1. Bipolar Affective Disorder

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
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
3.7%–3.9% lifetime prevalence of bipolar I and II disorders
Equal incidence in females and males
First episode for females: depression
First 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%

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
Gamma aminobutyric acid (GABA) depletion: inhibitory neurotransmission causes mania
Amygdala Kindling: increases in excitatory neurotransmitters aspartate and glutamate

7. Mania
At least 1 week of abnormal and persistently elevated, expansive, or irritable mood
Any time duration if hospitalized
Presence of 3 or more of the DIG FAST symptoms
4 if the mood is only irritable
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)
Faatimah was in an expansive mood, showering gifts on her friends, wearing her most brightly colored clothing even when it wasn't appropriate, engaging strangers in animated conversations, and generally acting as if her presence was the most important thing in the life of everyone she met

8. Hypomania vs. 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

9. Hypomania vs. Mania
Hypomania:At first when I'm high, it's tremendous ... ideas are fast ... like shooting stars you follow until brighter ones appear... All shyness disappears, the right words and gestures are suddenly there ... uninteresting people, things, become intensely interesting. Sensuality is pervasive, the desire to seduce and be seduced is irresistible. Your marrow is infused with unbelievable feelings of ease, power, well-being, omnipotence, euphoria ... you can do anything ... but somewhere this changes.
Mania:The fast ideas start coming too fast and there are far too many ... overwhelming confusion replaces clarity ... you stop keeping up with it … memory goes. Infectious humor ceases to amuse. Your friends become frightened ... everything is now against the grain ... you are irritable, angry, frightened, uncontrollable, and trapped.

10. What is a Major Depressive Episode?
Must last at least 2 weeks
At least 5 of the criteria with one including depressed mood or decreased interests
Must cause clinically significant impairment

11. What is a Major Depressive Episode?
Depressed mood and SIG-E-CAPS criteria
S: Suicidal ideation
I: decreased Interests
G: excessive Guilt (worthlessness, hopelessness)
E: decreased Energy
C: decreased Concentration
A: Appetite changes
P: Psychomotor retardation or agitation
S: Sleep disturbance

12. Mixed Features
Full criteria for a manic and depressive episode for the majority of at least 1 week

13. 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)

14. 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)

15. 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:
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)
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

16. 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:
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)
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

17. 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.

18. 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

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

21. Treatment

22. 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

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

24. Phases of treatment
Acute phase
Continuation phase
Maintenance phase

25. 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

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

27. Important Pearls regarding the Maintenance phase
Bipolar disorder is recurrent in over 90% of patients
Required by most patients
Determinants for maintenance therapy
a. Probability of a recurrence with or without a mood stabilizer
b. Consequences of a recurrence
One year of maintenance therapy recommended after every manic episode
Long-term treatment is indicated for patients with 2 manic episodes
No evidence that chronic dosing causes tolerance
Maintenance antidepressant therapy usually not employed

28. Treatment Mood Stabilizer Anticonvulsants Antipsychotics
Benzodiazepines
Antidepressants

29. 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)

33. 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 anti-suicide effect
Monitoring blood levels is critical with LITHIUM

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

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

36. Lithium Laboratory Monitoring Parameters
Lithium serum level monitoring:
12 hours after last dose
Periodic monitoring of lithium levels should occur every 6 months or more frequently if clinically indicated
Initial Workup
Safety and 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.

37. 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

38. 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.

39. 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

40. 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

41. Anticonvulsants
Sodium valproate
Carbamazepine
Lamotrigine

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

43. 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)

44. 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

45. 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
Rare, idiosyncratic, but potentially fatal adverse events with valproate include irreversible
Hepatic failure
Hemorrhagic pancreatitis
Agranulocytosis

47. 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

48. 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

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

50. 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
Anemia and agranulocytosis

51. 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

52. 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; up to 200mg daily

54. 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

55. 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

56. 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

57. 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

58. 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

59. 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 may induce a switch to mania (especially tricyclic antidepressants) 3. Simultaneously use mood stabilizer

60. Antidepressants
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

61. 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

62. 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

63. 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

64. 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

65. 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