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FHS Paper 1 > Psychiatric Disorders > Flashcards

Psychiatric Disorders Flashcards

1
Q

Matthyse 1973

A

DA hypothesis

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2
Q

Laruelle et al 1996

A

DA-enhancing drug amphetamine induces psychosis

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3
Q

Mackay 1982

A

Striatal DA and DR2 density increased in SCZ postmortem samples vs controls

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4
Q

Kaalund et al 2013

A

176 postmortem samples. Increased expression of presynaptic DR auto receptors and decreased post-synaptic variants in dorsolateral PFC vs controls.

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5
Q

Abi-Dargham et al 2000

A

SPECT to measure striata D2R with D2R antagonist PET ligand in untreated patients vs controls.
No difference initially but when gave dietary alpha-MPT (to deplete DA, reducing competition with PET ligand for D2R) saw an increase in binding 2x in patients vs controls.
Implies greater occupancy of D2Rs.
Correlates with drug responsiveness.

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6
Q

Howes et al 2012

A

Meta-analysis of in vivo evidence. Found that presynaptic striata DA increased in SCZ, including markers of synthesis, release, synaptic [DA], D2R occupancy.

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7
Q

Kapur et al 2003

A

Aberrant salience hypothesis. Disordered mesostriatal DA release -> excessive attribution of meaning to irrelevant environmental stimuli -> delusion and apprehension.

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8
Q

Lahti et al 1995

A

NMDAR antagonists e.g. ketamine worsen psychosis (but ketamine also affects DA release)

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9
Q

Goff et al 1999

A

Enhancing NMDAR function with D-cycloserine (partial agonist at glycine modulatory site) improved symptoms.

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10
Q

Hammond et al 2014

A

Postmortem studies suggest glutamate receptor localisation abnormality rather than a general deficit

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11
Q

Convergence of genetic risk loci in SCZ

A

GRIN2A (codes NMDAR subunit) and SRR (enzyme synthesised D-serine, an important NMDAR modulator)

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12
Q

Busillo et al 2014

A

1H-MRS study showing increased gln/glu in anterior cingulate cortex of patients with chronic SCZ.
Frontal gln/glu correlated with positive symptoms of SCZ.
Reported increase in ratio with age of patients, contrary to findings by Marsmann et al 2013.

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13
Q

Weinberger 1987

A

Integrated model, where mesolimbic DA hyperactivity is secondary to decreased inhibitory control.
Now thought that the glutamate dysfunction is primary.

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14
Q

Vernaleken et al 2013

A

In vivo, baseline D2/D3 availability is associated with the psychogenic effects of ketamine.
Implies link between the two systems?

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15
Q

Howes et al 2009

A

Striatal 18F-dopa uptake elevated in patients with prodromal symptoms

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16
Q

Kegeles et al 2010

A

Used PET to measure % change in D2R availability before and during drug-induced DA depletion.
Revealed temporal correlation between hyperDA and psychosis.
Original hyperDA thought to occur in mesolimbic system, but is rather the mesocortiyal system.
In associated striatum, acute DA depletion led to larger increase in D2R availability in patients vs controls (most in dorsal caudate) but no differences in limbic of sensorimotor striatum.

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17
Q

Slifstein et al 2015

A

In vivo evidence for DA deficit in DLPFC in SCZ (previously suggested by Kaalund et al 2013 postmortem studies).
Tested amphetamine-induced DA release in DLPFC (PET), then tested BOLD fMRI activation during a working memory task.
Found that DA release in DLPFC correlates with working memory-related activation, so blunted release of DA may affect cortical function.

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18
Q

Demjaha et al 2014

A

PET in healthy subjects, SCZ drug-responders and drug-resistant patients.
MRS for glutamate in cortex.
Patients who responded had elevated DA, whilst non-responders had elevated glutamate.

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19
Q

Schizophrenia Working Group 2014

A

GWAS in 37,000 cases and 113,000 controls found 108 significant loci, including associations at DRD2 and several genes involved in glutamate transmission.

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20
Q

SCZ Working Group 2017

A

21,000 case vs 20,000 controls. Found global enrichment of CNV burden in SCZ group. CNVs are rare but have a large effect size.

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21
Q

Langova et al 2020

A

Zebrafish to study SCZ-associated CNVs.
E.g. erratic swimming as indicator of positive symptoms. Impaired social behaviour in shoals as negative symptoms for example.
Predictive validity? Antipsychotics reduced hyperactivity.

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22
Q

Ursini et al 2018

A

1/3 to 1/2 GWAS loci intersect onto placenta e.g. placenta must synthesise growth factors and neurotransmitters for the foetus in the second trimester.
Found that genes driving interaction between polygenic risk scores and early life complications are involved in cellular stress response.

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23
Q

Seeman et al 1976

A

D2R binding affinity correlates with clinical potency of antipsychotics

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24
Q

Johnstone et al 1978

A

Only the D2R-binding isomer of flupenthixol had therapeutic efficacy vs placebo.

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25
Q

Kapur et al 2000

A

Dose occupancy for therapy is less than that which causes side-effects.
2/3 patients respond at 65% occupancy, and remaining 1/3 do not respond if increase.
Sweet spot difficult to calculate, and changes.

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26
Q

Aguilar et al 2021

A

Altered neural oscillations (decreased gamma oscillations) and behaviour in a genetic (NMDAR hypo function) model of SCZ.
KO animal showed social behaviour deficit.

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27
Q

2018 World Drug Report for illicit drug use

A

In 2016, 1/20 adults estimated to have used an illicit drug at least once.
Societal cost ~2% GDP.
31 million suffer from drug-use disorders.
450,000 deaths in 2015 (either directly or from acquired disease e.g. HIV/ Hep C)

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28
Q

DSM5 ‘substance use disorders’

A

Primary chronic disease of brain reward, motivation, memory and related circuitry.
Characterised by inability to consistently abstain, impairment in behavioural control, craving, impaired recognition of problems with one’s own behaviours and interpersonal relationships, and a dysfunctional emotional response.

29
Q

Amphetamine PET study

A

Measured amphetamine-induced change in 11C-raclopride binding to show that addictive drugs increase striatal DA

30
Q

Baler & Volkow 2006

A

Proposed model of addiction involving transition from prefrontal to striatal control of behaviour.

31
Q

Hollerman & Schultz 1998

A

Non-human primates discrimination learning task (picture cues and rewards to lever presses by awake monkeys).
Initially, when monkey does not know the rewarded stimulus, neuron activity in VTA/SN increases briefly after rewarded stimulus, and inhibited after unrewarded stimulus.
As monkey learns, both excitatory and inhibitory responses disappear => DA neurons only activated by unexpected rewards.
DA neurons then become activated by reward predicting cues.
So DA does not encode pleasure itself, rather wanting.

32
Q

Addictive drugs increase dynamic sub second DA signals

A

[Di Chiara & Imperato 1988] - increased DA after amphetamine detected with micro dialysis

[Daberkow et al 2013] - Fast-scan cyclic voltammetry to detect real-time DA signalling => found increase in DA signalling dynamically after amphetamine.

33
Q

Pascoli et al 2015

A

ChR2-YFP targeted to DA neutrons by injecting Cre-inducible AAV5 into DAT-Cre mice.
Lever pressing for self stimulation of VTA with light drives burst activity in VTA DA neurons and is strongly reinforcing.
Mice show cue-seeking of stimulation on withdrawal, characteristic synaptic plasticity and resistance to punishment.
Cocaine infusion limits self-stimulation => shares underlying neural circuits with ontogenetic stimulation?

34
Q

Nicotine

A

[Picciotto et al 1998] - KO of beta2-containing nAChRs prevents nicotine reinforcement.

[Li-W et al 2011] - Nicotine promotes firing rate and bursting of DA neutrons in VTA in rats.

[Rice & Cragg 2004] - Nicotine promotes activity-dependence of DA release in striatum.

35
Q

Opioids

A

[Johnson & North 1992] - Disinhibition of VTA neurons via inhibition of VTA GABA neurons.

Since then, DA-dependent of reinforcement questioned: antagonists, lesions and TH-KO mice thought not to prevent heroin/ morphine substance abuse/ conditioned place preference.

[Corre et al 2018] - Monitored genetically encoded DA and Ca indicators as well as cFos in mice to reveal that heroin activates DA neurons in the medial part of the VTA, projecting to the medial NAcc.
Chemogenetic and ontogenetic manipulations of VTA DA or GABAergic neurons establish causal link to heroin reinforcement.
- Inhibition of DA neurons blocked heroin self-administration
- Heroin inhibited optogenetic self-stimulation of DA neurons
- Heroin occluded the reinforcing effects of self-inhibition of VTA GABAergic neurons
=> supports model of disinhibition of VTA DA neurons in opioid reinforcement.

36
Q

Unless et al 2001; Saal et al 2003

A

LTP of glutamatergic synapses onto VTA DA neutrons after cocaine, amphetamine, morhpine, nicotine, ethanol.
Change in synaptic strength (AMPAR/NMDAR ratio increases)

37
Q

Hearing et al 2016

A

Drug exposure and sensitisation is accompanied by distinct changes in synaptic plasticity in the striatum (NAcc shell).
14d post-morphine injection, see LTP of glu synapses onto NAcc shell D1 MSNs and LTD of glu synapses onto NAcc shell D2 MSNs.
=> compounds that increase GLT-1 (glutamate transporter) have potential application for substance use disorders

38
Q

Robinson & Kolb 1997

A

Drug sensitisation accompanied by visible changes to neuronal structure e.g. dendritic changes in striatum (saline vs amphetamine, cocaine)

39
Q

Changes in gene expression?

A

GFs, TFs, chromatin remodelling factors, histone modifying factors (e.g. BDNF, cFos, deltaFosB, CREB, epigenetic factors).

[Samaha et al 2008] - increased c-fos mRNA after cocaine infusion (fluorescence imaging)

[Nestler et al 2008] - Accumulating deltaFosB after cocaine administration

Changes can last several months but not long enough to explain life-long addiction

*Induction or KO of deltaFosB/ histone enzymes modify drug sensitisation

40
Q

Donny et al 2003

A

Nicotine-associated contextual cues promote drug reinforcement and vice versa.
Compared responses on active lever for rats under different conditions (combinations of below)
- contingent Nic + visual stimulus vs non-contingent Nic + visual stimulus
- visual stimulus vs no visual stimulus
- nicotine vs saline

41
Q

Volkow et al 2003

A

Impaired PFC in humans with addiction. Enhanced value of drug in circuits for reward, motivation and memory exceeds executive control

42
Q

Chen-BT et al 2013

A

Prelimbic cortex neurons in rat model of compulsive (resistant to foot-shock) cocaine seeking are hypoactive.
Photoactivation of PFC after punishment suppresses cocaine-seeking in rats => DBS?

43
Q

Other addictions

A

[Steeves et al 2009] - decreased 11C-raclopride binding during gambling in PD patients with pathological gambling. Indicated enhanced DA release.

[Wang et al 2004] - decreased baseline 11C-raclopride binding in methamphetamine users and obese subjects

[Volkow et al 2011] - caudate activation after milkshake consumption is inversely correlated with BMI

44
Q

Who becomes addicted?

A

Cultural and societal norms

Genetics
[Thorgeirsson et al 2008] - CHRNA5-CHRNA3-CHRNB4 and CHRNA6-CHRNB3 loci in nicotine dependence.
Many genes in alcoholism e.g. GABRA2 variation, ALDH, CRH1 (stress-related).

Personality characteristics
[Belin et al 2008] - high novelty-seeking rats have a higher propensity to seek drugs, and highly impulsive rats are more likely to switch to compulsive drug-seeking.

45
Q

Depression epidemiology

A

Affects ~2 million in UK

5000-6000 suicides / year in UK

46
Q

Depression risk factors

A

Female, high neuroticism, low TRP, immune activation, childhood experience

47
Q

Depression Pharmacology Timeline

A 
1950s - 1st gen drugs
1960s - site of action discovered
1990s - SSRIs
2000s - DBS
Now - ketamine, psilocybin
48
Q

Cipriani et al 2018

A

Meta-analysis of 21 antidepressants vs placebo.

Most effective treatments were agomelatine, amitriptyline, escitalopram, meptazapine, paroxetine, venlafaxine, vortioxetine.

Least effective were fluoxetine, fluvoxamine, reboxetine, trazodone.

Best tolerated were agomelatine, citalopram, escitalopram, fluoxetine, sertraline, vortioxetine.

All antidepressant drugs analysed were more efficacious than placebo in adults with major depressive disorder.

49
Q

Delgado 1999

A

Rapid depletion of plasma TRP transiently reverses the antidepressant response in many patients with fluoxetine, implying that ADs are working through monoamines. However was only seen in 8/15 fluoxetine patients. Only 1/15 patients who received desipramine relapsed.

50
Q

Smith 1997

A

Took cohort of women with history of depression, but low depression scores at the time. TRP depletion induces relapse in drug-free patients (many patients experienced low mood within hours of TRP-free amino acid mixture).

51
Q

Evidence for monoamines

A

1960s: low urine noradrenaline, low CSF 5HT metabolites, low 5HT neuroendocrine response, low TRP

Recent: low 5HT receptors in PET studies, decreased 5HT transporter, increased MAO-A, association with 5HT gene variants (below)

[Caspi et al 2003] - short allele leads to lower 5HT transporter expression than long allele. Only correlates with depression once incorporate stressful life events => 5HT involved in plasticity?

52
Q

Monoamine hypothesis

A

Schildkraut theory in 1960s that depression is due to decreased release of monoamines

53
Q

Limitation of simple monoamine hypothesis

A

[Parsey et al 2006] - PET shows 5HT transporters are blocker immediately by ADs

[Sechler 1999] - Maximum therapeutic effect of ADs takes weeks

=> receptor super sensitivity hypothesis (1970s)
=> autoreceptor modulation hypothesis (1990s)
=> neural plasticity hypothesis (today)

54
Q

Neuronal plasticity evidence

A

[Santereli et al 2003] - Looked at % new neurons after treatment with saline vs fluoxetine => AD-induced plasticity

[Kang et al 2012] - post-mortem study showing decreased synapse number in PFC of subjects with depression

[MacQueen et al 2008] - Postmortem study reporting decreased volume of PFC and hippocampus

AD-induced plasticity requires course of treatment (not acute)
Absent in 5HT-KO => monoamine dependent

Neurotrophic factors and other genes e.g. Arc. (chronic stress is correlated with decreased Arc and BDNF in the brain)

55
Q

Decreased hippocampal volume in depression

A

[Chan et al 2016] - (clinical imaging) compared volumes between (1) never depressed patients with high neuroticism, (2) recovered depressed patients with matched neuroticism, and (3) never depressed patients with low neuroticism.

[MacQueen et al 2008] - Postmortem study reporting decreased volume of PFC and hippocampus

[Videbeck & Ravnklide 2004] - meta-analysis of 350 patients and 279 controls

56
Q

Covington et al 2010

A

decreased Arc, BDNF and synapses in depressed patients

57
Q

Issues of neural plasticity hypothesis

A

Unknown basis of decreased hippocampal volume, since post-mortem brains do not show decreased cell count or neuronal density

Not all ADs increase neurogenesis

Decreasing BDNF and neurogenesis often does not induce depression in mice

Causal link uncertain

Measures of neuronal plasticity often derived from the hippocampus

Mechanisms unclear

Do ADs act directly on BDNF receptor and not via monoamines? [Casarotto et al 2021]

58
Q

Targeting non-monoamine pathways in depression

A

Ketamine, a fast acting antidepressant, inhibits NMDAR

kappa opiate receptor antagonists in clinical trial (DA link)

Psilocybin, a 5HT2 agonist, had rapid antidepressant effects in a clinical trial

Drug repurposing?
e.g. ebselen lithium mimetic for mood stabilisation [Sharpley et al 2020]

59
Q

DBS in depression

A

Image brains of depressed patients to identify abnormal nodes, then target these with stereotaxically-implanted electrodes.

DBS of PFC has shown some benefit in treatment-resistant patients

Recent advancement [Scangoset et al 2021]

  • closed-loop sensing-stimulation approach
  • electrodes in brain detect neurophysiological biomarker changes linked to onset of low mood -> triggers stimulation of electrodes elsewhere in circuit
  • sensors in amygdala; stimulate ventral striatum
  • efficacious, however only studies one patient
60
Q

Inflammation in depression

A

Proinflammatory cytokines interact with monoamine (esp 5HT) systems and glutamatergic synapses

Increased immune activation correlates with decreased neuronal plasticity

Clinical trials reporting AD effects using anti-inflammatory strategies + ADs in treatment-resistant patients

61
Q

Neuronal plasticity model explains sex differences

A

2x as many women vs men have depression.
Oestrogen influences neurotransmitter activity, neurogenesis and neurotrophic factor expression (e.g. bdnf)

[Barouk. et al 2011] - Rat BDNF levels fluctuate with the oestrogen cycle. Administration of exogenous oestrogen increased expression of BDNF in the PFC and hippocampus.

62
Q

Yu et al 2012

A

Compared behavioural effects of different AD treatment classes (SSRI, tricyclics, ECT) between wt and bdnf KO mice. Found that behavioural improvements were blocked in KO mice.

63
Q

Ketamine for depression

A

Ketamine dissociative effects ~1hr vs therapeutic effects ~1week

Imply rapid changes in neuronal plasticity = attributed to activation of mTORC1, which in turn increased PFC synaptic number and function.

Studies blocking mTORC1 pharmacologically (rapamycin) prevented ketamine-induced increases in plasticity.

Concerns

  • Long-term side-effects e.g. ulcerative cystitis
  • Ethical concerns relating to self-treatment with illegally obtained ketamine
64
Q

Zhu et al 2010

A

Animal models supporting role of pro-inflammatory cytokines in depression.

Injected LPS (vs saline) into mice -> immune response. Then assayed midbrain synaptosomes (to measure SERT activity). Also did behavioural tests (tail suspension and forced swim tests).
LPS injection correlated with increased SERT activity and promoted depressive behaviour compared with saline controls, IL1R-deficient mice and mice under pharmacological inhibition of p38 MAPK.
65
Q

Microglia in depression?

A

Animal studies indicate a direct relationship between microglial activation and changes in synaptic function and plasticity (including LTP and LTD).
Involves microglial-derived cytokines, BDNF, ATP, ROS.

66
Q

Neuropsychological Approach

A

ADs work by promoting shift away from a negative affective bias to evaluation of emotional stimuli.

5HT at centre of approach

  • [Hayward et al 2005]- TRP depletion promotes negative bias in recognition of facial expressions
  • [Harmer et al 2004]- Citalopram (SSRI) opposite
67
Q

Jones et al 2018

A

Developed new model for studying behavioural aspects of depression.
Rats insert nose into food trough then hear one of two tones (signals either food reward or air puff).
Once learned task, ambiguous tone played in a later trial. Withdrawal implies negative cognitive bias.

68
Q

Griffiths et al 2006

A

Single high dose (25mg) psilocybin led to positive persisting changes in mood and well-being of healthy subjects.

Psilocybin = 5TH(2A)R agonist

Psychedelic experience thought to be important

Challenges of studying psilocybin:
- classification as illegal drug and previous ban on research -> expensive to research and limited supply of medical grade psilocybin

69
Q

Cassarotto et al 2021

A

Showed that ADs (fluoxetine, ketamine, imipramine) can increase phosphorylation of TRKB and its surface expression, and these effects can be blocked by inhibiting cholesterol.

Examined direct interaction, showing binding for the ADs, but not structurally similar compounds. Fluoxetine + BDNF promoted TRKB membrane trafficking, and all 3 ADs increased TRKB phosphorylation.

Fluoxetine enhanced long-term memory in wt mice but not BDNF-deficient mice, 5HT-KO mice or mice treated with pravastatin.

Limitations:

  • Conc of ADs needed to affect TRKB much greater than that needed for other direct actions
  • Lack of temporal association between molecular and behavioural effects they present
  • Other studies have shown that in 5HTT-KO mice, which presumably retain TRKB signalling, SSRIs lose their effect
  • If translates to humans, surprising that role of statins in mitigating efficacy of ADs has not been discovered

FHS Paper 1 (4 decks)

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