Bipolar Affective Disorder JAWZA ALSABHAN

Introduction Bipolar disorder (BPD) (manic-depressive illness) is one of the most severe forms of mental illness and is characterized by swinging moods Also known as manic depression, a mental illness that causes a person’s moods to swing from extremely happy and energized (mania) to extremely sad (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 wellness Patients rarely experience a single episode Relapse rates at more than 70% over 5 years Most patients are depressed most of the time

Epidemiology Epidemiological studies have estimated the lifetime prevalence of bipolar I and II disorders in the general population to be 3.7%–3.9% Incidence is equal in females and males. The first episode for females is usually marked by a depressive episode. For males, it is usually marked by a manic episode The average age at onset is 21 years of age, with bipolar I disorder onset somewhat earlier at 18 years of age The prevalence in samples of patients presenting with depression is much higher, ranging from 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

Pathophysiological hypothesis 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) Aminobutyric acid (GABA) depletion: inhibitory neurotransmission causes mania Amygdala Kindling: increases in excitatory neurotransmitters aspartate and glutamate

Classification Chronic mood disturbance of at least 2 years duration 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)

Bipolar Affective Disorder

Clinical Diagnosis 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: At least 1 week of profound mood disturbance is present, characterized by elation, irritability, or expansiveness. Three or more of the following symptoms are present: Grandiosity Diminished need for sleep Excessive talking or pressured speech Racing thoughts or flight of ideas Clear evidence of distractibility Increased level of goal-focused activity at home, at work, or sexually Excessive pleasurable activities, often with painful consequences The mood disturbance is sufficient to cause impairment at work or danger to the patient or others. The mood is not the result of substance abuse or a medical condition. If severe, may have psychotic symptoms

Clinical Diagnosis Hypomanic episodes are characterized by the following: The patient has an elevated, expansive, or irritable mood of at least 4 days' duration. Three or more of the following symptoms are present: Grandiosity or inflated self-esteem Diminished need for sleep Pressured speech Racing thoughts or flight of ideas Clear evidence of distractibility Psychomotor agitation at home, at work, or sexually Engaging in activities with a high potential for painful consequences The mood disturbance is observable to others. The mood is not the result of substance abuse or a medical condition. 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 Persons must meet both the criteria for mania and major depression; the depressive event is required to be present for 1 week only. The mood disturbance results in marked disruption in social or vocation function. The mood is not the result of substance abuse or a medical condition. The mixed symptomology is quite common in patients presenting with bipolar symptomology. This often causes a diagnostic dilemma. Higher risk of comorbid substance use/abuse and suicidality.

Clinical Diagnosis Depressive episode: Often misdiagnosed as a unipolar depressive episode Most 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

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

Treatment

Therapeutic Goals Acute Mania Depression Control symptoms Return patient to normal level of psychosocial function Control agitation, aggression, and impulsivity to ensure safety of self and others Depression Remission of symptoms Avoid precipitation of hypomania/mania

Therapeutic Goals Maintenance Relapse prevention Reduction of suicide risk Reduce cycling frequency Reduce mood instability Improve overall functioning Promote treatment adherence

Phases of treatment Acute phase Continuation phase Maintenance phase

Acute phase a. Manic phase 1) Mood stabilizer + Consider benzodiazepines or antipsychotic 2) Discontinue antidepressant b. Depressed phase 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

Maintenance phase Bipolar disorder is recurrent in over 90% of patients Most patients will require maintenance (prophylactic) therapy Determinants for maintenance therapy a. Probability of a recurrence with or without a mood stabilizer b. Consequences of a recurrence No evidence that chronic dosing causes tolerance One year of maintenance therapy recommended after every manic episode Long-term treatment is indicated for patients with 2 manic episodes 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 . Depressive: Lamotrigine, lithium, quetiapine (with or without adjunctive antidepressant) Bipolar II: lamotrogine, lithium?

Lithium 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 antisuicide effect Monitoring blood levels is critical with LITHIUM

Lithium Dosing Therapeutic serum concentration: 0.6–1.2 mEq/L Maintenance, preventive use: 400-1200 mg PO daily Acute manic episode: 600-2400 mg PO daily Therapeutic 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/L Serum concentrations should be drawn 4–5 days after the first dose

Lithium - pharmacokinetics t½ = 20-24 hours 100% bioavailability Peak serum levels Slow release preparations - 4 to 12 hours Excreted 95% unchanged by glomerular filtration

Lithium Laboratory Monitoring Parameters Lithium serum level monitoring: Measure at 3–5 days 12 hours after last dose Periodic monitoring of lithium levels should occur every 6 months or more frequently if clinically indicated Initial Workup Efficacy Renal function tests (BUN, SCr, urinalysis) CBC plus differential, electrolytes Thyroid panel Weight EKG (elderly, cardiovascular disease) Presence of dermatologic disorder Pregnancy test (if female and of childbearing age, pregnancy category D) Resolution of symptoms Assessments for adverse effects Neurologic exam Patient report on GI symptoms, urinary frequency, etc.

Lithium: Adverse Effects The high frequency of non-adherence to lithium treatment (30-50%) is often associated with adverse effects Cognitive impairment Tremor Acne Polyuria and polydipsia Muscle weakness Weight gain Long term adverse effects on thyroid functioning and the kidneys

Lithium Pregnancy Precautions D - 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 dosing Anything 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 Toxicity Mild 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 memory Moderate toxicity (serum levels 2–2.5 mEq/L):  Ataxia, lethargy, nystagmus, worsening confusion, severe GI upset, coarse tremors, and increased deep tendon reflexes Severe toxicity (serum levels > 3 mEq/L):  Severely impaired consciousness, coma, seizures, respiratory complications, and death

Effects of Abrupt Discontinuation of Lithium 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

Anticonvulsants Sodium valproate Carbamazepine Lamotrigine

Anticonvulsants Indications a. Prevention of recurrence b. When lithium is ContraIndication or ineffective c. For rapid cyclers ( 4 episodes/year)

Valproate 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 Advantages 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 Side Effects Mild, asymptomatic leukopenia and thrombocytopenia occur less frequently and are reversible upon drug discontinuation Other side effects that are often bothersome to the patient include Hair loss, Increased appetite, Weight gain Polycystic ovarian syndrome PCOS Rare, idiosyncratic, but potentially fatal adverse events with valproate include irreversible Hepatic failure Hemorrhagic pancreatitis Agranulocytosis.

Drug Interactions Increase Valproic acid levels: enzyme inhibitors (fluoxetine) Increase Free fraction of valproic acid : highly protein-bound drugs (aspirin) Decrease Valproic acid levels: enzyme inducers (carbamazepine) Increase Levels of concomitant medication: drugs undergoing oxidation: Phenobarbital Phenytoin Tricyclic antidepressants

Laboratory monitoring parameters Baseline: Liver function tests CBC plus differential; platelets Thyroid-stimulating hormone (TSH) Pregnancy test (category D) Plasma levels: Measure in about 5 days Therapeutic levels: 50–100 mg/mL (up to 150mg/mL) If > 150 withhold dose; contact physician

Carbamazepine Carbamazepine (CBZ) is considered second-line therapy for acute and prophylactic treatment of bipolar disorder Initial: 200 mg PO qd in divided doses with increments of 100 mg 2 times/wk; if adverse effects occur, decrease dose by 200 mg Dose range: 200-1600 mg PO qd Serum level range: (4-12 mcg/mL)

Carbamazepine Side Effects 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 leukopenia

Carbamazepine Monitoring Drug levels – 4-6 weeks after dose change CBC, electrolytes – every 2 weeks for 2 months; quarterly thereafter LFT, renal function – months 1, 4, 7, 10; annually thereafter D/C drug for – WBC < 3000; neutrophils < 1500, Hct < 32

Lamotrigine 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???

Lamotrigine Side Effects Serious 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 Effects Valproate 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

Antipsychotics 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 Haloperidol Chlorpromazine Second-generation agents (Atypical) D2 and 5-HT2 blockade Olanzapine Risperidone Quetiapine Asenapine Paliperidone

Antipsychotics Mechanism of Action Traditional agents – D2 blockade Haloperidol Chlorpromazine Second-generation (Atypical) agents D2 and 5-HT2 blockade Olanzapine Risperidone Quetiapine Asenapine Paliperidone

Antipsychotic Indications Treatment of manic episodes ± psychotic sx Initiated with mood stabilizer for antimanic effects for faster resolution in cases of severe mania May be used as monotherapy for acute mania Useful as an adjunct (on PRN basis) for acute agitation

Antipsychotics Adverse effects ↑ risk of tardive dyskinesia (movement disorder) May worsen depressive episodes Weight gain or metabolic effects may be exacerbated with concomitant lithium or valproate

Antidepressants A. Indications 1. Patients who cannot wait for 4- to 6-week delay before response to mood stabilizer 2. Patients who have a history of response to previous treatment with antidepressants 3. Patients who have not responded to mood stabilizers or psychotherapy in the past B. Limit antidepressants to management of acute episodes 1. Antidepressants may accelerate the course of bipolar disorder and induce rapid cycling 2. Antidepressants main induce a switch to mania (especially tricyclic antidepressants) 3. Simultaneously use mood stabilizer C. Maintain on antidepressant for 3–6 months, then slowly taper D. Choice of antidepressant 1. Bupropion may be less likely than tricyclic antidepressants to induce switch 2. Others: SSRIs, venlafaxine, nefazodone, mirtazapine 3. If atypical features: use SSRIs or monoamine oxidase inhibitors (MAOIs) 4 Avoid tricyclic antidepressants 5. Consider carbamazepine, lamotrigine

Antidepressant 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

Benzodiazepines Indications Agents May have faster onset: nonpsychotic agitation Agents Lorazepam PO: 0.5 mg q 2–6 hours not to exceed 20 mg daily Intramuscular Taper when agitation stabilizes (1–2 weeks) Clonazepam

Pregnancy 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

Patient Education Considerations Explanation of diagnosis and symptoms Knowledge of names and effects of each medication Information about side effects and management (esp. toxicity) Instruct to avoid or minimize alcohol use Recognize tendency to deny the existence and consequences of illness Recognize frequent noncompliance with treatment Encourage family education