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 sugar-

http://www.britishsugar.co.uk/isolated storage/94175874-67b5-4c33-gf38-3802...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