The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia

Horrobin, David F.

doi:10.1016/s0920-9964(97)00151-5

Cited by 409 publications

(226 citation statements)

References 108 publications

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“…This discrepancy might be due to Anandamide elevation in acute schizophrenia A Giuffrida et al differences in experimental procedures between the studies (eg whole blood vs serum) or to the small number of patients investigated by De Marchi et al (n ¼ 12). Second, the elevation in anandamide concentration was unlikely to be caused by a generalized alteration in lipid signaling, which is hypothesized to occur in schizophrenia (Horrobin 1998), because the levels of two closely related analogs of anandamide, OEA and PEA, were not increased in schizophrenics. It is noteworthy that we found that PEA levels in antipsychotic-naïve schizophrenics were lower than controls, thus correcting an earlier study from our lab, which reported elevated PEA levels in the CSF of a small set (n ¼ 11) of treated and untreated schizophrenics (Leweke et al, 1999b).…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal Anandamide Levels are Elevated in Acute Schizophrenia and are Inversely Correlated with Psychotic Symptoms

Giuffrida

Leweke

Gerth

et al. 2004

Neuropsychopharmacol

431

340

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The endocannabinoids are a family of bioactive lipids that activate CB 1 cannabinoid receptors in the brain and exert intense emotional and cognitive effects. Here, we have examined the role of endocannabinoid signaling in psychotic states by measuring levels of the endocannabinoid anandamide in cerebrospinal fluid (CSF) of acute paranoid-type schizophrenic patients. We found that CSF anandamide levels are eight-fold higher in antipsychotic-naïve first-episode paranoid schizophrenics (n ¼ 47) than healthy controls (n ¼ 84), dementia patients (n ¼ 13) or affective disorder patients (n ¼ 22). Such an alteration is absent in schizophrenics treated with 'typical' antipsychotics (n ¼ 37), which antagonize dopamine D 2 -like receptors, but not in those treated with 'atypical' antipsychotics (n ¼ 34), which preferentially antagonize 5HT 2A receptors. Furthermore, we found that, in nonmedicated acute schizophrenics, CSF anandamide is negatively correlated with psychotic symptoms (r S ¼ À0.452, P ¼ 0.001). The results suggest that anandamide elevation in acute paranoid schizophrenia may reflect a compensatory adaptation to the disease state.

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Section: Discussionmentioning

confidence: 99%

Cerebrospinal Anandamide Levels are Elevated in Acute Schizophrenia and are Inversely Correlated with Psychotic Symptoms

Giuffrida

Leweke

Gerth

et al. 2004

Neuropsychopharmacol

431

340

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“…42,43 Together this indicates a primary role for PLA2G6A activity in neuronal remodelling by apoptosis, while PLA2G4A and PLA2G2A act peripherally to manage inflammation. 44,45 PLA2s in schizophrenia Horrobin 46,47 suggested that schizophrenia might be a prostaglandin deficiency disease and consequently formulated the Membrane Phospholipid Hypothesis of schizophrenia. This hypothesis can be examined in the light of the combined functions of these three PLA2s.…”

Section: Memory Formation (Long-term Potentiation)mentioning

confidence: 99%

The role of phospholipases A2 in schizophrenia

Law¹,

Cotton²,

Berger

2006

Mol Psychiatry

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A range of neurotransmitter systems have been implicated in the pathogenesis of schizophrenia based on the antidopaminergic activities of antipsychotic medications, and chemicals that can induce psychotic-like symptoms, such as ketamine or PCP. Such neurotransmitter systems often mediate their cellular response via G-protein-coupled release of arachidonic acid (AA) via the activation of phospholipases A2 (PLA2s). The interaction of three PLA2s are important for the regulation of the release of AA -phospholipase A2 Group 2 A, phospholipase A2 Group 4A and phospholipase A2 Group 6A. Gene variations of these three key enzymes have been associated with schizophrenia with conflicting results. Preclinical data suggest that the activity of these three enzymes are associated with monoaminergic neurotransmission, and may contribute to the differential efficacy of antipsychotic medications, as well as other biological changes thought to underlie schizophrenia, such as altered neurodevelopment and synaptic remodelling. We review the evidence and discuss the potential roles of these three key enzymes for schizophrenia with particular emphasis on published association studies.

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“…[5][6][7][8] Over the past two decades, evidence has accrued that phospholipids, which play a critical role in the structure and function of membranes, seem to be impaired in schizophrenia. 9,10 Neuronal cell membranes form the vesicles in which neurotransmitters are stored and through which neurotransmitters are released and hence membrane lipid changes could have a direct effect on proper neurotransmission. In addition, recent studies have highlighted a growing concern over the potential for antipsychotic drugs, especially clozapine and olanzapine, to cause metabolic adverse effects such as weight gain, hyperglycemia and hypertriglyceridemia.…”

Section: Introductionmentioning

confidence: 99%

Metabolomic mapping of atypical antipsychotic effects in schizophrenia

Kaddurah‐Daouk

McEvoy

Baillie³

et al. 2007

Mol Psychiatry

238

181

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Schizophrenia is associated with impairments in neurotransmitter systems and changes in neuronal membrane phospholipids. Several atypical antipsychotic drugs induce weight gain and hypertriglyceridemia. To date, there has not been a comprehensive evaluation and mapping of global lipid changes in schizophrenia, and upon treatment with antipsychotics. Such mapping could provide novel insights about disease mechanisms and metabolic side effects of therapies used for its treatment. We used a specialized metabolomics platform 'lipidomics' that quantifies over 300 polar and nonpolar lipid metabolites (across seven lipid classes) to evaluate global lipid changes in schizophrenia and upon treatment with three commonly used atypical antipsychotics. Lipid profiles were derived for 50 patients with schizophrenia before and after treatment for 2-3 weeks with olanzapine (n = 20), risperidone (n = 14) or aripiprazole (n = 16). Patients were recruited in two cohorts (study I, n = 27 and study II, n = 23) to permit an internal replication analyses. The change from baseline to post-treatment was then compared among the three drugs. Olanzapine and risperidone affected a much broader range of lipid classes than aripiprazole. Approximately 50 lipids tended to be increased with both risperidone and olanzapine and concentrations of triacylglycerols increased and free fatty acids decreased with both drugs but not with aripiprazole. Phosphatidylethanolamine concentrations that were suppressed in patients with schizophrenia were raised by all three drugs. Drug specific differences were also detected. A principal component analysis (PCA) identified baseline lipid alterations, which correlated with acute treatment response. A more definitive long-term randomized study of these drugs correlating global lipid changes with clinical outcomes could yield biomarkers that define drug-response phenotypes.

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The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia

Cited by 409 publications

References 108 publications

Cerebrospinal Anandamide Levels are Elevated in Acute Schizophrenia and are Inversely Correlated with Psychotic Symptoms

Cerebrospinal Anandamide Levels are Elevated in Acute Schizophrenia and are Inversely Correlated with Psychotic Symptoms

The role of phospholipases A2 in schizophrenia

Metabolomic mapping of atypical antipsychotic effects in schizophrenia

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