Mood disorders Flashcards
1
Q
Give examples of 5HT2C antagonist properties
A
Antidepressant action
Disinhibition (enhancing) dopamine and norepinephrine release
Activating properties ( reduced fatigue, improved concentration. Therefore good for depressed patients with decreased positive affect.
Anti bulimia effect
2
Q
List drugs with 5HT2C antagonism
A
- Fluoxetine
- Trazodone
- Mirtazepine
- Agomelatine
- Some tricyclic antidpressants
- Quietiapine & Olanzepine (5HT2A/ Dopamine 2 receptor antagonists)
3
Q
What type of drug is Sertraline
A
SSRI with Dopamine transport (DAT) Inhibition and Sigma1 Binding
4
Q
Sigma 1 actions with drug Sertaline
A
Anxiolytic effect in psychotic and delusional depression
5
Q
Which drugs is Sertraline often combined with
A
Wellbutrin (bupropion), because both have weak DAT inhibitory properties
6
Q
What type of drug is Paroxetine
A
SSRI with Muscarinic anticholinergic and norepinephrine transporter inhibitory actions
7
Q
Why is Sertraline theoretically “activating”
A
It has Dopamine transporter inhibitory properties
8
Q
Why is Paroxetine “calming/ sedating”
A
Because it has anticholinergic actions
9
Q
Common side effect of paroxetine
A
Sexual dysfunction in men, due to Nitric oxide synthase enzyme inhibition
10
Q
What type of drug is Fluvoxamine
A
SSRI with sigma 1 receptor binding
11
Q
Pharmacological action of Fluvoxamine
A
Sigma 1 receptor agonist leading to a anxiolytic properties
12
Q
What type of drug is citalopram
A
SSRI, which has 2 enantiomers (R&S),
Mild antihistamine properties come from the R entantiomer
13
Q
Draw backs of Citalopram
A
Inconsistent therapeutic actions at low doses (often dose increases will be needed)
Limitations in dose increase (high doses lead to QT prolongation)
14
Q
What type of drug is Escitalopram
A
SSRI
15
Q
Why is escitalopram so well tolerated
A
Unwanted R enantiomer is removed (which removes antihistamine effects), no dosing restrictions (no risk for QT prolongation)
SSRI for which pure SERT inhibition most likely explains pharmacological effects.
Drug with fewest CYTP450 mediated drug interactions
16
Q
What type of drug is Vilazodone?
A
Serotonin Partial agonist reuptake inhibitor (SPARI)
17
Q
Which 3 actions do SNRI’s have|
A
- Increase serotonin
- Increase Norepinephrine
- Increase dopamine in the prefrontal cortex
18
Q
Which transporter is found in small amounts in the prefrontal cortex
A
Dopamine transporter.
The consequence of the above is that when dopamine is released in the prefrontal cortex, it is free to cruise away from the synapse (this is known as having a wide diffusion radius). Therefore dopamine can have a widespread effect.
19
Q
By which two mechanisms is dopamine inactivated in the prefrontal cortex.
A
Catechol o methyltransferase (degrades dopamine)
Uptake into the nerve terminal by NET (Norepinephrine transporter) - this reuptake stops the action of dopamine
Therefore when there is NET inhibition, there is an increase of norepinephrine and dopamine
20
Q
What type of drug is Venlafaxine?
A
Venlafaxine is a Serotonin and Norepinephrine reuptake inhibitor (SNRI)
21
Q
NET inhibition when Venlafaxine is given accounts for which 2 side effects?
A
- Sweating
- Elevated blood pressure
22
Q
Why does Desvenlafaxine have more predictable NET inhibition over Venlafaxine?
A
There are genetic polymorphisms of CYP450 2D6, ie poor metabolisers which can shift the ratio of the 2 drugs more towards Venlafaxine (parent) and away from active metabolite Desvenlafaxine.
23
Q
What type of drug is Duloxetine?
A
SNRI ( serotonin and norepinephrine reuptake inhibitor\0
24
Q
Which conditions can be treated with Duloxetine?
A
- Unipolar depression
- Pain conditions without depression
- Painful symptoms associated with depression.
- Cognitive symptoms of depression in geriatric depression
25
Which pain syndromes have shown improvement on Duloxetine?
Diabetic peripheral Neuropathic pain
Fibromyalgia
Chronic MSK pain
Lower back pain
26
What type of drug is Milnacipran?
SNRI
27
Which pharmacological property make Milnacipran well suited for treating pain syndromes.
Milnacipran has more potent NET Inhibition than SERT inhibition.
* The potent NET inhibition makes it useful in pain syndromes
This property also makes it well suited for the treatment of cognitive symptoms ( cognitive symptoms of unipolar depression and cognitive symptoms associated with fibromyalgia).
28
Why may Levomilnacipran be favourable over Milnacipran
Once daily dosing instead of BD
(controlled release formulation )
29
What type of drug is Bupropion?
Norepinephrine-dopamine reuptake inhibitor.
30
Why does bupropion NOT cause sexual dysfunction?
Bupropion has limited serotonergic action.
31
When should Bupropion be used for unipolar depression:
1. In patient's who cannot tolerate serotonergic side effects of SSRI's
2. In patient's who do not respond to serotonergic boosting
It is especially useful for dopamine deficient syndrome (patients lacking positive affect)
32
Which pharmacological properties does Agomelatine have?
1. Agonist actions at Melatonin 1 and Melatonin 2 receptors
2. Antagonist actions at 5HT2c
33
How does Agomelatine resynchronise circadian rhythms?
In the abscence of melatonin production from the Pineal gland, Agomelatin is able to act as a substitute melatonin and acts as an agonist on Melatonin 1 & 2 receptors In the suprachiasmic nucleus.
Additionally it also blocks 5HT2c receptors in the ventral tegmental area and locus coeruleus therefore promoting dopamine and norepinephrine release in the PFC.
34
Mirtazepine is a multifunctional drug, it has which 5 principal mechanisms of action?
5HT2a antagonism
5HT2c antagonism
5HT3 antagonism
alpha2 adrenergic antagonism
H1 histamine antagonism
35
h1 Antagonism causes
sedation and weight gain
36
5ht2A Antagonism causes:
Increase downstream release of dopamine in the prefrontal cortex.
Also improves slow wave sleep.
37
Alpha 2 antagonist actions ( as seen with Mirtazepine)
Alpha 2 autoreceptors on noradrenergic neurons are responsible for turning off norepinephrine release (auto receptor).
When this auto receptor is blocked, norepinephrine can no longer turn off its own release.
The same happens on alpha 2 heteroreceptors on the 5HT neuron
38
Where are 5HT3 receptors found in the body
Chemoreceptor trigger zone in the brainstem
(.where they mediate nausea and vomiting)
In the GI tract where they mediate nausea, vomiting and diarrhoea when stimulated by serotonin.
Therefore blocking 5HT3 receptors can protect against chemotherapy induced nausea and vomiting as well as serotonin induced Gi effects.
39
How does 5HT3 receptor antagonism ( Mirtazepine) have antidepressant effects.
5HT3 antagonism leads to disinhibition of glutamate release, and of acetylcholine and norepinephrine. These actions theoretically release neurotransmitters downstream to have antidepressant actions.
40
Which type of drug is trazodone?
Serotonin antagonist/ Reuptake inhibitor (SARI)
41
Which pharmacological actions does trazodone have (receptor)
5ht2a & 5ht2c receptor antagonism
5ht1d & 5ht7 receptor antagonism
alpha 1a, 1b, 2c, 2b antagonism
h1 receptor antagonism
5ht1A Agonism
42
Trazodone at low doses is used as a ...
Hypnotic agent,
A hypnotic agent can potentially relieve insomnia and increase remission rates of depression. Remember the common residual symptoms of depression are often insomnia
43
How does trazodone exert its hypnotic effects
Blocking 5HT2a, alpha1 subtypes and H1
blocking 5ht2a receptors enhances slow wave sleep
blocking alpha1 and h1 receptors interferes with monoamine arousal mechanisms.
44
Vortioxetine is especially good at improving...?
Cognitive symptoms in unipolar depression
45
Name 4 domains of Cognition (fab four)
1. Attention
2, executive function
3. Memory
4. Processing speed
46
pharmacological actions of Vortioxetine
SERT inhibition and 5ht1a agonism
(raised serotonin levels- SERT inhibition, raised dopamine, acetylcholine and norepinephrine- 5ht1a agonism)
SERT inhibition and 5HT1b/d antagonism
stimulation of 5ht1b/d autoreceptors by serotonin turns off further serotonin release. Therefore antagonism of 5ht1b/d inhibits this negative feedback, allowing continuous release of serotonin.
5ht1b partial agonism/ antagonism causes downstream release of neurotransmitters ( DA, NE, HA, ACh)
5ht3 antagonism causes release of pro cognitive neurotransmitters.
5ht7 Antagonism: Serotonin inhibits its own release by 5HT7 receptors. Therefore antagonism of 5ht7 causes serotonin release.
47
How does postpartum depression happen
Pregnant women have high circling brain levels of naturally occurring allopregnanolone. After delivery there is a decline in brain levels of neuroactive substances triggering a depressive episode.
48
How does the drug Brexanolone (neuroactive steroid) work.
It rapidly restores neuroactive steroid levels over a 60 hour IV infusion. Rapidly reverses depression.
The 60 hour time also provides the necessary time for postpartum patients to accommodate to their lower levels of Neuroactive steroids without relapsing.
Neuroactive steroids bind to benzodiazepine sensitive and benzodiazepine insensitive GABAa receptors.
GABAa benzodiazepine insensitive receptors are thought to have antidepressant effects.
49
Treatment resistant unipolar depression:
Olanzepine- Fluoxetine option
5HT2a blocking properties of olanzepine likely account for anti depressive effects.
Both fluoxetine and Olanzepine have 5HT2c antagonist properties.
Therefore this combination of drugs can be thought of as a potent SERT/ 5HT2c inhibitor.
Unfortunately this combination often leads to unacceptable weight gain and metabolic disturbances.
50
Treatment resistant unipolar depression:
Quetiapine
Action in depression likely linked to combined actions of quetiapine and its active metabolite norquetiapine at both 5HT2c receptors and at norepinephrine transporters.
It also acts at other relevant receptors: 5HT2a, 5HT7, alpha2a and agonist at 5HT1a
Issues: sedation, moderate weight gain and metabolic disturbance.
51
Treatment resistant depression:
Aripiprazole
Antidepressive properties attributed to 5HT1a partial agonist actions
secondary properties: D3, 5HT7, 5HT2c, alpha2 antagonist actions.
well tolerated, little weight gain, some may experience akathisia.
52
How does brexpiprazole exert its antidepressant effects:
1. Alpha1 receptor antagonism: This reduces glutamatergic output in the substantial nigra leading to reduced activity of the GABA interneuron and therefore disinhibition of the dopamanergic pathway (increasing dopamine)
*reduced dopamine in the motor striatum leads to reduction in Drug induced Parkinsonism.
2. Alpha1 receptor antagonism: reduces glutamateric output in the VTA leading to reduced activity in the GABA interneuron & therefore disinhibition (enhancing) mesocortical dopamine pathway.
3. 5HT2A antagonism
53
How does Ketamine exert its antidepressant effects?
IV ketamine is a racemic mixture of R & S ketamine, each have binding properties at NMDA subtype of glutamate receptor, and at sigma1 receptor.
The leading hypothesised theory is that ketamine has NMDA antagonism specifically at the open channel phencyclidine site.
54
Why does ketamine cause immediate improvement in depression?
IV administration of ketamine has rapid onset antidepressant effects and antisuicidal ideation effects.
Ketamine causes immediate improvement in neuronal plasticity. Neurotropic factors such as BDNF (brain derived neurotropic factor ) and growth factors such as VEGF ( vascular endothelial growth factor) are deficient in chronic stress and major depression.
*Loss of BDNF and VEGF are linked to neuronal atrophy in the hippocampus and and prefrontal Cortex.
55
How does ketamine cause its rapid antidepressant effects?
Ketamine causes an immediate burst of downstream glutamate release after blocking the NMDA receptor.
Glutamate release stimulates AMPA receptors. These receptors active ERK, AKT signal transduction, which leads to expression of dendritic spines and synaptogenesis. Increase in dendritic spines and synaptogenesis is hypothesised to be the cause of rapid antidepressance.
56
What is Esketamine used for
It is an intranasal preparation of ketamine can be given weekly or twice weekly.
May be used as an augmenting agent to standard antidepressant drugs
57
What is California rocket fuel?
It is the combination of an SNRI and Mirtazepine:
Its action is achieved by combining the serotonin and norepinephrine inhibition of the SNRI with the disinhibition of serotonin and norepinephrine release by alpha2 antagonist actions of mirtazepine.
Mirtazepine also has pro dopaminergic actions by 5ht2c.
58
Antidepressant actions of tricyclic antidepressants
Block serotonin and norepinephrine.
Additionally some may have antagonist actions at 5HT2A and 5HT2C receptors.
59
Name 4 unwanted effects of tricyclic antidepressants
1. Blockade of muscarinic cholinergic receptors
(dry mouth, blurred vision, urinary retention and constipation- anticholinergic effects)
2. H1 histamine receptors
(sedation and weight gain)
3. Alpha1 adrenergic receptors
(orthostatic hypotension and dizziness)
4. Voltage sensitive sodium channels.
(Blockage of sodium channels in the heart and the brain leading to seizures and arrhythmias)
60
How many subtypes of monoamineoxidase are there?
2, MAO A & B
61
List properties of MAO A
MAO A preferentialy metabolises the monoamines that are closely related to depression ( serotonin and norepinephrine)
MAO A also metabolises dopamine and tyramine
MAO A is found in the brain. MAO A is found in noradrenergic and dopaminergic neurons.
MAO A is the major form of enzyme found outside the brain.
Brain MOA A must be substantially inhibited for antidepressant effects to occur. This is because it is the enzyme primarily responsible for the breakdown of serotonin and norepinephrine which are 2 of the 3 monoamines linked to depression and antidepressant effects.
62
List properties of MAO B
Inhibition of MAO B is not effective as an antidepressant, because it has no effect on serotonin or norepinephrine metabolism.
When MAO B is selectively inhibited it can boost the action of concomitantly administered levodopa in Parkinson's disease and reduce on/off motor fluctuations.
63
Name the 3 MAO B inhibitors approved for use in Parkinson's
1. Selegiline
2. rasagiline
3. safinamide
64
Precautions with MAOIs
1. Tyramine containing foods are to be avoided. (cheese)
Tyramine releases norepinephrine which is usually destroyed by MOA A (tyramine ). In the presence of a MAOI, tyramine can elevate blood pressure because norepinephrine is not safely destroyed.
2. Drug drug interactions
avoid drugs that can raise BP by sympathomimetic action and those that can cause a potentially fatal serotonin syndrome by serotonin reuptake inhibition.
65
What similarities are there in Bipolar mania and Acute psychosis
Excessive dopamine levels and release in the mesostriatal dopamine neurons.
This explains why dopamine/ serotonin blockers work both in bipolar mania and acute psychosis
66
Which group of agents are used to treat bipolar depression and depression with mixed features, and which agents have fallen out of favour?
1. Serotonin/dopamine blocking agents are used.
*The monoamine reuptake inhibitors are used less commonly now...
However, Olanzepine + Fluoxetine is still approved for the treatment of bipolar depression.
67
Which properties make the combination of Olanzepine and Fluoxetine a good combination for bipolar depression.
5HT2a and 5HT2c antagonism.
68
Properties that make Quetiapine good for bipolar depression.
5HT2A and 5HT2c antagonism
alpha2 antagonism
AGONIST actions at 5HT1a
D2 antagonist properties of quetiapine will prevent spill over into mania
69
What is cariprazines action:
D3/D2 & 5HT1a partial agonism
70
Which agent I the most potent for the D3 dopamine receptor
Cariprazine
71
Postsynaptic blocking of D3 receptors in the limbic region may lead to...
Antipsychotic effects
72
What happens when D3 is blocked in the ventral tegmental area?
The function of D3 receptors in the VTA, is to act as auto receptors; their function is to detect dopamine and inhibit further release.
Dopamine receptors in the prefrontal cortex are D1.
When D3 antagonists act in the VTA, this disinhibits the dopamine neurons projecting to the prefrontal cortex and they release dopamine onto D1 receptors..This theoretically has antidepressant effects.
73
Name 3 possible mechanisms of action of Valproic Acid
1. Inhibiting voltage sensitive sodium channels
(Inhibits phosphorylation. Leading to less sodium being able to pass into the neuron which causes diminished release of glutamate and therefore less excitatory neurotransmission)
2. Boosting the actions of neurotransmitter GABA (therefore more inhibitory neurotransmission)
3. Regulating downstream signal transduction
74
side effects of valproate
Sedation
weight gain
hairloss
Bone marrow
Liver
Pancreas
Neuro tube defects
Menstrual disturbances, Polycystic ovaries
Insulin resistence
75
Mechanism of action of Carbamazepine
Acts by blocking voltage sensitive sodium channels, within the channel itself; the alpha subunit of VSSC.
76
Carbamazepine can be used to treat
Epilepsy
Manic phase of bipolar
Neuropathic pain
77
Side effects of Carbamazepine
Profound immediate bone marrow suppression (needs initial blood count monitoring)
Induction of Cytochrome P450 enzyme 3A4
Neural tube defects
78
Which enzyme does carbamazepine induce:
Cytochrome P450 3A4
79
Even though Lamotrigine is generally well tolerated, it can cause:
Rashes including Steven Johnson Syndrome
80
Why is Oxcarbazepine better than Carbamazepine
Less sedating
less bone marrow toxicity
Less CYTP450 3A4 interactions (making it more tolerable)
*currently. only for off label use, no proven efficacy.
81
Which two drug combinations are evidence based in bipolar mood disorder
1. 5HT/DA blocker + Lithium
2. 5HT/DA blocker = Valproate
*Practice based combo
5HT/DA blocker + lamictal/Lamotrigine
82
What is Dextromethorphan?
It is a NMDA antagonist, with strong binding affinity for SERT, and sigma 1 receptors.
It is rapidly metabolised by CYTP450 2D6 and therefore needs to be combined with a CYTP450 2D6 inhibitor; such as Bupropion or Quinidine.
Useful in major depressive disorder, treatment resistant depression and agitation in Alzheimers disease.
83
How does MDMA exert its effect ? (ecstasy/ Molly)
It is a powerful serotonin reuptake inhibitor with VMAT2 inhibition causing enhanced serotonin release.
Strong actions at 5HT2A.
84
What is Psilocybin
Hallucinogen in magic mushrooms
It has a similar structure to LSD.
It is rapidly converted to psilocin.
Both Psilocybin and Psilocin bind to a number of serotonin receptors including 5HT2A/2C
85
Core symptoms of depression
Depressed mood and loss of interest
86
Core symptoms of anxiety disorders
Excessive worry
Anxiety
87
Which symptoms overlap in Major depressive disorder and Anxiety disorders
Fatigue
concentration problems
Sleep disturbance
Psychomotor/arousal
88
Symptoms of generalised anxiety disorder
Core symptoms
1. Generalised anxiety and worry
2. Increased arousal
3. fatigue
4. difficulty concentrating
5. Sleep problems
6. irritability
7. Muscle tension
89
Symptoms of Panic disorder
Core symptoms
1. Anticipatory Anxiety and worry about panic attacks
2. Unexpected panic attacks
3. Phobic avoidance or behavioural changes
90
Symptoms of Social anxiety disorder
Core symptoms
1. Anxiety or dear over social performance & worry about social exposure
2. Expected (predicted ) panic attacks
3. Phobic avoidance of those situations
91
Symptoms of PTSD
Core symptoms
1. Anxiety while traumatic event is being re experienced
& worry about having the other symptoms of PTSD
2. Increased arousal
3. sleep difficulties (nightmares)
4. Avoidance behaviours
92
Neurobiology of Fear
1. Feelings of fear are regulated by connections between the amygdala and orbitofrontal cortex (over activation of these circuits)
2. Motor response to fear: Behaviours of avoidance, regulated by reciprocal connections between the amygdala and periaqueductal gray. eg: freezing, fight or flight
3. Endocrine output of fear: Increased cortisol, due to amygdala activation of the Hypothalamic pituitary adrenal axis. Prolonged cortisol release and activation of HPA axis leads to increased risk of coronary artery disease, T2DM and stroke
4. Breathing output: Changes in respiration in response to fear are regulated by the activation of the parabrachial nucleus via the amygdala.
Leads to increased resp rate, SOB, exacerbation of asthma or sense of being smothered.
5. Autonomic output of fear: increased HR, increased BP via recipricol connections between the amygdala and the locus coeruleus. This leads to increased risk of atherosclerosis, Cardiac ischaemia, MI, HR variability
93
Worry is mediated by which circuit
Cortico-striato-thalamo-cortical loops
94
Where do benzodiazepines have their action ( for anxiety)
Benzos modulate excessive output from the amygdala,. Benzos enhance phasic inhibition of GABA by positive allosteric modulation of postsynaptic GABAa receptors
95
Give 2 examples of Alpha 2 delta ligands
Pregabalin
Gabapentin
96
How do Alpha 2 Delta Ligands cause anxiolysis
The alpha2 ligands, pregabalin and gabapentin bind to the alpha2delta subunit of the presynaptic N and P/Q VSCC's, where they block the release of excitatory neurotransmitters such as glutamate.
Hypothetically they bind to open VSCC's in order to reduce fear and worry.
97
Where do SSRI's exert their anxiolytic effect
By actions on 5HT1a receptor (agonism)
98
Explain how fear conditioning takes place
Fear can be learnt when stressful situations are associated with emotional trauma.
Repetition of a sensory experience associated with a previous earlier exposure to a fearful event can trigger traumatic re-experiencing (hyperarousal states)
The Amygdala is responsible for 'remembering fear'. It does this by increasing the efficiency of neurotransmission at glutamatergic synapsis in the lateral amygdala as sensory input comes from the sensory cortex and thalamus.
This information is sent to the central amygdala where fear conditioning also improves the efficiency of neurotransmission at another glutamate synapse.
Both synapsis are restructured and permanent learning is is embedded into the NMDA receptors causing long term potentiation and synaptic plasticity. This causes sensory cortex and thalamus to successfully trigger same fear response from central amygdala output.
99
Facilitating fear extinction with NMDA receptor activation
Giving an agent that enhances NMDA action while an individual is receiving exposure therapy could increase the efficiency of glutamate neurotransmission at synapses involved in fear extinction. If this leads to long term potentiation and synaptic plasticity while the synapsis are being activated by exposure therapy, it could result in structural changes in the amygdala.
100
Name 3 types of primary afferent neurons
1. A- Beta
2. A-Delta
3. C fibers
101
Function of A-Beta primary afferent neuron
Detects small movement, light tough, hair movements and vibration
102
Function of A-Delta primary afferent neuron
Falls in-between A-Beta and C fibres: sensing noxious mechanical stimuli and sub-noxious thermal stimuli
103
Function of C fibres
These are bare nerve endings that are activated by mechanical, thermal or chemical stimuli
104
Which symptoms are associated with fibromyalgia
Fatigue, anxiety, pain, sleep difficulties, depression
105
Symptom based algorithm for Fibromyalgia
Pain: linked to transmission via thalamus
Fatigue: Striatum and spinal cord
Lack of interest, mental fatigue: Prefrontal cortex
Fatigue, low energy and lack of interest may also be related to nucleus accumbens
Disturbances of sleep and appetite: Ass with hypothalamus
Depressed Mood: Amygdala and orbitofrontal cortex
Anxiety: Amygdala
106
Which are of the brain is most associated with gray matter loss in chronic pain syndromes
Dorsolateral PFC, thalamus and temporal cortex
107
What determines whether one experiences pain
The degree of nociceptive neuronal activity determine whether one experiences acute pain. An action potential on a presynaptic neuron triggers sodium influx which in leads to calcium influx causing release of neurotransmitter.
If the generated action potential at the presynaptic neuron causes minimal neutransmitter release...there is minimal pain, if the action potential is stronger, then VSCC remain open for longer allowing more neurotransmitter release and therefore more stimulation at the postsynaptic neuron.
108
How does gabapentin and pregabalin work in neuropathic pain.
These agents bind to alpha2delta subunits on VSCC's decreasing amount of calcium influx and therefore reducing pain (Via decreased stimulation at postsynaptic neuron).
109
How is histamine action terminated:
N-methyltransferase and monoamine oxidase B
* there are no reuptake pums for histamine
110
Function of histamine H3 receptor
Autoreceptor, turns off further histamine release when histamine binds.
* novel drugs may bind here to promote further release of histamine
111
What happens when histamine binds onto H1 postsynaptic receptors
It results in wakefulness and normal alertness
112
Where is histamine produced
In the brain it is solely produced by cells in the tuberomamillary nucleus of the hypothalamus. From the TMN, histaminergic neurons project to most regions of the brain. The regions important for wakefulness are (PFC, Basal forebrain, thalamus, and brainstem neurotransmitter centers)
113
How is Orexin related to narcolepsy
Orexin neurons are localised in the hypothalamus. These hypothalamic neurons degenerate in narcolepsy. Loss of these neurons causes the inability of orexin to be produced and released downstream on neurotransmitters that promote wakefulness. Therefore wakefulness is not stabilised.
114
Name 2 types of Orexin and their postsynaptic receptor
Orexin A & B.
Orexin 1 & 2
* Orexin 1 are highly expressed on noradrenergic locus coeruleus. Orexin 2 receptors highly expressed on histaminergic tuberomammillary nucleus.
115
What is the role of Orexin
1. Stabilising wakefulness
2. Regulate feeding behaviour
3. Regulate reward.
*During wakefulness Orexin neurons are active and fire tonically to maintain arousal. When presented with a stimulus (eg external stressor or internal stressor such as increased CO2), Orexin neurons show more rapid firing which in turn leads to behavioral changes
*Orexins are not arousal neurotransmitters themselves, but rather stablelise wakefulness by downstream actions on other neurotransmitters.
eg ACh stimulation from the basal forebrain and the pedunculopontine and laterodorsal tegmental nuclei
(see diagram page 408)
116
The homeostatic sleep drive is dependant on the accumulation of...?
Adenosine.
This leads to disinhibition of the ventrolateral pre optic nucleus and the release of GABA, facilitating onset of sleep
117
The circadian wake cycle is stimulated by..?
Light acting upon the suprachiasmic nucleas, which stimulates the release of Orexin (Hypocretin)
During being of wakefulness histamine is released from the tuberomamillary nucleus onto neurons throughout the cortex and in the ventrolateral pre optic area, inhibiting the release of GABA.
118
Which stages make up non REM sleep
stage 1 & 2
119
Which stages make up REM sleep
Stage 3 & 4
120
Neuroanatomical abnormalities in insomnia
Reduced gray matter in left orbitofrontal cortex and hippocampus
121
Neurobiological abnormalities in insomnia
1.Decreased GABA levels in occipital and anterior cingulate cortices
2. Reduced nocturnal melatonin secretion
3. Increased glucose metabolism
4. Attenuated sleep-related reduction in glucose metabolism in wake promoting regions
5. Decreased serum BDNF
122
Autonomic nervous system Abnormalities associated with insomnia:
Heart rate elevations and variability
Increased metabolic rate
increased body temperature
HPA axis activation
Increased NE
123
Systemic inflammatory factors associated with insomnia :
IL6
124
Genetic factors associated with insomnia
CLOCK gene polymorphisms
GABA-A receptor gene polymorphisms
SERT gene polymorphisms
HLA gene polymorphisms
Epigenetic modifications affecting genes involved in the response to stress.
125
Criteria for Insomnia
Difficulty falling asleep ( sleep latency) >30 min
Wakefulness after onset of sleep >30 min
Decreased sleep efficiency < 85%
Total sleep time <6.5 hours
126
Name the Z drugs that may be used in insomnia
Zopiclone, Zaleplon, Zolpidem
* These are GABAa positive allosteric modulators
127
Which clinical effects does binding to alpha1 have
Sedation, daytime sedation, anticonvulsant actions and possible amnesia
128
Which clinical effects does binding to alpha2 & 3 have ?
anti anxiety, muscle relaxant, alcohol potentiating
129
How do DORA's (Dual Orexin Receptor Antagonist) )work
DORA's block the wake stabilising effects of Orexin, especially at Orexin 2 receptors.
This inhibits Orexins ability from promoting the release of wake promoting neurotransmitters (histamine, acetylcholine, norepinephrine, serotonin and dopamine)
130
Give 2 examples of DORA's ( Dual Orexin Receptor Antagonists)
Suvorexant & Lemborexant
131
Discuss the hypnotic/antidepressant Trazodone
5HT2a/ alpha1/ h1 antagonist.
Enhances sleep drive via blockade of arousal neurotransmitters.
132
What is Doxepin:
It is a tricyclic antidepressant with a high affinity for H1 receptor at low doses (much lower doses than what is needed for antidepressant effects).
It acts as an antagonist, and therefore has a hypnotic effect.
133
Criteria for diagnosis of idiopathic hypersonia
1. Excessive daytime sleepiness for at least 3 months
2. Short sleep latency (time to fall asleep)
3. Fewer than 2 cycles of REM at onset of sleep on polysomnography
* CSF levels of histamine may be low
* Generally have normal Orexin CSF levels
134
Describe some of the features of narcolepsy
Excessive daytime sleepiness
intrusion of sleep during periods of wakefulness
Abnormal REM sleep
Cataplexy (loss of muscle tone), may be triggered by emotions
Hypnagogic Hallucinations ( often present upon waking)
*Neuropathology: loss of Orexin Neurons in the lateral Hypothalamus.
Note that Orexin also stablises motor movements, allowing normal movements during the daytime when orexin is high and inhibiting movement at night when levels are low. Therefore when Orexin levels are low in the daytime (due to loss of orexin neurons), this destabilises motor movements during the daytime allowing intrusion of motor inhibition and loss of muscle tone.
*A CSF orexin level of <110 is diagnostic
135
Give 4 examples of circadian rhythm disorders
Advanced sleep phase disorder
Delayed sleep phase disorders
Shift work disorder
Non-24 hour sleep- wake disorder
136
Resetting circadian rhythms: Advanced sleep phase disorder
Early evening bright light
early morning melatonin
137
Resetting circadian rhythms: Delayed sleep phase disorder
Early morning bright light
Evening melatonin
138
Where is melatonin produced and where does it act
The pineal gland, the suprachiasmic nucleus
139
Name Melatonin agonist drugs
Ramelteon and Tasimelteon
Both are M1/M2 receptor agonists
Agomelatine: MT1/MT2 receptor agonist, as well as 5HTc and 5HT2b receptor antagonist
140
MOA of caffeine
Caffeine is an antagonist of Adenosine ( chemical which drives homeostatic sleep drive )
Also, D2 receptors can couple with adenosine receptors reducing the affinity of d2 receptors for dopamine. Caffeine blocks the adenosine receptor, and restores the affinity of D2 receptor for dopamine ( wake promoting and reducing fatigue)
141
Amphetamine and methylphenidate as wake promoting drugs
Classically referred to as stimulants
Their properties are norepinephrine- dopamine reuptake inhibitors and, in the case of amphetamines, as dopamine releasers and competitive VMAT2 inhibitors.
* Used in ADHD and narcolepsy
142
What is Modafenil
Wake promoting agent used in narcolepsy, obstructive sleep apnoea and shift work disorder.
They are inhibitors of the dopamine transporter DAT or Dopamine reuptake pump.
Modafenil has high affinity for the DATs, however only achieves incomplete occupancy of DAT. This leads to a slow rise in plasma levels and enhances tonic release. of dopamine rather than phasic large dopamine release which contributes to abuse.
143
What happens once dopamine is released after Modefanil administration
The dopamine arouses the cortex which can lead to downstream release of histmanine from the tuberomammilary nucleus and then activation of the lateral hypothalamus with orexin release to stabilise wakefulness.
144
What is Solriamfetol
wake promoting NDRI
used for daytime sleepiness, narcolepsy and as adjuncts to mechanical treatments for OSA.
145
What is Pitolisant
H3 autoreceptor antagonist. Therefore results in increased presynaptic release of histamine. Approved for use in narcolepsy, also useful for cataplexy
146
Negative side effects of Pitolisant
Very activating, may cause anxiety or insomnia
147
What is Sodium Oxybate:
Also known as Gabba hydroxybutyrate, acts as a partial agonist on GABAb receptors.
Acts as an antagonist when GABA levels are elevated, acts as agonist when GABA levels are low.
* It increases slow wave sleep and improves Cataplexy via actions on GABAb receptors.
148
trio of symptoms of ADHD
Inattention (executive dysfunction), hyperactivity and impulsivity.
149
Executive function in ADHD
Linked to inefficient information processing in the Dorsolateral prefrontal cortex.
1. Inability to sustain attention
2. Selective inattention (not being able to focus).. This is linked to the dorsal anterior cingulate cortex. ADHD patients may struggle to activate this part of the brain.
150
Which area of the brain is lined to impulsivity in ADHD
AND Which area is linked to motor hyperactivity.
1. Orbital frontal Cortex
2. supplementary motor area (pfc)
151
Name the test we can use to assess sustained attention
N-back test
152
Name the test we can use to assess selective attention
Stroop test
153
Optimal cognitive performance
Needs moderate stimulation of alpha 2 receptors by norepinephrine and d1 receptors by dopamine.
If stimulation is too high or too low, cognitive dysfunction can occur.
Norepinephrine actions at alpha2a receptors strengthens signal
Dopamine actions at D1 receptors weaken signal
(figure 11.18/19)
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Neurodevelopment and ADHD ( pathophysiology)
ADHD patients have delayed cortical development. Synaptogenesis in the PFC might be responsible for altered connections that could prime the brain for ADHD.
At age 6-7 synaptic pruning occurs, and weak synapses are deleted, errors in this process could affect development of executive function
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MOA of Methylphenidate
Norepinephrine and Dopamine reuptake blocker.
By blocking the NET and DAT. Methylphenidate binds to these receptors in different sites than where monoamines binds, ie allosterically
There are two isomers, D and L isomer.
D-isomer is much more potent.
156
MOA of Amphetamines
Block transporters for Norepinephrine and Dopamine.
Amphetamine is a competitive inhibitor of and pseudo-substrate for NET's and DAT's. It binds at the same sites as monoamines bind to the transporters, thus inhibiting NE and DA reuptake.
At high doses (drug abusers), amphetamine is transported as a 'hitch hiker' into the synaptic cleft. Once there it acts as a competitive inhibitor of VMAT2 for DA and NET.
I then hitch hikes a ride into the synaptic vesicles, causes dopamine content to be pushed out into the presynaptic cytoplasm.
This causes the DATs to reverse directions spilling DA into the synapse. Also opening presynaptic channels for more release of dopamine into the synapse.
157
How do stimulants such as Methylphenidate have the potential for abuse:
Rapid amplification of phasic neuronal firing of DA in the Nucleus Accumbens is associated with euphoria and abuse.
Immediate release formulations have higher risk for abuse due to increased PHASIC and tonic release of DA signalling
158
Describe properties of an ideal stimulant, for use in treatment of ADHD:
You want an agent which Targets both NET and DAT.
You want to occupy enough NET's in the PFC to enhance tonic NE signalling via Alpha2a receptors. Net inhibition also increasing tonic DA signalling in the PFC via d1 receptors.
This leads to a good therapeutic effect without stimulating the D2 receptor in the nucleus accumbens which would lead to phasic dopamine release.
159
How does Atomoxetine (ADHD)
Atomoxetine is a selective norepinephrine reuptake inhibitor.
It results in slow onset, long duration NET inhibition in the PFC, which restores tonic postsynaptic D1 and alpha2a signalling & downregulates phasic NE and DA actions.
160
Why is there a decreased abuse potential with Aomoxetine over stimulants
Atomoxetine blocks NET's in the PFC. Since there are a lack of NETs in the nucleus accumbens, this prevents an increase of norepinephrine and dopamine there.
Nucleus accumbens largely responsible for addiction and abuse.
161
Name 2 Alpha2 agonists used in the treatment of ADHD
Guanfacine and Clonidine (both only have controlled release versions which are approved for ADHD)
162
Which drug is more selective for the Alpha2a receptor, Guanfecine or Clonidine
Guanfacine
163
Name some of the off label uses of Guanfacine and Clonidine
Conduct disorder
Oppositional defiant disorder
Tourettes Syndrome
164
In theory when should Guanfacine be used in ADHD over stimulants.
Guanfacine is useful in situations were low NE levels are the primary reason for the patients ADHD symptoms.
( no way of determining this though, so trial of the drug needed ).
Also useful as an add on in patients that already have optimised dopamine levels ( or have inadequate response to a stimulant)
Also useful in oppositional defiant disorder.
165
Give 3 pathophysiological traits of Alzheimers disease
1. Amyloid-beta
2. Neurofribrallary tangles composed of hyperphosphorylated tau protein
3. Substantial neuronal loss
166
What is the most common type of Frontotemporal Dementias
Behavioral type frontotemporal dementia.
* The other 3 are Primary progressive aphasias
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Clinical characteristics of Behavioral variant frontotemporal dementia:
Progressive personality changes:
-lack of empathy/ sympathy
-Disinhibition
- apathy
Hyperorality
Perservaritive/ compulsive behaviours
Cognitive deficits
Cued memory and visuospatial spared
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The Amyloid cascade
Alzheimers disease is caused by the accumulation of toxic amyloid beta, which form plaques, hyperphosphorylaiton of tau, neurofibrillary tangle formation, synaptic dysfunction and ultimately neuron loss.
169
Which genes lead to a higher risk of Amyloid precursor protein processing.
Apolipoprotein E4, conveys highest risk for AD.
Apolipoprotein E3 had a risk that falls between E4 and E2
Apoliprotein E2 gene offers some protection from AD
170
Which gene offers some protection from Alzheimers disease
Apolipoprotein E2
171
Name the 3 stages of Alzheimers disease
1. Presymptomatic stage 1 ( asymptomatic amyloidoidosis)
Amyloid beta can be detected on PET scans as well as radioactive neuroimaging tracers which label Amyloid beta plaques
2. Minor cognitive impairment: episodic memory loss, onset of symptoms correlates with neurodegeneration ( elevated CSF tau, brain glucose hypo metabolism, volume loosen key brain regions on MRI)
3. Dementia: severe cognitive deficits.
172
Name the 3 circuits that are treatable for symptoms in dementia
Memory network
Psychosis network
Agitation network
173
Which drugs are useful in the memory network in Dementia
Acetylcholinesterase inhibitors
NMDA Antagonist Memantine
174
Which drugs are useful in the psychosis network in dementia
5HT2a Antagonist, Pimvanserin
175
Which drugs are useful in Agitation network in dementia
Dexomethorphan + Bupropion.
Brexpiprazole
176
Acetylcholine is produced from which 2 precursors
acetyl coenzyme A
choline
*brought together by choline acetyltransferase
177
how is acetylcholine action terminated:
1. acetylcholinesterase
2. butyrylcholinesterase
* both enzymes convert acetylcholine into choline which is transported out of the synaptic cleft and back into the presynaptic neuron into choline. it can then be recycled into acetycholine and stored in vesicles by vesicular acetylcholine transporter.
178
Muscarinic acetylcholine receptors
M1, M3, M5 are excitatory postsynaptic receptors, stimulate downstream second messaging
M2 and M4, are inhibitory presynaptic autoreceptors, preventing further release of acetylcholine.
M4 is also thought to be inhibitory postsynaptic receptors.
* M2 and M4 are also present on non cholinergic receptors (eg GABA and glutamate neurons). When acetylcholine diffuses away from the synapse and occupies these receptors , it can block neurotransmitters there
179
Nicotinic Acetylcholine receptors
Acetylcholine neurotransmission can be regulated by ligand gated excitatory ion channels known as nicotinic acetylcholine receptors.
*The alpha 7 subtype can exist presynaptically where they facilitate acetylcholine release, or postsynaptically where the regulate cognitive function in the PFC.
*The Alpha4Beta2 receptors are postsynaptic and regulate dopamine release in the nucleus accumbens.
180
Which drugs do we use in Alzheimers disease for cognitive and memory decline:
Acetylcholinesterase inhibitors
181
What is Donepazil:
Reversible, long acting Acetylcholinesterase inhibitor.
* has actions presynaptically, postsynaptically and in the periphery ( where it can cause GI side effects)
182
What is Rivastigmine
Intermediate acting acetylcholinesterase inhibitor. More selective for Acetylcholinestere than for Butyrylcholinesterase.
* Mainly acts at hippocampus and cortex.
* Also some action at Butyrylcholinesterase at glial cells beneficial in gliosis when corticol neurons die.
* Also causes GI side effects like Donapezil
183
What is Galantamine
Acetylcholinesterase inhibitor with positive allosteric modulation of nicotinic cholinergic receptors.
184
The role of glutamate in Alzheimers disease
Glutamate is thought to be released in excess in Alzheimers disease.
In the resting state, the NMDA receptor is blocked by magnesium.
In normal neurotransmission, glutamate binds to the NMDA receptor, if the neuron is depolarised and glycine binds simultaneously, the channels open and allow ion influx. This results in long term potentiation.
Neurodegeneration caused by plaques and tangles could cause a steady leak of glutamate and result in excess calcium influx in the postsynaptic neurons. This causes short term memory loss, and long term destruction of neurons due to accumulation of free radicals.
185
Which agent is approved for use in Parkinsons disease psychosis?
Pimvanserin: 5HT2a selective antagonist. Lowers normal serotonin stimulation to surviving glutamate neurons which have lost their GABA inhibition due to neurodegeneration.
see 12.42b/C
186
Where does agitation come from in Alzheimers disease:
Agitation occurs secondary to thalamic neurodegeneration.
Normal top down inhibition of sensory input prevents reflexive and thoughtless motor responses. (Sensory input able to break out of thalamus to cortex..motor responses). Top down cortisol inhibition filters out emotional input so that we don't generate emotional responses (emotional input unfiltered by thalamus allowed amygdala to increase limbic/ emotional stimulation)
Amydala output to the locus coeruleus elicits norepinephrine release in the cortex mobilising emotions and arousal.
187
Brexpiprazole in alzheimers disease
Targets multiple neurotransmitters:
1. Dopamine 2 partial agonist
2. 5HT1a partial agonist
3. 5HT2a antagonist
4. Alpha1 and alpha 2 adrenergic receptor blocker
*Reduces dopamine output in the VTA triggered by amygdala (Improves emotional filtering through thalamus)
*Alpha1&2 reduces norepinephrine output at locus coerulus, therefore reducing arousal and emotional responses.
188
How does dextromethorphan- Bupropion work in agitation
NMDA antagonist action.
Blocks excessive excitatory glutamate output from agitation network that leads to motor and emotional agitation. blocks NMDA receptors in cortex, LC, thalamus, amygdala, VTA.
189
Which agents would you give for pseufobulbar affect
Dextromethorphan-quinidine
of dextromethorphan- bupropion
