Bipolar Disorders

Objectives
•

•
BPAD

• Rapid cyclers: have four or more episodes per

year and a poorer long-term prognosis.
Pathophysiology
» Three principal neurotransmitters are norepinephrine,
dopamine, and serotonin
» Environmental or psychosocial stressors, immunologic
factors, and sleep dysregulation all have been associated
with bipolar disorder
» Dysregulation between excitatory and
inhibitory neurotransmitter systems; excitatory: NE, DA,
glutamate, and aspartate; inhibitory: 5-HT and GABA.
» Monoamine hypothesis
» Cholinergic hypothesis
» Secondary messenger system dysregulation
» Hypothalamic-pituitary-thyroid axis dysregulation
» Membrane and cation theories

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Diagnosis
• Mania :At least 1-week abnormally and persistently elevated mood and energy,
associated with at least three of the following symptoms (four if the mood is only
irritable):
• Inflated self-esteem (grandiosity)
• Decreased need for sleep
• Increased talking (pressure of speech)
• Racing thoughts (flight of ideas)
• Distractibility (poor attention)
• Increased goal-directed activity (socially, at work, or sexually) or psychomotor
agitation
• Excessive involvement in activities that are pleasurable but have a high risk for
serious consequences (buying sprees, sexual indiscretions, poor judgment in
business ventures
• Hypomania : At least 4 days of abnormally and persistently elevated mood
(expansive or irritable) and energy, associated with at least three of the above
symptoms (four if the mood is only irritable):

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Goals of treatment
Treatment options
Non-pharmacologic treatment
Acute manic episodes
Acute manic episodes
• Patients on long-term treatment.
• Inadequate symptom control: ensure that the highest well-tolerated dose of the current
treatment is offered
• Optimal doses fails to control symptoms: consider another first-line medication
• Adding an antipsychotic if not already prescribed or changing from one antipsychotic to
another
• Clozapine may be particularly effective in the treatment of refractory illness
• Alternative treatment options : adding carbamazepine or oxcarbazepine
• Electroconvulsive therapy (ECT) : Patients with severe or treatment-resistant mania
• Manic or mixed episodes with psychotic features : add antipsychotic medication
• Current episode is due to poor adherence, : offer appropriate intervention 13
 Acute manic episodes

• Discontinuation of short-term treatments.

• Medicines only used for the acute treatment of mania may be reduced in dose and discontinued
(tapering over 4 weeks or more) after full remission of symptoms has been achieved .
• Remission will often occur within 3 months but mood stability may require 6 months or more to
achieve.
• Any medication used adjunctively for symptomatic effect to promote sleep or sedation should be
discontinued as soon as symptoms improve

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 Acute depressive episode

New patients
• Consider quetiapine, lithium, lamotrigine, lurasidone or olanzapine
• Combination of fluoxetine with olanzapine
• Valproate alone (second line)
• Lurasidone +LI/VAL
• Antidepressants(SSRI) should be co-prescribed with a drug for mania in patients with a
history of mania
• Antidepressants should not consider as monotherapy

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 Acute depressive episode

For patients taking long-term treatment.

▰ Ensure that the current choice of long-term treatments is likely to protect the patient from manic relapse
▰ Address current stressors
▰ If the patient fails to respond to optimization of long-term treatment, and depressive symptoms are significant,
initiate treatment as New

▰ Depressive episodes with psychotic features : adjunctive treatment with an antipsychotic medication
▰ The dual-action monoamine re-uptake inhibitors carry a greater risk of switch to mania than single action
drugs(SSRI)

▰ Consider ECT for patients with high suicidal risk, treatment resistance, psychosis, severe depression during
pregnancy
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Short-term management of agitation

▰ Fist line : ▰ SECOND LINE

▰ Aripiprazole 9.75-15 mg IM ▰ ASENAPINE SC 10 mg
▰ Lorazepam IM 2-10 mg ▰ Haloperidol: IM 5-15 mg
▰ Olanzapine IM 2.5-10 mg ▰ Haloperidol +Promethazine:2.5-25 Mg
▰ Loxapine inhaled : 5-10 Mg ▰ Haloperidol with midazolam

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 Long-term treatment

• Consider lithium as initial monotherapy

• lithium is ineffective, poorly tolerated or if patients are unlikely to be adherent: consider valproate,dopamine antagonists/partial
agonists

• Lamotrigine and quetiapine may be considered as monotherapy in bipolar II disorder

• In bipolar I disorder, lamotrigine will usually require combination with an anti-manic long-term agent

• If the patient fails to respond to monotherapy consider long-term combination treatment

• When the burden of disease is mania, combine two predominantly anti-manic agents (e.g. lithium, valproate, antipsychotic )
• When the burden is depressive, a combination of lithium, lamotrigine, quetiapine, lurasidone or olanzapine may be more
appropriate
• Consider continuation of clozapine if effective in refractory mania
• Patients treated with an antipsychotic medication acute episode, the need for ongoing antipsychotic treatment should be reassessed
upon entering the maintenance phase.

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 Treatment in special situations
Children and adolescent Pregnancy: Always use the lowest effective dose of any
▪ For mania: Consider aripiprazole as first line (over 13
years) Or refer to adult recommendations; medication during pregnancy. » Monotherapy should also be
▪ olanzapine, quetiapine, and risperidone are considered
efficacious in adolescents
» Lithium : Ebstein’s anomaly
▪ Lithium and divalproex in children and adolescents
with bipolar disorder » Valproate, : Neural tube defects Administration of folate can
▪ Bipolar depression. Consider medicines and
psychological treatments reduce the risk of neural tube defects;

» Carbamazepine: Facial abnormality

» In elderly people. Consider lower doses of
psychotropic medicines of all classes for all phases of » Lamotrigine is the safest option
treatment
» Many elderly patients tolerate only low serum levels of » SGA safer choice
lithium (e.g., 0.4–0.6 meq/liter) and can respond to
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these levels.
 • Acute treatment of mania, at a plasma level of 0.8–
1.0 mmol/L may be up to 1.5
• Maintenance treatment plasma level in the range
0.6–0.8 mmol/L
• Prevent suicide in patients with mood disorders.
• Require 6 to 8 weeks to show antidepressant
Lithium efficacy.
• Abrupt discontinuation or noncompliance can
increase the risk of relapse.
• Indications: Classic mania , BPAD depression ,
Episodic illness, older age of onset, family history of
BPAD and response to family history
• Use with caution : renal impairment, hyponatremia,
dehydration (lithium toxicity)

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 ADRs
• GI and central nervous system (CNS) are often dose related
• Lowering the dose, taking smaller doses with food, using extended-release products, and once-daily dosing at bedtime
reduces GI symptoms

• Diarrhea can sometimes be improved by switching to a liquid formulation.

• A fine hand tremor usually resolves with continued treatment, or switching to a long-acting preparation, lowering the
dose, or adding propranolol, 20 to 120 mg/day are useful for tremors

• Polydipsia with polyuria with or without nephrogenic diabetes insipidus (DI) can occur.
• Nocturia is common and is managed by changing to once-daily dosing at bedtime
• Some skin conditions such as psoriasis and acne can be aggravated by lithium
• Lithium can also cause a metallic taste in the mouth, ankle edema and weight gain
• Long-term therapy is associated with risk of morphologic renal changes.
• Hypothyroidism (more common in women) and does not require discontinuation of lithium. Exogenous thyroid
hormone (ie, levothyroxine) can be added to the regimen 21
Lithium toxicity
• At levels >1.5 mmol/L : » Risk : sodium restriction, dehydration,
gastrointestinal effects (increasing
anorexia, nausea and diarrhea) vomiting, diarrhea, age greater than 50 years,
and CNS effects (muscle heart failure, drug interactions, heavy
weakness, drowsiness, confusion,
ataxia, coarse tremor and muscle exercise, sauna baths, hot weather, and
twitching). fever.
• Above 2 mmol/L, increased
disorientation and seizures usually » To maintain adequate sodium and fluid
occur, which can progress to intake and to avoid alcohol and excessive
coma, and ultimately death.
caffeine-containing beverages.

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Monitoring
• Baseline GFR, thyroid function and calcium,
cardiac conduction abnormality
• Plasma lithium, GFR and TFTs : 3-6 months.
• ECG : patients who have risk factors for, or
existing cardiovascular disease.
• A baseline measure of weight
• Plasma level after seven days then 7 days
after every dose change till it reach to the
desired level. Then every 3-6 months
• Women of child‐bearing age should be
advised to use a reliable form of
contraception.

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Valproate Sodium
» Valproate can cause both gastric irritation and
• More effective than lithium for rapid cycling, hyperammonemia
mixed states, and bipolar disorder with
substance abuse, MR,PTSD and comorbid » Lethargy and confusion can occasionally occur
migraine
• Lithium, carbamazepine, antipsychotics, with starting doses above 750 mg/day.
or benzodiazepines can augment the antimanic
effects of valproate. » Weight gain can be significant, particularly when
• The most frequent dose-related side effects of
valproate are GI complaints, fine tremor, and valproate is used in combination with clozapine.
sedation.
» Hair loss and peripheral edema can occur,
• Giving it with food, reducing the initial dose and
making gradual increases, or switching to the » Valproate can cause hyper androgenism in women
extended release formulation can help alleviate
the GI complaints and has been linked with the development of
• Prior to start monitor patient for hepatic and
hematological and bleeding problem polycystic ovaries;

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Lamotrigine
» Lamotrigine is not effective for acute mania compared with standard mood stabilizers,

» Can use for maintenance therapy of treatment-resistant bipolar I and II disorders.

» Clinically it is often used in the treatment of patients with bipolar depression

» Augmenting properties when combined with lithium or valproate, and has low rates of switching
patients to mania.

» Common adverse effects : headache, nausea, dizziness, ataxia, diplopia, drowsiness, tremor,
rash, and pruritus.

» Stevens-Johnson syndrome.

» Start with a dose 25 mg/day for 2 weeks

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Carbamazepine
» Carbamazepine is not a first-line agent for bipolar disorder, and is generally reserved for use after treatment
failure with lithium or divalproex sodium.

» The combination of carbamazepine with lithium, valproate, and antipsychotics is often used for treatment
resistant patients experiencing a manic episode.

» Common side effects include Dizziness, diplopia, drowsiness, ataxia, nausea and headaches can be avoided
by starting with a low dose and increasing slowly.

» Dry mouth, edema and hyponatremia are also common. Sexual dysfunction and generalized erythematous
rash also reported

» Carbamazepine is a known human teratogen

» Commonly causes agranulocytosis and/or aplastic anemia

» Monitor the LFT and CBC ,RFT prior to start

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Antipsychotic drugs in bipolar disorder

» Aripiprazole, asenapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone
are effective as monotherapy or adjunctive therapy in the treatment of acute mania

» Aripiprazole, olanzapine, quetiapine, and risperidone: Long-acting injection are effective

monotherapy options for maintenance treatment in bipolar disorder.

» First-generation depot antipsychotics (eg, haloperidol decanoate, fluphenazine decanoate)

can have a place in maintenance treatment of bipolar disorder in patients who are
noncompliant or treatment-resistant
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Rapid‐cycling bipolar disorder

» Rapid cycling is usually defined as bipolar disorder in which

four or more episodes of (hypo) mania or depression occur

in a 12‐month period.

» It is generally held to be less responsive to drug treatment

than non‐rapid cycling

Alternative Medication Treatments

• Benzodiazepines
• high-potency benzodiazepines such as clonazepam and lorazepam are used as alternative to or in
combination with antipsychotics in acute mania, agitation, anxiety, panic, and insomnia, or cannot
take mood stabilizers
• Available for intramuscular injection and is useful in the acute management of agitation.
• They can cause CNS depression, sedation, cognitive and motor impairment, dependence, and
withdrawal reactions.
• When no longer required, benzodiazepines should be gradually tapered and discontinued to avoid
withdrawal symptoms

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 • Adjunctive therapy for acute bipolar depression.
• Third line in treating acute bipolar depression, except in patients with

Antidepressants no history of severe and/or recent mania or potentially in bipolar II

patients.
• Before initiating therapy ensure that the patient is on a therapeutic
dosage or blood level of a primary mood stabilizer.
• Patients who have a history of mania after a depressive episode or
who have frequent cycling should be treated cautiously with
antidepressants.
• Gradually withdrawn 2 to 6 months after remission, and the patient
maintained on a mood-stabilizing agent.
• Antidepressants alone is not Recommended

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 • Verapamil has demonstrated mood-stabilizing
Calcium Channel properties
Antagonists • Nimodipine: more effective than verapamil for
rapid-cycling bipolar disorder because of its
anticonvulsant properties, high lipid solubility, and
good penetration into the brain.

• Calcium channel blockers are generally well

tolerated, and the most common adverse effects are
bradycardia and hypotension.

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 • Monitoring a patient’s psychiatric status and safety;
enhancing treatment adherence; promoting good
nutrition, sleep, and exercise; identifying stressors;
recognizing new mood episodes; and minimizing adverse
EVALUATION OF reactions and drug interactions.
THERAPEUTIC
OUTCOMES • » Patients who have a partial response or nonresponse
to established bipolar therapies should be reassessed for
an accurate diagnosis, concomitant medical or
psychiatric conditions, compliance with treatment and
medications or substances that exacerbate mood
symptoms.

• » Nonadherence to medication treatment, delusional

symptoms, alcohol or substance abuse, rapid cycling, or
mixed states are often associated with poorer treatment
outcomes 35
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Reference