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Affective Disorders Flashcards

1
Q

Affective disorders

A

Depression (mono depression) and anxiety

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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

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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)

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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

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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

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6
Q

Depression stats

A

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

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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

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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

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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 +

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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

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11
Q

Monoamine theory of depression

A

Elevating the levels of the NT available for signalling improves mood

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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

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13
Q

More tired after stress

A

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

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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

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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

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16
Q

MAO -A

A

Metabolises serotonin, noradrenaline and dopamine

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17
Q

MAO-B

A

Metabolise selectively dopamine

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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

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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

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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)

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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

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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

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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)

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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

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25
Detailed molecular explanation of transport protein
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
26
Noradrenaline serotonin delete give antidepressants
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
27
Heteroreceptor
Similar as auto receptor in action but on different neurones Block of this causes increase Activation of this causes decreases
28
Side effects of MAL inhibitors
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
29
Side effects of TCA drugs
Imipramine and clomipramine (block reuptake of monoamines non specifically, first generation reuptake inhibitors) - anyicholingergic (dry mouth, dizzy), hypertension, seizures. Interactions with CNS depressants (alcohol)
30
Selective serotonin reuptake inhibitor side effects
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
31
Noradrenergic and specific serotonergic antidepressants (NaSSA) side effects
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
32
Key idea of depression treatment
Modulation of MA specifically 5HT seems to be a high efficacy way of treating depression
33
Antidepressants paradox
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
Short term drug treatment
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
Medium term drug treatment
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
Long term drug treatment
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
Neurogenesis
Neuronal progenitor stem cells to serotonin cells
38
Excitation of serotonin mechanism that acts in depression
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
Ketamine
Old drug repurposed Same class as PCP and MK801 Cheap Vet medicine and drug abuse substance
40
Issues with old/original drugs to treat depression
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
Ketamine: Dose dependent impacts on behaviour producing distinct behavioural states
Anaesthetic: 3mg/kg, inhibits thalamus regions Dissociative symptoms: 1mg/kg, limits subcortical inhibition Antidepressant: 0.5mg/kg
42
Glutamates receptors
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
NMDA receptor binding sites
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
Ketamine (0.5 mg/kg) vs midazolam (0.045mg/kg)
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
ketamine function as antidepressant
Ketamine selectively induced acute and allows a sustained antidepressant activity due to plasticity
46
BDNF knock out animals do not show ketamine induced antidepressant activity
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
Explanation of ketamine as antidepressant
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
eEF2 with phosphate
Inhibits
49
eEF2 without phosphate
Active
50
Regular elongation
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
Circuit level explanation of ketamine as an anti depressant
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
Ketamines potential as antidepressant
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
Depression vs anxiety
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
Fear response
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
Anxiety definition
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
Fundamental to fearfulness
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
Difficult to classify fear disorder in one thing
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
Animal models for fear circuit
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
Amygdala and fear pathway
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
What relay/integrating centres can communicate with the amygdala?
Brainstem, hypothalamus, prefrontal cortex, septum, sensory cortex, thalamus, hippocampus
61
Routes to anxiety pharmacotherapuetic treatment of anxiety disorder
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
Prevalence and treatment
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
Benzodiapines
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
GABA receptor function
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
Subunits if GABAA receptors
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
What happens if there’s no gamma subunit
BZ insensitive eg a4Bns
67
Where are gamma containing receptors found
Synapse, point where GABA is being released on post synaptic neurone
68
Where are non gamma containing receptors found?
Do not exist at synapses Further away
69
Subunits associated with sedation (GABA receptors)
Alpha 1 and beta
70
Subunits associated with anxiolysis (GABA receptors
Alpha 2 and beta
71
Subunits associated with muscle relaxation (GABA receptors
A2 & B A3 & B A5 & B
72
Subunits associated with anti convulsive(GABA receptors)
A1 & B
73
Subunits associated with amnesia (GABA receptors
A1 & B A5 & B
74
Subunits associated with addiction (GABA receptors
A1 & B
75
What recptors are abundantly expressed in the amygdala
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
BZ pros
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
BZ cons
Tolerance and withdrawal problems. Acute treatment (profound effect on reward pathways so addiction) (sleeping pills) Taper BZ in combo with SSRI’s
78
Context if neuropharmacology of affective disorders is debated and incompletely understood
Therapies? Does not work for some
79
GABAA
Delta subunit - specific GABAA subtypes

Neuropharma Of CNS disorders (5 decks)

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