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BIPOLAR DISORDERS IN PRIMARY CARE Kimothi Cain, MD, MPH UNM Department of Psychiatry as presented by Emiliano Valles, MD Objectives 1. Discuss and promote the role of the primary care physician in bipolar disorders 2. Criteria for bipolar illnesses 3. Review treatment strategies for bipolar disorders with a focus on the primary care setting BIPOLAR DISORDERS IN PRIMARY CARE • Need for treatment at the primary care level • Common disorder with prevalence of 3.4 – 9% 1 • Half of all mentally ill patients are treated at the primary care level 2 • Shortage of psychiatrists: • Long waiting periods for an initial consultation • Community mental health centers are disappearing NICE Clinical practice recommendations* Assessment in primary care 2 4.4.2.1. Primary care clinicians should ask about hypomanic symptoms when assessing a patient with depression and overactive, disinhibited behavior. 4.4.2.3. PCPs should urgently refer patients with mania or severe depression who are a danger to themselves or other people, to [emergency services]. 4.4.2.4. When a patient with existing bipolar disorder registers with a practice, the [PCP] should consider referring them for assessment by specialist mental health services and, if appropriate, development of a care plan. 4.4.2.5. When a patient with bipolar disorder is managed solely in primary care, an urgent referral to/or consultation with psychiatry or emergency services should be made: •if there is an acute exacerbation, in particular the development of mania or severe depression •if there is an increase in the degree of risk, or change in the nature of risk, to self or others. 4.4.2.6. When a patient with bipolar disorder is managed solely in primary care, a review by psychiatry or increased contact with primary care should be considered if: •Significant decline in the patient’s or their condition responds poorly to treatment •treatment adherence is a problem *NICE: National Institute for Health and Care Excellence ADVANTAGES OF PRIMARY CARE MGMT • Earlier initiation of treatment • Continuity of care • Established therapeutic alliance • Management of co-occurring medical diseases BIPOLAR DISORDERS Spectrum of disorders: • 1. bipolar I-- requires a manic episode • 2. bipolar II-- requires a hypomanic episode + major depressive episode • 3. cyclothymic disorder-- 2 years of subsyndromal mood cycling (i.e., dysthymia and hypomania, instead). • 4. bipolar not otherwise specified (NOS) Making the Diagnosis 1. DSM categorical diagnosis (with screening instruments) 2. Additional (non-DSM) features of the disorder • Exam findings, course of illness • Probabilistic approach (BP vs. MDD) 3. Collateral information Screening Mood Disorder Questionnaire (MDQ) • 13 questions based off of DSM criteria • Fairly sensitive • Takes about 5 minutes • Screen every patient with depression • Self report version: http://www.dbsalliance.org/pdfs/MDQ.pdf Diagnosing Mania Mania: 3 • Criteria A: One week of elevated, expansive, irritable mood AND increased energy ... • Plus 3 of the following from B Criteria: • Distractibility • Indiscretion or Irresponsibility • Grandiosity • Flight of ideas • Activity (increased goal-directed activity) • Sleep (decreased need for sleep) • Talkativeness pressured speech) 4 Diagnosing Hypomania Hypomania: 3 • Same criteria as mania ...but does NOT cause significant functional impairment • Shorter time requirement (4 days) • Absence of psychosis Frequency of Symptoms in BPAD I 4 0 Mixed 12% (Hypo)mania 20% Depression 68% Depression (Hypo)mania) Mixed The Complex Bipolar Patient • Mixed episodes 3 • Both manic and depressive symptoms • comorbid substance use disorders • risk of suicide and psychosis • Rapid cycling 3 • 4 or more cycles/year with > 8 weeks of well periods • Occurs in Bipolar I and II Challenges in Diagnosis • Diagnosis is challenging with high rates of misdiagnosis 7 of 10 pts initially misdiagnosed 5 1 in 3 wait ten years before correct diagnosis 5,6 • (Dx is longitudinal, however, majority of the misdiagnosis attributable to lack of understanding about the disorder.) 7 Misdiagnosis Rates • MDD (60% ) • Anxiety Disorders (26%) • Schizophrenia (18%) • Personality disorder (BPD, ASP) (17%) • Substance use disorders (14%) 6,7 Also: Anxiety disorders, PDs, and SUDs frequently cooccurring with BPAD Diagnosis: MDD VS. BPAD BPAD MDD • Early onset depression < 25 years • Later onset depression > 25 years • Multiple depressive episodes (> 5) • Fewer episodes • 90% have recurrent MDEs • 50% have recurrent MDEs • MDEs vary in character (e.g. some episodes melancholic, some atypical) • Seasonality (depressed late fall/ winter; manic spring) • Index mood episode can be postpartum • Family history of bipolar disorder • MDEs similar in character • Seasonal pattern less likely • No bipolar history DDx Secondary mania 8 Secondary depression 8 Substance induced Intoxication or use: alcohol, LSD, amphetamines/sympathomimetics, benzodiazepines, corticosteroids, isoniazid, levodopa, thyroxine, zidovudine Withdrawal: alcohol, benzodiazepines, β-blockers Metabolic Hemodialysis, postoperative state, thyrotoxicosis, B12 deficiency, Cushing's syndrome Infectious Influenza, encephalitis, HIV, neurosyphilis Neurologic Neoplasm, complex partial seizure, Wilson's disease, Huntington's disease, multiple sclerosis, stroke Substance induced Intoxication or use: opiates, benzodiazepines, anticonvulsants, alcohol, reserpine Withdrawal: cocaine, amphetamines/sympathomimetics Metabolic Uremia, niacin deficiency (pellagra), B12 deficiency, anemia, hypothyroidism, Cushing's syndrome, Addison's disease, sleep apnea, heavy metal toxicity, paraneoplastic syndromes Infectious Lyme disease, neurosyphilis, HIV, Behçet's syndrome, meningitis Neurologic/ cerebrovascular Ischemia, stroke (especially left-sided), neoplasm, complex partial seizures, postictal state, normal pressure hydrocephalus, Parkinson's disease Medical Comorbidities • Pts with BPAD -- significantly higher rates of metabolic syndrome than the general population…37% according to a meta-analysis of 7000 pts. 9 • Multifactorial cause: • Some attributable to certain SGAs, but CV risk factors present before the widespread use of SGAs and in treatment naïve pts.10, 11 • Lifestyle: overeating, smoking, ETOH, inactivity • Possible genetic vulnerability independent of environmental/behavioral factors. 10 • BP -- patients have 1.5 - 2.5x higher CVD mortality risk. • All cause mortality, die 8-9 years earlier. 13 12 Medical burden BPAD patients with high medical burden have: Greater number of lifetime mood episodes 12 A higher number of prescribed psychotropics Longer duration of untreated illness Longer psychiatric IP stays 15 14 13 First-Line Agents for Acute Manic or Mixed Episodes a Class Agent Target Dose Notable Adverse Effects Notes Mood stabilizers Lithium b Sufficient for blood level of 0.6–1.2 mEq/L, usual dose 900–1,800 mg Sedation, dry mouth, polyuria; more rarely kidney or thyroid failure May be slower to control mania than other options Divalproex Titrate rapidly to a blood level of 85–125 μg/mL; up to 60 mg/kg Sedation, nausea, weight gain; may cause menstrual irregularities; rare pancreatitis or liver failure Very high risk of neural tube defects with fetal exposure; caution in women of childbearing age Aripiprazole 15–30 mg/d Akathisia and other EPS, sedation Among the least likely second-generation antipsychotics to cause weight gain Olanzapine c 15–20 mg/d Sedation, weight gain, less commonly EPS Weight gain; lipid and glucose derangements may be particularly severe Quetiapine b 400–800 mg/d Sedation, weight gain, less commonly EPS Titrate immediate-release form over 6 days. Weight gain; lipid and glucose derangements Risperidone 3–6 mg/d EPS, sedation, hyperprolactinemia Weight gain; lipid and glucose derangements Ziprasidone 40–80 bid EPS, sedation or agitation Taken with meals to improve absorption; contraindicated if history of prolonged QTc interval or in combination with QTc-prolonging medications Second-generation antipsychotics a Based b Not on Suppes, et al. 16 recommended as first-line for mixed episodes. C Olanzapine is not generally recommended as first-line due to metabolic adverse effects. Abbreviation: EPS = extrapyramidal symptoms. Medications for acute bipolar depression a First-line treatments Agent Target Dose Notable Adverse Effects Notes Quetiapine 300–600 mg/d Sedation, weight gain, less commonly EPS Titrate immediaterelease form over 6 days Olanzapine/fluoxetine combination Olanzapine 6–12 mg/fluoxetine 25–50 mg Sedation, weight gain, less commonly EPS Lamotrigine 200 mg/d Stevens-Johnson syndrome, especially with enzyme-inhibiting medications (eg, divalproex) Second-line treatments Lithium a Based on Suppes, et al. 16 Sufficient for blood level of 0.6–1.2 mEq/L; usual dose 900–1,800 mg Sedation, dry mouth, polyuria; more rarely kidney or thyroid failure Divalproex Titrate rapidly to a blood level of 85–125 μg /mL; up to 60 mg/kg Sedation, nausea, weight gain; may cause menstrual irregularities; rare pancreatitis or liver failure Combinations: SSRI or bupropion with SGA, lithium, or divalproex Antidepressants should Those of constituent be used only with an agents effective antimanic agent when treating bipolar depression Titrate to target dosage based on schedule May be used as monotherapy for BPAD II Very high risk of neural tube defects with fetal exposure; caution in women of childbearing age While these combinations are a common practice, evidence of their efficacy is controversial G.H. Vázquez et al. / Journal of Affective Disorders 183 (2015) 258–262 Long-term monitoring parameters for BPAD a Patient Is Maintained On: Check Monitor For: Lithium Serum level: once therapeutic level is achieved, every 3–6 mo Subtherapeutic or toxic level EUC: every 3–6 mo Renal insufficiency, nephrogenic diabetes insipidus Calcium, TSH, weight: after 6 mo and then annually Thyroid/parathyroid dysfunction Serum level: during initial therapy and then as clinically indicated Subtherapeutic or toxic level Weight, complete blood count, menstrual history, liver function tests every 3 mo for the first year and then annually Weight gain, thrombocytopenia, dysmenorrhea, liver failure Blood pressure, fasting blood glucose, lipid profile, bone densitometry (if risk factors) Metabolic syndrome, anticonvulsant-related osteopenia Serum level: during initial therapy and then as clinically indicated Subtherapeutic or toxic level Complete blood count, liver function tests, EUC monthly for 3 mo then annually Blood dyscrasias, liver failure, hyponatremia Bone densitometry and evaluation of oral contraceptive efficacy when applicable Anticonvulsant-related osteopenia, increased metabolism of oral contraceptives Divalproex Carbamazepine Monitor for rash Stevens-Johnson Syndrome Lamotrigine Monitor for rash Stevens-Johnson Syndrome Second-generation antipsychotics Weight monthly for 3 mo and then every 3 mo Weight gain Blood pressure, fasting blood glucose, lipid profile every 3 mo and then annually Metabolic syndrome Monitor for abnormal movements Acute dystonias, drug-induced parkinsonism, tardive dyskinesia Electrocardiogram, prolactin as clinically indicated QTc prolongation/dysrhythmias, hyperprolactinemia aBased on Ng et al.17 Abbreviations: EUC = electrolytes, urea, creatinine; TSH = thyroid-stimulating hormone. Maintenance • Primary goal: Maintenance of euthymia and is best achieved through the use of long-term medication. • Lithium as first-line treatment: Prevents both manic and depressive relapse, as well as suicide in meta-analytic reviews of randomized controlled trials.18,19 • Divalproex has somewhat less evidence than lithium, but may also be considered a first-line treatment. Caution with women of childbearing years: Ebstein anomaly and PCOS. 20 • Lamotrigine: efficacy in preventing depressive relapse and may be a good option for more depression-prone patients. 21 • SGAs: have demonstrated efficacy in preventing relapse among acute responders. 21 • Long acting injectables: prevent relapse based on randomized trials. For many patients, maintenance therapy will be the medication to which they responded acutely. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. Cerimele JM, Chwastiak LA, Dodson S, Katon WJ. The prevalence of bipolar disorder in primary care patients with depression or other psychiatric complaints: a systematic review. Psychosomatics. 2013;54(6):10.1016/j.psym.2013.05.009. doi:10.1016/j.psym.2013.05.009. Bipolar Disorder: The Management of Bipolar Disorder in Adults, Children and Adolescents, in Primary and Secondary Care. NICE Clinical Guidelines, No. 38. National Collaborating Centre for Mental Health (UK). Leicester (UK): British Psychological Society; 2006. DSM 5. 2013 American Psychiatric Association Hirschfeld RMA et al. Guideline Watch November 2005: Practice guideline for the treatment of patients with bipolar disorder. APA Practice Guidelines. American Psychiatric Association. Hirschfeld RM, et al. Perceptions and impact of bipolar disorder. J Clin Psychiatry. 2003 Muzina DJ, et al. Differentiating bipolar disorder from depression in primary care. Cleve Clin J Med. 2007 Lewis FT. An overview of primary care assessment and management of bipolar disorder. JAOA. 2004 Stern TA, Fricchione GL, Cassem NH, et al., editors. 5th edition. 69–82. Philadelphia, PA: Mosby; 2004. Massachusetts General Hospital Handbook of General Hospital Psychiatry; pp. 119–134. Vancampfort D, et al. Metabolic syndrome and metabolic abnormalities in bipolar disorder. Am J Psychiatry. 2013 Leboyer M, et al. Can bipolar disorder be viewed as a multi-system inflammatory disease? J Affect Disord. 2012 Weiner M, et al. Cardiovascular morbidity and mortality in bipolar disorder. Ann Clin Psychiatry. 2011 Crump C, etal. Comorbidities and mortality in bipolar disorder. JAMA Psychiatry. 2013. Kemp DE, et al. General medical burden in bipolar disorder. Acta Psychiatry Scand. 2013 Maina G, et al. General medical conditions are associated with delay to treatment in patients with bipolar disorder. Psychosomatics. 2013. Douzenis A, et al. Factors affecting hospital stay in psychiatric patients. BMC Health Serv Res. 2012 Suppes, T; Dennehy, E; Hirschfeld, R; Altshuler, L; Bowden, C; Calabrese, J; Ketter, T;. Sachs, G; Swann, A; The Texas Implementation of Medication Algorithms: Update to the Algorithms for Treatment of Bipolar I Disorder for the Texas Consensus Conference Panel on Medication Treatment of Bipolar Disorder. J Clin Psychiatry 2005;66(7):870-88.6 Ng F, Mammen OK, Wilting I, et al. International Society for Bipolar Disorders. The International Society for Bipolar Disorders (ISBD) consensus guidelines for the safety monitoring of bipolar disorder treatments. Bipolar Disord. 2009;11(6):559–595. Burgess S, Geddes J, Hawton K, et al. Lithium for maintenance treatment of mood disorders. Cochrane Database Syst Rev. 2001;3. Cipriani A, Pretty H, Hawton K, et al. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J Psychiatry. 2005;162(10):1805–1819. Macritchie KA, Geddes JR, Scott J, et al. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev. 2001;(3). Suppes T, Vieta E, Liu S, et al. Trial 127 Investigators. Maintenance treatment for patients with bipolar I disorder: results from a North American study of quetiapine in combination with lithium or divalproex (trial 127) Am J Psychiatry. 2009;166(4):476–488.