Implications of lipid biology for the

pathogenesis of schizophrenia

Gregor E. Berger, Stephen J. Wood, Christos Pantelis, Dennis Velakoulis,

R. Mark Wellard, Patrick D. McGorry

Objective: Preclinical and clinical data suggest that lipid biology is integral to brain
development and neurodegeneration. Both aspects are proposed as being important in the
pathogenesis of schizophrenia. The purpose of this paper is to examine the implications of
lipid biology, in particular the role of essential fatty acids (EFA), for schizophrenia.
Methods: Medline databases were searched from 1966 to 2001 followed by the cross-
checking of references.
Results: Most studies investigating lipids in schizophrenia described reduced EFA, altered
glycerophospholipids and an increased activity of a calcium-independent phospholipase A2
in blood cells and in post-mortem brain tissue. Additionally, in vivo brain phosphorus-31
Magnetic Resonance Spectroscopy (31P-MRS) demonstrated lower phosphomonoesters
(implying reduced membrane precursors) in first- and multi-episode patients. In contrast,
phosphodiesters were elevated mainly in first-episode patients (implying increased mem-
brane breakdown products), whereas inconclusive results were found in chronic patients.
EFA supplementation trials in chronic patient populations with residual symptoms have
demonstrated conflicting results. More consistent results were observed in the early and
symptomatic stages of illness, especially if EFA with a high proportion of eicosapentaenoic
acid was used.
Conclusion: Peripheral blood cell, brain necropsy and 31P-MRS analysis reveal a disturbed
lipid biology, suggesting generalized membrane alterations in schizophrenia. 31P-MRS data
suggest increased membrane turnover at illness onset and persisting membrane abnormal-
ities in established schizophrenia. Cellular processes regulating membrane lipid metabolism
are potential new targets for antipsychotic drugs and might explain the mechanism of action
of treatments such as eicosapentaenoic acid.
Key words: essential fatty acids, magnetic resonance spectroscopy, niacin, phospho-
lipases, phospholipids.

Australian and New Zealand Journal of Psychiatry 2001; 35:355–366

Our understanding of the importance of lipid biology
to neurodevelopment, neurodegeneration and behavioural
Gregor E. Berger, Senior Research Fellow (Correspondence); Patrick D.
McGorry, Professor
Early Psychosis Prevention and Intervention Centre, MH-SKY
(EPPIC), Locked Bag 10, 35 Poplar Rd, Victoria, 3052.
Email: gregor@unimelb.edu.au
Stephen J. Wood, Research Fellow; Christos Pantelis, Associate Professor;
Dennis Velakoulis, Senior Research Fellow
Cognitive Neuropsychiatry Research & Academic Unit, The University
of Melbourne & Sunshine Hospital
R. Mark Wellard, Postdoctoral Fellow
Brain Research Institute (BRI), Austin & Repatriation Medical Centre
Received 31 May 2001; revised 15 November 2001; accepted 22 January
2002.
neurobiology (all factors proposed as playing a pivotal
role in schizophrenia) has increased rapidly in recent
years [1]. Early reports of lipid alterations in the cerebro-
spinal fluid [2] or peripheral cell membranes of patients
with schizophrenia [3–5], together with clinical reports
suggesting a prostaglandin–deficit syndrome (metabo-
lites of membrane lipids) [6], led to the formulation of
the membrane hypothesis of schizophrenia [7–10]. In
addition, the observation that inherited neuronal lipid
storage diseases, such as adult-onset Tay-Sachs disease
(a GM2 gangliosidosis), present with psychotic symp-
toms in 30% to 50% of the cases, indicates the dramatic
consequences of a disturbed lipid metabolism [11]. This
article attempts to summarize the current English literature
356 LIPID BIOLOGY AND SCHIZOPHRENIA
investigating lipid biology in schizophrenia. Related areas
of interest such as oxidative damage of the cell mem-
brane [12], the relevance of bioactive lipids in movement
disorders [13] or the effects of oestrogens on lipid
metabolism [14] have been reviewed elsewhere.
Methods
Medline databases were searched for English language publications
dating from 1966 to February 2001 for the term schizophrenia
combined with each of the following medical subject headings: essen-
tial fatty acids (EFA); polyunsaturated fatty acids (PUFA); arachidonic
acid (AA, 20 : 5, n-6); docosahexaenoic acid (DHA, 22 : 5, n-3); eico-
sapentaenoic acid (EPA, 20 : 5, n-3); linoleic acid (LA, 18 : 2, n-6);
alpha-linolenic acid (α-LA, 18 : 3, n-3); eicosanoids; prostaglandins;
platelet-activating factor (PAF); arthritis (rheumatoid arthritis, RA);
phospholipids; phosphatidylethanolamine (PtdEtn); phosphatidylcholine
(PtdCh, also called ‘lecithin’); phosphatidylserine (PtdSer); phosphol-
ipases (PLA); diet; fish; and Phosphorus-31 Magnetic Resonance
Spectroscopy (31P MRS). Cross-checking of references led to the
identification of additional relevant references.
Background
Lipids make up a very high proportion of the brain (50–60% of
human dry brain weight). A major proportion of these lipids are
essential fatty acids (EFA) mainly bound to glycerophospholipids
(GPL). The term ‘essential’, in this context, describes substances that
cannot be synthesized de novo in the mammalian body. Due to their
unique chemical structure comprising a polar head group (e.g. choline)
and two non-polar arms (consisting mostly of one saturated and one
polyunsaturated fatty acid), GPL spontaneously form bi-layers and are
the basic molecules of all types of cell membranes. Different types of
GPL exist. In order of decreasing concentration in the adult human
brain they are phosphatidylethanolamine (PtdEtn), phosphatidylcho-
line (PtdCh, also called ‘lecithin’), phosphatidylserine (PtdSer) and
phosphatidylinositol (PI). PtdEtn and PtdSer are mainly located at the
inner, cytosolic layer, whereas PtdCh and sphingomyeline (SM) are
mainly part of the outer layer of the cell membrane.
Each type of GPL in a given tissue has a characteristic EFA composi-
tion. For example, white matter PtdEtn contains 3% DHA, whereas
grey matter PtdEtn contains 24% DHA [15]. There are two series of
fatty acids that are classified as essential, the n-3 and n-6 series (see
Fig. 1). The terms n-6 and n-3 are synonymous with omega-6 and
omega-3, and indicate the location of the last double bond, counted
from the carbon tail. Linoleic acid (LA, 18 : 2, n-6) and alpha-
linolenic acid (α-LA, 18 : 3, n-3) are the parent compounds of these
two EFA series, both with 18 carbon atoms. In this article we will
apply the term ‘essential fatty acids’ when we refer to n-3 and n-6 fatty
acids in general, although sometimes the term EFA is applied exclu-
sively to LA and α-LA, with their metabolites being called ‘derived
EFA’. Both series compete for the same enzymes (desaturases, elon-
gases, phospholipases) and cannot be interconverted (i.e. n-3 EFA
cannot be transformed into n-6 EFA and vice versa). ‘Derived EFA’
can be synthesized from their essential parent C-18 compounds or
obtained directly from diet (e.g. fish [16], and breast milk [17]).
The structure and fluidity of cell membranes are determined by their
EFA and cholesterol composition, which in turn modulates ion chan-
nels, receptor activity and neurotransmitter release (see Fig. 2) [18].
Excitable membranes such as synapses have a particularly high con-
centration of EFA. It is now becoming apparent that ‘derived EFA’
such as arachidonic acid (AA, 20 : 5, n-6), docosahexaenoic acid
(DHA, 22 : 5, n-3) or eicosapentaenoic acid (EPA, 20 : 5, n-3) and
their products (eicosanoids) such as prostaglandins, thromboxanes,
prostacyclins and leukotrienes, termed as ‘bioactive lipids’, regulate
processes such as neuronal migration, and determine synaptic plastic-
ity [19], factors proposed to be disrupted in schizophrenia [20,21]. In
addition, AA linked with ethanolamine as anandamide, or esterified
with glycerol, is an endogenous ligand for the brain cannabinoid
receptor [22], a receptor system proposed to be of relevance for the
pathogenesis of neurodegenerative disease [23].
Bioactive lipids in schizophrenia
As EFA have such an important role in brain development and nerve
functioning, the question emerges whether nutritional deficits in preg-
nancy and early childhood might contribute to an increased risk of
schizophrenia, in line with the neurodevelopmental concept of the
disorder [24]. The importance of EFA for normal brain development
during pregnancy and early infancy is well documented [25]. Despite
some evidence for a protective role for breastfeeding [26,27], there
have also been negative findings [28,29]. However, the results of the
case-control studies [26,27] may indicate a protective effect of breast-
feeding in ‘high-risk babies’ with other predisposing factors, such as a
family history of schizophrenia, very premature birth, birth complica-
tions, viral infections, or extreme forms of malnutrition, whereas
population-based studies [28,29] do not provide evidence of a pro-
tective effect of breastfeeding in the general population. Further
studies using carefully designed randomized case-control designs to
investigate the protective role of breastfeeding or EFA supplementa-
tion in ‘high-risk baby populations’ (selective prevention [30]) seem
warranted.
While it is well known that patients with schizophrenia live an
unhealthy lifestyle (increased intake of saturated fats, lower intake of
EFA, increased cigarette consumption and alcohol use, less exercise
and obesity), it remains unclear if the reduced intake of EFA associated
with this has a direct negative impact on the course of the illness [31].
A retrospective analysis [32] correlating the course and outcome
figures from the International Pilot Study of Schizophrenia (IPSS) [33]
with the national dietary characteristics of the eight participant coun-
tries suggested that the course of illness was better in those countries
where the diet contained less saturated (animal) and more polyunsat-
urated fats (e.g. vegetables and seafood). These results need to be
interpreted with caution, as the methodology was poorly described, the
study was retrospective, and the results may be better explained as due
to common underlying variables such as more urban living, migration
or stress factors [34]. Nonetheless, future epidemiological studies
should consider dietary factors as a potential cofactor especially in
subgroups with an increased risk of schizophrenia such as a family
history of mental disorders, or birth complications. In this context a
recent report of lower incidence of depression in populations with high
intake of marine or sea fish (rich in n-3 fatty acids) is noteworthy
[35,36].
 G.E. BERGER, S.J. WOOD, C. PANTELIS, D. VELAKOULIS, R.M. WELLARD, P.D. M CGORRY
Figure 1. Essential fatty
acid pathways.
Excess of bioactive lipids in rheumatoid arthritis – a
neuroprotective factor?
The negative association between rheumatoid arthritis (RA) and
schizophrenia give further evidence for the involvement of bioactive
lipids in the pathophysiology of schizophrenia [37,38]. Rheumatoid
Arthiritis is associated with an overproduction of bioactive lipids, in
particular platelet-activating factor (PAF), AA and its eicosanoids [6].
A recent meta-analysis of 16 published data sets [39] encompassing
over 70 000 patients with schizophrenia and over 350 000 patients
with other psychiatric conditions estimated that the rate of RA in
schizophrenia is less than a third of the rate of RA in other psychiatric
Figure 2. The cell membrane
GPL as ‘depot’ for lipid second
messengers.
357
diagnoses. The relative risk of RA in schizophrenia versus the general
population was estimated to be even lower at around 10%. These
findings would be in keeping with the hypothesis that schizophrenia is
associated with reduced EFA levels.
The niacin flush test, a marker for a prostaglandin deficit
in schizophrenia?
The oral intake of niacin (nicotinic acid, vitamin B3) in normal
volunteers induces a dose-dependant flush reaction of the face and
upper body that is proposed to be mediated via prostaglandin D2, a
metabolite of AA [40]. Early studies reported a reduced flush response
358 LIPID BIOLOGY AND SCHIZOPHRENIA
in some patients with schizophrenia [38,41] and its restoration after
remission of psychosis [42]. Two studies trying to quantify the flush
reaction using methodologies such as measuring malar temperature
changes [43] or plethysmography [44,45] to measure blood flow had
mixed results. Hudson and colleagues [46] used thermo-coupled
sensors to measure the skin temperature relative to the core body and
ambient room temperature after oral intake of 200 mg niacin and
demonstrated that 42.9% of the patients with schizophrenia had no
change in temperature, whereas 94% of patients with bipolar disorder
and 100% of normal controls did. In addition, the lack of flushing was
associated with low levels of EFA in red cell membranes. The conver-
sion from non-flusher to flusher was associated with an increase in
EFA levels in red cell membranes and treatment response [47].
In contrast, in a topical variant of the test, where different concen-
trations of niacin patches (0.1, 0.01, 0.001 and 0.0001 M) are put on
the skin, over 70% of patients with schizophrenia had either no or a
markedly reduced flush reaction compared with normal controls [48],
which was not explained by neuroleptic medication [49]. Shah and
colleagues [49] replicated the latter study using a score system that
integrated the oedema and could separate patients from normal con-
trols at all but the lowest niacin concentration (0.0001 M). Our own
group has confirmed these findings in a group of first-episode psy-
chosis patients using a new semiquantitative, descriptive assessment
scale that integrates erythema, oedema and time course to assess the
overall flush reaction. Using this scale we were able to separate normal
controls from first episode psychosis patients with a sensitivity of 81%
and a specificity of 81.5% (unpublished data). Normal controls had a
normal distribution, whereas first episode patients showed a bimodal
distribution supporting a previous report suggesting a bimodal distri-
bution of AA levels in patients with schizophrenia [50]. As membrane
fluidity correlates with the amount of AA in the skin and is proposed
to be predictive of relapse in schizophrenia, the topical niacin flush test
might have the potential to detect people at risk for transition or relapse
to psychosis [51] or to detect a subgroup of patients with lower AA
levels, proposed to be a subgroup of patients with negative symptoms
and poor prognosis [52]. There is also preliminary evidence that about
40–50% of first degree relatives of schizophrenia patients show an
impaired niacin flush response [53].
Reduced membrane EFA in schizophrenia
A recent review of 15 published studies (Fenton et al. [54]) found a
depletion of LA, AA and DHA in red cell membranes, thrombocytes,
and fibroblasts of patients with schizophrenia, which is thought to be
independent of drug treatment [55]. Primate studies have demonstrated
that peripheral EFA composition of blood cell membranes correlates
with EFA composition of nerve cell membranes [56]. Unsurprisingly
therefore reductions in EFA have also been found in post-mortem
brains of patients with schizophrenia, relative to normal control brains
[57,58]. Yao and colleagues [55] suggested a defective uptake of EFA
into membrane GPL as a possible aetiopathological mechanism in
schizophrenia, whereas Peet and colleagues [59], who also found an
increase in EFA peroxidation products, suggested an increased break-
down of membrane GPL. Glen and colleagues [47,50] demonstrated
that high levels of saturated fatty acids and low levels of red cell
membrane EFA (AA, 20 : 4,n-6 and DHA, 22 : 6,n-3) were found in a
subgroup of patients with predominantly negative symptoms of apathy
and withdrawal. Patients with positive symptoms showed a normal
EFA distribution, suggesting that EFA deficiency (in particular AA)
might be more relevant to negative symptom schizophrenia, and may
be relevant to a poorer prognosis or be relevant for a poorer treatment
response to antipsychotics.
Phospholipase A2 (PLA2) in schizophrenia and other
neurological conditions
Phospholipases are key enzymes in determining the composition of
the cell membrane, many regulatory processes and second messenger
pathways. The phospholipases A2 (PLA2) consist of a broad range of
enzymes (the PLA2 superfamily) defined by an ability to catalyze the
hydrolysis of the middle (sn-2) ester bond of substrate GPL in order to
release bioactive lipids, usually a free fatty acid (e.g. AA) and a
lysophospholipid (e.g. lyso-platelet-activating factor (lyso-PAF)) [60].
Historically PLA2 was classified as either calcium-dependant or
calcium-independent. Since the cloning of a cytosolic 85 kDa group IV
PLA2 (often referred to as cPLA2) the categorization is genetically
determined (currently XI subgroups) [60]. Most of the studies measur-
ing PLA2 activity in peripheral tissue of patients with schizophrenia
were carried out before acquisition of the current knowledge of the
different types of PLA2. Gattaz and colleagues [61–63] were the first
to demonstrate an over-active PLA2 in plasma, serum and platelets of
patients with schizophrenia, using a fluorometric methodology that
primarily measures a calcium-independent PLA2 (most likely the
cytosolic 85 kDa group IVA PLA2). Ross et al. [64] demonstrated that
contradictory findings in previous reports [62–69] could be explained
by different PLA2 test kits used. In accordance with a reduction of EFA
in peripheral and central cell membrane tissue in schizophrenia, an
increased calcium-independent PLA2 activity has also been demon-
strated in post-mortem studies of the temporal lobes of patients with
schizophrenia [70,71]. In contrast, calcium-dependent PLA2 activity
was decreased by 27–29% in the temporal cortex and prefrontal cortex
and by 44% in the putamen, relative to controls. Similar alterations
of changed PLA2 activity have been found in other psychiatric and
neurologic conditions [65], although it is known that PLA2 is inhibited
by neuroleptic medication [68]. Allelic association studies in families
with a history of schizophrenia suggest that the cPLA2 gene locus (Ban
I) might be a candidate gene predisposing an individual to schizophre-
nia [72–74], yet two studies not restricted to patients with a family
history of schizophrenia have failed to replicate such findings [75,76].
These studies did not stratify patients according to niacin flush
response [69,77].
Altered glycerolphospholipid (GPL) membrane
composition in schizophrenia
Whereas the evidence for reduced EFA and increased activity of the
calcium-independent PLA2 (probably the cytosolic 85 kDa group IVA
PLA2) seems to be quite robust, attempts to measure GPL composition
of the cell membrane were less conclusive [3–5]. Initial reports found
a marked increase in PtdSer (up to 50%) and a decrease in PtdEtn and
Phosphatidylcholine (PtdCho) [78,79] leading to the proposal that the
ratio of Phosphatidylethanolamine (PtdEtn) to Phosphatidylserine
(PtdSer) might even be a biochemical marker for schizophrenia. The
most consistent finding throughout most studies [3–5] was a decrease
in PtdEtn (9–47%), although two groups [80,81] failed to replicate
 G.E. BERGER, S.J. WOOD, C. PANTELIS, D. VELAKOULIS, R.M. WELLARD, P.D. M CGORRY
these findings. Significantly lower amounts of PtdEtn and PtdCho
were also found in post-mortem brain tissue from patients with schiz-
ophrenia [58], even after accounting for potential confounds. Serial
phospholipid analysis of peripheral cell membranes in first episode
drug-naïve patients and nonaffected first degree relatives in combina-
tion with measurement of enzyme activities (e.g. phospholipases) and
EFA analysis would be required to elucidate the exact mechanism
behind these membrane abnormalities.
In conclusion, the available evidence in peripheral tissue and post-
mortem tissue of patients with schizophrenia suggests that EFA, espe-
cially AA and its precursors (n-6), and DHA (n-3) are reduced, and the
enzyme for the cleavage of these EFA is more active. Whether these
alterations are related to a lack of EFA incorporation [55], an increased
breakdown of GPL by an over-active PLA2 activity or from an under-
lying disturbance (e.g. an intracellular dysfunctional EFA transport
[82]) remains to be clarified. Tests, such as the topical niacin flush test
[69], sensory gating [77], breath analysis [83] or cognitive tests might
clarify subgroups out of the schizophrenia spectrum where bioactive
lipids are of relevance.
In vivo membrane chemistry assessed by
31
Phosphorus Spectroscopy (31P-MRS)
Advances in brain imaging have allowed measurement of GPL
metabolites in vivo using 31P-MRS. For the purposes of this review,
there are two important resonances from this spectrum – the phospho-
monoester (PME) and phosphodiester (PDE) peaks [83]. The phospho-
monoester peak (PME) includes phosphatidylethanolamine (PtdEth)
and phosphatidylcholine (PtdCh) peaks (associated with cell mem-
brane precursors) that can be separated using proton-decoupling or
high magnetic field strengths. These two peaks account for approxi-
mately 45% of the PME peak [84]. The PDE peak can be separated
into glycerophosphatidylcholine (GPCh), glycerophosphatidyl-ethan-
olamine (GPEth) and the mobile phospholipids (MP). The PDE sub-
fractions GPCh and GPEth are associated with the breakdown products
of the cell membrane, but represent only about 15% of the total peak
area. The remaining signal most likely arises from underlying intra-
cellular mobile phospholipids (probably lysosomal and peroxisomal).
The role of 31P-MRS in the investigation of high-energy metabolites
[83,85,86] and other methodological aspects [87] are reviewed else-
where.
31
P-MRS in different stages of schizophrenia
In a landmark study, Pettegrew et al. [88] demonstrated decreased
PME and increased PDE peaks in the prefrontal cortex of drug-naïve
first-episode patients, indicative of a higher cell membrane turnover.
This pattern may also be present before the onset of psychosis [89].
Reduced PME and increased PDE peaks have also been identified in
the temporal lobes of drug-naïve first-episode patients [90]. Thus, the
previously described alterations of the cell membrane in peripheral
cells and post-mortem brain tissue have also been demonstrated
in vivo , in the early stages of schizophrenia. Indeed, first-episode
drug-naïve psychosis patients showed a strong correlation between an
elevated PDE peak in prefrontal cortex and low red cell membrane AA
359
levels, suggesting that alterations in peripheral tissue were closely
related to in vivo brain alterations of cell membrane metabolism [91].
Stanley et al. [92] examined whether this pattern was present at
different illness stages by examining three groups: drug-naïve; newly
diagnosed and medicated patients; and chronic medicated patients with
schizophrenia. PME were lower in all three groups when compared
to age and sex-matched control groups. However, PDE were only
increased in drug naïve and newly diagnosed medicated patients,
implying a higher membrane phospholipid turnover at the onset of
illness. Recently, the same group explored these findings using proton-
decoupling to distinguish subfractions of the phospholipid peaks [94].
Using this technique in chronic medicated patients with schizophrenia,
Potwarka et al. [94] presented results that were consistent with previ-
ous observations of decreased PME, but did not support the hypothesis
of increased membrane breakdown. Unexpectedly the glycerol-3-
phosphoethanolamine (GPEth) peak, and glycerol-3-phosphocholine
(GPCh) peak were both normal, but the mobile phospholipid (MP)
peak was higher suggesting an altered intracellular lipid metabolism.
In another study Blüml et al. [95] did not replicate these findings in an
examination of the parietal cortex in 11 chronic and 2 neuroleptic-
naïve patients. The single breakdown peaks (GPEth, GPCh) and
G-phosphocreatine were increased, but the total PDE peak was not
different. Further, while the total PME peak area was elevated, the
individual PtdEtn and PtdCh peak areas did not differ. While differ-
ences in subject age between studies may explain the observed differ-
ences [94], a more likely explanation is that these abnormalities may
be apparent in particular brain regions, such as prefrontal cortex and
temporal lobes. The latter would be consistent with the available
evidence implicating these areas in schizophrenia [96,97]. Preclinical
data also suggest that EFA distribution in the brain is specific for
different brain regions [98].
In conclusion, the majority of in vivo 31P-MRS studies have con-
firmed alterations in GPL metabolism, and most studies have shown a
reduced PME peak independent of treatment and stage of illness.
Furthermore, four studies have found an increased PDE peak in early
psychosis, while in chronic schizophrenia the pattern has been incon-
sistent. The changes observed are reported most often in frontal and
temporal lobes suggesting that there is increased membrane turnover in
these regions, particularly in drug-naïve first-episode patients. While
the evidence suggests that neuroleptic treatment is associated with a
reduction of the PDE peak, this reduction was associated with
improvements in symptoms [93]. Future serial 31P-MRS investigations
using proton-decoupling, high-field imaging (3 Tesla or higher), or
novel analysis techniques need to address the question of which phos-
pholipids are most relevant for the phosphoester alterations observed
in previous studies [99]. Longitudinal phosphorus MRS investigations
of drug-naïve first-episode psychosis patients, using a volume of
interest that maximizes the amount of grey matter (rich in EFA), with
concurrent examination of EFA composition and PLA2 activity in
peripheral cells, should clarify the implications of these findings for
the understanding and treatment of schizophrenia.
EFA-supplementation studies in animals and humans
The importance of bioactive lipids and EFA supplementation has
been studied extensively in animals (reviewed by Wainwright
 360
31
Table 1. P-MRS in schizophrenia (focus on phospholipid metabolites)

Stage of Patients Controls Data VOI PME PDE

illness processing
Pettegrew [88]
EP 11 10 FRO DPF ↓ ↑ First-episode drug-naïve patients
Fukuzako [90] EP 17 17 CSI TL ↓ ↑ First-episode drug-naïve patients; higher PDE peak correlated with
positive symptom score
Fukuzako [93] EP 25 25 CSI TL ↓ ↑ 16 first-episode drug-naïve patients repeated MRS procedure after
12 weeks of haloperidol treatment: a decrease in PDE correlated with
an improvement in positive and overall symptom scores
Stanley [92] EP 11 21 FRO DPF ↓ ↑ First-episode drug-naïve patients
8 Newly diagnosed treated patients
PDE correlated negatively with length of illness
CS 10 ↓ – Chronic drug-treated patients
Stanley [100] EP 7 10 FRO DPF ↓ ↑ PDE depend on stage of illness
CS 12 8 FRO ↓ –
Williamson [101] CS 10 7 DPF ↓ – PME levels reduced 26% in left frontal lobe
Hinsberger [102] CS 10 10 FRO DPF ↓ – No correlation between MRS and grey matter volumes
Calabrese [103] CS 11 9 ISIS TL – – Altered high energy metabolism
Deicken [104] CS 18 14 CSI TL – – Altered high energy metabolism
Deicken [105] CS 20 16 CSI DPF – ↑ Higher PDE levels in frontal lobes bilaterally, positive correlation with
‘‘‘‘ hostility-suspicious and anxiety-depression scales
TL No significant differences
Deicken [106] CS 16 13 CSI DPF ↓ ↑ Lower left frontal PME peak correlated with a worse outcome in the
WCST. Patients with a low PME peak found fewer categories
(r = 0.58, p = 0.018), made more perseverative errors and total
mistakes (r = – 0.51, P < 0.04).
Fukuzako [107] CS 16 16 CSI TL – ↑
Fukuzako [108] CS 31 31 CSI TL – ↑ Correlation between left temporal lobe PDE peak and positive symptoms
LIPID BIOLOGY AND SCHIZOPHRENIA

Shioiri [109] CS 26 26 DR DPF ↓ Reduced PME correlated with high negative symptom scores (r = – 0.68,
P < 0.001), high PDE correlated with low negative symptom scores.
In a further study reduced PME peak correlated with disorganized type
of schizophrenia [110]
Kato [111] CS 27 26 CSI DPF ↓ – A significant correlation between negative symptoms and reduced
PME peak
Fujimoto [112] CS 16 20 CSI TL – ↑ Central regions showed a reverse profile: C.callosum, Basal ganglia
PME ↑ (27%) and PDE ↓ (7–9%)
O’Callaghan [113] CS 18 10 SC TL – – Mixed patient population
Volz [114] CS 26 23 ISIS DPF ↑ – WCST performance positively correlated with high-energy metabolites
in normal controls
Volz [115] CS 50 36 ISIS – ↓ No association with neuroleptic medication
Potwarka [94] CS 11 11 CSI DPF – ↑ Mobile phospholipids increased (decoupled)
Blüml [95] CS 11 15 CSI OL – ↑ Breakdown products increased (decoupled), membrane precursors
(PE, PC) normal, total PME increased (younger control group)

EP, early psychosis; CS, Chronic Schizophrenia; SC, surface coil; CSI, chemical shift imaging; FROG, fast rotating gradient spectroscopy; ISIS, image selected in vito spectroscopy;
WCST, Wechsler Cart sorting Test.
 G.E. BERGER, S.J. WOOD, C. PANTELIS, D. VELAKOULIS, R.M. WELLARD, P.D. M CGORRY
[116,117]). Animals (mice, rats, cats, primates) fed an EFA deficient
or depleted diet showed significantly aberrant sleeping patterns, adip-
sia, polydipsia, anorexia, hyperalgesia, reduced self-grooming activity,
a decrease in exploration and social interaction, as well as a disruption
of established food-motivated lever-pressing responses. EFA supple-
mentation had a positive impact on 18 out of 24 altered behavioural
variables in EFA deficient animals (reviewed by Wainwright [117]).
Improvements in behavioural tasks after EFA supplementation were
correlated with alterations in brain lipid composition and were specific
for different brain areas such as the temporal lobe [114,118]. The n-3/
n-6 ratio in the diet was of particular importance in determining the
availability of EFA for the incorporation of EFA into animal brains
with a preference for n-3 EFA, especially EPA and DHA [117,119].
There is now growing evidence that EPA competes with AA by
inhibiting AA metabolism via inhibition of 5-lipoxygenase activity at
low concentrations and PLA2 activity at high concentrations [120].
The structural similarity between AA and EPA could explain the
enhanced effectiveness of EPA if it behaves as an analogue of AA
[121]. In addition, preclinical studies demonstrating an inhibitory
effect of EPA on protein kinase C [122,123] suggests it may be
neuroprotective [124].
In conclusion, preclinical data support the role of bioactive lipids,
especially EFA, in brain development and behavioural neurobiology,
which can be influenced by dietary intake of such lipids. These
findings raise the question about whether different types of EFA
supplementation can influence EFA deficiencies and GPL alterations
described in schizophrenia and whether normalization in EFA levels
has an impact on the pathogenesis or course of schizophrenia.
The first supplementation studies were in patients with tardive
dyskinesia (TD) (predominantly patients with chronic schizophrenia)
and used formulae with a majority of omega-6 EFA (e.g. one capsule
Efamol Evening Primrose Oil ® contains 360 mg LA, and 45 mg
γ -linolenic acid). Two initial small studies of Efamol Evening Prim-
rose Oil® supplementation in chronic patients with tardive dyskinesia
(TD) did not identify any beneficial effect on TD or symptomatology
[125,126]. However, in a double-blind randomized, crossover study
[127] there was marginal improvement in TD but an unexpected
moderate improvement in psychopathology (20–30%) and overall cog-
nitive functioning. During the entire trial period the effects of Efamol
Evening Primrose Oil® could not be explained by practice effects,
since there was clear deterioration when patients switched from
Efamol Evening Primrose Oil® to placebo.
Research investigating the effect of omega-3 EFA has been more
successful [128,129]. The latter study, using 10 g MaxEPA® per day
(enriched n-3 EFA formula; 171 mg EPA/g, 114 mg DHA/g), demon-
strated a significant improvement in psychopathology and TD [129]. In
addition, there was an inverse correlation between EPA and AA levels
in red cell membranes suggesting that mainly EPA were responsible
for its effect on the AA levels. Similar findings were also observed in
another small open-label study using 1 g of an EPA-enriched oil
(Kirunal®; EPA:DHA = 3 : 1) per day in 10 chronic, symptomatic
patients with schizophrenia [130]. On the basis of these results Peet et
al. [131] randomly allocated symptomatic patients with chronic schiz-
ophrenia to an EPA enriched oil (Kirunal) and a DHA enriched oil
(Doconal) or placebo. Only the group with the EPA enriched oil
improved in psychopathology, while patients taking the DHA-enriched
oil or placebo oil showed no significant changes. The greatest differ-
ence was between the EPA and DHA groups [131]. Consequently, Peet
361
and colleagues [131] undertook a randomized study to compare 2 g of
EPA enriched oil/day with placebo supplementation in 63 unmedicated
first and multi-episode patients with schizophrenia as an initial sole
treatment. After the study period of 12 weeks, only 66% of patients in
the EPA arm required neuroleptic medication (haloperidol), compared
with 100% of those in the placebo arm. Four out of 15 patients in the
EPA arm did not need antipsychotics at any time during the study
period. Total days on haloperidol were significantly lower (46.3 days
vs 71.7 days), and those in the EPA group showed a greater improve-
ment in positive and negative symptoms, despite a lower cumulative
antipsychotic dose. When the effect of different doses of EPA (1, 2,
and 4 g EPA per day) was studied in 117 symptomatic patients with
chronic schizophrenia, a significant impact on psychopathology was
only found for 2 g EPA, and normalization of RBC membrane AA
levels was only observed in the 2 g EPA group [132].
Recently, Fenton and colleagues [133] presented a randomized
study supported by the Stanley Foundation. The study was placebo-
controlled and included 87 patients with chronic schizophrenia and
residual symptoms. These patients had a mean age of 40 [range
18–65], an average duration of illness of 20 years and were supple-
mented with 3 g purified EPA/placebo daily for a period of 16 weeks.
The randomized trial showed no between-group differences for either
psychopathological parameters, or for cognitive functioning in patients
with chronic schizophrenia and residual symptoms. The selection of
chronic patients with residual symptoms on a stable neuroleptic medi-
cation and the use of a higher dose of EPA in comparison to Peet’s
study of younger and more acutely psychotic patients may explain the
difference in outcome between the two studies. Future placebo-
controlled studies should address issues such as illness duration, acuity
of symptomatology, background treatment (flexible or fixed dose), and
dose of EPA.
There are several limitations evident in the treatment studies
reported to date. Different combinations and doses of oils, some with
higher quantities of parent EFA compounds and others with different
n-3/n-6 ratios, make interpretation difficult. Some studies used a
sample of chronic treatment-resistant patients with TD, while other
studies used drug-naïve first episode patients. Neuroleptic treatment
has also been heterogeneous. In addition, the effects of sex steroids on
EFA metabolism, susceptibility of EFA to oxidation (from smoking,
starvation, and stress), developmental factors (e.g. birth complications,
breast-feeding), the dependency of EFA metabolism on age (e.g. loss
of desaturase activity) and environmental factors (e.g. cannabis use)
should also be considered. While diet might also have a confounding
effect, this would be unlikely, as the amount of EFA supplementation
used in clinical trials (usually 1–10 g EFA/day) is much higher than the
dietary intake, even if fish were consumed on a daily basis (a fish meal
of 100 g of Atlantic salmon contains 71 mg AA, 171 mg EPA and
378 mg DHA [134] which is around 10% of the amount of EPA used
in clinical trials).
In conclusion, while Peet et al. [132] and Horrobin et al. [53] have
presented some preliminary positive results in the acute and early
phase of psychotic illness, Fenton and colleagues [133] did not repli-
cate these findings in a chronic patient population. Independent
research groups should attempt to investigate the potential use of EPA
at different illness stages (e.g. its main effect may be in the onset phase
of illness) and elucidate the postulated dose-related mechanism(s) of
action, considering the low cost and high acceptance of such treat-
ments and the minimal side-effects.
362 LIPID BIOLOGY AND SCHIZOPHRENIA
Conclusions and limitations
The main findings from studies investigating the role
of bioactive lipids in patients with schizophrenia are
consistent with the notion of a membrane pathology
throughout the body. This is evidenced by a general
reduction of cell membrane EFA in peripheral tissue
(e.g. red blood cells, fibroblasts) and post-mortem brain
tissue, the most significant being in AA, its precursors
and DHA. Increased activity of the EFA metabolizing
enzymes such as an over-active calcium-independent
PLA2 (most likely the cytosolic, group IVA PLA2) sug-
gests an increased membrane breakdown of EFA. While
differences might be expected at different illness stages,
studies are predominantly of patients with established
schizophrenia, with no studies examining phospholipase
activity in drug-naïve first-episode psychosis.
In vivo 31P-MRS studies of patients with established
schizophrenia have generally revealed that PME are
reduced, while the results for PDE are inconsistent. Such
changes may be related to changes in intracellular phos-
pholipid transport [82,94]. In contrast, the few studies
examining the early course of the illness provide a more
consistent pattern, showing lower PME and higher PDE
peaks, indicating that membrane lipid turnover is high.
While the PDE peak could be influenced by anti-
psychotic treatment [92], the first-episode studies in
neuroleptic-naïve patients indicate that effects of medi-
cation do not explain the changes.
Related aspects, such as the impaired niacin flush
reaction and the reduced incidence of schizophrenia in
RA implying alterations of bioactive lipids originating
from AA, further support the notion of altered membrane
lipid chemistry in schizophrenia. Tools, such as the
topical niacin flush test, and blood and breath peroxida-
tion product analyses [83] may be of relevance in the
understanding of biochemical subgroups within the schizo-
phrenia spectrum. Such an understanding might expose
potential new treatment targets such as the development
and use of selective enzyme inhibitors (selective PLA2
inhibitors) or pharmacogenetic targets relevant for lipids
(e.g. expression of apolipoprotein D [135]) in the schizo-
phrenia spectrum.
The available preliminary data from intervention
studies provide some support for the notion that purified
EPA is effective in treating positive and negative psy-
chotic symptoms when used in the acute illness stage at
doses of 1–2 g/day. One multicentre study in patients
with established schizophrenia and residual symptoms
using 3 gram EPA/day failed to demonstrate an effect.
Most studies have used EPA as an adjunct to neuroleptic
medication with only one study using EPA alone. Further
studies examining the efficacy of EPA at different doses,
and at different illness stages would seem warranted. As
well as clinical outcome measures, future studies should
incorporate additional outcome measures related to lipid
metabolism, such as the measurement of enzyme activi-
ties (e.g. phospholipases), in vivo 31P-MRS (preferably
1
H-decoupled), EFA analysis, the topical niacin flush
test and breath peroxidation product analysis.
Finally, the question of specificity of the findings and
any proposed interventions needs to be addressed. For
example, in a study of patients with bipolar disorder,
Stoll et al. [136] demonstrated that n-3 EFA supplemen-
tation resulted in fewer relapses, an improvement in
global clinical outcomes and depressive symptoms. It is
likely that the changes in lipid biology identified in
schizophrenia may be relevant to other psychiatric con-
ditions and more generally to other neurodevelopmental
and neurodegenerative disorders.
Acknowledgements
Gregor Berger was supported by a Fellowship from the
Swiss National Science Foundation and M. and W. Lich-
tenstein Foundation (University of Basel), the University
of Melbourne and the North-Western Health Care Net-
work. Stephen Wood was supported by NH & MRC
grants (IDs: 145627, 981112). This work is supported by
an NHMRC grant (IDs: 209062) and a Stanley Founda-
tion grant (Berger et al. 2001). We thank David Horrobin
(Laxdale, UK), Ulrich Honegger (University of Bern,
Switzerland), Malcolm Peet (University of Sheffield, UK),
Peter Williamson (University of Western Ontario, Canada),
Martin Lambert (EPPIC, Australia) and Warrick Brewer,
University of Melbourne, for their comments on various
drafts of this review article. We thank the Mental Health
Library of the Royal Melbourne Hospital.
References
1. Yehuda S, Mostofsky D. Handbook of essential fatty acid
biology. Biochemistry, physiology, and behavioral neurobiology.
Totwa, NJ: Human Press, 1997.
2. Farstad M. Determination of fatty acids in cerebrospinal fluid. v.
The fatty acid content in the total lipids of cerebrospinal fluid in
psychiatric patients. Scandinavian Journal of Clinical and
Laboratory Investigations 1966; 18:343–346.
3. Rotrosen J, Wolkin A. Phopholipid and prostaglandin
hypotheses of schizophrenia. In: Meltzer H, ed.
Psychopharmacology the third generation of progress.
New York: Raven, 1987, 759–764.
4. Keshavan MS, Mallinger AG, Pettegrew JW, Dippold C.
Erythrocyte membrane phospholipids in psychotic patients.
Psychiatry Research 1993; 49:89–95.
5. Ripova D, Strunecka A, Nemcova V, Farska I. Phospholipids
and calcium alterations in platelets of schizophrenic patients.
Physiological Research 1997; 46:59–68.
6. Heleniak E, O’Desky I. Histamine and prostaglandins in
schizophrenia: revisited. Medical Hypotheses 1999; 52:37–42.
 G.E. BERGER, S.J. WOOD, C. PANTELIS, D. VELAKOULIS, R.M. WELLARD, P.D. M CGORRY
7. Horrobin D, Glen A, Vaddadi K. The membrane hypothesis
of schizophrenia. Schizophrenia Research 1994;
13:195–207.
8. 1st International workshop on cell membrane pathology in
schizophrenia. Augusta, Georgia, 30–31 March, 1993.
Proceedings. Schizophrenia Research 1994; 13:191–270.
9. Proceedings of 2nd International Workshop on Cell Membrane
Pathology in Schizophrenia London, United Kingdom, 6–8
October, 1995. Special issue dedicated to the memory of
Dr. Sukdeb Mukherjee. Prostaglandins, Leukotriens, and
Essential Fatty Acids 1996; 55:1–122.
10. Peet M, Glen I, Horrobin D. Phospholipid spectrum disorder.
In: Psychiatry. 1. Carnforth, UK: Marius, 1999.
11. MacQueen GM, Rosebush PI, Mazurek MF. Neuropsychiatric
aspects of the adult variant of Tay-Sachs disease. Journal of
Neuropsychiatry and Clinical Neurosciences 1998;
10:10–19.
12. Yao JK, Reddy RD, van Kammen DP. Oxidative damage and
schizophrenia: an overview of the evidence and its therapeutic
implications. CNS Drugs 2001; 15:287–310.
13. Vaddadi K, Gilleard C, Soosai E, Polonowita A, Gibson R,
Burrows G. Schizophrenia, tardive dyskinesia and essential fatty
acids. Schizophrenia Research 1996; 20:287–294.
14. Garcia-Segura LM, Azcoitia I, DonCarlos LL. Neuroprotection
by estradiol. Progress in Neurobiololgy 2001; 63:29–60.
15. Agranoff BW, Joyce AB, Hajra AK. Lipids. In: Siegel GJ,
Agranoff BW, eds. Basic neurochemistry: molecular, cellular
and medical aspects, 6th edn. Philadelphia: Lippincott-Raven,
1998, 47–68.
16. Torres IC, Mira L, Ornelas CP, Melim A. Study of the effects of
dietary fish intake on serum lipids and lipoproteins in two
populations with different dietary habits. British Journal of
Nutrition 2000; 83:371–379.
17. Cunnane SC, Francescutti V, Brenna JT, Crawford MA.
Breast-fed infants achieve a higher rate of brain and whole
body docosahexaenoate accumulation than formula-fed infants
not consuming dietary docosahexaenoate. Lipids 2000;
35:105–111.
18. Farooqui AA, Horrocks LA, Farooqui T. Glycerophospholipids
in brain: their metabolism, incorporation into membranes,
functions, and involvement in neurological disorders. Chemistry
and Physics of Lipids 2000; 106:1–29.
19. Bazan NG, Packard MG, Teather L, Allan G. Bioactive lipids in
excitatory neurotransmission and neuronal plasticity.
Neurochemistry Internation 1997; 30:225–231.
20. Akbarian S, Kim JJ, Potkin SG, Hetrick WP, Bunney WE Jr,
Jones EG. Maldistribution of interstitial neurons in prefrontal
white matter of the brains of schizophrenic patients. Archives of
General Psychiatry 1996; 53:425–436.
21. McGlashan TH, Hoffman RE. Schizophrenia as a disorder of
developmentally reduced synaptic connectivity. Archives of
General Psychiatry 2000; 57:637–648.
22. Devane WA, Axelrod J. Enzymatic synthesis of anandamide, an
endogenous ligand for the cannabinoid receptor, by brain
membranes. Proceedings of the National Academy of Sciences of
the USA 1994; 91:6698–6701.
23. Glass M. The role of cannabinoids in neurodegenerative
diseases. Progress in Neurology, Psychology and Biological
Psychiatry 2001; 25:743–765.
24. Brown AS, Susser ES, Butler PD, Richardson Andrews R,
Kaufmann CA, Gorman JM. Neurobiological plausibility of
prenatal nutritional deprivation as a risk factor for
schizophrenia. Journal of Nervous and Mental Disease 1996;
184:71–85.
25. Innis SM, Sprecher H, Hachey D, Edmond J, Anderson RE.
Neonatal polyunsaturated fatty acid metabolism. Lipids 1999;
34:139–149.
363
26. Peet M, Poole J, Laugharne J. Breastfeeding, Neurodevelopment,
and Schizophrenia. In: Peet M, Glen I, Horrobin D, eds.
Phospholipid Spectrum Disorder in Psychiatry. Carnforth, UK:
Marius, 1999, 159–166.
27. McCreadie RG. The Nithsdale Schizophrenia Surveys. 16.
Breast-feeding and schizophrenia: preliminary results and
hypotheses. British Journal of Psychiatry 1997; 170:334–337.
28. Sasaki T, Okazaki Y, Akaho R et al. Type of feeding during
infancy and later development of schizophrenia. Schizophrenia
Research 2000; 42:79–82.
29. Leask SJ, Done DJ, Crow TJ, Richards M, Jones PB. No
association between breast-feeding and adult psychosis in two
national birth cohorts British Journal of Psychiatry 2000;
177:218–221.
30. Mrazek PJ, Haggerty RJ. New directions in definition.
In: Mrazek PJ, Haggerty RJ, eds. Reducing risks for mental
disorders frontiers for preventive intervention research,
1st edn. Washington, DC: National Academy Press, 1994; 19–29.
31. Brown S, Birtwistle J, Roe L, Thompson C. The unhealthy
lifestyle of people with schizophrenia. Psychological Medicine
1999; 29:697–701.
32. Christensen O, Christensen E. Fat consumption and schizophrenia.
Acta Psychiatrica Scandinavica 1988; 78:587–591.
33. Jablensky A. Prevalence and incidence of schizophrenia
spectrum disorders: implications for prevention. Australian and
New Zealand Journal of Psychiatry 2000; 34 (Suppl.):S26–S34;
discussion S35–38.
34. Mahadik SP, Mulchandoni M, Mahabaleshwar HV, Ranjekar PK.
Cultural and socioeconomic differences in dietary intake of
essential fatty acids and antioxidants: effects on the course and
outcome of schizophrenia. In: Peet M, Glen I, Horrobin D, eds.
Phospholipid spectrum disorder in psychiatry, 1st edn.
Carnforth, UK: Marius, 1999, 167–179.
35. Stoll AL. Fish consumption, depression, and suicidality in a
general population. Archives of General Psychiatry 2001;
58:512–513.
36. Tanskanen A, Hibbeln JR, Tuomilehto J et al. Fish consumption
and depressive symptoms in the general population in Finland.
Psychiatric Services 2001; 52:529–531.
37. Mellsop GW. Schizophrenia and rheumatoid arthritis. Australian
and New Zealand Journal of Psychiatry 1972; 6:214.
38. Horrobin D. Schizophrenia as a prostaglandin deficiency disease.
Lancet 1977; 1:936–937.
39. Oken RJ, Schulzer M. At issue: schizophrenia and rheumatoid
arthritis: the negative association revisited. Schizophrenia
Bulletin 1999; 25:625–638.
40. Morrow JD, Awad JA, Oates JA, Roberts LJ. Identification of
skin as a major site of prostaglandin D2 release following oral
administration of niacin in humans. Journal of Investigational
Dermatology 1992; 98:812–815.
41. Hoffer A. Adverse effects of niacin in emergent psychosis.
Journal of the American Medical Association 1969; 207:1355.
42. Horrobin DF. Niacin flushing, prostaglandin E3 and evening
primrose oil. A possible objective test monitoring therapy in
schizophrenia. Journal of Orthomolecular Psychiatry 1980;
9:33–34.
43. Fiedler P, Wolkin A, Rotrosen J. Niacin-induced flush as a
measure of prostaglandin activity in alcoholics and
schizophrenics. Biological Psychiatry 1986; 21:1347–1350.
44. Wilson DW, Douglass AB. Niacin skin flush is not diagnostic of
schizophrenia. Biological Psychiatry 1986; 21:974–977.
45. Rybakowski J, Weterle R. Niacin test in schizophrenia and
affective illness. Biological Psychiatry 1991; 29:834–836.
46. Hudson CJ, Lin A, Cogan S, Cashman F, Warsh JJ. The niacin
challenge test: clinical manifestation of altered transmembrane
signal transduction in schizophrenia? Biological Psychiatry
1997; 41:507–513.
364 LIPID BIOLOGY AND SCHIZOPHRENIA
47. Glen AI, Cooper SJ, Rybakowski J, Vaddadi K, Brayshaw N,
Horrobin DF. Membrane fatty acids, niacin flushing and clinical
parameters. Prostaglandins, Leukotrienes and Essential Fatty
Acids 1996; 55:9–15.
48. Ward PE, Sutherland J, Glen EM, Glen AI. Niacin skin flush in
schizophrenia: a preliminary report. Schizophrenia Research
1998; 29:269–274.
49. Shah SH, Vankar GK, Peet M, Ramchand CN. Unmedicated
schizophrenic patients have a reduced skin flush in response to
topical niacin. Schizophrenia Research 2000; 43:163–164.
50. Glen AI, Glen EM, Horrobin DF et al. A red cell membrane
abnormality in a subgroup of schizophrenic patients: evidence
for two diseases. Schizophrenia Research 1994; 12:53–61.
51. Yao JK, van Kammen DP. Red blood cell membrane dynamics
in schizophrenia. I. Membrane fluidity. Schizophrenia Research
1994; 11:209–216.
52. Yao JK, van Kammen DP, Welker JA. Red blood cell membrane
dynamics in schizophrenia. II. Fatty acid composition.
Schizophrenia Research 1994; 13:217–226.
53. Horrobin DF, Bennett CN. The membrane phospholipid concept
of schizophrenia. In: Gattaz WF, Haefner H, eds. Search for the
causes of schizophrenia. Balance of the century. Volume IV.
Darmstadt: Springer, 1999, 261–279.
54. Fenton WS, Hibbeln J, Knable M. Essential fatty acids, lipid
membrane abnormalities, and the diagnosis and treatment of
schizophrenia. Biological Psychiatry 2000; 47:8–21.
55. Yao JK, van Kammen DP, Gurklis JA. Abnormal incorporation
of arachidonic acid into platelets of drug-free patients with
schizophrenia. Psychiatry Research 1996; 60:11–21.
56. Connor WE, Neuringer M, Lin DS. Dietary effects on brain fatty
acid composition: the reversibility of n-3 fatty acid deficiency
and turnover of docosahexaenoic acid in the brain, erythrocytes,
and plasma of rhesus monkeys. Journal of Lipid Research 1990;
31:237–247.
57. Horrobin DF, Manku MS, Hillman H, Iain A, Glen M. Fatty acid
levels in the brains of schizophrenics and normal controls.
Biological Psychiatry 1991; 30:795–805.
58. Yao JK, Leonard S, Reddy RD. Membrane phospholipid
abnormalities in postmortem brains from schizophrenic patients.
Schizophrenia Research 2000; 42:7–17.
59. Peet M, Laugharne JD, Mellor J, Ramchand CN. Essential fatty
acid deficiency in erythrocyte membranes from chronic
schizophrenic patients, and the clinical effects of dietary
supplementation. Prostaglandins Leukotrienes and Essential
Fatty Acids 1996; 55:71–75.
60. Six DA, Dennis EA. The expanding superfamily of
phospholipase A (2) enzymes: classification and
characterization. Biochimica Biophysica Acta 2000; 1488:1–19.
61. Gattaz WF, Brunner J. Phospholipase A2 and the hypofrontality
hypothesis of schizophrenia. Prostaglandins, Leukotrienes and
Essential Fatty Acids 1996; 55:109–113.
62. Gattaz WF, Schmitt A, Maras A. Increased platelet
phospholipase A2 activity in schizophrenia. Schizophrenia
Research 1995; 16:1–6.
63. Gattaz WF, Hubner CV, Nevalainen TJ, Thuren T, Kinnunen PK.
Increased serum phospholipase A2 activity in schizophrenia:
a replication study. Biological Psychiatry 1990; 28:495–501.
64. Ross BM, Hudson C, Erlich J, Warsh JJ, Kish SJ. Increased
phospholipid breakdown in schizophrenia. Evidence for the
involvement of a calcium-independent phospholipase A2.
Archives of General Psychiatry 1997; 54:487–494.
65. Noponen M, Sanfilipo M, Samanich K et al. Elevated PLA2
activity in schizophrenics and other psychiatric patients.
Biological Psychiatry 1993; 34:641–649.
66. Albers M, Meurer H, Marki F, Klotz J. Phospholipase A2
activity in serum of neuroleptic-naive psychiatric inpatients.
Pharmacopsychiatry 1993; 26:94–98.
67. Gattaz WF, Nevalainen TJ, Kinnunen PK. [Possible involvement
of phospholipase A2 in the pathogenesis of schizophrenia].
Fortschritte der Neurologie und Psychiatrie 1990; 58:148–153.
(In German.)
68. Gattaz WF, Kollisch M, Thuren T, Virtanen JA, Kinnunen PK.
Increased plasma phospholipase-A2 activity in schizophrenic
patients: reduction after neuroleptic therapy. Biological
Psychiatry 1987; 22:421–426.
69. Hudson C, Gotowiec A, Seeman M, Warsh J, Ross B. Clinical
subtyping reveals significant differences in calcium-dependent
phospholipase A2 activity in schizophrenia. Biological
Psychiatry 1999; 46:401–405.
70. Ross BM, Turenne S, Moszczynska A, Warsh JJ, Kish SJ.
Differential alteration of phospholipase A2 activities in brain
of patients with schizophrenia. Brain Research 1999;
821:407–413.
71. Ross MB. Brain and blood phospholipase activity in psychiatric
disorders. In: Peet M, Glen I, Horrobin D, eds Phospholipid
spectrum disorder in psychiatry, 1st edn. Carnforth, UK: Marius,
1999, 23–31.
72. Hudson CJ, Kennedy JL, Gotowiec A et al. Genetic variant near
cytosolic phospholipase A2 associated with schizophrenia.
Schizophrenia Research 1996; 21:111–116.
73. Wei J, Lee KH, Hemmings GP. Is the cPLA2 gene associated
with schizophrenia? Molecular Psychiatry 1998; 3:480–481.
74. Peet M, Ramchand CN, Lee J et al. Association of the Ban I
dimorphic site at the human cytosolic phospholipase A2
gene with schizophrenia. Psychiatric Genetics 1998;
8:191–192.
75. Doris A, Wahle K, MacDonald A et al. Red cell membrane fatty
acids, cytosolic phospholipase-A2 and schizophrenia.
Schizophrenia Research 1998; 31:185–196.
76. Frieboes RM, Moises HW, Gattaz WF et al. Lack of association
between schizophrenia and the phospholipase-A (2) genes
cPLA2 and sPLA2. American Journal of Medical Genetics 2001;
105:246–249.
77. Waldo MC. Co-distribution of sensory gating and impaired
niacin flush response in the parents of schizophrenics.
Schizophrenia Research 1999; 40:49–53.
78. Stevens JD. The distribution of the phospholipid fractions in the
red cell membrane of schizophrenics. Schizophrenia Bulletin,
1972; 6:60–61.
79. Henn FA. The biological concepts of schizophrenia. In: Baxter C,
Melnachuk T, eds. Perspectives in schizophrenia research. New
York: Raven, 1980, 209.
80. Lautin A, Cordasco DM, Segarnick DJ et al. Red cell
phospholipids in schizophrenia. Life Sciences 1982;
31:3051–3056.
81. Hitzemann R, Hirschowitz J, Garver D. Membrane abnormalities
in the psychoses and affective disorders. Journal of Psychiatric
Research 1984; 18:319–326.
82. Thomas EA, Dean B, Pavey G, Sutcliffe JG. Increased CNS
levels of apolipoprotein D in schizophrenic and bipolar subjects:
implications for the pathophysiology of psychiatric disorders.
Proceedings of the National Academy of Sciences of the USA
2001; 98:4066–4071.
83. Phillips M, Erickson GA, Sabas M, Smith JP, Greenberg J.
Volatile organic compounds in the breath of patients with
schizophrenia. Journal of Clinical Pathology 1995;
48:466–469.
84. Potwarka JJ, Drost DJ, Williamson PC. Quantifying 1H
decoupled in vivo 31P brain spectra. NMR in Biomedicine 1999;
12:8–14.
85. Vance AL, Velakoulis D, Maruff P, Wood SJ, Desmond P,
Pantelis C. Magnetic resonance spectroscopy and schizophrenia:
what have we learnt? Australian and New Zealand Journal of
Psychiatry 2000; 34:14–25.
 G.E. BERGER, S.J. WOOD, C. PANTELIS, D. VELAKOULIS, R.M. WELLARD, P.D. M CGORRY
86. Kegeles LS, Humaran TJ, Mann JJ. In vivo neurochemistry of
the brain in schizophrenia as revealed by magnetic resonance
spectroscopy. Biological Psychiatry 1998; 44:382–398.
87. Keshavan MS, Stanley JA, Pettegrew JW. Magnetic resonance
spectroscopy in schizophrenia: methodological issues and
findings-part II. Biological Psychiatry 2000; 48:369–380.
88. Pettegrew JW, Keshavan MS, Panchalingam K et al. Alterations
in brain high-energy phosphate and membrane phospholipid
metabolism in first-episode, drug-naive schizophrenics. A pilot
study of the dorsal prefrontal cortex by in vivo phosphorus 31
nuclear magnetic resonance spectroscopy. Archives of General
Psychiatry 1991; 48:563–568.
89. Keshavan MS, Pettegrew JW. Phosphorus 31 magnetic
resonance spectroscopy detects altered brain metabolism before
onset of schizophrenia. Archives of General Psychiatry 1991;
48:1112.
90. Fukuzako H, Fukuzako T, Hashiguchi T, Kodama S,
Takigawa M, Fujimoto T. Changes in levels of phosphorus
metabolites in temporal lobes of drug-naive schizophrenic
patients. American Journal of Psychiatry 1999; 156:1205–1208.
91. Yao JK, Stanley JA, Reddy RD, Keshavan MS, Pettegrew JW.
Correlation between RBC fatty acids and 31P MRS brain
measures in schizophrenia. Society for Biological Psychiatry
2000; 47:41.
92. Stanley JA, Williamson PC, Drost DJ et al. An in vivo study of
the prefrontal cortex of schizophrenic patients at different stages
of illness via phosphorus magnetic resonance spectroscopy
[published erratum appears in Archives of General Psychiatry
1995 October; 52 (10): 799]. Archives of General Psychiatry
1995; 52:399–406.
93. Fukuzako H, Fukuzako T, Kodama S, Hashiguchi T,
Takigawa M, Fujimoto T. Haloperidol improves membrane
phospholipid abnormalities in temporal lobes of schizophrenic
patients. Neuropsychopharmacology 1999; 21:542–549.
94. Potwarka JJ, Drost DJ, Williamson PC et al. A 1H-decoupled 31
P chemical shift imaging study of medicated schizophrenic
patients and healthy controls. Biological Psychiatry 1999;
45:687–693.
95. Bluml S, Tan J, Harris K et al. Quantitative proton-decoupled 31
P MRS of the schizophrenic brain in vivo. Journal of Computer
Assisted Tomography 1999; 23:272–275.
96. Velakoulis D, Wood SJ, McGorry PD, Pantelis C. Evidence for
progression of brain structural abnormalities in schizophrenia:
beyond the neurodevelopmental model. Australian and New
Zealand Journal of Psychiatry 2000; 34:113–126.
97. Wood SJ, Velakoulis D, Pantelis C. Volume of parahippocampal
gyrus and hippocampus in schizophrenia. British Journal of
Psychiatry 1999; 175:388–389.
98. Marteinsdottir I, Horrobin D, Stenfors C, Theodorsson E,
Mathe A. Changes in dietary fatty acids alter phospholipid fatty
acid composition in selected regions of rat brain. Progresses in
Neuropsychopharmacolology and Biological Psychiatry 1998;
22:1007–1021.
99. Stanley JA, Pettegrew JW. Postprocessing method to segregate
and quantify the broad components underlying the
phosphodiester spectral region of vivo (31) P brain spectra.
Magnnetic Resonance Medicine 2001; 45:390–396.
100. Stanley JA, Williamson PC, Drost DJ et al. Membrane
phospholipid metabolism and schizophrenia: an in vivo
31P-MR spectroscopy study. Schizophrenia Research 1994;
13:209–215.
101. Williamson PC, Drost DJ, Stanley JA, Carr TJ, Morrison S,
Mersky H. Localized phosporus 31 magnetic resonance
spectroscopy in chronic schizophrenic patients and normal
controls. Archives of General Psychiatry 1991; 48:578.
102. Hinsberger AD, Williamson PC, Carr TJ et al. Magnetic
resonance imaging volume tric and phosphorus 31 magnetic
365
resonance spectroscopy measurements in schizophrenia. Journal
of Psychiatry and Neuroscience 1997; 22:111–117.
103. Calabrese G, Deicken RF, Fein G, Merrin EL, Schoenfeld F,
Weiner MW. 31 Phosphorus magnetic resonance spectroscopy of
the temporal lobes in schizophrenia. Biological Psychiatry 1992;
32:26–32.
104. Deicken RF, Calabrese G, Merrin EL, Vinogradov S, Fein G,
Weiner MW. Asymmetry of temporal lobe phosphorous
metabolism in schizophrenia: a 31 phosphorous magnetic
resonance spectroscopic imaging study. Biological Psychiatry
1995; 38:279–286.
105. Deicken RF, Calabrese G, Merrin EL et al. 31 phosphorus
magnetic resonance spectroscopy of the frontal and parietal lobes
in chronic schizophrenia. Biological Psychiatry 1994;
36:503–510.
106. Deicken RF, Merrin EL, Floyd TC, Weiner MW. Correlation
between left frontal phospholipids and Wisconsin Card Sort Test
performance in schizophrenia. Schizophrenia Research 1995;
14:177–181.
107. Fukuzako H, Takeuchi K, Ueyama K et al. 31 P magnetic
resonance spectroscopy of the medial temporal lobe of
schizophrenic patients with neuroleptic-resistant marked positive
symptoms. European Archives of Psychiatry and Clinical
Neuroscience 1994; 244:236–240.
108. Fukuzako H, Fukuzako T, Takeuchi K et al. Phosphorus
magnetic resonance spectroscopy in schizophrenia: correlation
between membrane phospholipid metabolism in the temporal
lobe and positive symptoms. Progress in Neuro-
Psychopharmacology and Biological Psychiatry 1996;
20:629–640.
109. Shioiri T, Kato T, Inubushi T, Murashita J, Takahashi S.
Correlations of phosphomonoesters measured by phosphorus-31
magnetic resonance spectroscopy in the frontal lobes and
negative symptoms in schizophrenia. Psychiatry Research 1994;
55:223–235.
110. Shioiri T, Someya T, Murashita J et al. Multiple regression
analysis of relationship between frontal lobe phosphorus
metabolism and clinical symptoms in patients with
schizophrenia. Psychiatry Research 1997; 76:113–122.
111. Kato T, Shioiri T, Murashita J, Hamakawa H, Inubushi T,
Takahashi S. Lateralized abnormality of high-energy
phosphate and bilateral reduction of phosphomonoester
measured by phosphorus-31 magnetic resonance spectroscopy
of the frontal lobes in schizophrenia. Psychiatry Research
1995; 61:151–160.
112. Fujimoto T, Nakano T, Takano T, Hokazono Y, Asakura T,
Tsuji T. Study of chronic schizophrenics using 31 P magnetic
resonance chemical shift imaging. Acta Psychiatrica
Scandinavica 1992; 86:455–462.
113. O’Callaghan E, Redmond O, Ennis R et al. Initial investigation
of the left temporoparietal region in schizophrenia by 31 P
magnetic resonance spectroscopy. Biological Psychiatry 1991;
29:1149–1152.
114. Volz HP, Hubner G, Rzanny R et al. High-energy phosphates
in the frontal lobe correlate with Wisconsin Card Sort Test
performance in controls, not in schizophrenics: a 31
phosphorus magnetic resonance spectroscopic and
neuropsychological investigation. Schizophrenia Research
1998; 31:37–47.
115. Volz HP, Rzanny R, Rossger G et al. 31 Phosphorus magnetic
resonance spectroscopy of the dorsolateral prefrontal region in
schizophrenics – a study including 50 patients and 36 controls.
Biological Psychiatry 1998; 44:399–404.
116. Wainwright PE, Jalali E, Mutsaers LM, Bell R, Cvitkovic S.
An imbalance of dietary essential fatty acids retards behavioral
development in mice. Physiology and Behaviour 1999;
66:833–839.
366 LIPID BIOLOGY AND SCHIZOPHRENIA
117. Wainwright P. Essential Fatty Acids and behaviour. Is there a
role for the Eicosanoids? In: Yehuda S, Mostofky D, eds.
Handbook of essential fatty acid biology biochemistry,
physiology, and behavioral neurobiology. Totwa, NJ: Human
Press 1997, 299–341.
118. Goustard-Langelier B, Guesnet P, Durand G, Antoine JM,
Alessandri JM. n-3 and n-6 fatty acid enrichment by dietary fish
oil and phospholipid sources in brain cortical areas and
nonneural tissues of formula-fed piglets. Lipids 1999; 34:5–16.
119. Lin DS, Connor WE, Anderson GJ, Neuringer M. Effects of
dietary n-3 fatty acids on the phospholipid molecular species of
monkey brain. Journal of Neurochemistry 1990; 55:1200–1207.
120. Saku N, Kobayashi J, Kitamura S. Eicosapentaenoic acid
modulates arachidonic acid metabolism in rat alveolar
macrophages activated by silica. Prostaglandins, Leukotriens,
and Essential Fatty Acids 1999; 61:51–54.
121. Whelan J. Antagonistic effects of dietary arachidonic acid and
n-3 polyunsaturated fatty acids. Journal of Nutrition 1996;
126:1086S–1091S.
122. Padma M, Das UN. Effect of cis-unsaturated fatty acids on the
activity of protein kinases and protein phosphorylation in
macrophage tumor (AK-5) cells in vitro. Prostaglandins,
Leukotriens and Essential Fatty Acids 1999; 60:55–63.
123. Seung Kim HF, Weeber EJ, Sweatt JD, Stoll AL, Marangell LB.
Inhibitory effects of omega-3 fatty acids on protein kinase C
activity in vitro. Molecular Psychiatry 2001; 6:246–248.
124. Manji HK, Lenox RH. Ziskind-Somerfeld Research Award.
Protein kinase C signaling in the brain: molecular transduction of
mood stabilization in the treatment of manic-depressive illness.
Biological Psychiatry 1999; 46:1328–1351.
125. Vaddadi K, Gilleard C, Mindham R, Butler R. A controlled trial
of prostaglandin E1 precursor in chronic neuroleptic resistant
schizophrenic patients. Psychopharmacology 1986; 88:362–367.
126. Wolkin A, Jordan B, Peselow E, Rubinstein M, Rotrosen J.
Essential fatty acid supplementation in tardive dyskinesia.
American Journal of Psychiatry 1986; 143:912–914.
127. Vaddadi K, Courtney P, Gilleard C, Manku M, Horrobin D.
A double-blind trial of essential fatty acid supplementation in
patients with tardive dyskinesia. Psychiatry Research 1989;
27:313–323.
128. Rudin D. The major psychoses and neuroses as omega-3
essential fatty acid deficiency syndrome: substrate pellagra.
Biological Psychiatry 1981; 16:837–850.
129. Mellor JE, Laugharne JDE, Peet M. Omega-3 Fatty acid
supplementation in Schizophrenic Patients. Human
Psychopharmacology 1996; 11:39–46.
130. Shah S, Vankar GK, Telang SD, Ramchchand CN, Peet M.
Eicosapentanoic acid (EPA) as an adjunct in the treatment of
schizophrenia. Schizophrenia Research 1998; 29:158.
131. Peet M, Brind J, Ramchand CN, Shah S, Vankar GK. Two
double-blind placebo-controlled pilot studies of
eicosapentaenoic acid in the treatment of schizophrenia.
Schizophrenia Research 2001; 49:243–251.
132. Peet M, Horrobin DF. A multicenter trial of Ethyl
Eicosapentaenoic acid in schizophrenia. Schizophrenia Research
2000; 41:225.
133. Fenton WS, Dickerson FB, Boronow JJ et al. Placebo-
controlled trial of omega-3 fatty acid in schizophrenia.
VIII International Congress on Schizophrenia Research 2001;
49: 225, 227.
134. Nichols PD, Virtue P, Mooney BP, Elliot NG, Yearsley GK.
Seafood the good food. The oil (fat) content and composition of
Australian commercial fishes, shellfishes and crustaceans.
Hobart: CSIRO and the Fisheries Research and Development
Corperation, 1998.
135. Thomas EA, Danielson PE, Nelson PA et al. Clozapine increases
apolipoprotein D expression in rodent brain: towards a
mechanism of neuroeptic pharmacotherapy. Journal of
Neurochemistry 2001; 76:789–796.
136. Stoll AL, Severus WE, Freeman MP et al. Omega 3 fatty acids in
bipolar disorder: a preliminary double-blind, placebo-controlled
trial. Archives of General Psychiatry 1999; 56:407–412.