Jonny Gerkin, MD Asst Professor, UNC Psychiatry

1. The World’s Best Bipolar Assessment Lecture in the Worldwith a Treatise on the Scientific Proof of God as well as the Cure for Cancer Jonny Gerkin, MD Asst Professor, UNC Psychiatry

2. Bipolar I Disorder requires a history of a manic episode. • The easier, although not easy, question is: Is this individual currently manic? • http://www.youtube.com/watch?v=rdnAHvi2ynQ • The tougher question arises in the context of a patient that is not currently manic. Have they ever been manic? • http://www.youtube.com/watch?v=TiGRi0kGg_s&feature=related

3. The future… World Biol Psych. 2011 Sep 22. • Identification of a blood-based biological signature in subjects with psychiatric disorders prior to clinical manifestation. • Schwarz et al. Department of Chemical Engineering and Biotechnology, University of Cambridge , Cambridge , UK. Abstract • Objectives: To determine whether a molecular signature is present in blood of patients with psychiatric disorders before manifestation of symptoms. • Methods: Multiplex immunoassay analyses were carried out using serum obtained from two case-control studies of schizophrenia (n = 75) and bipolar disorder (n = 110) patients and their matched controls. The samples were drawn within 1 month before estimated onset of illness. Results. This led to identification of 20 molecules which were altered in pre-schizophrenia and 14 molecules in pre-bipolar disorder subjects compared to controls. Only two of these molecular changes were identical in both data sets and predictive testing confirmed that the biomarker signatures for pre-schizophrenia and pre-bipolar disorder were dissimilar. • Conclusion: The present results suggest that there are distinct serum alterations that occur before clinical manifestation of schizophrenia and bipolar disorder. These findings could lead to development of diagnostic tests to help clinical psychiatrists identify and classify vulnerable patients early in the disease process, allowing for earlier and more effective therapeutic intervention.

4. More of the future…for schizophrenia Mol Psychiatry 2011 Apr 12. • Identification of a biological signature for schizophrenia in serum. • Schwarz et al. Institute of Biotechnology, University of Cambridge, Cambridge, UK. Abstract • Biomarkers are now used in many areas of medicine but are still lacking for psychiatric conditions such as schizophrenia (SCZ). We have used a multiplex molecular profiling approach to measure serum concentrations of 181 proteins and small molecules in 250 first and recent onset SCZ, 35 major depressive disorder (MDD), 32 euthymic bipolar disorder (BPD), 45 Asperger syndrome and 280 control subjects. Preliminary analysis resulted in identification of a signature comprised of 34 analytes in a cohort of closely matched SCZ (n=71) and control (n=59) subjects. Partial least squares discriminant analysis using this signature gave a separation of 60-75% of SCZ subjects from controls across five independent cohorts. The same analysis also gave a separation of ∼50% of MDD patients and 10-20% of BPD and Asperger syndrome subjects from controls. These results demonstrate for the first time that a biological signature for SCZ can be identified in blood serum. This study lays the groundwork for development of a diagnostic test that can be used as an aid for distinguishing SCZ subjects from healthy controls and from those affected by related psychiatric illnesses with overlapping symptoms.

5. In the meantime… • Clinical exam, observation and exclusion of SECONDARY mania • For our purposes we will focus on the interview and exam

6. Screening questions • The most effective screening questions for mania ask about other people’s perceptions as well as the patient’s self-perception.

7. Screening questions continued.. • Have you ever had a period of a week or so when you felt so happy and energetic that your friends told you that you were talking too fast or that you were behaving differently and strangely?

8. Screening continued... • Has there been a period when you were so hyper and irritable that you got into arguments with people?

9. More example screening questions.. • Has there been a time when you felt just the opposite of depressed, so that for a week or so you felt as if you were on an adrenaline high and could conquer the world? (this might be a segue from depression screening questions)

10. More examples.. • Do you experience wild mood swings in which you feel incredibly good for a week or more and then crash down into a depression? • Interpret responses to this question cautiously, because some patients who respond with an emphatic “yes” are referring to recurrent episodes of depression without mania or hypomania.

11. More examples… • Has there been a time when you were so hyper and irritable that you got into arguments with people? • This gets at the diagnosis of irritable, mixed, or dysphoric mania. Obviously, false-positive responses abound here, and following up with questions establishing that this period of irritability represented a manic episode, rather than a depression or simply a transient foul mood, will be no small task. • Has anyone ever called you manic? • If someone answers “yes” to this, pay close attention. It’s not common for healthy people to have been called manic by someone.

12. Screening continued… • If you get yes to one or more of these, find out how long it lasted and when that period was. • If the patient cannot remember such a period lasting an entire week, you should suspect that mania is not the diagnosis. • Determine the circumstances of the elevated mood. Being really happy for a couple of days after matching into your top choice derm program, for example, is not mania.

13. How do we deal with the significant potential for false positives? • Like we said earlier: • ask about other people’s perceptions too. • determine the length of such a period of time. • explore the circumstances surrounding the change in mood, any substance use?

14. Also… • Continually refer to that period (when they profess to have had the expansive mood) when you ask about the diagnostic criteria for mania.

15. DIGFASTapparently refers to the speed with which a manic patient would dig a hole if put to the task. • In addition to expansive mood, the patient must qualify for three of the seven DIGFAST symptoms, or four of seven if the primary mood is irritable.

16. DIGFAST (manic episode) • Distractible (poorly focused) • Indiscretion (excessive pleasurable activities) • Grandiosity (unrealistic belief in one’s abilities) • Flight of Ideas • Activities (increased goal direction) • Sleep deficit (decreased need for sleep) • Talkativeness (pressured speech)

17. DIGFAST cont’d • When you ask about the symptoms of mania, precede your questions with something such as, “During the period last year when you felt high, were you…?” This way, you can ensure that all the symptoms have occurred within the same time frame. • See handout: DIGFAST Interviewing Tips

18. Other important aspects of assessment • History of hospitalization: If a patient was hospitalized during a “hyper” period, chances are good that this was indeed a manic episode. • Interview with relatives and friends: One of the hallmarks of mania is a lack of insight, making verification of historical information particularly important. • Family history of bipolar disorder: Bipolar disorder is one of the most inheritable of all psychiatric disorder.

19. DDX: • PsychiatricMood Disorder Due to a General Medical Condition; Dementia with Mood complications; Substance-Induced Mood Disorder; Other varieties of Mood or Bipolar Disorders (II), +/- Rapid Cycling; Schizoaffective Disorder; Schizophrenia (other primary psychotic illnesses); Borderline Personality Disorder (other , primarily Cluster B personality disorders); ADHD; PTSD; Anxiety Disorders (OCD) • MedicalSecondary Mood Syndromes caused by: Acquired Immune Deficiency Syndrome (AIDS), Cushing's Disease, Epilepsy, Hyperthyroidism, Premenstrual Syndrome, Migraines, Multiple Sclerosis, Neoplasm, Stroke, Systemic Lupus Erythematosus, Traumatic Brain Injury, Delirium (e.g. Uremia), Vitamin Deficiency/Excess, Wilson's Disease, Acute Intermittent Porphyria, Fahr's Syndrome, Huntington's Disease • Substances/DrugsAmphetamines/Stimulants, Illicits, Antidepressants (treatment or withdrawal), Dopaminergics (Bromocriptine), Gaba-ergics (Baclofen), Anticholinergics, Corticosteroids (including ACTH), Chemotherapeutic agents (Cyclosporin), Opiates, Supplments/CAM (Yohimbine, Ginseng)

20. Comorbitdity • Generally comorbid to Mood D/O’s are etoh abuse/dep, panic, OCD and social anxiety. • Bipolar I folks 2X as likely to have above comorbidities than MDD, BPII even higher • Men: substance use disorders • Women: anxiety, eating disorder

21. Some Epidemiology • Data on lifetime prevvaries; but it indicates a rate of around 0.5%–2.4% for bipolar I (MDD 5-17%), 0.3-4.8% for bipolar II, 0.5-6.3% for cyclothymia, 2.6-7.8% for hypomania. • Gender ratio generally 1:1 for BP1 (MDD 2:1, F:M)

22. Some genetics… • For bipolar I, the concordance rates in modern studies have been consistently put at around 40% in monozygotic twins, compared to 0 to 10% in dizygotic twins, these suggest genes explain only 50-70% of etiology implying predisposition is inherited • 3.5-8% risk with 1st degree relative • Multifactorial-threshold model (complex/heterogeneous) with variable expressivity (same gene or group of genes resulting in variety of forms of illness), also imprinting (different traits result from maternal/paternal transmission) may effect the penetrance (probability that someone will manifest a given trait given that they have a certain genotype) • Assortative Mating – mood disordered folks are more likely to marry other mood disordered folks

23. Predictive features (especially in combination) • Early age at onset, ave is 20 & ten years less than MDD onset • Psychotic depression before 25 yr old • PP depression, especially w/psychotic fx • Rapid onset/offset of depression (<3mo) • Depression w/marked psychomotor fx • Atypical fx (reverse vegatative signs) • Depressive mixed state (psychomotor excitement, irritable hostility, racing thoughts, sexual arousal during MD) • Seasonality • Family History • High-density 3 generation pedigrees • Trait mood lability (cyclothymia) • Hyperthymic temperament • Hypomania assoc’d with antidepressants • Repeated loss of efficacy of antidepressants (at least 3 times)

24. Broader indicators • Agitated depression • Cyclical depression • Episodic sleep dysregulation • Or combination of these • Refractory depression (as above) • Depression in someone with an extroverted profession • Periodic impulsivity (gambling, sexual misconduct, wanderlust) • Periodic irritability and/or periodic suicidal crises • Depression with erratic personality disorders

25. Psychodynamic view of Mania • Playing the manic game: Interpersonal maneuvers of the acutely manic patient. • Janowsky, David S.; Leff, Melita; Epstein, Richard S. 1970. • Describes the personality structure, patterns of interaction, and impact on others of the manic-depressive patient in a study of 15 patients in the acute manic phase of their illness. Hypotheses are presented concerning patient‘s conflicted needs for dependency and intimacy, manifested in attempts to control and manipulate others. It is stressed that firm limits and controls by the therapist can often reduce manic symptomatology by convincing the patient "that the therapist cares enough and is powerful enough to protect him from his self-destructive activities."

26. What about Bipolar II and Hypomania? • Hypomania can be hard and pretty unsatisfying to diagnose. Essentially, it amounts to a psychiatric diagnosis for exuberant and often very productive happiness. However, patients with bipolar II spend much of their non-hypomanic time in depression, which is why bipolar II is important not to miss. Use the same DIGFAST questions to diagnose hypomania that are used to diagnose mania. The patient with hypomania will describe definite high periods that have not caused real problems in her life. When hypomanic periods alternate with depressed periods, the proper diagnosis is bipolar, type II disorder.

27. DSM IV Criteria of BP1 • The essential feature of Bipolar I Disorder is a clinical course that is characterized by the occurrence of one or more Manic Episodes or Mixed Episodes. Often individuals have also had one or more Major Depressive Episodes. Episodes of Substance-Induced Mood Disorder (due to the direct effects of a medication, or other somatic treatments for depression, a drug of abuse, or toxin exposure) or of Mood Disorder Due to a General Medical Condition do not count toward a diagnosis of Bipolar I Disorder. In addition, the episodes are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified. . . .

28. DSM IV Criteria for Mania • A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary). • B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: • inflated self-esteem or grandiosity • decreased need for sleep (e.g., feels rested after only 3 hours of sleep) • more talkative than usual or pressure to keep talking • flight of ideas or subjective experience that thoughts are racing • distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli) • increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation • excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) • C. The symptoms do not meet criteria for a Mixed Episode. • D. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. • E. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatments) or a general medical condition (e.g., hyperthyroidism). Note: Manic-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of Bipolar I Disorder.

29. DSM IV Criteria for Mixed Episode • A. The criteria are met both for a Manic Episode and for a Major Depressive Episode (except for duration) nearly every day during at least a 1-week period. • B. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. • C. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism).

30. DSM IV Criteria for MDE (for completeness) • A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Note: Do not include symptoms that are clearly due to a general medical condition, or mood-incongruent delusions or hallucinations. • depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g. appears tearful). Note: In children and adolescents, can be irritable mood. • markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others) • significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. Note: In children, consider failure to make expected weight gains. • insomnia or hypersomnia nearly every day • psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) • fatigue or loss of energy nearly every day • feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) • diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) • recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide • B. The symptoms do not meet criteria for a Mixed Episode. • C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. • D. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). • E. The symptoms are not better accounted for by bereavement, i.e., after the loss of a loved one, the symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.

31. DSM IV Criteria for Hypomanic Episode • A. A distinct period of persistently elevated, expansive, or irritable mood, lasting throughout at least 4 days, that is clearly different from the usual nondepressed mood. • B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: • inflated self-esteem or grandiosity • decreased need for sleep (e.g., feels rested after only 3 hours of sleep) • more talkative than usual or pressure to keep talking • flight of ideas or subjective experience that thoughts are racing • distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli) • increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation • excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) • C. The episode is associated with an unequivocal change in functioning that is uncharacteristic of the person when not symptomatic. • D. The disturbance in mood and the change in functioning are observable by others. • E. The episode is not severe enough to cause marked impairment in social or occupational functioning, or to necessitate hospitalization, and there are no psychotic features. • F. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism). Note: Hypomanic-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of Bipolar II Disorder.

32. DSM IV Criteria for Cyclothymia(Again for completeness) • A. For at least 2 years, the presence of numerous periods with hypomanic symptoms and numerous periods with depressive symptoms that do not meet criteria for a Major Depressive Episode. Note: In children and adolescents, the duration must be at least 1 year. • B. During the above 2-year period (1 year in children and adolescents), the person has not been without the symptoms in Criterion A for more than 2 months at a time. • C. No Major Depressive Episode, Manic Episode, or Mixed Episode has been present during the first 2 years of the disturbance. Note: After the initial 2 years (1 year in children and adolescents) of Cyclothymic Disorder, there may be superimposed Manic or Mixed Episodes (in which case both Bipolar I Disorder and Cyclothymic Disorder may be diagnosed) or Major Depressive Episodes (in which case both Bipolar II Disorder and Cyclothymic Disorder may be diagnosed). • D. The symptoms in Criterion A are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified. • E. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hyperthyroidism). • F. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

33. DSM IV Criteria for Dysthymic D/O • A. Depressed mood for most of the day, for more days than not, as indicated either by subjective account or observation by others, for at least 2 years. Note: In children and adolescents, mood can be irritable and duration must be at least 1 year. • B. Presence, while depressed, of two (or more) of the following: • poor appetite or overeating • insomnia or hypersomnia • low energy or fatigue • low self-esteem • poor concentration or difficulty making decisions • feelings of hopelessness • C. During the 2-year period (1 year for children or adolescents) of the disturbance, the person has never been without the symptoms in Criteria A and B for more than 2 months at a time. • D. No Major Depressive Episode has been present during the first 2 years of the disturbance (1 year for children and adolescents); i.e., the disturbance is not better accounted for by chronic Major Depressive Disorder, or Major Depressive Disorder, In Partial Remission. Note: There may have been a previous Major Depressive Episode provided there was a full remission (no significant signs or symptoms for 2 months) before development of the Dysthymic Disorder. In addition, after the initial 2 years (1 year in children or adolescents) of Dysthymic Disorder, there may be superimposed episodes of Major Depressive Disorder, in which case both diagnoses may be given when the criteria are met for a Major Depressive Episode. • E. There has never been a Manic Episode, a Mixed Episode, or a Hypomanic Episode, and criteria have never been met for Cyclothymic Disorder. • F. The disturbance does not occur exclusively during the course of a chronic Psychotic Disorder, such as Schizophrenia or Delusional Disorder. • G. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). • H. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.