Schizophrenia Flashcards
Howes et al (2012)
meta-analysis of studies using PET or single-photon emission computed tomography to measure in vivo striatal DA function. Found that presynaptic DA function is altered in schizophrenia, no difference in DA transporter availability and small elevation in D2/3 receptor availability (less consistent)
• Abi-Dargham et al (2000):
Measured in vivo occupancy of striatal D2 receptors by DA in patients with schizophrenia and controls, before and during pharmacologically induced DA depletion (administration of α-MPT). Measured with SPECT during constant diffusion of radiolabelled D2 receptor antagonist. Acute depletion of intrasynaptic DA resulted in larger increase in D2 receptor availability in patients with schizophrenia than controls. Further elevated synaptic DA was predictive of good treatment response of positive symptoms to antipsychotic drugs. Indicated increased stimulation of D2 receptors by DA NEURONS
o Don’t know magnitude of DA depletion, based on assumption that comparable between groups
o Assumes no upregulation of D2 receptors detectable 1 week after depletion
• Howes et al (2009):
Individuals prodromal symptoms of schizophrenia before onset of psychosis, with schizophrenia and controls in vivo striatal DA with measuring PET WITH (18)F-dopa imaging. Found that striatal F-dopa uptake elevated in prodromal patients to an intermediate degree to those with schizophrenia, localised to the associative striatum. The degree of uptake was correlated with severity of prodromal psychopathology and neuropsychological impairment, Indicates that DA overactivity predates the onset of schizophrenia
• Slifstein et al (2015):
new radiotracer to measure amphetamine induced DA release in the dlPFC in schizophrenics or healthy controls with PET and used BOLD fMRI during working memory test. Showed that patients with schizophrenia show blunted amphetamine-induced DA release in the dlPFC in vivo, extended to other extrastriatal regions such as the midbrain. Observed a correlation between index of DA release capacity and WM-related activation of dlPF in overall sample
• Krystal et al (1994):
Healthy subjects on Ket or placebo for 40 minute intravenous administration and ketamine increase positive and negative symptoms of schizophrenia, elicited alterations in perception, impaired performance on tests of vigilance, verbal fluency, and WCST, evoked symptomso f dissociative states so seems to produce range of symptoms, behaviours and cognitive deficits that resemble aspects of psychoses, particularly schizophrenia
• Humphries et al (1996):
looked at expression of NMDAR in brains from a population of well characterised schizophrenic patients and found NR-1 mRNA levels in tissue homogenates of superior temporal cortex was reduced by 30% in cognitively impaired schizophrenic patients in controls, while those that showed no impairment showed no reduction
o Not a direct measure of NMDA
• Balla et al (2001):
Continuous NMDA antagonist (PCP) induced in rats and monitored striatal DA release to amphetamine by microdialysis and showed that PCP treated mice showed significant enhancement in amphetamine induced DA release. Along with significantly enhanced locomotor activity. NMDA hypofunction may therefore contribute to DA dysfunction in schizophrenia.
Aalto et al 2005
Found in healthy males that ketamine increase DA in the posterior cingulate/retrosplenial cortex, as indicated by PET. Ketamine associated psychotic symptoms were associated with changes of 11C-FLB457 in the dorsolateral prefrontal and anterior cingulate cortices.
• Demjaha et al (2014
used 18F-dopa PET and 1H-MRS to assess GA and glu function in schizophrenics. Found that striatal DA synthesis capacity in responders was significantly higher volunteers. Glutamate was significantly elevated in the anterior cingulate in TR compared to healthy, indicated difference in NT levels between TRs and responders
o Small sample size, difference of Glu and DA a cause or consequence or poor antipsychotic response
Ripke et al (2020):
GWAS finding common variant associations at 270 distinct loci. Genes associated with rarer disruptive coding variants in people with schizophrenia including GRIN2A and TF SP4 and were enriched in genes implicated by such variants in autism and developmental disorder. Strong peak at major histocompatibility locus
• Marshall et al (2017):
GWAS of CNV and found that CNV burden was enriched for genes associated with synaptic function and neurobehavioral phenotypes. Obtained for 8 loci
• Skene et al (2018):
scRNAseq and applying cellular taxonomy, evaluated whether genomic loci implicated in schizophrenia map onto specific brain cell types. Found connections to 4 of 24 brain cell types: MSNs, pyramidal cells in hippocampal CA1, pyramidal cells in S1 cortex and cortical interneurons (see diverse set of genes such as antipsychotic drug targets, synaptic function) robustly associated with SZ, were consistent across neuron types. Suggest that discrete cell types are central to the aetiology of schizophrenia.
o Coverage of cortical and striatal lacking,
o A gene can play an important role without being in one of the cell types they implicated such as C4A polymorphism
• Sekar et al (2016):
Found that schizophrenias association with the variation in MHC locus involves many structurally distinct C4 alleles that affect expression of C4A and C4B in the brain. Found C4 in mice promoted synapse elimination during the developmentally timed maturation of a neuronal circuit. These indicate that excessive complement activity n the development of schizophrenia which may help explain reduced number of synapses. Hypothesis thatC4 signal microglial and involved in tuning synapses (tagging for removal)
• Weinberger (1987)
Brain development theory
• Rosenberger et al (2008
Using diffusion tensor imaging (DTI) tactography in patients with schizophrenia compared to healthy (23-56 yrs), used fractional anisotropy to describe fibre integrity and found that patients revealed significant decline in FA with age in both the cingulum and uncinate so suggest age associated reduction of the frontal-temporal connectivity
o What about younger. Only males And chronic schizophrenic
