Long chain omega 3 polyunsaturated fatty acids supplementation in the treatment of elderly...

Introduction

The prevalence of depressive symptoms in free-livingelderly subjects ranges from 10% to 20% (1) and in elderlyhospitalized patients it ranges from 22% to 34% (1). Moreover,depression is observed in 50% of elderly patients with dementiaand in 20% of patients with Alzheimer disease (2). Depressionin the elderly is associated with higher mortality rate, due tosuicide or other causes, as compared to non depressed subjectsof similar age (3, 4).It has been hypothesized that one of the reasons of the

increase of depressive disorders, over the past century, may becorrelated with a marked decrease in the ratio of n-3 to n-6 longchain omega polyunsaturated fatty acids (LCPUFA), due to dietchanges (5). The two n-3 LCPUFA, eicosapentaenoic acid(EPA) and docosahesaenoic acid (DHA), play an important rolein the functioning of the central nervous system, and manystudies have demonstrated that patients suffering fromdepression or mood disorders have significantly lower dietaryintake and serum levels of n-3 LCPUFA (6-8).In presence of low concentration of LCPUFA, an abnormal

function and metabolism of various neurotransmitters has beenobserved in addition to a reduced activity of receptorsassociated to G-proteins and ionic channels (9). A reduction ofthe DHA and EPA body storage may limitate in animal modelthe learning process and may imply a derangement of cerebralactivity (10). The supplementation of omega-3 fatty acids ingeneral population reduces the occurrence of mooddisturbances, while a lower rate of symptoms is observed inpatients already affected by disturbances of mood or of thepersonality (11-13). Moreover, recent observations showedthat n-3 LCPUFA represent a potential treatment of depression(14-17). Stoll et al. showed that patients affected by bipolardisorder experience a clinical remission of the disease up to 4months, when orally supplemented with n-3 LCPUFA (18).Various experimental evidences demonstrate a positive

correlation between a decrease of omega 3 fatty acids andabnormal activity of dopaminergic, noradrenergic andserotoninergic systems (19-27). These observations are ofrelevant importance because several depressive events could beassociated with impairment of the serotoninergic and - at leastin part - of the adrenergic system (28, 29). Furthermore,

LONG CHAIN OMEGA 3 POLYUNSATURATED FATTY ACIDSSUPPLEMENTATION IN THE TREATMENT OF ELDERLY DEPRESSION:

EFFECTS ON DEPRESSIVE SYMPTOMS, ON PHOSPHOLIPIDS FATTY ACIDSPROFILE AND ON HEALTH-RELATED QUALITY OF LIFE

M. RONDANELLI1, A. GIACOSA2, A. OPIZZI1, C. PELUCCHI3, C. LA VECCHIA3, G. MONTORFANO4,M. NEGRONI4, B. BERRA4, P. POLITI5, A.M. RIZZO4

1. Department of Applied Health Sciences, Section of Human Nutrition and Dietetics, Faculty of Medicine, University of Pavia, Endocrinology and Nutrition Unit, Azienda di Servizi allaPersona di Pavia, University of Pavia; 2. Department of Gastroenterology and Nutritional Science, Policlinico di Monza, Milan; 3. “Mario Negri” Institute for Pharmacological Research,Milan, Italy; 4. Institute of General Physiology and Biochemistry “G. Esposito”, University of Milan; 5. Department of Applied Health Sciences, Section of Psychiatry, Faculty ofMedicine, University of Pavia. In memory of Professor Bruno Berra. Corresponding author and author for requests for reprints: Mariangela Rondanelli, Department of Applied Health

Sciences, Section of Human Nutrition and Dietetics, Faculty of Medicine, Azienda di Servizi alla Persona di Pavia, University of Pavia Istituto di Cura “Santa Margherita”, Via Emilia 32,27100 Pavia, Italy, Tel. International +39-0382-381149, + 39- 3382559239, Fax International +39-0382-381218,

E-mail: [email protected] ; [email protected]

Abstract: Objective: Recent observations showed that long chain omega 3 polyunsaturated fatty acids (n-3LCPUFA) could represent a potential treatment for elderly depression. To determine if a n-3 LCPUFAcontaining supplement improves depressive symptoms, changes phospholipids acids profile and amelioratesHealth related quality of life (HRQoL) in depressed elderly patients. Design: Two-months, randomized,double-blind, placebo-controlled trial. Setting: Nursing home in Pavia, Italy. Subjects: Forty-six depressedfemales, aged 66-95 years. Intervention: 22 depressed females were included in the intervention group (n-3group, that received 2.5 g/day of n-3 LCPUFA, with 1.67 grams of EPA and 0.83 grams of DHA), and 24patients in the placebo group. The primary endpoint was the improvement of depressive symptoms asevaluated by Geriatric Depression Scale (GDS). Secondary endpoints were the evaluation of modificationsof erythrocyte membrane phospholipids fatty acid profile and of of HRQoL, by using the Short-Form 36-Item Health Survey (SF-36). All parameters were assessed before and after the treatment period of 8 weeks.Results: The mean GDS at 2 months was significantly lowered only for the n-3 group. SF-36 physical andmental components were significantly increased in the intervention group. Compliance was good, asconfirmed by erythrocyte membrane phospholipid FA concentrations, with significant increase of EPA andDHA in the intervention group. Conclusion: The supplementation of n-3 LCPUFA in elderly female patientsreduces the occurrence of depressive symptoms, improves phospholipids fatty acids profile and health-related quality of life.

Key words: N-3 long chain polyunsaturated fatty acids, depression, elderly, AA/EPA.

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The Journal of Nutrition, Health & Aging©Volume 15, Number 1, 2011

JNHA: CLINICAL TRIALS AND AGING

Received May 5, 2009Accepted for publication January 22, 2010

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N-3 FA SUPPLEMENTATION AND ELDERLY DEPRESSION

depression promotes alterations that affect the quality of life inseniors, particularly by restricting their social life and graduallyreducing their independence, with increased risk of physicaland functional decline (30-32).The aim of the present study is to evaluate the effect of n-3

LCPUFA supplementation on depressive symptoms, onphospholipids fatty acids profile and on health-related qualityof life in depressed elderly subjects, by means of a double blindcontrolled study versus placebo.

Material and methods

SubjectsThe eligible participants were females aged between 65 and

95 years, with Body Mass Index (BMI) higher than 19 andlower than 30 kg/m2. Cases were recruited from a nursing homein Pavia, where they had been institutionalized for at least 3months, prior to enrollment. The protocol was approved by theEthics Committee of the Azienda Sanitaria Locale (ASL) ofPavia and all participants gave their written consent to thestudy.Data were gathered from the end of January 2006 to the end

of December 2007. All patients presenting depressive symptomsand having a Mini Mental State Examination (MMSE) scorehigher than 24 (33) underwent a psychiatric evaluation made bya senior psychiatrist after an in-depth clinical interview. Allsubjects admitted to treatment met the DSM-IV-TR (34) fullcriteria for Major Depression or Dysthymia. Exclusion criteriawere the following: (a) presence of a current comorbidpsychiatric diagnosis other than major depression or dysthymia;(b) presence of active suicide ideation; (c) presence of psychoticsymptoms; (d) current use of psychotropic drugs other thanbenzodiazepines (antidepressants, mood stabilizers,antipsychotics). Moreover, subjects with a clinicallyuncontrolled organic disease or with clinically relevantlaboratory abnormalities were excluded from the study.Depressive symptoms were assessed through the use of theGeriatric Depression Scale (GDS) (35) before and after thetreatment period (week 0 and 8). The GDS Long Form is themost widely used scale for the evaluation of depression in theelderly; it is a 30-item questionnaire in which participants areasked to respond by answering yes or no with reference to howthey felt over the past week. Scores of 0-4 are considerednormal, depending on age, education and complaints; 5-8indicate mild depression; 9-11 indicate moderate depression and12-15 indicate severe depression. The GDS may be used withhealthy, unhealthy and mild to moderately cognitively impairedelderly subjects. It has been extensively used in community,acute and long-term care settings. The validity and reliability ofthe tool has been supported through both clinical practice andresearch evidence (36). The scale is commonly used as a routinepart of a comprehensive geriatric assessment. The ongoingpharmacological treatment at the inclusion time (such as drugsfor insomnia, hypertension, diabetes, etc.) was maintainedduring the study. No intervention other than the administration

of omega 3 fatty acids was performed for depression. Inaddition, the studied subjects were tested with the Short-Form36-Item Health Survey (SF-36) (37), in order to evaluate theirquality of life. The SF-36 questionnaire is a valid genericmeasure for rating health-related quality of life in severalresearch fields, on the basis of its validity, high internalconsistency and high test-retest reliability (37). Furthermore, theSF-36 is easy to administer and to compile for respondents, ithas extensive psychometric validation and is responsive totreatment in several medical conditions (37). Response items areusually arranged in eight domains reflecting physical and mentalhealth-related quality of life: physical functioning (10 items),role limitations due to physical functioning (role-physicallimitation) (4 items), bodily pain (2 items), general health (5items), vitality (4 items), social functioning (2 items), rolelimitations due to emotional functioning (role-emotionallimitation) (3 items) and mental health (5 items). The 8 scaleswere scored from 0 to 100 (worst to best possible health status).For each dimension, the score represented the mean of itemvalues obtained by the subject when all the items werecompleted or when the number of missing values was no morethan half of the total items. Otherwise, the score was recorded asmissing. Moreover, the scales of SF-36 were summarized intotwo dimensions. The first five scales make up the "physicalhealth" dimension, and the last five form the "mental health"dimension. The vitality and general health scales are parts ofboth dimensions. Hence, each dimension includes three specificand two overlapping scales. The standardized summary scoresfor physical (PCS) and mental (MCS) components werecomputed and separately used as outcome measures. Also QolSF-36 was assessed before and after the treatment period. Thecapacity of the patients to care for themselves was assessed bythe Katz Index of Independence in Activities of Daily Living(ADL) (38) prior to enrollment.

Body composition and nutritional statusNutritional status was assessed using anthropometric

measurements. Body weight and height were measured andBody Mass Index (BMI) (kg/m2) was calculated. Skinfoldthicknesses (biceps, triceps, suprailiac, subscapular) weremeasured twice by an Harpender skinfold caliper at 5 minutesintervals in each site, using a standardized technique (39). TheMini Nutritional Assessment (MNA) was also performed in allthe studied subjects (40). MNA, which comprises simplemeasurements and a brief questionnaire, involves: ananthropometric assessment (weight, height and weight loss), ageneral assessment (lifestyle, medication and mobility) and adietary assessment (number of meals, food and fluid intake,autonomy of eating self assessment, self-perception of healthand nutrition). Patients ate three meals daily, with breakfastbetween 07:00 and 08:00 am, lunch between 12:00 and 1:00 pmand dinner between 6:00 and 7:00 pm. The food intake wasbased on a well balanced diet (with standard caloric and macroand micronutrient content) provided by the hospital kitchen.

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Biochemical analysesFasting venous blood samples were drawn between 08.00

and 10.00 a.m. with the subjects in a sitting position, forevaluation of white blood cell and red blood cell count,haemoglobin and haematocrit, platelets, total lymphocytes,total proteins, iron, albumin, gamma-GT, total bilirubin, liverenzymes, triglycerides, total and HDL cholesterol, glucose, uricacid, creatinine, electrolytes, C-reactive protein, thyroid-stimulating hormone (TSH), free thyroxin (FT4), freetriiodothyronine (FT3) and red blood cells membrane lipidprofile. Serum for Clinical chemistry parameters was rapidlyfrozen and stored at –80 °C until analysis (less than 1 monthlater). Whole blood (EDTA as anticoagulant) was used forhaematological parameters. Clinical Chemistry parameterswere detected on the Roche Cobas Integra 400 plus analyzer(Roche Diagnostics, Basel, Switzerland), with dedicatedcommercial kits provided by the manufacturer. LDLcholesterol was calculated according to the Friedewald formula(41). Haematological parameters were measured using aCoulter automated cell counter MAX-M (Beckman Coulter,Inc., Fullerton, USA). TSH, FT4 and FT3 levels were detectedin serum on a Roche Elecsys 2010 analyzer (RocheDiagnostics, Basel, Switzerland). In order to evaluate the redblood cells (RBC) membrane lipid profile, RBC were separatedfrom plasma by centrifugation and stored at -70 °C until usedfor analysis. The analysis was carried out blind to the subjectstatus. Cell membranes of RBC (ghosts) were prepared by lysiswith hypotonic buffer (phosphate 5 mM pH 8, EDTA 0.5 mM)and washed several times to eliminate haemoglobin residues.Ghosts lipids were extracted with chloroform/methanolaccording to Folch (42) and fractionated by silicic acidchromatography (200-400 mesh BIORAD) into non polarlipids, glycolipids and phospholipids. Fatty acids from purifiedmembrane phospholipids were determined by gas-chromatographic analysis. The fatty acid methylesters wereobtained after derivatization with sodium methoxide inmethanol 3.33% w/v and injected into gaschromatograph(Agilent Technologies 6850 Series II) equipped with a flameionization detector (FID) under the following experimentalconditions: capillary column: AT Silar length 30 m; filmthickness 0.25 µm; gas carrier: helium; temperature: injector250° C, detector 275° C, oven 50° C for 2 min, rate of 10° Cmin-1 until 200° C for 20 min. A standard mixture containingmethyl ester fatty acids was injected for calibration.

Study designThe study was a single-centre, 8-weeks, double-blind

randomized comparison of n-3 LCPUFA at 2.5 g/day versusplacebo (paraffin oil). The subjects were randomly assigned toone of the 2 groups in a double-blind parallel study. Thesubjects were supplemented with fish oil or placebo (paraffinoil). Both the intervention and placebo group were treated withliquid products. The intervention treatment was obtained with2.5 g/day of n-3 LCPUFA oil (1.67 g. of EPA and 0.83 g. ofDHA) with lemon flavour. The nutritional composition of the

product is reported in Table 1. The control group was treatedwith a placebo made of paraffin oil with the same lemon flavouras for the intervention product. Subjects were randomized toreceive one serving containing 2.5 g of n-3 LCPUFA oil, orally,once a day, before lunch, or an identical serving of placebo for 8weeks. The n-3 LCPUFA oil was manufactured by Also S.p.A.,Div. Also-Enervit, Zelbio (CO), Italy. Bottles of identical oilypreparation for each treatment group were assigned a subjectnumber according to a coded (AB) block randomization table,prepared by an independent statistician. Investigators wereblinded to the randomization table, the code assignments and theprocedure. As subjects were enrolled, they were assigned aprogressive subject number.

Table 1The nutritional composition of LCPUFA n-3 oil. Ingredients:fish oil standardized in PCPUFA n-3 (75%), lemon flavour,antioxidants: vitamin E (tocopherol), ascorbyl palmitate,

acidifier: citric acid

Nutrition Fact Servine size 1 Taplespoon(100 g) Dose

Calories 900 kcal 37,53 kcal3700 kJ 154,3 kJ

Protein 0 g 0 gTotal carbohydrate 0 g 0 gTotal fat 100 g 4,17 gSaturated fat 3,1 g 0,13 gMonounsaturated fat 11,5 g 0,48 gPolyunsaturated fat 85,4 g 3,56 g

Total Omega-3 fatty acids 75 g 3,13 gEicosapentaenoic acid (EPA) 40 g 1,67.1 gDocosahexaenoic acid (DHA) 20 g 0,83 gOther Omega-3 15 g 0,63 g

Primary endpointThe effect of n-3 LCPUFA supplementation on depressed

mood, assessed through the mean change from baseline to week8 in the GDS total score was considered the main outcomemeasure.

Secondary endpointsThe secondary endpoints were the effect of n-3 LCPUFA

supplementation on: 1) health-related quality of life, evaluatedwith SF-36, 2) RBC membrane phospholipids fatty acid profile,3) body composition, 4) nutritional status and 5) haematologicalparameters.

Statistical analysisCovariance analysis was performed to obtain adjusted post-

treatment means and differences between treatment and placebogroups for GDS, SF-36 functions and a number of biologicaloutcomes. Adjustment was made for a priori selected variables,including age, self-sufficiency at baseline and arthritis, and forbaseline measurement of each outcome considered; covariateadjustment for arthritis was considered due to the frequent useof omega 3 FA in the treatment of this disease in Italy, in

association to other drugs.

Results

Twenty-one subjects out of 247 institutionalized elderlyfemales were excluded a priori because they were receivingantidepressant medications at the time of interview; the reasonfor including female patients only is based on the fact that thefemale to male ratio in our Institute of 530 beds is 5 to 1 andthis is similar to what found in all Italian nursing homes.Sixty out of the remaining 226 subjects fulfilled the

diagnostic criteria of Major Depression or Dysthymia accordingto DSM-IV-TR. All of them were institutionalized since morethan three months and were not receiving antidepressant drugsat the time of observation. Nine of these 60 depressed patientswere not eligible for the study due to: creatinine >2 mg/dl intwo cases, severe ischemic heart disease in one case,uncontrolled diabetes in three cases, hypertension not properlycontrolled by pharmacological treatment at the observation timein one case, and increased transaminases values as compared tobaseline in two cases. Finally, five eligible patients refused toparticipate to the study, so the final number of randomisedpatients was 46, as shown in Figure 1. All subjects were fullyinformed about other treatment options, but they were chosento participate.

Figure 1Flow diagram of a trial of supplementation with LCPUFA n-3versus placebo in the treatment of elderly patients affected bydepression. The diagram includes the number of patientsanalysed for the main outcome (effect on depressed mood)

Twenty-two patients were randomly included in theintervention group (n-3 group), and 24 in the placebo group(placebo group). Population characteristics were similar in bothgroups (Table 2).

Table 2Characteristics of studied subjects1

n-3 group Placebo(n=22) group

(n=24)

N subjects studied 22 24Age (y) 84.9±6.9 83.0±7.3Level of schooling (y) 12.7±2.9 12±3Marital status:

Married subjects 3 4Widower subjects 19 20

Mini Mental State Examination (MMSE) score 25.9±2.0 26.2±1.8Activity Daily Living (ADL) score 5.6±0.4 5.4±0.5Geriatric Depression Scale (GDS) score 17.1±3.6 16.7±4.3

1. Values are means (±Standard Deviation)

Table 3Differences (95% CI) between n-3 and placebo group post-treatment means, adjusted for baseline value, age, self-

sufficiency at baseline (covariance analysis)

Adjusted Difference Significancepost- (95% CI)treatmentmean,n-3 group

Primary endpoints:Geriatric Depression Scale score 12.7 -3.2 (-5.9, -0.6) 0.017SF-36 physical function score 49.7 15.9 (9.9, 21.9) <0.001SF-36 mental function score 66.6 18.3 (12.9, 23.7) <0.001AA/EPA ratio 41.8 -28.2 (-44.4, -11.9) 0.001C 20:4 (arachidonic acid) 17.5 -0.5 (-2.6, 1.6) 0.63C 20:5 (eicosapentaenoic acid) 0.52 0.20 (0.07, 0.33) 0.003C 22:6 (docosahenoic acid) 4.2 0.26 (-0.46, 0.99) 0.46Secondary endpointsMini Nutritional Assessment (MNA) score 20.0 -0.2 (-1.2, 0.9) 0.77Body Mass Index (BMI) (kg/m2) 24.2 -0.6 (-1.3, 0.1) 0.08Arm Muscle Area (AMA) (cm3) 28.5 0.8 (-0.8, 2.3) 0.33

Primary endpointsIn terms of the mail outcome measures, the mean GDS score

at the week 8 was significantly lowered only for the n-3 group,as shown in table 3. Differences between the treatment groupswere found for the mean change in the SF-36 physical andmental function, as shown in table 3. As regards the SF-36eight domains reflecting physical and mental health-relatedquality of life, table 4 shows the results of comparison of thefrequency distribution of subjects in the n-3 and placebogroups, according to their health status after intervention(worsened, stable, improved), using the chi-square test orFisher’s exact test. HRQoL scores before the treatment weresimilar in the two groups. At 2 month, differences between thetreatment groups were found for the mean change in the SF-36physical activity, bodily pain, social functioning, role emotional



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and mental health.

Table 4Frequency distribution of subjects in the n-3 and placebogroups according to their health status after intervention(worsened, stable, improved), using the chi-square test or

Fisher’s exact test

n-3 group (n=18) Placebo group Significance(n=21)

SF-36 Physical activityPre-treatment mean (std.dev.) 9.7 (16.8) 7.1 (11.6)Post-treatment mean (std.dev.) 15.0 (19.8) 5.2 (8.9)Worsened, no. (%) 0 3 (14.3)Stable, no. (%) 10 (55.6) 18 (85.7)Improved, no. (%) 8 (44.4) 0 <0.001SF-36 role-physicalPre-treatment mean (std.dev.) 61.1 (46.4) 40.5 (49.0)Post-treatment mean (std.dev.) 73.6 (33.7) 27.4 (41.0)Worsened, no. (%) 1 (5.6) 4 (19.0)Stable, no. (%) 11 (41.1) 16 (76.2)Improved, no. (%) 6 (33.3) 1 (4.8) 0.06SF-36 Bodily painPre-treatment mean (std.dev.) 65.6 (35.7) 60.1 (34.4)Post-treatment mean (std.dev.) 71.2 (30.6) 50.8 (25.3)Worsened, no. (%) 2 (11.1) 9 (42.9)Stable, no. (%) 8 (44.4) 10 (47.6)Improved, no. (%) 8 (44.4) 2 (9.5) 0.017SF-36 General healthPre-treatment mean (std.dev.) 43.8 (16.5) 39.3 (12.6)Post-treatment mean (std.dev.) 46.3 (12.8) 40.0 (11.0)Worsened, no. (%) 1 (5.6) 5 (23.8)Stable, no. (%) 13 (72.2) 11 (52.4)Improved, no. (%) 4 (22.2) 5 (23.8) 0.28SF-36 VitalityPre-treatment mean (std.dev.) 39.4 (13.8) 41.7 (7.1)Post-treatment mean (std.dev.) 43.9 (11.2) 42.6 (11.2)Worsened, no. (%) 3 (16.7) 8 (38.1)Stable, no. (%) 3 (16.7) 6 (28.6)Improved, no. (%) 12 (66.7) 7 (33.3) 0.15SF-36 Social functioningPre-treatment mean (std.dev.) 68.0 (35.4) 60.7 (31.7)Post-treatment mean (std.dev.) 76.4 (28.1) 50.8 (25.4)Worsened, no. (%) 0 11 (52.4)Stable, no. (%) 10 (55.6) 9 (42.9)Improved, no. (%) 8 (44.4) 1 (4.8) <0.001SF-36 Role-emotionalPre-treatment mean (std.dev.) 79.6 (38.2) 52.3 (47.8)Post-treatment mean (std.dev.) 94.4 (23.6) 39.7 (46.7)Worsened, no. (%) 0 6 (28.6)Stable, no. (%) 14 (77.8) 14 (66.7)Improved, no. (%) 4 (22.2) 1 (4.8) 0.018SF-36 Mental healthPre-treatment mean (std.dev.) 57.8 (13.7) 47.6 (12.9)Post-treatment mean (std.dev.) 63.3 (11.3) 44.9 (10.8)Worsened, no. (%) 3 (16.7) 11 (52.4)Stable, no. (%) 0 2 (9.5)Improved, no. (%) 15 (83.3) 8 (38.1) 0.01

a. Calculated according to the chi-square test or Fisher’s exact test

As regards the parameters of body composition andnutritional status, were found to be similar in the n-3 group andin the placebo group, both before onset and after 2 months. Intable 3 is reported the covariance analysis for MNA, BMI andAMA.As regards the mean changes in the studied biochemical

parameters, no significant difference these were found in the n-3group and in the placebo group, either before or after the

intervention treatment.

SafetyBoth the omega 3 and placebo supplementation were well

tolerated, and no serious adverse event was observed over the 8weeks of the study. The definition of serious side effects of fishoil supplementation was represented by increased risk ofbleeding (due to the antiaggregatory effect of fish oil on bloodplatelets) and by gastrointestinal symptoms, such as severenausea and diarrhoea (43).

Discussion

This double blind intervention study shows that thesupplementation with 2.5 g/day of n-3 LCPUFA for two monthsis associated with a significant reduction of the depressivesymptoms among elderly patients with major depression ordysthymia. The covariance analysis of the GDS score betweenn-3 and placebo group after treatment, adjusted for baselinevalue, age and self-sufficiency at baseline, shows a significantdifference between the two groups. The relation withsupplementation of a long chain omega 3 polyunsaturated fattyacids is confirmed by a significant decrease of the AA/EPA ratioin red blood cells membrane, which proves the compliance totreatment. Recent scientific evidence shows a correlationbetween the bioavailability of n-3 LCPUFA and prevention ortreatment of various neurological disorders such as depression,schizophrenia, dyslessia, dyspraxia, autism and attentiondeficit/hyperactivity disorder of the child (ADHD) (44-46).Based on the tight correlations between n-3 LCPUFA andneurological disorders, in the present study were also evaluatedthe effects of n-3 LCPUFA supplementation on thephospholipids fatty acids profile of elderly patients with clinicalevidence of depression and its correlation with the clinicaloutcome. It has been supposed that the increase of depressivedisorders over the past century may be correlated to a largeincrease in the ratio of n-3 to n-6 LCPUFA consumed in themodern diet (47). The two LCPUFAS n-3, eicosapentaenoicacid (EPA) and docosahesaenoic acid (DHA) play an importantrole in the functioning of the central nervous systems, and mustbe obtained from dietary sources (48). Many studies havedemonstrated that patients suffering from depression or mooddisorders, have significantly lower levels of LCPUFA n-3 inplasma, adipose tissues and red blood cell (RBC) membrane(49). The association of dietary fats with diseases risk oroutcome could be determined from epidemiological studiesand/or from food frequency questionnaires; however the FAcomposition of the plasma lipids and the membranes ofplatelets and erythrocytes provides a better assessment of thedietary intake of the long-chain n-3 FAs (50-53). PUFA status inhuman can be assessed on several blood lipid classes.Erythrocyte phospholipids fatty acid status presents severaladvantages: (1) it is a reflexion spread over time of habitualdietary fat intake in relation to the biological half life oferythrocytes (54); (2) the level of EPA can be used as a specific



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marker for the intake of fish and fish oil (55); (3) phospholipidsare a model of fatty acid incorporation into a cellular membrane;(4) it gives an image of hepatic and extrahepatic fatty acidmetabolism; (5) erythrocyte phospholipids are in equilibriumwith structural phospholipids of tissues; (6) it has been correlatedreasonably well with the food- frequency questionnaire (ffq) forthe dietary intakes of polyunsaturated fatty acids (56). Howeverthe ffp is time consuming and tedious and can lack accuracy incomparison with the precision of erythrocyte fatty acidmeasurements. Our studies on the AA/EPA ratio determined onerythrocyte phospholipids as a biomarker of fatty acid intake orsupplementation, demonstrate its reliability. The positive effectof n-3 LCPUFA supplementation in depressed elderly patientsappears of relevant clinical importance because depression iscommon in late life (1). Depression is not a natural part of agingand is often reversible with prompt and appropriate treatment.However, if left untreated, depression may result in the onset ofphysical, cognitive and social impairment, as well as delayedrecovery from medical illness and surgery, increased health careutilization, and suicide (57-58). Mischoulon (59) reported thatthe results of recent studies of omega-3 fatty acidsupplementation, including the use of eicosapentaenoic acid(EPA), are promising in treatment of depression. In addition, theomega-3 fatty acids have been shown to be safe and might beuseful in specific populations, such as the elderly and people withmedical co-morbid conditions. A number of controlled trials anda few open studies have suggested that supplementation withdoses of EPA and docosahexaenoic acid (DHA) that are about

five times higher than the standard dietary intake in the USAmay have antidepressant or mood-stabilizing effects. Theresults obtained in the present study confirm variousepidemiological and intervention studies already published inthis field (10-14). An inverse correlation between n–3 PUFAintake and depressed mood has also been reported in variousclinical studies (60-61). Lower concentrations of n–3 PUFAhave been reported in plasma or in red blood cell membranes ofpatients with a DSM IV major depressive disorder diagnosis,compared with matched non-depressed control subjects (62,63). In addition to this, the positive effect of omega 3 fattyacids in the treatment of depression has been shown in a recentmeta-analysis published by Lin (64). Unbalance PUFA status isobserved in numerous conditions and especially in diseaseschronic and/or degenerative accompanied by deficiency of theantioxidant system. Thus, the early diagnosis of suchimpairment is of crucial importance, since it is recognized thatthe dietary PUFA balance could help in the prevention and thecontrol of such diseases, like depression. Another relevantadvantage observed in this study is that the supplementationwith n-3 LCPUFA is associated with a significant ameliorationof quality of life. After two months of treatment, the group ofpatients who received the supplement showed a significantamelioration of the physical and mental function, asdemonstrated by the SF-36 score. This observation has neverbeen achieved before and it appears of great value from theclinical point of view, due to the importance of these aspects inthe elderly population. The concept of quality of life is defined



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Table 5Effect of LCPUFA n-3 supplementation on red blood cell membrane fatty acids profile compared to placebo at 2 months

n-3 group (n=22) Placebo group (n=24) TestsPre-treatment Post-treatment Pre-treatment Post-treatmentMean (Std.dev.) Mean (Std.dev.) Mean (Std.dev.) Mean (Std.dev.) 1 2 3 4

AA/EPA 70.8 (37.4) 41.9 (24.2) 82.1 (40.8) 69.3 (30.7) *** **C:16Palmitic acid 28.2 (3.8) 26.5 (4.0) 28.0 (3.6) 26.8 (3.0)C 16:1Palmitoleic acid 0.94 (0.53) 1.28 (0.74) 0.75 (0.63) 0.62 (0.37)C:18Stearic acid 18.6 (2.1) 16.7 (4.1) 18.7 (1.3) 18.7 (1.2)C 18:1Oleic acid 19.0 (2.6) 18.9 (1.8) 18.1 (2.2) 18.0 (2.1)C 18:2Linoleic acid 9.3 (1.1) 9.5 (1.3) 9.8 (1.4) 9.8 (1.6)C 18:3Linoleic acid 0.29 (0.30) 0.61 (0.43) 0.31 (0.34) 0.54 (0.77)C 20:4Arachidonic acid 16.5 (4.7) 17.5 (3.3) 16.6 (4.0) 17.5 (3.0)C 20:5Eicosapentaenoic acid 0.26 (0.14) 0.51 (0.21) 0.27 (0.15) 0.31 (0.16) *** **C 22:6Docosahexaenoic acid 3.22 (1.33) 4.06 (1.16) 3.68 (1.29) 3.92 (0.96) *

1. Student’s paired t-test or Wilcoxon signed-rank test to compare post-treatment to baseline values within n-3 group; 2. Student’s paired t-test or Wilcoxon signed-rank test to compare post-treatment to baseline values within placebo group; 3. Unpaired t-test or Wilcoxon rank sum test to compare baseline values between n-3and placebo group; 4. Unpaired t-test or Wilcoxon rank sum test to compare changes from baseline values between n-3 and placebo group; * p<0.05; ** p<0.01;*** p<0.001

as a perceived global satisfaction and satisfaction within anumber of key domains, with special emphasis on well-being(30). Therefore, the amelioration of quality of life in depressedelderly patients after supplementation with n-3 LCPUFA is animportant finding.Moreover, the intervention with n-3 LCPUFA appears to be

safe. No relevant side effects were observed in the interventiongroup, not even adverse gastrointestinal effects, as reported inprevious studies (65). On the contrary, the antidepressant drugsusually prescribed in these patients are frequently associatedwith unwanted symptoms and complications.In addition to these observations, a wealth of evidence

indicates that consumption of fish or dietary fish oilscontaining long chain omega 3 polyunsaturated fatty acids,such as eicosapentaenoic acid (EPA) and docosahexaenoicacid (DHA), is associated with cardiovascular benefit,including a reduction in circulating triglycerides and reducedmortality from coronary heart disease (66). These datarepresent an additional advantage of the use of n-3 LCPUFA inelderly depressed female patients.In conclusion, the supplementation of n-3 LCPUFA in

elderly female patients reduces the occurrence of depressivesymptoms, improves phospholipids fatty acids profile andhealth-related quality of life.

This study was supported by a research grant from Regione Lombardia.

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