week 7- Mental Health and Affective Disorders Sway Flashcards
what are are risk factors for depressive diorders?
-stress
-chronic stress increases cortisol release from adrenal cortex due to CRH produced in the hypothalamus (HPA axis)
• Genetic factors – high heritability of depressive disorders in twin
studies
• Family history
• Intensive efforts made to find genes linking to depression but GWAS
have given few clues
• Candidate gene studies have identified ~200 genes, SLC6A4 is one
• Substance abuse
what is the first theory for the pathophysicology of depression? what it means?
-monamine theory
-If we identify the cause of depression = we can effectively treat it
-there was a functional deficit of monoamine
neurotransmitters (5-HT and noradrenaline) and dopamine in areas of the brain
-
what is the effect of Tricyclic antideppressants and how do they work?
Block monoamine reuptake Enhance mood
what is the effect of MAO inhibitors and how do they work?
Prevent degradation of
monoamines
Enhance mood
what is the effect of tryptophan and how do they work?
Increase 5-HT synthesis
enhance mood
what is the effect of reserpine and how do they work?
Inhibit monoamine storage Reduce mood
what is the effect of α-Methyltyrosine and how do they work?
Inhibit noradrenaline synthesis
Reduce mood
what is the effect of Methyldopa and how do they work?
Inhibit noradrenaline synthesis
Reduce mood
what neurotransmitters can cause depression?
NA and 5-HT (SEROTONIN)
what are the drug targets for depressive disorders?
- the reuptake transporers for both 5-HT and NA
- they are in the SLC6 family
- known as SERT and NET
what does SERT stand for?
seretonin reuptake transporters
-SLC6A4
what does NET stand for?
Norarenaline reuptake transporters
-SLC6A2
what type of transporter is SERT and NET?
-symporters
-use co-transporter of sodium as a driving force for carrying their substrate (neurotransmitter) across the plasma membrane
-• Dependent on extracellular Cl-
• Some SLC transporters also move K+
what is the structure of SERT?
• 12 transmembrane domains• Intracellular N and C-termini• Large glycosylated EC loop between TM3 and 4 • Alternating access model • Substrate binding site is accessible to either the external or internal medium
how is the substrate is moved across the plasma membrane through SERT?
- substrate and Na+ comes in
- it becomes bound and occuluded
- then transporter opens and the substate and counter transporter ion is rleased
where are SERT and NET found?
on the pre synatic terminals of the seretinergic and noradrenergic neurones
how do reuptake inhibitors work/
-only work once the neurotrasmitters have been released
• Prevent the reuptake of serotonin or NA into the neurons
• Enhances the synaptic levels of serotonin and/or noradrenaline within the synapse and lengthen the amount of time the Neurotrasmitter is avavliable to then bind to the receptor on the post synpatic neuron
what are some examples of of anti-depressants?
• SSRIs:
Fluoxetine, paroxetine, sertraline, citalopram, escitalopram, fluvoxamine
• SNRIs:
Buproprion, reboxetine, atomoxetine
• Mixed (non-selective both):
Venlafaxine, duloxetine
• Tricyclic antidepressants (non selective)
Imipramine, desipramine(selective for NA), amitryptyline, clomipramine
what does SSRI mean?
selective serotonin reuptake
inhibitors
what does SNRI mean?
serotonin & noradrenaline
reuptake inhibitors
WHAT ARE THE CONSEQUENCES OF INCREASED 5-HT AND NA?
• Increased signalling through 5-HT receptors and NA receptors
- Pre-synaptic and post-synaptic
• Gene expression changes, neurogenesis – chronic adaptive changes
how is controlling serotonin levels with reuptake inhibitors?
• Acute action – increases synaptic 5-HT by reducing reuptake
• But 5-HT acts on 5-HT1A on soma/dendrites to inhibit 5-HT release
• This cancels out some of the effect of SSRIs
• Chronic administration – elevated 5-HT level will induce
desensitisation of 5-HT1A receptors
• This in turn will reduce the inhibitory effect of 5-HT
• This need for desensitisation could explain the slow onset of action
how is NA controling 5-HT levels?
• Noradrenaline can control 5-HT release
• NA can act on excitatory α1
receptors to enhance 5-HT release
• α2 receptors are downregulated by antidepressants
• α2 receptor antagonists could
further enhance 5-HT releasee.g. mirtazapine, mianserin
what is monoamine oxidase (MAO)
• Monoamine Oxidase (MAO) controls the degradation of monoamine
neurotransmitters
• There are two forms of MAO –A and B(dopamine preference)
• MAO-A has substrate preference for 5-HT and NA
• Inhibitors of this enzyme will cause an increase in tissue monoamines (5-HT, NA, Dopamine)
how do MAO inhibitors work?
• Increase cytoplasmic stores of noradrenaline and 5-HT in nerve
terminals
• Irreversible non-competitive inhibitors – e.g. phenelzine, iproniazid
• Most are non-selective for different forms of MAO
• Reversible MAO-A selective inhibitors – moclobemide
• Can be increase in spontaneous release of neurotransmitter and
increase in release by sympathomimetic amines (e.g.tyramine)
what are some side effects of MAO Inhibitor?
- Hypotension – common side effect
- Central stimulation – tremors, excitement, insomnia
- Increased appetite causing weight gain
- Drug & food interaction – the cheese reaction
• Ingestion of tyramine in foods such as ripe cheese and marmite
• Typically degraded in gut by MAO
• With MAOI – tyramine absorbed into circulation and has sympathomimetic
effect
• Acute hypertension and severe headaches
what is the neuroendocrine mechanism?
-stimulation of the hypothalmus causes the release of CRF
-CRF which then acts on on the piturity gland which then releases ACTH which then acts on the adrenal cortex which releases gluccorticosteriod
• Increased plasma cortisol levels in severe depression
• Impaired glucocorticoid induced feedback control
• Injection of CRH (CRF) into brain can mimic aspects of
depression
• Cushing’s syndrome – often causes depression
• No current clinical intervention
why are gluccorticosteriod important?
-they regulate the brain
what is the inflammatory mechanism in causing depression?
-comes from sickness behaviour
• Behavioural changes experienced with infections can mimic depressive-like behaviour
• Cytokines cause these changes
• Infusion of particular cytokines induces depression in humans and rodents
• IL-2 and IFN-γ
• People with autoimmune disease more likely to have depression
• Post-mortem evidence of microglial activation in patients with depression
what is the structural changes in the brain?
• Regional specific neuronal cell loss, changes in synaptic activity
causing the imbalances in neurotransmitters
• Functional imaging studies show a decrease in gray matter volume in
pre-frontal cortex and hippocampus
• Smaller volume of important brain structures
• Post-mortem studies conform a loss in GABAergic neurons, astrocytes and oligodendrocytes in the pre-frontal cortex
what is the neuroplasticity and neurogenesis?
• Neurogenesis – formation of new neurons from pluripotent stem cells
• Neuroplasticity – growth and adaptability of neurons
• Neurogenesis is controlled by trophic factors such as BDNF
• Humans – reduced BDNF in CSF of patients
• Antidepressants can raise BDNF levels
• In animal models reducing neurogenesis can prevent the action of
antidepressants
• injection of BDNF has an antidepressant effect
what is esketamine?
• Ketamine derivative • No delay in the anti-depressant effect of esketamine • NMDA receptor non-competitive channel blocker • Approved by EMA for treatmentresistant depression in 2019 • Proposed mechanism: blocking NMDA receptors on GABA interneurons prevents tonic activity – causes a glutamate surge which increases BDNF signalling
what are some problems with antidepressants?
• Do not work in everybody
• Side effects for SSRIs include nausea, insomnia, sexual dysfunction,
paroxetine linked to increased suicidality, risk of drug interactions CYP
• Tricyclics can have a sedating effect, anticholinergic effects, confusion, motor incoordination effect, higher risks with overdose
• SNRIs side effects include sedation, dizziness, nausea and some can
have withdrawal effect
• Monoamine oxidase inhibitors (MAOI) side effects include CNS
stimulation, weight gain, insomnia, postural hypotension
• Major problem with MAOI is the cheese reaction – tyraminecontaining foods – increased tyramine causes sympathomimetic
effect (acute hypertension, headache)
what are the two types of bipolar?
• Bipolar I (episodes of mania) and bipolar II (episodes of
hypomania and depression)
what is the pathophysiology of bipolar disorder?
• Pathophysiology involves
dendritic spine loss, altered
cellular connectivity and neural
plasticity
what is some treatment for bipolar disorder?
• Stabilisation of mood is the overall goal
• Lithium - taken orally as lithium carbonate
• Used in prophylaxis and treatment of mania
• Carbamazepine, valproate and lamotrigine anti-epileptic drugs can be used• Quetiapine, olanzepine and other anti-psychotic drugs can be used
• Benzodiazepines can be used for calming effect
• Use of anti-depressants is not recommended – can lead to switching to
manic phase
how does lithium work in bipolar disorder?
• Lithium is a monovalent cation • Lithium is thought to accumulate inside cells, cause inhibition of inositol phosphate pathway and inhibition of GSK3 affecting cellular responses -accumulates as it isnt pumped out the cells through sodium potassium symporter
what antiepileptic drugs can be used to treat bipolar disorder?
• Carbamazepine, valproate and lamotrigine – affect NaV channels
• Blocking action on NaV channels prevents action potential generation
• These drugs show use dependence therefore more activity is seen with higher firing rates (e.g. in epilepsy)
• Lamotrigine has a broader mechanism of action – also affects neurotransmitter
release and may have activity on CaV channels
• Mechanism of action in bipolar disorder – due to reduction in neuronal excitation• Better side effect profile than lithium
what atypical antipsychotics can be used to treat bipolar disorder?
- Olanzepine, quetiapine, risperidone, aripiprazole – act as antagonists at D2 and 5-HT2A receptors
- Also may have activity at several other receptors including α1, H1, 5-HT1Aand mAChR
- Second generation antipsychotics
- Effective against treatment of mania
what are anxiety disorders?
• Chronic disorder • Depression is often co-morbid with anxiety • Clinical recognised anxiety states include: - Generalised anxiety disorder (GAD) - Social anxiety disorder - Phobias - Panic disorder - PTSD - OCD
what are the pathophysiology of anxiety disorders?
• Anxiety arises from an abnormal regulation of fear response
• Fear – subjective response to threatening stimulus
• Anxiety is longer lasting and can persist due to lack of signs of safety
• Disorders are distinguished based on
• symptoms
• precipitating factors
• Genetic component – run in families
• Amygdala is activated by induction of fear – neuroimaging suggests
patients have heightened activity in amygdala circuits
what is the treatment for anxiety disorder?
• Psychological approaches are used as well as medication
• Main drugs used:
1. Antidepressants (SSRIs, SNRIs) – increase 5HT and NA levels
• E.g. Escitalopram and paroxetine, venlafaxine, duloxetine
2. Benzodiazepines – enhance action of GABA on GABAA
receptors containing α2 subunit e.g. lorazepam, diazepam, flurazepam
Benzodiazepine side effects are sedation, confusion, tolerance and dependence
3. Buspirone (5HT1A receptor agonist) – can be used to treat generalised anxiety disorder
• 5HT1A receptors can act as inhibitory autoreceptors on serotonergic neurons, postsynaptic 5HT1A receptors are involved in emotional behaviour
4. Gabapentin, pregabalin, valproate – affect NaV and CaV channels – anxiolytic properties
5. Atypical antipsychotics – olanzepine, quetiapine – can be effective in GAD and PTSD
6. Propranolol - a β-blocker which can be used for relief of situational anxiety, GAD
7. Non-pharmacological treatments:
Counselling
Cognitive therapy
Dietary and lifestyle changes
