BIPOLAR DISORDER
CLINICAL PHARMACY 1
BIPOLAR DISORDER
● a brain disorder that causes changes
in a person's mood, energy, and ability
to function
● is a mood disorder characterized by
one or more episodes of mania or
hypomania
Mania - extreme or severe form of mood
swings or behavior. It can be characterized by
extreme episodes of excitement or being
depressed. It may also trigger a break from
reality (psychosis) and require
hospitalization.
Hypomania - milder version of mania that
lasts for a short period of time. It also doesn’t
require hospitalization.
MOOD EPISODES
MANIC - highly energized level of physical
and mental activity and behavior.
Symptoms:
● OVERLY HAPPY TALKING
● VERY FAST JUMPING FROM
ONE IDEA TO ANOTHER
● BEING EASILY DISTRACTED
● BEING RESTLESS
● HAVING AN UNREALISTIC
BELIEF IN ONE'S ABILITIES
DEPRESSED - you experience a low or
depressed mood and/or loss of interest in
most activities
Symptoms:
● FEELING TIRED OR "SLOWED DOWN"
● HAVING PROBLEMS
CONCENTRATING, REMEMBERING,
AND MAKING DECISIONS
● BEING RESTLESS OR IRRITABLE
● CHANGING EATING, SLEEPING, OR
● OTHER HABITS THINKING OF DEATH
OR SUICIDE, OR ATTEMPTING
SUICIDE.
MIXED- you experience both manic and
depressed episode at the same time
WHEN AND WHO GETS IT?
First onset often surfaces when you are in
your twenties, regardless of sex.
Although onset may occur in early childhood
to the mid-40s.
Research shows that the initial depressive
episode in men tends to arise about 5 years
earlier than in women.
Early onset of bipolar disorder is associated
with greater comorbidities, more mood
episodes, a greater proportion of days
depressed, and greater lifetime risk of suicide
attempts, compared to bipolar disorder with a
later onset.
● Substance abuse and anxiety
disorders are more common in
patients with an early onset.
Late onset of bipolar disorder starts later in
adulthood, from 50s and on. It is very difficult
to diagnose, but it is not too late to manage
it. The condition can also be probably
secondary to medical causes.
 BIPOLAR DISORDER
CLINICAL PHARMACY 1
Men Are Less Likely To Seek Treatment
than Women who tend to be more open to
seeking therapy.
PEDIA- approach is similar to that used in
adults, with monotherapy as first-line
therapy, but only lithium is FDA-approved for
children and adolescents as young as age 12;
support divalproex, carbamazepine,
olanzapine, quetiapine, and risperidone.
-they are more likely than adults to
experience significant weight gain due to
atypical antipsychotic drugs.
GEATRICS- requires special care because of
increased risks associated with concurrent
non-psychiatric medical conditions and
drug-drug interactions.
Pregnancy - Treatment is best managed
when the pregnancy is planned
For a patient with severe bipolar disorder, a
history of multiple mood episodes, rapid
cycling, or suicide attempt, discontinuing
treatment, even for a planned pregnancy, is
unwise
Patients who decide to discontinue drug
therapy prior to pregnancy should taper
medications slowly in order to reduce risk of
relapse.
CAUSE
The precise cause of bipolar disorder is
unknown.
PATHOPHYSIOLOGY
Bipolar disorder is caused by an imbalance
of cholinergic and catecholaminergic
neuronal activity. Serotonin (5-HT) has been
suggested to modulate catecholamine activity.
Dysregulation of this relationship could cause
a mood disturbance.
An early theory was that elevation of
norepinephrine (NE) and dopamine (DA)
caused mania, and a reduction caused
depression.
It can affect the Prefrontal Cortex
(responsible for mood changes)
Gray Matters (low volume) Hippocampus
(reduced size)
CONTRIBUTING FACTORS
TRAUMA AND STRESS - when you
experience a death of a loved one or other
traumatic event, it can trigger manic or
depressive episodes.
CHANGES IN YOUR BRAIN - partly caused by
an underlying problem with the balance of
neurotransmitters.
GENETICS - you can get it from at least one
close biological relative with the condition.
★ Lifetime risk of bipolar
disorder in relatives of a
bipolar patient is 40% to 70%
for a monozygotic twin and
5% to 10% for another
first-degree relative.
TYPES OF BIPOLAR DISORDER
BIPOLAR 1
 BIPOLAR DISORDER
CLINICAL PHARMACY 1
● diagnosis necessitates at least one
episode of mania, for at least 1 week
or longer
● can also be defined by manic
symptoms that are severe that the
person needs an immediate hospital
care
● affects men and women equally
● age between 12 & 24
● In males, the initial episode in bipolar
I disorder is more likely to be mania,
and the number of
● manic episodes is equal to or greater
than depressive episodes
BIPOLAR 2
● when a person has a pattern of
hypomanic and depressive episodes
but not the full-blown manic
episodes (hypomania)
● hypomanic episodes need to last for 4
days
● seen in bipolar I illness more
common in women
● age between 18 & 29
CYCLOTHYMIC DISORDER
● a chronic mood disturbance generally
lasting at least 2 years and
characterized by mood swings
including periods of hypomania and
depressive symptoms
● Psychotic features are not found in
cyclothymic disorder
BIPOLAR DISORDER, NOT OTHERWISE
SPECIFIED
● diagnosed when a person has
symptoms of the illness but doesn't
meet the diagnostic criteria for
either bipolar 1 or 2.
● symptoms may not last long enough
or may have too few symptoms but
the symptoms is clearly out of the
normal range of a person's behavior
RAPID CYCLING - four or more manic,
hypomanic, or depressive episodes have
taken place within a twelve-month period.
DIAGNOSIS
Physical exam - physical exam and lab tests
to identify any medical problems that could
be causing your symptoms
Psychiatric assessment - a doctor may refer
you to a psychiatrist, who will talk to you
about your thoughts, feelings and behavior
patterns. (A thorough medical history, which
will include asking about your symptoms,
lifetime history, experiences and family
history.)
Mood charting - You may be asked to keep a
daily record of your moods, sleep patterns or
other factors that could help with diagnosis
and finding the right treatment.
Criteria for bipolar disorder - Your
psychiatrist may compare your symptoms
with the criteria for bipolar and related
disorders in the Diagnostic and Statistical
Manual of Mental Disorders (DSM-5).
a person must have experienced at least
one episode of mania or hypomania to be
diagnosed with bipolar disorder
 BIPOLAR DISORDER
CLINICAL PHARMACY 1
SUICIDE
● Patients with bipolar disorder have a
high risk of suicide.
● Factors that increase that risk are
early age at disease onset, high
number of depressive episodes,
comorbid alcohol abuse, personal
history of antidepressant-induced
mania,and family history of suicidal
behavior.
COMORBID PSYCHIATRIC AND MEDICAL
CONDITIONS
● Lifetime prevalence rates of
psychiatric comorbidity co-existing
with bipolar disorder are 42% to
50%.
Psychiatric comorbidities include:
● Personality disorders
● Alcohol and substance abuse or
dependence
● Anxiety disorders, including panic
disorder, obsessive compulsive
disorder, and social phobia
● Eating disorders
● Attention-deficit/hyperactivity
disorder
Medical comorbidities include:
● Migraine
● Multiple sclerosis
● Cushing’s syndrome
● Brain tumor
● Head trauma
TREATMENT
NONPHARMACOLOGIC THERAPY
Cognitive-behavioral therapy (CBT) is a
type of psychotherapy that combines
cognitive and behavioral theories. It stresses
the importance of recognizing patterns of
cognition (thought) and how thoughts
influence subsequent feelings and behaviors.
An advantage of CBT is that patients are
taught self-management skills to change their
negative thoughts in order to feel and
function better, even if external circumstances
do not change.
Electroconvulsive therapy (ECT) is the
application of prescribed electrical impulses
to the brain for the treatment of severe
depression, mixed states, psychotic
depression, and treatment-refractory mania
in patients who are at high risk of suicide.
Psychoeducation for patients, their families,
and groups regarding chronicity of bipolar
disorders; self-management through sleep
hygiene, nutrition, exercise, and stress
reduction; and abstinence from alcohol or
drugs is critical to the success of supporting
the individual in managing bipolar disorder.
PHARMACOLOGIC THERAPY
Mood-Stabilizing Drugs
- desired effects =treatment of acute
mania,treatment of acute bipolar
depression, prevention of manic
relapse,and prevention of bipolar
depression relapse
 BIPOLAR DISORDER
CLINICAL PHARMACY 1
________________________________________________
Lithium
MOA: reduces excitatory (dopamine and
glutamate) but increases inhibitory (GABA)
neurotransmission
- altered ion transport, increased
intraneuronal catecholamine
metabolism, neuroprotection or
increased brain-derived neurotrophic
factor, inhibition of second messenger
systems, and reprogramming of gene
expression
- First approved mood-stabilizing drug.
- It remains a first-line agent.
- It has anti manic efficacy, prevents
bipolar disorder relapse ,and has
more modest efficacy for bipolar
depression.
- It is most effective for patients with
few previous episodes, symptom-free
interepisode remission, and a family
history of bipolar disorder with good
response to lithium
-
- Divalproex Sodium and Valproic Acid
- Patients with rapid cycling bipolar
disorder are less responsive to lithium
- It may also be less effective in patients
with mixed mood episodes, and in
mania secondary to non-psychiatric
illness.
- Lithium reduces the risk of deliberate
self-harm or suicide by about 70%
- Lithium is usually initiated at a dosage
of 600 to 900 mg per day; most
commonly given in a divided dosage,
once-daily dosing is acceptable
- has a narrow therapeutic index (the
toxic dosage is not much greater than
the therapeutic dosage)
It is common for lithium to be combined with
other mood stabilizing drugs or antipsychotic
drugs, if necessary, in order to achieve more
complete remission of symptoms
SIDE EFFECTS: gastrointestinal upset, tremor,
and polyuria (dose related) ; nausea,
dyspepsia, and diarrhea (minimized by co
administration with food)
Other common adverse effects include poor
concentration, acneiform rash, alopecia,
worsening of psoriasis, weight gain, metallic
taste, and glucose dysfunction
D-D INTERACTION: Common and significant
drug interactions involve thiazide diuretics,
nonsteroidal anti-inflammatory drugs
(NSAIDs), and angiotensin converting enzyme
inhibitors (ACEIs). loop diuretics such as
furosemide are less likely to increase lithium
retention.
MOA: It blocks ion channels and inhibits
sustained repetitive neuronal excitation;
increasing brain GABA concentrations, and
Na+ channel inhibition
- was developed as an antiepileptic
drug, but also has efficacy for mood
stabilization and migraine headache
- FDA-approved for the treatment of the
manic phase of bipolar disorder
 BIPOLAR DISORDER
CLINICAL PHARMACY 1
- generally equal in efficacy to lithium
and some other drugs for bipolar
mania
- not FDA-approved for relapse
prevention
- It has particular utility in bipolar
disorder patients with rapid cycling,
mixed mood features, and substance
abuse comorbidity
- can be used as monotherapy or in
combination with lithium or an
antipsychotic drug
- Divalproex is often initiated at 500 to
1000 mg per day but a therapeutic
serum valproic acid
concentration can be reached more
quickly through a loading dose
approach of 20 to 30 mg/kg per day
SIDE EFFECTS: gastrointestinal (loss of
appetite, nausea, dyspepsia, and diarrhea),
tremor, and drowsiness.
- less common effects include alopecia
or a change in hair color or texture
- Polycystic ovarian syndrome
associated with increased androgen
production has been reported
The delayed-release and
extended-release formulations are less
likely to cause gastric distress than the
immediate-release valproic acid.
D-D INTERACTION: antiepileptic drugs and
tricyclic antidepressants.
- The risk of a dangerous rash due to
lamotrigine is increased when given
concurrently with divalproex
the metabolism of divalproex can be
increased by enzyme-inducing drugs such
as carbamazepine and phenytoin, while
divalproex may simultaneously slow
metabolism of the other agents.
Carbamazepine
MOA: It blocks ion channels and inhibits
sustained repetitive neuronal excitation, but
whether this explains its effect as a
mood-stabilizing drug is not known.
- an extended-release formulation of
carbamazepine has only recently
received FDA approval for treatment
of bipolar disorder
- considered possibly less desirable as a
first-line agent because of safety and
drug interactions.
- reserved for patients who fail to
respond to lithium or for patients
with rapid cycling or mixed bipolar
disorder
- used as monotherapy or in
combination with lithium or an
antipsychotic drug
- usually initiated at 400 to 600
mg/day; sustained-release
formulation can be given in two
divided doses.
SIDE EFFECTS: common adverse effects are
drowsiness, dizziness, ataxia, lethargy, and
confusion; also causes diplopia and
dysarthria.
- minimized through dosage
adjustments, use of sustained-release
formulations, and giving more of the
drug late in the day.
 BIPOLAR DISORDER
CLINICAL PHARMACY 1
D-D INTERACTION: Carbamazepine induces
the hepatic metabolism of many drugs,
including other antiepileptic drugs,
antipsychotics, some antidepressants, oral
contraceptives, and antiretroviral agents
- the metabolism of carbamazepine can
be slowed by enzyme-inhibiting drugs
such as some antidepressants,
macrolide antibiotics
- Carbamazepine should not be given
concurrently with clozapine because
of the added risk of agranulocytosis
Lamotrigine
MOA: involve blockage of ion channels and
effects on glutamate transmission
- effective for the maintenance
treatment of bipolar disorder
- more effective for depression
relapse prevention than for mania
relapse.
- sometimes used in combination with
lithium or divalproex, although
combination with divalproex increases
the risk of rash, and lamotrigine
dosage adjustment is required
- usually initiated at 25 mg daily for
the first 1 to 2 weeks, then
increasing in a dosedoubling fashion
every 1 to 2 weeks to a target
dosage of 200 to 400 mg per day
- lamotrigine is added to divalproex,
the starting dosage is 25 mg every
other day with a slower titration to
reduce the risk of rash
SIDE EFFECTS: greatest significance is a
maculopapular rash, occurring in up to 10%
of patients.
- usually benign and temporary, some
rashes can progress to life-threatening
Stevens-Johnson syndrome
- dizziness, drowsiness, headache,
blurred vision, and nausea
D-D INTERACTION:
- usually due to induction or inhibition
of its metabolism by other drugs
- divalproex slows the rate of
elimination of lamotrigine by about
half, necessitating dosage reduction.
- carbamazepine increases the rate of
lamotrigine metabolism. Upward
adjustment in the lamotrigine dosage
may be needed as a result.
Oxcarbazepine
- is an analogue of carbamazepine,
developed as an antiepileptic drug.
- advantage over carbamazepine is that
routine monitoring of hematology
profiles and serum
- concentrations are not indicated, as
the drug is less likely to cause
hematologic abnormalities.
- drug interactions are less significant,
although it is at least a mild inducer of
certain metabolic pathways, and
vigilance for drug interactions is
needed, especially with oral
contraceptives
SIDE EFFECTS: include drowsiness,
dizziness, gastrointestinal upset, and
hyponatremia, the latter two of which may be
more likely than with carbamazepine.
 BIPOLAR DISORDER
CLINICAL PHARMACY 1

OTHERS ( aripiprazole for bipolar disorder is 20 to 30

High-potency benzodiazepine agents such as
clonazepam have been used as adjunctive
therapy, especially during acute mania
episodes, to reduce anxiety and improve
sleep.
Topiramate is commonly used for its putative
mood-stabilizing effects, but unpublished,
well-designed, randomized, controlled trials
sponsored by the manufacturer showed no
difference
between topiramate and placebo for
treatment of bipolar disorder.
mg per day)
( olanzapine is more likely to cause
metabolic side effects.)
The combination of olanzapine and
fluoxetine is approved for treatment of
bipolar depression.
Quetiapine is approved for treatment of
bipolar depression.
Antipsychotic Drugs
they should be combined with a
mood-stabilizing drug to reduce the risk of
mood switch to hypomania or mania

depressive episodes in bipolar disorder

PHARMACOLOGIC THERAPY patients presents a particular challenge
because of the risk of a pharmacologic mood
Antipsychotic Drugs switch to mania, although there is not
complete agreement about such risk;
chlorpromazine and haloperidol have long
been used in the treatment of acute mania Treatment guidelines suggest lithium or
lamotrigine as first-line therapy
ATYPICAL ANTIPSYCHOTIC DRUGS
- are equivalent in efficacy to lithium Olanzapine has also demonstrated efficacy in
and divalproex for treatment of acute treatment of bipolar depression, and
mania. quetiapine is under review for approval of
- less likely than conventional agents to treatment of bipolar depression.
cause neurologic side effects,
especially movement abnormalities.
- they are more likely to cause
metabolic side effects such as weight
gain, glucose dysregulation, and
dyslipidemia

Aripiprazole and olanzapine are also

approved for maintenance therapy.