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Clinical Pearls
Bipolar Affective Disorders
Dr. Ahmed Shoka
Consultant Psychiatrist
1
The Task
What is a Mood Stabiliser ?
Interesting Epidemiology
Case Studies
Clinical Pearls
2
What Is a Mood Stabiliser?
Mood stabiliser is a categoric designation that
has been widely used for nearly 50 years, but it
still lacks a consensus definition.
Definitions published in the past decade
indicate that the mood stabilizer concept is
amenable to scientific definition. These
definitions refer to primary treatment objectives
for bipolar disorder-relief of acute and
prevention of recurring episodes(mania and/or
depression)
3
Mood Stabiliser
These definitions might be constructed as a single
overarching objective ( euothymia), or as many as four
primary therapeutic objectives.
According to Gary S.Sachs,the definition of the term
mood stabiliser does not require antidepressant or
antimanic efficacy ,per se, merely that the
medication”decrease vulnerability to subsequent
episodes of mania or depression” and not to
exacerbate the current episode or maintenance phase
of treatment.
4
Mood stabiliser
The American Psychiatric Association’s
Practice Guideline for Treatment of Patients
With Bipolar Disorder (1994) defines mood
stabilizers as “ medications with both antimanic
and antidepressive actions”.
From time to time research has been
contradictory about the efficacy of lithium as an
antidepressant ( keck and McElory 1996)
5
Mood stabilisers - the story so
far….
1949 Cade reports efficacy of Lithium in bipolar disorder
1967 Valproate licensed for treatment of Epilepsy in France
1973 Okuma reports efficacy of Carbamazepine in bipolar
disorder
1995 Depakote (valproate semisodium or divalproex)
marketed for mania in the USA. Depakote has higher
bioavailability, and is a different compound than valproate
1996 Walden reports efficacy of lamotrigine in Bipolar
disorder
1999 Valproate described as ‘a milestone in drug therapy’.
More than 5,000 publications devoted to the various forms
of Valproate. New indications are still being studied
6
Types
Most definitions, however, honour Lithium as
the prototype mood stabiliser, and require that
a mood stabiliser demonstrates efficacy
against depression and mania ( Bimodal
Efficacy).
Lithium
Antiepileptics
Antidepressants
Antipsychotics ( typicals/ atypicals)
7
Bipolar Affective Disorder
Multidimensional illness with symptoms that
extend beyond simple mania or depression.
The 6th leading cause of disability worldwide
according to the WHO.
The term” spectrum” was 1st used in the field of
psychiatry by Kety et al in schizophrenia
spectrum and later by Akiskal et al to identify
the cyclothymic-bipolar spectrum.
The spectrum model provides a useful
dimensional approach to mood
psychopathology.
8
Serious Cost
Bipolar illness is associated not only with
decreased QOL for patients and their families,
but also with high utilization of psychiatric and
general medical services, and increased
mortality rates due to suicide and other medical
conditions. Lish et al estimated that BAD
reduces life expectancy by 10 years and costs
the afflicted individual an average of 9 years of
productive adult life.
9
Mortality in Bipolar Disorder
Up to 20% of patients with Bipolar Disorder who
are followed up may commit suicide
30 times population rate
Up to 50% attempt suicide at least once
1.5% annual suicide rate for first 10 years
Indirect cost of suicide- £179 million per year
1. Montgomery & Cassano, 1996 Management of Bipolar Disorder, p6
2. Das Gupta R & Guest, 2002
Economic Impact and
Disability
With onset in mid to late 20’s effectively lose 9
years of life, 12 years of normal health and 14
years of normal activity1
Increases likelihood of divorce by 3x1
Total annual cost UK £2 billion2
Direct NHS annual cost £199 million2
35% of cost spent on inpatient stay
4% of NHS cost is GP prescribed pharmaceuticals2
1. Montgomery SA, Cassano GB. Management of Bipolar Disorder. 1996, p5,
2. Gupta and Guest, BJ Psych 2002, 180,227-233 11
3 Confusing Terms
Discontinuation Syndrome; recurrence of the
underlying disorder ( for which the drug was
prescribed) or the emergence of novel
symptoms.
Rebound Phenomenon; exaggeration of
certain aspects of the original symptoms.
Withdrawal Effect; misleading term as it implies
dependence on a drug with tolerance, an
inability to control the drug use (addiction).
12
Problems In Diagnosis Of BAD
Experienced clinicians and researchers debate
whether BAD is under-diagnosed or over-
diagnosed, but there is no debating that it is
often poorly diagnosed. There are no
diagnostic laboratory tests for BAD and
symptoms can vary and are unreliable.
Lish et al. report that nearly a decade passes
from onset of the first clear cut episode before
bipolar patients are correctly diagnosed.
13
What Causes Misdiagnosis?
Surprisingly one of the biggest factors may be
the ICD-10 or DSM-IV itself.
A depressive episode is the initial presentation
of BAD in more than half of newly-ill patients.
Patients having a first episode of depression
will be diagnosed as having a unipolar mood
disorder until the occurrence of a manic or
hypomanic episode.
14
Pearl
Understanding the illness and the
limitation of our nosology can reduce the
gap between having a treatable condition
and getting treatment.
15
Protective & Risk Factors In BAD
Protective factors Risk factors
*Use of prophylactic *Antimanic agents
medications *Antidepressants
*Abstinence from alcohol *Alcohol/ Drugs
/ recreational drugs *Cognitive distortions
*Structured schedule *Stress
*Regular awaking and *Lack of psycho-
sleep times education/
* Schedule of recurring Psychotherapy
social activities *East-West travel
*Support system *Abrupt discontinuation
*Family / Friends of medications
16
Epidemiology
Prevalence of bipolar I disorder is about 1%
(range 0.5-1.2%) and a female:male gender
ratio close to 1:1.
Prevalence of all subtypes of bipolar illness
ranges from 3-12%
Typically the first episode of BAD has its onset
during the 2nd or 3rd decade of life (peak age of
onset 15-25 years).
17
Epidemiology and Morbidity
of Bipolar Disorder
Lifetime Prevalence 0.5%-7.5% (Reflects uncertainty over
diagnosis)
Equal sex distribution for Bipolar 1, more females Bipolar 2
NICE estimates 546,000 sufferers in the UK
4454 new cases diagnosed per year
Onset before 30 years old in 90% patients
Recurrent illness in vast majority of patients - up to 84% have
more than 5 episodes, and up to 42% more than 11
Bipolar sufferers account for 5-15% of new long-stay hospital
admissions
Inadequate treatment responsible for most costs
1. Montgomery & Cassano, 1996 Management of Bipolar Disorder 2. Nice draft HTA on Acute mania, 2003 (available
online at http://www.nice.org.uk) 3.Das Gupta R & Guest, 2002
Bipolar patients are
symptomatic
almost half their lives
6%
9%
32% 53%
Weeks asymptomatic Weeks depressed
Weeks manic / hypomanic Weeks cycling / mixed
n=146; 12.8-year follow-up Judd et al 2002
19
Course
The initial episode may be followed by a longer
remission than subsequent episodes (4.5 years
median).
Some studies have suggested that the periods of
remission shrink progressively over the course of the
first 3 to 5 episodes and then tend to stabilise, with an
average of about one episode per year. More recent
data corrected for number of episodes also suggest an
average of about one per year, but find a more
constant rate of recurrence.
20
21
Case 1
CK , female,27 years old, single mother
Long history of BAD
Admitted under section 3 MHA, in a mixed
affective state
Became full blown manic without psychotic
symptoms
Very irritable, arrogant, aggressive
No insight, however accepted medications
22
Case 1
Combination of Depakote and Quetiapine
Less severe manic symptoms, less irritable but mood
remained very elated with no insight
Clonazepam was added with very good response
Became informal, gradual home leave till discharged
Clonazepam was discontinued during OPD follow ups
Remained well on Quetiapine and Depakote
No depressive symptoms after full remission
23
Case 2
KA, Female,43 years old, married with one daughter
Long history of BAD and long history of poor
compliance
85% of previous admissions were due to manic
episodes
Admitted under section 3 MHA, in a severe manic
episode with psychotic symptoms and markedly
disinhibited behaviour
No insight
Refused any oral medications initially
24
Case 2
Started on depot injection; Haldol decanoate
Accepted oral medications, so was stared on
depakote with very good effect in controlling
the elated mood and reducing the irritability but
remained disinhibited and psychotic
Quetiapine was initiated by gradual sliding
scale with very good response in reducing the
psychotic symptoms and controlling the
disinhibited behaviour
25
Structure of a Recurrent
Illness
Precipitant
Episode
Underlying illness
26
Bipolar disorder is
multidimensional
Mania
Mania
hypomania
Maintenance
dysthymia
Depression
27
Treatment in the real
world….
• Ideal Reality
Good research evidence for In practice no reductions in
the efficacy of Lithium hospital admissions may be
seen
‘Medications for the treatment
of mania generally exert 10 fold increase in Lithium
some appreciable clinical use in Edinburgh associated
effect by the 10th to the 14th with a threefold increase in
day of treatment.’ admissions
(APA Guidelines)
Mania predicts the longest
inpatient stay on admission
wards of all diagnoses
Creed et al, Psychol Med 1997, 27,961-6, Dixon WE Kendal RE Psy Med 1996,16:521-530
Lithium use and discontinuation
in a health maintenance
organization
100
90 LITHIUM IS UNDERUSED
80 • Only 8% of patients used Li for 90%
70 of days enrolled
Percentage
60 • Median continuous use = estimates between 76-433
days
50
40
30
20
10
0
0 500 1,000 1,500 2,000
Days
Length of first continuous period of lithium use (n=1,594)
Adapted from Johnson, 1996
Consequence of Rapid
Discontinuation
of Lithium in Bipolar I Patients
Percent remaining in remission
100
Gradual (N=15)
80
60
40
20 Rapid (N=108)
0
0 10 20 30 40 50 60
Time after stopping Lithium (months)
30
From Suppes et al, 1991.
Valproate 1
Valproate has been established as
significantly superior to placebo in
alleviation of acute manic episodes in 2
random,double-blind studies in which no
neuroleptics were allowed and only
limited ,brief use of BDZ was permitted
(Pope et al 1991, Bodwen et al 1994)
31
Valproate 2
Open reports of valproate in the
prophylaxis of bipolar disorder indicate
reduction in both the frequency and
intensity of episodes with suggestion of
greater benefit on manic symptomatology
(Puzynski and Klosiewicz 1984,
Calabrese et al 1992)
32
Depakote in lithium
failures
60%
54%
50%
MRS mean Change From Baseline
40%
30%
20%
10% 5%
0%
Depakote Placebo
P = 0.03 Dep vs Pla
Median improvement in YMRS by 1-3 weeks
33
Pope et al Arch Gen Psych 1991
Predictors of Response 1
Two studies have shown that Depaokte was
more effective than Lithium in patients with
mixed manic episodes (Freeman et al 1992,
Bodwen 1995, Swann et al 1997)
Further analysis of the study by Bodwen et al
indicated that presence of two or more purely
depressive symptoms distinguished patients
with poor response to Lithium.
34
Predictors of Response 2
Open reports indicate that Depakote is
also effective in patients with hypomanic
states and cyclothymic disorders
(Lambert 1984, Jocobsen 1993)
Valproate is effective in reduction of
frequency of migraine headache which is
highly associated with bipolar disorder
(Siberstein et al 1993, Jensen et al 1994,
Breslau et al 1994)
35
Mania vs Mixed mania
80%
72%
70%
60% 58%
51%
50%
% Patients
40% 37%
29%
30%
20%
10%
0%
Mania Mixed mania
1 2
P = 0.01 DepDepakote
vs Pla Lithium PlaceboDep vs Li
P = 0..027
30% Improvement in MRS in 21 days 20% Improvement in MRS by day 5
36
1.Data on file M88-267, 2Bowden J Clin Psych 1995
Efficacy of Depakote in Rapid
Cycling
Depakote is highly effective in rapid cycling patients1
80% 74%
Complete cessation Complete cessation
of symptoms/cycling of symptoms/cycling
Mixed Mania Mania
n=10 n=19
Percentage of patients achieving complete cessation of symptoms/cycling with Depakote in a prospective, longitudinal, naturalistic study
Treatment of choice for all types of bipolar rapid cycling2
37
1.Calabrese JR et al. Predictors of valproate response in bipolar rapid cycling. J.Clin Psychopharmacol 1993; 13: 280-283
2.Sachs GS et al (Eds), Medication treatment of bipolar disorder : a special report in the Expert Consensus Guidelines Series, April 2000, Mc Graw-Hill, New York
Bipolar depression
Bipolar depression,the most common phase of
bipolar disorder,causes significant morbidity
and mortality.
Traditional drugs such as lithium, lamotrigine or
antidepressants each offer some clinical
efficacy.
Lamotrigine is associated with rash in
approximately 10% of patients and serious
rash in up to 0.1% of patients.
38
Pearl
Initial findings suggest that atypical
antipsychotics may prove to be important
future treatments for patients with bipolar
depression ( Olanzapine & Quetiapine)
39
Bipolar Depression 1
Lamotrigine is the only anticonvulsant
compound for which there is evidence
supporting a significant clinical benefit in
acute bipolar depression.
The serotonergic actions of some of the
atypical antipsychotics may make them
unusually efficacious in depressed
states.
40
Bipolar Depression 2
It is usually recommended that antidepressants
be discontinued after the acute resolution of
symptoms. This reflects a belief that
antidepressants tend to destabilize the course
of the illness in bipolar patients.
In cases where depression occurs despite
adequate lithium maintenance –breakthrough
depression-some experts suggest that raising
lithium levels will optimize antidepressant
efficacy ( Jann et al 1982, Price et al 1984)
41
Pearl
Antidepressants have a lower risk of
precipitating a relapse into mania if used
with a mood stabliser. Use of tricyclics
carries a higher risk of manic switch than
SSRIs.Early relapse into mania is a
specific early risk of abrupt Lithium
discontinuation. 42
Pearl
As many as 50% of cyclothymic patients
go on to develop bipolar I or II illnesses
(Goodwin and Jamison, 1990)
43
Substance abuse in
Bipolar Disorder
Substance abuse reported in 60% of Bipolar
patients, 46% of which is alcohol abuse1
Risk of substance abuse 11 times greater for
patients with bipolar disorder1
Substance abuse may greatly complicate
treatment1
Highest for all psychiatric disorders
More likely to respond to Depakote than
Lithium
1. Regier DA et al. Comorbidity of mental disorders with alcohol and other drug use. JAMA 1990; 264: 2511-18, Goldberg J Substance abuse
complicates Remission from Acute Mania, J Clin Psych 60:11. 733-740 44
Substance Abuse and
Response to
100Treatment
80
% Recovering
60
40
20
0
Lithium DVPX/CBZ Li + AC
SA No SA
X2=6, P < .05 45
Goldberg et al, 1999
Depakote and
Cholesterol Metabolism
Short and long term valproate treatment has
been shown to lower cholesterol in bipolar
disorder, epilepsy, and migraine
Valproate prevented increased cholesterol
by antipsychotics in schizophrenia
Valproate inhibits cholesterol synthesis in
vitro 46
Depakote Rates of Full Response for 1-
Year among Patients responding to
Depakote in open Phase
50%
*
40% *p=0.002, D >P
†p=0.027, L >P
41% †
30%
20%
24%
10%
13%
0%
Depakote (n=70) Placebo (n=38) Lithium (n=42)
Days in 209 155 143 123 162 146
Maintenance
Responders to an acute treatment are less likely to continue to remain well if
they are switched to alternative treatment
47
Bowden CL et al. Arch Gen Psychiatry. 2000; 57:481-489.
Prevention of Bipolar depression
– relapse due to a depressive episode
(risk ratio)
Study Risk ratio %
(95% CI) Weight
Lamotrigine
Calabrese, 2003 (57/165 47/119) 0.87 (0.64, 1.19) 74.0
Bowden, 2003 (8/58 21/69) 0.45 (0.22, 0.95) 26.0
Subtotal 0.77 (0.58, 1.02) 100.0
Lithium
Kane et al, 1982 (1/4 4/7) 0.44 (0.07, 2.69) 3.6
Calabrese, 2003 (46/120 47/119) 0.97 (0.71, 1.33) 58.1
Bowden, 2003 (10/44 21/69) 0.75 (0.39, 1.43) 20.1
Bowden, 2000 (9/91 15/94) 0.62 (0.29, 1.34) 18.2
Subtotal 0.84 (0.65, 1.10) 100.0
Valproate semisodium
Bowden, 2000 (12/187 15/94) 0.40 (0.20, 0.82) 100.0
Subtotal 0.40 (0.20, 0.82) 100.0
0.01 0.1 0.5 1 2 Risk ratio
48
Favours active drug Favours placebo
Summary of Meta-analysis
Results
Preventing mood episodes
Lithium, Depakote and lamotrigine all
approximately half the risk of relapse vs placebo
Depakote may be superior to Lithium and is very
unlikely to be significantly inferior
Preventing Mania
Lamotrigine was inferior to Lithium
Depakote may be superior to Lithium in and is
unlikely to be significantly inferior
Preventing Depression
Depakote was the only treatment to demonstrate
clear efficacy, more than halving the risk 49
Conclusions 1
The term mood stabiliser is likely to be
bestowed increasingly liberally on any
drug active against one pole of the illness
and shown not to make relapse to the
other pole more likely.
Depakote may be as effective as Lithium
in the prevention of relapse, but
Carbamazepine is less effective than
Lithium.
50
Conclusions 2
Lithium reduces the risk of suicide
Lithium and Olanzapine prevent relapse of mania,but
are relatively less effective against depression
Successful long-term management often appears to
require combination treatment
Combining an antipsychotic with Lithium or Depakote
facilitate the acute treatment response.
Antidepressants are effective for treating depression in
bipolar disorder, but are best used in combination with
an agent that will reduce the risk of mania( Lithium,
Valproate or possibly an antipsychotic)
51
Conclusions 3
Adding an antipsychotic to a mood stabiliser
increases the likelihood of response by just
over 1.5 times
Adding olanzapine to a mood stabiliser
increases the likelihood of withdrawal due to
adverse events by 6 times
The mood stabilisers valproate semisodium
(Depakote) and lithium as well as
antipsychotics are all evidence-based options
for the treatment of mania as both 52
monotherapy and in combination therapy
53
Thank
you
54
Introduction
State the purpose of the discussion
Identify yourself
55
Topics of Discussion
State the main ideas you’ll be talking
about
56
Topic One
Details about this topic
Supporting information and examples
How it relates to your audience
57
Topic Two
Details about this topic
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How it relates to your audience
58
Topic Three
Details about this topic
Supporting information and examples
How it relates to your audience
59
Real Life
Give an example or real life anecdote
Sympathize with the audience’s situation
if appropriate
60
What This Means
Add a strong statement that summarizes
how you feel or think about this topic
Summarize key points you want your
audience to remember
61
Next Steps
Summarize any actions required of your
audience
Summarize any follow up action items
required of you
62
