Mood Disorders

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Mood Disorders

• Neurobiological Causes and Pharmacological
  Intervention

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Key issues and questions

• Target of antidepressant or mood-stabilizing
  drugs
• 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?

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Mood Disorders

• The structure of mood disorders
• Normal affective responses on a continuum-brief
  in duration vs. dominant and sustained
• Unipolar Mood Disorder
• A state of depression (or mania)
• Mostly depression
• Bipolar Mood Disorder
• Alternation between depression and mania
• Subtypes
• Bipolar I (full manic episodes)
• Bipolar II (hypomanic episodes)
• Cyclothymia (moodiness up and down)
• Anxiety Disorders

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Nature of Unipolar Mood Disorders

• Depressive Disorders
• Melancholic depression (40-60)-symptoms
• Atypical depression (15)-symptoms
• Dysthymia-symptoms
• 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?

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Facts Statistics

• 7-8 lifetime prevalence
• Usually recurrent
• Major Depression or Dysthymia Females gt Males
• 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
• Similar in children and adults, 80 concordance
  in monozygotic twins

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Genetic influence on depression
Risk of developing unipolar depression increases
with multiple family members with depression
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Behaviors addressed by antidepressant drug use

• DSM IV Criteria 1-4 for major depressive episode
  (5/9)
• Persistence of depressed mood nearly every day (gt
  2 weeks)
• Diminished interest or pleasure, eg., loss of
  libido (anhedonia and vegetative)
• Weight fluctuations and loss of appetite
  (vegetative)
• Insomnia or hypersomnia (vegetative)

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Specific behavioral changes that need to be
targeted by antidepressant drugs

• DSM IV Criteria 5-9 for Depression
• Psychomotor agitation or retardation (feelings of
  restlessness or being slowed down)
• Fatigue or loss of energy
• Worthlessness guilt
• Inability to think, concentrate or act decisively
  
• Preoccupation with thoughts of death or suicidal
  ideation

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Anxiety Disorders

• Panic Attack
• 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
• Agoraphobia
• Panic Disorder w/o agoraphobia (GAD)
• Social Anxiety Disorder
• fear in social situations
• exposure to social situations provokes anxiety
• social situations avoided
• distress interferes with normal routine
• Obsessive Compulsive Disorder

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Depression Subtypes

• Melancholic
• anxious, loss of pleasure in all activities
• dread future
• insomnia, early morning awakening
• loss of appetite
• symptoms worst in the morning
• excessive inappropriate guilt

• Atypical
• 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

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Physiological Correlates

• Neurochemical changes
• reduced or elevated norepinephrine levels
• differences in the number of serotonin receptors
  - may be regulated by dysfunction in serotonin
  activity
• biogenic amine hypothesis

• Dysfunction in cortisol secretion

what is the basis of this elevation in cortisol?
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Stress Response

• CRF-corticotropin releasing factor
• 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?

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Hypothalamic-Pituitary-Adrenal Axis
-
Hypothalamus
-
PFC
Hippocampus (glucocorticoid receptors)
CRH
-
Pituitary
ACTH
NE
Adrenal cortex
Cortisol
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Hypothalamic-Pituitary-Adrenal Axis
-
Hypothalamus
-
PFC
Hippocampus (glucocorticoid receptors)
CRH
-
Pituitary
ACTH
5HT
Adrenal cortex
Cortisol
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Dexamethasone Suppression Test-not a diagnostic
tool

• 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

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Dexamethasone Suppression Test-continued

• 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

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Melancholic vs. Atypical Depression

• Melancholic hypercortisolism may explain
  symptoms of depression
• impaired feedback loop
• hyperactive, anxiety, insomnia, loss of appetite
• 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

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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

• Evidence against
• response to SSRIs 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

• Effects on the following
• Monoamine neurotransmitters
• Norepinephrine (noradrenaline) NE
• Dopamine DA
• Serotonin (5-hydroxytryptamine) 5-HT

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Treatment of Depression

• Pharmacotherapy
• Tricyclic antidepressants (TCA)
• Heterocyclic or 2nd and 3rd generation
• Monoamine oxidase inhibitors (MAOI)
• Selective serotonin reuptake inhibitors (SSRI)
• Non-Pharmacologic
• Electroconvulsive therapy (ECT)

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Action of Antidepressant Drugs on CNS

• Increase synaptic neurotransmitter levels
• Impair natural mechanisms for reducing monamine
  actions
• Reuptake pumps
• Enzymatic inactivation (MAO)
• Autoreceptors
• Alter receptor levels (after repeated use)

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Synaptic Effects
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drug inactivates monoamine oxidases
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Synaptic Transmission the Synapse
normal reuptake of NT substance from synaptic
cleft to presynaptic neuron
inhibition of reuptake pumps more NT in synapse
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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
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Serotonergic Distribution in the Brain
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Synthesis of Norephinephrine
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Noradrenergic distribution in the brain
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Receptor Subtypes (transmembrane proteins)

• 5-HT
• nine know receptor subtypes
• grouped into class 1, 2 and 3
• 5-HT1a is both presynaptic (autofeedback loop)
  and postsynaptic
• NE
• acute use vs. chronic use
• altered sensitivity/number receptors
• which types?

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Classes of Antidepressant Therapy

• MAOi
• TCA
• Also used for anxiety disorders and pain
• Panic and phobia (MAO)
• Obsessive-Compulsive Disorder (TCA)
• Pain (TCA)
• SSRI (selective serotonin reuptake inhibitors)
• anxiety
• OCD clomipramine, fluvoxamine, paroxetine,
  sertraline

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The receptor hypothesis of antidepressant action
Alterations in receptor expression
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Receptor Subtypes in Depressed Patients

• Not all studies find an association
• Increased number if 5HT1a neurons
• increased inhibition of 5HT transmission
• Altered number of 5HT2 receptors
• Presynaptic and postsynaptic
• Changes match chronic stress animal model

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Therapeutic Lag

• Theory improved mood following SSRI treatment
  corresponds to augmented serotonergic
  transmission
• this enhanced 5-HT activity is partially due to
  autoreceptor blockade
• New therapy combine SSRI with 5HT1a antagonist
• Problems antidepressant efficacy correlated
  with postsynaptic 5HT1a receptor affinity

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The altered gene (s) hypothesis of antidepressant
action

• 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)
• BDNF does not appear to be associated with disease

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Relationship of SSRIs to BDNF levels and
neuronal function
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Interaction of stress, corticosteriods and
depression
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Side effects

• MAO inhibitors
• dietary restrictions
• serotonin syndrome-
• Tricyclic Antidepressants
• cardiac arrhythmias, respiratory depression
• serotonin syndrome
• severe sedation

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Side effects

• Blockade of NE uptake
• tachycardia
• tremors
• Blockade of 5-HT uptake
• GI disturbances
• interactions with l-tryptophan
• increase/decrease in anxiety (dose dependent)
• sexual dysfunction
• Blockade of histamine receptors
• potentiation of depressant drugs
• sedation
• weight gain
• hypotension
• Blockade of Ach receptors
• blurred vision,
• drymouth
• constipation

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Efficacy of Antidepressant Therapy

• 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

• MAOi
• atypical and refractory (fail to respond to other
  types of medications)

• TCA
• melancholic depression
• not effective in reactive depression

• SSRI
• mild to moderate depression
• better tolerated than TCAs
• do not take with MAOi

• Heterocyclics
• use when severe insomnia is present
• useful in elderly