Pennsylvania Academy of Family Physicians Foundation & UPMC 43rd Refresher Course in Family Medicine CME Conference March 10-13, 2016 Disclosures: Bipolare Disorder Initial Evaliaton and Referral Criteria Roger Haskett, MD Speaker has no disclosures and there are no conflicts of interest. The speaker has attested that their presentation will be free of all commercial bias toward a specific company and its products. The speaker indicated that the content of the presentation will not include discussion of unapproved or investigational uses of products or devices.
Bipolar Disorder: Initial Evaluation and Treatment Guidelines Roger F Haskett MD University of Pittsburgh School of Medicine Western Psychiatric Institute and Clinic 1 Disclosure / Conflict of Interest Statement Neither I nor any of my immediate family have any relevant financial relationship with any organization associated with the manufacture, license, sale, distribution or promotion of a drug or medical device to disclose. 2 Learning Objectives 1. Recognize prevalence, course and clinical presentations (signs and symptoms) of bipolar disorder 2. Address issues in differential diagnosis including distinctions between unipolar and bipolar disorder 3. Recognize common disorders that co occur with bipolar disorder 4. Appraise evidence based treatment options for bipolar disorder 3 1
Manic Depressive Illness: Bipolar Disorders and Recurrent Depression Second Edition Frederick K Goodwin MD & K Redfield Jamison PhD Oxford University Press, 2007 4 Depression and Bipolar Support Alliance DBSA www.dbsalliance.org 5 Emil Kraepelin 1856-1926 1902 Manic Depressive Insanity Dementia Praecox 6 2
Bipolar Unipolar Distinction Leonhard 1957 Angst & Perris 1966 Validated by family history study 7 Bipolar Disorder: Natural History Onset late adolescence and early adult (peak 15 24) secondary mania more common > 60 yrs Course recurring lifelong disorder decreasing inter episode intervals 8 Longitudinal Course of Bipolar Disorder Elevated Mood Mania Threshold Severity Subsyndromal Period Major Depression Threshold Depressed Mood Acute Bipolar Mania 9 3
Subtypes of Bipolar Disorder Bipolar I Disorder Bipolar II Disorder Cyclothymia Substance/Medication Induced Bipolar Disorder Bipolar Disorder Due to Another Medical Condition Other Specified Bipolar Disorder 10 Epidemiology of Bipolar I Disorder ECA Study 1981 Lifetime prevalence = 1.2% 3.1 million in US National Comorbidity Study 1994 Lifetime prevalence = 1.6% 4.2 million in US Gender distribution M = F 11 Epidemiology of Bipolar Disorders Bipolar II Disorder Lifetime prevalence = 3% Females > Males Bipolar Spectrum Disorders Lifetime prevalence = 4 5% PC or MH clinics prevalence = 20 50% 12 4
Genetic Factors Lifetime risk of Bipolar Disorder in first degree relatives 40 70% in monozygotic twin 5 10 % in all other relatives 13 Those? Oh, just a few souvenirs from my bipolar-disorder days 14 Bipolar Disorder: Morbidity Illness recurrent in 90% patients Depressive phase is 3 4 times more frequent than the Manic phase Functional recovery often lags behind symptomatic and syndromal recovery Recurrent severe episodes may result in persistent deterioration in functioning Increased number of episodes may affect subsequent treatment response and outcome Rapid cycling and mixed states more common in Females 15 5
Bipolar Disorder: Comorbidity Medical burden influences the psychiatric outcomes in patients with BP Disorder Severity of medical comorbidities and depression are closely linked in BP I patients BP I patients with more severe medical comorbidities while depressed have worse prognoses Medical comorbibities may disrupt sleep and other circadian rhythms causing mood destabilization Childbirth may trigger a hypomanic episode in 10 20% females 1/3 individuals with Bipolar Disorder report lifetime history of suicide attempts 16 Diagnostic criteria for a Manic Episode A. Abnormally and persistently elevated, expansive, or irritable mood increased goal directed activity or energy lasting at least 1 week DSM-5 17 Diagnostic criteria for a Hypomanic Episode A. Abnormally and persistently elevated, expansive, or irritable mood increased goal directed activity or energy lasting at least 4 days DSM-5 18 6
Diagnostic criteria for a Manic Episode B. 3 of the following; present to a significant degree and represent a noticeable change from usual behavior: 1. inflated self esteem or grandiosity 2. decreased need for sleep 3. more talkative than usual or pressure to keep talking 4. flight of ideas or subjective experience of racing thoughts 5. Distractibility (unable to censor immaterial external stimuli) 6. increase in goal directed activity (socially, at work or school, or sexually) or psychomotor agitation 7. excessive involvement in activities with high potential for painful consequences (engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) DSM-5 19 Is this a real proposal, or are you off your medication? 20 Diagnostic criteria for a Hypomanic Episode B. 3 of the following; present to a significant degree and represent a noticeable change from usual behavior 1. inflated self esteem or grandiosity 2. decreased need for sleep 3. more talkative than usual or pressure to keep talking 4. flight of ideas or subjective experience of racing thoughts 5. Distractibility (unable to censor immaterial external stimuli) 6. increase in goal directed activity (socially, at work or school, or sexually) or psychomotor agitation 7. excessive involvement in activities with high potential for painful consequences (engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) DSM-5 21 7
Diagnostic criteria for a Manic Episode C. Marked impairment in social or occupational functioning or necessitate hospitalization to prevent harm to self or others, or there are psychotic features. DSM-5 22 Diagnostic criteria for a Manic Episode D. Episode is not attributable to the physiological effects of a substance or to another medical condition DSM-5 23 Diagnostic criteria for a Hypomanic Episode C. Episode is associated with an unequivocal change in functioning that is uncharacteristic when not symptomatic D. Disturbance in mood and change in functioning are observable by others DSM-5 24 8
Diagnostic criteria for a Hypomanic Episode E. Episode not severe enough to cause marked impairment in social or occupational functioning or to necessitate hospitalization (psychotic features = manic episode) DSM-5 25 Diagnostic criteria for a Hypomanic Episode F. Episode is not attributable to the physiological effects of a substance (e.g. drug of abuse, medication, other treatment) DSM-5 26 Secondary Mania Medications, drugs of abuse: corticosteroids phencyclidine levodopa Endocrine: thyrotoxocosis Cushing's disease Metabolic: postoperative delirium dialysis CNS pathology: infection, neoplasm, infarct, trauma AIDS multiple sclerosis 27 9
Stages of Mania Euphoria (lability, irritability) Increased psychomotor activity, tangential thinking Expansive, grandiose, overconfident Increased sexuality, spending money, telephone use, letter writing Not out of control Carlson & Goodwin 1973 28 Stages of Mania Increasing dysphoria (overt anger, explosive, assaultive) Psychomotor acceleration, pressured speech Flight of ideas, cognitive disorganization Paranoid / grandiose delusions Carlson & Goodwin 1973 29 Stages of Mania Marked dysphoria (desperate, hopeless) Frenzied psychomotor activity (bizarre) Incoherent, loose associations Bizarre, idiosynchratic delusions Hallucinations Disorientation Carlson & Goodwin 1973 30 10
Longitudinal Course of Bipolar Disorder Elevated Mood Mania Threshold Severity Subsyndromal Period Major Depression Threshold Depressed Mood Acute Bipolar Mania 31 Problems in Diagnosing Bipolar Disorder 7 of 10 patients are initially misdiagnosed 3.5 misdiagnoses and 4 consultations, on average, before receiving an accurate diagnosis 1/3 will seek help for ten years before being accurately diagnosed NDMDA Constituent Survey 2001 32 Differential Diagnosis of Bipolar Disorder Nonpsychotic: Major depression Generalized anxiety, panic, or PTSD Secondary mania Personality disorder ADHD Rating scales? 33 11
Differential Diagnosis of Psychotic Syndromes Schizophrenia Manic Episode Major Depressive Episode Substance Induced ( Drug of Abuse / Prescribed Medication ) Intoxication, withdrawal General Medical Condition delirium 34 Treatment of Bipolar Disorder Pharmacological Acute antimanic antidepressant Maintenance/Prophylactic Psychosocial Compliance 35 Ellen, I wish you d had the chance to know me before my medication was adjusted. 36 12
Pharmacological treatment of mania lithium anticonvulsants antipsychotics benzodiazepines ECT 37 You may believe you ve been overcharged, but, remember, you re overmedicated. 38 Lithium salts in the treatment of psychotic excitement by John F. J. Cade M.D. The Medical Journal Of Australia September 3, 1949 39 13
Lithium Antimanic Efficacy 1954 1971 lithium superior to placebo (4 controlled trials) 75 80% improved within 2 weeks 20% failed to improve on lithium 40 Lithium Prophylaxis against mania and depression Studies in 1960s & early '70s lithium significantly superior to placebo failure rate: lithium = 33% placebo > 80% % time in episode: lithium = 17% placebo = 57% Coppen et al, 1971 41 Lithium Effects on Risk of Suicidal Behaviors Advantage for Lithium vs. DVPX vs. CARB Suicide attempts: ER 1.8 (1.4 2.2) * 1.4 (1.0-2.0) Suicide attempts: Admission 1.7 (1.2-2.3) * 2.9 (1.9-4.4) * Suicide attempts: Death 2.7 (1.1-6.3) * 1.5 (0.3-7.0) Goodwin, et al. JAMA 2003;290:1467-1473 14
Endocrine Effects of Lithium Hypothyroidism, goiter (5 15%)? autoimmune thyroiditis (AB in > 50%, M:F = 1:4) Nephrogenic diabetes insipidus AVP effect on adenylate cyclase in distal renal tubules treatment : thiazide, amiloride Hypercalcemia ( P) PTH; hyperparathyroidism Insulin like effect: improved glucose tolerance 43 Lithium in Pregnancy relative risk for Ebstein s anomaly = 400 (1 / 20,000 general population) risk of major congenital abnormality 1 2 : 1000 in lithium treated women 1 : 20,000 in general population 20 40 times higher but small absolute risk neonatal toxicity 44 Resistance to Lithium as Treatment for Bipolar Disorder Fears of adverse effects/toxicity Inconvenience of blood level monitoring Lack of continuity in follow up Patient refusal Lithium should be considered if: Patient consents and can reliably comply Li is tolerated No medical contraindications Rasmussen 2014 45 15
Laboratory Monitoring of Lithium Treatment Standardized estimation: Blood sample drawn in am, 12 hrs after last dose of lithium Steady state levels: 5 days at constant dose Therapeutic range: 0.4 1.2 meq/l 46 Anticonvulsants divalproex Depakote carbamazepine Tegretol oxcarbazepine Trileptal gabapentin Neurontin lamotrigine Lamictal topiramate Topamax 47 Temporal Shifts in Prescription of Lithium and Divalproex 90 80 Market Share 70 60 50 40 30 Lithium Divalproex 20 10 Total N: 20,638 0 1994 1995 1996 1997 1998 1999 2000 2001 Goodwin, et al. JAMA 2003;290:1467-1473 16
divalproex Antidepressant: limited evidence of efficacy Meta analysis identified 4 RCTs* N=142, Bipolar I or II Reduction of depression valproate > placebo Small medium effect size; NNT = 5 Prophylaxis in bipolar illness: open trials show moderate efficacy alone or with lithium * Smith et al 2010 49 APA Practice Guidelines 2002: Acute Therapy Manic or mixed episodes 1st line severe: lithium + atypical antipsychotic or valproate + atypical antipsychotic 1st line less severe: lithium or valproate or atypical antipsychotic Breakthrough episodes 1st line: Optimize dose 2nd line: Add another 1 st line medication 50 Issues in Anticonvulsant Use valproate elevated liver enzymes thrombocytopenia menstrual disorders, polycystic ovaries, hyperandrogenism teratogen carbamazepine elevated liver enzymes leukopenia teratogen plasma levels unhelpful oxycarbazepine 51 17
Issues in Anticonvulsant Use Gabapentin no evidence of efficacy lamotrigine rash Stevens Johnson syndrome topiramate cognitive impairment 52 Anticonvulsants and Pregnancy valproate 5 9% neural tube malformations? Folic acid protective Neonatal hypoglycemia, liver toxicity and withdrawal symptoms Additional educational needs of children carbamazepine 11% craniofacial defects 0.5 1% neural tube defects 53 Second Generation antipsychotics clozapine Clozaril* 25 300mg bid risperidone Risperdal 2 6 mg/day olanzapine Zyprexa 5 20 mg/day quetiapine Seroquel 400 800 mg/day ziprasidone Geodon 40 80 mg bid aripiprazole Abilify 10 30 mg/day lurasidone Latuda 20 120 mg/day 54 18
Treatment of Mania: Summary Although divalproex has replaced lithium as the first line standard, lithium s utility should not be underestimated Inconsistent evidence for novel anticonvulsants Strong evidence for all second generation antipsychotics Attention to adherence, lifestyle, self monitoring, and psychotherapeutic needs is essential 55 Tiered Treatment of Bipolar Depression Tier 1: SGA olanzapine +fluoxetine quetiapine monotherapy lurazidone monotherapy and adjunctive Tier 2: Mood Stabilizers lithium lamotrigine 56 Tiered Treatment of Bipolar Depression Tier 3: other clinical options adjunctive antidepressants adjunctive modafinil other mood stabilizers: divalproex, carbamazepine other SGAs electroconvulsive Therapy adjunctive psychotherapy From Ketter TA, 2015 57 19
Advances in the Treatment of Bipolar Disorder Pharmacological innovations anticonvulsants second generation antipsychotics Attention to comorbidity substance abuse general medical disorders Psychosocial interventions individual psychotherapy family education 58 Summary Depression and Bipolar Disorder have major public health concerns Effective treatments are available Treatment adherence: a major problem Coordination of care: important for optimal outcome as general medical comorbidity is common 59 20