Increased lactate levels and reduced pH in postmortem brains of schizophrenics: Medication confounds

Abstract

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 (0.8 mg/kg/day) and clozapine (5 mg/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.

Metabolic abnormalities in fronto-striatal-thalamic white matter tracts in schizophrenia

“…While two earlier NMR studies of frontal cortex and thalamus reported no statistically significant differences in these metabolites in schizophrenia (Omori et al 1999, Prabakaran et al 2004), small reductions in both lactate and alanine levels were noted in the thalamus (Omori et al 1999). However, our finding of lower lactate in ventral ALIC differs from two previous post-mortem studies that found higher lactate levels in frontal white matter (Prabakaran et al 2004) and cerebellum (Halim et al 2008) in schizophrenia. Glycogen is rapidly converted into lactate post-mortem.…”

“…No other protein measures showed significant correlations with age, PMI, pH or duration of storage. Lactate levels were inversely correlated with pH (rho=−0.576, p=0.001) as expected from previous studies (Halim et al 2008). Lactate is a major determinant of brain pH; therefore we did not use pH as a covariate in the metabolite analysis.…”

“…Halim and colleagues propose that increased lactate could reflect an elevation in glycogen levels due to antipsychotic treatment. It should be noted that in the previous two studies (Halim et al 2008, Prabakaran et al 2004) the schizophrenia group had a lower mean pH than the controls and were obtained from patients with high lifetime prescribed doses of antipsychotic medication. In contrast, in the present study pH was slightly higher in the schizophrenia group and only two of our samples had detectable levels of antipsychotic drugs.…”

Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance

“…In humans, the use of higherrange therapeutic doses of Met is unlikely to be of consequence unless elimination of Met is compromised (i.e., renal failure). That said, serious mental illnesses such as schizophrenia and bipolar disorder have been associated with mitochondrial dysfunction and increased lactate levels (Halim et al 2008, Regenold et al 2009, Herberth et al 2011, which raises the unexplored possibility that our patients may require more judicious dosing of Met to obtain maximal benefits. Translation of findings from rodents to clinic may, however, be complicated by genetic factors mediating metabolism and therapeutic action of Met (Shu et al 2007).…”

Mechanism and properties of positive allosteric modulation of N -methyl- d -aspartate receptors by 6-alkyl 2-naphthoic acid derivatives

“…One is that under pathological conditions such as hypoxia and schizophrenia, the extracellular pH in the brain can change (Chesler and Kaila, 1992; Halim et al, 2008; Siesjo, 1985) which in turn can change the effect of NMDAR modulators (Kostakis et al, 2011; Mott et al, 1998). Secondly, as exemplified by the potentiating actions of spermine on NMDARs (Traynelis et al, 1995), reversing proton inhibition is a potential mechanism of action for an NMDAR PAM.…”