Bipolar Diagnosis and Treatment

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Slide 1:

Section 1: Recognition and Diagnosis of Bipolar Disorder and Its Spectrum

Spectrum of Bipolar Disorders:

Spectrum of Bipolar Disorders Bipolar I and II Hypomania Bipolar NOS Cyclothymia Rapidly changing mood swings Major depression with a strong family history of bipolar disorder Antidepressant-induced mania and hypomania Secondary mania, due to other illness or drugs Adapted from American Psychiatric Association. Practice Guideline for the Treatment of Patients with Bipolar Disorder. 2nd ed. Washington, DC; 2002.

Bipolar Terminology:

Bipolar Terminology A distinct period of abnormally and persistently elevated, expansive, or irritable mood Mania Lasting at least 1 week with a significant decline in function Hypomania Lasting at least 4 days, (clearly different from the usual non-depressed mood), but without a significant decline in function and no psychosis American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000.

Bipolar Terminology (cont):

Bipolar Terminology (cont) Mixed Episode The criteria are met both for a manic episode and for a major depressive episode (bipolar I disorder) Cyclothymia Alternating mood states that do not meet full criteria for depressive, manic, or mixed episode for at least 2 years Bipolar NOS A mood episode that does not meet specific criteria for any specific bipolar disorder American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000.

296.80 Bipolar Disorder NOS:

296.80 Bipolar Disorder NOS Very rapid alternation (over days) between manic symptoms and depressive symptoms that meet symptom threshold criteria but not minimal duration criteria for manic, hypomania, or major depressive episodes Recurrent hypomanic episodes without intercurrent depressive symptoms A manic or mixed episode superimposed on delusional disorder, residual schizophrenia, or psychotic disorder not otherwise specified Hypomanic episodes, along with chronic depressive symptoms that are too infrequent to qualify for a diagnosis of cyclothymic disorder Situations in which the clinician has concluded that bipolar disorder is present but is unable to determine whether it is primary, due to a general medical condition, or substance induced The Bipolar Disorder Not Otherwise Specified category includes disorders with bipolar features that do not meet criteria for any specific bipolar disorder. Examples include: American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000.

Diagnostic Criteria for Major Affective Disorders (DSM-IV):

Diagnostic Criteria for Major Affective Disorders (DSM-IV) Disorder Depressive Episode Manic or Mixed Episode Hypomanic Episodes Bipolar I Disorder Common but not required ≥ 1 required Common but not required Bipolar II Disorder ≥ 1 required None allowed ≥ 1 required Bipolar Disorder NOS* Common but not required None allowed Required, but do not meet criteria for a specific bipolar disorder Cyclothymic Disorder Dysthymia, but not major depression None allowed Numerous periods over 2 years required Major Depressive Disorder ≥ 1 required None allowed None allowed Dysthymic Disorder ≥ 2 years required but not major depression None allowed None allowed *NOS = Not otherwise specified Adapted from the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000:345-428.

Diagnosing Bipolar Disorder: Challenges:

Diagnosing Bipolar Disorder: Challenges Variability of age of onset and presentation Commonly presenting in the depressed phase and being misdiagnosed as unipolar depression Prepubertal onset depression or dysthymia carries a 20 – 40% risk of bipolar illness Symptom overlap with other psychiatric conditions Previous misdiagnosis common Many clinically prominent psychiatric and medical comorbidities Thomas P. J Affect Disord. 2004;79(suppl 1):S3-S8. Berk M, et al. Med J Aust. 2006;184:459-462.

The Bipolar Spectrum: Stronger:

The Bipolar Spectrum: Stronger Bipolar I  4 Days Bipolar II Bipolar NOS “Bipolar III” Antidepressant-related hypomania Adapted from Akiskal HS, Pinto O. Psychiatr Clin North Am. 1999;22:517-534. < 4 Days  1 week

The Bipolar Spectrum: Weaker:

The Bipolar Spectrum: Weaker Hyperthymic “Bipolar IV” Depressive Mixed State “IV ½” Recurrent “Unipolar” Depression “Bipolar V” Adapted from Akiskal HS, Pinto O. Psychiatr Clin North Am. 1999;22:517-534. Akiskal HS, et al. J Affective Disorders . 2006;96:197-205.

Bipolar “Missed States!” (Mixed States):

Bipolar “Missed States!” (Mixed States) Bipolar mixed states: depression and mania co-occurring Dysphoric mania common especially in women Depressive mixed states Core of depression, but with racing thoughts More likely to switch into mania with monotherapy antidepressant treatment (Frye et al, 2007) Berk M, et al. Aust N Z Psych. 2005;39:215-221. Suppes T, et al. Arch of Psych. 2005;62:1089-1096.

Screening Tools: Self Rated The Mood Disorder Questionnaire (MDQ):

Screening Tools: Self Rated The Mood Disorder Questionnaire (MDQ) Hyper or more energetic than usual Predominately or thematically irritable Distinctly self-confident, positive or self-assured Less sleep than usual More talkative or speaking faster than usual Racing thoughts Easily distracted Problems at work and socially More interest in sex Taking unusual risks Excessive spending Hirschfeld RM, et al. J Clin Psychiatry. 2003;64:53-59.

Bipolar Disorder Diagnosis Is Often Missed:

Neither bipolar disorder nor depression diagnosis Bipolar Disorder Diagnosis Is Often Missed > 85,000 US adults surveyed Positive screen rate for bipolar illness: 3.7% ( > 6 million people in US) For those with positive screen Only 20% of those with a positive screen had been told by their doctors that they had bipolar disorder Hirschfeld RM, et al. J Clin Psychiatry. 2003;64:53-59. Diagnosed with bipolar disorder Diagnosed with depression but not bipolar disorder 20% 31% 49%

High Rate of Misdiagnosis as Unipolar Depression:

High Rate of Misdiagnosis as Unipolar Depression Retrospective, single site study, N = 85 37% of patients misdiagnosed as unipolar depression (even though they had seen a mental health professional after their first manic/hypomanic episode) Delay of 8 – 10 years from illness onset to treatment for bipolar disorder Antidepressants were used earlier with 23% experiencing new or worsening rapid-cycling Ghaemi SN, et al. J Clin Psychiatry. 2000;61:804-808.

Unipolar Misdiagnosis May Lead to Inappropriate Treatment:

Bipolar disorder misdiagnosed as unipolar depression in 37% of patients (N = 85) Ghaemi SN, et al. J Clin Psychiatry . 2000;61:804-808. Unipolar Misdiagnosis May Lead to Inappropriate Treatment Patients (%) 0 20 40 60 80 100 Mania/ Hypomania Rapid Cycling n = 38 55% 23% n = 35 Development of mania/hypomania or rapid cycling while taking antidepressants.

The Hazards of Misdiagnosis and Delayed Diagnosis in Bipolar Disorder:

The Hazards of Misdiagnosis and Delayed Diagnosis in Bipolar Disorder Increased risk of: Rapid cycling or mixed features Suicide attempts or completion Violent behavior; impulsive behavior Sexual and other indiscretions Worsening substance abuse Loss of job or significant other Treatment resistant

Self-Report Diagnostic Tools For Screening Bipolar Disorder:

Self-Report Diagnostic Tools For Screening Bipolar Disorder Scale Description Limitations Mood Disorder Questionnaire (MDQ) 13 item questionnaire (  7 is a positive screen) More sensitive for bipolar I than II, should not replace a full diagnostic interview Bipolar Spectrum Diagnostic Scale (BSDS) Screens for subtle versions of bipolar and can rate the probability of bipolar as high, moderate, low, or unlikely Should not replace a full diagnostic interview Quick Inventory for Depression Symptomatology (QIDS) 16 item inventory, each item rated 0-3 Takes an average of 15 minutes to implement ?

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Scale Description Limitations Young Mania Rating Scale (YMRS) 11 item scale, each with a varied rating scale based on severity (mania = 12, depression = 3, euthymia = 2) Usefulness of scale is limited in populations with diagnoses other than mania Bipolarity Index Evaluation of bipolar presentation based on 5 “dimensions”—each worth up to 20 points for a total of 100 Time consuming, not peer reviewed Hamilton Rating Scale for Depression (HAM-D) 17-21 item scale initially intended for identifying depressed patients Relies heavily on clinical interviewing skills and experience of the rater Montgomery-Asberg Depression Rating Scale (MADRS) 10 selected items are rated on a scale of 0-6 with anchors at 2-point intervals Cost prohibitive and time consuming Clinician Administered Diagnostic Tools For Screening Bipolar Disorder ?

Subthreshold Bipolar Disorder (The “Soft” Bipolar Spectrum):

Subthreshold Bipolar Disorder (The “Soft” Bipolar Spectrum) Boundaries of bipolarity have expanded over the past decade Suggest that the diagnostic criteria for hypomania need revision Further study is needed to evaluate the ‘hard’ and ‘soft’ definitions of bipolar II, minor bipolar disorder, and hypomania A more expansive definition of bipolar II yields a cumulative prevalence rate of 10.9%, compared to 11.4% for broadly defined major depression Akiskal HS. Curr Psychiatry Rep . 2002;4:1-3. Angst J, et al. J Affect Disord. 2003;73:133-146.

The Rule of 3 Hinting at Soft Bipolarity (NOS) in a Clinically Depressed Person:

The Rule of 3 Hinting at Soft Bipolarity (NOS) in a Clinically Depressed Person Three or more: Major depressive episodes Failed marriages Failed antidepressants trials Distinct professions First degree relatives (or generations) with affective illness Fields of eminence in the family Substances of abuse Impulsive behaviors (gambling, car racing, sexual, etc.) Individuals dated simultaneously Simultaneous jobs Languages (for US-born citizens) Triad of past histrionic, psychopathic, or borderline diagnoses Triad of red car, necktie, or belt Akiskal HS. J Affect Disord. 2005;84:279-290.

Importance of Interviewing the Patient and Their Family:

Importance of Interviewing the Patient and Their Family Patients admitted with major depression NIMH study Step 1: Patient screened for bipolar disorder Step 2: Family member interviewed (by another investigator interested in genetics) Result: Twice as many bipolar I diagnoses from interviewing both the patient and a family member Blehar MC, et al. Psychopharmacol Bull . 1998;34:239-243.

Physicians Must Use Patient Perspectives to Improve Diagnosis and Care:

Physicians Must Use Patient Perspectives to Improve Diagnosis and Care Factors Necessary for Recovery: Communication between patient and physician: best chance for recovery when patient feels he’s being heard; physician must try to understand how the world looks through patient’s eyes Treatment plans that include patient input and preferences; physician must discuss all options so patient has complete understanding of illness Recovery-oriented treatment based on mutually agreed goals so patient feels like a partner in care Lewis L, et al. Adm Policy Ment Health . 2005;32:497-503.

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Bipolar disorder can masquerade in different or mixed mood states Bipolar disorder is often misdiagnosed as depression due to the prevalence of depressive episodes often as the presenting phase Misdiagnosis can have serious detrimental effects on treatment effectiveness and outcomes Summary

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Section 2: Comorbidities

Comorbidities…The Rule Not the Exception The Multidimensionality of Bipolar Disorder:

Comorbidities…The Rule Not the Exception The Multidimensionality of Bipolar Disorder McIntyre RS, et al. Human Psychopharmacol. 2004;19:369-386. Anxiety Disorders Diabetes Mellitus Impulse Control ADHD Personality Disorders Migraine Bipolar Disorder Eating Disorders Substance Abuse Obesity Cardio- vascular Pain Disorders Comorbidities: Medical Psychiatric

Psychiatric Comorbid Conditions in Bipolar Disorder Patients :

Psychiatric Comorbid Conditions in Bipolar Disorder Patients Condition Percentage Comorbidity Substance abuse 33%–70% 1,2 Anxiety disorders 12%–37% 1 Obsessive compulsive disorder 13%–25% 1 Attention deficit hyperactivity disorder 24% 3 Non-psychiatric disorders* 3% –1 3% 4 1. Hilty DM, et al. Psychiatr Serv. 1999;50:201-213. 2. Regier DA, et al. JAMA . 1990;264:2511-2518. 3. Strober M, et al. J Affect Disord. 1988;15:255-268. 4. Cal a brese JR, et al. J Clin Psychiatry . 2003;64:425-432. * Allergies, asthma, migraine, and chronic fatigue

Psychiatric Comorbidities Occur Frequently and Can Complicate Diagnosis of Bipolar Disorder:

Psychiatric Comorbidities Occur Frequently and Can Complicate Diagnosis of Bipolar Disorder Additional axis I disorder 65% of bipolar patients have 1 or more Nearly 25% have 3 or more Lifetime prevalence 61% substance abuse 42% anxiety disorders Comorbid conditions can mimic mood symptoms, mask them, or exacerbate them McElroy SL, et al. Am J Psychiatry. 2001;158:420-426. ?

High Number of Lifetime Comorbid Axis I Disorders in Both Bipolar I and II Patients:

High Number of Lifetime Comorbid Axis I Disorders in Both Bipolar I and II Patients Percent McElroy SL, et al. Am J Psychiatry. 2001;158:420-426.

Bipolar Disorder and Anxiety Disorder:

Bipolar Disorder and Anxiety Disorder An anxiety disorder is the most prevalent Social phobia; generalized anxiety disorder; panic disorder; obsessive-compulsive disorder; posttraumatic stress disorder Co-occurrence of anxiety disorder associated with: Earlier age of onset of mood symptoms Greater number of depressive symptoms Suicidality Greater comorbidity of substance abuse and eating disorders Keck PE, et al. J Clin Psychiatry . 2006;67(suppl 1):8-15.

Bipolar Disorder and Anxiety Disorder:

Bipolar Diso rd er and Anxiety Disorder Range Obsessive Compulsive Disorder (OCD) 2 – 39% Generalized Anxiety Disorder (GAD) 2 – 43% Simple Phobia 2 – 67% Panic Disorder 4 – 38% Social Phobia 4 – 47% Posttraumatic Stress Disorder (PTSD) 5 – 40% Agoraphobia 6 – 62% McIntyre RS, et al . Bipolar Disord . 2006;8:665-676.

Bipolar Disorder and Posttraumatic Stress Disorder :

Bipolar Disorder and Posttraumatic Stress Disorder Prevalence rates vary from 5 – 40% 1,2,3,4,5 More likely in women, separate course from bipolar disorder 4 Arises in about 1/3 of adults with bipolar disorder who survived severe childhood abuse 3 In 137 patients with bipolar disorder following September 11 terrorist attacks, PTSD was associated with hypomanic, manic, or mixed mood state at the time of trauma 6 Manic symptoms may predispose to adverse sequelae following traumatic event 1. Kessler R, et al. Arch Gen Psychiatry . 1995;52:1048-1060. 2. McElroy SL, et al. Am J Psychiatry . 2001;158:420-426. 3. Goldberg JF, et al. J Psychiatr Res . 2005;39:595-601. 4. Strakowski SL, et al. J Clin Psychiatry. 1998;59:465-471. 5. McIntyre RS, et al . Bipolar Disord . 2006;8:665-676. 6. Pollack MH, et al. J Clin Psychiatry . 2006;67:394-399.

Treatment of Bipolar Disorders and Psychiatric Comorbidities:

Treatment of Bipolar Disorders and Psychiatric Comorbidities Keck PE, et al. J Clin Psychiatry . 2006;67(Suppl 1):8-15. Class Agent Use Anticonvulsants Valproate May have efficacy as adjunct to serotonergic drugs in OCD; some efficacy in PTSD Carbamazepine Open trials suggest some efficacy in PTSD Lamotrigine Open trials suggest some efficacy in PTSD Antipsychotics Risperidone Open trials suggest efficacy as adjunct to SSRIs for OCD in patients without bipolar disorder Olanzapine Reduces panic attacks; some efficacy in OCD in combination with SSRIs; open trials suggest some efficacy in PTSD Quetiapine Reduces OCD symptoms, improves PTSD symptoms Novel Antiepileptics Gabapentin Randomized trials show efficacy in social anxiety disorder; panic disorder Pregabalin Randomized trials show efficacy in social anxiety disorder, generalized anxiety disorder; may induce mania Antidepressants may trigger mania or destabilize bipolar disorder

Bipolar Disorder and ADHD:

Bipolar Disorder and ADHD Common features Impulsivity Attention problems Conduct problems Distinguishing features Bipolar Disorder ADHD Onset of clear cut symptoms after age 8 Onset with dysthymia or depression Episodic Family history of mood disorders Variable or negative response to stimulants Response to mood stabilizers Onset of clear cut symptoms age 3-4 Onset with hyper or disruptive behaviors Continuous Family history of disruptive disorders Response to stimulants Variable or no response to mood stabilizers Slide courtesy of Roger McIntyre, MD and Robert M. Post, MD. Substance use Poor school or work performance Relationship problems Comorbidity more common in childhood than adult onset bipolar disorder.

Lifetime Prevalence of Substance Use Highest in Bipolar Disorder:

Lifetime Prevalence of Substance Use Highest in Bipolar Disorder 61% 48% 47% 36% 33% 31% 27% 0 1 2 3 4 5 6 7 8 9 Bipolar I Bipolar II Schizophrenia Panic OCD Dysthymia Major Depression Odds Ratio – 0 – 10 – 20 – 30 – 40 – 50 – 60 – 70 Percent Regier DA, et al. JAMA . 1990;264:2511-2518.

Bipolar Disorder and Substance Abuse:

Bipolar Disorder and Substance Abuse Common features Mood symptoms Anxiety symptoms Family history of mood/anxiety problems Distinguishing features Bipolar Disorder Substance Abuse Problem substance abuse before age 13 Cocaine and amphetamine use Episodic Mood problems in the absence of substance use Hypomania/mania present Family history bipolar or other mood disorders Problem substance abuse after age 13 Polysubstance abuse Continuous Substance use without any mood problems Hypomania/mania usually absent Family history externalizing and anxiety disorders Slide courtesy of Roger McIntyre, MD. Disruptive behaviors Relationship problems

Primary or Secondary Substance Use:

Primary or Secondary Substance Use STEP-BD, N = 917 47.7% lifetime SUD 33.5% dependence, 14.2% abuse 42.8% alcohol, 12.8% other, 44.4% both 62.4% Bipolar 1 ° , 26.4% SUD 1 ° SUD both SUD, bipolar later Early onset of bipolar more deleterious Fossey MD, et al. Am J Addict. 2006;15:138-143.

Impact of Substance Abuse on Bipolar Course of Illness:

Impact of Substance Abuse on Bipolar Course of Illness More Early onset - unmasking Suicidality Mixed or dysphoric mania Rapid cycling ER visits and hospitalizations Neuronal loss? Goodwin & Jamison. Manic Depressive Illness. 1990. Goldberg JF, et al. J Clin Psychiatry . 1999;60:733-740. Frye MA, et al. Mod Probl Pharm. 1997;25:88-113. Strakowski SM, et al. Int J Psychiatry Med . 1994;24:305-328. Less Compliance Symptom remission Treatment (lithium) response

Treatment of Co-occurring Bipolar Disorder and Substance Use Disorders:

Treatment of Co-occurring Bipolar Disorder and Substance Use Disorders Few controlled treatment studies in bipolar disorder Must make inferences from data in primary substance disorders Combination of psychotherapeutic interventions and pharmacotherapies targeting both disorders optimally Earlier recognition and treatment of bipolar disorder may prevent substance disorder Levin FR, et al. Biol Psychiatry . 2004;56:738-748.

Bipolar Disorder and Substance Abuse: Treatment Response:

Bipolar Disorder and Substance Abuse: Treatment Response Tohen et al. 1990 24 lithium-treated BP patients - alcoholism predicted shorter remission Weiss et al. 1998 Self-report compliance: 21% compliance lithium vs 50% divalproex in 44 bipolar-SUD patients Goldberg et al. 1999 204 substance abusers who received valproate or carbamazepine had remission of their bipolar disorder more often than substance abusers who received lithium alone ( P < 0.05) Salloum IM. 2005 VPA found to be effective with co-occurring alcohol dependence Weiss et al. 2005 Patients with bipolar disorder who experience sustained recovery from SUDs have a better QOL than with an active SUD Patients with no SUD history had the best QOL Tohen M, et al. J Affect Disord . 1990;19:79-86. Weiss RD, et al. J Clin Psychiatry. 1998;59:172-174. Goldberg JF, et al. J Clin Psychiatry. 1999;60:733-740. Salloum IM, et al. Arch Gen Psychiatry . 2005;62:37-45. Weiss RD, et al. J Clin Psychiatry. 2005;66:730-735.

Accelerated Cycling Bipolar Disorder and Borderline Function or Personality Disorder :

Accelerated Cycling Bipolar Disorder and Borderline Function or Personality Disorder Distinguishing Features Bipolar Disorder Borderline Function or Personality Disorder Onset of mood symptoms before puberty Biphasic mood dysregulation Mood symptoms meet threshold criteria of MDD Reasonable functioning during euthymic periods Family history of bipolar disorder Onset of mood symptoms after puberty Mood dysregulation in the depressive spectrum Mood symptoms often do not reach threshold for MDD Dysfunction persists even in euthymic periods Family history of deprivation and abuse Slide courtesy of Roger McIntyre, MD.

Bipolar Disorder and Borderline Personality Disorder:

Bipolar Disorder and Borderline Personality Disorder Only modest association Patients with borderline personality disorder vs other personality disorders had higher co-occurrence (19.4%) of bipolar disorder Those with other personality disorders and bipolar disorder had more new onset borderline personality disorder (25%) than those without bipolar disorder (10%) Gunderson JG, et al. Am J Psychiatry . 2006;163:1173-1178.

Medical Comorbidity in Bipolar Disorder: A Population-Based Survey:

Medical Comorbidity in Bipolar Disorder: A Population-Based Survey Percentage with doctor-diagnosed disease Canadian household population (36,984), aged 40 – 64 *Significantly higher than no bipolar ( P < 0.05) Adapted from: McIntyre RS, et al. Psychiatr Serv. 2006;57:1140-1144. No Bipolar Bipolar I Migraine 11.6 20.3* High blood pressure 17.8 16.8 Asthma 7.1 14.7* Heart disease 4.8 8.3* Diabetes 5.8 6.6* Cancer 2.0 2.3 Effects of stroke 0.8 0.6

Medical Comorbidities With Bipolar Disorder:

Medical Comorbidities With Bipolar Disorder Cardiovascular disease Increased mortality in male inpatients with bipolar disorder = 1.87 Obesity Central obesity more common, especially with antipsychotics Diabetes Increased prevalence = 9.9%; expected prevalence = 3.4% Neurological disorders Migraine: prevalence = 25% of men, 27% of women; rate in men is almost 5 x general population Chronic pain syndromes Elmslie JL, et al. J Clin Psychiatry . 2000;61:179-184; Cassidy F, et al. Am J Psychiatry. 1999;156:1417-1420; Weeke A, et al. J Affect Disord. 1987;13:287-292; Mahmood T, et al. J Affect Disord. 1999;52:239-241; Schiffer RB, et al. Am J Psychiatry. 1986;143:94-95.

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Correlates of Obesity in Patients With Bipolar Disorder Male Exposure to ≥ 1 weight - increasing psychotropic Comorbid binge-eating disorder > 4 manic episodes ≥ 1 suicide attempt Limited occupational functioning Hypertension Diabetes mellitus Arthritis Stanley Foundation Bipolar Treatment Outcome Network (N = 644) McElroy SL, et al. J Clin Psychiatry. 2002;63:207-213.

Bipolar Disorder and Type II Diabetes:

Bipolar Disorder and Type II Diabetes 1. Cassidy F, et al. Am J Psychiatry . 1999:156;1417-1420. 2. Regenold WT, et al. J Affect Disord. 2002:70;19-26. 3. Ruzickova M, et al. Can J Disord. 2003:40;458-461. 4. Kilbourne AM, et al. Bipolar Disord . 2004;6:368-373. Investigators Date BP Subjects Diabetes Rate Bipolar vs General Population Cassidy, et al 1 1999 N = 345 3 times greater Regenold, et al 2 2002 N = 243 2 times greater Ruzickova, et al 3 2003 N = 222 2 times greater Kilbourne, et al 4 2004 N = 4310 2 times greater

Comorbid Restless Leg Syndrome (RLS) and Iatrogenic Mania:

Comorbid Restless Leg Syndrome (RLS) and Iatrogenic Mania Dopamine agonists (such as pramipexole, ropinirole, L-dopa, used to treat RLS and Parkinson’s disease) may induce iatrogenic mania such as: Gambling Hypersexuality Impulsive shopping Singh A, et al. Am J Psychiatry . 2005;162:814-815.

Unique Treatment Challenges of Parkinson’s Disease:

Unique Treatment Challenges of Parkinson’s Disease Depression and anxiety are common Motor “on-off” phenomenon common and associated with mood fluctuations Patients with major affective disorder have about 2-fold increased likelihood of developing Parkinson’s disease Dopamine agonists may worsen mania in persons with co-occurring bipolar disorder Some dopamine agonists, such as pramipexole, also have demonstrated antidepressant efficacy as adjuncts to mood stabilizers, with low risk of inducing mania, in preliminary placebo-controlled trials Physicians treating Parkinson’s patients should be alert for symptoms of bipolar disorder Ferreri F, et al. Can Med A J. 2006;175:1545-1552. Nilsson FM, et al. Acta Psychiatr Scand . 2001;104:380-386. Goldberg JF, et al. Am J Psychiatry. 2004;161:564-566. Zarate CE Jr, et al. Biol Psychiatry. 2004;56:54-60.

Medical Comorbidities With Bipolar Disorder:

Medical Comorbidities With Bipolar Disorder Some medications increase risk for weight gain, diabetes, metabolic syndrome, and cardiovascular disease Measure waist circumference, BMI, weight, blood pressure, glucose Encourage diet and exercise Monitoring for drug toxicity is essential Routine monitoring of mood stabilizers recommended every 6 months Thyroid function tests for lithium, CBC and hepatic function for valproate and carbamazepine Triglycerides Kilbourne AM, et al. J Affect Disorders . Epub ahead of print. Suppes T, et al. J Clin Psychiatry . 2005;66:870-886.

General Principles in Treatment of Comorbidity in Bipolar Disorder:

General Principles in Treatment of Comorbidity in Bipolar Disorder Address bipolar disorder and its comorbidities concurrently Use medications that treat both disorders Use medication with least abuse potential and least toxicity Use doses that are below the side effects threshold Most treatment of psychiatric comorbidities is “off-label” Maximize the use of nonpharmacologic treatment Patients with comorbidities are at greater risk for medication nonadherence

Section 3: Treatment of Bipolar Disorder:

Section 3: Treatment of Bipolar Disorder

Therapies With Bipolar Disorder Indications:

Therapies With Bipolar Disorder Indications * Limited data; ** Emerging data Physicians’ Desk Reference ® . 61st ed. Montvale, NJ: Medical Economics Co; 2007. Therapy Bipolar Mania Bipolar Depression Maintenance Mixed States Valproate Yes No * No Yes Lithium Yes No * Yes No Carbamazepine Yes No No Yes Lamotrigine No No ** Yes No Aripiprazole Yes No Yes Yes Olanzapine Yes No Yes Yes Quetiapine Yes Yes No No Risperidone Yes No No Yes Ziprasidone Yes No No Yes Olanzapine+fluoxetine (OFC) No Yes No No

TIMA Algorithm for Treatment of Acute Manic Episodes (Stages 1–2):

Stage 1: Monotherapy * 1A Lithium, valproate, atypicals excluding olanzapine and clozapine Nonresponse: Try alternate monotherapy Partial response Response: Continue with therapy Stage 2: Two-drug combination * Lithium, valproate, atypical antipsychotic Choose 2 (not 2 atypicals, not aripiprazole or clozapine) Response: Continue with therapy 1B: Olanzapine † or carbamazepine † Partial response or nonresponse: Further medical consult or referral for other treatment options *Use targeted adjunctive treatment as necessary before moving to next stage. Agitation/Aggression─clonidine, sedatives; Insomnia─hypnotics; Anxiety─benzodiazepines, gabapentin. † All agents in Stage 1A and 1B are indicated for acute mania associated with bipolar I disorder. Safety and other concerns led to placement of olanzapine and carbamazepine as alternate first-stage choices. Suppes T, et al. J Clin Psychiatry. 2005;66:870-886 . TIMA Algorithm for Treatment of Acute Manic Episodes (Stages 1 – 2)

TIMA Algorithm for Treatment of Acute Manic Episodes (Stages 3–4):

Suppes T, et al. J Clin Psychiatry. 2005;66:870-886. Partial response or nonresponse Stage 4: Electroconvulsive therapy (ECT) as well as clozapine or 3-drug combination Response: Continue with therapy Response: Continue with therapy Partial response or nonresponse Stage 3: Two-drug combination with larger set of medication choices * Aripiprazole, oxcarbazepine, or older antipsychotics TIMA Algorithm for Treatment of Acute Manic Episodes (Stages 3 –4)

Mixtures of Manic and Depressed Symptoms Are Commonly Seen:

Mixtures of Manic and Depressed Symptoms Are Commonly Seen Mania MDE MDE = major depressive episode 1. Benazzi F. Psychiatry Res. 2004;127:247-257. 2. Maj M, et al. Am J Psychiatry. 2003;160:2134-2140. 3. Akiskal HS, et al. J Affect Disord. 2005;85:245-258. Agitated depressions? 2,3 Depressive Mixed States 1 Mixed Mania Dysphoric Mania Full Mania Full MDE Full Mania Full MDE 2+ Mania Symptoms 2+ Depressive Symptoms

Conventional vs Atypical Antipsychotics: Side-Effect Profiles:

Conventional vs Atypical Antipsychotics: Side-Effect Profiles Key: 0 = absent;  = minimal; + = mild; ++ = moderate; +++ = severe TRZ: Thioridazine; HAL: haloperidol; CLZ: clozapine; OLZ: olanzapine; RIS: risperidone; QTP: quetiapine; ZIP: ziprasidone; ARI: Aripiprazole a Minimal weight gain in long-term treatment. Tandon R, Jibson MD. Psychoneuroendocrinology . 2003;28(suppl 1):9-26. Physicians’ Desk Reference ®. 61st ed. Montvale, NJ: Medical Economics Co; 2007. Side Effect TRZ HAL CLZ OLZ QTP RIS ZIP ARI Dose-related EPS ++ +++ 0 + 0 ++ + 0 Tardive dyskinesia +++ +++ 0 Low Low Low Low Low Prolactin elevation ++ +++ 0   +++ ± 0 Anticholinergic +++  +++ +   ± ± QTc prolongation ++  +    + - Hypotension +++ + +++ + ++ ++ + + Sedation +++ + +++ ++ ++ + + + Weight gain ++ + +++ +++ ++ a ++ + + ?

FDA Black Box Warnings:

FDA Black Box Warnings Clozapine Agranulocytosis, seizures, hypotension, myocarditis Valproate Fetal neural tube defects, hepatic failure, hemorrhagic pancreatitis Lamotrigine Serious rashes Lithium Toxicity close to therapeutic levels Carbamazepine Agranulocytosis Aplastic anemia Second generation antipsychotics Increased mortality in elderly patients with dementia-related psychosis Prescribing Information. In: Physicians’ Desk Reference ® . 61st ed. Montvale, NJ: Medical Economics Co; 2007; Pellock JM. Epilepsia . 1987;28(suppl 3):S64-S70; Leppik I. Contemporary Diagnosis and Management of the Patient With Epilepsy. Newtown, PA: Handbooks in Health Care; 2001. ?

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Monotherapy or combination therapy* Lithium Novel antipsychotics Anticonvulsants Other strategies Add-on antidepressant (not as monotherapy) Electroconvulsive therapy (ECT) *While monotherapy is the goal of most practitioners, the inherent nature of bipolar disorder makes combination therapy the rule rather than the exception. *Young LT. J Psychiatry Neurosci. 2004;29:87-88. American Psychiatric Association. Am J Psychiatry . 2002;159:1-50. Treating Bipolar Depression

TIMA Bipolar: Treatment of Acute Depressive Episodes (Stages 1–3):

TIMA Bipolar: Treatment of Acute Depressive Episodes (Stages 1–3) Stage 1 Stage 2 Stage 3 Increase to ≥ 0.8 mEq/L (continue) a Note safety issue described in reference listed below (ie, olanzapine is associated with weight gain, quetiapine is associated with sedation and somnolence). Li = lithium; LTG = lamotrigine; OFC = olanzapine-fluoxetine combination; QTP = quetiapine. Suppes T, et al. J Clin Psychiatry. 2005;66:870-886. Antimanic + LTG LTG Partial response or nonresponse OFC a or QTP a Combination from Li, LTG, QTP, or OFC Taking no antimanic, with history of severe and/or recent mania Taking no antimanic, without history of severe and/or recent mania Taking Li Taking other antimanic Response: Continue with therapy Response: Continue with therapy Partial response or nonresponse

TIMA Bipolar: Treatment of Acute Depressive Episodes (Stages 4–5):

TIMA Bipolar: Treatment of Acute Depressive Episodes (Stages 4–5) Stage 4 Stage 5 Suppes T, et al. J Clin Psychiatry . 2005;66:870-886. Li, LTG b , OFC, VPA, or CBZ + SSRI c , BUP, or VEN or ECT or QTP * a Note safety issue described in reference listed below (ie, olanzapine is associated with weight gain, quetiapine is associated with sedation and somnolence). b Lamotrigine has limited antimanic efficacy and, in combination with an antidepressant, may require the addition of an antimanic. c SSRIs include citalopram, escitalopram, fluoxetine, paroxetine, sertraline, and fluvoxamine. *Evidence supported by randomized controlled clinical trials with large effect sizes. AAP = atypical antipsychotic; BUP = bupropion; CBZ = carbamazepine; CONT = continuation; ECT = electroconvulsive therapy; Li = lithium; LTG = lamotrigine; MAOI = monoamine oxidase inhibitor; OFC = olanzapine-fluoxetine combination; OXC = oxcarbazepine; QTP = quetiapine; SSRI = selective serotonin reuptake inhibitor; VEN = venlafaxine; VPA = valproate. MAOIs, tricyclics, pramipexole, other AAPs a , OXC, other combinations of drugs at stages, inositol, stimulants, thyroid Response: Continue with therapy Response: Continue with therapy Partial response or nonresponse Partial response or nonresponse

Quetiapine Monotherapy for the Treatment of Bipolar Depression:

‡ Quetiapine Monotherapy for the Treatment of Bipolar Depression † P < 0.01 vs placebo, ‡ P < 0.001 vs placebo Mean Change From Baseline a Improvement 1 2 4 3 6 5 7 8 0 QTP 600 mg/d (n = 170) Placebo (n = 169) QTP 300 mg/d (n = 172) Study Week BOLDER I N = 511 ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ 1 2 4 3 6 5 7 8 0 Study Week BOLDER II N = 467 QTP 600 mg/d (n = 151) Placebo (n = 161) QTP 300 mg/d (n = 155) ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ † ‡ MADRS Total Score Calabrese J, et al. Am J Psychiatry . 2005;162:1351-1360. a Values are least squares mean Thase ME, et al. J Clin Psychopharmacol. 2006;26:600-609. -20 -16 -12 -8 -4 0 -20 -16 -12 -8 -4 0

BOLDER II: MADRS Items:

* P < 0.05; † P < 0.01; ‡ P < 0.001 vs placebo ( P -values: ANCOVA, change from baseline) Thase ME, et al. J Clin Psychopharmacol. 2006;26:600-609. BOLDER II: MADRS Items % Improvement from Baseline in Mean Score Apparent sadness Reported sadness Inner tension Reduced sleep Reduced appetite Concentration difficulties Lassitude Inability to feel Pessimistic thoughts Suicidal thoughts Quetiapine 600 mg (n = 151) Quetiapine 300 mg (n = 155) † * * * * ‡ Placebo (n = 161) ‡ ‡ ‡ † † † † † 0 10 20 30 40 50 60 70 80

Olanzapine-fluoxetine Combination Treatment for Bipolar I Depression:

Slide Modified: Review: Reviewer Memo: Source: Memo: * P < 0.05 olanzapine vs placebo † P < 0.05 vs OFC Olanzapine-fluoxetine Combination Treatment for Bipolar I Depression N = 788 Tohen M, et al. Arch Gen Psychiatry . 2003;60:1079-1088. -20 -18 -16 -14 -12 -10 -8 -6 -4 -2 0 0 1 2 3 4 5 6 7 8 Week MADRS Change From Baseline Olanzapine (N = 351) Placebo (N = 355) OFC (N = 82) * † * † * † * † * † * † † † † Improvement

Comparison of Olanzapine and Olanzapine/Fluoxetine in Bipolar I Depression: MADRS Items:

Mean Change From Baseline in MADRS score Comparison of Olanzapine and Olanzapine/Fluoxetine in Bipolar I Depression: MADRS Items OFC = olanzapine + fluoxetine N = 788 * P < 0.05 vs placebo; † P < 0.05 vs olanzapine Week 8 assessment * † * * * * * * -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0.0 Olanzapine (n = 351) Placebo (n = 355) OFC (n = 82) * † * † * † * † Suicidal thoughts Pessimistic thoughts Inability to feel Lassitude Concentration difficulties Reduced appetite Reduced sleep Inner tension Reported sadness Apparent sadness Tohen M, et al. Arch Gen Psychiatry . 2003;60:1079-1088.

TIMA Guidelines for Maintenance Treatment: Most Recent Episode Depressed:

TIMA Guidelines for Maintenance Treatment: Most Recent Episode Depressed 1. Safety issues warrant careful consideration of this option for potential long-term use 2. Relatively limited information is currently available on this agent in long-term use Level I: Level II: Lithium Level III: Combination of Antimanic and Antidepressant That Has Been Effective in the Past, including Olanzapine/Fluoxetine Combination 1 Level IV: Valproate, Carbamazepine, Aripiprazole, 2 Clozapine, 1 Olanzapine, 1 Quetiapine, 2 Risperidone, 2 Ziprasidone 2 Level V: Typical Antipsychotics, 1 Oxcarbazepine, 2 ECT Patients With Recent and/or Severe History of Mania Lamotrigine Combined With Antimanic Agent All Other Patients Lamotrigine Monotherapy It is an option to remain on well-tolerated, effective, acute-phase treatments Available evidence supports the options presented for maintenance treatment Suppes T, et al. J Clin Psychiatry . 2005;66:870-886.

Maintenance Treatment:

Maintenance Treatment FDA-indicated agents: Lithium Lamotrigine Olanzapine Aripiprazole * Physicians’ Desk Reference ® . 61st ed. Montvale, NJ: Medical Economics Co; 2007.

Slide 66:

Lithium vs Placebo in Maintenance 0 0.2 0.4 0.6 0.8 1 1.2 0 10 20 30 40 50 60 Lithium Placebo Probability of Remaining Well Follow-Up (weeks) Keck PE Jr, et al. Biol Psychiatry. 2000;47:756-761.

Lithium Reduces Mortality:

Lithium Reduces Mortality Outcome Odds Ratio 95% Confidence Interval Suicide 0.26 0.09 – 0.77 Suicide and Deliberate Self-Harm 0.21 0.08 – 0.50 All Causes of Death 0.42 0.21 – 0.87 Cochrane Controlled Trials Registry: 32 Randomized Trials 1389 patients randomized to lithium; 2069 randomized to active comparators Cipriani A, et al. Am J Psychiatry . 2005;162:1805-1819.

Slide 68:

18 months % of patients 70 60 50 40 30 20 10 0 37 22 Goodwin GM, et al. J Clin Psychiatry. 2004;65:432-441. Lamotrigine or Placebo: Time to Intervention for Any Mood Episode Combined Analysis 100 90 80 70 60 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Month Estimated % of Pts Intervention-Free Lamotrigine 100-400 mg (n = 223) Placebo (n = 188) LTG vs PBO, P < 0.001 18 68%

Slide 69:

Lamotrigine or Placebo: Time to Intervention for a Depressive Episode Combined Analysis *Some patients considered intervention-free for depressive episodes could have had intervention for manic episodes. 18 months % of patients 57 41 70 60 50 40 30 20 10 0 39% 100 90 80 70 60 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Month Estimated % of Pts Intervention-Free* Lamotrigine 100-400 mg (n = 233) Placebo (n = 188) LTG vs PBO, P = 0.009 18 Goodwin GM, et al. J Clin Psychiatry. 2004;65:432-441.

Slide 70:

Lamotrigine or Placebo: Time to Intervention for a Manic Episode Combined Analysis * Some patients considered intervention-free for manic episodes could have had intervention for depressive episodes. 18 mo % of patients 70 60 50 40 30 20 10 0 65 53 22% 100 90 80 70 60 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Month Estimated % of Pts Intervention-Free* Lamotrigine 100-400 mg (n = 223) Placebo (n = 188) LTG vs PBO, P = 0.034 18 Goodwin GM, et al. J Clin Psychiatry. 2004;65:432-441.

Maintenance Treatment:

Maintenance Treatment Atypical antipsychotics Olanzapine is recommended as an alternate first-line therapy Aripiprazole is recommended as a second-line therapy Other atypical antipsychotics (quetiapine, risperidone, ziprasidone) are potential maintenance treatments Suppes T, et al. J Clin Psychiatry. 2005:66:870-886. Yatham LN, et al. Bipolar Disord . 2005;7:5-69.

Olanzapine Versus Placebo: Relapse Into Mania or Depression:

Olanzapine Versus Placebo: Relapse Into Mania or Depression Tohen M, et al. Am J Psychiatry. 2006;163:247-256. P < 0.001 P < 0.001 Days to Relapse Into Mania Only Probability of Remaining Relapse Free 0 50 100 150 200 250 300 350 400 0.0 0.2 0.4 0.6 0.8 1.0 Subjects receiving placebo (N = 136) Subjects receiving olanzapine (N = 225) Days to Relapse Into Depression Only 0 50 100 150 200 250 300 350 400 0.0 0.2 0.4 0.6 0.8 1.0 Subjects receiving placebo (N = 136) Subjects receiving olanzapine (N = 225)

Aripiprazole for Maintenance Treatment of Bipolar Disorder:

Aripiprazole for Maintenance Treatment of Bipolar Disorder Keck PE Jr, et al. J Clin Psychiatry . 2006;67:626-637. 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 28 56 84 112 140 168 196 Days in Study Aripiprazole (N = 77) Placebo (N = 83) Log rank P = 0.008 HR = 0.309 (95% CI = 0.123 to 0.774) Proportion of Patients Without Relapse Proportion of Patients Without Relapse 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 28 56 84 112 140 168 196 Aripiprazole (N = 77) Placebo (N = 83) Log rank P = 0.683 HR = 0.833 (95% CI = 0.345 to 2.011) Days in Study Manic Relapse Depressive Relapse

Maintenance Treatment:

Maintenance Treatment Antidepressants Maintenance antidepressants efficacy has been established in unipolar but not bipolar depression Increased cycling on antidepressants has been shown in three placebo-controlled studies Not recommended, but if used, must be used with an antimanic agent in bipolar I disorder When antidepressants are used in acute therapy, taper and discontinue them after recovery from depression; maintain them only in those who repeatedly relapse soon after discontinuation (about 20% of bipolar patients) Ghaemi SN, et al. Bipolar Disord . 2003;5:421-433. Suppes T, et al. J Clin Psychiatry. 2005;66:870-886. Yatham LN, et al. Bipolar Disord . 2005;7:5-69.

Maintenance Treatment:

Maintenance Treatment Anxiolytics Systematic evaluation of benzodiazepines as prophylactic agents in bipolar disorder has not been conducted Issues such as dependence, rebound anxiety, memory impairment argue against their long-term use Yatham LN, et al. Bipolar Disord . 2005;7:5-69.

Maintenance Treatment:

Maintenance Treatment Mood stabilizer combinations Some efficacy demonstrated: Lithium plus valproate Lithium plus carbamazepine Olanzapine-fluoxetine combination has shown efficacy Many other combinations are used but with limited evidence Suppes T, et al. J Clin Psychiatry. 2005;66:870-886. Yatham LN, et al. Bipolar Disord . 2005;7:5-69.

Relapse Prevention:

Relapse Prevention Features associated with increased risk of recurrence: ≥ 20 previous episodes of depression or (hypo)mania Residual manic symptoms at response More days depressed/anxious in previous year associated with depressive recurrence More time spent in manic/hypomanic state in past year associated with shorter time to manic/hypomanic/mixed episode recurrence Suggests bipolar disorder remains a highly recurrent, predominantly depressive illness Targeting residual symptoms in maintenance treatment may reduce risk of recurrence Perlis RH, et al. Am J Psychiatry . 2006;163:217-224.

The Importance of Subsyndromal Symptoms in Bipolar Disorder:

The Importance of Subsyndromal Symptoms in Bipolar Disorder Subsyndromal (subthreshold) symptoms (those that fail to meet full diagnostic criteria for mood episode) are a significant public health issue: May be related to poor outcomes Are associated with deficits in social and occupational functioning Increase the risk of relapse Are significantly associated with functional impairment in multiple domains Altshuler LL, et al. J Clin Psychiatry. 2006;67:1551-1560. Marangell LB. J Clin Psychiatry . 2004;65(suppl 10):24-27.

Subsyndromal Symptoms Are Associated With Functional Impairment in Over 50–75% of Patients:

Subsyndromal Symptoms Are Associated With Functional Impairment in Over 50 – 75% of Patients Altshuler LL, et al. J Clin Psychiatry. 2006;67:1551-1560. Role Function Not Depressed (N = 292) Subsyndromally Depressed (N = 291) Syndromally Depressed (N = 176) P -value Duties at work/school 64 (31) 108 (64) 61 (87) < 0.0001 Duties at home 107 (38) 209 (75) 142 (93) < 0.0001 With family 90 (34) 151 (59) 112 (77) < 0.0001 With friends 48 (18) 144 (56) 116 (81) < 0.0001 Total—all domains 91 (32) 205 (70) 157 (92) < 0.0001

Treating Subsyndromal Mood Symptoms in Bipolar Disorder: Evaluation of Maintenance Trials:

Treating Subsyndromal Mood Symptoms in Bipolar Disorder: Evaluation of Maintenance Trials Two 18-month, randomized, placebo-controlled maintenance trials for bipolar I disorder were evaluated for incidence, time course, impact of pharmacotherapy on subsyndromal symptoms Subsyndromal symptoms occurred in 25% of all visits Compared with placebo (54.8%), higher mean percentage of visits in remission with lamotrigine (63.0%, P = .020) but not with lithium (60.0%, P = 0.165) Lithium and lamotrigine delayed onset of subsyndromal symptoms and time from onset of relapse Further studies are needed to assess whether treatment interventions can minimize subsyndromal symptoms or prevent relapse Frye MA, et al. J Clin Psychiatry . 2006;67:1721-1728.

Treatment-Resistant Bipolar Depression: STEP-BD:

Treatment-Resistant Bipolar Depression: STEP-BD Nierenberg AA, et al. Am J Psychiatry . 2006;163:210-216. Open randomized trial Prior nonresponse to MS + AD LTG 150-250 mg/day INO 10-25 gms/day RIS up to 16 mg/day Up to 16 weeks Recovery: < 2 sxs for ≥ 2 mos Lamotrigine (N = 21) Inositol (N = 23) Risperidone (N = 23) 0 5 10 15 20 25 Recovery Rate (%)

Recommendations for Combination Therapy in Bipolar Disorder:

Recommendations for Combination Therapy in Bipolar Disorder Combination therapy is the rule, not the exception Use evidence-based data when available Add drugs to the treatment regimen that specifically targets residual symptoms Bowden CL. J Clin Psychiatry. 2004;65(suppl 15):21-24.

Summary:

Summary Goal is to stabilize depression without causing mania and minimizing side effects Monotherapy antidepressants can destabilize bipolar depression Evidence-based treatment for bipolar depression includes lithium and lamotrigine Quetiapine is the only approved monotherapy for bipolar depression OFC is the only FDA approved combination therapy for bipolar depression Some novel antipsychotics may have a role in treating bipolar depression as monotherapy while stabilizing mania

Section 4: Use of Antidepressants in Bipolar Disorder:

Section 4: Use of Antidepressants in Bipolar Disorder

Treatment of Bipolar Depression:

Treatment of Bipolar Depression Fewer studies than for mania Limited approved treatments Antidepressants lack evidence and may cause mood destabilization Ghaemi SN, et al. J Clin Psychiatry . 2001;62:565-569. Ghaemi SN, et al. Am J Psychiatry . 2004;161:163-165. Muzina DJ, Calabrese JR. Int J Neuropsychopharmacol . 2003;6:285-291.

Use of Antidepressants in Bipolar Disorder:

Use of Antidepressants in Bipolar Disorder Bipolar disorder is associated with considerable depressive morbidity Risk-to-benefit ratio of antidepressants as adjuncts to mood stabilizers is an area of controversy and disagreement Antidepressants may increase risk of iatrogenic mania, mixed states, rapid cycling APA 2002 guidelines recommend conservative use of antidepressants Although evidence of their safety and efficacy is limited, antidepressants are commonly used in treatment of bipolar depression

Slide 87:

Bipolar Depression and Antidepressants: General Clinical Guidelines and Risks Conservative approach to antidepressant use: Risk of antidepressant induced mood-cycling in about 15 – 30% of patients Mood stabilizers (lithium, lamotrigine) are effective in acute and prophylactic treatment of depression; lithium is effective in suicide prevention Antidepressants should be reserved for severe cases of acute bipolar depression and not used routinely Cost/risk benefit ratio for antidepressant treatment of bipolar depression is unfavorable Antidepressants should be discontinued after recovery from depressive episode (mixed evidence for this recommendation) Ghaemi SN, et al. Am J Psychiatry . 2004;161:163-165. Ghaemi SN, et al. Bipolar Disord . 2003;5:421-433. American Psychiatric Association. Am J Psychiatry . 2002;159:1-50.

No Antidepressant Advantage For Paroxetine or Imipramine If Lithium Levels Are Therapeutic:

No Antidepressant Advantage For Paroxetine or Imipramine If Lithium Levels Are Therapeutic Nemeroff CB, et al. Am J Psychiatry. 2001;158:906-912. % Responders per Hamilton Criterion ≤ 7 Switch Rates: Li+PBO: 2.3% Li+IMI: 7.7% Li+PAR: 0% 0 10 20 30 40 50 60 Overall Efficacy Li ≤ 0.8 mEq/L Li + PBO Li + PAR Li + IMI PBO = Placebo PAR = Paroxetine IMI = Imipramine N: 15 15 14 7 10 7 P = NS P = 0.05

Antidepressant Efficacy: Stanley Network:

Antidepressant Efficacy: Stanley Network Leverich, et al. Am J Psychiatry . 2006;163:232-239. N: 32 42 37 15 22 22 48.5% 55.3% 43.0% 62.5% 68.8% 71.0% % With CGI 1 or 2 0 10 20 30 40 50 60 70 80 Acute 10-week 1-Year Continuation Bupropion Sertraline Venlafaxine

Time Until Switch With Antidepressants: Stanley Bipolar Network:

Time Until Switch With Antidepressants: Stanley Bipolar Network Leverich GS, et al. Am J Psychiatry. 2006;163:232-239. Time to Switch (days) Cumulative Proportion Without a Switch

Ratio of Threshold Switches to Subthreshold Brief Hypomanias:

Ratio of Threshold Switches to Subthreshold Brief Hypomanias Leverich GS, et al. Am J Psychiatry. 2006;163:232-239. Ratio of Threshold Switches to Subthreshold Brief Hypomanias More Subthreshold Than Threshold Phenomena More Threshold Than Subthreshold Phenomena Acute Antidepressant Trials (10 weeks) Continuation Antidepressant Trials ( ≤ 1 year)

Maintenance Antidepressants in Bipolar:

Maintenance Antidepressants in Bipolar Maintenance antidepressants efficacy has not been established in bipolar disorder Increased cycling on antidepressants has been shown in three placebo-controlled studies When antidepressants are used in acute therapy, taper and discontinue them after recovery from depression Maintain antidepressants only in those who repeatedly relapse soon after discontinuation (about 20% of bipolar patients) Ghaemi SN, et al. Bipolar Disord . 2003;5:421-433.

TIMA 2005 Bipolar Acute Depression:

TIMA 2005 Bipolar Acute Depression Stage 1 (Increase Li to ≥ 0.8 mEq/L) (continue) Antimanic + Lamotrigine Taking Li Other Antimanic No Antimanic, Severe or Recent Mania No Antimanic, No Severe or Recent Mania Lamotrigine Suppes T, et al. J Clin Psychiatry . 2005;66:870-886. Lamotrigine is a mood stabilizer not antimanic Lithium is an antimanic If history of recent or severe mania, add or optimize antimanic Otherwise, lamotrigine monotherapy may be appropriate

TIMA 2005 Bipolar Acute Depression:

Suppes T, et al. J Clin Psychiatry . 2005;66:870-886. Designed to minimize cycle risk Note no anticonvulsant except LTG until Stage 4 Overlap and taper Follow ADA guidelines regarding metabolic monitoring Stage 2 Partial Response or Nonresponse Quetiapine or Olanzapine/Fluoxetine Stage 3 Combination from Li, LTG, QTP, or OFC Partial Response or Nonresponse Response CONT TIMA 2005 Bipolar Acute Depression

TIMA 2005 Bipolar Acute Depression:

CONT Partial Response Or Nonresponse Response Stage 4 Li, LTG, QTP, OFC, VPA, or CBZ + SSRI, BUP, or VEN or ECT Combinations (OFC combinations = 3 drugs) – Lamotrigine should not be combined with AD without antimanic Includes VPA and CBZ at this point – SSRIs include CTP, FLX, PRX, SRT, and FLV – Some advocate the use of AD earlier but evidence is lacking – Venlafaxine associated with more mania induction BUP = bupropion; CBZ = carbamazepine; CTP = citalopram; ECT = electroconvulsive therapy; Li = lithium; LTG = lamotrigine; OFC = olanzapine-fluoxetine combination; QTP = quetiapine; SSRI = selective serotonin reuptake inhibitor; VEN = venlafaxine; VPA = valproate Suppes T, et al. J Clin Psychiatry . 2005;66:870-886. TIMA 2005 Bipolar Acute Depression

Bipolar Depression and Antidepressants General Guidelines and Risks:

Bipolar Depression and Antidepressants General Guidelines and Risks Always use mood stabilizer in bipolar I patients, even while depressed Promptly wean the antidepressant if evidence of hypomania or mania emerges Antidepressants may trigger mania (mood destabilization) or accelerate mood cycle Up to 33% of patients with bipolar disorder may be susceptible to antidepressant-induced manias Possibly less efficacious in bipolar than unipolar depression Few standard antidepressants have been studied in bipolar depression Dantzler A, Osser DN. Psychiatr Ann . 1999;29:270-284. Frances AJ, et al. J Clin Psychiatry . 1998;59(suppl 4):73-79. Goldberg JF, Ernst CL. J Clin Psychiatry. 2002;63:985-991. Goldberg JF, Truman CJ. Bipolar Disord. 2003;5:407-420. M ö ller HJ, et al. J Affect Disord. 2001;67:141-146. ?

Section 5: Nonpharmacologic Treatment Approaches:

Section 5: Nonpharmacologic Treatment Approaches

Goals of Psychotherapy:

Goals of Psychotherapy Establish and maintain a therapeutic alliance Provide education about the disease and its treatment Promote regular patterns of activity and sleep Identify cognitive distortions linked with depression Identify sources of interpersonal discord (eg, expressed emotion) and promote healthy responses to stress Detect early warning signs of mood episodes Minimize the negative impact of the illness Promote the regular use of medications

Enhancement of Adherence and Improving Illness Outcome in Bipolar Disorder:

Enhancement of Adherence and Improving Illness Outcome in Bipolar Disorder Patients with bipolar disorder are often poorly adherent to their medical regimens While psychotherapy for bipolar disorder is known to generally improve illness outcome, it has been reported that interventions that focus on treatment adherence may yield positive results in this specific area Cochran SD. J Consult Clin Psychol. 1984;52:873-878. Colom F. Bipolar Disord. 2002;4(suppl 1):102. ?

Psychosocial Treatment Options:

Psychosocial Treatment Options Brief technique-driven interventions: 6 to 12 individual sessions Cognitive therapy Interpersonal social rhythm therapy (IPSRT) Family or couples therapy Group psychoeducation

Evidence-Based Therapies:

Evidence-Based Therapies Impact on relapse and rehospitalization rates: Group psychoeducation 25% hospitalized vs 35% in unstructured group 1 Cognitive behavioral therapy (CBT) 1 year relapse 44% vs 75% usual care 2 2-year follow-up found no reduction in relapse rates after first 6 months 3 Family focused treatment (FFT) 2 year relapse 28% with FFT vs 60% with individual support 4 Perceived criticism may be an indicator 5 1. Colom F, et al. Arch Gen Psychiatry . 2003;60:402-407. 2. Lam DH, et al. Arch Gen Psychiatry . 2003;60:145-152. 3. Lam DH, et al. Am J Psychiatry . 2005;162:324-329. 4. Rea MM, et al. J Consult Clin Psychol . 2003;71:482-492. 5. Miklowitz DJ, et al. Psychiatry Res . 2005;136:101-111. ?

Interpersonal Social Rhythm Therapy: Focus:

Interpersonal Social Rhythm Therapy: Focus IPSRT focuses on: The link between mood and life events The importance of maintaining regular daily rhythms The identification and management of potential precipitants of rhythm dysregulation with attention to interpersonal triggers The identification and management of affective symptoms Frank E, et al. Biol Psychiatry. 2000;48:593-604 .

Benefits of Psychotherapy Interventions:

Benefits of Psychotherapy Interventions Adjustment to Dx and Rx Enhanced adherence Improved self-esteem Reduced risky behaviors Modification of destabilizing biopsychosocial factors Management of stressors Learning coping strategies Early recognition Modification attitudes/beliefs Scott J, Gutierrez MJ. Bipolar Disord. 2004;6:498-503.

Psychotherapy Reduces Relapse Rate:

Psychotherapy Reduces Relapse Rate Therapy Experimental Control IPSRT 16/39 12/43 Relapse prevention 22/34 27/35 CBT 75/221 107/216 FFT 11/31 38/70 Psychoeducation 23/60 36/60 Fixed combined (5) Random 147/385 220/445 Scott J, et al. J Psychopharmacol . 2006;20:46-50. Effect Lower Upper P value 1.81 0.71 4.52 0.21 0.54 0.19 1.56 0.25 0.52 0.36 0.77 0.00 0.45 0.19 1.11 0.08 0.41 0.20 0.86 0.02 0.54 0.40 0.74 0.00 0.54 0.37 0.73 0.00 0.1 1 10 Favours therapy Logarithmic scale of odds ratio 1 Significant reduction in relapse rate (40%) compared to standard treatment alone.

Complicated Bipolar Relapse :

Complicated Bipolar Relapse

Presentation:

Presentation 32-year-old female Brought to ER by police Family called 911 after altercation at home escalated

History of Present Illness:

History of Present Illness Sister tells ER doctor that patient has been getting more irritable for last 6 weeks Missed outpatient psychiatrist appointment 2 weeks ago Spent disability check and couldn't afford to fill prescription Sister suspects patient has started abusing cocaine again

Past Psychiatric History :

Past Psychiatric History Diagnosed with bipolar disorder at age 21 5 prior hospitalizations (3 manic episodes, 2 depressive episodes with suicidality) Sporadic outpatient attendance with partial medication compliance Responded to lithium, but patient discontinued due to tremor Responded to valproic acid, but patient discontinued due to weight gain Noncompliance associated with cocaine abuse

Points of Consideration:

Points of Consideration

Recent Psychiatric History:

Recent Psychiatric History More irritable Feels her sister is checking on her too much Feels she can make a new start and called CNN and NBC seeking audition as newscaster Poor sleep pattern

Past Medical History:

Past Medical History Hypertension Obesity (BMI 32) Gallstone surgery

Social and Family History:

Social and Family History Social History Cigarette smoker 2 DUIs On disability for bipolar disorder Family History Mother has bipolar disorder First cousin committed suicide Patient has longstanding difficulties in her family relationship Divorced twice 1 child has ADHD, 1 cousin with bipolar disorder

Mental Status Examination:

Mental Status Examination Intoxicated and irritable in ER Angry with her sister, vague threats (“she better watch out if she continues to be so pushy”) Speech pressured Tells ER doctor she doesn't want to be hospitalized because she is setting up interview with CNN If she doesn't get the job, “it will be over”

Points of Consideration:

Points of Consideration

Differential Diagnosis:

Differential Diagnosis Bipolar disorder, manic relapse Polysubstance abuse

Laboratory Tests:

Laboratory Tests Urinary drug screen: positive for cocaine, benzodiazepines Pregnancy test: negative Glucose and triglycerides: normal Cholesterol: mildly elevated Liver function tests: normal

Points of Consideration:

Points of Consideration

Clinical Course:

Clinical Course Initially refuses admission and becomes belligerent in ER Calmed by intramuscular (IM) injection of antipsychotic – Later on required a second IM injection and admitted to the hospital Still irritable, pressured in speech, and sleeping 3 hours a night Quetiapine started with gradual titration to 600 mg/day

Possible Questions:

Possible Questions

Clinical Course (cont):

Clinical Course (cont) Patient decided to try lithium monotherapy for outpatient care Becomes more agreeable and engaged in treatment Reluctantly agrees to aftercare substance abuse day program Says she'll take her medications but that "they better not make me fatter"

Case Summary:

Case Summary Female with dual diagnosis bipolar disorder I Cardiovascular/weight comorbidities Intermittent noncompliance and substance abuse underlie poor long-term course and heightened risk of injurious behavior Doctor's capacity to achieve persistent clinical stability strongly influenced by patient's perceived effectiveness (‘risk versus benefit’ appraisal) of medications

Key Messages:

Key Messages Therapeutic engagement is a critical first step to treatment adherence Careful assessment of: Medical and psychiatric comorbidities in bipolar disorder Treatment options (agents, formulations) in managing acutely agitated bipolar patients Treatment goals (choice agents, risk-benefit appraisal) in stabilization of bipolar patients Treatment priorities, decisions, and transition to outpatient maintenance therapy

The Bland Chef:

The Bland Chef

History:

History 37 - year-old single female, without children, employed as a chef at a local hotel Chief complaint: “I’m depressed and wired” Diminished interest in her work, which she previously was passionate about No suicidal ideation Hyperphagia, hypersomnia, racing thoughts, feels “anxious and hyper,” irritable with friends, severe premenstrual worsening Mood instability admixed with nonrefreshing sleep, led to previous diagnosis of major depression

History of Present Illness:

History of Present Illness Current episode began approximately six months ago in the absence of identifiable interpersonal stressors Confluence of depressive symptoms, increasing severity Has noted decreased sleep by approximately 1 – 2 hours; on occasion “my mind won’t stop when my head hits the pillow” Has noted panic attacks, generalized anxiety, and mood lability woven into depressive symptoms, no suicidal ideation, psychotic features, alcohol or substance abuse

History of Present Illness (cont):

History of Present Illness (cont) Although patient maintains normal working hours, spends less time creating new menu items On days off, has been exercising less and becoming socially withdrawn Current antidepressant, an SSRI, offers minimal symptom relief and may even “worsen my anxiety” Adherent with medication; prescribed 8 weeks ago

Points of Consideration:

Points of Consideration

Past Psychiatric History :

Past Psychiatric History Recalls being anxious as a child No externalizing behavioral disorder or history of trauma Index depressive episode as sophomore, age 21 after breakup with boyfriend Depressive episodes typically last 2 – 4 months in duration with suggestion of worsening in the fall

Past Psychiatric History (cont):

Past Psychiatric History (cont) Has received three previous antidepressants, all of which she described as “not working” Further history reveals that previous antidepressants “worsened anxiety” Has been in therapy on one previous occasion for three months, but “my therapist didn’t understand me” Occasionally takes benzodiazepines when agitation is severe No prior hospitalization

Points of Consideration:

Points of Consideration

Recent Psychiatric History:

Recent Psychiatric History Prior to onset of current depression, patient was awarded Chef of the Year by local state licensing board Was spending most of her social time with friends and had recently joined a book club Was exercising on a regular basis, and planning a mountain bike trip with friends

Past Medical History:

Past Medical History Nonsmoker Allergic to penicillin History of migraines No diabetes, obesity, or heart disease Menstrual cycle has been chronically irregular

Social and Family History:

Social and Family History Father has history of alcohol abuse, mother has history of depression; patient has two older brothers Does not know if brothers have been treated for mental disorder, but refers to older brother as a “pot head” No family history of suicide or schizophrenia Born and raised in city currently resides in Close relationship with mother, father is somewhat distant No history of trauma Employed as chef for the past seven years Currently in a relationship for the past year

Mental Status Examination:

Mental Status Examination Looks stated age; although well groomed, appears tired and fatigued Speech slow, affect congruent with depressed mood, decreased range; normal thought form; no suicidal ideation; preoccupied with diminished interest in her career; good insight; no gross impairment of judgment or cognition

Points of Consideration:

Points of Consideration

Differential Diagnosis:

Differential Diagnosis Major depressive disorder Bipolar spectrum disorder Anxiety disorder comorbidity Mood disorder due to a general medical condition Substance induced mood disorder

Laboratory Tests:

Laboratory Tests CBC, electrolytes, renal and liver function all within normal range TSH above medium but within normal range Normal blood glucose and lipids BMI = 26

Points of Consideration:

Points of Consideration

Clinical Course:

Clinical Course Diagnosis of bipolar NOS was applied due to a lack of history of hypomania Antidepressant discontinued Divalproex refused, concern regarding polycystic ovarian syndrome Lamotrigine initiated, but discontinued after rash despite benign appearance of cutaneous reaction Olanzapine 10 mg/day provided as “mood stabilizer” Cognitive behavioral therapy provided to target subsyndromal depressive symptoms Exercise encouraged Symptom burden considerably reduced, need for antidepressants in the future was required intermittently

Case Summary:

Case Summary 37 - year-old female presenting with depression, previously diagnosed with major depressive disorder Suboptimal trials of antidepressants Anxiety and medical comorbidity overlap Atypical/seasonal depressive pattern Depressive symptoms presage medical service utilization Menstrual cycle exacerbation

Key Messages:

Key Messages Bipolar spectrum disorder (BSD) presenting as depression symptoms/episodes Most individuals with BSD underrecognized and/or diagnosed with depression Anxiety and medical comorbidity differentially affect individuals with BSD Antidepressants not reliable treatments in BSD, potentially harmful All depressive presentations to be screened for BSD

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