ReviewEssential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia
Introduction
Identifying an effective, low cost, supplemental treatment with few side effects would be a major advance in schizophrenia therapeutics. In this context, recent reports of abnormalities in membrane phospholipid metabolism Hudson et al 1996a, Hudson et al 1996b, an association between dietary fatty acid intake and prognosis in schizophrenia (Christensen and Christensen 1988) and the possibility that supplementation of neuroleptic treatment with essential fatty acids may improve clinical response Puri and Richardson 1998, Peet and Mellor 1998 are intriguing. At present, even optimal modern pharmacologic treatment for schizophrenia leaves many patients with significant symptoms and disabilities; only 1 in 5, for example, recovers sufficiently to return to full-time work (Lehman 1995). Although augmentation of available antipsychotics is often attempted, no single agent or strategy has demonstrated clear superiority (Conley and Buchanan 1997). As a consequence, patients, families and clinicians remain keenly interested in exploring new therapeutic approaches.
What are fatty acids? Are tissue levels disrupted in schizophrenia? If so, what are possible biological causes and consequences of this disruption? Until recently, the evaluation of hypotheses relating to membrane lipid pathology in schizophrenia has not been in the mainstream of schizophrenia research Rotrosen and Wolkin 1987, Mahadik et al 1994. Although innovative hypotheses have often been articulated Horrobin 1998, McCreadie 1997, Gattaz and Brunner 1996, empirical clinical findings have been diverse, and to our knowledge, have not been comprehensively or critically reviewed.
In this article, we review clinical research on abnormalities in membrane fatty acid metabolism and therapeutic trials of fatty acid in schizophrenia. In addition, the biochemistry of membrane phospholipids is reviewed in sufficient detail to provide a rational framework for evaluating empirical findings.
Section snippets
Methods
This review is limited to studies of membrane fatty acids and fatty acid metabolism in schizophrenia. Abnormalities in phospholipids broadly (Rotrosen and Wolkin 1987), EFA use in dyskinesias (Vaddadi 1996), and studies of oxidative membrane damage (Mahadik and Mukherjee 1996) have been reviewed elsewhere.
Potentially relevant English-language articles were identified from the psychiatric and psychological literature with the aid of computer searches using such key words as lipids,
Background
Glycerophospholipids and cholesterol largely make up the membrane bilayer that form the matrix in which receptors, ion channels and other proteins involved in inter- and intra-cellular signal transduction are embedded. Glycerophospholipids include a phosphate-containing, hydrophilic head group and 2 acyl side chains (tail) derived from fatty acids. The specific hydrophilic head group varies and includes phosphatidyl (P)-ethanolamine, (P)-choline, (P)-serine, (P)-inositol. Hydrocarbon tails can
Membrane hypothesis of schizophrenia
The phospholipid membrane hypothesis of schizophrenia originates with suggestions by Feldberg (1976) and Horrobin (1977) that schizophrenia might be caused by a prostaglandin (PG) excess or deficiency. These proposals were based historical reports of a clinical association between fever and symptom remission in psychosis (Lipper and Werman 1997), the relative resistance to PG mediated pain and inflammation (Marchand et al 1969) and a reduced rate of rheumatoid arthritis in patients with
Clinical studies
Empirical studies related to the membrane hypothesis have focused on 5 areas: 1) assessment of PG and their EFA precursors in the tissues (plasma, red blood cell [RBC] membrane, platelet, fibroblast, postmortem brain) of patients with schizophrenia; 2) evaluation of the niacin flush test as a possible diagnostic marker; 3) evaluation of phospholipase enzyme activity; 4) NMR spectroscopy studies of phospholipid metabolism; and 5) therapeutic trials of PGE1 or EFA precursors for the treatment of
NMR spectroscopy
Pettegrew et al (1991) first used phosphorus 31 (p31) NMR spectroscopy to directly assess in vivo brain membrane phospholipid metabolism. When 11 drug naive first episode schizophrenia patients were compared to 10 matched healthy control volunteers, schizophrenia patients had significantly reduced levels of phosphomonoesters (PME) and increased phosphodiesters (PDE) in dorsal prefrontal cortex. PME are precursors to phospholipid membrane synthesis and PDE membrane phospholipid breakdown
EFA/absorption and metabolism
Free fatty acids are rapidly and completely absorbed. Large chain fatty acids are normally more than 99% bound to serum proteins. Protein binding is accompanied by a rapid dissociation rate and rapid exchange between the brain and blood of unbound and unincorporated EFA. As a result, the uptake by the brain of free fatty acids is rapid, buffered against short-term fluctuations in blood levels, and primarily reflects the metabolic needs of the brain (Banks et al 1997).
Tissue levels of n-3 fatty
Safety and general health effects of EFA supplementation
Omega-3 fatty acids are designated GRAS (Generally Regarded as Safe) provided that daily intakes of DHA and EPA from menhaden oil do not exceed 3 grams per day (Department of Health and Human Services 1997). General medical effects of fish oil supplements rich in omega-3 fatty acids have recently been reviewed (Drug Therapy Bulletin, 1996). Interest in fish oils is based on the observation that death from coronary artery disease (CAD) is rare among Inuit population of the Arctic who have
Treatment studies in schizophrenia
Membrane EFA or PG deficiency hypotheses have provided the rationale for attempts to treat symptoms of schizophrenia with omega-6, omega-3 fatty acids and PGE1. Open-label or double-blind clinical trials and case reports that assess supplementation of neuroleptic treatment are summarized in Table 2.
Omega-6 trials
Three of 4 small double-blind trials of omega-6 fatty acid supplementation of neuroleptic medication have yielded negative results. After preliminary case reports Vaddadi 1979, Vaddadi et al 1986 randomly assigned 21 long stay treatment resistant schizophrenia inpatients to 1 of 3 treatment groups in a 3 month prospective randomized trial: 1) depot phenothiazine and 1 gm DGLA (20:3n-6); 2) placebo depot injections and 1 gm DGLA (20:2n-6) acid; and 3) placebo injections and placebo capsules. At
Omega-3 trials
In contrast to omega-6 trials, all published studies of omega-3 EFA treatment report positive results. Rudin (1981) initially provided case reports of 3 patients with relapsing schizophrenia who improved after supplementation with omega-3 rich linseed oil. In an open study, Mellor et al Mellor et al 1995, Peet et al 1996 supplemented 20 hospitalized patients with chronic schizophrenia with 10 grams maxEPA fish oil daily for 6 weeks. Over the trial, a 17% improvement in PANSS symptom ratings and
Prostaglandin e1
Kaiya (1984) and colleagues (Kaiya et al 1985) intravenously administered prostaglandin E1 for 8 to 21 days to 7 unmedicated patients with acute schizophrenic symptoms. Two patients were described as responding (4 showing transient improvement, and 1 no effect). Minimal side effects were noted.
Discussion
Empirical findings concerning essential fatty acid and lipid membrane abnormalities and efforts to treat schizophrenia with fatty acids derive from a diverse set of investigations conducted over more than 2 decades. In each of the 5 areas that have been subject to empirical study, intriguing, but inconclusive and at times contradictory results are apparent.
Little empirical data support the hypothesis that a simple prostaglandin deficiency is related to schizophrenia. At the same time, depletion
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