Haloperidol Improves Membrane Phospholipid Abnormalities in Temporal Lobes of Schizophrenic Patients

Abstract

Functional neuroimaging studies have revealed abnormalities in the brains of schizophrenic patients, especially in the frontal and temporal lobes, basal ganglia, and thalamus (Bertolino et al. 1996;Andreasen et al. 1997;Egan and Weinberger 1997;McClure et al. 1998). Frontal lobe dysfunction generally has been associated with "negative" symptoms and the disorganization syndrome (Liddle et al. 1992;Kaplan et al. 1993;Shioiri et al. 1994;Deicken et al. 1995), whereas temporal lobe dysfunction may be related to "positive" symptoms (Fukuzako et al. 1996;Klemm et al. 1996;Nordahl et al. 1996;Sabri et al. 1997). The effects of neuroleptic treatment on regional cerebral blood flow (rCBF) and metabolism are not yet clear . Several researchers have found, however, that neuroleptic treatment produced changes in rCBF in the frontal and temporal lobes of schizophrenic patients. Nilsson et al. (1977) demonstrated a widespread reduction in cortical perfusion, especially in frontotemporal regions, after several weeks of treatment with haloperidol. Changes in positive symptom scores correlated well with changes in both frontal and temporal CBF (Berman et al. 1996). Single-dose haloperidol administration in schizophrenic patients ameliorated hypoactivity in the frontal lobes and suppressed hyperactivity in the temporal lobe and adjacent occipital and parietal areas (Matsuda et al. 1991). These CBF changes were not de- Received September 17, 1998; revised January 12, 1999; accepted April 5, 1999. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 21 , NO . 4 Phosphorus Metabolite Changes by Haloperidol 543 tected when the drug was administered to normal volunteers. These observations suggest that neuroleptics alleviate schizophrenic symptoms by actions in the frontal and temporal lobes.Phospholipase A 2 (PLA 2 ) is a key enzyme in the metabolism of phospholipids that also affects receptor function and signal transduction (Farooqui et al. 1992). In a biochemical study, Gattaz et al. (1995) found platelet PLA 2 activity to be greater in schizophrenic patients than in healthy controls; this elevation was reduced by neuroleptic treatment. Neuroleptics may alter brain phospholipid metabolism and composition by regulating PLA 2 activity in a manner similar to that seen in platelets and red blood cells. Possible effects of neuroleptics like haloperidol on membrane phospholipid metabolism and composition are under investigation. In one study, haloperidol was found to reduce synthesis of various phospholipids in rat brain (Singh and Shankar 1996).Disturbed phospholipid metabolism has been proposed as a neurodevelopmental pathogenesis of schizophrenia (Horrobin 1998 P-MRS, increased levels of phosphodiesters (PDE) and decreased levels of phosphomonoesters (PME) have been observed in the frontal lobes of drug-naive schizophrenic patients compared with levels in healthy subjects (Pettegrew et al. 1991;Stanley et al. 1995). Increased ␤ -phosphates of 5'-adenosine triphosphate ( ␤ -ATP) and decreased inorganic orthophosphate (Pi) also have been repor...

Phospholipase A2 activity is associated with structural brain changes in schizophrenia

“…In prefrontal brain regions, deficits of membrane lipid precursors were found more pronounced in follow-up investigations after antipsychotic treatment (Keshavan et al, 1989). Increased breakdown products of membrane lipids normalized after antipsychotic treatment in prefrontal (Stanley et al, 1995) and temporal (Fukuzako et al, 1999) brain regions. Therefore, the effects in several regions are likely to reflect the different etiology as well as timing of changes in these brain regions.…”

Bioactive lipids in schizophrenia

“…At least crosssectional comparison of PLA2 activity (Smesny et al, 2005), niacin sensitivity and in vivo 31P-MRS (Smesny et al, 2005;Stanley et al, 1995) between first episode and chronic schizophrenia patients and matched controls support the notion of a stage dependency of membrane lipid changes. While the membrane breakdown could be influenced by antipsychotic treatment (Fukuzako et al, 1999b), the first-episode studies in neuroleptic-naïve patients indicate that medication effects do not explain the observed membrane changes at the on-set of illness.…”

“…However, PDEs were only increased in drug naïve and newly diagnosed medicated patients, implying a higher membrane phospholipid turnover at the onset of illness. Another explanation for this finding may be that antipsychotics inhibit the breakdown of membrane phospholipids (Fukuzako et al, 1999b). Using proton-decoupling in chronic medicated patients with schizophrenia, Potwarka et al (1999) unexpectedly found that the glycerol-3-phosphoethanolamine (GPEth) peak, and glycerol-3-phosphocholine (GPCh) peak were both normal, but the broader underlying phospholipid peak (probably lysosomal or peroxisomal) was higher, potentially suggesting excessive pruning (Keshavan et al, 1994) or excessive apoptotic activity (Ferri & Kroemer, 2001).…”

Antipsychotika und Phospholipidmetabolismus bei der Schizophrenie

“…Diese Ergebnisse wurden in einer späteren Studie bestätigt und korrelierten mit Positivsymptomen gemessen mit der Brief Psychiatric Rating Scale (BPRS) [15]. In einer weiteren Studie reduzierte die Behandlung mit Haloperidol bei vorher unmedizierten Patienten die initiale Erhöhung der PDE im temporalen Kortex, allerdings nur teilweise, so dass die medizierten Patienten am Ende immer noch höhere Werte als die Kontrollpersonen aufwiesen [16].…”