1. Neurobiological Causes and Pharmacological Intervention
Mood Disorders
Neurobiological Causes and Pharmacological Intervention

2. 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?

3. 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

4. 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?

5. 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

6. Genetic influence on depression
Risk of developing unipolar depression increases with multiple family members with depression

7. 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)

8. 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

9. Anxiety Disorders Panic Attack Agoraphobia
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

10. Depression Subtypes Melancholic Atypical
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

11. 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?

12. 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?

13. Hypothalamic-Pituitary-Adrenal Axis
Hypothalamus
PFC
Hippocampus
(glucocorticoid receptors)
CRH -
Pituitary
ACTH NE
Adrenal cortex
Cortisol

14. Hypothalamic-Pituitary-Adrenal Axis
Hypothalamus
PFC
Hippocampus
(glucocorticoid receptors)
CRH -
Pituitary
ACTH
5HT
Adrenal cortex
Cortisol

15. 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

16. 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

17. 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
lethargic, fatigued, hyperphagic, hypersomnic,

18. Animal Models of Depression
Diathesis-Stress concept
Antidepressant drugs screened on the following preclinical paradigms:
Behavioral Despair/Learned Helplessness
HPA transgenic
Olfactory Bulbectomy

19. 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

20. Action of Antidepressant Drugs on CNS
Effects on the following
Monoamine neurotransmitters
Norepinephrine (noradrenaline): NE
Dopamine: DA
Serotonin (5-hydroxytryptamine): 5-HT

21. 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)

22. 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)

23. Synaptic Effects

24. drug inactivates monoamine oxidases

25. Synaptic Transmission: the Synapse
normal reuptake of NT substance from synaptic cleft to presynaptic neuron
inhibition of reuptake pumps: more NT in synapse

26. 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

27. MAO metabolizes serotonin in the presynaptic neuron

28. Serotonergic Distribution in the Brain

29. Synthesis of Norephinephrine:

30. Noradrenergic distribution in the brain
Locus
coeruleus

31. 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?

32. 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

35. The receptor hypothesis of antidepressant action
Alterations in receptor expression
Introduction of drug therapy
RECEPTOR
Clinical effect
neurotransmitter
High level
or mood
Low level

36. 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

37. 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

38. 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

39. Relationship of SSRI’s to BDNF levels and neuronal function

40. Interaction of stress, corticosteriods and depression:

41. Side effects MAO inhibitors Tricyclic Antidepressants
dietary restrictions –
serotonin syndrome-
Tricyclic Antidepressants
cardiac arrhythmias, respiratory depression
serotonin syndrome
severe sedation

42. Side effects Blockade of NE uptake Blockade of 5-HT 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

43. 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

44. Efficacy subtypes MAOi TCA Heterocyclics
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