1. BIPOLAR DISORDER Indra Singh MD

2. Burden of the disease Bipolar Disorder (BD)is an episodic, potentially life-long, disabling disorder Bipolar Disorder (BD)is an episodic, potentially life-long, disabling disorder Characterized by Mood elevation Characterized by Mood elevation Associated with significant Morbidity and Mortality if untreated Associated with significant Morbidity and Mortality if untreated Often underdiagnosed. Often underdiagnosed.

3. Epidemiology Lifetime prevalence Lifetime prevalence BD I : 1.0% BD I : 1.0% BD II : 1.1 % BD II : 1.1 % Gender: Gender: BPD I : Affects men and women equally BPD I : Affects men and women equally BPD II : is more common in women BPD II : is more common in women Age of Onset : 15-30 years Age of Onset : 15-30 years

4. Genetics Lifetime risk in relatives of BD probands is Lifetime risk in relatives of BD probands is 40-70% for MZ twins 40-70% for MZ twins 5-10% for a first degree relative 5-10% for a first degree relative 0.5-1.5 % for an unrelated person 0.5-1.5 % for an unrelated person Linkage studies implicate TPH2 gene Linkage studies implicate TPH2 gene No candidate gene identified No candidate gene identified

5. Diagnostic criteria BD I BD I Episodes of Mania Episodes of Mania Often have depression Often have depression BD II BD II One or more depressive episodes One or more depressive episodes At least one episode of hypomania At least one episode of hypomania

6. Manic episode Persistently elevated or irritable mood, lasting at least 1 week Persistently elevated or irritable mood, lasting at least 1 week 3 additional sx in the same period affecting 3 additional sx in the same period affecting self-esteem self-esteem sleep sleep Speech Speech Thoughts Thoughts Attention Attention PMA PMA Functioning Functioning

7. Hypomania Unlike Mania Unlike Mania shorter duration of manic symptoms (at least four days), shorter duration of manic symptoms (at least four days), less severe level of symptoms. less severe level of symptoms. Absence of Psychoses Absence of Psychoses mild functional impairment mild functional impairment Often does not often lead to hospitalization; Often does not often lead to hospitalization;

8. Depression Dx requires 5/9 sx during the same period Dx requires 5/9 sx during the same period with one must be either depressed mood or loss of interest. with one must be either depressed mood or loss of interest. Symptoms should be present daily or for most of the day for at least two weeks. Symptoms should be present daily or for most of the day for at least two weeks. The symptoms must cause clinically significant distress or impairment in functioning, The symptoms must cause clinically significant distress or impairment in functioning,

9. Unipolar v Bipolar depression Patients with Bipolar depression more likely to have Patients with Bipolar depression more likely to have Family hx of BD Family hx of BD Early age of Onset Early age of Onset Pts. Presenting with depression should be asked about past Mania or Hypomania Pts. Presenting with depression should be asked about past Mania or Hypomania

10. Mixed Presence of both depressive and mood elevated sx simultaneously. Presence of both depressive and mood elevated sx simultaneously. May thus occur with bipolar I or bipolar II disorder. May thus occur with bipolar I or bipolar II disorder. The frequency is estimated between 20 and 70 % The frequency is estimated between 20 and 70 % The most common symptoms were The most common symptoms were irritability, irritability, racing or crowded thoughts, racing or crowded thoughts, psychomotor agitation, psychomotor agitation, or increased talkativeness or increased talkativeness concurrent with symptoms of depression. concurrent with symptoms of depression.

11. BD 3 SUBTYPES 3 SUBTYPES BD I BD I At least 1 manic episode At least 1 manic episode Major depression frequent, but not required for dx Major depression frequent, but not required for dx BD II BD II One hypomanic + at least 1 episode of major dep One hypomanic + at least 1 episode of major dep BD NOS BD NOS Features do not meet criteria of BD I or II Features do not meet criteria of BD I or II

12. Course of BD 90% of pt.'s with BD have at least one psych hospitalization 90% of pt.'s with BD have at least one psych hospitalization Course influenced by high rates of comorbid alcohol or substance abuse. Course influenced by high rates of comorbid alcohol or substance abuse. Comorbid anxiety disorder is also common Comorbid anxiety disorder is also common Suicide rates are high Suicide rates are high Rapid Cycling if four or more mood episodes occurred during the previous 12 months Rapid Cycling if four or more mood episodes occurred during the previous 12 months

13. Course of BD BD I BD I marked by relapses and remissions, marked by relapses and remissions, often alternating manic with depressive episodes. often alternating manic with depressive episodes. Ninety percent of individuals have a second manic episode within five years Ninety percent of individuals have a second manic episode within five years Depressive sx frequent over the course of bipolar disorder than manic sx Depressive sx frequent over the course of bipolar disorder than manic sx 3 x more frequently than mania in BD I 3 x more frequently than mania in BD I 37 x more frequently than hypomania in BD II 37 x more frequently than hypomania in BD II

14. BD Assessment and Rx for Assessment and Rx for Mania Mania Hypomania Hypomania MIxed MIxed

15. Clinical Assessment Medical comorbidity Medical comorbidity Psychiatric comorbidity Psychiatric comorbidity Psychosocial Stressors Psychosocial Stressors Medications current and past Medications current and past Suicide risk Suicide risk Substance Use Substance Use

16. Assessment Stop Anti Depressants Stop Anti Depressants Beware of discontinuation syndromes symptoms Beware of discontinuation syndromes symptoms Dizziness Dizziness Headache Headache Paresthesias Paresthesias Nausea Nausea Diarrhea Diarrhea Insomnia Insomnia Irritability Irritability

17. Reasons for Hospitalization Delirium Delirium Marked psychotic symptoms Marked psychotic symptoms Severe mania Severe mania Suicidality or homicidality Suicidality or homicidality Potential for violence Potential for violence ideas / intent to harm others; ideas / intent to harm others; hx of violent behavior; hx of violent behavior; severe agitation or hostility; severe agitation or hostility; active psychosis active psychosis Substance withdrawal or intoxication Substance withdrawal or intoxication

18. GOALS FOR Rx Acute Phase Acute Phase Focus on managing Sx and pt. safety Focus on managing Sx and pt. safety Hospitalization often necessary Hospitalization often necessary Continuation phase Continuation phase remission of symptoms is preserved remission of symptoms is preserved The goal is to prevent relapse of the mood episode. The goal is to prevent relapse of the mood episode. maintenance phase maintenance phase and aims to prevent recurrence of a new mood episode. and aims to prevent recurrence of a new mood episode. Long-term or lifetime maintenance is recommended for patients who have suffered one manic episode Long-term or lifetime maintenance is recommended for patients who have suffered one manic episode

19. Rx Principles for Mood Elevated Syndromes Assess for risk of suicide, aggressiveness, and violence to others. Assess for risk of suicide, aggressiveness, and violence to others. Discontinue ADs Discontinue ADs Reduce their use of alcohol, caffeine, and nicotine. Reduce their use of alcohol, caffeine, and nicotine. In breakthrough episode assess for adherence to Rx In breakthrough episode assess for adherence to Rx Treatment of mood elevated syndromes is based upon studies in BD I Treatment of mood elevated syndromes is based upon studies in BD I

20. Acute Phase Drugs used to induce remission Drugs used to induce remission Lithium Lithium Anticonvulsants Anticonvulsants Antipsychotics Antipsychotics allow up to two weeks before determining the drug’s clinical effectiveness. allow up to two weeks before determining the drug’s clinical effectiveness.

21. Acute Phase Efficacy mostly similar across first line medications Efficacy mostly similar across first line medications With or without Psychoses With or without Psychoses Mania or mixed Mania or mixed With or without rapid cycling With or without rapid cycling Response independent of Response independent of Lifetime number of episodes Lifetime number of episodes Hx of lifetime comorbid SUD Hx of lifetime comorbid SUD

22. Acute Phase If no remission within 2 weeks If no remission within 2 weeks Switch Switch If no response If no response Add Add If partial response If partial response Goal of Rx is full remission Goal of Rx is full remission

23. Choice of Drug Overall First line drugs have better response than placebo Overall First line drugs have better response than placebo Efficacy similar across first line medications Efficacy similar across first line medications Lithium associated with reduced risk of suicide attempts Lithium associated with reduced risk of suicide attempts Monotherapy maybe sufficient for less severely ill patients Monotherapy maybe sufficient for less severely ill patients Combination therapy frequently for pts with manic or mixed episodes Combination therapy frequently for pts with manic or mixed episodes Combination therapy is Combination therapy is Li + Antipsychotic Li + Antipsychotic Valproate + Antipsychotic Valproate + Antipsychotic

24. Choice of Drug Past response to medications Past response to medications Side-effect profiles Side-effect profiles Comorbid medical illness Comorbid medical illness Pregnancy Pregnancy Concurrent medications Concurrent medications Cost Cost

25. Lithium More controlled trials demonstrating the efficacy of lithium monotherapy than any other medication More controlled trials demonstrating the efficacy of lithium monotherapy than any other medication The starting dose of lithium is usually 300 mg BID The starting dose of lithium is usually 300 mg BID increased by 300 to 600 mg every 3-5 days increased by 300 to 600 mg every 3-5 days Serum level Serum level target 0.8 and 1.2 meq/L target 0.8 and 1.2 meq/L measured five to seven days after each dose increase. measured five to seven days after each dose increase. levels should be drawn 12 hours after the last dose levels should be drawn 12 hours after the last dose Check s Cr, Cr Cl, TFTs, CBC D annually Check s Cr, Cr Cl, TFTs, CBC D annually

26. Lithium Acute side effects include Acute side effects include nausea, nausea, tremor, tremor, polyuria and thirst, polyuria and thirst, weight gain, weight gain, loose stools, and loose stools, and cognitive impairment cognitive impairment Severe or a sudden worsening of side effects may be a sign of lithium toxicity. Severe or a sudden worsening of side effects may be a sign of lithium toxicity. long term adverse effects of lithium involve long term adverse effects of lithium involve the kidneys and the kidneys and thyroid gland. thyroid gland. cardiac rhythm disturbances almost always occur in patients with preexisting cardiac disease. cardiac rhythm disturbances almost always occur in patients with preexisting cardiac disease.

27. LITHIUM TOXICITY Lithium conc.s/s of toxicityManagement 1.2 -1.5 mEq/LWorsening tremor, n/v, diarrhea, drowsiness Hold lithium till serum conc. Returns to normal 1.6.2.5 meq/LCoarse tremors, apathy, drowsiness, slurred speech, ataxia, increase in s.creatinine Hold lithium, repeat levels, assess electrolytes and renal fx, may require admission > 2.5 mEq/LMedical emergency n/v, diarrhea, involuntary movements, dysarthria, coarse tremors, delirium, sz, coma Admit inpt.

28. Lithium drug interactions Increase Li concDecrease Li concNeurotoxicity Thiazides Lasix Caffeine Desmopressin ACEIs ARBs NSAID Reduced Na intake Theophylline Verapamil Osmotic diuretics Na bicarb antacids Increased Na intake Antipsychotics Carbamazepine Methyldopa SSRIs MAOIs Verapamil

29. VALPROATE starting dose of 250 mg 2-3 times per day. starting dose of 250 mg 2-3 times per day. Increased by 250 mg - 500 mg every 1-3 days to reach a therapeutic serum level, Increased by 250 mg - 500 mg every 1-3 days to reach a therapeutic serum level, Oral loading and rapid titration to a full dose within one to two days by prescribing 20 mg/kg/day Oral loading and rapid titration to a full dose within one to two days by prescribing 20 mg/kg/day Target serum level between 50 and 125 mcg/mL. Target serum level between 50 and 125 mcg/mL. Levels should be drawn 12 hours after the last dose Levels should be drawn 12 hours after the last dose efficacy increased as serum levels increased efficacy increased as serum levels increased Levels should be checked at 6 to 12 month intervals. Levels should be checked at 6 to 12 month intervals. Annual CBC D, LFTs, BMP Annual CBC D, LFTs, BMP

30. Valproate Common side effects include Common side effects include weight gain, weight gain, nausea, vomiting, nausea, vomiting, hair loss, easy bruising, and hair loss, easy bruising, and tremor. tremor. Divalproex is generally used rather than valproate to minimize gastrointestinal distress. Divalproex is generally used rather than valproate to minimize gastrointestinal distress. Hepatic failure and thrombocytopenia have rarely been associated with valproate use; Hepatic failure and thrombocytopenia have rarely been associated with valproate use; liver function tests and platelets should be monitored at 6 to 12 month intervals in all patients taking the drug liver function tests and platelets should be monitored at 6 to 12 month intervals in all patients taking the drug

31. Carbamazepine Starting Dose 100 mg to 200 mg 1-2 times per day, Starting Dose 100 mg to 200 mg 1-2 times per day, Increase dose by 200 mg every 1-4 days, to a final dose of about 800 to 1000 mg per day, Increase dose by 200 mg every 1-4 days, to a final dose of about 800 to 1000 mg per day, effective dose range 200 and 1800 mg per day. effective dose range 200 and 1800 mg per day. Therapeutic serum levels have not been established for BD. Therapeutic serum levels have not been established for BD. However, many clinicians use levels established for treatment of epilepsy: 4 to 12 mcg/mL. However, many clinicians use levels established for treatment of epilepsy: 4 to 12 mcg/mL.

32. Atypical APs Olanzapine Olanzapine Start 10-15mg /day Start 10-15mg /day Max 20 mg daily Max 20 mg daily Side effects include Side effects include Somnolence Somnolence dry mouth dry mouth Dizziness Dizziness Weight gain Weight gain Monotherapy or combination with Li/Depakote Monotherapy or combination with Li/Depakote

33. Risperidone Start 1mg BID Start 1mg BID Increase to 6mg/day Increase to 6mg/day Onset of action between 1-6 days Onset of action between 1-6 days Mono or combination therapy Mono or combination therapy Side effects Side effects Somnolence Somnolence EPSE EPSE

34. Ziprasidone Start 40mg BID Start 40mg BID Max 80mg BID Max 80mg BID Onset of action at day 2 Onset of action at day 2 Monotherapy Monotherapy Side effects: Side effects: Nausea Nausea Akathisia Akathisia tremors tremors

35. Aripiprazole Start 15mg/day Start 15mg/day Max 30mg /day Max 30mg /day Mono or combination therapy Mono or combination therapy Separates form placebo by day 4 Separates form placebo by day 4 Side effects Side effects N/V N/V insomnia insomnia akathisia akathisia

36. Quetiapine 100mg day 1 100mg day 1 Up to 800mg daily Up to 800mg daily Superior to placebo at day 21 Superior to placebo at day 21 Side effects Side effects Dry mouth Dry mouth Dizziness Dizziness Weight gain Weight gain somnolence somnolence

37. Metabolic effects of Atypicals Weight gain Weight gain Clozapine and olanzapine : most wt. gain Clozapine and olanzapine : most wt. gain Risperidone and Quetiapine : moderate Risperidone and Quetiapine : moderate Aripiprazole and Ziprasidone : minimal Aripiprazole and Ziprasidone : minimal Hyperlipidemia Hyperlipidemia DM DM

38. Monitoring parameters Weight and BMIBaseline, 2, 8 and 12 weeks then @ 3 months, annually Waist circumferenceBaseline, annually BPBaseline,12 weeks,anually Fasting Plasma GlucoseBaseline,12 weeks then annually Fasting Lipid ProfileBaseline,12 weeks, every 5 years Pregnancy testBaseline

39. Effective Meds in Bipolar Mania/Hypomania or Mixed Episodes Likely BeneficialUnlikely to be Beneficial or Maybe Harmful ManiaLithium, valproate, carbamazepine, Atypical APs Combining (lithium or valproate) with Atypical APs Gabapentin Lamotrigine Topiramate AD Monotherapy Mixed EpisodeValproate, carbamazepine, aripiprazole, olanzapine, risperidone, or ziprasidone Gabapentin Lamotrigine Topiramate

40. Acute Phase Reassess every 1-2 weeks for 6 weeks Reassess every 1-2 weeks for 6 weeks Monitor treatment response at 4 to 8 weeks after initiation of treatment, after each change in treatment, and periodically until full remission is achieved. Monitor treatment response at 4 to 8 weeks after initiation of treatment, after each change in treatment, and periodically until full remission is achieved. Remission Remission In Mania : if free from significant symptoms for two months In Mania : if free from significant symptoms for two months In Mixed episode : if free from significant symptoms of mania or depression for 2 months In Mixed episode : if free from significant symptoms of mania or depression for 2 months

41. Continuation Phase Check for Compliance. Check for Compliance. Assessment of ADR. Assessment of ADR. Monitoring of serum concentration Monitoring of serum concentration Monitor for metabolic syndrome for those on Atypical APs Monitor for metabolic syndrome for those on Atypical APs Assess for improvement or change of the core symptoms of mania and mixed Assess for improvement or change of the core symptoms of mania and mixed Careful risk assessment for those with s/i. Careful risk assessment for those with s/i.

42. BD Rx for Bipolar depression Rx for Bipolar depression

43. Acute Phase Rx for BD Depression Monotherapy Monotherapy Lithium Lithium Lamotrigine Lamotrigine Quetiapine Quetiapine Olanzapine +/- fluoxetine Olanzapine +/- fluoxetine Combination Strategies Combination Strategies Li+ Lamictal Li+ Lamictal Augmentation with ADs for short term Augmentation with ADs for short term

44. Effective meds in BD depression Likely BeneficialUnlikely to be beneficial Lithium Quetiapine Lithium with lamotrigine Abilify Neurontin AD Monotherapy

45. Goal of Maintenance Therapy reduce residual symptoms, reduce residual symptoms, delay and prevent recurrence of new mood episodes, delay and prevent recurrence of new mood episodes, reduce the risk of suicide, and reduce the risk of suicide, and enhance psychosocial functioning. enhance psychosocial functioning.

46. Indications of Maintenance BD I BD I BD II BD II BD NOS BD NOS

47. Medications for Maintenance Lithium Lithium Lamotrigine Lamotrigine Risperidal Consta Risperidal Consta 2 nd line 2 nd line Depakote Depakote Aripiprazole Aripiprazole Olanzapine Olanzapine