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Guest Editorial
Culture and Psychiatry, or “The Tale of the Hole and the Cheese”
Morton Beiser
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In Review
Cultural Consultation: A Model of Mental Health Service for Multicultural Societies
Laurence J Kirmayer, Danielle Groleau, Jaswant Guzder, Caminee Blake, Eric Jarvis
(PDF)

Why Should Researchers Care About Culture?
Morton Beiser
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Culturally Competent Psychotherapy
Hung-Tat Lo, Kenneth P Fung
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Original Research
Spirituality and Religion in Canadian Psychiatric Residency Training
Andrea D Grabovac, Soma Ganesan
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Are Mental Health Services for Children Distributed According to Needs?
Régis Blais, Jean-Jacques Breton, Mylène Fournier, Marie St-Georges, Claude Berthiaume
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A Random-Assignment, Double-Blind, Clinical Trial of Once- vs Twice-Daily Administration of Quetiapine Fumarate in Patients with Schizophrenia or Schizoaffective Disorder: A Pilot Study
KN Roy Chengappa, Haranath Parepally, Jaspreet S Brar, Jamie Mullen, Ann Shilling, Jeffrey M Goldstein
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Review Paper
Essential Fatty Acids and the Brain
Marianne Haag
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Brief Communication
Symptom Outcome 1 Year After Admission to an Early Psychosis Program
Jean Addington, Erin Leriger, Donald Addington
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Book Reviews
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A Beautiful Mind.
Reviewed by
Vivian Rakoff, MA, MBBS, FRCPC

Staying Human During Residency Training. 2nd edition.
Reviewed by
Emmanuel Persad, MBBS, FRCPC

Letters to the Editor
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La mémoire est une faculté qui oublie

Clinical and Family History Markers of Bipolar II Disorder

Re: Clinical and Family History Markers of Bipolar II Disorder

Effect of Olanzapine on the Liver Transaminases

In Review

Essential Fatty Acids and the Brain

Marianne Haag, MSc, DSc¹

Of all organs in the human body (excluding adipose tissue), the nervous system has the highest lipid content. The dry weight of an adult brain is 50% to 60% lipid, and 35% of the lipid content is accounted for by PUFAs (1) (See Table 1 for a list of abbreviations used in this paper). AA and DHA, which contain 20 and 22 carbons, respectively, appear in the highest concentrations (2,3).

Table 1  List of abbreviations in text

AA                  arachidonic acid AC                  adenylate cyclase ALA                alpha-linolenic acid, parent compound of                        omega 3 family Ca                  calcium Ca-ATPase    Ca-dependent adenosinetriphosphatase cAMP            cyclic adenosine monophosphate Ca2+-CM-PK  Ca2+-calmodulin-dependent protein kinase DGLA            dihomogammalinolenic acid DHA              docosahexanoic acid (key omega-3) DPA              docosapentanoic acid EPA              eicosapentanoic acid (key omega-3) IFN                interferon IFN-gamma   interferon-gamma IL                  interleukin (IL-5, IL-6) K                   potassium LA                 linoleic acid, parent compound of omega-6                      family LC-PUFA       long-chain polyunsaturated fatty acid Na                 sodium Na, K-ATPase Na, K-dependent adenosinetriphosphatase PK                 protein kinase (PKA, PKC) PLA2                    phospholipase A2 PLC               phospholipase C PUFA             polyunsaturated fatty acid TNF-alpha     tumour necrosis factor alpha

DHA, a key omega-3 acid, is especially important during prenatal human brain development: it is incorporated into nerve growth cones in events leading to synaptogenesis (4,5). Jones and coworkers have recently presented evidence that DHA is involved in cholinergic synaptic transmission (6). The brain growth spurt that takes place from the third trimester of pregnancy until 18 months after birth also correlates well with DHA accretion in brain phospholipids (7,8). Nature makes doubly sure that the infant brain is provided with the necessary LC-PUFAs: both the placenta (9) and breast feeding (10,11) supply predominantly DHA and AA to the growing young. DHA deficiency can have marked consequences, including retarded visual acuity (11), cognitive impairment (12), cerebellar dysfunction (13), and various other neurological disorders (14).

Providing a persuasive historical backdrop for this topic, Chamberlain (15) and Broadhurst and others (16) have proposed the necessity of LC-PUFAs for human intellectual evolution. Their reviews correlate the marked enlargement of the hominid cerebral cortex during the last 2 million years (when the genus Australopithecus died out and the Homo species emerged) with a relatively high dietary fish intake. The numerous freshwater lakes in the Rift Valley in Eastern Africa, where early hominid development took place, provided a diet rich in LC-PUFAs.

This review aims, first, to explain briefly why the structure of highly unsaturated fatty acids enables them to play such an important role in brain cell membranes. The possible role of PUFAs in neurotransmission, gathered from in vitro and in vivo animal experiments, is described. Finally, PUFA supplementation studies in human cohorts with various psychiatric conditions are reviewed.

Methods

This review was presented in 2001, at the University of Pretoria, as a lecture to introduce postgraduate medical students in psychiatry to the field. Material was gathered by searching Medline databases for articles using the following key words: polyunsaturated fatty acids, essential fatty acids, omega-3 fatty acids, docosahexanoic acid, eicosapentanoic acid, arachidonic acid, neurotransmission, phospholipase A2, depression, schizophrenia, mental performance, attention- deficit hyperactivity disorder, and Alzheimer’s disease. Biochemistry textbooks were consulted on the role of fatty acids in membrane function, neurotransmission, and eicosanoid formation.

PUFA Synthesis and Structure

LC-PUFAs cannot be formed de novo but can be synthesized from the essential fatty acids LA and ALA, as illustrated in Figure 1. LA is the parent compound of the so-called omega-6 family of fatty acids, as is ALA of the omega-3 family. These parent fatty acids are desaturated and lengthened progressively by microsomal enzyme systems (17) to form the important, highly unsaturated, long-chained AA and DHA. Members of the 2 families are not interconvertible. They also compete for the same enzyme systems.

Fatty Acids Can Be Kinked
Saturated fatty acids have straight carbon chains. Cis-desaturation of a fatty acid has spectacular consequences for its 3-dimensional structure: progressive insertion of cis-double bonds causes the carbon chain to become more curved (Figure 2). The hydrophobic ends of these kinked chains are probably curled around one another in the cell membrane. The more kinked the fatty acid is, the more space it will take up when it is built into cell membrane phospholipids, thereby increasing the fluidity and, probably, the functionality of the cell membrane (18). In contrast, industrial heating and multiple pressing procedures cause formation of trans fatty acids (19) that are straight and rigid, similar to saturated fatty acids. Since human fatty acid intake is reflected in cell membrane fatty acid composition (20,21), these facts do not bode well for Western humans’ cell membranes: their tendency to consume large amounts of saturated animal fats and processed oils has increased alarmingly during the 20th century. Interestingly, their intake ratio of omega-6 to omega-3 fatty acids has also increased, with a plethora of ill consequences for health (22,23).

Figure 1 PUFA synthesis from parent essential fatty acids

LA: linoleic acid; GLA: gamma-linolinolenic acid; DGLA: dihomogammalinolenic acid; AA: arachidonic acid; ALA: alpha-linolenic acid; EPA: eicosapentanoic acid. In the shorthand notation used here, the first number denotes the number of carbon atoms in the fatty acid molecule, and the number after the colon denotes the number of double bonds it contains.

Membrane Phospholipid Turnover

The cell membrane is in a constant state of flux: fatty acids are released from the membrane by phospholipases (Figure 3). PLA2 can release AA, DGLA, and EPA from the sn-2 position of membrane phospholipids, but with vastly differing consequences: DGLA and AA (both omega-6), as well as EPA (omega-3), can be transformed into prostaglandins and thromboxanes of the 1-, 2-, and 3-class, respectively. The 2-class is highly proinflammatory, and the 1-class has intermediate properties, whereas the 3-class is antiinflammatory. It has been hypothesized that a highly reactive PLA2 is found in various psychiatric disorders (24,25). When coupled with a high omega-6 PUFA content in the cell membrane, it would thus lead to aggravated inflammatory conditions. This would, of course, be limited by the presence of sufficient omega-3 fatty acids in the membrane.

Fatty Acids and Signalling Pathways in the Nervous System

PUFAs can modulate many of the signal transduction mechanisms operating in neuronal membranes and, thus, in the synaptic cleft. Figure 4 presents the most important membrane second-messenger mechanisms. (The shaded dots show loci where PUFA effects have been demonstrated). Various neurotransmitters—for example, serotonin, the catecholamines, and acetylcholine (26–28)—interact with members of a heptahelical transmembrane receptor family. G proteins linked to these receptors transduce their signals; the role of DHA in this regard has recently been discussed by Salem and others (29).

AC drives the cAMP messenger system. This pathway is used by 5-HT1 (serotonin) receptors, alpha-2 and beta-adrenergic (noradrenaline and adrenaline) receptors, and both D1 and D2 (dopamine) receptors. PUFAs can influence this pathway at 2 points: they can increase both AC (30,31) and PKA (32) activity. Conversely, PLC starts the phosphoinositide signalling pathway, where PUFAs can exert their effects on PLC (33) and PKC (34)—both of which are involved in 5-HT2 and alpha-1 adrenergic transmission. The 2 other membrane phospholipases, D and A2, are also affected by PUFAs (35–37) and play an important role in neurotransmission. PLA2 can be activated by dopamine D2 receptors (38), serotonin 5-HT2 receptors (39), glutamate receptors (40), and muscarinic acetylcholine receptors (41). PLA2 liberates fatty acids from the sn-2 position of phospholipids, and these can subsequently be used as precursors for prostaglandins, thromboxanes, lipoxins, and leukotrienes. These eicosanoids themselves can have many effects on signal tranduction (42). The different effects of prostaglandins could be caused by the different signalling systems they use: prostaglandins of the 2 family transduce signals via a Gs protein, thus elevating cAMP levels, whereas those of the 3 family use a Gi protein, which has the opposite effect. Prostaglandins of the 1 family use a phosphoinositide signalling system (43).

PUFAs can also modulate ion channels (for example those for Ca2+ and Na+) (44,45). Further events in the process of neurotransmission, and eventual release of neurotransmitters from synaptic vesicles, are ushered in by activation of Ca2+-CM-PKs; here also, PUFA effects have been noted (46). The thousandfold concentration gradient between extra- and intracellular Ca2+ is maintained by Ca-ATPase in neuronal membranes: Kearns and Haag have recently noted an inhibition of this enzyme by both DHA and EPA (47).

Figure 2 Atomic molecular models of selected essential fatty acids

Figure 3 Role of PUFAs in signal transduction

1: G_s  protein; 2: adenylate cyclase; 3: protein kinase A; 4: G_p protein; 5: phospholipase C;  6: protein kinase C; 7: tyrosine kinase; 8: ion channel; 9: phospholipase A₂; AA: arachidonic acid; DGLA: dihomogammalinolenic acid; EPA: eicosapentanoic acid; PL: phospholipid; PIP₂: phosphatidylinositol pyrophosphate; DAG: diacyl glycerol; ER: endoplasmic reticulum; IP₃ and IP₄: inositoltris- and tetrakisphosphates.

Figure 4 Membrane phospholipid turnover

PLA₂ (Phospholipase A₂) hydrolyses phospholipids in the cell membrane, forming fatty acids which are precursors of eicosanoids. CoAIT (Coenzyme A-independent transacylase) and ACLAT (Acyl-coenzyme A: lyso-phospholipid acyltransferase) replenish fatty acids in membrane phospholipids. AA: arachidonic acid; DGLA: dihomogammalinolenic acid; EPA: eicosapentanoic acid; COX: cyclo-oxygenase; FA: fatty acid; LO: lipoxygenase.

PUFA Supplementation in Animal and Human Models

Dietary Supplementation in Experimental Animals
As early as 1989, Bourre and coworkers compared young rats fed sunflower oil, which is low in omega-3 PUFAs, with rats that had been fed soybean or rapeseed oil, which is adequate in omega-3 (2). Rats in the first group had more anomalies in their electroretinograms and were more seriously affected in learning responses, as measured with a shuttle box test, compared with rats in the second group. In addition, Na,K-ATPase activity in brain nerve endings was depressed in 40% of the omega-3–deprived group, compared with the omega-3–adequate group. This enzyme is of utmost importance in maintaining nerve membrane potential.

Subsequent studies by Delion and colleagues (48,49) compared peanut oil supplementation in a diet deficient in omega-3 with peanut plus rapeseed oil supplementation in a diet with adequate omega-3. They reported a lower density of D2 receptors and lower dopamine levels in the cerebral cortex of the omega-3–deprived group, coupled with increased serotonin levels and 5-HT2 receptor density, accompanied by a low ratio of omega-3 to omega-6 PUFA content in the membrane. Driving this line of investigation still further, Chalon and coworkers increased the ratio of omega-3 to omega-6 PUFA by using fish oil plus palm oil in the diet (50). This resulted in increased dopamine receptors as well as increased dopamine levels in the cerebral cortex. By contrast, however, this dietary strategy also decreased both ambulatory activity and dopamine binding in the striatum. Reporting from the same laboratory, Zimmer and others showed that dopamine breakdown was higher in omega-3–deficient rats than in control rats and proposed that the internalization of dopamine in the storage pool of the cerebral cortex was modified in the omega-3–deprived group (51,52). Recently, De la Presa Owens and Innis (53) have also published evidence showing that PUFA-deprived rats have higher dopamine and serotonin levels in the frontal cortex than do control rats. Unfortunately, however, this study does not allow differentiation between the effects of omega-3 and omega-6 PUFAs.

Researching the influence of omega-3 PUFA deprivation on learning, Okuyama (54) and colleagues compared rats fed safflower oil (which is omega-3 deficient) with rats fed perilla oil (which is omega-3 adequate). They demonstrated that the rats fed safflower oil showed inferior learning ability (according to the brightness discrimination test) and a 30% decreased synaptic vesicle density in the hippocampal CA1 region. Okuyama and colleagues also reported increased hippocampal acetylcholine levels and improved passive avoidance in stroke-prone, spontaneously hypertensive rats supplemented with DHA (55).

PUFA Intervention Trials in Human Subjects
Infant Mental Development. The importance of adequate LC-PUFA supply in infant mental development (measured according to the Mental Development Index) has been the subject of intense research. As part of an impressive body of results since 1990, Carlson and colleagues have shown that DHA in the infant diet is associated with higher mental development scores (56), shorter look-durations to novel stimuli (57), and better visual acuity as a measurement of infant brain maturation (58). Surprisingly, it is also associated with poorer psychomotor development (59). This last finding is not consistent with Agostini and others’ positive report in this regard (60). The work of 2 other groups also deserves mention: that of Birch and colleagues (12,61,62) and that of Willats and coworkers (63). Birch and colleagues supplemented full-term infants with DHA and AA during their first 4 months and were able to show a correlation between DHA levels measured in red blood cell lipids at age 4 months, but not at age 12 months. They also demonstrated a correlation with the mental performance index in the same toddlers at age 18 months. A reevaluation of the cohort at age 4 years is currently underway to determine whether the differences in cognitive function measured in this trial have some degree of permanence. Willats and others reported a trial in which full-term infants were supplemented with a mixed LC-PUFA preparation for the same time period as the group studied by Birch. The problem- solving activity (determined according to the 3-step toy- retrieval test) of the cohort was measured at age 10 months, with the supplemented group achieving significantly higher problem-solving scores. Although this type of score reportedly correlates with IQ and vocabulary scores measured at age 3 years (64), caution is still advisable in correlating PUFA intake and mental performance in older children. The dosage of PUFA supplementation and the exact time of MDI measurement seem to be of prime importance in this regard: Scott and others, for example, could not show beneficial effects with a somewhat lower PUFA dosage and MDI measured at age 12 months (65).

Attention-Deficit Hyperactivity Disorder (ADHD). ADHD has also been linked to LC-PUFA deficiency: a low serum ratio of omega-3 to omega-6 PUFA, coupled with a possible delta-6-desaturase deficit, has been reported in boys with this condition (66). However, a recent randomized double-blind placebo-controlled trial could not improve the symptoms of ADHD, although higher plasma DHA levels were attained with a regime of omega-3 supplementation (67).

Psychological Stress. Looking for possible protective effects of PUFAs in psychological stress, Maes and coworkers recently surveyed a sample of students, measuring levels of proinflammatory cytokines (IFN-gamma, TNF-alpha, IL-5, and IL-6) both before and after a difficult oral examination. These levels were correlated with the serum ratio of omega-3 to omega-6; a low ratio of omega-3 to omega-6 predisposed subjects to higher rises in cytokine production during stress (68).

Depression. Twenty years ago, Horrobin and Manku had already noted the possible causative role of prostaglandins and their parent fatty acids in depression (69). In 1995, Hibbeln and Salem (70) proposed a link between the marked increase in depression rates in the 20th century (71) and increased intake of PUFAs containing omega-6 in the form of plant oils. The 1996 report of Adams and coworkers supported this hypothesis (72). These researchers showed a significant positive correlation in 20 subjects between depression severity (measured according to the Hamilton Depression Rating Scale as well as a linear scale that omits anxiety) and the ratio of AA (omega-6) to EPA (omega-3) in erythrocyte phospholipids. In a similar vein, Edwards and others reported a significant depletion of omega-3 PUFAs in the red blood cell membranes of 10 subjects with a diagnosis of a major depressive episode according to DSM-IV criteria, compared with matched normal control subjects (73). This study rated participants according to the Beck Depression Inventory and controlled fully for possible confounders such as diet, smoking, and stress. Maes and colleagues have since also reported trials with similar results (74,75). Pursuing the possibility that omega-3 fatty acids may reduce vulnerability to depression, Stoll and coworkers reported a trial in which fish-oil supplementation, albeit in relatively high dosages, had beneficial effects in treating patients with bipolar disorder during their depressive phases (76). In contrast to the foregoing results, 2 early studies (77,78) demonstrated increased EPA and DHA in erythrocyte membranes of a mixed group of patients with bipolar affective disorder and reactive or mild depression. The discrepancy in these results may be owing to the fact that the subjects in these trials were not selected by as strict diagnostic criteria as were subjects in the later trials.

Schizophrenia. Mellor and colleagues have conducted trials investigating phospholipid abnormalities in schizophrenia patients. Twenty subjects with chronic schizophrenia (according to DSM-III-R criteria) and taking neuroleptic medication showed decreased ratios of omega-3 to omega-6 in red blood cell membranes. This abnormality was also found in their brain tissue post mortem. Fish-oil supplementation of 10 g daily did, however, ameliorate the symptoms of surviving patients, according to their total Positive and Negative Syndrome Scale and Abnormal Involuntary Movement Scale scores (79,80). These results are corroborated by Yao and others (81,82). However, all these studies are difficult to interpret, since in most cases patients have already received some form of medication that could influence the outcome. A case in point is the most recent report by Peet and others (83). Their study could only show important and statistically significant beneficial effects of 2 g daily EPA in the presence of clozapine, while their placebo group receiving antipsychotics alone also showed a positive response. Further, Fenton and others, researching a relatively large cohort of 75 subjects with schizophrenia, could find no effect of 3 g daily ethyl-EPA on all ratings measured (84). As stated in a recent review by Joy and others (85), more results are urgently needed before fish oil or ethyl-EPA can be regarded as beneficial in the treatment of schizophrenia.

Multiple Sclerosis (MS). Dietary fat has been implicated in the etiology of MS since the early 1950s. An early Norwegian study showed a lower incidence of MS in coastal communities with a high fish intake, compared with inland rural communities where consumption of saturated fat is higher (86). Thus, a shortage of dietary PUFAs may be a risk factor in MS. Indeed, later studies found decreased levels of both omega-3 and omega-6 PUFAs in red blood cells, plasma, and adipose tissue of patients diagnosed with MS (87). Because MS is associated with an activated inflammatory response and omega-3 highly unsaturated fatty acids can suppress IFN, IL, and TNF production in MS subjects (88), treatment with omega-3 fatty acids seems to have a reasonable theoretical basis. In 2000, Nordvik and others reported a study in which 16 newly diagnosed MS patients were treated with 0.9 g EPA plus DHA daily (89). In addition, they were given dietary advice. After 2 years, there was a reduction in the mean annual exacerbation rate and the mean Expanded Disability Status Scale, compared with their status before the study. Conversely, a study of 195 new cases of MS, undertaken by Zhang and others and also published in 2000, could show no difference from any type of dietary fat intake between MS patients and control subjects (90).

Alzheimer’s Disease and Huntington’s Chorea. The normal aging process is characterized by decreased delta-6- desaturase activity (91,92), increased inflammatory response (93), and oxidative damage to the cell membrane (94). Lynch and colleagues have recently reported that, in rats, EPA can prevent oxidative stress triggered by apoptotic cell death in the hippocampus (95). They have also shown that age-related decreases in long-term potentiation and glutamate release can be reversed by omega-3 supplementation (96). In a study by Yehuda and coworkers (97), symptoms of Alzheimer’s disease, such as short-term memory loss, depressed mood, and inability to sleep (symptoms often found in the elderly), were markedly ameliorated by treatment with SR-3 (an essential fatty acid preparation containing omega-3). Thus, PUFAs may well be used clinically. For a small cohort of 8 patients suffering from end-stage Huntington’s disease, ethyl-EPA at a dosage of 2g daily was also beneficial in treating the orofacial abnormalities associated with this condition (98).

Conclusion

Increasing evidence shows that a correct balance between omega-3 and omega-6 fatty acids in brain cell membranes is important to mental health. This paper has reviewed some clinical evidence that higher dosages of omega-3 fatty acids (2 to 4g daily) may ameliorate the symptoms of several psychiatric conditions. However, more data are required to reach conclusive answers in this regard. DHA and AA play the most important role in nerve function: they are long, highly unsaturated fatty acids from the omega-3 and omega-6 fatty acid families. (The role of the longest omega-6 fatty acid, DPA [22:5], in cell membrane function still needs to be ascertained.) The current Western diet does not supply omega-3 and omega-6 fatty acids in the desired proportion (1:4). In the UK and Western Europe, the ratio is as low as 1:15 (99). It is important that the public, dieticians, the medical profession, and policy-makers in charge of nutrition programs be conscious of this recommendation and work toward ensuring an adequate daily DHA-plus-EPA intake by the population.

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Author(s)

Manuscript received August 2002, revised, and accepted December 2002.

1. Associate Professor, Department of Physiology, University of Pretoria, Pretoria, South Africa.

Address for correspondence: Prof M Haag, Department of Physiology, University of Pretoria, PO Box 2034, Pretoria 0001, South Africa

e-mail: mhaag@medic.up.ac.za

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