Bipolar Affective Disorder

Bipolar disorder (BPD) (manic-depressive illness) is one of the most severe forms of mental illness and is characterized by swinging moodsAlso known as manic depression

Chronic illness; can be life-threatening

Introduction

First diagnosed in adolescence or early adulthood after several years of symptoms

Symptoms:Periods of mania, hypomania, psychosis, or

depression with periods of relative wellnessPatients rarely experience a single episode

Relapse rates at more than 70% over 5 yearsMost patients are depressed most of the time

Introduction

3.7%–3.9% lifetime prevalence of bipolar I and II disorders

Equal incidence in females and males First episode for females: depressionFirst episode for females: mania

Average age at onset: 21 y/o

Bipolar I disorder onset: 18 y/o

Prevalence in patients presenting with depression: 21% to 26%

Epidemiology

Risk factors for bipolar disorder: a. Family history b. ECT c. Antidepressant therapy d. Separated or divorced, higher socioeconomic level e. Hyperthyroidism

Epidemiology

The etiology is unknown; however, the leading theory is a genetic hypothesis of transmission (chromosome 18)

Permissive hypothesis: hydroxytriptamine [5-HT] increase norepinephrine [NE] in mania; decrease NE in depression

Gamma aminobutyric acid (GABA) depletion: inhibitory neurotransmission causes mania

Amygdala Kindling: increases in excitatory neurotransmitters aspartate and glutamate

Pathophysiological hypothesis

At least 1 week of abnormal and persistently elevated, expansive, or irritable moodAny time duration if hospitalized

Presence of 3 or more of the DIG FAST symptoms4 if the mood is only irritable

DistractibilityInsomniaGrandiosity (inflated self-esteem)Flight of ideasAgitation (or increase in goal-directed activity)Speech pressured/more talkativeTaking risks (activities with a high potential for painful

consequences)

Mania

Hypomania Common Shared Symptoms

Mania

*Sustained or continuous excessive energy, little need for sleep, irritability, excitement or aggression*This mood is usually not connected to anything happening in the person's life*No symptoms of psychosis (hallucinations, delusions or paranoia)

*Not needing much sleep *Fast talking that may be difficult for others to understand*Behaving inappropriately *Spending money recklessly*Grandiose thinking *Hypersexuality

*Mania must last for at least one week or require hospitalization*Sustained and abnormally elevated or irritable mood *Causes personal problems at home, with one’s associates, an d at work

Hypomania vs. Mania

Hypomania vs. Mania

Must last at least 2 weeksAt least 5 of the criteria with one including

depressed mood or decreased interestsMust cause clinically significant impairment

What is a Major Depressive Episode?

Depressed mood and SIG-E-CAPS criteriaS: Suicidal ideationI: decreased InterestsG: excessive Guilt (worthlessness,

hopelessness)E: decreased EnergyC: decreased ConcentrationA: Appetite changesP: Psychomotor retardation or agitationS: Sleep disturbance

What is a Major Depressive Episode?

Full criteria for a manic and depressive episode for the majority of at least 1 week

Mixed Features

Classification Disorder Definition

Bipolar I disorder

Manic or mixed episode with or without psychosis and/or major depression

Characterized by manic or depressive episodes followed by symptom-free periods

Bipolar II disorder

Hypomanic episode with major depression; no history of manic or mixed episode

Episodes usually do not require hospitalization

Cyclothymia Chronic mood disturbance of at least 2 years duration

Hypomanic and depressive symptoms that do not meet criteria for bipolar II disorder; no major depressive episodes

Bipolar disorder not otherwise specified

Does not meet criteria for major depression, bipolar I disorder, bipolar II disorder, or cyclothymia (i.e. less than one week of manic symptoms without psychosis or hospitalization)

The diagnosis of bipolar I disorder requires the presence of a manic episode of at least 1 week's duration that leads to hospitalization or other significant impairment in occupational or social functioning

The episode of mania cannot be caused by another medical illness or by substance abuse

These criteria are based on the specifications of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)

Clinical Diagnosis

Manic episodes are characterized by the following symptoms:

1. At least 1 week of profound mood disturbance is present, characterized by elation, irritability, or expansiveness.

2. Three or more of the following symptoms are present: DistractibilityInsomniaGrandiosity (inflated self-esteem)Flight of ideasAgitation (or increase in goal-directed activity)Speech pressured/more talkativeTaking risks (activities with a high potential for painful consequences)

3. The mood disturbance is sufficient to cause impairment at work or danger to the patient or others.

4. The mood is not the result of substance abuse or a medical condition.

5. If severe, may have psychotic symptoms

Clinical Diagnosis

Hypomanic episodes are characterized by the following: 1. The patient has an elevated, expansive, or irritable mood of at

least 4 days' duration. 2. Three or more of the following symptoms are present:

Distractibility Insomnia Grandiosity (inflated self-esteem) Flight of ideas Agitation (or increase in goal-directed activity) Speech pressured/more talkative Taking risks (activities with a high potential for painful consequences)

3. The mood disturbance is observable to others. 4. The mood is not the result of substance abuse or a medical

condition.5. Less severe form of mania and it is not severe enough to

affect social or occupational functioning; hospitalization generally not required

Clinical Diagnosis

Mixed episodes are characterized by the following: Occurrence of manic and depressive symptoms at the same time

1. Persons must meet both the criteria for mania and major depression; the depressive event is required to be present for 1 week only.

2. The mood disturbance results in marked disruption in social or vocation function.

3. The mood is not the result of substance abuse or a medical condition.

4. The mixed symptomology is quite common in patients presenting with bipolar symptomology. This often causes a diagnostic dilemma.

5. Higher risk of comorbid substance use/abuse and suicidality.

Clinical Diagnosis

Depressive episode: Often misdiagnosed as a unipolar depressive

episodeMost common mood state in bipolar disorder

About 95% of patients with bipolar disorder will experience depressive episodes

Psychotic symptoms are more common than in unipolar depressive episodes

Clinical Diagnosis

Use the Mental Status Examination (MSE) Appearance Affect/mood Thought content Perceptions Suicide/self-destruction Homicide/violence/aggression Judgment/insight

Physical Diagnosis

Acute ManiaControl symptomsReturn patient to normal level of psychosocial

functionControl agitation, aggression, and impulsivity

to ensure safety of self and othersDepression

Remission of symptomsAvoid precipitation of hypomania/mania

Therapeutic Goals

MaintenanceRelapse preventionReduction of suicide riskReduce cycling frequencyReduce mood instabilityImprove overall functioningPromote treatment adherence

Therapeutic Goals

Phases of treatment

Acute phase

Continuation phase

Maintenance phase

Acute phase

a. Manic phase

b. Depressed

phase

• 1) Mood stabilizer + Consider benzodiazepines or antipsychotic

• 2) Discontinue antidepressant

• 1) Mood stabilizer• 2) Consider

antidepressant or thyroid hormone

Continuation phase

6- to 12-week period when

risk of relapse is relatively

high

Continue mood stabilizers at same dosage effective in

acute episodes

Important Pearls regarding the Maintenance phase 1. Bipolar disorder is recurrent in over 90% of

patients2. Required by most patients3. Determinants for maintenance therapy

a. Probability of a recurrence with or without a mood stabilizer

b. Consequences of a recurrence

4. One year of maintenance therapy recommended after every manic episode

5. Long-term treatment is indicated for patients with 2 manic episodes

6. No evidence that chronic dosing causes tolerance

7. Maintenance antidepressant therapy usually not employed

Treatment

Mood Stabilizer

Anticonvulsants

Antipsychotics

Benzodiazepines

Antidepressants

Pharmacotherapy options by subtypes

Classical Mania: lithium,Valproic acid,carbamazepine, Atypical Antipsychotic

Rapid cycling: Valproic acid only ,lamotrogine, Atypical Antipsychotic

Bipolar II: lamotrogine, lithium?. Depressive: Lamotrigine, lithium, quetiapine (with or without adjunctive antidepressant)

Considered a first-line agent for long-term prophylaxis in bipolar illness, especially for classic bipolar disorder with euphoric mania

Used to treat acute mania, although cannot be titrated up to an effective level as quickly as valproic acid

Evidence suggests that lithium, unlike any other mood stabilizer, may have a specific anti-suicide effect

Monitoring blood levels is critical with LITHIUM

Lithium

DosingAcute manic episode: 600-2400 mg PO dailyMaintenance, preventive use: 400-1200 mg PO

dailyTherapeutic serum concentration: 0.6–1.2 mEq/L Acute treatment: 1.0–1.2 mEq/L Maintenance treatment: 0.6–1.2 mEq/L Toxicity concentration: Less than 2.5 mEq/LSerum concentrations should be drawn 4–5 days

after the first dose

Lithium

t½ = 20-24 hours 100% bioavailability Peak serum levels Slow release preparations -

4 to 12 hours Excreted 95% unchanged by glomerular

filtration

Lithium - pharmacokinetics

Laboratory Monitoring Parameters

Lithium serum level monitoring:12 hours after last dosePeriodic monitoring of lithium levels should occur

every 6 months or more frequently if clinically indicated

Lithium

Initial Workup Safety and Efficacy

Renal function tests (BUN, SCr, urinalysis)CBC plus differential, electrolytesThyroid panelWeightEKG (elderly, cardiovascular disease)Presence of dermatologic disorderPregnancy test (if female and of childbearing age, pregnancy category D)

Resolution of symptoms Assessments for adverse effectsWeightNeurologic examPatient report on GI symptoms, urinary frequency, etc.

The high frequency of non-adherence to lithium treatment (30-50%) is often associated with adverse effects Cognitive impairmentTremorAcnePolyuria and polydipsiaMuscle weakness Weight gain Long term adverse effects on thyroid

functioning and the kidneys

Lithium: Adverse Effects

PregnancyD - Fetal risk shown in humans; use only if benefits outweigh

risk to fetus (Ebstein's cardiac anomaly)Precautions

Patient should have adequate renal function as evidenced by elevated creatinine levels or BUN levels, and they should drink plenty of fluids to prevent dehydration; excessive sodium loss can produce lithium toxicity (avoid excessive sweating); use lower doses in elderly individuals; do not perform ECT when being administered; avoid rapid increases in dosingAnything causing hyponatremia increases levels and could cause toxicity; toxicity is closely related to serum levels and can occur at therapeutic doses; serum lithium determinations are required to monitor therapy.

Lithium

Lithium ToxicityMild toxicity (serum levels 1.5–2 mEq/L): Gastrointestinal (GI) upset (nausea, vomiting, diarrhea); muscle weakness; fatigue; fine hand tremor; and difficulty with concentration and memoryModerate toxicity (serum levels 2–2.5 mEq/L): Ataxia, lethargy, nystagmus, worsening confusion, severe GI upset, coarse tremors, and increased deep tendon reflexesSevere toxicity (serum levels > 3 mEq/L): Severely impaired consciousness, coma, seizures, respiratory complications, and death

Lithium should only be discontinued gradually when it has been used successfully for prophylaxis in bipolar disorder

This discontinuation should be achieved over 2-3 months, and not before 4 weeks if possible

Abrupt or rapid discontinuation (less than 2 weeks) is associated with significantly higher relapse rates not only in the first few months but also over 3-5 years

Effects of Abrupt Discontinuation of Lithium

Anticonvulsants

Sodium valproate

Carbamazepine

Lamotrigine

• a. Prevention of recurrence

• b. When lithium is ContraIndication or ineffective

• c. For rapid cyclers ( 4 episodes/year)

Indications

Anticonvulsants

Usual Adult Dose 750-3000 mg/d (250 mg t.i.d)Blood level: 50–125 mcg/ml

Oral loading (within 3 days)Standard dosing (within 5 days)

Valproate

May be more useful for manic/mixed episodes and rapid cyclers

Effective independent of the number of lifetime episodes

Effective acutely in patients with comorbid conditions (eg, substance abuse, anxiety disorders, general medical disorders, migraine)

In maintenance treatment, a positive response to divalproex during mania predicts a positive prophylactic response

Valproate Advantages

1. Mild, asymptomatic leukopenia and thrombocytopenia occur less frequently and are reversible upon drug discontinuation

2. Other side effects that are often bothersome to the patient include

Hair loss Increased appetite Weight gain

3. Polycystic ovarian syndrome 4. Rare, idiosyncratic, but potentially fatal adverse events

with valproate include irreversible Hepatic failure Hemorrhagic pancreatitis Agranulocytosis

Valproate Side Effects

A. Increase Valproic acid levels: enzyme inhibitors (fluoxetine)

B. Increase Free fraction of valproic acid : highly protein-bound drugs (aspirin)

C. Decrease Valproic acid levels: enzyme inducers (carbamazepine)

D. Increase Levels of concomitant medication: drugs undergoing oxidation:A. PhenobarbitalB. PhenytoinC. Tricyclic antidepressants

Drug Interactions

Baseline: Liver function testsCBC plus differential; plateletsThyroid-stimulating hormone (TSH)Pregnancy test (category D)

Plasma levels:Measure in about 5 daysTherapeutic levels: 50–100 mg/mL (up to

150mg/mL)If > 150 withhold dose; contact physician

Laboratory monitoring parameters

Carbamazepine (CBZ) is considered second-line therapy for acute and prophylactic treatment of bipolar disorder

Initial: 400mg PO qd in divided doses with increments of 100 mg 2 times/wk; if adverse effects occur, decrease dose by 200 mgDose range: 200-1600 mg PO qdSerum level range: (4-12 mcg/mL)

Carbamazepine

The most common dose-related side effects of carbamazepine include neurological symptoms, such as diplopia, blurred vision, fatigue, nausea, and ataxia

These effects are usually transient and often reversible with dose reduction

Less frequent side effects include mild liver enzyme elevations occur in 5%-15% of patients.

Hyponatremia may be related to water retention caused by carbamazepine's antidiuretic effect occurs in 6%-31% of patients

Mild asymptomatic leukopeniaAnemia and agranulocytosis

Carbamazepine Side Effects

MonitoringDrug levels – 4-6 weeks after dose changeCBC, electrolytes – every 2 weeks for 2

months; quarterly thereafterLFT, renal function – months 1, 4, 7, 10;

annually thereafterD/C drug for – WBC < 3000; neutrophils <

1500, Hct < 32

Carbamazepine

First-line therapy for the maintenance treatment of bipolar depression

Lamotrigine should be administered at 25 mg/day for the first 2 weeks, then 50 mg/day for weeks 3 and 4. After that, 50 mg can be added per week as clinically indicated; up to 200mg daily

Lamotrigine

Lamotrigine Side EffectsSerious rash, including Stevens-Johnson syndrome

and toxic epidermal necrolysis, was found to be high.

The incidence of serious rash was approximately 0.3% in adults

Lamotrigine Side EffectsValproate increases lamotrigine plasma level;

need to decrease lamotrigine starting dose and increase more slowly than otherwise; reports of increased incidence of rash; reports of tremor

Most atypical antipsychotics are FDA approved for the acute and maintenance treatment of mixed or manic episodes in bipolar disorder, either as monotherapy or in combination with lithium or valproic acid (except for clozapine)First-generation agents (Typical) – D2 blockade

HaloperidolChlorpromazine

Second-generation agents (Atypical) D2 and 5-HT2 blockadeOlanzapineRisperidoneQuetiapineAsenapinePaliperidone

Antipsychotics

Treatment of manic episodes ± psychotic sxInitiated with mood stabilizer for antimanic

effects for faster resolution in cases of severe mania

May be used as monotherapy for acute maniaUseful as an adjunct (on PRN basis) for acute

agitation

Antipsychotic Indications

Adverse effects↑ risk of tardive dyskinesia (movement

disorder)May worsen depressive episodesWeight gain or metabolic effects may be

exacerbated with concomitant lithium or valproate

Antipsychotics

A. Indications1. Patients who cannot wait for 4- to 6-week

delay before response to mood stabilizer2. Patients who have a history of response to

previous treatment with antidepressants3. Patients who have not responded to mood

stabilizers or psychotherapy in the past

B. Limit antidepressants to management of acute episodes1. Antidepressants may accelerate the course of

bipolar disorder and induce rapid cycling2. Antidepressants may induce a switch to mania

(especially tricyclic antidepressants)3. Simultaneously use mood stabilizer

Antidepressants

C. Maintain on antidepressant for 3–6 months, then slowly taper

D. Choice of antidepressant1. Bupropion may be less likely than tricyclic

antidepressants to induce switch2. Others: SSRIs, venlafaxine, nefazodone,

mirtazapine3. If atypical features: use SSRIs or monoamine

oxidase inhibitors (MAOIs)4 Avoid tricyclic antidepressants5. Consider carbamazepine, lamotrigine

Antidepressants

If used, monitor closely for both efficacy and manic/hypomanic symptoms

It should be used only in combination with a mood stabilizer and only for a necessary period

Antidepressant

IndicationsMay have faster onset: nonpsychotic agitation

AgentsLorazepam

PO: 0.5 mg q 2–6 hours not to exceed 20 mg dailyIntramuscularTaper when agitation stabilizes (1–2 weeks)

ClonazepamPO: 0.5 mg q 2–6 hours not to exceed 20 mg daily

Benzodiazepines

First-trimester exposure to lithium, valproate, or carbamazepine is associated with a greater risk of birth defects

With lithium exposure the absolute risk for Ebstein's anomaly

Exposure to carbamazepine and valproate during the first trimester is associated with neural tube defects at rates of up to 1% and 3%-5%, respectively

Both carbamazepine and valproate exposure have also been associated with craniofacial abnormalities

Pregnancy

Women who choose to remain on regimens of lithium, valproate, or carbamazepine during pregnancy should have maternal serum a-fetoprotein screening for neural tube defects before the 20th week of gestation, with amniocentesis

Women should also be encouraged to undergo high-resolution ultrasound examination at 16-18 weeks gestation to detect cardiac abnormalities in the fetus

At delivery, the rapid fluid shifts in the mother will markedly increase lithium levels unless care is taken to either lower the lithium dose, ensure hydration

Pregnancy

1. Explanation of diagnosis and symptoms2. Knowledge of names and effects of each

medication3. Information about side effects and

management (esp. toxicity)4. Instruct to avoid or minimize alcohol use5. Recognize tendency to deny the existence

and consequences of illness6. Recognize frequent noncompliance with

treatment7. Encourage family education

Patient Education Considerations