Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Neuropharma Of CNS disorders > Affective Disorders > Flashcards

Affective Disorders Flashcards

1
Q

Affective disorders

A

Depression (mono depression) and anxiety

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Diagnosis of psychiatric diseases basis

A

Largely based on categorisation: clinical classification based on what you have (inclusion) and don’t have (exclusion)
DSM V & ICD 11

Pros: improved diagnosis
Cons: not considered symptom overlap, lacks pathophysiological definition, do not resolve causation so hindering mechanism and drug development

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Categorisations does not take into account dimensional expression or causes of psychiatric disorder and disease

A

Clinical syndromes, dragonet of neuro developmental impairment (number of circuits disturbed) symptoms (negative, positive, mood disturbances), risk factors (psychosocial environmental, early brain insult, CNVs, no. Of mutations)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Research domain criteria (RDoC) basic science approach

A

Physiology and interaction with environment
Biology of brain: genes, molecules, cells, circuits, physiology, behaviour, self report
Behavioural domains: negative and positive valence, cognitive systems, systems for social processes, arousal/regulatory systems, sensorimotor systems

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Why the change in approach to diagnose

A

Clearer indication of pathology
Help understand and treat

Synptom based categories > interstates data > data driven categories and then better diagnosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Depression stats

A

Cost £12 billion/year in lost revenue
Major health problem 6% of adults

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Animal models of depression

A

Difficult to create animal model

Rat in water = move and try to get out
Rat in water expression depression stuff = immobile

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Biological context of depression

A

Mood reflects a change in behavioural state
Low mood = negative thoughts
Averseness = reinforcer to modify behaviour, associated with “concentration”
Evolutionary advantage
Depression (sustained reflection on negative thoughts) debilitates focus

A) pathways controlling focus (eg prefrontal cortex)
B) modulation of pathways that control ficus (5HT)
Dysfunction of a+b = disease

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Diagnosis criteria of psychiatric disorders (depression)

A

Primary indicators: persistent low mood, loss of interest, fatigue

Persistence: at least 2 weeks

Associated symptoms: disturbed sleep, poor focus and indecisiveness, loss of confidence, change in appetite, suicidal thoughts, agitation, slow movements, guilt

No. Of symptoms = diagnosis
Not depressed <4, mild 4, moderate 5/6, severe 7 +

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Biological basis for multiple dysfunction in depression

A

Depressed mood - limbic system/arousal centres
Irritability - anygdala/hypothalamus
Low self esteem - amygdala
Modified appetite - hypothalamus
Guilt - limbic system
Weight change - hypothalamus
Loss of focus - hippocampus/cortex
Change in sleep - superchiasmatic nucleus
Decreased interest - nucleus accumbens, ventral tegmental area
Suicidal thoughts - amygdala

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Monoamine theory of depression

A

Elevating the levels of the NT available for signalling improves mood

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Stress pathway

A

Hypothalamus = key in stress pathway

Paraventricular nucleus release of CRF in response to stressful environment
CRF acts in pituitary to release ACTH (adrenocorticotropic hormone) into blood stream
ACTH target tissue or organ will amplify signal, pass through hypothalamus and pituitary which will stimulate adrenal cortex which release corticosteroid into blood
Corticosteroid = increase vigilance and metabolism (coping with stress event)
Negative feedback then stops loop

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

More tired after stress

A

Organised homeostatic response to overcome stress and so dispensed lots of energy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Persistent stress response

A

1) stress = prima facts in triggering depressions
2) dysregulation if feedback inhibition elevating corticotrophin releasing factor (CRF)
3) elevated glucocorticoid kill cells and synapse loss, glucocorticoids inhibitory to synaptogenesis and neurogenesis in the hippocampus
4)CRF1 and CFR2 receptors exist in outside hypothalamic pituitary axis eg amygdala
5) changes in CRF receptor lvls in PM brains in depressed patients
6)antagonists against CRF receptors have some indications in treatment

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

History & evidence of monoamine theory of depression

A

Iproniazid (trialed for TB) patients mood elevated. Target: inhibition of monoamine oxidase and so increase neuroactive monoamine

Imipramine trialed as antipsychotic. Patients mood elevated. Blocks reuptake of released NT into cells by blocking the transport proteins
Adrenaline>serotonin> dopamine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

MAO -A

A

Metabolises serotonin, noradrenaline and dopamine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

MAO-B

A

Metabolise selectively dopamine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Normal monoamine signalling

A

monoamine exists in in cytoplasm. Signal first in vesicles. Neurone stimulated. NT released into synaptic cleft and act on MA receptor. After activation terminate transmission via diffusion away and reuptake. This can be either used as NT again or metabolised by MA oxidase so inactive form

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Monoamine hypothesis of depression in neurobiological context (inhibited monoamine neuron)

A

Blocked MA oxidase MA increase pool. More likely to be used a NT

Blocked reuptake transporter: slow or prevent reuptake and so increased potential to signal to the receptors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Evidence for monoamine hypothesis of depression

A

Drugs that increase content or synthesis (tryotophan) or sensitivity to monoamine are antidepressants
Drugs that deplete storage (reserpine) or synthesis of monoamines (alpha methyltyrosine) act as depression
Measuring metabolites in CSF or urine. 5HT increase during manic phase but when depressed evidence unclear
Measurable but Not major alterations in number of monoamine receptors especially 5HT 2A in PM brain tissue
Genetic mutations associated with deficits in 5HT synthesis predispose to depressive episodes (serotenergic transporters)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What happens when you elevate monoamines?

A

Serotonin - dorsal raphe to diffuse
Dopamine - Ventral tagmental area substantial nigra diffuse mainly front
Noradrenaline- locus coerelus to diffuse

Act on broad numbers of receptor
DA- 5
5HT- 15
NE- 10

Histamine receptors - 2

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Modifying the potency at sites responsible for the increase in transmitted levels

A

Tricyclic antidepressant - imipramine (tofranil) - blocks reuptake and transport of all 3 NTs

Selective serotonin reuptake inhibitor - fluoxetine (Prozac) - only blocks reuptake of serotonin mainly (still has a small effect on others) REDUCED SIDE EFFECTS

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

NT reuptake transporters

A

Secondary transporters - drug binding site and co transport Na+ and Cl- into cell with substrate
Substrate binds within transmembrane domains
Uptake inhibitors occupy substrate binding site and prevent translocation of MA into cytoplasm - competitive antagonism (mainly)
Some evidence for more than 1 SsRI binding site (eg citalipram)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

More complicated drug binding in transporter protein

A

2 binding sites (found by crystal structures)
Substrate binding site occupied by molecules escitopram. Second binding site above prevent release of bound drug. Prolongs binding and so increases efficacy of drug

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Detailed molecular explanation of transport protein

A

Key: 1 and 6 domains

Unlocked: Folded together to create the binding site for 5HT and fluoxetine
Sodium and chloride ions

Locked: additional binding site (allosteric) change chemical activity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Noradrenaline serotonin delete give antidepressants

A

Complement therapeutic intervention of depression
Eg mianserine and mirtazapine

Selective increase in noradrenalin by auto receptor block, selective increase in serotonin by heteroreceptor block. Additional blocking or activating on subclasses of receptor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Heteroreceptor

A

Similar as auto receptor in action but on different neurones
Block of this causes increase
Activation of this causes decreases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

Side effects of MAL inhibitors

A

Ipronazid (irreversible inhibition of MAO A and B) - several side effects

Phenelzihe (non selective but irreversible) - tyramine increase, noradrenaline accosiated systems activated so hot flushes, dizziness, insomnia, liver damage

Moclobemide (MAO selective and short acting) - drug interactions with opioids and sympathomimetic drugs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

Side effects of TCA drugs

A

Imipramine and clomipramine (block reuptake of monoamines non specifically, first generation reuptake inhibitors) - anyicholingergic (dry mouth, dizzy), hypertension, seizures. Interactions with CNS depressants (alcohol)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

Selective serotonin reuptake inhibitor side effects

A

Fluoxetine ( selective for serotonin) - nausea, diarrhoea, insomnia, inhibit other drug metabolism by p450 risk of interactions

Fluvoxamine (improved tolerance compared to MAO and TCA drugs) - reduced nausea compared to other SSRI’s

Can take up to 4 weeks to work

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

Noradrenergic and specific serotonergic antidepressants (NaSSA) side effects

A

Mirtasepine (blacks alpha 2, H1, 5HT2 and muscarinic receptors. Elevates MA by preventing inhibition release) - dry mouthed and sedation but faster acting than other antidepressants

Quicker improvement

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

Key idea of depression treatment

A

Modulation of MA specifically 5HT seems to be a high efficacy way of treating depression

33
Q

Antidepressants paradox

A

Drug administration: rapid effect on monoamine lvls in CNS
Generally consistent with inhibition of monoamine degradation (MAO) of inhibition of monoamine uptake
2-8 weeks of drug treatment to see effect on clinical signs of depression

Paradox predicts long term change in brain structure function in response to drug
Short term > medium term > long term

34
Q

Short term drug treatment

A

Inhibit uptake monoamine so increased signalling
Measured by micro dialysis as increased in raphe nucleus, locus coeruleus and cortex.
Locally inhibit neuronal firing and release by activating negative auto receptors

35
Q

Medium term drug treatment

A

Prolonged treatment leads to down regulation of auto receptors reduced feedback l. Inhibition leads to increase neuron firing and chemical transmission

Other things
Down regulated b2 postsynaptic receptors
Down regulated a2 auto receptors
Down regulated 5HT2 receptors

BASICALLY BACK TO SIGNALLING BEFORE TREATMENT

36
Q

Long term drug treatment

A

Above indicative of adaptive response after treatment and serotonin has been implicated in longer term and more sustained changes: neurogenesis and synaptogenesis
Sustained requiring of circuits associated with mood

37
Q

Neurogenesis

A

Neuronal progenitor stem cells to serotonin cells

38
Q

Excitation of serotonin mechanism that acts in depression

A

Excitation of discrete subset of prefrontal cortical project neurones regulates a motivated state (antidepressant)

Dorsal raphe, locus coreolus, ventral tegmental area, basal forebrain structures are all communicating and responding to the prefrontal cortex

Forced swim test (learned helplessness) - measure how long they don’t swim
Molecular entity experiment driven by: channel redopsin (retinol association so light sensitive) - ion channel function, flux sodium or calcium, activate polarises neurone

PFC inject with virus encoding channel redopsin, expressed in cell bodies, transported out into connecting regions

Stimulating dorsal raphe so release 5HT and modify and mitigate depression behaviour
Stimulating from distance away from where NT released and motivation/motility drops

39
Q

Ketamine

A

Old drug repurposed
Same class as PCP and MK801
Cheap
Vet medicine and drug abuse substance

40
Q

Issues with old/original drugs to treat depression

A

Original drugs: 20/30% don’t respond, possible misdiagnosis, many reasons for non responders (non compliance to genetic background), not helped by limited insight into mechanisms
Take time- self harm and suicidal thoughts prolonged so dangerous

41
Q

Ketamine: Dose dependent impacts on behaviour producing distinct behavioural states

A

Anaesthetic: 3mg/kg, inhibits thalamus regions
Dissociative symptoms: 1mg/kg, limits subcortical inhibition
Antidepressant: 0.5mg/kg

42
Q

Glutamates receptors

A

Glutamate released and worked on NMDA (target for ketamine, helps AMPA but not as fast, implicated in loss of plasticity in nervous system) and AMPA (activated and quickly responds to influx causing depol) receptors

43
Q

NMDA receptor binding sites

A

Needs two agonists - Glutamate and glycine
Magnesium binding sites in channel so blocks it
Slight Depol of membrane drops magnesium
Ketamine is a non competing e inhibitor of NMDA receptor

44
Q

Ketamine (0.5 mg/kg) vs midazolam (0.045mg/kg)

A

Sample, flushed of medication, assigned either treatment
Baseline rating of depression
Given drug and assed 1 day after antidepressant
Some follow up if patients responded

  1. Ket 50% reduction in MADRS scores (less depressed)
  2. Longer term effect, relapse below 50% reduction
  3. Adverse effects for both and 15% ket reported dissociation
45
Q

ketamine function as antidepressant

A

Ketamine selectively induced acute and allows a sustained antidepressant activity due to plasticity

46
Q

BDNF knock out animals do not show ketamine induced antidepressant activity

A

Ketamine activity requires acute induction if BDNF protein that depends on translational (protein synthesis) but not transcriptional control - (more BDNF available after the treatment with ketamine)

Confirmed as translational inhibitors (anisomycin) but not transcriptional inhibitors prevent ketamine effects

Selective modulation of translational machinery that turns mRNA into proteins

47
Q

Explanation of ketamine as antidepressant

A

Counterintuitive
Anti effect of drug (double negative)

Ketamine is a blocker of neural activity Blocks influx of Ca2 via NMDA receptor. reduces activity of eEF2 kinase so eEF2 phosphorylation levels of elongation de repressed the block (activating) translation so greater plasticity via synaptogenesis, neurogenesis and potential induced signalling

48
Q

eEF2 with phosphate

A

Inhibits

49
Q

eEF2 without phosphate

A

Active

50
Q

Regular elongation

A

eEF2 catalysed GTO- dependent ribosomal translocation step. Inhibited when eEF2is phosphorylase’s by eEF2 kinase
eEF2 kinase regulated by Ca2+ through Ca2+/calmodulin

Neuronal context, neural activity (through glutermatergic) to increase Ca2+

51
Q

Circuit level explanation of ketamine as an anti depressant

A

Can happen same or independent of biochemical explain

Excitatory (glutamate) neuron connected to GABA (inhibitory neurone. Stimulate glutamatergic neurone, release glutamate on inhibitory (GABA) neurone, excites it so inhibit first neurone via GABA.

NMDA receptor. Block. Reduced activation of inhibitory neurone. derepression so increased excitation of first neuron

Change plasticity within weeks

52
Q

Ketamines potential as antidepressant

A

Fast tracked for FDA approval in us
Nasal formulation - eskatamine
Delayed prescription in the uk - due to side effects like kidney failure
Don’t know long term impacts in terms of psychological impact
Long term efficacy short term rising
May be other explanations for ketamines efficacy

53
Q

Depression vs anxiety

A

Pathway - depression (mood), anxiety (fear)
Definition - d (symptoms and length of time are reported), a (symptom classification and self reporting)
Animal model - d (forced swim test), a (fear conditioning)
Brain pathways - d (circuit level connectivity), a ( circuit level connectivity amygdala)
Transmitter pathway - d (monoamines), a (GABA)
Molecular target - d (transmitter transporter), a (inhibitory GABA receptor)
Drug class - d (reuptake inhibitor), a (benzodiazepines)
Clinical confounds - d (side effects), a (withdrawal and addiction)

54
Q

Fear response

A

Normal pshysiological response for survival
Heightened sensory state - vigilance, Hyper aroused, heart and metabolic rate, fight or flight response
Fearful response is a learned response

55
Q

Anxiety definition

A

Pathophysiological state that detracts from normal function and impedes organisms success

Important cognitive component
Increased heart rate, decreased salivation, upset stomach, increase respiration, scanning and vigilance, bumpiness, frequent toilet breaks, fidgeting, freezing to regular stuff

56
Q

Fundamental to fearfulness

A

Ability to use past experience to modulate or modify the behaviour.
Eg monkey no scared of snake. Snake bites. Monkey scared.

Neuro modularity mechanism and pathways underlying fear response and anxiety pathophysiology

57
Q

Difficult to classify fear disorder in one thing

A

Panic attack, agoraphobia, panic disorder, specific phobia, social phobia, obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), acute stress disorder, generalised anxiety disorder

Cues and triggers to anxious
Time if length (panic attack 10 mins, panic disorder up to a month, ptsd more than 1 month)
Symptoms
Comordities (anxiety similar to withdrawal)

58
Q

Animal models for fear circuit

A

Context conditioning
Unsignalled shock in blue square, blue square fear, moved to other cage no fear
Signalled shock in blue square, blue square fear, signal no shock fear

1)accessing core fear circuit
2)implicating additional modulation
3)making a clear case for neuronal plasticity

59
Q

Amygdala and fear pathway

A

Association pathways (limbic system) eg hypothalamus, prefrontal cortex and hippocampus signal to amygdala (core fear centre) which lead to emotion response which are controlled by distinct output regions of the brain eg central amygdalaral self which send out info to ANS. eg orbital cortex (choice behaviour and emotional memory), hippocampus (learning and place), central amygdala, bed nucleus stria terminalis (autonomic responses, attention), striatum (avoidance behaviour)

60
Q

What relay/integrating centres can communicate with the amygdala?

A

Brainstem, hypothalamus, prefrontal cortex, septum, sensory cortex, thalamus, hippocampus

61
Q

Routes to anxiety pharmacotherapuetic treatment of anxiety disorder

A

Drugs regime and therapy focus

  1. SSRIS (increase 5HT lvls)
  2. Tricyclic antidepressant ( increase 5HT and noradrenalin lvls)
  3. Benzodiazepines (potentiates GABA mediated inhibition in CNS & periphery) (increase inhibition of nervous system with drug, increase inhibition, decrease activation)
  4. anticonvulsant drugs (stabilise nerve activity eg valproate) (complicated and difficult to treat)

Monoamine oxidase inhibitors (elevate 5HT lvls) not factored

62
Q

Prevalence and treatment

A

Panic disorder - 4% - 5HT therapies especially TCA
Generalised anxiety disorder - 5% - anxiety and help sleep
Social anxiety disorder - 10% - target dysfunction at point required eg beta blockers when public speaking
Ptsd - 7-8% - reoccurring stress <30% treatment success across treatments dosing, tapering and combined therapies

63
Q

Benzodiapines

A

First chlordiazepoxide (accidentally) then benzodiazepine

BZ bind to distinct site (allosteric modulator)
Inhibit nerve activity by GABA indicted Cl- flux, BZ agonist increases flux (anxiolytic) (potentiated response in presence of GABA) - creates less anxiety. Sedative, muscle relaxant

BZ inverse agonist decrease flux (anxiogenic) - creates more anxiety

64
Q

GABA receptor function

A

GABA MEDIATED CHLORIDE CHANNEL, agonist GABA, binds, opens hole, flux cl- from outside to inside of neurone, increasing negative charge inside the neurone so hyperpolerisation, make more inhibited

65
Q

Subunits if GABAA receptors

A

5 subunits
2 Alpha 2 beta subunits 1 gamma
Chloride channel in the middle (total 60%, cortex broadly)

Alpha 1 subunits define the GABA binding site
Gamma 2 subunit essential for BZ binding site

66
Q

What happens if there’s no gamma subunit

A

BZ insensitive eg a4Bns

67
Q

Where are gamma containing receptors found

A

Synapse, point where GABA is being released on post synaptic neurone

68
Q

Where are non gamma containing receptors found?

A

Do not exist at synapses
Further away

69
Q

Subunits associated with sedation (GABA receptors)

A

Alpha 1 and beta

70
Q

Subunits associated with anxiolysis (GABA receptors

A

Alpha 2 and beta

71
Q

Subunits associated with muscle relaxation (GABA receptors

A

A2 & B
A3 & B
A5 & B

72
Q

Subunits associated with anti convulsive(GABA receptors)

A

A1 & B

73
Q

Subunits associated with amnesia (GABA receptors

A

A1 & B
A5 & B

74
Q

Subunits associated with addiction (GABA receptors

A

A1 & B

75
Q

What recptors are abundantly expressed in the amygdala

A

A2 containing GABA recptors

So without changing receptor function but changing amount of expression in certain parts of the brain so degree of selectivity in how they work

76
Q

BZ pros

A

Rapidly acting (vs SSRI 8-12 weeks)
Anxiolytic, sedative, hypnotic, muscle relaxant (know GABAA receptors responsible)
Degree of selectivity
Good efficacy but amnesic
Less toxic

77
Q

BZ cons

A

Tolerance and withdrawal problems. Acute treatment (profound effect on reward pathways so addiction) (sleeping pills)

Taper BZ in combo with SSRI’s

78
Q

Context if neuropharmacology of affective disorders is debated and incompletely understood

A

Therapies?
Does not work for some

79
Q

GABAA

A

Delta subunit - specific GABAA subtypes

Neuropharma Of CNS disorders (5 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions