Transcript Lecture-27-2012-Bi

Bi / CNS 150
Lecture 27
Monday December 2, 2012
Mood Disorders
Henry Lester
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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).
In order to maximize student response, you may wish to announce these dates to your
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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
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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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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
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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.
(“Anhedonia”)
From Berton and Nestler, Nature Reviews
Neuroscience, 7: 137, 2006
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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.)
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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
Next lecture
antipsychotic effects.”
S. E. Hyman, E. Nestler, R. Malenka, 2008
Molecular Neuropharmacology : A Foundation for Clinical Neuroscience, 2nd Edition
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SSRIs bind tightly to, and stabilize, intermediate state(s) of the serotonin transporter.
Cao, Li, Mager, Lester. J Neurosci 1997
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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
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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
of neuronal intrinsic properties.
2) 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
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Two Serotonergic Fiber Types in the Forebrain Demonstrated by
Immunocytochemical Labeling for Serotonin
10 µm
D-System - small arrows
M-System - large arrows
from Tork, Ann. N.Y. Acad. Sci., 1990
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“Nearly” cell-autonomous actions of SSRI antidepressant treatment
Kellermann group
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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
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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
Most experts
ask,
Noradrenergic
Systems
in the CNS
“How does blockade of noradrenaline reuptake relieve depression?”
Locus coeruleus
from Feldman et al., Principles of Neuropsychopharmacology, Sinauer, 1997
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Acute low-dose ketamine produce antidepressant effects within 2 hr?
How?
The effects
(1) involve BDNF synthesis & release,
(3) require protein synthesis,
(2) occur in the dendrites,
(4) do not require gene activation.
Monteggia & Duman groups suggest . . .
Outside-in
NMDA Receptor
Ca2+
BDNF
secretion
Decreased
Ca2+ flux
Dendritic
Golgi
kinases↓
Dendritic
ER
BDNF↑
BDNF
mRNA
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Bipolar Disease
1. Clinical description
2. Genetics
3. Possible causes
4. Heterozygote advantage?
5. Therapeutic approaches
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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)
79%
97%
monozygotic,
reared apart
(n = 12)
69%
dizygotic
(n = 52)
24%
38%
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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
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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)
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People with bipolar disorder are often fascinating in the early stages.
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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
1886
1887
1887-88
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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
Dr. Gachet
June 1890
Early 1889
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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
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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
←Next lecture
Schizophrenia
Iron-deficiency anemia
Bipolar affective disorder
Hearing loss, adult onset
HIV/AIDS
Chronic OPD
Osteoarthritis
Road traffic accidents
00
22
44
66
88
10
10
16
12
Percent of Total
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
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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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