Module 3: Neurodevelopment, Mental Health and Mental Illness Flashcards
1
Q
What are the positive symptoms of schizophrenia?
A
- Delusions
- Hallucinations
- “voices”
- Disorganised speech
2
Q
What are the negative symptoms of schizophrenia?
A
- Social withdrawal
- Apathy
- Emotional blunting
3
Q
What are cognitive problems associated with schizophrenia?
A
Problems with
- Memory
- Attention
- Processing speed
4
Q
What % of the population suffer from schizophrenia?
A
- 1% of population
5
Q
What factors can cause schizophrenia?
A
- Genetics
- Paternal age
- Maternal famine or infection
- Hypoxia
- Season
- Urban dwelling
- Cannabis use
- Migration
6
Q
What is the risk of developing schizophrenia in identical twins?
A
- 48%
7
Q
What is the risk of developing schizophrenia in fraternal twins?
A
- 17%
8
Q
What can be used to find common gene variants in schizophrenia?
A
- GWAS
9
Q
What are the characteristics of the 108 loci associated with schizophrenia?
A
- 75% are protein coding genes/groups of genes, 40% are single genes
- 8% are within 20kb of a gene
- Notable associations with existing knowledge (aetiology/treatment) e.g. DRD2
- Main associations found in genes involved in glutamate neurotransmission and synaptic plasticity, GRM3, GRIN2A, GRIA1, SRR, voltage gated calcium channel subunits, CACNA1I, CACNA1C, CACNB2
10
Q
What are the main findings of the Schizophrenia GWAS?
A
- Estimated that 8,300 independent, mostly common SNPs contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability
- Hits converge on genes that are expressed in brain and immune tissues
- MHC locus consistently strongest association
- The leucocyte antigenic system HL-A as a possible genetic marker of schizophrenia. Br J Psychiatry. 1974 125:25-7.
- Enriched for genes in glutamate signalling
pathway - DRD2 implicated for the first time!
- Results consistent across sites showing ‘schizophrenia’ is good enough phenotype
11
Q
What are some rare schizophrenia alleles?
A
- DISC1- a gene affected by a translocation that causes various forms of mental illness in some carriers
- 22q11 deletion syndrome- a deletion that can cause a variety of symptoms including various forms of mental illness in some carriers
12
Q
What is 22q11 deletion syndrome?
A
- Velo-cardio-facial syndrome
- Hypoparathyroidism
- Underdeveloped thymus or absent thymus, which results in problems in the immune system
- Heart defects
- Cleft lip and/or palate
- Up to 1/3 VCFS patients may develop schizophrenia or other psychiatric illness
- Approximately 1% of patients with schizophrenia have 22qDS
- The schizophrenia in 22qDS is indistinguishable by symptoms, treatment response, neurocognitive profile, or MRI brain anomalies.
13
Q
What are characteristics of rare schizophrenia-associated loci?
A
- Highly but not completely penetrant
- Not specific to schizophrenia
14
Q
What are de Novo variants?
A
- Present in child but not in either parent
- Sufficiently rare (0-3 per exome) that could be possible to identify casual variants
- Very successful approach to identifying the cause of Mendelian diseases through sequencing
15
Q
Describe de Novo variants in schizophrenia
A
- Examine “sporadic” cases
– Very difficult to find, depending how you define
them - Compare frequency of de novos in cases vs.
controls - Make assumptions about causality for those
present in cases
16
Q
What have GWAS and rare variant studies have found?
A
- Studies of common (GWAS) and rare (sequencing ) variants have all started to implicate synaptic pathways in schizophrenia
- These pathways have also been implicated in
large scale studies of autism and epilepsy - Maybe not surprising biologically?
- Less useful for drug development?
17
Q
Describe the zinc transporter (ZnT3)
A
- Significantly decreased in schizophrenia
- impact on synaptic transmission
- Highly brain specific - present in SV sub-populations
- Suboptimal Zn nutrition during gestation in rate causes long-term effects on brain (Aimo et al 2010)
- Zn supplementation beneficial in unipolar depression (Nowak et al 2003)
18
Q
What is the genetic association of the synaptic vesicle specific zinc transporter with schizophrenia?
A
- Significant allelic association was observed for four SNPs with disease status in our UK cohort.
- Genotypic associations were observed for all four SNPs tested, consistent with a dominant model for disease penetrance.
- Haplotype analysis further supported these associations with 4 SNP haplotype associated with risk for disease, after correcting for multiple comparisons.
19
Q
What are different types of Cognitive Behavioural Therapy (CBT)?
A
- Cognitive Analytical Therapy
- Interpersonal psychotherapy
- Brief solution focussed therapy
- Psychodynamic psychotherapy
- EMDR
- Family therapy
- Dialectical Behavioural Therapy (DBT)
- Motivational interviewing
20
Q
Why is language an issue regarding CBT?
A
- CBT and the associated lexicon were developed in HICs, whose language (e.g. English) differ (sometimes very substantially) from LIMCs
21
Q
What is the hierarchy in patient-therapist relationship?
A
- Patient-therapist relationship in LAMICs is typically hierarchical
- Patients see the therapist as the expert and expect him/her to act as such- by showing authority and being directive
- A therapist attempting to be collaborative in such contexts may be unwittingly convey the impression of lack of expertise to the patient
22
Q
How is distance a problem in therapist-patient relationships in LAMICs?
A
- The patient may travel very long distances at huge expenses and personal hazard to see a therapist
- It is not uncommon that the patient may never see the therapist again
23
Q
Describe service organisation in CBT in LAMICs
A
- Referral pathways for CBT may not exist or if it is exists it is not understandable or accessible to clinician or the patient
- So the clinician seeing the patient may be the only one who can offer the patient CBT techniques (the patient may never be seen again)
24
Q
What are the benefits of group intervention in CBT?
A
- More cost-effective
- Fits the collectivist culture in LAMICs
- Meta-analyses of CBT in depression and anxiety consistently find group therapy to be as effective as individual therapy
25
Why can CBT be delivered by lay/non-specialist workers?
- The principle of CBT is relatively easy to convey to non-specialist health workers and other non-health professionals such as teachers
- CBT lends itself readily to manualisation
- Several RCTs of CBT in LIMCs have shown good outcomes with treatments delivered by trained non-specialists using manuals developed and supervised by specialists
26
What are the benefits of behavioural techniques in CBT?
- Easier to explain- especially by less skilled clinicians
- Quicker to understand and relatively easier to use
- As effective as cognitive interventions or full CBT
27
What other factors are important to consider in CBT?
- More directive approach (hierarchial nature of patient-therapist relationship)
- Language (Adapt, translate into local languages, idioms and metaphors
- Incorporating existing helpful cultural/religious coping strategies
28
When is it logical to promote/encourage religious coping?
- If religious coping is helpful in a culture
| - Religious practice/coping is high in that culture
29
What are the negative effects of religion on mental health?
- Guilt
- Promotion of anhedonia
- Promote stigma
- Harmful practices e.g. chaining and beating
- Reduced treatment adherence e.g. fasting
30
What are the positive effects of religion on mental health?
- Finding meaning in one's life
- More positive appraisal of negative events e.g. story of Job
- External attribution of negative events e.g. blame the Devil
- Promotion of positive affect e.g. count your blessings
- Social support e.g. reduced isolation
- Positive social guidance e.g. teaching of moderation
- Opportunity to give or serve - which improves positive affect
- Promoting or sustaining Hope in otherwise hopeless circumstances (which could reduce suicidality)
31
What is the benefit of involving families in CBT?
- Involving families is consistent with the collectivist, extended family and kinship orientation in LAMICs
- Families can remind the patient of the CBT techniques you taught them (since you may never see the patient again)
32
What are potential opportunities in using the Internet and mobile phones for CBT?
- Online/mobile phone delivery platforms for psychological therapy
- Remote supervision of therapists
33
Why might CBT not be helpful?
- Typical cognitive therapy may not be as helpful if the patient's negative cognitions are e.g.
- Genuine loss following a bereavement
- Genuine fear e.g. from bullying or persecution
- But some behavioural interventions may be helpful even in such situations (e.g. Using relaxation techniques to cope)
34
What are alternatives to CBT?
- Medication (SSRIs for anxiety, depression, OCD, PTSD)
- Supportive therapy e.g. bereavement counselling following a loss
- Practical problem solving and advocacy e.g. if negative cognitions are driven up genuine problems such as bullying
- Family therapy - if the underlying low mood or anxieties are driven by negative family dynamics
- Dialectical Behavioural therapy incorporating
- Radical acceptance
- Distress tolerance
- Mindfulness
35
What is radical acceptance?
- Accepting a painful reality you can’t help AND accepting that life can still be worth living despite that pain (e.g. loss of a loved one, terminal illness, seeing a perpetrator of crime against you acquitted by a jury and walk free from Court etc)
- Not accepting a pain that is unavoidable prolongs suffering and agony, and interferes with the patient’s capacity to move on from the past and take up new opportunities presenting themselves now and in future
- Challenges traditional (but unrealistic) Western beliefs that pain should not be tolerated and perpetual comfort (hedonism) is achievable
36
What are some distress tolerance techniques?
- Positive distraction – e.g. Music, watching funny video clips on YouTube, doing puzzles, painting/drawing, baking, walking the dog, gym, running etc
- Relaxation techniques e.g. deep slow breathing, progressive muscle relaxation, positive imagery, yoga,
- Positive self talk
- Helping others – volunteer for a charity
- Prayer
- Mindfulness
37
What is Mindfulness?
- Idea from Eastern philosophy especially Buddhism
Can be a therapy on its own or part of DBT or part of CBT (MCBT)
- Mindfulness is paying attention to things in the present rather than ruminating about the past or worrying about the future.
- It is consciously bringing back our mind from wandering off – often into negative thoughts
- “The wise man thinks about his troubles only when there is some purpose in doing so; at other times he thinks about others things.”–Bertrand Russell, British author, mathematician, and philosopher, 1872 -1970
38
Describe a mindfulness example regarding the dentist (from the lecture)
- E.g. if you are waiting to see a dentist, you are likely to get the thought “this is going to hurt” .
- However, rather than ruminate about how painful your last dental procedure was or how painful the procedure you are about to have might be
You could switch your attention to another experience in that environment. You might notice a fascinating pattern made by sun rays coming through the window and absorb your thoughts with the beauty of it until the dentist invites you into.
- The dental procedure will be painful (you can’t help it), but with mindfulness, you have avoided spending the 20 minutes wait worrying about the pain (i.e. you gained a 20 minutes pain-free life)
39
What is psychosis?
- Presence of hallucinations, delusions or severe abnormalities in behaviour
- Psychotic illnesses include: Schizophrenia and Bipolar disorder
40
When and what was schizophrenia first identified as?
- 1st identified by Emil Kraepelin as Dementia praecox in 1889 - i.e. progressive decline with early age of onset
41
What are the 4As of schizophrenia?
- Eugen Bleuler (1857 - 1939) characterised the diagnostic features: 4As --->
- Loosening of Associations (incoherent speech)
- (Flat) Affect
- Autism (social withdrawal)
- Ambivalence (both positive and negative feelings towards someone/something
42
What is Affect?
- How one's mood presents (different from subjective perception of mood)
43
What are the different subtypes of schizophrenia?
- Paranoid: Persecutory/Grandiose delusions
- Hebephrenic: Thought disorder, Flat affect
- Catatonic: Motor disorder, Posturing
- Simple: Progressive decrease in Mental Health | No clinical prevalence, no longer used
44
What is Crow's 2 syndrome model?
- Type 1: +ve syndrome, acute, good outcomes, Increased DAr
| - Type 2: -ve syndrome, chronic, poor outcomes
45
What is Liddle's 3 syndrome model?
- Psychomotor poverty
- Disorganisation syndrome (flat affect)
- Reality distortion (delusions/hallucinations)
46
What is positive syndrome?
- Hallucinations, Delusions | Well controlled by treatment
47
What are hallucinations (in the context of schizophrenia)?
- typically Auditory hallucinations (voices, 3rd person, running commentary, thought echo, commands)
48
What are delusions?
- Belief that lacks rational reasoning e.g. Grandiose | Paranoid | Nihilistic | Erotomanic
49
What is a thought disorder?
- Disconnected speech (thought implied from speech)
- Tangential
- Derailment
- Word salad
50
What are features of positive syndrome?
- Hallucinations
- Delusions
- Thought disorder
51
What is negative syndrome?
- Flat Affect
- Avolition
- Anhedonia
- Associated with decreased outcomes
52
What are features of negative syndrome?
- Expressive deficits
| - Social withdrawal
53
What are expressive deficits?
- Alogia (decreased verbal output)
| - Affective flattening (decreased non-verbal cues, situation-specific affect dissociation)
54
What are features of social withdrawal?
- Avolition (decreased motivation)
- Asociality (decreased social)
- Anhedonia (decreased pleasure from positive stimuli)
55
What are primary and secondary negative symptoms due to?
- Primary symptoms due to schizophrenia
| - Secondary symptoms due to positive psychotic symptoms, depression, PD
56
What is disorganisation?
- Thought disorder
57
What types affective disturbance are seen in schizophrenia?
- Hopelessness
| - Hypomania
58
What types of disturbed behaviour are seen in schizophrenia?
- Social withdrawal
| - Depressed features
59
How is social cognition impaired in schizophrenia?
- Lack of empathy
60
How is neurocognitive function affected in schizophrenia?
- Attention
- Memory
- Executive function
- All associated with decreased outcomes
61
Describe schizophrenia disease progression
(1) Premorbid (asymptomatic)
(2) Prodromal (sleep disturbance, paranoia, withdrawal)
(3) Progression (episodes of psychosis)
(4) Stable/Relapsing (more stable with treatment)
62
Why do SCZ individuals have increased mortality?
- Worse physical health (diabetes, CVD)
- Decreased accessibility
- Social deprivation
- Decreased adherence
63
What is the suicide risk of SCZs?
- 12x more than the general population
- Higher rates in Males, young patients, early stages
- Treatment is protective
64
What is the age of onset of schizophrenia?
- Early adulthood (16 - 35)
65
How does gender affect schizophrenia?
- Male > Female (1.4 : 1)
- Males (early 20s)
- Females (peak later)
66
How do genetics affect schizophrenia?
| Barnes lecture
- Many susceptibility genes (Neuregulin 1, Dysbindin, DISC1)
- Increased Paternal age at conception (de novo mutations in sperm)
- GWAS associated with MHC locus (C4 allele associated with SCZ, C4 marks synapses to be pruned by Microglia, C4 controls pruning in PFC in Adolescence
- Excess pruning ---> SCZ
67
How does cannabis affect SCZ?
- Cannabis users have significantly early onset of Schizophrenia (population cohort studies)
- Cannabis increases risk of Schizophrenia? Or SCZ more likely to use cannabis (Dysphoric Sx turn to cannabis)
- Individuals who have ever used cannabis ---> 40x increased risk of psychosis | Dose response effect
- Substance use is more common in SCZ than general population
- Any substance abuse wipes out any benefit of antipsychotic medication, even compliant individuals - Hunt 2002
68
What factors influence SCZ?
| Barnes lecture
- Maternal infection
- Hypoxia at birth
- Urban dwelling
- Migration
- Season at birth
69
Give an example of a genetic-environmental interaction in SCZ
- Relationship between age of first cannabis use and COMT polymorphism
- COMT gene (encodes for COMT in DA metabolism)
- MM: no risk
- VM: slight risk
- VV: high risk
70
How does dopamine dysregulation lead to psychosis?
- Decreased prefrontal dopamine activity & increased mesolimbic dopamine activity
---->
- Predisposes to psychosis
71
What factors affect vulnerability of dopamine dysregulation?
- Neurodevelopmental genes (Neuregulin, Dysbindin, DISC-1)
- Environmental brain insults (Obstetric events)
- Neurotransmitter genes (COMT gene)
- Substance use (Cannabis)
- Chronic social adversity (Migration, Depression)
72
What are short-term treatment goals for schizophrenia?
- Treating behavioural disturbance, +ve symptoms
73
What are long-term treatment goals for schizophrenia?
- Preventing relapse
- Maintain adherence
- Improve -ve symptoms/cognitive deficits (limited options)
74
What is the Nigrostriatal pathway?
- SNpc ---> Caudate/Putamen
- Role in movement
- Role in PD
75
What is the mesocorticolimbic pathway?
- Mesolimbic: VTA ---> Limbic regions (NAcc, Amygdala, Hippocampus) | Role in Reward | Affected by Schizophrenia
- Mesocortical: VTA ---> Frontal cortex
76
What is the tuberoinfundibular pathway?
- Hypothalamus ---> Median eminence
- Role in prolactin
- DA antagonists ---> Increased prolactin
77
What does increased dopamine in striatum lead to?
- +ve symptoms of Schizophrenia
- Amphetamine ---> Increased DA ---> de novo psychosis and worsens psychotic Sx of schizophrenia patients in remission- Angrist, 1980
- L-DOPA ---> Increased DA ---> worsen symptoms, may cause hallucinations
- Neuroimaging studies show increased DA synthesis in SCZ when psychotic
78
What does decreased dopamine in the prefrontal cortex lead to?
- Cognitive and negative symptoms of schizophrenia
- Neuroimaging studies show decreased DA in Frontal cortex in SCZ (and its role in working memory deficits)
- Clinical efficacy of DA antagonist Antipsychotics correlates with their affinity for D2 receptor
79
What is the clinical threshold for Antipsychotics?
- Roughly 65% blockade of D2 receptors (antipsychotic effect)
- >65% ---> Extrapyramidal S/E
80
What is increased DA in ventral midbrain associated with?
- Motivational salience of environmental stimuli
| - Goal-directed behaviour to threat/reward e.g. Knife wielder in lecture theatre, shift focus to threat
81
How does environmental/genetic predisposition lead to aberrant "motivational salience"?
- Environmental/Genetic predisposition ---> Dysregulated firing of dopamine ---> Aberrant "motivational salience"
---->
- Brain told motivational salience (something important), changes focus but NO obvious stimuli
---->
- Cognitive schema to explain aberrant experience ---> Delusional mood ---> Pick up more evidence to re-inforce delusion
- Antipsychotics block motivational salience (for delusions and normal functioning - similar to -ve symptoms?)
- If medications are stopped, delusions start again
82
What is the supersensitivity hypothesis of psychosis?
- Antipsychotics block D2 receptor ---> Increased number of receptors ---> breakthrough psychosis
- Abrupt withdrawal of medication ---> endogenous DA acts on highly sensitive receptors ---> Huge psychosis (rebound psychosis)
- Those who stop medication, only a few have a quick withdrawal psychosis | Would depot be better?
83
How has pharmacological treatment of schizophrenia advanced since the first antipsychotic drug, chlorpromazine?
- 1st generation antipsychotics e.g. Chlorpromazine was 1st antipsychotic invented in 1950s (blocked many receptors, dirty drug)
- Haloperidol = D2 receptor antagonist | Flupentixol: depo medication
- 2nd generation antipsychotics e.g. Clozapine 1989 - 1st antipsychotic demonstrated higher efficacy risk (risk Neutropenia - monitor bloods)
- Others had diff S/E
84
What is the pharmacological efficacy of antipsychotics?
- 2nd generation antipsychotics: increased responders, decreased symptoms, decreased relapse rate
- Clozapine has a larger efficacy than other antipsychotics
- Minimal differences in efficacy between other antipsychotics
85
What is the difference in S/E profiles between antipsychotics?
- 1st generation ---> movement disorders
| - 2nd generation ---> metabolic effects e.g. weight gain
86
What percentage of people will respond to antipsychotics?
- 80%
- Bulk of improvement over first year occurs in 1st month (quick improvement)
- Early response is an indicator for continued responsiveness to treatment
87
What percentage of people will not respond to antipsychotics?
- 10%
88
What does staying on antipsychotics lead to?
- Decreased relapses
| - Decreased risk of hospitalisations
89
What does discontinuation of antipsychotics lead to?
- 5 times increased risk of relapse
- Rapid discontinuation have 2 times higher risk of relapse rate (over 6 months) - Super-sensitivity hypothesis
- NICE guidelines recommends Relapse prevention for every Schizophrenic at least 1-2 years
90
What are the risks of NOT treating schizophrenia?
- Increased relapses: repeated psychosis associated with decreased prognosis, worse symptoms, decreased quality of life, increased neuroinflammation
- Risk of harm to self and others
- Disruption of personal relationships
- Possible loss of efficacy of medication (Increased study duration associated with smaller reduction in relapse rate - controversial)
91
What are the risks of treating/adverse effects of antipsychotic medication?
- Metabolic side effects (1 in 3 develop metabolic syndrome)
- Changes in brain structure (Parietal lobe, basal ganglia)
- Cardiotoxic effects | Increased risk of CVD, stroke and CHF
92
What is Duration of Untreated Psychosis (DUP)?
- Time from onset of psychotic symptoms to starting treatment | DUP: roughly 1-2 years - Barnes 2000
- Increased DUP/delays in accessing care associated with decreased outcomes
- Why? Untreated psychosis is damaging (antipsychotics may attenuate this) or those with poorer prognosis present later to services due to differences in symptom profile (shouting about aliens in street vs hallucinations in bedroom)
93
What percentage of SCZ patients are poorly or non-adherent?
- 50%
| - 50% of patients take less than 70% prescribed doses
94
How does substance abuse affect antipsychotic medication?
- Wipes out any benefits of antipsychotic medication, even in compliant individuals
- (Non-compliant +/- Substance abuse) and (Compliant + Substance Abuse) have similar relapse rates
- Compliant + No substance abuse ---> 50% relapse-free by 4 years
95
What are the advantages of depot/long-acting injection antipsychotic preparations?
- Avoid covert non-adherence
- Follow-ups are useful (assess S/E)
- Simplification of treatment regimen
- Swedish trial: Depot ---> Decreased 20% risk of rehospitalisation (compared to Oral)
96
What are the disadvantages of depot/long-acting injection antipsychotic preparations?
- Slow dose titration
- Longer time to achieve steady state
- Pain
97
Describe the validity of depot RCTs
- Depot have slightly higher efficacy (modest) than Oral antipsychotics
- Those who are content are more compliant | Studies may be too short | Trials have increased clinical attention
98
What is the validity of depot observation studies?
- No binding | Increased clinical attention in Depot group
99
What should be checked if no adequate response to 2 trials of Antipsychotics?
- DDx
- Exclude treatment reluctant
- Adequate antipsychotic dose, duration and adherence
- Adverse effect masking response
- Co-morbid conditions
- Substance misuse
100
(Continuation from no.99)
If excluded, what should be considered?
- High dose antipsychotic medication OR switch antipsychotic
101
(Continuation from no.100)
If no benefit what should be given?
- Clozapine
- CUTLASS 2 Trial: Schizophrenia with poor treatment response to 2 or more antipsychotics should start Clozapine
- Average delay to meet NICE criteria for Treatment-Resistant SCZ to start Clozapine is roughly 4 years
- Once TRS is diagnosed, if you wait >3 years, Clozapine is less effective - Yoshimura, 2017
102
If Clozapine doesn't work then what?
- Combination and augmentation therapies?
| - Target specific symptoms?
103
Describe Clozapine
- 1960s: Clinical trials confirmed for antipsychotic efficacy and lack of extrapyramidal S/E
- 1975: Clozapine result in 7 deaths due to Agranulocytosis ---> Withdrawn
- Risk of agranulocytosis is highest early on ---> requires regular blood tests
- Kane 1988: Clozapine shown to be significantly more effective than other antipsychotics
- Clozapine is superior to other antipsychotics in decreasing positive symptoms, negative symptoms and overall symptom score
104
What receptors does Clozapine block?
- Dopamine
- Adrenergic
- Histamine
- Serotonin
- Muscarinic
105
What is the prognosis of Clozapine use?
- 1/3 have good long-term outcome
- 1/3 intermediate outcome
- 1/3 poor outcome
106
What are affective/mood disorders according to the ICD-10?
- Where the fundamental disturbance is a change in affect or mood to depression (with or without associated anxiety) or to elation
- The mood change is usually accompanied by a change in the overall level of activity
- Most of the other symptoms are either secondary to, or easily understood in the context of, the change in mood and activity
- Most of these disorders tend to be recurrent and the onset of individual episodes can often be related to stressful events or situations
107
What are the diagnostic criteria of Bipolar disorder?
- Depressive low phase
- Low mood
- Loss of enjoyment
- Loss of interest and motivation for everyday activities
- Poor sleep
- Hypomanic phase
- Constant elation
- Irritable mood, getting into arguments easily
- Increased energies
- Overestimating personal ability
108
What is emotional information processing?
- A series of processes involving attentional, perceptual, appraisal and response preparation operations occurring in individuals during salient internal and external events, impacting on the experience of and responses to the events
- Cognitive biases in
- Attention
- Memory
- Perception of facial expressions ---> Emotional (dys)regulation
109
How does depression affect attention bias?
- Depression is characterised by biases in maintaining/shifting attention = difficulties for depressed people to disengage from negative material
110
What are the neurofunctional abnormalities of attention biases in depression?
- Sustained amygdala response to negative stimuli
- Prefrontal cortex
- Perigenual ACC (BA 24, 25 and 32) appears to mediate negative attentional biases
- lateral inferior frontal cortex associated with the impaired ability to divert attention from task-irrelevant negative information
111
What are some memory components?
- Implicit memory: priming, implicit associations
| - Explicit memory: recognition and recall
112
What is the relationshipp between depression and memory biases?
- Depression: strong evidence for biased memory processes
- Preferential recall of negative compared to positive material = one of the most robust findings in the depression literature
- Negative bias:
Free recall tasks meta-analysis = 10% more neg vs pos words
Higher-level conceptual memory tasks vs purely perceptual tasks
- Bias: Toward negative material or Away from positive material
- Memory biases also present in individuals at risk (neuroticism) and in recovered depressed individuals.
113
What are the neurofunctional abnormalities of memory biases in depression?
- Depressed patients show greater amygdala response and enhanced amygdala-hippocampal connectivity to subsequently remembered negative pictures
- Bilateral amygdala response during the encoding of emotional material predicted increased recall of negative (but not of positive) words
114
How does depression affect facial expression recognition?
- Increased recognition of negative faces and/or decreased recognition of happy faces
- Meta-analysis (Dalili et al., Psych Med 2014)
- robust strong evidence of Emotion Recognition deficits in MDD
- reduced recognition of all basic emotions except for sadness
- small effect size: may be confounded by medication?
- At risk: in neuroticism reduced recognition of happy faces (Chan et al, 2007; Fruhholz et al, 2010)
115
What are the neurofunctional abnormalities of depression in facial expression processing?
- Enhanced amygdala response to negative faces (Fu et al., 2004, 2008; Sheline et al., 2001; Surguladze et al., 2005)
- Even in the absence of awareness (Suslow et al., 2010; Victor et al., 2010)
- But not always replicated (Dannlowski et al., 2008; Gotlib et al., 2005; Keedwell et al., 2005; Lawrence et al., 2004) - possibly due to medication effects?
116
What are voluntary emotion regulation strategies?
- emotion suppression, rumination, catastrophising, worry, cognitive reappraisal, self-disclosure, use of autobiographical memories, use of positive prospection etc.
117
What emotion regulation strategies are used in depression?
- Increased emotion suppression, rumination, catastrophising
- Decreased reappraisal, self-disclosure, positive autobiographical memories
- Also in recovered individuals (Ehring et al. 2008)
- Emotion processing cognitive biases modulate emotion regulation strategies:
- facilitate the use of maladaptive strategies (i.e. brooding)
- hinder adaptive strategies (i.e. positive reappraisal)
- Depressed individuals report habitual use and selection of dysfunctional emotion regulation strategies but not impaired abilities to implement them (Liu & Thompson, 2017)
118
What neurofunctional abnormalities are seen in emotion regulation during depression?
Maintain = passive exposure
- Increased activity in amygdala, hippocampus, ACC, vmPFC
Regulate = cognitive appraisal
- Increased activity in amygdala, insula, anterior cingulate and inferior lateral PFC
- Decreased activity in DLPFC (to both positive and negative stimuli)
119
Describe facial expression modulation by an acute dose of antidepressants
Healthy volunteer models
Acute single dose
- Noradrenergic antidepressants (reboxetine, duloxetine): better recognition of happy faces
- Serotonergic antidepressants:
- mirtazapine: decreased recognition of fearful faces
- SSRI citalopram: mixed results (sometimes found to increase fear recognition)
- Neurofunctional: both increased and reduced amygdala response to SSRIs
120
Describe facial expression modulation by 7 day treatment of antidepressants
- Noradrenergic & serotonergic antidepressants: reduced recognition of anger and fear
- Neurofunctional: reduced amygdala and mPFC response to fear
121
What are the different types of trials?
- Phase 0: drug studies that aim to find how a drug behaves in humans. Usually low doses of the drug small numbers
- Phase I: Safety studies
- Phase II: Exploratory (pilot) trials to see if it can be done
- Phase III: Larger explanatory trials to see if it efficacious in controlled conditions, or effective in real-world clinical setting
- Phase IV: post-marketing surveillance
122
What are potential problems in trials?
- Lack of power - sample (Type II error vs cost)
- Selection criteria (broad vs narrow)
- Choice of outcomes
- Multiple aims and measures (Type I error)
- Self selection of participants
- Drop out
- Researcher bias
- Problems of side-effects (mild or severe)
123
What are potential solutions to trial problems?
- Sample size - Power calculation (90%)
- Selection criteria - explanatory – narrow, pragmatic – broad
- Choice of outcomes - Literature, stakeholders, qualitative data
- Outcome measures - A single primary outcome. Trial registration
- Self selection of participants - recruitment strategy, CONSORT diagram
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Describe sample size calculation
- Dichotomous or continuous outcome data
- An estimate of the size of the effect that is clinically important (usually based on pilot data)
- Power. The power of a study = 1-β (where β = probability of a type II error)
- Level of statistical significance – α (the probability at which the null hypothesis will be rejected)
- Randomisation ratio
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What is data analysis in clinical trials?
- Intention to treat
- The need to include all those randomised to intervention and control treatments in the data analysis.
- People who are compliant with the intervention may be different from those who do not comply. Differences may include those associated with better outcomes.
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What are potential solutions to observer bias?
- Blinding/ masking researchers to the exposure status of the participant: ensuring that observers are well trained, tell participants that they must not know their allocation status, having clear rules and procedures in place for the experiment.
- Blinding/ masking participants: placebos in drug trials, active control treatments in trials of complex interventions
- Blinding/ masking researchers to the study hypothesis
- Use of explicit, objective criteria for assessing study outcome (e.g. routine data from independent records, such as admission to hospital)
- Training researchers to use validated questionnaires in a consistent manner
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What is mood instability?
- Rapid oscillations of intense affect, with a difficulty in regulating these oscillations or their behavioural consequences
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What percentage of people with anxiety and depression have mood instability?
- 40-60%
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What percentage of the population have mood instability?
- 13.9%, peak aged 16–24, decline over time
- Adolescents: greater daily variability and more extremes of mood that progressively reduce in young adults
- Part of prodromal symptoms of depression and bipolar disorder in young people
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What is the clinical relevance of mood instability?
- Associated with self-harm and addiction
| - Associated with trauma in BPD, BP
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What is a traditional way of measuring mood instability?
- Self-report scales of trait constructs (“rate how the following describe how you are normally / apply to you in your daily life”): Affective Lability Scale, Affective Intensity Measure, Affect Control Scale
- Weekly (or longer) retrospective ratings of symptoms (remember memory biases in depression?)
- Mean, maximum and SD
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What is a newer way of measuring mood instability?
- STEP-BD: clinician rated assessments (initially weekly, then longer):
- Root Mean Square Successive Difference (rMSSD): reflects both the size and the temporal order of changes in mood
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Describe digital measurement of mood instability
- Ecological Momentary Assessment (EMA)
- Repeated sampling of subjects' current behaviours and experiences in real time, in subjects' natural environments
- minimize recall bias, maximize ecological validity
- study of micro-processes that influence behaviour in real-world
- BD group with self-reported higher variability of symptoms:
- feasibility of using MoodZoom for EMA
- twice daily auto-generated monitoring – more convenient, preferable and user friendly than questionnaires
- Mobile phone mood ratings significantly correlated with clinician-rated depressive symptom severity vs. paper-and-pencil ratings
- Electronic self-monitoring of mood in depression appears to be a valid measure of mood in contrast to self-monitoring of mood in mania
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Describe Daylio
- increasing trend towards the use of digital tracking methods
- mood, sleep, finances, exercise, and social interactions
- positive experiences: self-reflection and agency regarding health management
- challenges: poor usability or difficulty interpreting self-tracked data
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What are the emotional processing biases in BD?
- Negative memory biases
| - Prospective instability in depressive symptoms and manic symptoms
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Describe attentional dysfunction in disorders with mood instability
- Abnormal Attention Network Test performance in:
- ADHD with high Mood Disorders Questionnaire (MDQ) scores
- BPD with high affective lability subscale scores
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Describe the neurocognitive models in mood instability
- Brain areas involved in mood instability = emotion dysregulation areas dysfunctional in BP or BPD:
- connectivity btw ventromedial PFC & amygdala (increased mood)
- vs. connectivity btw ACC & amygdala (decreased mood)
- ACC increased activity during emotion processing tasks: compensatory mechanism?
- Inf Frontal Cortex reduced activity during emotion regulation tasks
- Dysfunctional intrinsic (during rest) connectivity of Central Executive Network & Salience Network
- Longitudinal study in at risk population (9-17 years old):
- worsening affective lability (scale) = increased amygdala and ventrolateral PFC activity over time
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What is mental imagery?
- Occurs when perceptual information is accessed from memory giving rise to the experience of ‘seeing with the mind’s eye’, ‘hearing with the mind’s ear’ and so on. By contrast, perception occurs when information is directly registered from the senses
- Mental images need not result simply from the recall of previously perceived objects or events; they can also be created by combining and modifying stored perceptual information in novel ways
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What are examples of mental imagery in depression?
- Negative intrusive images of past negative events
- Example: “I am a failure, I am completely alone”
- Lack of positive imagery
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What are features of suicidal imagery?
- “Flash-forward” images associated with the act or suicide or its aftermath
- e.g. image of jumping off a cliff; seeing others at ones funeral
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What is an example of imagery in anxiety?
- image of seeing oneself from the outside, as red as a tomato, covered in sweat
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What do lab experiments about mental imagery confirm?
- imagery has a direct impact on emotion, motivation, cognition and behaviour (stronger or different than verbal thoughts)
- imagery can shape perception, attention, action etc. via shared pathways in the brain
- frequency and quality of imagery can modulate affect (and behaviour) in clinical samples
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What are different types of perinatal mental illness?
- Perinatal depression
- Anxiety disorders
- Maternal OCD
- Psychotic disorders
- Eating disorders
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What are risks of pharmacological intervention in pregnant women?
- Teratogenicity
- Obstretric complications
- Neonatal toxicity and withdrawal symptoms
- Neonatal complications
- Risk mediated by incompatibility with breastfeeding
- Neuro-developmental disorders (Autism)
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What are the effects of untreated mental illness on the mother?
- Increased risk of relapse
- Increased risk of hospitalisation
- Worsening of long-term prognosis
- Suicide
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What are the risks of untreated mental illness on the foetus and neonates?
- Antenatal depression~premature delivery
- Anxiety~adverse foetal outcome: evidence inconsistent
- Maternal anorexia nervosa~(LBW)
- SCZ~LBW, pre-term delivery, still birth
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What are the effects of perinatal mental illness on the infant and child?
- Infant regulatory disturbances (excessive crying, feeding or sleeping difficulties and bonding/attachment
- Internalising difficulties: risk of depression and anxiety
- Externalising difficulties: risk of ADHD/Conduct disorder
- Attachment disorders: Maternal depression~Insecure Attachment, predicts future psychopathology in later life
- Impaired cognitive impairment
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What are the main classes of psychotropic medications used in perinatal mental illness?
- Antipsychotics/neuroleptics e.g. Risperidone
- SSRIs e.g. Fluoxetine
- SNRIs e.g. Venlafaxine
- Mood stabilisers e.g. Valproate
- Anxiolytics and sedatives e.g. Diazepam
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What is parenting?
- The process of promoting and supporting the physical, emotional, social, financial and intellectual development of a child from infancy to adulthood
- The quality of parenting e.g. sensitive, responsive parent-child relationship is one the most important predictors of healthy psychological development.
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What are research approaches to parenting?
- Psychological (cognitions, emotions, behaviours) correlates of parenting
- Neurobiological correlates of parenting
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What is attachment and bonding?
- Attachment = Flows from baby to mother (gradual)
| - Bonding = Flows from caregiver to baby (rapid)
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What are characteristics of sensitive parenting promoting secure attachment?
- Attunement
| - Mind-mindedness or reflective function
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What is attunement?
- Contigency = Baby and caregiver must be in sync
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What is mind-mindedness or reflective function?
- Parent treating baby as a conscious human being ---> Increased secure attachment ---> Increased functioning in adulthood
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What are the neurobiological correlates of parenting?
- Neuropeptides and dopamine reward pathways
| - Mirror neurons
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Describe relevance of neuropeptides and dopamine reward pathways in parenting
- Neuropeptides oxytocin and vasopressin link social stimuli to dopamine pathways
- Mother plays with baby who smiles ---> activates DA circuitry ---> Reward ---> Renforcement
(Insel and Young, Nature Reviews Neuroscience 2001;vol 2;120-136)
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Describe relevance of mirror neurons in parenting
- Matching observation and execution of goal related motor actions.
- Involved in a more general mind reading ability
Gallese and Goldman, Trends in Cognitive Science 2:12, 1998)
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What are key parent-infant interaction observation domains?
- Infant positioning
- Eye contact, vocalisation
- Engagement, synchrony
- Warmth and affection
- Attunement to stress
- Mind-mindedness
- Holding and handling
- Bodily intrusiveness
- Turn taking
- Expectations, empathy
- Self-soothing
