Mental Health Pharmacology Depression, Anxiety and Bipolar Flashcards
Name clinically recognised states of anxiety:
GAD
Social anxiety disorder
Phobias
Panic disorder
PTSD
OCD
Describe the pathophysiology of anxiety:
Anxiety arises from an abnormal regulation of fear response
Genetic component- runs in families
Amygdala is activated by induction of fear-neuroimaging suggests patients have heightened activity in amygdala circuits
Name the main drugs used for anxiety:
- Antidepressants (SNRIs and SSRIs)
- Benzodiazepines
- Buspirone (5HT1a receptor agonist) (for GAD)
- Gabapentin, pregabalin, valproate
- Atypical antipsychotics
- Propranolol
- Non-pharmacological
Describe antidepressants used in anxiety:
Increase 5HT and NA levels- need 2 weeks to see improvement
e.g escitalopram and paroxetine, venlafaxine, duloxetine
Describe benzodiazepines used in anxiety:
Enhance action of GABA on GABAa receptor containing a2 subunit (G2 and a2 subunits needed)
e.g lorazepam, diazepam, flurazepam- more acute treatment
SEs are sedation, confusion, tolerance and dependence
Describe buspirone used in anxiety:
5HT1A receptor agonist
5HT1Ar can act as inhibitory auto receptors on serotonergic neurones, post synaptic 5HT1Ar are involved in emotional behaviour
Can take few weeks for clinical effect due to desensitisation of 5HT1Ar
Describe how gabapentin, pregabalin and valproate are used in anxiety:
Valproate- Effect NaV channels
Gaba and pregab- effect CaV channels
Anxiolytic properties
Describe how atypical antipsychotics are used in anxiety:
Olanzapine, quetiapine
Effective in GAD and PTSD
Describe how propranolol can be used in anxiety:
BB which can be used for relief of situational anxiety, GAD
Describe the non-pharmacological anxiety treatments:
Counselling
Cognitive therapy
Dietary and lifestyle advice
Describe the pathophysiology of bipolar:
Dendritic spine loss, altered cellular connectivity and neural plasticity
Describe the MoA of lithium in BPD:
Monovalent cation
Mimic role of sodium (move through NaV)-but not pumped out by Na/K ATPase
Thought to accumulate inside cells, cause inhibition of inositol phosphate pathway and inhibition of GSK3 affecting cellular responses
Inhibit GSK3- the phosphorylate important downstream proteins
Name anti epileptics which are used for BPD:
Carbamazepine, valproate, lamotrigine
Describe the use of anti epileptics in BPD:
Affect NaV channels
Blocking action of NaV (inactivated) channels prevents A/P generated
These show use dependance therefore more activity is seen with higher firing rates (e.g in epilepsy)
Describe the MoA of anti epileptics in BPD:
Lamotrigine had a broader MoA, also affects NT release and may have activity on CaV
Due to decrease in neuronal excitation leads to stabilisation in mood
Better SE profile than lithium
Name atypical antipsychotics used in BPD:
Olanzepine
Quetiapine
Risperidone
Aripriprazole
Describe the MoA of atypical antipsychotics in BPD:
Act as antagonists at D2 (GPCR) and 5HT2Ar
Also may have activity at several other GPCRs including a1, H1, 5HT1A and mAChr
Effective against mania
Describe the monoamine theory of depression:
Functional deficit of MAO NTs (5HT and NA) in areas of brain
Arose due to clinical effects on drugs that alleviated symptoms or caused depressive symptoms
Describe the pharmacological evidence for MAO theory which increase mood:
TCA- block MAO uptake
MAOi- prevent degradation of MAO
Tryptophan- increases 5HT synthesis
Describe the pharmacological evidence for MAO theory which decreased mood:
Reserpine- inhibits MAO storage
a-methyltyrosine and methyldopa- inhibits NA synthesis
Describe the findings of the MAO theory:
Inhibition of NA and 5HT NT reuptake equally effective
Direct neurochemical actions are rapid but clinical antidepressants effect takes weeks to develop
2º adaptive changes are thought to be responsible (trophic)
Drugs may have acute effects on cognition- a +ve effect on emotions
Name drug targets for depressive disorders:
SLC6 transporters:
SERT (SLC6A4)
NET (SLC6A2)
Describe the SLC6 transporters:
Symporters, use co-transporter Na+ as driving force
Dependent on extracellular Cl-
Some SLC transporters also move K+
Describe the SERT transporter:
12 TMD
Intracellular N and C terminal
Large glycosylated extracellular loop between TM3 and 4
Describe the alternative access model for the SCL6 transporters:
Substrate binding site is accessible to either the external or internal medium
Onward facing (open)-> inward facing (open)
What are reuptake inhibitors?
Found on SERT and NET neurons
Prevent the reuptake of serotonin or NA into the neurons
Enhances the synaptic levels of serotonin and/ or NA
Name SSRIs:
5HT selective
Fluoxetine
Paroxetine
Sertraline
Citalopram
Escitalopram
Fluvoxamine
Name SNRIs:
NA selective
Bupropion
Reboxetine
Atomoxetine
Name mixed (non-selective) reuptake inhibitors:
Venlafaxine
Duloxetine
Name TCAs:
Imipramine
Desipramine (NA selective)
Amitriptyline
Clomipramine
What are the consequences of increasing 5HT and NA?
Increases signalling through 5HT and NA r
-pre and post synaptic
Gene expression changes, neurogenesis and chronic adaptive changes
Describe 5HT reuptake in the absence of a reuptake inhibitor:
Serotonergic neuron- serotonin0 actis on post synaptic 5HT
Serotonin then reuptake in pre-synaptic by SERT
Describe the acute action of serotonin reuptake inhibitors on the conc of 5HT:
Increase synaptic 5HT by decreased reuptake
But 5HT acts on 5HT1A on some dendrites to inhibit 5HT release
This cancels out some effects of SSRIs
Describe the chronic action of serotonin reuptake inhibitors on the conc of 5HT:
Elevated 5HT level will induce desensitisation of 5HT1Ar
This in turn will decrease the inhibitory effect of 5HT
This need for desensitisation could explain the slow onset of action
Describe how NA can control 5HT levels:
NA can control 5HT release
NA can act on excitatory a1r to enhance 5HT release
a2r are down regard by antidepressants- removing -ve regulation of serotonin release
a2r antagonists could further enhance 5HT release e.g mirtazapine, mianserin
Describe MAO:
MAO controls the degradation of MAO NTs
There are 2 forms MAO-A and B
MAO-A has a substrate preference for 5HT and NA, MAO-B prefers dopamine
Inhibitors of this enzyme will cause an increase in tissue MAO
Describe the effect of MAOi:
Increase in cytoplasmic stores of NA and 5HT in nerve terminals
Name and describe irreversible non-competitive MAOi:
Phenelzine, iproniazid
Most are non-selective for different forms of MAO
Name and describe reversible MAOi:
A selective inhibitor- moclobemide
Can decrease SEs
Can be increased in spontaneous release of NT and increase in release by sympathomimetic amines (e.g tyramine)
Name and describe side effects of MAOi:
Hypotension- common
Central stim- tremors, excitement, insomnia
Increased appetite causing weight gain
Name the drug/ food interaction with MAOi:
The cheese reaction
Ingestion of tyramine in foods such as ripe cheese and marmite
Tyramine typically degrades in gut by MAO
With MAOi- tyramine not metabolised into gut and instead absorbed into circulation and has sympathomimetic effect
Acute HTN and severe headaches
Name other hypotheses for depression:
- Neuroendocrine mechanism-HPA axis
- Inflammatory mechanisms- sickness behaviour
- Structural changes in the brain
- Neuroplasticity and neurogenesis
Describe the HPA axis:
Hypothalamus, Pituitary, Adrenal axis
Normal:
Hypothalamus, CRF (corticotrophin releasing hormone), Pituitary, ACTH (Adrenocorticotropic hormone), Adrenal cortex, corticoids which reg brain
Describe the neuroendocrine mechanism for depression:
Increased plasma cortisol levels in severe depression
Impaired glucocorticoid induced feedback control
Describe evidence of the neuroendocrine mechanism for depression:
Injection of CRH (CRF) into brain can mimic aspects of depression
Cushing’s syndrome (increased cortisol) often causes depression
No current clinical intervention
Describe the inflammatory mechanism for depression:
Behavioural changes experienced with infections can mimic depressive like behaviour
Cytokines cause these changes act directly on neurons, astrocytes microglia
Describe evidence of the inflammatory mechanism for depression:
Infusion of particular cytokines induces depression in humans and rodents
IL2 and IFN-Y
People with AID more likely to have depression
Post mortem evidence of microglial activation in pts with depression
Describe the structural changes in the brain for depression:
Regional specific neuronal cell loss, changes in synaptic activity causing imbalances in NT
Describe evidence of the structural changes in the brain for depression:
Function imagine studies show a decrease in grey matter volume in pre-frontal cortex and hippocampus
Smaller volume of important brain structures
Post mortem studies confirm a loss in GABAergic neurons, astrocytes and oligodendrocytes in the pre frontal cortex
What does neurogenesis mean?
Formation of new neurons from pluripotent stem cells- hippocampus
What does neuroplasticity mean?
Growth and adaptability of neurons
How is neurogenesis controlled?
Is controlled by trophic factors e.g BDNF (brain derived neurotrophic factors)
Describe neuroplasticity and neurogenesis in depression:
Humans- decreased BDNF in CSF of patients
Antidepressants can raise BDNF levels
In animal models, decreased neurogenesis can prevent the action of ADs
Injection of BDNF has an AD effect
Describe esketamine as a treatment for resistant depression:
Nasal spray
No delay in the AD effect
NMDAr non-competitive channel blocker
MoA blocking NMDAr on GABA interneurons prevent tonic activity
Causes a glutamate surge which sig increases BDNF
