Bpad course

1. Course and outcome of
bipolar affective disorder
Ravi Philip Rajkumar
Associate Professor,
Department of Psychiatry,
JIPMER, Puducherry
Time to
relapse
Cycle
length
Rapid cycling
% of time
spent in
illness
Predominant polarity Age at
onset

2. Outline
 History
 Definitions and other terms
 Research methods
 Prodrome and short-term course (≤2 years)
 Long-term course
 Outcomes
 Predictors of course and outcome
 Future directions

3. An ancient debate...
Is bipolar disorder....
“a form of mental illness
with an episodic course,
full recovery,
and no deterioration
in personality
or lasting deficits?”
(Emil Kraepelin)
“...a terrible, incurable
form of insanity?”
(Jules Falret)
OR

4. First, some definitions
 Course is the longitudinal description of the
illness
 Outcome is the clinical or functional end-point
at a specified period after the onset of illness;
therefore, it is cross-sectional

5. Terms used to describe the course
of bipolar disorder
 Age at onset
 Number of episodes
 Episode frequency (≈ cycle length)
 Spontaneous cycling
 Time to mania / depression / any relapse
 Rapid cycling (and its variants)
 Seasonality
There are certainly others!

6. Types of outcome
 Clinical or symptomatic
recovered, syndromal, subsyndromal?
 Functional
social, occupational, marital / familial...
 Neurocognitive
deficits and their progression...
 Mortality
any cause, medical, accidental, suicide...
 Morbidity (?)
higher risks of certain medical disorders...

7. Remember....
 Clinical outcome (control of symptoms)
DOES NOT ALWAYS CORRELATE WITH
Functional outcome (employment, marriage,
day-to-day functioning, quality of life)

8. How do we study course?
 Longitudinal follow-up studies
best, but also most resource-intensive...
 Retrospective and catch-up studies
easier, but subject to bias and missing data...
 Chart reviews
easiest, but of relatively lower value

9. Studies of short-term course and
outcome

10. The bipolar prodrome
Subsyndromal or non-specific symptoms
In children and
adolescents
(Egeland et al., 2000)
In adults
(Zeschel et al., 2013)
Episodic sad mood
Episodic irritability
Anger dyscontrol
Episodic changes in energy
level
Demanding behaviour
Conduct symptoms
Sleep disturbance
In mania
Increased energy level
Racing thoughts
Agitation
Overtalkativeness
In depression
Low mood
Reduced energy
Fatigue
Insomnia

11. First-episode mania: time to
recovery – United States
(Tohen et al., AJP 2003)

12. First-episode mania: time to relapse
– United States
(Tohen et al., AJP 2003)

13. 1-year outcomes following
admission – United States
(Keck et al., AJP 1998)

14. 2-year outcomes for bipolar I
disorder: Australia
(Kulkarni et al., BMC Psychiatry 2012)

15. 2-year outcomes for bipolar I
disorder: EMBLEM study (France)
(Azorin et al., BMC Psychiatry 2009)

16. Cognition: short-term outcomes
29 stable patients with BP, 30 healthy controls
3-month follow-up
Baseline deficits in attention, processing speed
HAM-D, YMRS, cognition assessed
Over follow-up:
Change in depressive symptoms associated
with decreased verbal fluency
No cognitive effect of changes in manic symptoms
(Chaves et al., 2011)

17. Cognition: short-term outcomes
 53 patients with first episode mania
 1 year follow-up
 Deficits in verbal, nonverbal, working memory
at baseline
 Patients who remained well over 1 year
showed improvements in cognition
 Recurrences were associated with further
declines
(Kozicky et al., 2014)

18. Functioning: short-term outcomes
Study Study sample and
follow-up
Results
Goetz et al., 2007
(EMBLEM)
3681 patients with
acute mania; 1 year
28% good work
outcome;
68% high work
impairment
Reed et al., 2010
(EMBLEM)
1393 patients with
acute mania; 2 years
41% high work
impairment; good
outcome correlated
with independent
housing, living
together
Bearden et al., 2011 79 recovered BP-I; 9
months
45 (57%)
occupationally
recovered at
baseline; a further 8
(10%) recovered at
follow-up

19. Studies of long-term course and
outcome

20. What happens to “soft” bipolar
disorders?
 57 patients with
cyclothymia or
BPAD-NOS
 4.5 years follow-
up
 42.1% changed to
bipolar type II
 10.5% changed to
bipolar type I
(Alloy et al., 2012)

21. What happens to “soft” bipolar
disorders?
 140 youth with
BPAD-NOS
 5 years follow-up
 23% changed to
bipolar type I
 22% changed to
bipolar type II
(Axelson et al., 2011)

22. How stable is the diagnosis of
bipolar disorder?
 Over 10 years, 77.8% of 95 patients with BP
retained their diagnosis at final follow-up
 However, this was unchanged only in 69.5%;
8.4% had diagnostic disputes in the interval.
 In a study of first-episode BP patients over 10
years, only 50.3% maintained the diagnosis at
all follow-ups; 49.7% had at least one change
in between.
(Bromet et al., 2011; Ruggero et al., 2010)

23. How much time do patients spend in
different phases?
Bipolar I disorder
146 patients
Follow-up 12.8 years
Symptomatic 47.3% of
the time
31.9% depressive, 8.9%
manic, 5.9% mixed
Subsyndromal symptoms
3 times more common
than full syndromes
Bipolar II disorder
86 patients
Follow-up 13.4 years
Symptomatic 53.9% of
the time
50.3% depressive, 1.3%
hypomania, 2.3% mixed
Subsyndromal symptoms
3 times more common
than full syndromes
(Judd et al., 2002, 2003)

24. Do the symptom patterns change
with age?
 Depressive
symptoms are
more prominent
in the third, fourth
and fifth decades
of life.
 Time spent in
mania is not
influenced by
age.
(Coryell et al., 2009)

25. How long do episodes last?
219 patients with bipolar I disorder; 5-year follow-up
* Only two cases
(Solomon et al., 2010)
Episode type Time to recovery for
50% patients
(weeks)
Time to recovery for
75% patients
(weeks)
Mania 7 15
Depression 15 35
Hypomania 3 6
Mixed* 7 76

26. Do cycle lengths shorten with time?
A review of older reports (summarized in Baldessarini et al.,
2012) found evidence of shortening in approximately 1/3 of 40
published studies.
Study Study sample and follow-
up
Results
Turvey et al., 1999 165 patients with BP-I; 10
years
No shortening observed
Cusin et al., 2000 244 patients with BP, 182
with depression; 14 years
Shortening in both groups,
but more prominent in BP
Dittmann et al., 2002 152 patients with BP, 2.5
years
Shortening in the majority of
patients
Baldessarini et al., 2012 128 patients with BP, 5.7
years
Random course common;
shortening rare
Subramaniam et al.
(unpublished)
150 patients with BP;
retrospective
Weak evidence of shortening

27. Course on treatment: 20 years ago
(United States)
 4.3 year follow-up of 82 outpatients with DSM-
III bipolar disorder
 73% relapse rate
 37% relapsed by 1 year
 2/3 of these (49%) had multiple relapses
 Mean survival time 2.92 years
 Relapses not due to drug default
(Gitlin et al., 1995)

28. Course on treatment: the latest
results (Austria)
 4-year follow-up of 300 patients (158 BP-I, 142
BP-II)
 68% relapse rate
 Mean time to relapse: 208 days
 Not much difference between BP-I and BP-II
 Lithium prolongs time to any relapse
 Either patient- or doctor-initiated medication
changes shorten the time to relapse (!)
(Simhandl et al., JCP 2014)

29. Course of rapid-cycling bipolar
disorder
89 patients with rapid
cycling BP, 13.7 year
follow-up
More weeks in depression /
hypomania
Higher likelihood of serious
suicidal attempts
In 80% of cases, rapid
cycling resolved over 2
years
(Coryell et al., 2003)

30. Course of cognitive deficits
68 BP-I, 45 healthy
controls
≈9 year follow-up
Baseline impaired
attention, memory,
executive functions
Attention improved
slightly over time
Executive function
worsened with time
(Torrent et al., 2012)

31. Course of cognitive deficits:
older adults
33 patients with BP,
mean age 69.7 years
36 healthy controls
3-year follow-up
Accelerated cognitive
decline compared to
controls
(Gildengers et al., 2009)

32. But are we sure?
 Meta-analysis of studies from 1990-2014
 Mean follow-up period 4.62 years
 14 cognitive measures
Scores remained stable
Accept the null hypothesis?
(Samame et al., 2014)

33. Functioning: long-term outcomes
Study Study sample and follow-up period Result
Coryell et al., 1993 148 BP, 240 depression; 5 years Significant fall in job
status, income even after
recovery; BP=MDD
Goldberg et al., 1995 51 BP, 49 depression; 4.5 years Good outcome in only
41% of BP; significant
work disability
Judd et al., 2005 158 BP-I, 133 BP-II; 15 years Symptom improvement
and functioning related;
depression, not mania,
predicts disability
Goldberg and Harrow
2010
34 BP, 89 depression; 10 years Good outcome in 50% of
BP; functional decline in
30-40%
Burdick et al., 2010 33 BP, 15 years Poor work outcome in 15
(45.5%) patients
Goldberg and Harrow
2011
46 BP, 49 depression; 15 years Good outcome in 35%
BP vs 73% depression

34. How common is “poor-outcome”
bipolar disorder?
Earlier results suggest that around 15-20% of
patients have poor functional outcomes
(Hastings, 1958; Tsuang et al., 1979)
A later meta-analysis found that at least 30% of
patients do not reach premorbid levels
(MacQueen et al., 2001)
A recent study of out-patients found that 14 of 54
(26%) had severe disability
(Rosa et al., 2014)

35. What happens to antidepressant-
induced switches?
Study Sample description Results
Navarro et al., 2014 2-year follow-up of
patients who
developed
hypomania on
antidepressants
No new cases of
hypomania, despite
antidepressant
continuation
Wada et al., 2013 1-year follow-up of 33
patients admitted for
antidepressant-
induced hypomania
or mania
6 patients (18.2%)
converted to bipolar
disorder

36. Seasonality
Seasonal peak Reported in
Summer peak of mania United Kingdom, Australia, Taiwan
Spring peak of mania United States
Late winter-spring peak of mania Brazil, India*
Winter peak of mania North India
No specific pattern for mania India, England, Canada, and one
multi-centric study spanning both
hemispheres
Winter peak of depression England
No specific pattern for depression Canada
Summer peak for depression North India
Potential influence for many variables: day length, sunlight
exposure, humidity, rainfall, latitude...
* Unpublished data

37. Suicide as an outcome
Suicide attempts in 182 of 4360 patients
Completed suicide in 8 of these
(Dennehy et al., STEP-BD, 2011)
8 deaths from suicide in a UK cohort of 235 patients,
collected over a 35-year period
(Dutta et al., 2007)

38. Predictors of suicide
 Early onset
 Family history of suicide
 Depressive symptoms / mixed states
 Severe episodes
 Rapid cycling
 Axis I comorbidity
 Substance use comorbidity
(Hawton et al., 2005)

39. Violent crime as an outcome
Systematic review: odds ratio of 2-9 for a patient
with BP to commit a violent crime
Prospective study: 8% (314 of 3743) Swedish
patients with BP committed violent crime.
However, this was significant only in those
with comorbid substance use.
No relationship to episode type / symptom profile
(Fazel et al., 2010)

40. Death as an outcome
 10922 Taiwanese patients with either
depression or bipolar disorder (1542 BP)
 1.3 fold increase in overall mortality in BP
 4-fold increased risk of suicide
 2-fold increased risk of accidental death
 Cardiovascular comorbidity correlates with
suicide
(Chang et al., 2012)

41. What is the scenario in India?
Chopra et al., 2006
 Retrospective life chart study of 34 patients
 Community health setting (Sakalawara)
 Mean 4.4 episodes over 20.2 years
 72% of episodes were mania
 Mean duration of mania: 13 weeks
 Mean duration of depression: 18 weeks
 Cycle length shortened, but not significantly

42. What is the scenario in India?
Subramanian et al., 2015
 Retrospective life chart study of 150 patients
 General hospital psychiatry unit (JIPMER)
 Mean 5.7 episodes over 13.4 years
 Mania ≈5 times commoner than depression
 52.7% had only recurrent mania
 Median time to relapse: 24 months
 Weak trend to shortening of cycle length in
time

43. Predictors of course and outcome

44. Age at onset
 Higher episode frequency
 Shorter time to relapse
 More time spent in depression
 More suicidal attempts
 Poorer functioning and quality of life
 More rapid cycling
 Higher substance use comorbidity
Onset < 13 years has the greatest impact
(Kupka et al., 2005; Perlis et al., 2009; Lev-Ran et al., 2013)

45. Gender
Men Women
More alcohol and drug use
disorders
More violent suicide attempts
Longer time to recovery from
acute mania
Depressive onset
Predominant depressive
polarity
More psychotic depression
More rapid cycling
More Axis II comorbidity
More lifetime suicide attempts
Faster recovery from acute
mania
Higher risk of depression after
acute mania
(Kupka et al., 2005; Miquel et al., 2011; Nivoli et al., 2011)
♂ ♀

46. Adverse life events
1. Childhood adversity
 Overall childhood trauma associated with early
onset, poor functioning
 Physical and sexual abuse associated with a
higher number of episodes
 Physical abuse also associated with self-harm
and poor functioning
 Childhood physical / sexual abuse associated
with rapid cycling
(Kupka et al., 2005; Larsson et al., 2013)

47. Adverse life events
2. Current stressors
Negative life events can trigger both unipolar and
bipolar depression; not much difference
In some studies, negative life events exacerbate
depression
Chronic stressors associated with depression, but
not mania
Low social support predicts depression
No consistent evidence for an effect of life events
on the onset or severity of mania
(Weinstock and Miller, 2010; Gershon et al., 2013;
reviewed in Johnson, 2005)

48. Comorbid substance use
1. Alcohol
 Alcohol use commonly precedes or
accompanies bipolar depression
 Time sequence is important; “bipolar first” has
a worse outcome than “alcohol first”
 Greater time spent in affective episodes
 Possible greater risk of cycling into mania
 Poorer response to lithium
 Greater risk of suicide
(O'Connell et al., 1991; Strakowski et al., 2005; Baethge et al., 2008;
Ostacher et al., 2010; Farren et al., 2011)

49. Comorbid substance use
2. Other substances
 Cannabis use commonly precedes or
accompanies mania
 Possible greater risk of cycling into mania
 Higher rates of nicotine and alcohol use
 Higher rates of dissocial personality disorder
 Earlier onset
 Greater episode frequency and rapid cycling
 Greater risk of violent crime
(Ostacher et al., 2010; Fazel et al., 2010; Lev-Ran et al., 2013)

50. Comorbid substance use
3. Effects of recovery
 In a sample of 1000 patients from STEP-BD,
recovery from substance use was associated
with improved role functioning.
 Treatment of comorbid BP and alcoholism with
valproate may reduce heavy drinking and the
number of drinks consumed over 6 months.
(Weiss et al., 2005; Salloum et al., 2005)

51. Comorbid anxiety
 Three-fold increase in depressive morbidity
 Prolonged recovery from depression
 Risk of earlier relapse
 Poorer short-term (12 month) quality of life and
role function
 Poorer 3-year global and illness outcomes
 Require more intensive psychotherapy during
depressive episodes
 Worse impact for GAD and social phobia
(Otto et al., 2006; Coryell et al., 2009; Deckersbach et al., 2014)

52. Family history of mood disorders
Data from 2600 STEP-BD patients
 Earlier age at onset
 More rapid cycling
 More suicide attempts
 Elevated depressive symptoms
 Poorer quality of life
 Higher neuroticism and personality disorder
traits
(Antypa and Serretti, 2014)

53. Spontaneous cycling
 Switching polarity within an episode is
associated with a poor overall outcome
 Polyphasic switching (more than 2 in an
episode) associated with more time in an
episode, and poor symptomatic and functional
outcomes over 10 years.
 Some evidence of an association with
substance use
(Turvey et al., 1999; Maj et al., 2002; Vieta et al., 2009)

54. Psychotic symptoms
Over a 4-year follow-up, 73.2% of patients with
psychotic BP reached premorbid levels
Baseline first-rank symptoms predicted a poorer
outcome
(Carlson et al., 2012)
Mood-incongruent psychotic symptoms predict
poorer symptomatic and functional outcomes
(Miklowitz, 1992; Marneros et al., 2009)

55. Polarity of the index episode
 Retrospective study of 320 BP-I patients
 Index polarity appears to predict long-term
polarity
 Rapid cycling and suicide attempts more
common with depressive onset
 Psychotic symptoms less common with
depressive onset
 Mixed onsets associated with suicide attempts
and chronicity
(Perugi et al., 2000)

56. Cognitive deficits
 Memory, scanning and processing speed
predict short-term (9 month) work outcomes.
 Baseline processing speed predicts 15-year
global outcome
 Verbal learning deficits predict long-term work
outcome
 Baseline verbal memory deficits predict low
functioning over 9 years.
(Burdick et al., 2010; Bearden et al., 2011; Torrent et al., 2012)

57. Future directions

58. Staging bipolar disorder?
Stage Description
Stage I Return to premorbid status between
episodes
Stage II Have comorbidites or residual symptoms
needing treatment; can manage daily
activities
Stage III Require social and occupational
rehabilitation; have difficulty with daily
activities
Stage IV Patient unable to live independently or
maintain self-care
These stages correlate with cognitive impairment and
structured assessments of functioning.
(Kapczinski et al., 2009; Rosa et al., 2014)

59. Using technology to assess course?
 62 patients with BP (47 BP-I, 15 BP-II), 36 weeks
 Text messages (n=54) or e-mail prompts (n=8)
 Weekly self-report; 75% compliant
Results:
47.7% time in depression
7% in mania, 8.8% in mixed states
36.5% in euthymia
Good agreement with existing results
(Bopp et al., 2010)

60. Cross-national and cross-cultural
differences?
 Indian data has shown a preponderance of
mania, including “unipolar” mania, in contrast
to “Western” studies
 Outcomes after a first episode of mania were
uniformly better in Taiwan than in the United
States
(Strakowski et al., 2007; Narayanaswamy et al., 2014;
Subramanian et al., 2015)

61. Tackling unanswered questions...
 Is there a bipolar “DOSMD challenge”?
 The “juvenile bipolar” controversy
 Genetic or biological markers of course
 Better delineation of the prodrome
 Tracking cognitive and real-world outcomes
 Novel predictors of outcome (sleep, body mass
index)

62. And one final thought...
Rapport et al., Acad. Psychiatry, 2013
 121 charts of BP outpatients
 41 treated by residents, 80 by consultants
 Improvement similar across groups
 Remission was 26/80 for consultants but
only 5/41 for residents
....but???