L8 - Drugs Action in the CNS - Depression Flashcards
What is unipolar depression?
Mood swings always in same direction – low mood
Can be secondary to other diseases
What is unipolar depression usually associated with?
Anxiety
Eating disorders
Drug addiction
What are the 3 different causes of unipolar depression?
Reactive - 75%
- Specific triggers – stressful situations
Endogenous - 25%
- Unrelated to external stress, no clear cause
Genetic
- 40% of people with depression have a family member with it
What brain regions are involved in depression?
Prefrontal cortex, amygdala and hippocampus all implicated
When is it classed as depression?
Medically diagnosed if symptoms persist longer than 2 weeks or if affects day-to-day life
What is bipolar disorder?
Depression alternates with mania
Characterized by excessive exuberance, enthusiasm
Self-confidence combined with irritability, impatience, aggression
Hereditary but no genes identified
Episodes last several weeks
What are the symptoms of depression?
Low mood, negative thoughts, misery, pessimism, irritability
Apathy - loss of interest in daily activities
Severe loss or gain in weight
Low self-esteem, feelings of worthlessness or guilt
Sleep disturbance
Lack of concentration
What are the 4 key brain regions implicated in depression?
Subgenual cingulate cortex and nucleus accumbens
Limbic system
Amygdala
Hippocampus
How is the hippocampus affected in depression?
Loss of BDNF signalling trigged by the action of cortisol (stress hormone)
How is the amygdala affected in depression?
Important limbic node for processing fear responses
Becomes activated when you see a frightening face
How is the limbic system affected in depression?
Increased activity-dependent release of BDNF within dopamine circuit mediates susceptibility to social stress
- Due to activation of CREB by phosphorylation
How is the subgenual cingulate cortex and nucleus accumbens affected in depression?
Deep brain stimulation of these areas has antidepressant effect on individuals who have treatment-resistant depression
What is post-natal depression?
Occurs 2-8 weeks after delivery
In some cases stays even a year after the birth of the baby
Babies brain waves can become altered if the mother is depressed
Why is counselling and antidepressants normally prescribed?
Antidepressants are important because depression can cause changes in brain chemistry
Even if reason for depression is gone people will stay depressed due to biochemical changes at synapses
How do you create animal models of depression?
You make an animal depressed by causing them prolonged stress
- E.g. forced swim test
- E.g. alternate the kind of stress the animal experiences daily for 2 weeks
See changes in brain chemistry
What changes are seen in the force to swim experiment when anti-depressants are given?
When given anti-depressants that we know interfere with mono-amine transmission in the brain, even after the repeated force swim they continue to try to escape
Same delays in response to anti-depressants also seen in animals
What are the causes of depression?
Little evidence of substantial brain pathology
Disturbance of hormonal function
High blood cortisol levels
What led to the development of the monoamine hypothesis?
Drugs which cause depletion of monoamines (e.g. reserpine) can lead to depression
Drugs which inhibit breakdown of monoamines (e.g. MAO inhibitors) alleviated depression symptoms
Monoamine Hypothesis - deficit in noradrenaline and 5HT
- Long term trophic effects – takes weeks to see alleviation of symptoms
- Neurotransmitter and its receptors alters transcription and receptor levels
BDNF and its receptor TrkB reduced neurogenesis
Glutamate and its receptor NMDA neurodegeneration implicated
What are 3 examples of amine neurotransmitters?
Noradrenaline
Serotonin
BDNF
Stress activated CREB in Nucleus Accumbens triggers?
Depression like responses
Biology of depression - amine neurotransmitter
There receptors may be targeted by anti-depressants
In depressed patient – reduced signalling through receptors leads to harmful gene transcription
- This can lead to loss of neurones
- Loss of active synapses
Biology of depression - glutamate
Through NMDA receptors it is associated with neuronal loss as a results of excess activation of the receptors
Sub anaesthetic doses of Ketamine are good anti-depressants - especially in individuals resistant to other drugs that affect amine receptors
What evidence is there supporting monoamine hypotheses of depression?
Iproniazid - first specific antidepressant, is an MAOI
Reserpine - produces depression and Parkinson’s, depletes stores of monoamine transmitters
Tricyclic antidepressants – inhibit reuptake of 5-HT and/or noradrenaline
What are the 3 main classes of antidepressants?
Monoamine oxidase inhibitors
Selective serotonin reuptake inhibitors
Classical Tricyclic antidepressants
New idea - monoamine receptor antagonists
What are monoamine oxidase inhibitors?
E.g. Phenylzine, moclobemide
Causes build up of amine neurotransmitters in cytosol of neurones
A subtype is prevalent in the CNS
Side effects are those you’d expect with increased sympathetic drive – hypertension
What are selective serotonin reuptake inhibitors?
E.g. fluoxetine
Work at the level of the transporters – for serotonin - SSRIs
What are classical tricyclic antidepressants?
E.g. imipramine
Work at the level of the transporters – for noradrenaline
Causes build up of amine neurotransmitter at synapses leading to increased receptor activation
What are monoamine receptor antagonists?
Targets receptors directly involved in depression
What are the functions of the noradrenergic pathways in the CNS?
Pain
Arousal/attention
Mood
Blood pressure regulation
Noradrenaline’s role in regulating sensory processing relates it to?
Withdrawal
Increased sleep and anorexia
Deficiency in central noradrenergic transmission contributes to?
Depression
Inhibition of noradrenaline re-uptake in frontal cortex improves?
Mood
How is noradrenaline synthesised?
- Tyrosine
- DOPA
- Dopamine – conversion dependent on expression of appropriate enzymes
- Dbh and pnmt
- Noradrenaline
How is noradrenaline broken down?
Enzymes COMT and MAO
Action of re-uptake transporter
To which neurones is noradrenaline restricted to?
Neurones that express dopamine beta hydroxylase
What is the role of MAO?
Found inside neurones - regulates levels of amine
Plays important role in inactivation of ingested amines
- E.g. Tyramine
Where is tyramine found?
Rich in cheese, beer, wine, soya
What is the impact of anti-depressants of tyramine levels?
People on classic anti-depressants (which inhibit MAO) have affected noradrenaline breakdown and processing of tyramine
- Leads to the cheese effect
What is the cheese effect?
If the patients on anti-depressants eat cheese the MAO inhibition leads to build up of endogenous amines
It is taken back up into the neurones by transporters
Causes displacement of noradrenaline from vesicles
Will leak out from nerve terminals – sympathetic drive effect – severe hypertension
What are the functions of 5-HT pathways in the CNS?
Hallucinations Sleep and wakefulness Mood and emotion Feeding behaviour Sensory pathways and nociception Body temperature Vomiting
Drugs acting on 5-HT transmission are used to treat?
Depression Anxiety Migraine Anti-emetic - chemotherapy Antipsychotic
5-HTs role in regulating limbic processing links to?
Anhedonia
How is 5-HT synthesised?
- Tryptophan – tryptophan hydroxylase
- This is the rate limiting step
- 5-hydroxytrytophan
- 5-hydroxytryptamine
How is 5-HT breakdown?
COMT and MAO
What is the selectivity of TCA and SSRI uptake inhibitors?
Drugs that interfere with noradrenaline or 5-HT transmission
They have different selectivity towards transporters
- 5-HT selective
- Venlafaxine
- Noradrenaline selective
- Maprotiline
- Non-selective
Neutrophins in depression - BDNF hypothesis
- Activation of serotonergic receptors is known to lead to phosphorylation of CREB
- This in turn controls the synthesis of BDNF
- This then stabilises synaptic connections
- BDNF released from post-synaptic neuron acts retrogradely on the nerve terminal forming that synapse
- This strengthens the synapse
What is the effect of depression on BDNF signalling?
In depressed patient there is reduced excitation at synapses
- Reduced release of BDNF
- Synapse not maintained
What is the effect of anti-depressants on BDNF signalling?
Increase BDNF signalling
What are other approaches to treating depression?
Antiepileptic drugs and atypical antipsychotics - mood stabilizers
Electroconvulsive shock therapy, electromagnetic therapy, deep brain and vagus stimulation
What are other approaches to treating bipolar disorders?
Use lithium - narrow therapeutic window, plasma levels need monitoring
Permeates voltage-gated Na channels
Inhibits inositol monophosphatase, AKT signalling and glycogen synthase kinase 3 signalling
