Depression and Alziehmers Flashcards
List 5 symptoms of depression
Loss of pleasure/interest
Depressed mood
Fatigue
Decreased concentration
Insomnia or hypersomnia
Discuss the pathophysiology of depression
Monoamine hypothesis
The monoamine hypothesis states that depression is caused by a functional deficiency in monoamine neurotransmission (noradrenaline, serotonin, depression)
However, Various factors are likely contributing to depressive symptoms in a multifactorial manner.
The monoamine hypothesis is insufficient as an explanation for depression.
What is depression suggested to be associated with?
Neuro-degeneration and reduced neurogenesis in the hippocampus and pre-frontal cortex
(hippocampus is responsible for memory and prefrontal cortex responsible for executive tasks)
What are psychedelics?
A class of psychoactive substances that can alter perception and mood and affect numerous cognitive processes.
What are the two main sub-types of psychedelics?
Dopaminergic-like psychedelics; linked with energetic and empathogenic like effects (DOPAMINE-LIKE)
Serotonergic-like psychedelics; linked with hallucinogenic and disorienting like effects (SEROTONIN-LIKE)
How do psychedelics mediate their response?
Mediate their effects by binding to endogenous neurotransmitter receptors (Serotonin, dopamine receptors)
Psychedelics can act as partial or full agonists at multiple receptor sub-types at pre and post synaptic locations.
Psilocybin’s psychedelic and anti-depressant effects are a result of 5HT2a receptor agonism > leads to down regulation of 5HT2a receptors
What is Psilocybin?
A naturally occurring substance with psychoactive properties within magic mushrooms.
Shares structural similarities with serotonin
What form is psilocybin?
Psilocybin is a prodrug > converted into Psilocin (pharmacologically active) within the body
What causes psilocybins psychedelic effects?
Psilocybin’s psychedelic and anti-depressant effects are a result of 5HT2a receptor agonism > leads to down regulation of 5HT2a receptors
Psilocybin induces decreased activity in brain regions and networks associated with depression (including the amygdala)
What could psilocybin potentially treat?
Depression
What is PTSD, list 5 symptoms
Post traumatic stress disorder is characterised by distress triggered by the recall of past traumatic experiences.
What is MDMA
3,4 methylendioxymethamphetamine
Is a synthetic psychoactive drug with psychostimulant and psychedelic properties
What does MDMA share properties/structures with?
Monoamines (dopamine and noradrenaline)
What has MDMA been proposed to treat?
PTSD
What are the stages of MDMA moa
1- MDMA is competitively reuptaken into the pre-synaptic nerve terminal via the dopamine transporter (DAT), Noradrenaline transporter (NAT) and Serotonin transporter (SERT)
2- Leads to less dopamine, Noradrenaline and Serotonin being taken up into the pre-synaptic nerve terminals (as MDMA is competitively taken up in its place)
3- MDMA inhibits Vesicular monoamine transporter (VMAT1/2) - DA, NA and 5HT accumulates in the cytosol
4- MDMA activates intracellular TAAR1 receptors leading to the reversal of DAT, NET, SERT and the removal of DAT, NET and SERT from the plasma membrane
5-Increase in DA, NA and 5-HT in the synaptic cleft leads to increased DA, NA and 5HT post synaptic receptor activation
MDMA induces decreased activity in brain regions and networks associated with anxiety, including the amygdala & increased connectivity between amygdala - hippocampus to allow reprocessing of traumatic memories.
Define Dementia
Clinical syndrome characterised by a significant decline in performance in one or more cognitive domains that interfere with activities of daily living
Dementia is an umbrella term used to describe clinical syndromes characterised by cognitive deficits.
What is the pathophysiology of Alzheimer’s
Amyloid plaques
Amyloid plaques; an accumulation of abnormally folded amyloid B (AB) proteins 40 or 42 amino acid residues in length (these are by products of amyloid precursor protein (APP) metabolism)
Abeta42 is most abundant within plaques due to its higher rate of fibrillation and insolubility
Add picture of amyloid plaque formation here
What is tau?
Tau is the microtubule-associated protein involved in microtubule stabilisation
The phosphorylation of tau regulates binding in microtubules
What is the pathophysiology of Alzheimer’s
Neurofibrillary tangles of tau
Hyperphosphorylation of tau results in the formation of neurofibrillary tangles
Leads to the disruption of neuronal transport > leading to neuronal degeneration
Describe the amyloid hypothesis of Alzheimer’s
Proposes the accumulation and deposition of oliogmeric or fibrillar amyloid-beta peptide is the primary cause of Alzheimer’s disease
Proteolytic cleavage of APP produced Abeta42
Toxicity of the amyloid oligomers and fibrils lead to the cascade of tau hyperphosphorylation
Tau hyperphosphorylation = formation of neurofibrillary tangles. leading to neuronal cell death
Occurs in the hippocampus first the becomes more widespread.
What are the current treatments for Alzheimer’s
Give the MOA
In patients with mild-to-moderate
Alzheimer’s disease, the
acetylcholinesterase (AChE) inhibitors;
donepezil
AChE inhibitors prevent the breakdown of ACh
by the enzyme acetylcholinesterase (AChE)
* AChE inhibitors therefore increase ACh levels and can thus alleviate cognitive symptoms in
Alzheimer’s disease patients
In patients with moderate-to-severe
Alzheimer’s disease, the NMDA receptor
antagonist; memantine
Memantine is a low-affinity NMDA receptor antagonist that blocks excessively open NMDA receptor ion
channels to reduce glutamate mediated neurotoxicity
- NMDA receptor overactivation and subsequent glutamate mediated neurotoxicity has been associated with Alzheimer’sdisease
Anti-amyloid and anti-tau strategies
AChE inhibitors and NMDA receptor antagonists have benefits for patients but its clinical outcomes are limited
Aducanumab
Human monoclonal antibody that selectively binds to amyloid beta fibrils and soluble oligomers and reduces amyloid burden in a dose and time dependent manner.
Lecanemab
Lecanemab targets amyloid as it begins
to form amyloid fibrils
Donanemab
Donanemab targets amyloids once
amyloid fibres have formed amyloid
plaques
What are the differences between Lecanemab and Donanemab?
Lecanemab and donanemab are two alternate human monoclonal antibodies
that target amyloid protein – but target amyloid at different stages.
