Transcript Managing Dementia - Interface with Primary Care

Sugar, Schizophrenia
and Selectivity of antipsychotics
sugar – the British history
• the ‘north atlantic triangle’ (1655 – 1807)
• cane sugar refining (150 factories, 1750)
• new technology - sugar from beet (1799)
• tax on sugar removed (Gladstone, 1875)
• widespread reporting of
‘dementia praecox’ (Kreapelin, 1894)
dementia praecox
(later schizophrenia)
• cognitive deficits seen as a core feature
• hallucinations, delusions, thought disorder
• self neglect due to inattention and apathy
• evidence of progressive deterioration (~30%)
• needed an asylum network
epidemiology
• perinatal deficits
(low birth weight, obstetric complications)
• teachers pick up ‘odd’ traits aged 7 – 11
• young (adolescent) onset
• predominantly urban / inner city
• family history of psychosis, OCD and diabetes
clinical findings in
untreated patients
• undirected speech and movements
• higher rates (5%) of hyperglycaemia (2009)
• effectiveness of low dose Insulin / diet (1957)
• effectiveness of neuroleptics (1958 onwards)
• respite from performance stress and high
expressed emotion beneficial (1977)
moving on…
structural imaging findings
• patchy but generalised loss of gray and white
matter in group studies
• associated ventricular enlargement
• no sulcal atrophy (or gliosis)
• progressive gray matter loss
on serial scanning of individuals
• reduced cortical receptor load involving
Dopamine1,Glutamate (non NMDA) and 5HT2a
functional imaging
• ‘hypofrontality’- with reduced DA input
• ‘hot spots’ of increased blood flow and
metabolism in Broca’s area (speech producer)
– sp. When hallucinating
• reduced activity in association areas
• increased DA supply to cingulate and
mesolimbic areas
• ? secondary to hypofrontality (diversion)
genetic findings
• vast majority of cases unexplained
• however, 60% ‘familial’
(Schizophrenia, BPAD, OCD)
• no clear explanation for higher 1st degree
relatives with DM (both type 1 and 2)
• recent interest in ‘single nucleotide
polymorphisms’ (SNIPs)
• ongoing efforts to match features to genome
blue sky thinking
pathogenesis of
schizophrenia
• prior to imaging findings, pharmacology
based (e.g. Dopamine theory)
• post mortem brain findings led to
dysconnectivity theories (dysplastic net)
• imaging findings have modified above – how
do you explain hypofrontality and ‘hot spots’?
• developmental versus degenerative
• or, both ( e.g. the GLUT theory)
GLUT
• Glucose transporter proteins, sited across membranes
(500 amino acids, 7 sub types, funnel shaped)
• GLUT 4 present peripherally (e.g. muscle and fat)
– sensitive to Insulin
• GLUT 1 and 3, mainly in brain – Insulin insensitive
(GLUT 3 neurones, GLUT 1 endothelial cells)
• GLUT 1 and 3 crucial to brain –fixed availability,
with Glucose being the only nutritional substrate
• In starvation, increased GLUT 1 and 3 production, and
reduced GLUT 4 (GLUT 2 glucose sensors present in
hypothalamus and systemically, e.g. portal vain)
The GLUT hypothesis
(McDermott and de Silva, 2005)
• schizophrenia due to deficits in GLUT 1 and 3
(numbers or structural deficits)
• malnutrition of neurones (gradual loss of gray
matter)
• excess sugar intake will further down
regulate GLUT 1 and 3
• hyperactivity of Broca’s area (hallucinations)
• excess / inappropriate use of memory stores
and decision maker (thought disorder and
delusions)
also explains….
• perinatal findings
(placenta only uses GLUT 1 and 3)
• adolescent onset
(increased demand of nutrients)
• higher rates of hyperglycaemia in drug free subjects
(brain uses 20% glucose, backlog producing Insulin
resistance)
• higher DM in 1st degree relatives
• effective treatments
(Insulin and non Doperminergic anti psychotics)
how do anti psychotics
really work?
selectivity of anti psychotics
(Dwyer and Donohoe, 2003)
• all effective anti psychotics block GLUT
• strongest GLUT blocker is Clozepine
• followed by Olanzepine, Quetiapine,
Risperidone
• Haloperidol weakest GLUT blocker
• most atypicals competitive blockers,
Risperidone not.
consequences of GLUT blockade
peripherally
• can cause / worsen hyperglycaemia
(rat and human studies)
• alternatively, hyperlipidaemia
• raised leptin secondarily
(fat stores saturated)
• excess appetite (mimics starvation)
• eventually, metabolic syndrome
consequences of GLUT blockade
in brain
• increases production of GLUT 1 and 3
(apparent starvation)
• at higher doses, reduces metabolic
activity in hot spots (e.g. Broca’s area)
• similar to chemotherapy (higher doses
reducing overall brain metabolism)
• pulse therapy and/or low dose
prophylaxis?
conclusions
• we need to think ‘outside the box’
on schizophrenia
• need to utilize treatment models
used in chemotherapy regimes
• need to explain treatment
objectives and associated
difficulties to patients / carers
• need to be aware of potential
problems with high sugar intake
selected references
• the history of sugarhttp://www.britishsugar.co.uk/isolated
storage/94175874-67b5-4c33-gf383802...25/08/2005
• Impaired glucose tolerance in drug
naïve schizophrenics Kirkpatric,B et al.,Schizophrenia
Research 2009; 107 (2-3): 122-127
• Anti psychotics and glucose
intolerance – Smith et al., (meta
analysis) BJPsych 2008, 192, 406-417
selected references
• Progressive gray matter loss (MRI over
5 years)- Di Lisi, L.E., 2008
Schizophrenia Bulletin 34, 312-321
• GLUT hypothesis – McDermott, E., de
Silva, P., 2005,
Medical Hypothesis 65, 1076 – 1081
• GLUT blockade by atypicals – Dwyer,
D.S., Donohoe, D. 2003
Pharmacology, Biochemistry and
Behaviour 75, 255-260
thank you