Schizophrenia Flashcards
Schizophrenia
Symptoms
Positive, florid symptoms = auditory hallucinations; paranoid, delusional/disorganised thought processes; change in the perception of the external world
Negative symptoms - these do not present upon the initial diagnosis (positive symptoms emerge first)
= apathy, lack of emotion, flattened affect, catatonic posture
Cognitive = deficits in cognitive processing
ie. Working memory, language function, spatial learning
Pathological Timeline
RISK –> PRO-DROMAL –> PSYCHOTIC –> RESIDUAL
Risk = genetic susceptibility
ie. DISC-1 = Disrupted In SZ-1
Involved in: neurodevelopment, neurosignalling, synaptic functioning
Relationship with qualitative traits such as: WM, cognitive deficits, grey matter volume
Pro-dromal = characterised retrospectively; pre-psychotic
The period between the appearance of initial symptoms (early adulthood) and the full development
If early diagnosis + intervention –> could intervene prior to display stressful changes
Often have cognitive impairments ie. impaired WM
Psychotic
Residual = the chronic nature of the disease - residual symptoms remaining (usually negative); the ability to function effectively decreases after each psychotic episode
Dopamine hypothesis: Evidence
FOR + AGAINST
Post-mortem:
- Increased [dopamine] striatum
- Increased D2 receptors
Chlorpromazine = D2 antagonist
- Seredipitously discovered
- Relieves positive, florid symptoms
- Reverses amphetamine-induced psychosis
- BUT = does not provide relief against negative/cognitive symptoms
- Correlation between clinical potency + IC50
- No correlation with D1 receptors
Amphetamines
- Increase [dopamine] in the synaptic cleft via DAT/VMAT
- Causes positive, florid symptoms
- Vulnerable people/used in excess/remitting SZ patient = can induce a psychotic episode
Rodents
- Administration of DAergic stimulants = induces stereotyped, repeated behaviours such as sniffling, chewing, locomotion
AGAINST
- Typical psychotics only treat positive symptoms; they do not treat negative symptoms
- Some SZ patients are not helped by drugs which decrease dopamine
- Limited evidence showing that SZ Ps have more dopamine/DAergic receptors
Typical Anti-Psychotics
ie. Chloropromazine
D2 antagonist
Treat positive, florid symptoms
Can reverse amphetamine-induced psychosis
Side effects:
- Extra-pyramidal = dyskinesias (permanent after prolonged use = tardive dyskinesias), jerky movements, involuntary face movements
- Effect the cholinergic system, cause parasympatholysis
ie. dry mouth - Sedation
BUT
Do not treat negative or cognitive symptoms
Undesirable side effects
Atypical Anti-Psychotics
ie. Clozapine
Mainly antagonist 5-HT2 receptors; weak effect at DAergic receptors
Treats negative symptoms
Dopamine Hypothesis
Overactivity of the MESOLIMBIC (reward) pathway = positive, florid symptoms
VTA –> hippocampus –> amygdala –> nucleus accumbens
ie. Amygdala - increased response to salient stimuli = over-interpret negative/neutral stimuli - incorporated into paranoid, delusion thoughts
Underactivity of the MESOCORTICAL pathway
VTA –> PFC
- Negative + cognitive symptoms
- Produce hypofrontality
Hyprofrontality = reduced cerebral blood flow to the PFC during cognitive tasks (PET Scan)
- Due to diminished mesocortical activity
- Cognitive tasks involving executive function, working memory and sustained attention; often develop prior to the psychotic stage (pro-dromal) and also affects 1st degree relatives
- Deficits in social cognition have been linked to abnormalities in the left prefrontal cortex
- Deficits in WM
Pathophysiology of SZ
Ventricular enlargement
SZ men = more likely to exhibit negative symptoms
SZ women = more likely to exhibit positive symptoms
White matter reduction = frontal lobe
Grey matter reduction = temporal lobe
White matter reduced to a similar extend in medicated + unmedicated Ps
Grey matter loss is related to duration of illness + higher doses of medication
= Brain loss is related to a combination of early neurodevelopment processes and illness progression
Working Memory Study
Matching task = SZ Ps had a performance deficit - they performed significantly worse compared to controls
Evoked Response Potentials (ERPs) = recordings are obtained from 3/4 midline potentials, and the gross change in electrical activity was measured
= frontal, central, parietal, occipital
Early components (N100) = reflect immediate response to exogenous stimuli Later components = reflect endogenous processing information (meaning/interpretation/consolidation of info)
Sz Ps = large changes in N100 irrespective of WM load
SZ Ps - have deficits in early visual processing = early visual deficit - which therefore impacts ability to encode information accurately
Consistent with hypofrontality deficit!
Hypofrontality
Underlies cognitive deficits
Prefrontal pathology has been shown to precede and be necessary for the development of SZ symptoms (occurs in the pro-dromal stage)
Suggests that deficits in inhibitory functions within the PFC allow for the emergence of psychotic + cognitive symptoms
Humans - PFC is one of the last structures to be hard-wired; development does not finish until late adolescence/early adulthood which coincides with 1st psychotic episode
Therefore - intervene earlier (pro-dromal stage) –> help neurowiring to occur in a more neurotypical manner
Glutamatergic Hypothesis
Hypofunction of NMDARs on GABA inhibitory interneurones = hypostimulation of interneurones
Preclinical/clinical studies with NMDAR antagonists show that midbrain mesocortical projections are sensitive to disturbances/alterations in glutamatergic input – SZ might be attributed to diminished NMDA function and a downstream disturbance in dopaminergic signalling, which causes hypofrontality
Glutamatergic Hypothesis
Evidence
FOR
Chronic intermittent doses of PCP = produce a pattern of metabolic (PET) + neurochemical changes in the rodent brain which mirrors SZ patients
PCP = can induce psychosis, hallucinations (although not auditory), formal thought disorder, out-of-body experiences in healthy volunteers = positive and negative symptoms
Post-mortem = reduced GAD1 (GABA synthesising enzyme), reduced GABA in the PFC
Hypofunction of GABAergic interneurones = disrupt cortical waves (due to phasic GABA - critical for establishing cortical activity profiles), particularly beta/gamma oscillations
(Similar implications in PD = possibly patterns of firing can be disease-causing)
= impairments in neural synchrony due to decreased synchronous firing of pyramidal cells
Glutamate hypothesis + cortical signalling
High levels of glutamate = disorganised levels of network activity caused by asynchronous firing rates in pyramidal cells = decreased power of beta/gamma oscillations
Dysfunctional glutamate activity paradoxically causes increased glutamate release + hypERmetabolsim in corticolimbic regions (cingulate + frontal regions)
Experiment:
- Analysed ket-induced brain flow in healthy + SZ Ps with PET scan
- Both had psychosis
- SZ Ps = increased activity (hypERmetabolism) in the cingulate
HypERactivity thought to be responsible for disordered thoughts and diminished cognitive abilities elicited by NMDAR blockade
Glutamate hypothesis + NMDA receptors experiment
NMDA tracer with SPET (Single Photon Emission Topography)
Significant reductions in LEFT hippocampal NMDAR binding = normalised to healthy volunteer with anti-psychotic medication
Reduced hippocampal NMDAR = a feature of both SZ and bipolar
BUT SZ only = LHS reductions in GluN1 subunit expression
OR an alternative hypothesis = might simply be due to altered localisation of NMDARs (as opposed to altered NMDA function/hypofunction)
Animal Models
Drug-Induced
Amphetamine = repeated administration causes neurochemical + structural changes
Induces psychotic-like changes
BUT - just positive symptoms
PCP = induces delusions/hallucinations
BUT - given to adult rats so no construct validity for neurodevelopmental origin
Animal Models
Environmental
Post-weaning social isolation = social deprivation alters brain development and causes behavioural deficits in adulthood
BUT
Affects can be easily reversed
Animal Models
Genetic
DISC-1 knock-out = several pathological + behavioural alterations in DISC1 K/O mice resemble SZ symptoms
BUT - discrepancies based on rat strain
Animal Models
Lesions
Neonatal ventral hippocampal lesion on P7 using acid (ventral hippocampus has the largest connectivity with the PFC)
Animal Models
Developmental
Gestational MAM = pregnant mother given MAM (intraperitoneal injection); targets neuroblast proliferation + affects brain development
Face + construct validity
BUT = complicated procedure
Genetics of SZ
~48% concordance rate (identical twins)
GWAS = identified SNPs + CNVs
DISC1 - Disrupted in SZ-1 = very strongly supported risk gene
ZNF804A = encodes a zinc finger protein
Both DISC1 + ZNF804A are implicated in BP –> is there a genetic overlap?
Val-Met COMT polymorphism
Prefrontal dopamine = important for the performance of frontal cognitive functions!
Val = increased enzymatic activity of COMT, therefore decreased PFC [dopamine]
Met = 2-4-fold decrease in enzymatic activity of COMT (degrades dopamine), therefore increased PFC [dopamine]
- Less error rates (due to more PFC [dopamine])
DPX (Dot Probe Expectancy) test = linked to frontal functioning; highly dependent on PFC DAergic levels - highlights context processing deficits
Context processing - linked to specific academic skills
ie. non-verbal problem solving
Val = more errors (context processing deficits), due to decrease prefrontal dopamine; showed increased activation of DLPFC
Because - greater activation (‘working harder’) required for the same level of cognitive performance (compared to Met)
Shows “inefficiency” of PFC functioning
Family-based association analysis = significant increase in the Val allele to the SZ-offspring
- Suggests that the Val allele, because it increase PF dopamine catabolism + thus impairs PF cognition, therefore puts individual at a higher risk for SZ
ALSO
Overall enhancement of PFC activity appears to contradict hypofrontality
BUT - the hypofrontal state could be due to a hyperactive PFC (due to a reduction of PFC GABAergic function)
Environmental factors
Increased rate of SZ in urban populations
Cannabis
- Epidemiological studies = risk associated with cannabis consumption was increased in subjects presenting with genetic markers of vulnerability (ie. Val allele)
- Cannabis is probably a combinational causal component of psychosis if there is an underlying susceptibility
Alternative: 5-HT
Evidence
Hallucinogenics such as LSD = 5-HT2a agonists
Cause altered PFC activity
Symptoms are similar to the 1st psychotic episode = hallucinations, psychosis, agitation, anxiety
Cause a down-stream increase in glutamate
Chronic lower doses of LSD administered to a rodent - exhibit behavioural syndromes which persists after administration has stopped
ie. anhedonia, hypersensitivity to noise, social withdrawal, locomotor changes such as chewing
Atypical anti-psychotics ie. Clozapine = 5-HT2a antagonists - relive cognitive and negative effects - unsure why
5-HT2a antagonists can block the effect of NMDAR-antagonists = therefore serotinergic mechanisms must be affected within ketamine-induced psychosis
Alternative: Nicotine
Evidence
Sz Ps significantly higher tobacco use compared to other mentally ill patients
- May be due to self-medicating = relieving negative and cognitive symptoms
Post-mortem = significant decrease in nicotinic subunits - a4 + a7
a7 agonist developed = early trials but promising results
** proof-of-concept study = positive effects on neurocognition in Sz Ps
BUT - longer trials are required to determine the clinical utility of the novel treatment strategy
Nicotine reported to improve PPI in NMDAR antagonism model
Potential therapeutic targets
A7 nicotinic subunit
mGlu2/3 (Gi.o) = autoreceptors
Agonists
Glycine transporter blocker (increase EC [glycine])
Co-agonist at NMDARs - therefore enhance function
Bitopertin = BUT failed Phase III due to lack of efficacy compared to placebo
Inhibition of phosphodiesterase (PDE)
PDE regulates IC [cyclic nucleotides] via hydrolysing cAMP/cGMP
GWAS study identified a CBV in PDE gene
Bloclade = effective in pre-clinical animal models - PCP-hyperactivity (positive, florid symptoms)
