Bipolar Disorder

1. Bipolar Disorder Boadie Dunlop, MD March 19, 2009

2. Varieties of Bipolar Disorder – According to DSM-IV • Bipolar I disorder • One Manic or Mixed Episode, ever! • Bipolar II disorder • Never a manic episode • At least one Hypomanic episode • At least one Major depressive episode • Cyclothymic disorder • At least 2 years of hypomanic episode(s) and low mood not severe enough to meet Major depression criteria • 15-50% risk of developing Bipolar Disorder I or II • Bipolar disorder NOS • Mood elevations not meeting criteria for above • E.g. Recurrent hypomanic episodes without intercurrent depressive symptoms

4. DSM-IV CRITERIA FOR A MANIC EPISODE Manic Episode is defined by a distinct period during which there is an abnormally and persistently elevated, expansive, or irritable mood. This period of abnormal mood must last at least 1 week (or less if hospitalization is required). The mood disturbance must be accompanied by at least three additional symptoms from this list: -inflated self-esteem or grandiosity, -decreased need for sleep, -pressure of speech, -flight of ideas, -distractibility, -increased involvement in goal-directed activities or psychomotor agitation, and -excessive involvement in pleasurable activities with likelihood of painful consequences If the mood is irritable (rather than elevated or expansive), at least four of the above symptoms must be present . . . . The disturbance must be sufficiently severe to cause marked impairment in social or occupational functioning or to require hospitalization, or it is characterized by the presence of psychotic features . . . . .

5. Screening Questions for Mania/Hypomania • Have you ever had a period of a week or so when you felt so happy and energetic that your friends told you that you were talking too fast or that you were behaving differently and strangely? • Has there been a period when your mood was so high, hyper or excited that you got into arguments with people? • Have you ever gone 4 nights in a row with very little sleep and not missed it, so that you were not tired despite the lack of sleep?

6. Manic Episode: DIGFAST MOOD ELEVATION plus at least 3 of the following for at least one week (unless hospitalized): • Distractibility • Attention easily drawn away from current focus • Impulsivity/Indiscretions • Pursuing pleasure regardless of risk (sex, gambling, buying) • Grandiosity (i.e. Inflated sense of self) • Flight of Ideas • Ideas coming so fast you can’t keep up; ideas going off like popcorn in your head. • Agitation/Activity increase • Sleep need decreased • Talkativeness • Pressured speech, such that others have a hard time getting a word in. NOTE: If mood is only Irritable, need 4 of these symptoms

7. Mixed Episode • Criteria are met for both a manic episode and a major depressive episode (except duration) nearly every day for at least one week. • PSYCHOSIS • Patients with manic, mixed or depressed episodes can develop psychotic symptoms

8. Bipolar Disorder N.O.S. • Rapid cycling (days) between manic and depressive symptoms • Recurrent hypomanic episodes without intercurrent depressive symptoms • Hypomanic episodes, along with chronic depressive symptoms, that are too infrequent to qualify for a diagnosis

9. Rapid-Cycling Specifierfor Bipolar Disorder • Defined as greater than four mood episodes within 12 months • More common in women • Poorer prognosis • Better response to VPA than Li (maybe) • Thyroid dysfunction common • Much worse with antidepressant monotherapy!

10. Bipolar Disorder: Under-Recognized as a Cause of Disability in Young Adults Anemia Schizophrenia Violence Wars Bipolar disorder Self-inflicted injuries Alcohol use Road traffic accidents Tuberculosis Major depression 0 10,000 20,000 30,000 40,000 50,000 Lost years of healthy life (DALYs; thousands) Leading causes of disability; ages 15–44 (global; 1990). DALYs = Disability Adjusted Life Years. One DALY equals one lost year of healthy life. Murray CL, Lopez AD, editors. The Global Burden of Disease. Harvard University Press, 1996.

11. Standardized Mortality Ratios (SMR) of Treated and Untreated Bipolar Patients NS = no significant difference; O = number of deaths observed. *Different from 1.0 (P<0.05; two-tailed). **P<0.05 one-tailed. Angst J et al. J Affect Disord. 2000.

12. Lifetime Prevalence of Bipolar Disorder: Major Studies *Revised downwards from 1.6% following exclusion of false positives. **Plus further 2.8% with recurrent brief hypomanias. DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth edition. ECA = Epidemiological Catchment Area. NCS = National Comorbidity Survey.

13. Issues that Impede Diagnosis and Recognition of B.D. • Unwillingness of the patient to seek treatment • No definitive test for diagnosis Bipolar Disorder • Clinicians are not looking for manic/hypomanic episodes • Misdiagnosed as unipolar depression • Children, adolescents and young adults are often diagnosed with ADHD • People often do not have clear cut, discrete mood episodes • Mania if often unrecognized or considered irritability/ aggression • Psychotic features are often mistaken for Schizophrenia

14. 2000 National DMDA Bipolar Survey • Misdiagnosis occurred in 69% • Most frequent misdiagnoses • Depression (60%) • Anxiety disorders (26%) • Schizophrenia (18%) • Borderline or antisocial personality disorder (17%) • Alcohol/substance abuse (14%) • 35% of patients waited 10 years or more for a correct diagnosis of bipolar disorder

15. The Comorbidity Triangle Bipolar Disorder Anxiety Substance Abuse

16. Substance Abuse and Bipolar Disorder • B. D. is the highest Axis I disorder comorbid/concurrent with substance abuse • 21-61% of people with B.D. abuse or are addicted to substances as compared to 3-13% in the general population • B.D. is second to antisocial personality disorder in terms of concurrent substance abuse • Substance use adversely effects medication, produces earlier onset of symptoms and often leads to hospitalization

18. Schizoaffective Disorder • At some point, met criteria for Bipolar I, II or Major Depressive Disorder • Also have Psychotic symptoms that last at least one month. • Hallucinations • Delusions • Disorganized speech or behavior • Also, the Psychotic symptoms must be present for at least 2 weeks in absence of mood disturbance. • This feature distinguishes Schizoaffective Disorder from “Bipolar Disorder with Psychotic Features” • In BDw/PF, psychosis is only present when the mood disturbance is present

19. Epidemiology of Bipolar Disorder • Lifetime Incidence: 0.4-1.6% • No gender difference in incidence • Avg. age onset = 20 • May onset in childhood • May onset in middle adulthood • Requires greater suspicion of medical or substance-induce causes of mood change. • >95% have recurrent episodes • 60-70% of manic episodes occur before or after a depressive episode

20. Course/Prognosis • High rates of recurrence • Episodes of mania usually immediately preceed or follow episodes of depression • Untreated manic episode mean duration is 3 months • Intervals between episodes decrease as patients age • For untreated patients, mean of 4 episodes every 10 years • 5-15% are rapid cyclers = >4 episodes per year • Most patients regain function between episodes, but 20-30% continue to have significant impairment or symptoms

21. Bipolar Disorder-Major Public Health Issue • Overall economic burden is estimated at $45 billion dollars annually • Costs of treatment for an individual exceed $17,000 per year • 1 in 3 people with bipolar disorder fail to comply with medications • Non-adherence to treatment can result in hospitalization or suicide

22. FDA-Approved Treatments • Bipolar Mania • Carbamazepine (Equetro), Lithium, Valproic Acid • Aripiprazole, Olanzapine, Quetiapine, Risperidone, Ziprasidone • Bipolar Depression • Quetiapine, Symbyax (Olanzapine+Fluoxetine) • Maintenance • Litihium, Lamotrigine • Aripiprazole, Olanzapine, Quetiapine (adjunct to Li/VPA)

24. Lithium Formulations • Lithium Carbonate (peak in 1.5 hours) • Lithium Citrate • May be better tolerated in case of nausea • Eskalith CR (controlled release lithium; peak in 4h) • Lower peak levels, so potentially lower cognitive and sedative effects • However, may increase renal toxicity • Lithobid • Dose range: 600-1500 mg/d (usual 900-1200 mg/d) • Therapeutic Range: 0.5-1.2 ng/dL • Maintenance target: 0.8 ng/dL

25. Lithium Action and Dosing • Action probably through interaction with G-proteins and PIP pathway. • Can dose once daily qhs (24±6 hour half-life) • Can split dose if cognitive side effects • Start with generic lithium carbonate 600 mg qhs • If GI intolerance, switch to lithium citrate • If cognitive side effects, switch to controlled release lithium (Eskalith, Lithobid)

26. Lithium Monitoring • Narrow therapeutic index • Metabolized solely through kidney • Avoid dehydration, sodium restriction, excessive alcohol • Check Li level weekly until therapeutic level, then q3-6 months. • Check level 12 hours after last dose. • Monitor thyroid (TSH and free T4) and kidney (BUN, Cr) function: • Prior to treatment • 1 week and 1 month after initiation • Q3 months for first year • Q6 months thereafter

27. GI distress Weight gain Insulin-like effect Fine Tremor Cognitive Impairment “Fuzzy thinking” Rash Worsening acne/psoriasis Alopecia Benign Leukocytosis Dry Mouth/Polydipsia Polyuria Nephrogenic Diabetes Insipidus Reduced ADH sensitivity Renal Failure (long-term) Glomerular effect Hypothyroidism 5% total Sinoatrial node dysfunction Teratogenic: Cardiac malformation Lithium Side Effects

28. Lithium concentrations and their effects N Ghaemi, Mood Disorders, 2nd edition, p.170

31. Valproic Acid (Depakote/Depakene) • Valproic Acid: Peak in 2 hours • Depakote (ER) = Divalproex sodium: Bound molecules of Sodium valproate and valproic acid • Enteric Coated: Better GI tolerability • Depakene = Single valproic acid molecule • Cheaper • Peak in 3-8 hours • Highly protein bound • Half-life: 8-17 hours • Metabolized in liver via CYP 2C9/19

32. Valproic Acid (VPA) • Start at 250 mg TID, OR • Load dose: 20 mg/kg/d in healthy adults, divided TID (i.e. 500 mg TID) • Usual dose 1000-1500 mg/d • Max dose 60 mg/kg/d • Therapeutic range 50-125 mcg/ml • Assess every 1-2 weeks for first 1-2 months • Draw 12 hours after last dose • Check VPA level, CBC with diff and LFTs q6 months • Educate about signs/symptoms of hepatic dysfunction

33. VPA Toxicity Side Effects • Nausea/vomiting • Tremor/Sedation/ataxia • Weight gain • Alopecia (give MVI with selenium and Zn) • Thrombocytopenia (Risk increases >110 ug/ml) Severe Risks • Hepatotoxicity • Pancreatitis • Teratogenic: Neural tube defect

34. Carbamazepine (Equetro, Tegretol) • Blockade of voltage-gated sodium channels. • Slow absorption (4-8 hours) • Half-life initially 35-60 hours, but decreases to 12-20 hours due to hepatic autoinduction after about 6 weeks • Liver metabolism by 3A4 and 2C8 • Dose 200 mg BID or TID • Usual dose 800-1200 mg/d, divided BID • CBZ levels every 1-2 weeks in first 2 months • Watch for decrease in levels due to enzyme induction

35. Carbamazepine (Tegretol) • Serious Adverse Events: • BAD Rash (SJS, Toxic Epidermal Necrolysis) • Especially HLA-B*1502 allele carriers • Primarily Asian (Up to 15% of Chinese) • Screen Asian populations for this allele prior to initiation • Aplastic Anemia/Agranulocytosis • Hepatitis • Pancreatitis • Teratogen: Craniofacial defects; Developmental delay

36. CNS Dysarthria, Diplopia, Dizzineess, Ataxia, Confusion GI: N/V/D/C Mild LFT increases Hyponatremia Cardiac conduction abnormalities Oxcarbazepine (Trileptal): No proven benefit Structural analog of CBZ, metabolized differently, so no epoxide metabolite. Does not induce autoinduction Oxcarbazepine metabolite monohydroxy derivative (MHD) blocks N/P- and R-type calcium channels, while carbamazepine blocks L-type calcium channels Carbamazepine Side Effects and Oxcarbazepine

37. Lamotrigine (Lamictal) • Glutamate antagonist • Maintenance therapy in bipolar I disorder, especially vs depression. • Dosing Caution: BAD Rash! (Stevens Johnson Syndrome) • Start 25 mg/d, increase by 25 mg q week • If on Valproic Acid, use half this dose • Maintenance Dose: 50-100 mg BID • Side Effects: Headache, diplopia, ataxia, n/v/d.

38. Monitoring Atypical Antipsychotics ADA et al, Diabetes Care, 2004;27:596-601

39. Augmenting Agents • Benzodiazpeines: Not FDA-approved for bipolar disorder, yet effective for adjunctive mood stabilization. • Use long-acting agent: Clonazepam (Klonopin) • Start 0.5 mg qhs. Usual dose 1-3 mg/d • Verapamil: 80 mg BID to max 320 mg/d • Clonidine 0.1 mg BID up to 0.2 mg TID • Topiramate • ECT • Treatment refractory • Psychotic/Catatonic

40. Predictable Problems • Non-adherence to treatment • Reject diagnosis • Miss those manias/hypomanias! • Side Effects • Weight gain • Episode breakthrough • Overdose

41. Role of Psychotherapy • Types of psychotherapeutic interventions include: • Individual psychoeducational • Inpatient family intervention • Couples therapy • Case management • Psychosocial rehabilitation • Family-focused treatment • Cognitive behavioral therapy • Social rhythm therapy

42. Value of Psychotherapy • Acceptance of illness • Education about the illness • Monitoring for early breakthrough symptoms and management • Increase medication adherence • Reduce family conflict • Mood improvement through cognitive behavioral therapy (CBT)