LECTURE 17 - anxiety and depression Flashcards
What are the 3 main types of mental health conditions?
- anxiety disorders
- depression
- bipolar
last 2 are disorders of MOOD or ‘affect’ e.g. affective disorders
- not disorders of thought (those are psychoses)
What is anxiety disorder?
‘An inappropriate, or excessive, anticipatory manifestation of the fear response, often to a stressor’
- defensive behaviours
- autonomic reflexes
- corticosteroid secretions
- -ve emotions
- -> interference with normal life
What are the different types of anxiety disorder?
General anxiety disorder
- somatic & autonomic effects: restlessness/ agitation, tachycardia, sweating, sleep disturbance
Others
- Phobic anxiety
- Panic disorder
=> useless to clump them together as psychopathology is not the same
What is the Hypothalamic-Pituitary-Adrenocortical (HPA) axis?
Hypothalamus releases CRF (corticotropin-releasing factor) –> anterior pituitary releases ACTH –> adrenal gland –> releases cortisol to inhibit hypothalamus releasing CRF (-ve feedback, turns itself down)
What happens to the HPA axis in an anxiety disorder?
Anticipatory (stressor not necessary)
Could be due to
- amygdala
- hippocampus
Upsetting normal balance of activity affects -ve feedback loop
Balance between amygdala and hippocampus somehow causes hyperactivity - unsure how
How are anxiety disorders treated?
- psychological treatment e.g. phobias, neuroplastic change can sometimes be reversed
- pharmacological interventions- very diverse
What are benzodiazepines?
- anti-anxiety drugs
- e.g. diazepam, nitrazepam
How do benzodiazepines work?
- target GABAa receptors
- binds to allosteric (modulatory) sites
- increased GABA infinity –> increased Cl-
- hyperpolarisation due to Cl- = less activation
- however there are GABAa receptors everywhere in the brain so drugs may not affect place we want it to
What are the useful effects of benzodiazepines?
- reduction in anxiety and aggression - anxiolytic
- sleep inducing - hypnotic
=> pharmacokinetic properties of drugs important, want a long duration of action
diazepam and flurazepam last a long time and have a high metabolite 1/2 life
What are the problems with benzodiazepines?
- sedation
- acute overdose
- -> profound sedation
- -> with alcohol = serious respiratory depression
Long term use
- tolerance (‘tissue tolerance’), receptors stop responding how they used to
- dependence: leads to withdrawal –> increased anxiety, tremor, seizure, insomnia, depression
may be long-lasting therefore
What are novel anxiolytics?
5-HT(1A) partial agonists
- busprione, precise mechanism unclear, slow to act (1-2 weeks)
- assume some change in circuitry occurs in this time
effects of busprione
- no sedation/ motor impairment
- non-addictive, without withdrawal effect
What other drugs can be used to treat anxiety disorders?
B-adrenoceptor antagonists
- reduces somatic symptoms of anxiety e.g. tremor, palpitations, sweating etc
- used for situational phobias e.g. stage fright
- works in periphery so alleviates symptoms not cause
Anti-Depressant (AD) drugs e.g. serotonin-selective reuptake inhibitors (SSRI)
=> questions if there is a link between anxiety and depression
What is Major Depressive Disorder (MDD)?
- ~20% experience during lifetime
- Symptoms
- misery, despair, loss of motivation, appetite, suicidal thoughts
- reactive (75%) e.g. bereavement vs endogenous (25%), something occurring in circuity
- neurobiology not understood as well as neuropharmacology
What is the history of MDD?
Monoamine Theory of Depression: depression is due to hypoactivity at monoaminergic (NA and 5-HT) synapses in brain
Evidence for:
- ADs increase monoamine levels in brain rapidly in some animals
Evidence against:
- ADs take >1-3 weeks to work in people
- amphetamine and cocaine affect monoamines but neither are ADs
How is MDD treated?
- psychotherapy
- electroconvulsive therapy (ECT)
- antidepressant drug classes:
1. Monoamine oxidase inhibitors (MAOIs)
2. Tricyclic antidepressants (TCAs)
3. SSRIs
4. Newer antidepressants
Monoamine oxidase inhibitors (MAOIs)
- immediate effect = euphoria
- true AD action - 4 weeks
- examples: Moclobemide - reversible binding, MAO-A selectively increases 5-HT
- unwanted effects:
- unmetabolsited tyramine from diet (e.g. fermented things such as red wine, cheese, yeast)
- displaces NA from vesicles in sympathetic neurones (e.g. increased heart rate)
- anti-muscarinic effects
- alpha-1 antagonism
Tricyclic antidepressants
- e.g. amitriptyline, imipramine
- slow onset
Mechanism - 5-HT/NA reuptake inhibition
Unwanted effects - anti-muscarinic
- sedative (H1 antagonism)
SSRIs
- e.g. fluoxetine (Prozac), paroxetine (Seroxat), Citalopram
Mechanism - immediate increase in synaptic levels 5-HT
- 2-4 weeks delay due to clinical effect
Unwanted effects: - better than MAOIs and TCAs
- age of patients impacts how useful they are and side effects
Newer drugs
- various uptake/ receptor mediated effects for 5-HT, NA, dopamine
- but there is still a delay to action
What is the network hypothesis of depression?
- new theory to understand MDD
- MDD –> increased [CRF] and [cortisol] in CSF
- reversed by successful AD
- shows some link between 5-HT and HPA axis
- suggests somehow hyperactivity/ sensitisation of neuroendoricne stress response can lead to depression
Perhaps chronic stress –> anxiety disorder –> depression
What is the mechanism of the network hypothesis?
Chronic stress
- changes in hippocampus
- -> decreased glucocorticoid receptors and BDNF (important for synapse formation)
- -> decreased neurogenesis (new neurone production) and neuroplasticity
AD changes monoamine which restores ability for neuroplasticity and neurogenesis
- could explain delay in effect as restoration and formation of new neurones has to happen
Do AD drugs work?
- ~30% of patients don’t respond
- trial and error required
- pharmecogenomics - personalised medicine
Future developments
- linking MA and neuroendocrine dysfunction
- requires increased understating of neurobiology: neuroplasticity, neurogenesis and role of BDNF
- hard to produce new drugs as difficult to evaluate efficacy
- -> animal models not that useful as can’t ask how they feel
- -> clinical trials difficult: slow onset of action, mood is variable, high placebo effect
- -> finding new targets/ drugs is difficult
