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Bi / CNS 150

Lecture 27

Monday December 2, 2013

Mood Disorders

Henry Lester

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Review Session here Thursday 12/ 5 7 PM No sections this week! Problem set 6 is due Friday 12/6, 11 AM

Final exam posted Friday 12/6

Final exam is due Friday 12/13 4:30 PM.

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

How?

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

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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 27

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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