatment of bipolar disorder

Early and late onset bipolar disorder

A staging model of bipolar disorder
Treatment in the elderly
Cognition and bipolar disorder
Conclusions

Diagnosis, pathophysiology and etiology

Diagnostic categories

Clinical syndromes
Behavioral changes and clinical symptoms
Disregulation of systems

Vulnerability / etiologic factors

Diagnostic categories

Clinical syndromes
Behavioral changes and clinical symptoms
Disregulation of systems

Vulnerability / etiologic factors

Diagnostic categories

Clinical syndromes
Behavioral changes and clinical symptoms
Disregulation of systems

Vulnerability / etiologic factors

Schizophrenia
Bipolar
Depression
Diagnostic
categories
Disorder

Clinical syndromes
Behavioral changes and clinical symptoms
Disregulation of systems

Vulnerability / etiologic factors

Diagnosis: clinical approach

Bipolar Disorder: the simple version

weeks
Mania

years
Interval

Depression

months
Manic-Depressive Cycle

Bipolar Disorder: M-D-I course

NIMH-LifeChart from the Stanley Foundation Bipolar Network

1 year

Bipolar Disorder: single and biphasic episodes

NIMH-LifeCharts from the Stanley Foundation Bipolar Network

Patient a

Patient b

Patient c

Patient d

Patient e

1 year

Bipolar Disorder: rapid cycling and mixed episodes

NIMH-LifeCharts from the Stanley Foundation Bipolar Network

Patient f

Patient g

Patient h

1 year

Bipolar disorder has a heterogenous longitudinal course

Patient 1

Patient 2

Patient 3

Patient 4

5 years

Bipolar Disorder: manic, depressive and mixed episodes with

ultradian cycling(female, 48)

NIMH-LifeCharts from the Stanley Foundation Bipolar Network

1 year

Polarity and Cyclicity are key elements

of bipolar disorder

Mania

Depression
1 year
1 jaar

Classification of mood disorders

Mood spectrum
Mania

Hypomania

Euthymia

Depression

Manic-Depressive Illness by Kraepelin

Das Manisch-Depressive Irresein

Mood disorders by Wernicke, Leonhard and Angst

Bipolar Disorder

Unipolar Depression

Mood disorders in DSM-5

Cyclothymia
Bipolar I
Dysthymia

Unipolar Depression

Bipolar II

Worldwide prevalence of mood disorders

(WHO, Merikangas, 2011)

Lifetime Prevalence in the Netherlands (age 18-64; n=6646)

NEMESIS 2 (2007-2009), De Graaf, ten Have & van Dorselaar (2010)

USA Lifetime prevalence of mood disorders

(NCS-R, Kessler, 2005)

Age

DSM-IV

DSM-5

BIPOLAR DISORDERS:

BIPOLAR AND RELATED DISORDERS:

Bipolar I disorder

Bipolar I disorder

Bipolar II disorder

Bipolar II disorder

Cyclothymic disorder

Cyclothymic disorder

Bipolar disorder NOS

Other specified bipolar and related

disorder
Unspecified bipolar and related
disorder

Mood disorder due to [general

medical condition]

Bipolar and related disorder due to

another medical condition

Substance-induced mood disorder

Substance/medication-induced
bipolar and related disorder

(with depressive/manic/mixed features)

Mixed features specifier

Manic episode, with mixed features

Bipolar disorder
Hypomanic episode, with mixed features
Major depressive episode,
with mixed features

Major depressive disorder,

if no lifetime mania / hypomania

Bipolar disorder,
if lifetime mania / hypomania

Unipolar Bipolar distinction in DSM-5

Bipolar I disorder

Bipolar II disorder

Other specified Bipolar disorder

Major depressive disorder,

with mixed features

Major depressive disorder

Antidepressant-induced (hypo)mania
in DSM-5
A full manic/hypomanic episode that emerges during
antidepressant treatment (e.g., medication, ECT)
but persists at a fully syndromal level beyond the physiological
effect of that treatment
is sufficient evidence for a manic/hypomanic episode, and
therefore, a bipolar I/II disorder.
However, caution is indicated so that one ore two symptoms
(particularly increased irritability, edginess, or agitation
following antidepressant use) are not taken as sufficient for
diagnosis of a hypomanic episode, nor necessarily indicative of
a bipolar diatheses.

Increased acitivity as second core symptom

of mania / hypomania in DSM-5
Manic episode / hypomanic episode, criterion A:
A distinct period of abnormally and persistently elevated,
expansive, or irritable mood
AND abnormally and persistently increased goal-directed
activity or energy,
lasting at least 1 week, or any duration if hospitalization is
necessary(mania), or 4 consecutive days (hypomania)

and present most of the day, nearly every day.

Mania and hypomania are similar but not the same!

manic episode
hypomanic episode
Mania and hypomania have the same symptoms,
only differ in severity and consequences!
Hypomania:

change in functioning not characteristic for person

observable for others

no marked impairment in social or occupational functioning

no psychotic features

no hospitalisation necessary

Diagnosis over time: illness progression

Retrospectieve Life Chart (part 1: 1929-1966)

Male, born 1929, first episode at age 17
1929

1966

End of
high
school

Military
service

37 years
SFBN 500-018

Retrospectieve Life Chart (part 2: 1966-1996)

Male, born 1929, continuous cycling started at age 50
1966

1996

Started
medication
divorced

30 years
SFBN 500-018

Prospectieve Life Chart (part 3: 1996-1998)

Male, born 1929, continuous rapid cycling
1996

1997

1998

Stopped all
medication

3 years
SFBN 500-018

Age at first symptoms (N=495 BP I / II)

(Stanley Foundation Bipolar Network)
Depression first

Depression and
(hypo)mania at
same age

N= 267

80
70

N= 156

60
50

40

30
20

(hypo)mania first

10

N= 72
0
0

10

20

30

age first depressive symptoms

40

50

60

70

Retrospective assessments

Unipolar depression may convert

to bipolar disorder

bipolar II disorder

Major depressive disorder

bipolar I disorder

Staging model of bipolar disorder

(modified from Berk et al, Bipolar Disorders, 2007; 9: 671- 678)
Unipolar
depresion

Bipolar
disorder

Interepisodic
impairment
Rapid cycling

at risk

Stage 0

prodromal
1a

1b

mania

recurrent bipolar

chronic/resistant
3a

Age of onset

3b

3c
4

Cumulative risk factors

in the longitudinal course of bipolar disorder
Diagnostic
delay

Family
History of BD

Childhood
trauma
Substance
abuse

Treatment
nonadherence

Psychosocial
and circadian
disruption

Medical
comorbidity

Cognitive
deficits
Multiple
mood
episodes
(Kindling)

Kapczinskis model for staging of bipolar disorder

Kapczinski et al, 2010

Treatment of bipolar disorder

Nomenclature of illness course and treatment

DEPRESSION

MANIA

Episode

Response

Interval

Relapse

Episode

Recurrence
mania

switch

Recurrence
depression

Remission

Acute
treatment

Recovery

Continuation
treatment

Long-term
prophylaxis

Acute
treatment

Treatment of bipolar disorder

Pharmacotherapy
Supportive treatment & Selfmanagement
Psychoeducation
Psychotherapy
Mania
Depression

Functional
impairment

Acute
treatment

Continuation
treatment

Maintenance
treatment

WEEKS

MONTHS

YEARS

Pharmacotherapy of bipolar disorder:

Mania

Pharmacotherapy of bipolar disorder:

Mania

Pharmacotherapy of bipolar disorder:

Depression

Pharmacotherapy of bipolar disorder:

Maintenance treatment

Pharmacotherapy of bipolar disorder

Haloperidol, Olanzapine, Quetiapine, Risperidone

Lithium / Valproate
ECT

LITHIUM

Mania

Quetiapine / Olanzapine

Depression

Valproate / Lamotrigine

Quetiapine
Olanzapine + Fluoxetine
Lamotrigine / Lithium / Valproate

Moodstabilizer + SSRI / Bupropion

ECT

Acute
treatment

Continuation
treatment

Maintenance
treatment

WEEKS

MONTHS

YEARS

Early and late onset bipolar disorder

Age at onset of bipolar disorder

(data from 7 studies including N=2968 patients; Goodwin & Jamison 2007)

Age-at-onset of bipolar disorders

(WHO, Merikangas, 2011)

Age at first symptoms (N=495 BP I and BP II; age 18-82)

(Stanley Foundation Bipolar Network)
Depression first

Depression and
(hypo)mania at
same age

N= 267

80
70

N= 156

60
50

40

30
20

(hypo)mania first

10

N= 72
0
0

10

20

30

age first depressive symptoms

40

50

60

70

Retrospective assessments!

Looking back at bipolar disorder in late life

Age < 50 yrs

Age > 50 yrs

Bipolar disorder in late life: various presentations

Early onset
bipolar disorder
Age of onset

Early onset depression

converting in late life
to bipolar disorder

Age of onset

Late onset
(bipolar) mood disorder

Age < 50 yrs

Age of onset

Age > 50 yrs

Early and Late Onset Bipolar Disorder

Depp & Jeste (review, 2004)
Early onset

(< 50 years)

Late onset

(> 50 years)

30
Early onset

50

Late onset
65

Bellivier et al (admixture analysis, 2001;2003)

Early onset (mid-adolescence)

mean 16.9 years [17.6]

Intermediate onset (young adult)

mean 26.9 years [24.6]

Late onset (older adult)

mean 46.2 years [39.2]

Correlates of age of onset

of bipolar disorder
Early onset:
higher familial risk
worse illness course (e.g. rapid cycling, suicide attempts)
more psychiatric comorbidity

30
Early onset

50

Late onset
65

Late onset:
neurological sequelae
more somatic comorbidity

Treatment in the bipolar elderly:

focus on lithium

Pharmacotherapy of bipolar disorder

is essentially not different in the elderly
Haloperidol, Olanzapine, Quetiapine, Risperidone

Lithium / Valproate
ECT

LITHIUM

Mania

Quetiapine / Olanzapine

Depression

Valproate / Lamotrigine

Quetiapine
Olanzapine + Fluoxetine
Lamotrigine / Lithium / Valproate

Moodstabilizer + SSRI / Bupropion

ECT

Acute
treatment

Continuation
treatment

Maintenance
treatment

WEEKS

MONTHS

YEARS

Studies of lithium in elderly bipolar patients

N

leeftijd

design

Dosis- concentratie

(range)
Van der Velde, 1970

12

Himmelhoch et al, 1980

81

67

Duur

Resultaten (uitkomstmaat)

(weken)
R

onbekend

2-156

onbekend

3-8

33% herstel van manie (global rating scale)

(60-74)
63.3
(55-88)
Abou-Saleh &Coppen, 1983
Murray, 1983

69% response van depressieve of manische symptomen (scale for clinical

efficacy)

57.1

onbekend

52

25

(60-78)

onbekend

104

43% remissie van manie en depressie (affective morbidity index)

Vergeleken met jongere patinten bleek klinisch effect
(onderhoudsbehandeling) niet afhankelijk van leeftijd

Schaffer & Garvey, 1984

14

69

900mg 0.58mEq/ml

>2

(65-77)
Stone, 1989

48

70.3

(71%)
R

onbekend

26

(65-82)
Sharma et al, 1993

68.5

41 (72)

67.2

40% geen klinisch terugval na 6 maanden, geen verschil in herstel van

manie tussen lithiumgebruikers (n=48) en niet-lithium gebruikers (n=44).

300-600mg/dag

40-78

(66-71)
Sanderson, 1998

10 patinten hadden klinische verbetering van manische symptomen

Response in alle rapid-cycling patinten, 2/4 een aanzienlijk herstel van

depressieve of manische symptomen

onbekend

Duur van opname (manie en depressie) was gelijk voor lithiumgebruikers

(n=41), valproaat gebruikers (n=20) en carbamazepine gebruikers (n=11)

Chen et al, 1999

30

69.4

onbekend

2.3

(>55)

Manie verbetert bij 67% van lithium gebruikers (n=30) vs 35% van
valproaat gebruikers (n=29). Bij therapeutische spiegel verbetert 83% van
lithium gebruikers (>0.8mmol/L) vs 75% van valproaat gebruikers (6590microg/L)

Goldberg et al, 2000

76;

71
Sajatovic et al, 2005

34

60.1

27

(>53)

900mg/dag - 0.43mmol/L
RCT

(55-82)
Geddes et al, 2010

600mg/dag - 0.63mmol/L;

750mg/dag

lithium na toxiciteit
76

0.8-1.1mmol/l
P

0.4-1.0mmol/L

Remissie van depressieve en manische episodes bij herintroductie van

Lithium (n=34) is effectiever dan placebo (n=31) in het voorkomen van

terugval in (hypo)manie, 29% stopte met de studie

104

Lithium is even effectief (n=27) als de combinatie lithium-valproaat (n=22)

en effectiever dan valproaat alleen (n= 31) bij terugvalpreventie.

Studies of anticonvulsants in elderly bipolar patients

N

leeftijd

design

Dosis- concentratie

(range)

Duur

Resultaten (uitkomstmaat)

(weken)

Valproaat

McFarland et al, 1990

66

(56-74)
Sharma et al, 1993

68.5

500mg/dag

50-150microg/mL
P

1000-1250mg/dag

70

70

24

71.3

40-78

1000-1500mg/dag

74.8

20

67.2

na

Combinatie van lithium en valproaat geeft response in alle

Herstel van manische symptomen in alle patinten

1000 mg/dag(100-1750)

>1

Significante verbetering van met name manische symptomen

>2

Effectief in 62% van de manische patinten met een

57nanog/mL (34-82)
R

743mg/dag (250-2000)

52-115mg/L

adequate behandeling
72-156

(65-81)
Sanderson, 1998

symptomen

2-4

53mg/L (11-102)
Schneider & Wilcox, 1997

manische

50-75microg/ml

(63-81)
Kando et al, 1996

van

rapid-cycling patinten, 2/4 een aanzienlijk herstel

(65-73)
Puryear et al, 1995

verbetering

valproaat additie bij therapie resistentie

(66-71)
Risinger et al, 1994

Significante

Remissie na valproaat additie bij lithiumtherapie in manische

rapid-cyclers

onbekend

Duur van opname was gelijk voor lithiumgebruikers (n=41),

valproaat gebruikers (n=20) en carbamazepine gebruikers

(n=11).
Niedermier

&

Nasrallah,

23

1998

67

(60-86)

Noaghiul et al, 1998

21

71

Chen et al, 1999

29

71.2 (>55)

1.029mg/dag (500-2250)

>1

72mg/L (36-111)

87% response (CGI) bij manische, depressieve en gemengde

episode

1.405mg/dag 72mg/L

1-7

onbekend

2.3

(60-82)

19 patinten hadden duidelijke klinisch herstel (CGI) van

manie

Manie verbetert bij 67% van lithium gebruikers (n=30) vs

35% van valproaat gebruikers (n=29). Bij therapeutische
spiegel verbetert 83% van lithium gebruikers (>0.8mmol/L)
vs 75% van valproaat gebruikers (65-90microg/L).

Mordecai et al, 1999

70.8

(64-75)

250-1000mg/dag

2-43

23-51.7

3 patinten stabiel met valproaat monotherapie

2 lithiumgebruikers verbeterden na valproaat additie
Zowel manische as depressieve symptomen

Geddes et al, 2010

31

(>53)

750-1250mg/dag

104

Lithium is even effectief (n=27) als de combinatie lithiumvalproaat (n=22) en effectiever dan valproaat alleen (n= 31)
bij terugvalpreventie.

Studies of anticonvulsants in elderly bipolar patients (contd)

Carbamazepine
Cullen et al, 1991

Sanderson, 1998

11

57

(48-72)
67.2

200-1200mg/dag

>1

2236Umol/L
R

onbekend

2/3 patinten herstelde aanzienlijk van therapieresistente melancholische depressie

Duur van opname was gelijk voor lithiumgebruikers

(n=41),

valproaat

gebruikers

(n=20)

en

carbamazepine gebruikers (n=11).

Lamotrigine
Robillard & Conn, 2002

71.5 (65-

33

60.1

25-100mg/dag

12

100-400mg/dag

76

85)
Sajatovic et al, 2005

50% reductie van depressie symptomen (HDRS) in 3

rapid cyclers

RCT

(55-82)

Lithium (n=34) is effectiever dan placebo (n=31) in

het voorkomen van terugval(manie/depressie).
18% stopte met de studie.

Sajatovic et al, 2011

57

66.5

(60-90)

150.9mg/dag

57.4% remissie (MADRS)

64.8% response
33% drop-out

Studies of atypical antipsychoticsin elderly bipolar patients

N

leeftijd

design

Dosis- concentratie

(range)

Duur

Resultaten (uitkomstmaat)

(weken
)

Aripiprazol
Gupta et al, 2004

Sajatovic et al, 2008

22

64

40mg/dag

56

Klinisch verbetering ook van M. Parkinson symptomen

59.6

10.3mg/dag

12

Significante verbetering van manische en depressieve

(50-83)

symptomen (YMRS en HAM-D)

Quetiapine

Sajatovic et al, 2008

59

62.9

RCT

400-800mg/dag

3-12

(55-79)

Al op dag 4 response (YMRS) in quetiapine (n=28) vs

placebo (n=31), en ook na 12 weken.

Risperidone
Madhusoodanan

et

al,

71-79

1-2mg/dag

2-3

1 patint herstelde van gemengde episode

85

2.5mg/dag

24

Remissie van katatone symptomen in 4 dagen, stabiel na

1995
Olanzapine
Nicolato et al, 2006

6 maanden
Clozapine
Shulman et al, 1997

72
(70-74)

25-112.5mg/dag

44

Klinische response (CGI) van psychotische manie in

therapie resistente patinten

Balancing benefits and risks of long-term

lithium treatment in the elderly
BENEFITS:

RISKS:

Best efficacy in prophylaxis

Narrow therapeutic window

Anti-suicidal efficacy

Toxicity due to altered pharmacokinetics

Neuroprotective

Nephropathy

Risks of lithium treatment in the elderly

RISKS:
Narrow therapeutic window (0.4 1.2 mmol/l)
Toxicity due to altered pharmacokinetics
Nephropathy

Especially in the elderly:

Treatment adherence (forgetfulness)

Cognitive impairment (+ cognitive side effects)

More susceptible to side effects and neurotoxicity
Somatic comorbidity (cardiovascular, renal, dehydration, neurological)
Somatic medications (diuretics, NSAID, ACE-i)
Same lithium blood levels with lower dose than in younger adults

Regular monitoring is essential: Lithium level, TSH, creatinine, GFR, calcium

Lithium-related renal adverse events

Pathophysiology

Frequency

Clinical symptoms

Treatment

Nephrogenic
Diabetes Insipidus

Frequent

Polyuria, nocturia,
polydipsia

Dose reduction;
amiloride, thiazides

Chronic lithium
nephropathy

Rare

Asymptomatic

Lithium withdrawal;
symptomatic

Nephrotic syndrome Very rare

Edema

Lithium withdrawal;
Corticosteroids if
persistent

Lithium intoxication: Rare (?)

acute renal failure

Symptoms of
lithium intoxication

Dialysis

Adapted from: Schou & Kampf. Lithium and the kidneys.

In: Bauer, Grof, Mller-Oerlinghausen (eds.). Lithium in neuropsychiatry. 2006

Lancet, 2012

Cognition in bipolar disorder

Cognitive dysfunction

Cognitive dysfunction in bipolar disorder

controls

Unaffected firstdegree relatives of

bipolar patients

bipolar disorder

schizophrenia

Goldberg & Burdick,Cognitive dysfunction in bipolar disorder. American Psychiatric Press 2008

Cognition in bipolar disorder

episode

interval

episode

MANIA

Effect of
medication ?

DEPRESSION

Effect of long-term
illness and repeated
episodes ?

Effect of acute
mood state on
test performance ?

Effect of
subsyndromal
symptoms ?
Effect of comorbidy ?
(substance abuse !)

Cognitive dysfunction in euthymic bipolar disorder

Impaired attention:
selective attention
attentional shifting
sustained attention

Impaired execitive functioning:

planning and decision making
impulse control

cognitive inflexibility during problem solving

Verbal memory

Medication and cognitive dysfunction

Pros and cons of medication with regard to cognitive (dys)functioning
are still open to debate.

Lithium may have reversible, dose-related cognitive side-effects (esp.

memory).

Anticonvulsants, antidepressants and antipsychotics may have (mild)

cognitive adverse effects.

But: lithium and valproate have neuroprotective properties.

Lithium treatment reduced the risk for dementia in bipolar disorder

(Kessing et al, 2010)

Conclusions

Conclusions
Bipolar disorder is a heterogeneous condition that may start at any point
in life, including old age
It is unclear whether childhood-onset BD, adolescent/adult onset BD and
late life onset BD have distinct etiological and pathogenetic backgrounds

Diagnosis and treatment in the elderly are not essentially different than
in younger adults
Elderly patients with mania / BD may have longstanding early onset BD,
previous recurrent depressions, or true late onset BD
Late onset bipolar disorder may have somatic causes (secondary
mania)
Altered pharmacokinetics, somatic comorbidity, polypharmacy and poor
treatment adherence may complicate pharmacotherapy in the elderly

Thank you for your attention