Post on 18-Jan-2016
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Bi / CNS 150
Lecture 27
Monday November, 30 2015
Mood Disorders
Henry Lester
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Discussion sections this Thursday, as usual Problem set 6 is due Tuesday, as usual
Final exam posted Friday 12/4
Final exam is due Friday 12/11 4:30 PM.
This week: no quiz.Extra credit for emailing Ralph or Henry a question for Friday’s session:What is a challenge for neuroscience in the remainder of the 21th Century?Give at least one reference from a journal (not a web site; not the text).
We have received no request for a final review session.
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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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From Berton and Nestler, Nature Reviews Neuroscience, 7: 137, 2006
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.
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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.
A major depressive episode includes at least 5 of the symptoms below. Each must be evident daily or at least for > 2 weeks.
DSM-5 emphasizes that the diagnostic criteria for a major depressive episode as “the requirement for clinically significant distress or impairment in social, occupational, or other important areas of life”
(“Anhedonia”)
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Major Depression is Treatable
Somatic TreatmentsMedications,Vagal nerve stimulation Deep brain stimulation in anterior cingulate cortex, Electroconvulsive therapy
Psychotherapy(Cognitive-Behavioral Therapy, Interpersonal Therapy)Changes in attitude toward sleep (NYT editorial, 11/23/2013)
Other(diet, exercise, etc.)
II. More Characteristics of Major DepressionA. Untreated episodes of major depression usually last from 7 - 14 months.B. Major depression is a recurring disorder, usually worsening with age if untreated.C. The reported incidence of depression is 3 times higher in women than in men.
However, men show irritability in analogous situations.
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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.”
S. E. Hyman, E. Nestler, R. Malenka, 2008Molecular Neuropharmacology : A Foundation for Clinical Neuroscience, 2nd Edition
How do psychiatric drugs work?
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Next lecture
SSRIs bind tightly to, and stabilize, intermediate state(s) of the serotonin transporter.
Cao, Li, Mager, Lester. J Neurosci 19979
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)
B. Norepinephrine or noradrenaline
C. Dopamine
5-HT
NE
DA
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Possible downstream consequences of changed regulation of serotonergic systems:1) Short term derangement of modulation of synaptic strength and possibly also
of neuronal intrinsic properties.2) Long term change in modulation of neuronal gene expression.
Most experts re-state this, “How does blockade of serotonin re-uptake relieve depression?”
How does the SSRI-SERT Interaction relieve depression?
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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.
To most experts, success of serotonin-selective reuptake inhibitors (SSRIs) Implies participation of serotonergic systems in the brain . . .
. . . but nonspecifically
Midbrain Raphe nuclei
Feldman et al., Principles of Neuropsychopharmacology, ©Sinauer Associates, 1997
Rostral System
Caudal System
~ 15 serotonin receptor genes, only one serotonin transporter gene
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Two Serotonergic Fiber Types in the Forebrain Demonstrated by Immunocytochemical Labeling for Serotonin
D-System - small arrowsM-System - large arrows
10 µm
from Tork, Ann. N.Y. Acad. Sci., 1990 13
“Nearly” cell-autonomous actions of SSRI antidepressant treatment
Kellermann group14
Postulated Role for Brain-derived Neurotrophic Factor (BDNF) in Depression
From Berton and Nestler, Nature Reviews Neuroscience, 7: 137, 2006
SSRIs enhance increase expression of BDNF mRNA and protein.
This, in turn ameliorates some of the structural effects of major depression.
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16Samuels & Hen, Eur J. Neurosci, 2011
How do antidepressants cause adult neurogenesis?
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
Noradrenergic Systems in the CNS
Locus coeruleus
from Feldman et al., Principles of Neuropsychopharmacology, Sinauer, 1997
Some Antidepressants are “SNRIs”, Serotonin/Noradrenaline Reuptake Inhibitors
Most experts ask, “How does blockade of noradrenaline reuptake relieve depression?”
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How does acute ketamine produce antidepressant effects within 2 hr?
Monteggia & Duman groups suggest . . .
(1) involve BDNF synthesis & release, (2) occur in the dendrites,(3) require protein synthesis, (4) do not require gene activation.
The effects
NMDA Receptor
kinases↓
BDNFsecretion
BDNF mRNA
BDNF↑
Dendritic Golgi
Outside-in Ca2+
+
Decreased Ca2+ flux
DendriticER
NH2+
H3C
H+
O
Cl
NHH3C
O
Cl
Perhaps . . .
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Inside-out
BDNFsecretion
?
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Bipolar Disease
1. Clinical description
2. Genetics
3. Possible causes
4. Heterozygote advantage?
5. Therapeutic approaches
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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.
1. Clinical description, based on DSM-5.
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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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DSM-4 bipolar diagnoses have persisted in DSM-5
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No single gene causes bipolar disorder.
Data for concordance among twins in bipolar disorder:
“narrow”
definition
“broad”
definition
monozygotic
(n = 55)79% 97%
monozygotic,
reared apart
(n = 12)
69%
dizygotic
(n = 52)24% 38%
2. Genetics
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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.
3. Possible causes of bipolar disease
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Touched 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 Jamison
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from 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)
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1887 1887-88
Vincent Van Gogh 1853-1890750 paintings; 1600 drawings; 700 letters
Life 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
1886
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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
Early 1889
Dr. GachetJune 1890
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July 1890
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People with bipolar disorder are often fascinating in the early stages.
We provided examples from the arts,
Also, people with bipolar disorder seem to be over-represented in many high-functioning environments, including among students and faculty at prestigious college campuses.
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://counseling.caltech.edu/
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0 2 4 6 8 10 12
Percent of Total
Disease Burden by Illness - DALY United States, Canada and Western Europe, 2008
15-44 year olds
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 2 4 6 8 10 16
Source: WHO – World Health Report
Disability Adjusted Life Years
(incomprehensible units)
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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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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
Surgical and electrical intervention
Therapeutic approaches to bipolar disorder
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Therapeutic approaches to bipolar disorder
Drugs for BD
Li+ ion
Therapeutic effects begin in ~ 5 d, require several wk.
Li+ is quite poisonous at higher doses.
Psychiatrists state that It is usually a very bad idea to treat bipolar disorder with antidepressants.
This can cause a manic episode.
Valproic acid and other anticonvulsants
These also require several wk for full effects.
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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, and Li+ would compete for Na+ binding sites.
How does Li+ act?
Three exemplar patients in the early days of Li+
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Bi / CNS 150
End of Lecture
Henry Lester’s office hours today 1:15 – 2 PM, Red Door
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.
Mood disorders also involve dysfunction of many brain areas
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