Increased lactate levels and reduced pH in postmortem brains of schizophrenics: medication confounds.
A number of postmortem studies have found decreased pH in brains of patients with schizophrenia. Insofar as lower pH has been associated with decreased mRNA expression in postmortem human brain, decreased pH in schizophrenia may represent an important potential confound in comparisons between patients and controls. We hypothesized that decreased pH may be related to increased concentration of lactic acid. However, in contrast to the previous notion that an increase in lactic acid represents evidence for primary metabolic abnormalities in schizophrenia, we hypothesized that this increase is secondary to prior antipsychotic treatment. We have tested this by first demonstrating that lactate levels in the cerebellum of patients with schizophrenia (n=35) are increased relative to control subjects (n=42) by 28%, p=0.001. Second, we have shown that there is an excellent correlation between lactate levels in the cerebellum and pH, and that this correlation is particularly strong in patients (r=-0.78, p=3E-6). Third, we have shown in rats that chronic haloperidol (0.8mg/kg/day) and clozapine (5mg/kg/day) increase lactic acid concentration in the frontal cortex relative to vehicle (by 31% and 22% respectively, p<0.01). These data suggest that lactate increases in postmortem human brain of patients with schizophrenia are associated with decreased pH and that these changes are possibly related to antipsychotic treatment rather than a primary metabolic abnormality in the prefrontal cortex of patients with schizophrenia.
Halim
Nader D
ND
Graduate Program in Molecular and Cell Biology, Bethesda, MD 20814, USA.
Lipska
Barbara K
BK
Hyde
Thomas M
TM
Deep-Soboslay
Amy
A
Saylor
E Michael
EM
Herman
Mary M
MM
Thakar
Jay
J
Verma
Ajay
A
Kleinman
Joel E
JE
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D016477:Artifacts; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D001928:Brain Diseases, Metabolic / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003024:Clozapine / Q000494:pharmacology; D015986:Confounding Factors, Epidemiologic; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D019344:Lactic Acid / Q000378:metabolism*; D008297:Male; D011180:Postmortem Changes; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D014150:Antipsychotic Agents; D019344:Lactic Acid; D003024:Clozapine; D006220:Haloperidol