CNS 4 - Antidepressants Flashcards
What are the 2 classes of depression?
- Unipolar depression
- Bipolar disorder
What is unipolar depression?
Mood swings always in the same direction (negative)
What are the 2 types of unipolar depression?
- Reactive (75%)
- Endogenous (25%)
What is reactive unipolar depression?
Depression brought on by an event
What is endogenous unipolar depression?
Can’t identify an underlying cause for the depression
What is bipolar depression?
Depression alternates with mania
What are the symptoms of unipolar depression? (7)
- Low mood (anhedonia)
- Apathy
- Severe weight loss/gain
- Low self esteem (worthlessness)
- Insomnia/excessive sleep
- Loss of libido
- Diminished ability to think/concentrate
What is anhedonia?
Inability to get pleasure from activities you would usually enjoy
What is apathy?
Loss of interest in daily activities
How is depression diagnosed?
Patient must be exhibiting depressive symptoms for over 2 weeks and symptoms are disrupting normal daily life
What are the risk factors for developing depression? (3)
- Stressful life event
- Genetic risk
- Secondary to illness/drug side effects
Which areas of the brain are involved in depression?
- Cingulate nucleus
- Nucleus accumbens
- Amygdala
- Hippocampus
What happens in the nucleus accumbens which is linked to depression? (2)
- Increased firing of dopaminergic neurons in this region
- Increased secretion of BDNF
What happens in the hippocampus which is linked to depression? (2)
- Decreased activation of CREB leads to decreased levels of BDNF
- This is associated with high cortisol levels
What causes the abnormal feeding behaviours seen in depression?
Disruption in ghrelin and leptin signalling
How can epigenetic changes cause depression?
Children of women with postnatal depression can develop epigenetic changes due to lack of normal interaction with the mother which makes them more susceptible to depression later in life
What animal models are used to study depression? (2)
- Acute stress models
- Chronic stress models
What is an example of an acute stress model for depression?
Forced swimming test:
- Measure how long it takes the animal to give up trying to escape
- Antidepressant treatment reduces the tendency to give up
- Used for assessment of efficacy of antidepressants affecting monoamines
What are chronic stress models for depression?
- Repeated stressors which cause animals to develop a learned helplessness
- Causes structural, transcriptional and epigenetic changes in several brain regions which mimics those seen in humans
- E.g. repeated electric shock until the rodent stops trying to get away from the shock
Which neurotransmitters are involved in depression? (2)
- Noradrenaline
- Serotonin (5HT)
(Monoamines)
Why does it take several weeks to see an improvement in symptoms with antidepressant treatments?
It is believed that noradrenaline and serotonin have long term trophic effects on neurogenesis aswell as short term action
Which receptor does BDNF act on?
TrkB
How is BDNF involved in depression?
- Patients have reduced production of BDNF
- Reduced activation of TrkB receptors
- Associated with changes in neurogenesis (changes in brain structure)
How is glutamate involved in depression?
Overactivation of NMDA receptors is linked to neurodegeneration associated with depression
What is the monoamine hypothesis of depression?
Depression is caused by a deficiency/imbalance in the monoamine neurotransmitters
What is the evidence in support of the monoamine hypothesis of depression? (3)
- The first antidepressant iproniazid is an MAO inhibitor
- Reserpine depletes monoamine stores and causes depression
- Tricyclic antidepressants inhibit reuptake of 5-HT and noradrenaline and alleviates symptoms
What types of drugs are used to treat depression? (4)
- MAO inhibitors
- Tricyclic antidepressants
- SSRIs
- Monoamine receptor antagonists
What are examples of MAO inhibitors? (2)
- Phenelzine (suicide inhibitor)
- Moclobemide (reversible inhibitor)
What is an example of a tricyclic antidepressant?
Imipramine
How do tricyclic antidepressants work?
Block the reuptake of monoamine neurotransmitters
What is an example of an SSRI?
Fluoxetine
What is fluoxetine also known as?
Prozac
What are the 2 types of MAO?
- Type A
- Type B
Which type of MAO is inhibited causing antidepressant effects?
Type A
When is it useful to inhibit MAO type B?
Treatment of Parkinson’s
What is the cheese effect?
- Side effect of MAO inhibitors
- MAOs in the periphery also inhibited
- Inability to break down amines from food such as tyramine so taken up into sympathetic neurons and displaces noradrenaline
- Causes leakage of noradrenaline from sympathetic nerves which leads to hypertensive crisis
What are the side effects of the non-selective tricyclic antidepressants (TCAs)? (7)
- Dry mouth
- Blurred vision
- Constipation
- Postural hypotension
- Sedation
- Confusion and mania
- Cardiac dysrhythmias
Why are SSRIs preferred over TCAs?
More selective and fewer side effects/toxicity
Where are dopaminergic neurons mainly located in the brain?
Locus coeruleus
Where are serotonergic neurons mainly located in the brain?
Raphe nuclei
What can drugs acting on 5HT transmission be used to treat? (5)
- Depression
- Anxiety
- Migraines
- Anti-emetic
- Antipsychotic
Which amino acid is 5HT made from?
Tryptophan
What foods are high in tryptophan?
- Chocolate
- Protein rich foods
Which serotonin receptors are involved in depression?
5HT1 receptors
What kind of receptors are 5HT1 receptors?
G protein coupled
Which G protein are 5HT1 receptors coupled to?
Gi/o (inhibitory)
What is the slow working mechanism of action of SSRIs?
- Inhibitory 5HT1A receptors are found on pre and postsynaptic neurones and inhibit serotonin release
- When initially taking SSRIs, more serotonin = more signalling via 5HT1A inhibitory receptors = worsening of depression
- Over time, 5HT1 receptors become desensitised and are lost which causes increase in serotonin levels
What does BDNF do?
- Released by postsynaptic neurons and acts on the presynaptic neuron to stabilise the synapse
- Occurs in regularly used synapses
How is BDNF linked to depression?
Lower neuronal activity means that BDNF is not produced by postsynaptic neurons synapses are lost
What alternative methods can be used to treat depression? (4)
- Anti-epileptic drugs
- Atypical antipsychotics
- Electroconvulsive shock therapy
- Deep brain stimulation
What is used to treat bipolar disorder?
Lithium
What is BDNF?
- A growth factor
- Stimulated by some antidepressants
