Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Slide 41Slide 42Slide 43Slide 44Slide 451Bi 1 “Drugs and the Brain” Lecture 24 Thursday, May 18, 2006 Revised 5/21/06Bipolar Disease Parkinson’s Disease2Bipolar Disease1. Clinical description2. Genetics3. Possible causes4. Heterozygote advantage?5. Therapeutic approaches3Bipolar disorder affects 1-1.5% of the population in most modern societies.Like depression, bipolar disorder is a mood disorder. It was formerly termed manic-depressive disorder, because patients have one or more manic or nearly manic episodes, alternating with major depressive episodes.1st episode often in mid-20’s.Bipolar disorder often leads to suicide.1. Clinical description, based on DSM-IV.4From DSM-IVSummary description of a manic episodeManic Episode is defined by a distinct period during which there is an abnormally and persistently elevated, expansive, or irritable mood. This period of abnormal mood must last at least 1 week (or less if hospitalization is required). The mood disturbance must be accompanied by at least three additional symptoms from this list: -inflated self-esteem or grandiosity,-decreased need for sleep, -pressure of speech, -flight of ideas, -distractibility, -increased involvement in goal-directed activities or psychomotor agitation, and Excessive involvement in pleasurable activities with likelihood of painful consequencesIf the mood is irritable (rather than elevated or expansive), at least four of the above symptoms must be present . . . .The disturbance must be sufficiently severe to cause marked impairment in social or occupational functioning or to require hospitalization, or it is characterized by the presence of psychotic features . . . . .5People with bipolar disorder are often fascinating in the early stages.6No single gene causes bipolar disorder.Data for concordance among twins in bipolar disorder: “narrow”definition“broad”definitionmonozygotic (n = 55)79% 97%monozygotic,reared apart(n = 12)69%dizygotic(n = 52)24% 38%2. Genetics7From Lecture 23:Polygenicthe disease occurs only if several genotypes are present togetherGenetically Multifactorialseveral distinct genes (or sets of genotypes) can independently cause the diseasePartially penetrantnongenetic factors may also be required, or the disease could be inherently stochasticPolygenicGenetically Multifactorial PartiallyPenetrantThree concepts used in describing complex diseases8“Candidate genes” are investigated thoroughly using SNPs. No overwhelming candidate, yet.20%80%60%40%20%80%30%70%Locus AChomosome 12no linkage toschizophreniaLocus BChomosome 1may be near a gene that helps to cause schizophreniasequence A1sequence A2sequence A1sequence A2ControlsSchizophrenicssequence B1sequence B2sequence B1sequence B2Hunting for Genes with SNPsfrom Lecture 23:9Each new advance in neuroscience has been tried out on bipolar disorder--as for schizophrenia. There is no satisfactory explanation yet. As for schizophrenia, present theories invoke: circuit propertiesearly developmental events rather than individual neurotransmitter systems.3. Possible causes of bipolar disease10Touched With Fire : Manic Depressive Illness and the Artistic Temperamentby Kay Redfield Jamison"This is meant to be an illustrative rather than a comprehensive list . . .Most of the writers, composers, and artists are American, British, European, Irish, or Russian; all are deceased . . . Many if not most of these writers, artists, and composers had other major problems as well, such as medical illnesses, alcoholism or drug addiction, or exceptionally difficult life circumstances. They are listed here as having suffered from a mood disorder because their mood symptoms predated their other conditions, because the nature and course of their mood and behavior symptoms were consistent with a diagnosis of an independently existing affective illness, and/or because their family histories of depression, manic-depressive illness, and suicide--coupled with their own symptoms--were sufficiently strong to warrant their inclusion." 4. Heterozygote advantage?autobiography:An Unquiet Mind by Kay Redfield Jamison11from JamisonKEY:H= Asylum or psychiatric hospital; S= Suicide; SA = Suicide Attempt Writers Hans Christian Andersen, Honore de Balzac, James Barrie, William Faulkner (H), F. Scott Fitzgerald (H), Ernest Hemingway (H, S), Hermann Hesse (H, SA), Henrik Ibsen, Henry James, William James, Samuel Clemens (Mark Twain), Joseph Conrad (SA), Charles Dickens, Isak Dinesen (SA), Ralph Waldo Emerson, Herman Melville, Eugene O'Neill (H, SA), Mary Shelley, Robert Louis Stevenson, Leo Tolstoy, Tennessee Williams (H), Mary Wollstonecraft (SA), Virginia Woolf (H, S) Composers Hector Berlioz (SA), Anton Bruckner (H), George Frederic Handel, Gustav Holst, Charles Ives, Gustav Mahler, Modest Mussorgsky, Sergey Rachmaninoff, Giocchino Rossini, Robert Schumann (H, SA), Alexander Scriabin, Peter Tchaikovsky Nonclassical composers and musicians Irving Berlin (H), Noel Coward, Stephen Foster, Charles Mingus (H), Charles Parker (H, SA), Cole Porter (H) Poets William Blake, Robert Burns, George Gordon, Lord Byron, Samuel Taylor Coleridge, Hart Crane (S) , Emily Dickinson, T.S. Eliot (H), Oliver Goldsmith, Gerard Manley Hopkins, Victor Hugo, Samuel Johnson, John Keats, Vachel Lindsay (S), James Russell Lowell, Robert Lowell (H), Edna St. Vincent Millay (H), Boris Pasternak (H), Sylvia Plath (H, S), Edgar Allan Poe (SA), Ezra Pound (H), Anne Sexton (H, S), Percy Bysshe Shelley (SA), Alfred, Lord Tennyson, Dylan Thomas, Walt Whitman Artists Richard Dadd (H), Thomas Eakins, Paul Gauguin (SA), Vincent van Gogh (H, S), Ernst Ludwig Kirchner (H, S), Edward Lear, Michelangelo, Edvard Meunch (H), Georgia O'Keeffe (H), George Romney, Dante Gabriel Rossetti (SA)1218871887-88Vincent Van Gogh 1853-1890750 paintings; 1600 drawings; 700 lettersLife history: born and raised in the NetherlandsParis 1886-88Arles 1888 (1st episode; cut off his own ear)hospitalized 1888-1890Auvers-sur-Oise 3 months. Shot himself 7/27/1890 188613I should like to do portraits which will appear as revelations to people in a hundred years' time.-- Letter to his sister Wil, 3 June 1890 Early 1889Dr.