Transcript Document

Mood Disorders
Neurobiological Causes and
Pharmacological Intervention
Key issues and questions
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Target of antidepressant or mood-stabilizing drugs:
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People with Mood Disorders!
What constitutes a “Mood Disorder”?
What is the neurochemical basis of clinically significant
mood change?
What is the neurochemical basis of changes produced by
drugs that treat mood disorders?
How well do the drugs work?
Mood Disorders
The structure of mood disorders
Normal affective responses on a continuum-brief in
duration vs. dominant and sustained
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Unipolar Mood Disorder
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A state of depression (or mania)
Mostly depression
Bipolar Mood Disorder
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Alternation between depression and mania
Subtypes
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Bipolar I (full manic episodes)
Bipolar II (hypomanic episodes)
Cyclothymia (“moodiness” – up and down)
Anxiety Disorders
Nature of Unipolar Mood
Disorders
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Depressive Disorders
Melancholic depression (40-60%)-symptoms
 Atypical depression (~15%)-symptoms
 Dysthymia-symptoms
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If there are different levels of depression, and
different types, is the underlying neurochemical
problem different in nature or degree?
Therefore, are pharmacological therapies
different for each subtype?
Facts & Statistics
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7-8% lifetime prevalence
Usually recurrent
Major Depression or Dysthymia: Females > Males
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Mean age of onset: 25 yrs
~50% concordance for monozygotic twins
Length of episode varies
Remission is common
Risk of suicide
Bipolar Disorders: Females = Males
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Similar in children and adults, ~80% concordance in
monozygotic twins
Genetic influence on depression
Risk of developing unipolar depression increases with multiple family
members with depression
Behaviors addressed by antidepressant
drug use
DSM IV Criteria 1-4 for major depressive episode
(5/9):
1. Persistence of depressed mood nearly every
day (> 2 weeks)
2. Diminished interest or pleasure, eg., loss of
libido (anhedonia and vegetative)
3. Weight fluctuations and loss of appetite
(vegetative)
4. Insomnia or hypersomnia (vegetative)
Specific behavioral changes that need to
be targeted by antidepressant drugs
DSM IV Criteria 5-9 for Depression
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Psychomotor agitation or retardation (feelings of
restlessness or being slowed down)
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Fatigue or loss of energy
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Worthlessness; guilt
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Inability to think, concentrate or act decisively
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Preoccupation with thoughts of death or suicidal
ideation
Anxiety Disorders
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Panic Attack
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Agoraphobia
Panic Disorder w/o agoraphobia (GAD)
Social Anxiety Disorder
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period of intense fear or discomfort in which the following occurs:
sweating, trembling, choking, chest pain, nausea, dizziness, fear of losing
control, derealization or depersonalization, chills or hot flashes
fear in social situations
exposure to social situations provokes anxiety
social situations avoided
distress interferes with normal routine
Obsessive Compulsive Disorder
Depression Subtypes
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Melancholic
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anxious, loss of pleasure in all
activities
dread future
insomnia, early morning
awakening
loss of appetite
symptoms worst in the morning
excessive inappropriate guilt
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Atypical
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lethargic, fatigued
increase in appetite
symptoms best in morning
extreme sensitivity to
environmental stimuli
(perceived or actual/positive or
negative)
Dysthymia
 symptoms of depression chronic but less severe
Physiological Correlates
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Neurochemical changes
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reduced or elevated
norepinephrine levels
differences in the number
of serotonin receptors may be regulated by
dysfunction in serotonin
activity
“biogenic amine
hypothesis”
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Dysfunction in cortisol
secretion
what is the basis of this elevation in
cortisol?
Stress Response
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CRF-corticotropin releasing factor
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orchestrates behavioral/endocrine/immune response to
stress-interaction with NE
interactions with brain areas responsible for fear reaction,
transforming experiences into feeling and memory system
CRF administered to laboratory rats results in symptoms of
“depression”
excessive levels may explain behavioral symptoms of sleep
disturbances, appetite changes, psychomotor symptoms
CRF has two receptor subtypes-novel targets of
antidepressant therapy?
Hypothalamic-Pituitary-Adrenal Axis
Hippocampus
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Hypothalamus
PFC
(glucocorticoid receptors)
CRH
Pituitary
NE
ACTH
Adrenal cortex
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Hypothalamic-Pituitary-Adrenal Axis
Hippocampus
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Hypothalamus
PFC
(glucocorticoid receptors)
CRH
Pituitary
5HT
ACTH
Adrenal cortex
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Dexamethasone Suppression Testnot a diagnostic tool
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Dexamethasone – synthetic
glucocorticoid
Reduces ACTH production
“normal” patients show
reduction (suppression) in
cortisol levels in blood
depressed patients do not
abnormal negative feedback
loop-most prominent in
melancholic depression
Dexamethasone Suppression Test-continued
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Some, but not all, depressed
individuals show lack of
dexamethasone suppression of
cortisone
Marginal differences between
“suppressors” and “nonsuppressors”
in response to pharmacotherapy
Some depressed patients, despite
elevated cortisol, show no problems
with adrenal or pituitary glands
Melancholic vs. Atypical Depression
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Melancholic: hypercortisolism may explain
symptoms of depression
impaired feedback loop
 hyperactive, anxiety, insomnia, loss of appetite
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Atypical: CRF does not stimulate cortisol
response
impaired feedback loop
 lethargic, fatigued, hyperphagic, hypersomnic,
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Animal Models of Depression
Diathesis-Stress concept
Antidepressant drugs screened on the
following preclinical paradigms:
 Behavioral Despair/Learned Helplessness
 HPA transgenic
 Olfactory Bulbectomy
Biogenic Amine Hypothesis
Evidence for:
altered serotonin and
norepinephrine levels in
depressed and suicide victims
(blood and CSF)
drugs which reduce NE/5-HT
result in depression/suicidal
tendencies (reserpine)
drugs which elevate serotonin
and NE (MAOi,
amphetamine) also alleviate
symptoms
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Evidence against:
response to SSRI’s is slow
effect on serotonin reuptake is
similar, but between-patient
variability
melancholic depressed patients
show high NE - may be
driving by high CRF levels
answer: not a simple
relationship
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Action of Antidepressant Drugs
on CNS
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Effects on the following
Monoamine neurotransmitters
Norepinephrine (noradrenaline): NE
 Dopamine: DA
 Serotonin (5-hydroxytryptamine): 5-HT
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Treatment of Depression
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Pharmacotherapy
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Tricyclic antidepressants (TCA)
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Heterocyclic or 2nd and 3rd generation
Monoamine oxidase inhibitors (MAOI)
 Selective serotonin reuptake inhibitors (SSRI)
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Non-Pharmacologic
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Electroconvulsive therapy (ECT)
Action of Antidepressant Drugs
on CNS
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Increase synaptic neurotransmitter levels
Impair natural mechanisms for reducing
monamine actions
Reuptake pumps
 Enzymatic inactivation (MAO)
 Autoreceptors
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Alter receptor levels (after repeated use)
Synaptic Effects
drug inactivates
monoamine oxidases
Synaptic Transmission: the Synapse
normal
reuptake of
NT substance
from synaptic
cleft to
presynaptic
neuron
inhibition
of
reuptake
pumps:
more NT
in
synapse
Serotonin/Permissive Hypothesis:
Serotonin as “inhibitory” neurotransmitter
 Inhibit rage – self rage (suicide?)
 Mood disorders: release of inhibitory damper
serotonin norepinephrine = mania
 Balance of 5HT and NE regulates mood
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MAO
metabolizes
serotonin in
the
presynaptic
neuron
Serotonergic Distribution in the Brain
Synthesis of Norephinephrine:
Noradrenergic distribution in the brain
Locus
coeruleus
Receptor Subtypes
(transmembrane proteins)
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5-HT
nine know receptor subtypes
 grouped into class 1, 2 and 3
 5-HT1a is both presynaptic (autofeedback loop) and
postsynaptic
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NE
acute use vs. chronic use
altered sensitivity/number receptors
 which types?
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Classes of Antidepressant Therapy:
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MAOi
TCA
Also used for anxiety disorders and pain
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Panic and phobia (MAO)
Obsessive-Compulsive Disorder (TCA)
Pain (TCA)
SSRI (selective serotonin reuptake inhibitors)
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anxiety
OCD – clomipramine, fluvoxamine, paroxetine, sertraline
The receptor hypothesis of
antidepressant action
Alterations in
receptor expression
RECEPTOR
neurotransmitter
Clinical effect
Introduction of drug
therapy
High level
or mood
Low level
or mood
Receptor Subtypes in Depressed
Patients
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Not all studies find an association
Increased number if 5HT1a neurons
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increased inhibition of 5HT transmission
Altered number of 5HT2 receptors
Presynaptic and postsynaptic
Changes match chronic stress animal model
Therapeutic Lag
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Theory: improved mood following SSRI
treatment corresponds to augmented
serotonergic transmission
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this enhanced 5-HT activity is partially due to
autoreceptor blockade
New therapy: combine SSRI with 5HT1a
antagonist
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Problems: antidepressant efficacy correlated with
postsynaptic 5HT1a receptor affinity
The altered gene (s) hypothesis
of antidepressant action
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Excess neurotransmitter leads to alterations in:
 Genes that code for receptors
 receptor expression
 sensitivity of receptors
 differences in expression in pre- and post-synaptic receptors
 upregulate or sensitize 5HT1a in hippocampus
 desensitize 5HT2 receptors elsewhere in the brain
 Genes that serve to protect and/or facilitate neuronal function (eg.,
brain derived neurotrophic factor)
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BDNF does not appear to be associated with disease
Relationship of SSRI’s to BDNF levels and neuronal function
Interaction of stress, corticosteriods and
depression:
Side effects
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MAO inhibitors
dietary restrictions –
 serotonin syndrome
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Tricyclic Antidepressants
cardiac arrhythmias, respiratory depression
 serotonin syndrome
 severe sedation
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Side effects
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Blockade of NE uptake
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Blockade of 5-HT uptake
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GI disturbances
interactions with l-tryptophan
increase/decrease in anxiety (dose dependent)
sexual dysfunction
Blockade of histamine receptors
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tachycardia
tremors
potentiation of depressant drugs
sedation
weight gain
hypotension
Blockade of Ach receptors
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blurred vision,
drymouth
constipation
Efficacy of Antidepressant Therapy
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Use of a placebo or active control (randomized,
controlled clinical trial) or any control
Consistency of study populations
Efficacy of one group over another?
Treatment guidelines
dose, duration, compliance
 starting dose-enduring response
 patient compliance-adverse events
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Efficacy subtypes
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MAOi
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atypical and refractory
(fail to respond to other
types of medications)
SSRI
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mild to moderate depression
better tolerated than TCAs
do not take with MAOi
TCA
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melancholic depression
not effective in reactive
depression
Heterocyclics
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use when severe insomnia is
present
useful in elderly