Anxiety & Depression

BMS2 Neuroscience2

Mental Health Conditions Types of Anxiety Disorder

• Anxiety Disorders • Multiple types

• Depression
• General anxiety disorder
• Bipolar Disorder
• Somatic & autonomic effects
• restlessness / agitation, tachycardia, sweating, sleep
disturbance
Anxiety Disorder
“An inappropriate, or excessive, anticipatory manifestation of the fear
response to a stressor“ • Others
• defensive behaviours • Phobic anxiety
• autonomic reflexes • Panic disorder
• corticosteroid secretions
• negative emotions

Hypothalamic-Pituitary-Adrenocortical Major Anxiolytic Drugs

(HPA) axis 1. Benzodiazepines e.g. diazepam, nitrazepam

• Mechanism of Action
• GABAA receptor
AMYGDALA
• binds to allosteric site
• Useful effects
Corticotropin-releasing
1. reduction in anxiety and aggression
factor
(+) 2. sleep inducing
CRF ANTERIOR
CORTEX HYPOTHALAMUS
(-)
paraventriular nucleus (+) PITUITARY
• Problems
Adrenocorticotropic
(-) • Sedation
hormone ACTH
• Acute overdose → profound sedation
HIPPOCAMPUS cortisol (+) • Long-term use
ADRENAL • Tolerance
GLAND • Dependence
• withdrawal

Novel anxiolytics Major Depressive Disorder

2. 5-HT1A partial agonists
• Buspirone • ∼ 20% experience during lifetime
- slow to act (1-2 weeks) • Symptoms
• Adverse effects • misery, despair, loss of motivation, appetite, suicidal thoughts,….
• better than BZDs • Reactive (75%) vs endogenous (25%)
• no sedation/motor impairment

• The Monoamine Theory of Depression

Other drugs • “depression is due to hypoactivity at monoaminergic (NA and 5-HT)
synapses in the brain”

• β-Adrenoceptor Antagonists • Evidence for:

• reduce somatic symptoms of anxiety • ADs ↑ MA in brain rapidly
• used for “situational phobias” • Evidence against:
• AD drugs eg SSRI • ADs take >1-3 weeks to work
•amphetamine & cocaine

Reading: Bear et al; Rang & Dale

Dr A J Cooper Castren: Is Mood chemistry?
A.J.Cooper@bham.ac.uk Nature (2005) 6:241-246
Anxiety & Depression
BMS2 Neuroscience2

Central Monoaminergic Synapse

Treatment of Depression
• Psychotherapy
• [electroconvulsive therapy (ECT) ] Presynaptic Terminal
• Antidepressant drug classes:
1. Monoamine oxidase inhibitors (MAOIs) biosynthesis
2. Tricyclic antidepressant (TCAs) T
3. Selective re-uptake inhibitors (SSRIs &SNRIs) mitochondria storage
4. newer antidepressants vesicle
T
metabolism

re-uptake release

postsynaptic
receptor

Postsynaptic Neurone

Monoamine Oxidase Inhibitors Tricyclic Antidepressants

• Eg amitriptyline, imipramine
• Immediate effect = euphoria • Slow onset
• AD action - 4 weeks
• Mechanism
• Examples
• moclobemide • 5-HT/NA reuptake inhibition
• reversible binding • Unwanted effects
• MAO-A selectivity • Anti-muscarinic
• Unwanted effects of MAOIs • Sedative (H1 antagonism)
• “cheese reaction” • Overdose
• unmetabolised tyramine from diet
Selective Serotonin Re-uptake Inhibitors (SSRIs)
• displaces NA from vesicles
• Anti-muscarinic effects • Examples
• α1 antagonism • Fluoxetine (Prozac®), Paroxetine (Seroxat®),
• Mechanism
• 2-4 weeks delay to clinical effect
• Unwanted effects
• < MAOIs & TCAs

Do AD drugs work?
New theory – network hypothesis
• ∼30% patients don’t respond
• Trial and error required
• Depression → ↑[CRF] & [cortisol] in CSF
?Hyperactivity / sensitisation of the neuroendocrine stress response
→ depression? Future developments
• Mechanism? • Linking MA and neuroendocrine dysfunction
• Chronic stress • Requires
→ ↓ glucocorticoid receptors in hippocampus ↑understanding of neurobiology
→ ↓ neurogenesis & neuroplasticity • Adaptations?
• AD → ↑MA → ↑neurogenesis/plastiocity → restore network • Neurogenesis/network remodelling
• Developing new drugs?
• Difficult to evaluate efficacy
• Animal models
• clinical trials difficult to conduct
• Slow onset of action
• Mood is variable
• High placebo effect

Reading: Bear et al; Rang & Dale

Dr A J Cooper Castren: Is Mood chemistry?
A.J.Cooper@bham.ac.uk Nature (2005) 6:241-246