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NMH BSc > Module 3: Part 2 > Flashcards

Module 3: Part 2 Flashcards

1
Q

What is PTSD?

A
  • Experience of a severe traumatic event of an exceptionally threatening nature which is likely to cause distress in anyone
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2
Q

What are the three main cluster of syndromes?

A
  • Re-experiencing
  • Hyperarousal
  • Avoidance
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3
Q

What are features of reliving?

A
  • Flashbacks
  • Recurring memories related to the traumatic event
  • Recurring dreams of the event
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4
Q

What are features of hyperarousal?

A
  • Difficulty falling asleep
  • Irritability and outbursts of anger
  • Difficulty concentrating
  • Exaggerated startle response (noise, fireworks)
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5
Q

What are features of avoidance?

A
  • Efforts to avoid thoughts, feeling associated with the trauma
  • Efforts to avoid activities, place and people that arouse recollections of the trauma
  • Feeling detached from others
  • Reduced interest in participation in important
    activities
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6
Q

What is the 4th factor of PTSD according the DSM-2013 four-factor model?

A
  • Negative alterations in cognition and mood
    • Persistent negative cognitions about, self,
      others and the world
    • Persistent negative emotional states (anger,
      shame, fear)
    • Diminished interest in significant activities
    • Inability to experience positive emotions.
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7
Q

What are different types of trauma?

A
  • Combat trauma
  • Torture
  • Terrorism
  • Rape
  • Witnessing violent death of others (war)
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8
Q

What are more types of trauma?

A
  • Type I trauma - a single traumatic event (Terr,
    1991)
  • Type II trauma - prolonged and repeated
    trauma
  • Interpersonal vs natural disaster
  • Intergenerational trauma
  • Concept of catastrophic trauma (ICD 10,
    1992)
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9
Q

What is the aetiology of PTSD?

A
  • Not clear why some people develop PTSD and
    some not
  • Heritability 30% (Goldberg et al., 1990)
  • Impaired sensitivity of HPA axis (Yehuda et al.,
    1991)
  • Reduced hippocampal volume
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10
Q

What is the prevalence of PTSD?

A
  • Lifetime prevalence in general population 8%
    (Kessler et al., 1995)
  • Lifetime prevalence of PTSD in general
    practice 14% (Gomez-Beneyto et al., 2006)
  • 31% of Vietnam war veterans (The
    National Vietnam Veterans Readjustment
    study) had lifetime PTSD (Kulka et al. 1990)
  • PTSD more prevalent in victims of
    interpersonal trauma than disaster victims
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11
Q

What are features of a PTSD history?

A
  • Current Mental state (triad of symptoms)
  • Past psychiatric Hx (first contacts with mental health services, admissions; ?under section)
  • Developmental Hx
  • Employment Hx
  • RIsk of self harm and harm to others
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12
Q

What are some comorbidities of PTSD?

A
  • Alcohol abuse/dependence – M-52%; F-27%
    (Kessler et al. 1995)
  • Drug misuse – 34%
  • MDD -48%
  • Physical health problems (stomach ulcer)
    more prevalent than in general population
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13
Q

What are some treatments for PTSD?

A
  • Watchful waiting in mild/moderate PTSD for first
    4/52
  • Pharmacotherapy
    • Mirtazapine, paroxetine, sertraline, olanzapine
  • Psychological interventions
    • No evidence of benefit of single session debriefing
    • Trauma focussed CBT
    • Eye movement desensitization and reprocessing
      (EMDR)
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14
Q

Describe PTSD Management

A
  • Severe PTSD - engagement problems
  • Ongoing evaluation of risk to self and others
  • Treat comorbidity (substance misuse)
  • Physical health checks
  • Social support
  • Voluntary week/employment
  • Carer’s assessment
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15
Q

What is the prognosis of PTSD?

A
  • 56% improve after receiving psychotherapy (no
    longer meeting diagnostic criteria for PTSD)
  • 38% continue to have some residual symptoms
  • Highest remission rates in PTSD survivors of natural
    disasters 60%
  • Trauma severity, the lack of social support and
    additional post-trauma life stressors important rrisk
    factors
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16
Q

What are the problems with the current DSM diagnostic classification of PTSD?

A
  • Complex PTSD (Herman, 1992)
  • Disorder of extreme stress, not otherwise specified,
    DESNOS (Van der Kolk et al. 1996)
  • Enduring personality change after catastrophic
    experience, EPCACE (ICD 10)
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17
Q

What is Enduring Personality Change After Catastrophic Experience EPCACE?

A
  • a change of at least four years duration in a
    person’s pattern of perceiving, relating to, or thinking about the environment and self following exposure to catastrophic stress
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18
Q

What are the main features of EPCACE?

A
  • Permanent hostile and distrustful attitude
  • Social withdrawal
  • A constant feeling of emptiness and/or hopelessness (may be associated with increased dependency on others, prolonged depressive mood without evidence of depressive disorder before trauma)
  • Feeling of being ‘on edge’ or threatened
  • Permanent feeling of being changed or different to others
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19
Q

What are some conditions for EPCACE?

A
  • No history of existing personality pathology prior
    traumatic experience
  • May or may not be preceded by PTSD
  • Not related to other mental health disorders or
    organic brain injury
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20
Q

What is the aetiology of EPCACE?

A
  • Catastrophic trauma
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21
Q

What is Catastrophic trauma?

A
  • catastrophic trauma would involve prolonged exposure to life-threatening circumstances with imminent possibility of being killed (for example exposure to war trauma, concentration camp experience, being tortured, hostage situations and sexual assault)
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22
Q

What is PTSD according to ICD-11?

A
  • PTSD – three clusters of symptoms
    remain
  • Complex PTSD introduced as a new
    diagnostic category
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23
Q

What is complex PTSD (ICD-2018)

A
  • Exposure to an event or series of events of an extremely threatening or horrific nature, most commonly prolonged or repetitive events from which escape is difficult or impossible (torture, slavery, genocide campaigns, prolonged domestic violence,
    repeated childhood sexual or physical abuse)
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24
Q

What are other features of Complex PTSD?

A
  • Problems with affect regulation
  • Feelings of worthlessness, shame and guilt
  • Difficulties with sustaining relationships
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25
Q

What are the problems with the definition of Complex PTSD?

A
  • CPTSD criteria overlap with criteria for PD –
    this could lead to diagnostic confusion both
    clinically and in research
  • Risk factors (sexual and physical abuse)- the
    same for CPTSD and PD
  • ?preference for CPTSD - Stigma attached to
    PD diagnosis
  • ?treatment for CPTSD vs treatment for PD
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26
Q

What is the ICD 11 criteria of harmful substance use?

A
  • Damage to mental or physical health of the user in absence of Dx of dependence syndrome
  • Damage observed over 12 months if episodic use, one month if continuous use
  • Harm due to one or more of the following:
    • behaviour related to intoxication;
    • direct or secondary toxic effects on body organs and systems
    • or a harmful route of administration.
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27
Q

What is dependence?

A
  • Sense of compulsion
  • Difficulty in controlling (onset/termination/level of use, all-or-nothing
  • Withdrawal state (physical/cognitive state)
  • Tolerance
  • Progressive neglect despite harmful consequences
  • DSM V: Abuse and dependence combined to single disorder, added gambling
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28
Q

What increases dopamine levels in ventral striatum (nucleus accumbens)?

A
  • Food
  • Sex
  • Drugs e.g. cocaine, amphetamine, alcohol, MDMA
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29
Q

How does cocaine work?

A
  • Blocks dopamine transporter

- Increases dopamine signalling

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30
Q

How does amphetamine?

A
  • Blocks dopamine transporter

- Enhances dopamine release

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31
Q

What are different types of dopamine family receptor imaging?

A
  • 11C-PHNO
    Agonist
    DRD3 preferring
    Extra striatal binding
  • 11C-raclopride
    Antagonist
    DRD2 > DRD3
    Striatal
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32
Q

Where does cocaine increase dopamine in? Ventral or dorsal striatum?

A
  • Dorsal Striatum
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33
Q

In alcoholics, which areas does alcohol activate?

A
  • Ventral striatum
  • Anterior cingulate
  • Ventromedial prefrontal cortex
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34
Q

What is the dopamine system modulated by?

A
  • GABA: inhibitory on dopamine neuron

- Opioids: inhibitory on GABA-ergic neuron

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35
Q

What are endorphins?

A
  • Natural opiates in the brain
  • Exercise and endorphin rush
  • Improve mood
  • Substance of abuse may increase the release of endorphins which then stimulate the dopamine system
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36
Q

How does the μ-opioid receptor activation lead to DA neuronal firing?

A
  • μ-opioid receptors are inhibitory
  • when activated, GABA neuron is shut down
  • Results in increase in DA neuronal firing
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37
Q

What does naltrexone do?

A
  • Block the μ-opiate receptor
  • Allows GABA ‘brake’ to function
  • Leads to reduced dopaminergic activity
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38
Q

Is there more or less opioid receptor availability in alcoholics?

A
  • Less

- Alcoholic dependent individuals have more opioid receptors than control

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39
Q

What would contribute to the differences between earlier and recent studies of opioid release?

A
  • Recent imaging has lower availability of mu opioid receptor and early abstinence
  • Higher mu opioid receptor availability has been associated with craved and response to naltrexone
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40
Q

How does tissue damage lead to inflammation?

A
  • Tissue damage —> Foreign pathogens —> Cytokine release —> Increased permeability —> Immune cells invade —> Inflammation
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41
Q

What is inflammation characterised by?

A
  • Rubor
  • Calor
  • Dalor
  • Loss of function
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42
Q

How is neuroinflammation different to general inflammation?

A
  • No pain
  • Loss of function more significant
  • Different immune cells
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43
Q

What are triggers of neuroinflammation?

A
  • Classical: Infectious, Autoimmunity, Toxins

- Neurogenic (due to increased neuronal activity e.g. seizures

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44
Q

What are microglia?

A
  • CNS macrophages that orchestrate an immune response and exacerbate damage by releasing toxic factors
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45
Q

What toxic factors do microglia release?

A
  • Reactive oxygen species
  • Prostaglandins- COX-2
  • Cytokines - TNF-alpha, IL-1
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46
Q

How do you work out Units of alcohol?

A
  • % x Volume (L)
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47
Q

What is the daily limit of alcohol?

A
  • 2 units (with 2> alcohol free days)
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48
Q

What is a binge?

A
  • 2x daily limit
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49
Q

What are the three types of alcohol problems?

A
  • Hazardous drinking
  • Problem drinking
  • Dependent drinking
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50
Q

What is hazardous drinking?

A
  • Numbers are too high (Increased BP), raising risk of problem
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51
Q

What is problem drinking?

A
  • Evidence of harmful consequences

- Physical, psychological or social

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52
Q

What is dependent drinking?

A

3 or more of following in the last 12 months

  • Craving/Compulsion to use
  • Withdrawal symptoms
  • Continuing in spite of harm
  • Tolerance
  • Neglect of other interests
  • Difficulty controlling use
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53
Q

What structural changes do abstinent ‘Healthy’ alcohol dependent individuals have?

A
  • Atrophy (narrow gyri, widening sulci) - ICAM study
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54
Q

What are different types of alcohol-related brain damage?

A
  • Thiamine deficiency: Wernicke’s-Korsakoff syndrome
  • Direct neurotoxicity
  • Alcoholic liver disease: peripheral inflammation can cross BBB to start neuroinflammation
  • Head injury: alcohol —> Increased risk of falls —> Increased risk of head injury —> neuroinflammation —> cognitive dysfunction
  • Increased risk of CVD —> Increased risk of stroke
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55
Q

What brain areas are affected by alcohol-induced neuroinflammation?

A
  • Caudate
  • Putamen
  • Hippocampus
  • Medulla
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56
Q

How does alcohol cause neuroinflammation?

A
  • Alcohol activates Microglia via TLR4 —> Neuroinflammation
  • Activated microglia present for 14 days after last alcohol dose in Rat model of dependence
  • TLR4 KO mice protected against alcohol induced neuroinflammation
  • Post-mortem alcohol dependent brain show increased microglia and increased inflammatory cytokines
  • Microglia activation seen during alcohol intake and withdrawal
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57
Q

Describe PET imaging in alcohol neuroinflammation

A
  • 11C-PBR28 PET ligand binds to TSPO to detect Microglia (must assess binding affinity of patient as can affect signal)
  • Alcohol-dependent have decreased hippocampal binding for PBR28 (Tracer for activated microglia) - Microglia loss or dysfunction?
  • Decreased hippocampal TPSO expression associated with decreased memory function
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58
Q

What is the relationship between alcohol and Alzheimer’s?

A
  • Peripheral inflammation or high TNFα in Alzheimer’s Disease is associated with deterioration in cognition
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59
Q

Describe the amyloid hypothesis of neurodegeneration

A
  • APP cleaved by beta and gamma secretase

- Dynamic equilibrium of Monomers, Oligomers, Protofibrils, Fibrils, Plaques

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60
Q

What are the direct actions of alcohol on neuroinflammation and AD?

A
  • Alcohol binds to TLR-4 on Microglia —> activate Microglia —> Cytokine release —> Neuroinflammation
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61
Q

What are the indirect actions of alcohol neuroinflammation and AD?

A
  • Thiamine deficiency —> Increased beta-amyloid plaque deposition
    • Thiamine-deficit rats have increased amyloid plaque deposition
    • Alcohol dependence is the most common cause of thiamine deficiency
  • Fibrillar beta-amyloid binds to TLR-4 activates microglia —> Neuroinflammation —> Neuronal death (AD Sx) —> Cycle
  • Systemic inflammation superimposed on Neurodegenerative diseases accelerates disease progression
  • TBI
  • Withdrawal effects
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62
Q

What are the different roles of pharmacotherapies in alcohol addiction?

A
  • Substitution
  • Withdrawal
  • Abstinence
  • To prevent harms e.g. brain damage, infections etc
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63
Q

Describe substitution in alcohol addiction treatment

A
  • Diazepam (Benzodiazepine)
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64
Q

Describe withdrawal in alcohol addiction treatment

A
  • Diazepam (Benzodiazepine) +/- Acamprosate (anti-glutaminergic)
    • Decreased withdrawal symptoms (Gold standard for alcohol withdrawal)
  • Carbamazepine (Anticonvulsants) - treat seizures, alternative to BDZ
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65
Q

What is the MOA of alcohol?

A
  • Binds to GABA-A receptor —> Acute: Increased GABA, Chronic: GABA receptor desensitised therefore decreased GABA function
  • Binds to NMDA receptor —> Acute: NMDA antagonist, Chronic: NMDA receptor upregulation (associated with decreased memory)
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66
Q

What is the MOA of alcohol withdrawal?

A
  • Decreased alcohol —> Glutamate acts on Increased Glutamate receptors —> Increased Ca2+ —> Hyperexcitability —> Seizures
  • Alcohol withdrawal associated with Increased Ca2+ influx (NMDA), decreased GABA-ergic activity, decreased Mg2+ inhibitory system (NMDA)
  • During alcohol withdrawal —> Increased Glutamate
    With treatment —> Decreased glutamate
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67
Q

What is multiple detoxification associated with?

A
  • Increased withdrawal symptoms
  • Increased risk of relapse
  • Impaired cognitive function
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68
Q

How does vitamin supplementation help alcoholics?

A
  • Thiamine deficit —> Risk of wernicke’s encephalopathy —> Korsakoff’s syndrome
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69
Q

How is abstinence maintained in treatment for alcohol addiction?

A
  • Disulfiram
  • Bromocriptine
  • Baclofen
  • Naltrexone
  • Nalmefene
  • Acamprosate
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70
Q

How do dopamine receptors relate to addiction?

A
  • Now think addicts have high DA
  • Low levels of DRD2 associated with ‘drug-liking’ & impulsivity
  • Low levels of DRD2 seen in stimulant & alcohol addicts.
    • Higher levels of DRD3 subtype in stimulant addiction, no change in alcoholism
  • Release of dopamine is blunted or none is apparent.
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71
Q

What is the MOA of disulfiram?

A
  • Inhibits alcohol dehydrogenase (Increased acetaldehyde —> N&V)
  • Inhibits dopamine beta-hydroxylase in Brain (blocks DA —> NA therefore increased DA)
  • S/E: psychosis
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72
Q

How does bromocriptine work?

A
  • DA agonist
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73
Q

How does Baclofen work?

A
  • GABA agonist —> Increased GABA brake —> Decreased DA
74
Q

How does naltrexone work?

A
  • mu-opiate receptor antagonist —> Increased GABA firing —> Decreased DA
  • Decreased relapse rates, decreased pleasurable effects of alcohol, can safely drink
75
Q

How does nalmefene work?

A
  • k-opiate receptor antagonist

- Decreased relapse rates, decreased pleasurable effects of alcohol, can safely drink

76
Q

How does acamprosate work?

A
  • Taurine derivative (MOA unknown)
  • Decreased pleasurable effects of alcohol, decreased relapse rate
  • Equal efficacy to Naltrexone
77
Q

Which medication and when to start alcohol relapse prevention?

A
  • Starting detox
    • Support abstinence : acamprosate, disulfiram
    • Reduce risk of relapse in ‘samplers’ : naltrexone
    • Support abstinence in those with prominent anxiety : baclofen
  • Start whilst drinking to reduce drinking
    • Nalmefene (naltrexone)
78
Q

What are the different roles of pharmacotherapy in opiate addiction?

A
  • Substitution (main approach for opiate addiction) e.g. methadone, buprenorphine, naltrexone
  • Treat Withdrawal
  • Maintain abstinence
  • To prevent harms
79
Q

What is the aim of substitution?

A
  • Decrease street used
  • Decrease crime
  • Decreased IV risk
80
Q

How does methadone work?

A
  • Full agonist
  • Risk of respiratory depression
  • Long half life
  • PET: Methadone does not reduce PET signal therefore Methadone dose depends on clinical judgement + clinical trials
81
Q

How does buprenorphine work?

A
  • Partial agonist
  • Long half-life
  • Heroin gives no further high, no resp depression
  • If increased opioid, partial agonist antagonises
  • If no opioid, partial agonist activates receptors —> prevent withdrawal
  • PET imaging useful to determine dose (no tracer binding beyond 16mg)
82
Q

How does naltrexone work for opiate addiction?

A
  • Opiate antagonist
  • No intrinsic activity
  • Antagonist effects predominant even if full agonist given
83
Q

How to treat opiate withdrawal?

A
  • Prevent noradrenergic storm
84
Q

How do you maintain abstinence from opiate addiction?

A
  • Naltrexone
85
Q

How to prevent harm in treating opiate addiction?

A
  • Providing clean needles
86
Q

Describe treatment for Nicotine addiction

A
  • Substitution (MAIN APPROACH FOR NICOTINE ADDICTION)
    • Nicotine replacement
    • Varenicline (nicotinic partial agonist)
  • Treat withdrawal- to prevent complications
    • Nicotine replacement
    • Varenicline (nicotinic partial agonist)
  • Maintain abstinence
    • Varenicline
    • Bupropion (dopaminergic/noradrenergic)
87
Q

What addiction treatments are in development?

A
  • Vaccines
    • Still waiting - poor bioavailability
  • New approaches
    • Reduce stress by antagonising
      • NK1
      • Corticotropin releasing hormone/factor
      • Neuropeptide Y
  • Modulate appetitive drive by antagonising Orexin, Ghrelin or GL1 agonist
88
Q

What is a drug?

A
  • A chemical which produces a physiological change
89
Q

How are drugs regulated in the UK?

A
  • MHRA Medicines Act —> Drugs with Health benefit
    • Controlled by Class: higher class, higher penalties (for possession and supply)
  • Misuse of Drugs Act —> Recreational drugs
  • Regulated drugs: Age of Sale
  • Unregulated: Tea and Coffee
90
Q

What the types of drugs in the UK?

A
  • Depressants: Alcohol, Opioids, Benzodiazepines, Ketamine
  • Stimulants: Cocaine, Amphetamine, Ecstasy
  • Psychedelics: LSD
  • Cannabis
91
Q

What is the difference between classes and schedules?

A
  • Classes determine legality

- Schedules determine its medical use

92
Q

What are different types of harms of drugs?

A
  • Harms from Route of Use (Infection- Sepsis, Skin popping, Needle marks, Tooth loss)
  • Harms from drugs (acute toxicity & chronic effects)
  • Harms from addiction to drugs
93
Q

What are the acute effects of harms from drugs?

A
  • Respiratory depression: Opioids (esp mixed with alcohol/BSZ
  • Hyperthermia: Stimulants (esp MDMA)
  • Hypothermia: Ketamine, Alcohol
  • Hyponatraemia: MDMA
  • Cardiac symptoms: Cocaine, Amphetamine
  • Hepatitis: MDMA
  • Confusion/Delirium: Depressants (esp Ketamine)
  • Paranoia/Delusion states: Stimulants (cocaine), Cannabis
  • Anxiety attacks: Stimulants, Cannabis, Psychedelics
94
Q

Describe the ISCD Drug Harms Model (2010)

A
  • All drugs harms classified into 16 variables, Examined 20 drugs, Each criterion scored out of 100 related to highest chosen
  • Results: Alcohol is the most harmful drug - Alcohol is 3x more harmful than cocaine
  • No correlation between UK Drugs Act and Harmfulness of the Drug
95
Q

Which drugs have the highest related drug deaths in the UK?

A

Tobacco then Alcohol

96
Q

How much does alcohol cost the UK to treat?

A
  • 3 billion pounds
97
Q

How many men or women need to stop smoke to prevent one case of Schizophrenia?

A
  • 5000 men or 7000 women
98
Q

What brain regions are activated in response to palatable food or food-associated cues?

A
  • Amygdala (Emotional response)
  • NAcc (motivation, drive)
  • Dorsal striatum (habitual behaviour, learning association)
  • Orbitofrontal cortex (salience evaluation)
  • VTA
  • Lateral hypothalamus
99
Q

What do the people with high food addiction scores correlate with?

A
  • Heightened ventromedial PFC activation to the anticipation of a chocolate milkshake
  • Greater Positive and Negative Urgency reflecting proneness to act impulsively during intense mood states
  • Greater temporal impulsivity to money (delay discounting)
100
Q

GHADD Summary 1

A
  • Anticipatory food reward/food cue reactivity engages mesocorticolimbic brain regions
  • Predicts food intake
  • Influenced by nutritional state, appetitive gut hormones (including ghrelin, GLP-1) and bariatric surgery
  • Ghrelin stimulates and GLP-1/PYY attenuates food cue reactivity in humans mimicking effects of fasting and food intake
  • Gastric bypass surgery increases GLP-1 and PYY and attenuates food cue reactivity and hedonics
101
Q

GHADD Summary 2

A
  • Food intake +/- gastric bypass surgery attenuate reward-limbic responses during monetary reward anticipation and negative emotional reactivity ?via gut hormones
  • Similar neural networks processing food and alcohol or cigarette cues
  • Reviewed pre-clinical and clinical data for effect of GLP-1 to decrease and ghrelin to increase consumption of drugs of abuse
  • Previewed proof-of-concept Gut Hormone in Addiction Study for GLP-1 and ghrelin systems as targets to prevent relapse in smoking and alcohol dependence by modulating addictive behaviours, as well as in obesity
  • Preliminary data says that GLP-1 analogue Exendin-4 attenuates high energy food cue reactivity in ex-smokers and abstinent alcohol dependence
  • Preliminary data that Exendin-4 attenuates alcohol cue reactivity in humans with obesity and alcohol dependence
  • Gut hormone based therapies may have potential for treating drug craving and preventing relapse in addicted populations and obesity.
102
Q

What are novel psychoactive substances (NPS)?

A
  • Psychoactive drugs not prohibited by UN Drug Convention but may pose a public health threat compared to those listed in the convention (UK Home office, Legal Definition)
103
Q

What is the most commonly used illicit drug in the UK?

A
  • Cannabis
104
Q

Describe what was going on in 2008 regarding heroin and crack

A
  • Good treatment penetration
  • Low HIV rates
  • Aging cohort who established their drug use a decade or more earlier
  • Young people NOT initiating heroin or crack cocaine
105
Q

What was the first wave of NPS?

A
  • Mephedrone
  • Cathinone (amphetamine like effects)
  • Widely available, cheap
  • Rapid market penetration
  • Snorted, injected, swallowed
  • Outside organised crime structures
106
Q

What were the three waves of NPS?

A
  • (1) Methadrone —> (2) Synthetic Cannabinoids —> (3) Synthetic Opioids (big problem in US)
107
Q

What are synthetic drugs?

A
  • Drugs which aim to mimic the traditional psychoactive drugs
108
Q

What new changes are seen regarding NPS?

A
  • New availability: street —> online —> social media apps
  • New users: Clubbers | Gay men (chemsex) | Young professionals (as undetectable) | Psychonauts | Prisoners esp. Spice
  • New health frontline: Young people view NHS Drug Treatment services as Heroin users therefore present to Mental Health or A&E
  • New harms: Harms similar to ‘traditional drugs’ | New harms e.g. Hallucinogen Persisting Perception Disorders, Ketamine Bladder,
109
Q

How do synthetic cannabinoids compare with natural cannabinoids?

A
  • Natural cannabis contains THC (main psychoactive component, CB1) and cannabidiol (anti-psychotic effect, CB2)
  • SCRAs bind to same receptor with higher potency | SCRAs lack cannabinoids (may explain more psychosis)
110
Q

What are the demographics of SCRA users?

A
  • Prisoners
  • Homeless
  • Mental Health patients
  • Professionals
111
Q

How does the illicit drug market respond to the rise of NPS?

A
  • Increase purity of cocaine and MDMA
  • Now legality not an issue, traditional illicit drugs can directly compete with NPS
  • Signs that organised crime taking over NPS supply?
112
Q

What drugs feature in the Third Wave NPS?

A
  • Benzodiazepine NPS (Xanax)

- Opioid NPS (Fentanyl analogues)

113
Q

Describe Yellow Card strategies

A
  • Report Illicit Drug Reactions (RIDR)

- RIDR Quarterly Dashboard

114
Q

What were the challenges to the ICCAM Study?

A
  • Recruitment
  • Retention
  • Loss to follow-up
  • Co-morbidity
  • Multiple dependencies
115
Q

What were the strengths of the ICCAM Study?

A
  • Double-blind
  • Placebo-controlled
  • Cross-over design- increased power but possibility of drop-outs and missing data
  • Multi-faceted data-rich data set
  • Baseline and follow-up sessions allow possibility of assessing predictive value
116
Q

What were the design limitations of the ICCAM Study?

A
  • Pseudo-randomised
  • Abstinent (not current) users, applicability
  • Single dose
  • Multi-dimensional data gives potential problem of false positives due to multiple comparisons (high chance of Type I error)
    • Need for hypothesis-driven research questions
117
Q

What is the BOLD signal?

A
  • The ratio change in oxyhaemoglobin to deoxyhaemoglobin in the blood
  • An indirect measure of neuronal activity
118
Q

Why fMRI in addiction?

A
  • Can locate disturbances at a population (“Biomarkers” of Addiction)
  • Substances of addiction can interfere with neuronal processes that govern behaviour
119
Q

What is the dopamine reward deficiency syndrome?

A
  • Hypothesis suggests Addiction is a deficit of dopamine circuitry for non-drug awards
  • E.g. non-drug awards no longer elicit a normal response only substances of abuse can produce a normal reward response
120
Q

What are the brain areas involved in addiction?

A
  • Nucleus Accumbens
  • Mesolimbic pathways
  • Amygdala
  • Orbitofrontal cortex
121
Q

Describe fMRI and Reward

A
  • Addicts in drug-deprived state devaluate non-drug awards
  • Methods: Nicotine dependent and deprived subjects, guess correct —> win money, after smoke or not? $
  • When those who cannot resist smoking, win money —> weak bilateral Ventral Striatal response (less interest)
  • When those who can resist smoking, win money —> strong bilateral Ventrial Striatal response
122
Q

Describe the ICCAM Study

A
  • Patients receive either placebo, mu antagonist, D3 antagonist or NK1 antagonist at each visit (4 visits)
  • Follow up appointments to see who relapsed or remained abstinent
123
Q

What were the main neuroimaging markers being investigated in the ICCAM Study?

A
  • Reward sensitivity
  • Reponse inhibition
  • Emotional responses
124
Q

How did the alcohol and polydrug compare to the controls? (Impulsivity, anxiety)

A
  • Both alcohol and poly-drug dependent individuals were more impulsive in questionnaire measures of impulsivity and delay discounting task
  • Scored higher on anxiety, depression and stress
  • Poly drug group had greater incidence of childhood trauma
  • Both alcohol and PD had higher negative urgency
  • Both alcohol and control group had same sensation seeking but polydrug was higher
125
Q

Spatial working memory imp

A
  • Alcohol showed significant spatial working memory impairment
    (No different in number of errors or strategy for task completion)
  • PD showed no significant difference to control in SWM impairment
  • Significant WM/GM loss in alcohol group which is necessary for spatial working memory
126
Q

Impairment in decision making during Gamble Task

A
  • No difference in risk or money being bet
  • Alcohol and PD take longer to make the right decision
  • PD make worse choices in quality of decision
127
Q

Describe reward response

A
  • Can measure both reward anticipation and reward recepit
  • Ventrial striatum/NAcc recruitment in line with its role in encoding predictive value of reward cues
  • Ventral striatal BOLD response to reward predicting cues (anticipation period) is often used as an index of incentive motivation for rewards
  • Majority of studies show blunting of reward response in striatal regions in addiction
128
Q

What areas are activated in the MID anticipatory phase of the ICCAM Study

A
  • Ventrial Striatum
  • Insular
  • Thalamus
  • Some visual cortical activation
  • SMA/ACC
  • Reduction of striatal response in Alcohol/PD control compared to control
129
Q

What does striatal response correlated with in ICCAM Study?

A
  • Striatal response negatively correlates with impulsivity measures (more likely to get striatal blunting, the more impulsive)
  • More anxious, the more striatal blunting
  • ?More anxious, more impulsive, the more addicted
  • No correlation with months abstinent
130
Q

Describe the effect of Naltrexone on striatal response

A
  • Naltrexone does make a difference in striatal response
  • D3 antagonist reverses striatal blunting in ventral striatum and in ventral pallidum (this area has high number of D3 receptor)
  • PD with primary opiate dependence didn’t respond but primary alcohol dependence did have a normalised response
  • NK1 repector antagonist increases striatal response in alcohol group not in PD group
131
Q

What is the relationship between striatal response and abstinence at baseline?

A
  • Those with higher level of striatal response at baseline were more likely to be abstinent
132
Q

What are neural substrates of response inhibition?

A
  • Motor action: Activation of premotor cortex and putamen, inhibiton of globus pallidus, disinhibition of thalamus and activation of primary motor cortex (M1)
  • Response inhibition: IFC responsible for generating the No-Go signal which leads to inhibition of thalamus and of motor responses in the primary motor cortex (via Subthalamic nucleus and globus pallidus)
133
Q

What is MDMA?

A
  • Ecstasy AKA 3,4-Methyl​enedioxy​methamphetamine
  • Typical dose: 60-120mg
  • Effect after 20-60 mins
  • Peak after 60-90 mins
  • Duration: 3-5 timer
134
Q

What are the effects of MDMA?

A
  • Increased energy

- Euphoria

135
Q

How does MDMA work?

A
  • It blocks the SERT on the pre-synapatic hormone
  • Serotonin works on the 5HT2A pre-synaptic receptor
  • It inhibits the resynthesis of serotonin
136
Q

Describe fMRI work with MDMA

A
  • 25 healthy volunteerrs (5 females)
  • Double-blind, placebo-controlled. Two scans, 7 days apart
  • 100mg MDMA-HCL orally administered 45 mins before
  • 60 mins functional scanning
  • Resting state ASL and BOLD state were tested
137
Q

What were the results of the fMRI MDMA study?

A

ASL: Decreases in CBF (cool) after MDMA vs Placebo
(Cluster corrected p < 0.05)

  • As subjective intensity increases, right amygdalal and right hippocampal CBF under MDMA decreases
  • Less activity in left temporal lobe, less negative effect
138
Q

Describe MDMA and Functional Connectivity

A
  • Connectivity in Resting State Network (mPFC and post. cingulate cortex) decreased
  • Decreased mPFC-Hipp connectivity correlated with subjective intensity and positive mood ratings
139
Q

Describe MDMA and recollection of best memories

A
  • Make vividness of positive memories stronger

- Increased emotion of positive memories

140
Q
  • Describe MDMA and worst memories
A
  • Worst personal memories become less negative

- Bad memories were less salient

141
Q

What does increase in serotonin do to the amygdala response to negative emotional states?

A
  • Increasing serotonin decreases amygdala response to negative emotional states
142
Q

Describe MDMA for PTSD

A
  • MDMA-assisted psychotherapy are positive
  • Decreases symptoms of PTSD and still significant after 2 years
  • Small samples but are safe to do
143
Q

Where are the serotinergic neuron cell bodies

A
  • Raphe nucleus in the midbrain
144
Q

Do Ecstasy users have more or less SERTs compared to the general population?

A
  • Ecstasy users have fewer SERTs
  • Some studies show increase in 5HT2A receptor availability and some decrease
  • High number of receptors due to compensatory upregulation for future use
145
Q

Describe reversibility of SERT

A
  • The longer since last MDMA use, the more ‘normal’ SERT binding
  • 212 days recovery time in striatum
  • Same pattern in amygdala, thalamus and midbrain
  • No reversibility in neocortex
146
Q

Describe psychedelics and SERT binding

A
  • No difference in SERT binding between hallucinogen preferring users and controls
  • Psychedelics just bind directly to 5HT2A receptors
147
Q

What does chronic MDMA use and acute tryptophan depletion do to the amygdala?

A
  • Increased amygdala activation when processing negative emotional states
148
Q

Describe effects of MDMA on cognition

A
  • MDMA has subtle cognitive effects

- Difficult as it is hard to find users who just use MDMA

149
Q

Name some psychedelics

A
  • DMT
  • Psilocybin
  • Mescaline
  • LSD
150
Q

What is a psychedelic?

A
  • A drug which, without causing physical addiction, craving, major physiological disturbances, delirium, disorientation or amnesia, more or less reliably produces thought, mood, and perceptual changes otherwise rarely experienced except in dreams, contemplative and religious exaltation, flashes of involuntary memory and acute psychosis
151
Q

How do psychedelics work in the brain?

A
  • Post-synaptic 5HT2A agonists
152
Q

Apart from their dopaminergic effect, how do anti-psychotics work?

A
  • Non-selective 5HT2A antagonists
153
Q

What is a peak experience?

A
  • Rare, exciting, oceanic, deeply moving, exhilarating, elevating experiences that generate an advanced form of perceiving reality, and are even mystic and magical in their effect upon the experimenter
154
Q

What are aspects of non-drug related mystical experiences?

A
  • Sense of unity
  • Transcendence of time and space
  • Deeply felt positive mood
155
Q

How do psychedelics affect CBF

A
  • Decreases CBF
156
Q

How does acute psilocybin affect mPFC?

A
  • Decreases activity in mPFC
157
Q

How does psilocybin affect functional connectivity?

A
  • Decreases PCC to mPFC after psilocybin

- Decreases rumination

158
Q

How does resting state networks change from childhood to adulthood?

A
  • Resting state network becomes more defined and separated
159
Q

Describe psilocybin and recollection of personal autobiographical memories

A
  • Personal autobiographical memories were more vivid, visual

- May be useful for depression as sufferers have difficulty in recalling positive memories (negative bias)

160
Q

What is increased 2A binding associated with?

A
  • Increasing 2A binding related to neuroticism, pessimism in depression and negativism in females
161
Q

How many people in the UK are pathological gamblers?

A
  • 500,000

- 2 million at risk

162
Q
  • What is a gambling disorder according to the DSM5?
A
  • Persistent and recurrent problematic gambling behaviour leading to clinically significant impairment or distress as indicated by the individual exhibiting four or more of the following in a 12-month period
  • Needs to gamble with increasing amounts of money in order to achieve the desired excitement
  • Is restless or irritable when attempting to cut down or stop gambling
  • Has made repeated unsuccessful efforts to control, cut back, or stop gambling
  • Is often preoccupied with gambling (e.g., having persistent thoughts of reliving past gambling experiences, handicapping or planning the next venture, thinking of ways to get money with which to gamble).
163
Q

When may people gamble?

A
  • When feeling distressed e.g. helpless, guilty, anxious, depressed
  • Losing money gambling, often returns another day to get even (chasing one’s losses
164
Q

What is gambling disorder according to ICD-11?

A
  • Impaired control
    ‘
  • Increasing priority
  • Continuation/Escalation OG Gambling despite negative consequences
165
Q

How many adults (16+) have gambled in the past year?

A
  • 63%
166
Q

What proportion of men and women gamble?

A
  • Men- 66%

- Women- 59%

167
Q

What is problem gambling associated with?

A
  • Gender- men are more likely to experience problems than women across all cultures
  • Age- young people are more likely to experience PG problems
  • Homelessness- Our study from 2013 shows X10 prevalence rates compared to normal London population.
  • IMPULSIVITY – Strong predictor of problems at a young age and high levels of impulsivity in our patient population. ( Slutske et al 2012)
  • IMPAIRED FUNCTIONING IN BRAIN REGIONS THAT RELATE TO DECISION MAKING . Ventromedial PFC and Striatum. These are the reward pathway areas that are showing significant differences between PGs and controls. (Petry2015)
168
Q

Describe genetics and PG

A
  • PGs more likely to have a PG parent
  • In Treatment seeking samples 10-44% have one or more parents with PG
  • Twin studies: genetic risk appears stronger in men than women. ( As with alcohol)
169
Q

Describe the neurobiology of PG

A
  • In both substance misuse and PG there is a DYSFUNCTIONAL REWARD SYSTEM with REWARD ANTICIPATION being disregulated
  • Both substance misuse and PG patients display HYPORESPONSIVE REWARD CIRCUITRY
  • These findings support the theory of a DOPAMINERGIC DYSFUNCTION in both PG and Substance misuse
  • The fMRI studies mentioned are consistent with the PET evidence indicating REDUCED DOPAMINE RECEPTOR LEVELS IN ADDICTION
  • However, other studies have reported INCREASED rather than decreased responses to monetary reward in PGs( Hewig et al 2010)
170
Q

Describe functional neuroimaging

A
  • Several fMRI studies of PGs have reported BLUNTED neural responses to monetary gains primarily in

Ventral Striatum and Ventromedial/Dorsolateral PFC

171
Q

What are associated problems with PG?

A
  • Loss of employment
  • Crime
  • Physical health
  • Social isolation
  • Pressure on families and carers
172
Q

Describe naltrexone in PG

A
  • Three significant systematic reviews have looked at pharmacological interventions for PG: only 2 RCT studies high enough quality to be included
  • Outcome showed that Naltrexone and Nalmefene ( Opioid receptor antagonists) are promising although as yet neither are approved by BNF.
  • Naltrexone is a mu kappa opioid receptor antagonist used currently as an adjunct to prevent relapse in both alcohol and drug addiction
173
Q

What is cognitive control?

A
  • The ability to inhibit behaviours
174
Q

What brain areas are involved in cognitive control?

A
  • ACC
  • Dorsolateral prefrontal cortex
  • Inferior frontal gyrus
  • Anterior insular cortex
175
Q

Describe fMRI and cognitive control

A
  • Cocaine addicts in early abstinence: Decreased activation in cognitive network areas involved in overriding prepotent response
    • Unable to hold information, plan and inhibit prepotent response (do not press if letter is in your list)
  • Chronic cannabis users have decreases activation in cognitive control networks during unaware errors
    • Inhibit if word-colour conflict or if immediate repeat and indicate error awareness on next trial if mistake
  • Decreases cognitive control associated with increased drug use and increased risk of relapse
176
Q

What is the relation between stress response and drugs of abuse?

A
  • Dysfunctional stress response may be involved in motivation to use drugs of abuse (stress may be prerequisite for risk of relapse
177
Q

Describe fMRI and stress

A
  • Clear gender effects in the neural correlates in stress (F > M) and craving (M > F) - Marc et al
178
Q

How can fMRI predict risk of relapse?

A
  • fMRI activation (during decision-making task) can predict relapse (95%) in early abstinent methamphetamine-dependent patients
    • fMRI of abstinent meth addicts predict where stimulus would appear on screen | Compare relapsers and non-relapsers
  • In later trials, abstinent have increased activation compared to decreased activation in relapsers
    • Multiple trials of Rock, Paper, Scissors | Too taxing for relapsers (engage less) | Abstinent up their game - stay abstinent?
  • Neural cue-reactivity can identify individuals at highest risk for future problematic drinking - Dager
    • fMRI response to alcohol cues | Transitioners have highest activation vs Moderate or Heavy drinkers
179
Q

How does fMRI facilitate medication development?

A
  • Methylphenidate —> enhanced ability of cocaine addicts to inhibit a response (Increased signal in medial PFC and ACC)
  • Modafinil acutely improves performance (neural correlates of this improvement can be mapped using fMRI)
180
Q

What are the limitations of fMRI?

A
  • Artefacts (movement, respiration)
  • Cannot infer neurochemistry
  • Artificial environment (not represent day to day)

NMH BSc (7 decks)

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