Bi / CNS 150 Lecture 27 Monday December 2, 2012 Mood Disorders Henry Lester 1

Dear Faculty, Instructors, and Teaching Assistants: The Teaching Quality Feedback Report (TQFR) survey period for FA 2012-13 will open next Monday, December 10, 2012. Students will have several weeks to submit their reviews; however, you will be able to view student responses beginning on Monday, December 17 via the TQFR Reports link in access.caltech ( https://access.caltech.edu

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In order to maximize student response, you may wish to announce these dates to your class; you may use REGIS to send email to your students using the email functionality available from Class Roll Sheets. Some faculty members have obtained very high TQFR response rates by telling their students that they appreciated the feedback and that student comments were helpful. It was also valuable to ask the students to focus feedback on specific aspects of the course, such as the quality of the textbook or the class demonstrations.

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no later than Thursday, December 6.

If you have any questions or comments about the TQFR, please email [email protected]

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Office of the Registrar 2

From a Caltech faculty member: “ I am concerned about the economic implications of Caltech faculty devoting substantial time and effort towards interacting with on-line students who are not paying tuition. This means corresponding less time and effort is devoted to on-campus students who are paying tuition. I realize this issue is counterbalanced by increased impact Caltech makes on the world but the cost in reduced internal impact of any increased external impact needs to be quantified.” Bi/CNS 150 students are Henry Lester’s favorite students, world-wide.

$50,000 vs $0.

Still, let’s look at Coursera. https://class.coursera.org/drugsandbrain-2012-001/admin/index 3

Disclaimer This lecture deals with psychiatric disease.

Henry Lester and Ralph Adolphs are not psychiatrists--not even physicians.

Don’t change any medical treatment that you might now be receiving on the basis of these lectures.

Don’t give any medical advice based on these lectures or problem sets.

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Brain Areas that Regulate Mood FC: Frontal cortex (esp. prefrontal and cingulate) - cognitive function, attention HP: Ventral Hippocampus - cognitive function, memory NAc: Nucleus Accumbens (ventral striatum) - reward and aversion Amy: Amygdala - mediates responses to emotional stimuli HYP: Hypothalamus regulates sleep, appetite, energy, sex VTA: Ventral Tegmental Area - Sends dopaminergic projections to other areas DR: Dorsal Raphe nuclei - send serotonergic input to other areas LC: Locus Coeruleus - sends noradrenergic input to other areas.

From Berton and Nestler, Nature Reviews Neuroscience, 7: 137, 2006 5

Major Depression I.Depression is defined as the affective state of sadness that occurs in response to a variety of human situations such as loss of a loved one, failure to achieve goals, or disappointment in love. Major depression differs only in intensity and duration or quality of the emotional state.

(“Anhedonia”) From Berton and Nestler, Nature Reviews Neuroscience, 7: 137, 2006 6

A.

B.

C.

II. More Characteristics of Major Depression Untreated episodes of major depression usually last from 7 - 14 months.

Major depression is a recurring disorder, usually worsening with age if untreated.

The reported incidence of depression is 3 times higher in women than in men.

Major Depression is Treatable

Somatic Treatments Medications, Vagal nerve stimulation Deep brain stimulation in anterior cingulate cortex, Electroconvulsive therapy Psychotherapy (Cognitive-Behavioral Therapy Interpersonal Therapy) Other (diet, exercise, etc.) 7

How do psychiatric drugs work?

1.

“The mood-elevating effects of fluoxetine [Prozac] are not evident after initial exposure to the drug but require its continued use for several weeks. This delayed effect suggests that it is not the inhibition of serotonin transporters per se, but some adaptation to sustained increases in serotonin function that mediates the clinical actions of fluoxetine. However, where these adaptations occur in the brain, and the nature of the adaptations at the molecular level, have yet to be identified with certainty.” SSRI’s help ~ 50% of major depressive disorder patients 2.

“All current antipsychotic drugs exert their full therapeutic actions over weeks, suggesting that, like lithium and antidepressants, slowly developing adaptations (in this case to initial D2 dopamine receptor blockade) are required for their antipsychotic effects.” Next lecture S. E. Hyman, E. Nestler, R. Malenka, 2008

Molecular Neuropharmacology : A Foundation for Clinical Neuroscience, 2n

d Edition 8

SSRIs bind tightly to, and stabilize, intermediate state(s) of the serotonin transporter.

Cao, Li, Mager, Lester.

J Neurosci

1997 9

Two of the three Biogenic Amine pathways seem involved in antidepressant action The biogenic amines are a group of amine neurohormones that are usually modulatory in their action.

A.

Serotonin or 5-hydroxytryptamine (5-HT) 5-HT B. Norepinephrine or noradrenaline NE C. Dopamine DA 10

How does the SSRI-SERT Interaction relieve depression?

Most experts re-state this, “How does blockade of serotonin re-uptake relieve depression?” Possible downstream consequences of changed regulation of serotonergic systems: 1) Short term derangement of modulation of synaptic strength and possibly also 2) of neuronal intrinsic properties.

Long term change in modulation of neuronal gene expression.

The clinical observation that anti-depressants usually take a few weeks to a month to have full efficacy suggests that modulation of gene expression plays the dominant role.

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To most experts, success of serotonin-selective reuptake inhibitors (SSRIs) Implies participation of serotonergic systems in the brain . . .

. . . but nonspecifically Rostral System Midbrain Raphe nuclei Caudal System ~ 15 serotonin receptor genes, only one serotonin transporter gene from Feldman et al., Principles of Neuropsychopharmacology, Sinauer, 1997 12

Two Serotonergic Fiber Types in the Forebrain Demonstrated by Immunocytochemical Labeling for Serotonin D-System - small arrows M-System - large arrows 10 µm from Tork, Ann. N.Y. Acad. Sci., 1990 13

“Nearly” cell-autonomous actions of SSRI antidepressant treatment Kellermann group 14

Postulated Role for Brain-derived Neurotrophic Factor (BDNF) in Depression SSRIs enhance increase expression of BDNF mRNA and protein. This, in turn ameliorates some of the structural effects of major depression.

From Berton and Nestler, Nature Reviews Neuroscience, 7: 137, 2006 15

How do antidepressants cause adult neurogenesis?

Samuels & Hen,

Eur J. Neurosci, 2011

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Neurogenesis in the SGV In adult animals, new neurons are formed continuously from progenitor cells located in the subgranular zone (SGV) Those neurons differentiate and become incorporated into neuronal circuits in the dentate gyrus Warner-Schmidt and Duman (2006) Hippocampus 16: 239 17

Some Antidepressants are “SNRIs”, Serotonin/Noradrenaline Reuptake Inhibitors Noradrenergic Systems in the CNS “How does blockade of noradrenaline reuptake relieve depression?” Locus coeruleus from Feldman et al., Principles of Neuropsychopharmacology, Sinauer, 1997 18

Acute low-dose ketamine produce antidepressant effects within 2 hr?

How?

The effects (1) involve BDNF synthesis & release, (3) require protein synthesis, Monteggia & Duman groups suggest . . .

Outside-in NMDA Receptor Ca 2+ BDNF secretion Decreased Ca 2+ flux Dendritic Golgi (2) occur in the dendrites, (4) do not require gene activation.

Dendritic ER BDNF

↑

BDNF mRNA

kinases ↓

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Bipolar Disease 1. Clinical description 2. Genetics 3. Possible causes 4. Heterozygote advantage?

5. Therapeutic approaches 20

1. Clinical description, based on DSM-IV.

Bipolar 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.

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From DSM-IV

Summary description of a manic episode

Manic 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 consequences If 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 . . . . .

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2. Genetics No single gene causes bipolar disorder.

Data for concordance among twins in bipolar disorder: “narrow” definition “broad” definition monozygotic (n = 55) monozygotic, reared apart (n = 12) dizygotic (n = 52) 79% 69% 24% 97% 38% 24

3. Possible causes of bipolar disease Each 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 properties early developmental events rather than individual neurotransmitter systems.

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4. Heterozygote advantage?

Touched With Fire : Manic Depressive Illness and the Artistic Temperament by 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."

autobiography:

An Unquiet Mind

by Kay Redfield Jamison 26

from Jamison

KEY: 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) 27

People with bipolar disorder are often fascinating in the early stages.

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1886 Vincent Van Gogh 1853-1890 750 paintings; 1600 drawings; 700 letters Life history: born and raised in the Netherlands Paris 1886-88 Arles 1888 (1st episode; cut off his own ear) hospitalized 1888-1890 Auvers-sur-Oise 3 months. Shot himself 7/27/1890 1887 1887-88 29

Early 1889

I 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 Dr. Gachet June 1890 30

July 1890

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Suicide in America

Approx 30,000 suicides/year (approx 18,000 homicides) Third leading cause of death in adolescence Males outnumber females by 4:1 By definition, 90% have mental disorder http://www.counseling.caltech.edu/depression 34

Disability Adjusted Life Years Disease Burden by Illness - DALY United States, Canada and Western Europe, 2008

15-44 year olds

(incomprehensible units)

Unipolar depressive disorders

Alcohol use disorders

Schizophrenia

Iron-deficiency anemia

Bipolar affective disorder

Hearing loss, adult onset HIV/AIDS Chronic OPD Osteoarthritis Road traffic accidents

0 0 2 2

←Next lecture

4 4 6 6 Percent of Total 8 8

Source: WHO – World Health Report

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5. Therapeutic approaches to bipolar disorder Many bipolar patients avoid therapy or remain partially compliant, because they do not wish to give up the pleasant feelings during the manic phase.

Noncompliant patients may risk suicide.

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Therapeutic approaches to bipolar disorder Surgical and electrical intervention Surgery to remove large portions of the brain (1950’s-60’s) Electroconvulsive shock therapy (ECT).

Now administered under anesthesia. Various electrode placements, pulse widths, and frequencies “In situations where medication, psychotherapy, and the combination of these interventions prove ineffective, or work too slowly to relieve severe symptoms such as psychosis (e.g., hallucinations, delusional thinking) or suicidality, electroconvulsive therapy (ECT) may be considered. ECT is a highly effective treatment for severe depressive episodes.“ -- National Institute of Mental Health Over a hundred theories have been offered to account for the efficacy of ECT.

http://www.acnp.org/G4/GN401000108/CH106.html

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Therapeutic approaches to bipolar disorder Psychiatrists state that It is usually a very bad idea to treat bipolar disorder with antidepressants.

This can cause a manic episode.

Drugs for BD Li + ion Therapeutic effects begin in ~ 5 d, require several wk.

Li + is quite poisonous at higher doses.

Valproic acid and other anticonvulsants These also require several wk for full effects.

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Three exemplar patients in the early days of Li + How does Li + act?

1. We don’t know, but there are now some good guesses.

2.

All ideas about Li + assume an intracellular target. Li + enters cells freely through several channels and ion-coupled transporters that normally serve for Na + . Intracellular concentrations of Li + are probably several mM. 3.

Most ideas about Li + involve enzyme inhibition.

Most of the suspected enzymes manipulate high-energy phosphate bonds.

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Bi / CNS 150 End of Lecture 27 40

Mood disorders also involve dysfunction of many brain areas  Along with changes in mood, the symptoms of Major Depression and Bipolar Disorder include disruption of basic drives (eating and sleeping), as well as cognitive disturbances (ruminations, guilt, indecisiveness, persistent thoughts of suicide).  This constellation of symptoms suggest involvement of cortical structures, a number of limbic brain structures, including the hippocampus, amygdala, and mesolimbic dopamine neurons (“reward centers”), and also midbrain structures controlling appetite.

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