Bipolar

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

Vulnerability / etiologic factors

Disregulation of systems

Clinical syndromes

Diagnostic categories

Behavioral changes and clinical symptoms

Vulnerability / etiologic factors

Disregulation of systems

Clinical syndromes

Diagnostic categories

Behavioral changes and clinical symptoms

Schizophrenia Bipolar Disorder

Depression

Diagnosis: clinical approach

Mania

Depression

Manic-Depressive Cycle

Interval

Bipolar Disorder: the simple version

weeks

months

years

1 year

Bipolar Disorder: M-D-I course NIMH-LifeChart from the Stanley Foundation Bipolar Network

1 year

Patient a

Patient b

Patient c

Patient d

Patient e

Bipolar Disorder: single and biphasic episodes NIMH-LifeCharts from the Stanley Foundation Bipolar Network

1 year

Patient f

Patient g

Patient h

Bipolar Disorder: rapid cycling and mixed episodes NIMH-LifeCharts from the Stanley Foundation Bipolar Network

5 years

Patient 1

Patient 2

Patient 3

Patient 4

Bipolar disorder has a heterogenous longitudinal course

Bipolar Disorder: manic, depressive and mixed episodes with

ultradian cycling(female, 48)

NIMH-LifeCharts from the Stanley Foundation Bipolar Network

1 year

1 jaar

Mania

Depression

Polarity and Cyclicity are key elements

of bipolar disorder

1 year

Classification of mood disorders

Mania

Mood spectrum

Depression

Hypomania

Euthymia

Das Manisch-Depressive Irresein

Manic-Depressive Illness by Kraepelin

Bipolar Disorder

Unipolar Depression

Mood disorders by Wernicke, Leonhard and Angst

Bipolar I

Unipolar Depression

Dysthymia

Cyclothymia

Mood disorders in DSM-5

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 (with depressive/manic/mixed features)

Substance/medication-induced bipolar and related disorder

Manic episode, with mixed features

Hypomanic episode, with mixed features

Major depressive episode,

with mixed features

Mixed features specifier

Major depressive disorder,

if no lifetime mania / hypomania

Bipolar disorder,

if lifetime mania / hypomania

Bipolar disorder

Bipolar I disorder

Bipolar II disorder

Major depressive disorder,

with mixed features

Unipolar Bipolar distinction in DSM-5

Other specified Bipolar disorder

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.

manic episode

hypomanic episode

Mania and hypomania are similar but not the same!

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

SFBN 500-018

37 years

End of

high

school

Military

service

1966 1996

Retrospectieve Life Chart (part 2: 1966-1996)

Male, born 1929, continuous cycling started at age 50

SFBN 500-018

30 years

divorced

Started

medication

1996 1997 1998

Prospectieve Life Chart (part 3: 1996-1998)

Male, born 1929, continuous rapid cycling

SFBN 500-018

3 years

Stopped all

medication

age first depressive symptoms

706050403020100

ag

e f

irst

(hy

po

)ma

nic

sym

pto

ms

80

70

60

50

40

30

20

10

0

Age at first symptoms (N=495 BP I / II) (Stanley Foundation Bipolar Network)

Depression first

N= 267

(hypo)mania first

N= 72

Depression and

(hypo)mania at

same age

N= 156

Retrospective assessments

bipolar I disorder

bipolar II disorder

Major depressive disorder

Unipolar depression may convert

to bipolar disorder

Staging model of bipolar disorder (modified from Berk et al, Bipolar Disorders, 2007; 9: 671- 678)

Unipolar depresion

Bipolar disorder

Rapid cycling

Interepisodic impairment

Stage 0

1a 1b

2

3a 3b 3c

4

at risk

Age of onset

prodromal

mania recurrent bipolar

chronic/resistant

Cumulative risk factors

in the longitudinal course of bipolar disorder

Family

History of BD

Childhood

trauma

Substance

abuse

Diagnostic

delay Treatment

non-

adherence

Multiple

mood

episodes

(Kindling)

Cognitive

deficits

Medical

comorbidity

Psychosocial

and circadian

disruption

Kapczinski et al, 2010

Kapczinskis model for staging of bipolar disorder

Treatment of bipolar disorder

switch

Episode Interval

Acute

treatment

Continuation

treatment

Long-term

prophylaxis

MA

NIA

D

EP

RE

SS

ION

Remission Recovery

Response

Recurrence depression

Recurrence mania

Relapse

Acute

treatment

Episode

Nomenclature of illness course and treatment

Treatment of bipolar disorder

Depression

Mania

Acute

treatment

Continuation

treatment

Maintenance

treatment

WEEKS MONTHS YEARS

Pharmacotherapy

Supportive treatment & Selfmanagement

Psychoeducation

Psychotherapy

Functional impairment

Pharmacotherapy of bipolar disorder:

Mania


Depression


Maintenance treatment

Pharmacotherapy of bipolar disorder

Depression

Mania

Acute

treatment

Continuation

treatment

Maintenance

treatment

WEEKS MONTHS YEARS

Haloperidol, Olanzapine, Quetiapine, Risperidone

Lithium / Valproate

ECT

Quetiapine

Olanzapine + Fluoxetine

Lamotrigine / Lithium / Valproate

Moodstabilizer + SSRI / Bupropion

ECT

LITHIUM

Quetiapine / Olanzapine

Valproate / Lamotrigine

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 first depressive symptoms

706050403020100

ag

e f

irst

(hy

po

)ma

nic

sym

pto

ms

80

70

60

50

40

30

20

10

0

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

Depression first

N= 267

(hypo)mania first

N= 72

Depression and

(hypo)mania at

same age

N= 156

Retrospective assessments!

Looking back at bipolar disorder in late life

Age > 50 yrs Age < 50 yrs

?

Bipolar disorder in late life: various presentations

Age of onset

Age of onset

Age of onset

Age > 50 yrs

Early onset

bipolar disorder

Early onset depression

converting in late life

to bipolar disorder

Late onset

(bipolar) mood disorder

Age < 50 yrs

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]

Early onset Late onset

65

30

Depp & Jeste (review, 2004)

Early onset (< 50 years)

Late onset (> 50 years)

50

Early and Late Onset Bipolar Disorder

Early onset Late onset

65

30

50

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

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

Depression

Mania

Acute

treatment

Continuation

treatment

Maintenance

treatment

WEEKS MONTHS YEARS

Haloperidol, Olanzapine, Quetiapine, Risperidone

Lithium / Valproate

ECT

Quetiapine

Olanzapine + Fluoxetine

Lamotrigine / Lithium / Valproate

Moodstabilizer + SSRI / Bupropion

ECT

LITHIUM

Quetiapine / Olanzapine

Valproate / Lamotrigine

N leeftijd

(range)

design Dosis- concentratie Duur

(weken)

Resultaten (uitkomstmaat)

Van der Velde, 1970 12 67

(60-74)

R onbekend 2-156 33% herstel van manie (global rating scale)

Himmelhoch et al, 1980 81 63.3

(55-88)

R onbekend 3-8 69% response van depressieve of manische symptomen (scale for clinical

efficacy)

Abou-Saleh &Coppen, 1983 7 57.1 P onbekend 52 43% remissie van manie en depressie (affective morbidity index)

Murray, 1983 25 (60-78) P onbekend 104 Vergeleken met jongere patinten bleek klinisch effect

(onderhoudsbehandeling) niet afhankelijk van leeftijd

Schaffer & Garvey, 1984 14 69

(65-77)

P 900mg 0.58mEq/ml >2 10 patinten hadden klinische verbetering van manische symptomen

(71%)

Stone, 1989 48 70.3

(65-82)

R onbekend 26 40% geen klinisch terugval na 6 maanden, geen verschil in herstel van

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

Sharma et al, 1993 4 68.5

(66-71)

P 300-600mg/dag 40-78 Response in alle rapid-cycling patinten, 2/4 een aanzienlijk herstel van

depressieve of manische symptomen

Sanderson, 1998 41 (72) 67.2 R onbekend 5 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

(>55)

R onbekend 2.3 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)

Goldberg et al, 2000 2 76;

71

P 600mg/dag - 0.63mmol/L;

900mg/dag - 0.43mmol/L

3 Remissie van depressieve en manische episodes bij herintroductie van

lithium na toxiciteit

Sajatovic et al, 2005 34 60.1

(55-82)

RCT 750mg/dag

0.8-1.1mmol/l

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

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

Geddes et al, 2010 27 (>53) P 0.4-1.0mmol/L 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 lithium in elderly bipolar patients

N leeftijd

(range)


(weken)


Valproaat

McFarland et al, 1990 6 66

(56-74)

R 500mg/dag

50-150microg/mL

4 Significante verbetering van manische symptomen na

valproaat additie bij therapie resistentie

Sharma et al, 1993 4 68.5

(66-71)

P 1000-1250mg/dag 40-78 Combinatie van lithium en valproaat geeft response in alle

rapid-cycling patinten, 2/4 een aanzienlijk herstel

Risinger et al, 1994 4 70

(65-73)

R 1000-1500mg/dag

50-75microg/ml

2-4 Herstel van manische symptomen in alle patinten

Puryear et al, 1995 7 70

(63-81)

R 1000 mg/dag(100-1750)

57nanog/mL (34-82)

>1 Significante verbetering van met name manische symptomen

Kando et al, 1996 24 71.3 R 743mg/dag (250-2000)

53mg/L (11-102)

>2 Effectief in 62% van de manische patinten met een

adequate behandeling

Schneider & Wilcox, 1997 4 74.8

(65-81)

R 52-115mg/L 72-156 Remissie na valproaat additie bij lithiumtherapie in manische

rapid-cyclers

Sanderson, 1998 20 67.2 R onbekend 4 Duur van opname was gelijk voor lithiumgebruikers (n=41),

valproaat gebruikers (n=20) en carbamazepine gebruikers

(n=11).

Niedermier & Nasrallah,

1998

23 67

(60-86)

R 1.029mg/dag (500-2250)

72mg/L (36-111)

>1 87% response (CGI) bij manische, depressieve en gemengde

episode

Noaghiul et al, 1998 21 71

(60-82)

R 1.405mg/dag 72mg/L 1-7 19 patinten hadden duidelijke klinisch herstel (CGI) van

manie

Chen et al, 1999 29 71.2 (>55) R onbekend 2.3 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 6 70.8

(64-75)

R 250-1000mg/dag

23-51.7

2-43 3 patinten stabiel met valproaat monotherapie

2 lithiumgebruikers verbeterden na valproaat additie

Zowel manische as depressieve symptomen

Geddes et al, 2010 31 (>53) P 750-1250mg/dag 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

Carbamazepine

Cullen et al, 1991 3 57

(48-72)

R 200-1200mg/dag

2236Umol/L

>1 2/3 patinten herstelde aanzienlijk van therapie-

resistente melancholische depressie

Sanderson, 1998 11 67.2 R onbekend 4 Duur van opname was gelijk voor lithiumgebruikers

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

carbamazepine gebruikers (n=11).

Lamotrigine

Robillard & Conn, 2002 5 71.5 (65-

85)

P 25-100mg/dag 12 50% reductie van depressie symptomen (HDRS) in 3

rapid cyclers


(55-82)

RCT 100-400mg/dag 76 Lithium (n=34) is effectiever dan placebo (n=31) in

het voorkomen van terugval(manie/depressie).

18% stopte met de studie.


(60-90)

P 150.9mg/dag 57.4% remissie (MADRS)

64.8% response

33% drop-out

Studies of anticonvulsants in elderly bipolar patients (contd)

N leeftijd

(range)


(weken

)


Aripiprazol

Gupta et al, 2004 1 64 R 40mg/dag 56 Klinisch verbetering ook van M. Parkinson symptomen


(50-83)

P 10.3mg/dag 12 Significante verbetering van manische en depressieve

symptomen (YMRS en HAM-D)

Quetiapine


(55-79)

RCT 400-800mg/dag 3-12 Al op dag 4 response (YMRS) in quetiapine (n=28) vs

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

Risperidone

Madhusoodanan et al,

1995

2 71-79 P 1-2mg/dag 2-3 1 patint herstelde van gemengde episode

Olanzapine

Nicolato et al, 2006 1 85 R 2.5mg/dag 24 Remissie van katatone symptomen in 4 dagen, stabiel na

6 maanden

Clozapine

Shulman et al, 1997 3 72

(70-74)

P 25-112.5mg/dag 44 Klinische response (CGI) van psychotische manie in

therapie resistente patinten

Studies of atypical antipsychoticsin elderly bipolar patients

Balancing benefits and risks of long-term

lithium treatment in the elderly

BENEFITS: Best efficacy in prophylaxis

Anti-suicidal efficacy

Neuroprotective

RISKS: Narrow therapeutic window

Toxicity due to altered pharmacokinetics

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

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: acute renal failure

Rare (?) Symptoms of lithium intoxication

Dialysis

Lithium-related renal adverse events

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 in bipolar disorder

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

controls schizophrenia bipolar disorder

Unaffected first-

degree relatives of

bipolar patients

Co

gn

itiv

e d

ysfu

nctio

n

episode episode M

AN

IA

DE

PR

ES

SIO

N

interval

Effect of

subsyndromal

symptoms ? Effect of acute

mood state on

test performance ?

Effect of

medication ?

Effect of comorbidy ?

(substance abuse !)

Effect of long-term

illness and repeated

episodes ?

Cognition in bipolar disorder

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

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

Conclusions

Thank you for your attention

Bipolar

Documents

disorder bipolar

year bipolar disorder

treatment of bipolar

lundbeck bipolar disorder

angst bipolar

late onset bipolar disorder

years patient

related disorders