1. Bipolar Affective Disorder

2. Introduction Bipolar disorder (BPD) 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

3. Classification 1.Bipolar I disorder a. Mood disorder with at least one manic or hypomanic episode and one major depressive episode b. Characterized by manic or depressive episodes followed by symptom- free periods 2. Bipolar II disorder a. Recurrent major depressive episodes with hypomania b. Episodes usually do not require hospitalization 3. Cyclothymic disorder a.Chronic mood disturbance of at least 2 years duration involving numerous hypomanic and depressive episodes.

4. 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)

5. Clinical Diagnosis Manic episodes are characterized by the following symptoms: 1 week 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: 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 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.

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

7. Clinical Diagnosis Mixed episodes are characterized by the following: 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.

8. Bipolar Affective Disorder

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

10. Epidemiology epidemiological studies have estimated the lifetime prevalence of bipolar I and II disorders in the general population to be 3.7%–3.9% The prevalence in samples of patients presenting with depression is much higher, ranging from 21% to 26%

11. Pathophysiological hypothesis A. Leading theory is a genetic hypothesis of transmission (chromosome 18) B. Permissive hypothesis hydroxytriptamine [5-HT] increase norepinephrine [NE] in mania; decrease NE in depression) C. aminobutyric acid (GABA) depletion: inhibitory neurotransmission causes mania D. Amygdala Kindling: increases in excitatory neurotransmitters aspartate and glutamate

13. General Goals of Therapy To treat and reduce acute episodes of mania or depression when they occur. To reduce the frequency of episodes. To avoid cycling from one phase to another. To help the patient function as effectively as possible between episodes.

14. Phases of treatment Acute phase Continuation phase Maintenance phase

15. 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

16. Continuation phase 6- to 12-week period when risk of relapse is relatively high Continue mood stabilizers at same dosage effective in acute episodes

17. Maintenance phase 1.Bipolar disorder is recurrent in over 90% of patients 2.Most patients will require maintenance (prophylactic) therapy 3.Determinants for maintenance therapy a. Probability of a recurrence with or without a mood stabilizer b. Consequences of a recurrence 4. No evidence that chronic dosing causes tolerance 5. One year of maintenance therapy recommended after every manic episode 6. Long-term treatment is indicated for patients with 2 manic episodes 7.Maintenance antidepressant therapy usually not employed

18. Treatment Mood StabilizerAnticonvulsantsAntipsychoticsBenzodiazepinesAntidepressants

19. Pharmacotherapy options by subtypes

23. 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

24. Lithium Dosing – Maintenance, preventive use: 400-1200 mg (0.6-1 mmol/L) PO qd – Acute manic episode: 600-2400 mg (0.8-1.2 mmol/L) PO qd

25. Lithium - pharmacokinetics t½ = 20-24 hours 100% bioavailability Peak serum levels Slow release preparations - 4 to 4.5 hours Excreted 95% unchanged by glomerular filtration

26. Lithium Laboratory Monitoring Parameters – Baseline: thyroid function tests renal function tests (BUN, SCr, urinalysis) CBC plus differential, electrolytes presence of dermatologic disorder electrocardiogram (ECG) if > 40 years old – Lithium serum level monitoring: measure at 3–5 days 12 hours after last dose

27. 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

28. Lithium Pregnancy – 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

29. Lithium Toxicity At levels 1.5 to 2 mEq/L, – Severe GI effects – Neurotoxic effects – (drowsiness, tremors, hypertonicity, slurred speech) At levels greater than 2 (mEq/L) – Cardiovascular effects – (arrhythmias, AV block, bradycardia, myocarditis), convulsions, coma, and death

30. 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

31. Anticonvulsants Sodium valproateCarbamazepineLamotrigine

32. Anticonvulsants

33. Valproate Dosing Dose 1000–1500 mg/d (250 mg t.i.d) Blood level: 50–125 mcg/ml – Oral loading (within 3 days) – Standard dosing (within 5 days)

34. Valproate Advantages Effective in manic patients independent of depressive or irritable features (mixed mania), 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.

35. Valproate Side Effects 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 PCOS 4.Rare, idiosyncratic, but potentially fatal adverse events with valproate include irreversible – hepatic failure – hemorrhagic pancreatitis – agranulocytosis.

36. Drug Interactions 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: phenobarbital phenytoin tricyclic antidepressants

37. Laboratory monitoring parameters Baseline: – liver function tests – CBC plus differential, platelets, – thyroid-stimulating hormone, b. Plasma levels: – measure in about 5 days – therapeutic levels: 50–150 mg/ml – if > 150 withhold dose; contact physician

38. Carbamazepine 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: 300-1600 mg PO qd Serum level range: (4-12 mcg/mL)

39. Carbamazepine Drug Interaction Carbamazepine is able to induce drug metabolism, including its own, through cytochrome P-450 oxidation and conjugation. This enzymatic induction may decrease levels of concomitantly administered medications such as valproate, lamotrigine, oral contraceptives, protease inhibitors, benzodiazepines, and many antipsychotic and antidepressant medications.

40. 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

41. Lamotrigine Dosing 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

42. 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

43. 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

44. Antipsychotics 1. Haloperidol a. PO: 5–10 mg QD b. Taper when agitation or psychosis stabilizes (1–2 weeks) 2. Clozapine a. Treatment-resistant bipolar disorder 3. Olanzapine a. Structurally similar to clozapine

45. 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

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

47. 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

48. 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.

49. Patient Education Considerations 1.Explanation of diagnosis and symptoms 2. Knowledge of names and effects of each medication 3.Information about side effects and management (esp. toxicity) 4.Instruct to avoid or minimize alcohol use 5.Recognize tendency to deny the existence and consequences of illness 6. Recognize frequent noncompliance with treatment 7.Encourage family education