1. Bipolar Affective Disorder
JAWZA ALSABHAN

2. 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

3. 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

4. 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%

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

6. 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

7. 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)

8. Bipolar Affective Disorder

9. 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)

10. 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

11. 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

12. 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.

13. 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

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

15. Treatment

16. 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

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

18. Phases of treatment
Acute phase
Continuation phase
Maintenance phase

19. 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

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

21. 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

22. Treatment Mood Stabilizer Anticonvulsants Antipsychotics
Benzodiazepines
Antidepressants

23. 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?

27. 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

28. Lithium Dosing Therapeutic serum concentration: 0.6–1.2 mEq/L
Maintenance, preventive use: mg PO daily
Acute manic episode: 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

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

30. 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.

31. 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

32. 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.

33. 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

34. 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

35. Anticonvulsants
Sodium valproate
Carbamazepine
Lamotrigine

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

37. 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)

38. 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

39. 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.

41. 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

42. 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

43. 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: mg PO qd Serum level range: (4-12 mcg/mL)

44. 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

45. 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

46. 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???

48. 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

49. 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

50. 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

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

52. 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

53. 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

54. 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

55. 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

56. 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

57. 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

58. 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 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

59. 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