Diagnostic Boundaries of Bipolar Disorders. Terence A. Ketter, M.D.

Diagnostic Boundaries of Bipolar Disorders Terence A. Ketter, M.D.

Disclosure Information Research Support / Consultant / Speaker Abbott Laboratories, Inc. AstraZeneca Pharmaceuticals LP Bristol Myers Squibb Company Cephalon Inc. Corcept Therapeutics Elan Pharmaceuticals, Inc. Eli Lilly and Company Forest Laboratories, Inc. GlaxoSmithKline Janssen Pharmaceutica Products, LP Jazz Pharmaceuticals, Inc. Merck & Co., Inc. Novartis Pharmaceuticals Corporation Pfizer Inc. Shire Pharmaceuticals Group plc. Solvay Pharmaceuticals, Inc. UCB Pharmaceuticals Wyeth Pharmaceuticals

Overview Complex, variable phenomenology Different subtypes, mood states, courses Age dependent presentations Crucial differential diagnosis Major depressive disorder Confounding comorbidities Disruptive behavioral disorders (ADHD, ODD, CD) Substance abuse, anxiety, cluster B disorders Measures to enhance diagnostic accuracy Collateral information Screening instruments Mood Disorders Questionnaire Bipolar Spectrum Diagnostic Scale Bipolarity Index

Manic Depressive Psychosis A Unitary Entity (Kraepelin, 1899) Later dichotomized into unipolar versus bipolar (Angst 1966; Perris 1966; Winokur & Clayton 1969) Bipolar Unipolar

DSM IV Classification of Bipolar Disorders Bipolar I Bipolar II Cyclothymia Secondary Bipolar (due to other illnesses or drugs) Bipolar NOS Current episode features Severity Catatonic Melancholic Atypical Post partum onset Course specifiers Full interepisode recovery Seasonal pattern Rapid Cycling DSM IV TR: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Text Revision. 2000.

Akiskal Bipolar Spectrum BP I BP II 4 d BP II½ Cyclothymic Depression BP III Pharmacologic Hypomania Antidepressants Akiskal HS, Pinto O. Psychiatr Clin North Am 1999;22:517 34.

Other Proposed Akiskal Bipolar Spectrum Subtypes BP IV Hyperthymia + Depression Depressive Mixed State Recurrent Unipolar Hyperthymic Temperament Akiskal, et al. J Affect Disord 2000;59(Suppl 1):S5 S30.

Bipolar Spectrum Concept Recurrent brief hypomania (<4 days) Sporadic brief hypomania Medication or substance induced hypomania Cyclothymia Recurrent depression (+ family history of mania)? Seasonal affective disorder? Atypical depression Angst J. J Affect Disord. 1998;50:143 51; Dunner DL, et al. Arch Gen Psychiatry. 1976;33:117 20; Klerman GL. ComprPsychiatry. 1981;22:11 20

High Bipolarity Risk in Prepubertal and Severe Adolescent / Young Adult Major Depression Prepubertal Major Depression (Age at intake 10.3 yrs) 49% Bipolar at 10 year follow up Adolescents / Young Adults Hospitalized for Major Depression (Age at intake 23.0 yrs) 41% Bipolar at 15 year follow up 51.4% (37/72) Not BP 33.3% (24/72) BPI 59.4% (44/74) Not BP 14.8% (11/74) BPI 25.6% (19/74) BPII 15.3% (11/72) BPII Geller B, et al. Am J Psychiatry 2001;158:125 7. Goldberg JF, et al. Am J Psychiatry 2001;158:1265 70.

Most Bipolar Disorder Patients Have Lifetime Comorbid Axis I Diagnoses 80 70 Percent of Patients 60 50 40 30 20 10 All BP BP I BP II 0 None 1 or more 2 or more 3 or more Number of Lifetime Comorbid Axis I Diagnoses McElroy SL, et al. Am J Psychiatr. 2001;158:420 6.

Comorbidities More Common with Mania/Hypomania than Depression National Comorbidity Survey Replication (N = 9,282 adults) Substance Use Disorders Alcohol Abuse* Alcohol Dependence* Drug Abuse Disruptive Behavioral Disorders Attention Deficit/Hyperactivity Disorder* Oppositional Defiant Disorder Conduct Disorder Anxiety Disorders Panic Disorder Social Anxiety Disorder Intermittent Explosive Disorder *correlation with Mania/Hypomania at least 0.1 > than with Depression Kessler et al. Arch Gen Psychiatry 2005;62:617 27.

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

Clues That Unipolar Unipolar Depression May Be Bipolar Depression Early age of onset Postpartum mood disorders Seasonal mood changes Hypersomnia and/or psychomotor slowing Severe anhedonia Depression with catatonia and/or psychotic features Bipolar family history Pharmacological induced mania or hypomania History of recurrent but brief depressive episodes Marchand WR. Hosp Physician. 2003;39:21 30. Geller B, Luby J. J Am Acad Child Adolesc Psychiatry. 1997;36:1168 1176. Akiskal HS, et al. J Affect Disord. 1983;5:115 128.

Symptom Differences in Bipolar Depression (BP) versus Unipolar Depression (UP) Total sleep time Fragmented REM sleep Shut down depressions Postpartum episodes Weight loss BP > UP BP > UP BP > UP BP > UP UP > BP Bowden CL. Psychiatr Serv. 2001;52:51 5.

Unipolar versus Bipolar Depression Symptoms Unipolar depression Somatic anxiety Appetite disturbances Physical complaints Irritability Bipolar depression Psychic anxiety Fatigue Fewer physical complaints Psychomotor retardation Hypersomnia Anger attacks Bowden CL. J Affect Disord. 2005;84:117 125. Mitchell PB, et al. J Clin Psychiatry. 2001;62:212 216. Perlis RH, et al. J Clin Psychiatry. 2005;66:159 166.

Clinical Differences Between Bipolar & Unipolar Depression Bipolar depression associated with Bipolar family history Earlier onset age Greater number of prior depressive episodes More anxiety Atypical features Loss of response to antidepressants Cycle acceleration with antidepressants Perlis RH, et al. Am J Psychiatry 2006;163:225 31; Ghaemi SN, et al. Am J Psychiatry 2004;161:163 5.

3 44 Year Prospective Prediction of Bipolar Outcome in 41 of 205 Depressives Variable % Sensitivity % Specificity Pharmacologic hypomania Bipolar family history Loaded pedigree Hypersomnic retarded Psychotic depression Postpartum onset Onset <26 years 32 56 32 59 42 58 71 100 98 95 88 85 84 68 Akiskal HS, et al. J Affect Disord. 1983;5(2):115 128.

Characteristics Differentiating Bipolar Versus Unipolar Depression History of mania or hypomania Temperament Sex ratio Age at onset Onset of episode Number of episodes Postpartum episodes Psychotic episodes Psychomotor activity Sleep Family history of BPD Family history of UPD Bipolar Yes Cyclothymic Equal Teens, 20s, and 30s Often abrupt Numerous More common More common Retardation > agitation Less common Less common Agitation > retardation Hypersomnia > insomnia Insomnia > hypersomnia High High Unipolar No Dysthymic Women > men 30s, 40s, 50s More insidious Fewer Low High Adapted from Akiskal HS. J Affect Disord 2005;84:107 15.

History of Bipolar I Disorder in Outpatients* with History of Major Depressive Episode 70 Percentage with History of Mania on Psychiatric Diagnostic Interview 60 50 40 30 20 10 Risk Factor History of psychosis 1 relative with mania Depression onset < 25 yrs Overall 26.9% (200/744) 14.7% (32/217) Odds Ratio 3.28 2.56 1.93 19.3% (62/322) 48.8% (84/172) 66.7% (22/33) 0 *Mean age 37.5; p < 0.0001 None One Two Three Number of Risk Factors Othmer E, et al. The Psychiatric Diagnostic Interview (PDI). West Psychol Serv, Los Angeles. 1981; Othmer E, et al. J Clin Psychiatry 2007;68:47 51.

Summary of Clinical Features of Risk of Bipolar Diathesis in Depression Onset Early 1 3, postpartum 1 Depressive episodes Hypersomnic retarded, catatonic, psychotic 1 Acute, severe, psychotic 2,4 Comorbidity Substance abuse, minor antisocial acts 2 Course Long, tempestuous course; brief well intervals 2 Educational, marital, occupational disruption 2 Temperament Mood lability, energy activity, daydreaming (BPII) 2 Family history Bipolar / consecutive generation mood disorder 1 Treatment response Pharmacologic hypomania 1 1 Akiskal HS, et al. J Affect Disord 1983;5:115 28; 2 Akiskal HS, et al. Arch Gen Psychiatry 1995;52:114 23; 3 Geller B, et al. Am J Psychiatry 2001;158:125 7; 4 Goldberg JF, et al. Am J Psychiatry 2001;158:1265 70.

Steps to Avoid Misdiagnosis of Patients Presenting With Depressive Symptoms Involve family / significant others in evaluation Ask about Personal history of mania or hypomania Family history of bipolar disorder Administer bipolar disorder screening instrument Hirschfeld RM, et al. J Clin Psychiatry. 2004;65(suppl 15):5 9.

Mood Disorder Questionnaire: Overview 7/13 DSM mood elevation criteria Mood symptoms concurrent At least moderate consequences Family history of bipolar Diagnosed as bipolar Hirschfeld RM, et al. Am J Psychiatry 2000;157:1873 5.

Bipolarity Index: Five Bipolarity Domains (DSM IV TR and beyond) I. Episode Characteristics (DSM IV TR) Mania; hypomania; cyclothymia II. III. IV. Onset Age (non DSM) Especially 15 19 yrs Course (non DSM) Recurrence and remission; comorbidity Treatment Effects (non DSM) Mood stabilizers effective Antidepressants ineffective, adverse effects V. Family History (non DSM) Bipolar; recurrent unipolar Sachs GS. Acta Psychiatr Scand Suppl 2004;422:7 17.

Categorical Dimensional Mood Disorders Schema Bipolarity Index 100 Bipolar Domain Equivalents 5 Bipolar I Disorder (BP I) 80 4 Bipolar II Disorder (BP II) 60 3 40 20 0 Bipolar Disorder NOS (BP NOS) Major Depressive Disorder (MDD II) (Highly recurrent, antidepressant resistant subgroup) Major Depressive Disorder (MDD I) (Minimally recurrent, antidepressant responsive subgroup) I = Exclusive Phenotype; II = Inclusive Phenotype 2 1 0

Conclusions Complex, variable phenomenology Different subtypes, mood states, courses Age dependent presentations Crucial differential diagnosis Major depressive disorder Confounding comorbidities Disruptive behavioral disorders (ADHD, ODD, CD) Substance abuse, anxiety, cluster B disorders Measures to enhance diagnostic accuracy Collateral information Screening instruments Mood Disorders Questionnaire Bipolar Spectrum Diagnostic Scale Bipolarity Index

Neuroimaging Study of Reward Circuitry People with mania, manic depression or bipolar disorder Earn $25 per hour Participants must: be in good physical health have no neurological disorders other than Bipolar Disorder be 18 60 years of age be a US citizen or non citizen with a Green Card Participants will, if eligible: be interviewed about mood changes do various computer activities participate in a safe, non invasive fmri brain scan For more information call (650) 725 5970 or email Stanford.RewardsStudy@gmail.com For further information regarding questions, concerns, or complaints about research, research related injury, and questions about the rights of research participants, please call (650) 723 5244 or call toll free 1 866 680 2906, or write the Administrative Panel on Human Subjects in Medical Research, Administrative Panels Office, Stanford University, Stanford, CA 94305 5401

Coming Soon: New Collaborative Bipolar Disorder Studies Pritzker/Prechter Clinical Genetics Study Clinical evaluation Neuropsychological evaluation Neuroendocrine evaluation Neuroimaging evaluation Genetic analyses Lithium Treatment Moderate dose Use Study (LiTMUS) 6 month randomized trial Lithium+Treatment as Usual versus Treatment as Usual