Mood Disorders Neurobiological Causes and Pharmacological Intervention
Mood Disorders Neurobiological Causes and Pharmacological Intervention
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?
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
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?
Facts & Statistics
7-8% lifetime prevalence
Usually recurrent
Major Depression or Dysthymia: Females > 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
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):
Persistence of depressed mood nearly every day (> 2 weeks)
Diminished interest or pleasure, eg., loss of libido (anhedonia and vegetative)
Weight fluctuations and loss of appetite (vegetative)
Insomnia or hypersomnia (vegetative)
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
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
Depression Subtypes
Dysthymia
symptoms of depression chronic but less severe
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)
Physiological Correlates
what is the basis of this elevation in cortisol? 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
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?
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
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
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,
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 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
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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