Lower serum high-density lipoprotein cholesterol (HDLC) in major depression and in depressed men...

Acta Psychhtr Scand 1997: 95: 212-221 Printed in OK - all rights reserved

Copyright 0 Munksgaard 1997 ACTA PSYCHIATRICA

SCANDINAVICA ISSN 0001 -690X

Lower serum high-density lipoprotein cholesterol (HDL-C) in major depression and in depressed men with serious suicidal &temots: relationshir, with immune-inflammatorv markirs

Maes M, Smith R, Christophe A, Vandoolaeghe E, Van Gastel V, Neels H, Demedts P, Wauters A, Meltzer HY. Lower serum high-density lipoprotein cholesterol (HDL-C) in major depression and in depressed men with serious suicidal attempts: relationship with immune-inflammatory markers. Acta Psychiatr Scand 1997: 95: 212-221. 0 Munksgaard 1997.

Recently, there have been some reports that changes in serum lipid composition may be related to suicide, major depression and immune- inflammatory responses. Findings from our laboratory suggest that major depression is accompanied by reduced formation of cholesteryl esters and perhaps by impairment of reverse cholesterol transport. The latter is reportedly accompanied by lower serum high-density lipoprotein cholesterol (HDL-C). The aim of this study was to examine whether (i) major depression is accompanied by lower serum HDL-C or by abnormal levels of serum total cholesterol, triglycerides, low-density lipoprotein-C (LDL-C) or vitamin E, (ii) suicidal attempts are related to lower serum HDL-C and (iii) there are significant associations between serum HDL-C and immune/inflammatory markers. A total of 36 subjects with major depression, of whom 28 patients showed treatment resistance, as well as 28 normal control subjects, had blood sampled for the assay of the above lipids, serum zinc (Zn), albumin (Alb) and flow cytometric determination of the T-helper/T-suppressor (CD4+/ CD8+) T-cell ratio. In total, 28 depressed subjects had repeated measures of these variables both before and after treatment with antidepressants. Serum HDL-C and total cholesterol, as well as the HDL-C/cholesterol ratio, were significantly lower in subjects with major depression than in normal controls. Serum HDL-C levels were significantly lower in depressed men who had at some time made serious suicidal attempts than in those without such suicidal behaviour. Treatment with antidepressants for 5 weeks did not significantly alter either serum HDL-C or other lipid variables. Serum HDL- C levels were significantly and negatively correlated with the (CD4+/CD8+) T-cell ratio, and positively correlated with serum Alb and Zn. These results suggest that (i) lower serum HDL-C levels are a marker for major depression and suicidal behaviour in depressed men, (ii) lower serum HDL-C levels are probably induced by the immunehflammatory response in depression and (iii) there is impairment of reverse cholesterol transport from the body tissues to the liver.

M. Maes12, R. Smith3, A. Christophe4, E. Vandoolaeghe', A. Van Gastel', H. Neels5, P. Demedts5, A. Wauters', H. Y. MeltzerZ 'University Department of Psychiatry, AZ Stuivenberg, Antwerp. Belgium, 'Department of Psychiatry. Vanderbilt University, Nashville, TN, USA, 3Sierra Pacific Seminars, Morgan Hill, CA, USA, 'Department of Endocrinology and Metabolic Disease, University Hospital of Ghent. Ghent and 'Laboratory of Clinical Chemistry. Antwerp, Belgium

Key words: depression; suicide; lipids; cholesterol; immunology

Michael Maes, Clinical Research Center for Mental Health, University Department of Psychiatry, AZ Stuivenberg, 267 Lange Beeldekensstraat, 2060 Antwerp, Belgium

Accepted for publication June 29, 1996

Introduction

There is now some evidence that alterations in lipid metabolism may be related to major depression (1-5). Morgan et al. found that depression is

three times more common in elderly (aged >70 years) subjects with lowered serum cholesterol levels (6). Other authors have observed lower serum

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Lower HDL-C in major depression

cholesterol levels in patients with affective disorders (7). Our laboratory found a lower esterified cholestero1:total cholesterol ratio in depressed subjects (4). However, other groups have been unable to detect a significant association between lower serum cholesterol levels and depression (8-10). Adams et al. observed a positive relationship between severity of depression and the ratio of arachidonic acid (AA) (C20:406) to eicosapentanoic acid (EPA) (C20:503) in serum phospholipids and erythrocyte membranes of depressed subjects (11). Our laboratory has reported a significantly higher C20:4~6/C20:503 ratio in both serum cholesteryl esters and phopholipids, and an increased total 06:03 ratio in cholesteryl esters of patients with major depression compared to normal controls (5) .

Taken together, the above results suggest that there is an abnormal intake and/or metabolism of essential fatty acids and a decrease in the formation of cholesteryl esters in major depression (4, 5). The latter may be related to decreased activity of 1ecithin:cholesterol acyltransferase (LCAT) (EC 2.3.1.43) (4, 5), since most of the cholesteryl esters in humans are formed in serum under the activity of LCAT, which reacts preferentially with free cholesterol of the high-density lipoprotein (HDL) particles (12, 13). This esterification of free cholesterol to its ester form is important in reverse cholesterol transport, and consequently for the elimination of cholesterol from the body and the protection of membranes and cells from the dam- aging effects of large amounts of free cholesterol (14, 15). Lower serum HDL-C levels reportedly occur in LCAT insufficiency and are related to a reduction in reverse cholesterol transport (14, 15).

Primary prevention trials designed to lower serum cholesterol levels by diet, drugs or both have been shown to increase the number of deaths due to suicide (16-19). Golier et al. reported that men with low cholesterol levels were twice as likely to have made a medically serious suicide attempt at some time (19), and Sullivan et al. found a significant association between low cholesterol levels and increasing rates of suicidality (20).

Changes in serum lipids could have a role in the serotonergic (21) or catecholaminergic (22) pathophysiology of major depression or suicide. Engelberg (17) has postulated that alterations in the cholesterol/phospholipid ratio may modulate the microviscosity of membranes, and consequently influence biogenic amines or related functions, such as tryptophan hydroxylase activity, serotonin (5-HT) uptake, monoamine oxidase activity, 5-HT and 5-hydroxyindole acetic acid (5-HIAA) (the major metabolite of 5-HT) concentrations in the

brain, al-adrenergic receptors and brain catecholamine concentrations (4, 5 , 13, 17).

Specific changes in fatty acid composition in depression may be related to the immune and acute phase (AP) response, and to increased production of eicosanoids in that illness (23, 24). Important markers of the AP and immune response in major depression are lower levels of serum albumin (Alb), a negative AP protein, lower serum zinc (Zn), and an increased T-helper/T-suppressor (CD4+/CD8+) T-cell ratio (23,24). An increase in the production of pro-inflammatory cytokines, such as interleukin- 1 (IL-1) and interleukin-6 (IL-6), may underlie the above immune-inflammatory changes in major depression (23, 24). We have suggested that the increased C20:406/C20:503 ratio and the imbalance in 06/03 polyunsaturated fatty acids (PUFAs) in major depression may be related to increased production of pro-inflammatory cytokines and eicosanoids (3, 5). Indeed, C20:406 is the most abundant eicosanoid precursor in people consu- ming a Western diet (3), and C20:503 inhibits the formation of eicosanoids, such as prostaglandin E2 (25). An imbalance in the ratio of 0 6 to 0 3 PUFAs, as has been observed in major depression (3, may induce the production of pro-inflammatory cytokines (26). Moreover, an AP response is accompanied by lower serum cholesterol and higher serum triglyceride levels (27, 28), and by lowered activity of LCAT, which may induce a large decrease in cholesteryl esters in HDL particles without a significant decrease in total cholesterol levels (29).

It is interesting to note that there is an important comorbidity between major depression and coronary heart disease and myocardial infarction (2,3, 30). The increased C20:4061C20:03 ratio in both depression (5) and coronary heart disease (13, 31) is one factor which may underlie the comorbidity between the two diseases. Lowered serum HDL-C is another factor which may underlie the increased risk for coronary heart disease (32-35) and perhaps depression.

Only a limited amount of research has been undertaken on the effects of antidepressant treatments on lipid composition. Pollock et al. reported that nortriptyline treatment did not alter total cholesterol levels, although levels of triglycerides and very-low-density lipoprotein-C (VLDL-C) were significantly increased (36).

The aim of the present study was to examine (i) whether serum HDL-C levels are reduced in major depression or in patients who have at some time made serious suicide attempts, (ii) whether this decrease is related to the clinical response to antidepressant therapy, (iii) whether there are significant relationships between serum HDL-C

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Maes et al.

and established immune-inflammatory markers of major depression, e.g. increased (CD4+/CD8+) T- cell ratio, and lower serum Alb and Zn, and (iv) whether changes in HDL-C levels are accompanied by changes in other lipid variables, such as total cholesterol, LDL-C, triglycerides and a fat-soluble vitamin, namely vitamin E (37).

Material and methods

Subjects

A total of 64 subjects participated in this study, consisting of 28 control volunteers and 36 subjects with major depression. The study period extended from November 1994 to November 1995. All of the subjects were Caucasians. Patients were classified according to DSM-III-R criteria (38) for major depression on the basis of a semi-structured interview (39), and were admitted to the Treatment- Resistant Depression (TRD) ward of the University Department of Psychiatry, AZ Stuivenberg, Antwerp, Belgium. There were 22 subjects with major depression without melancholia and 14 subjects with melancholia. Severity of illness was measured using the Hamilton Depression Rating Scale (HDRS) (40). Staging of depression, based on previous treatment response, was made according to the criteria of Thase and Rush (41), i.e. O=no single adequate trial with antidepressants, 1 =no response to one adequate trial, 2=no response to two adequate trials with antidepressant agents from different classes, e.g. tricyclics or selective serotonin reuptake inhibitors (SSRIs), 3=stage 2 plus failure to respond to one augmentation therapy, 4=stage 3 plus failure to respond to two augmentation strategies, and 5=stage 4 plus no response to ECT. TRD was defined as a lack of response to at least two trials with different types of antidepressant agents (41). A history of previous suicide attempts was obtained by means of a semi-structured interview of patients and family members. Suicide attempts were classified as either half-hearted attempts (e.g. parasuicide with benzodiazepine overdose) or medically serious suicide attempts (i.e. violent suicidal acts, such as cutting, hanging, or serious overdoses resulting in admission to intensive-care units).

Normal controls were free of any medication for at least 1 month prior to blood sampling, and none of them had ever taken psychotropic drugs or consumed alcohol regularly. They were screened for past and present history and family history of psychiatric disorder by means of a semi-structured interview, and subjects with a positive history were excluded from the study. The following depressed patients were excluded: patients with other Axis-I

diagnoses, such as organic mental disorder; patients with a history of substance abuse (during the 6 months prior to the study); patients with schizo- phrenia or primary anxiety disorders. Patients who had been taking fluoxetine during the actual depressive episode were also excluded from the study. All subjects had normal blood tests, including serum electrolytes, urea, creatinine, liver function tests such as yGT, SGPT and SGOT, and thyroid function tests such as T4 and basal thyroid- secreting hormone. All subjects were free of medical illnesses such as endocrine disorders (e.g. Cushing’s disease) or metabolic or immune (e.g. autoimmune) disorders. They had also been free of any infections, inflammatory or allergic reactions for at least 2 weeks prior to the study, and were free of drugs known to affect immune or endocrine functions and lipid levels (e.g. cholesterol-lowering drugs), and hormonal preparations, including con- traceptive drugs. Subjects on a low-fat diet, or with essential hypertension or atherosclerosis were excluded. None of the subjects was taking vitamin supplements. In the present study, it was decided not to monitor the dietary intake of each subject during the study period (e.g. by self-reports or by calculation of the mean calorie or lipid intake). Indeed, any attempt to monitor dietary intake may induce changes in eating behaviour and consequently in normal calorie or lipid intake. Our patients and controls consumed a normal Belgian diet (i.e. a diet with a mean PS ratio of 0.54f0.43).

Methods

Blood was drawn from both normal controls and subjects with major depression at 07.45 hours (f15min) for the determination of serum lipids, vitamin E and immune-inflammatory markers of depression. Blood was drawn from patients 10 days after hospitalization. Antidepressant drugs were discontinued upon hospital admission, and patients subsequently underwent a wash-out period of 10 days A total of 28 depressed patients had blood samples taken for assay of serum lipids and vitamin E at baseline (i.e. 10 days after hospital admission) and after a 5-week treatment period. The HDRS score was completed on the same day that blood was sampled for assay of baseline and post-treatment levels of serum lipids and vitamin E. A good clinical response is defined as a decrease of at least 50% in the baseline HDRS score (41). Patients were treated with trazodone 100 mg daily (n=9), trazodone 100 mg daily+pindolol 7.5 mg daily (n=8), or trazodone 100 mg daily+fluoxetine 20 mg daily (n=ll) . Five weeks after treatment, fasting blood was sampled in these 28 depressed subjects at 07.45 hours (f15 min) for assay of serum

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lipids, vitamin E and immune-inflammatory markers.

Cholesterol and triglycerides were determined enzymatically using dry chemistry technology (Kodak Ectachem 700 XRC - Kodak, Vilvoorde, Belgium). Samples for HDGC analysis were initially precipitated by a phosphotungstic acidmagnesium ion solution and assayed for cholesterol using the CHOD-PAP method on a Hitachi 911 (Boehringer test packs for HDL-C and cholesterol). LDL-C levels were calculated using the formula proposed by Tietz (42). Vitamin E (a-tocopherol) was determined by means of HPLC (43). The analytical inter- and intra-assay coefficients of variation (CV) obtained in our laboratory were, respectively, as follows: cholesterol, 3.1 Yo and 0.56%; triglycerides, 1.26% and 0.69%; HDL-C, 4.77% and 3.40%; vitamin E, 5.49% and 2.73%. Serum Zn was determined by means of an atomic absorption spectro- metric method using the Perkin Elmer 2380. In our laboratory, the inter-assay CV is 8.5% (n=25). The level of Alb as a percentage of total serum protein (TSP) was assayed by means of the Beckman Paragon SPE agarose system (Analis, Namur, Belgium) with densitometric quantitation of the protein fraction. The inter-assay CV for Alb was 3.05%. TSP was determined using the Kodak Ektachem Analyzer (Kodak, Vilvoorde, Belgium). The inter-assay CV obtained in our laboratory was 2.16%. White blood cell and lymphocyte counts were determined by means of a Coulter STKS fully automated total blood cell counter. Three parameters of the sample were measured simultaneously in the flow cell, namely volume, radio-frequency conduc- tion and light scatter. The inter-assay CV values were 1.5% for leucocytes and 3.1% for lymphocytes. Flow cytometry of peripheral blood leucocytes was used to calculate the CD4+ and CD8+ subset populations by surface markers (Cytostat Coulter Clone). After incubation for 20min at 20°C with fluorescein-labelled monoclonal anti- body, red blood cells were lysed, leucocytes were fixed using the Q-Prep method (Coulter), and fluorescence was determined with EPICS Profile 2. The results were expressed as the percentage of positive lymphocytes bearing the surface markers, and the CD4+/CD8+ ratio was calculated.

Statistical analysis

The independence of classification systems was ascertained by means of analysis of contingence (Chi-square test). Normality of distribution was checked by means of the Kolmogorov-Smirnov test, and transformations were used to achieve normality of distribution or to adjust for heterogeneity of variance between study groups (i.e. triglycerides

in In transformation). Group mean differences were examined by analysis of variance (ANOVA), analysis of covariance (ANCOVA) or linear dis- criminant analysis (LDA). A priori comparisons between group means were checked by means of the Dunn test. Repeated-measures ANOVAs were used to investigate the serum lipid and vitamin E levels before and after antidepressant treatment. The relationships between variables were checked by means of Pearson’s product moment or Spearman’s rank order correlation coefficients, or by multiple regression analysis. The diagnostic performance of the variables for major depression was assessed by means of receiver operating characteristics (ROC) analysis with computation of the area under the ROC curve, sensitivity, specificity and predictive value of a positive test result (PV+), and with kappa statistics. The significance was set at a=0.05 (two-tailed).

Results

Demographic data

The median (q25-q75) HDRS score for the patients was 24.5 (q25=22.0; q75=27.0). The number of depressed patients categorized in the stages based on treatment resistance was as follows: 0, n=3; 1, n=5; 2, n=19; 3, n=7; 4, n = l ; 5 , n = l . Thus 28 subjects with major depression suffered from TRD as defined by a lack of response to at least two trials with antidepressant agents. The median number of previous depressive episodes in the patients was 2.0 (q25=1.0; q75=4.0), and the median duration of the actual depressive episode was 10 (q25 =5; q75 = 16) months. The median duration of the illness was 10 (q25=9; q75=18) years.

There were no significant differences in mean age (_+SD) between subjects with major depression (51.1f13.7 years) and normal controls (47.7f14.2 years) (F=0.9, df=1/62, NS), and there was no significant difference in the ma1e:premenopausal fema1e:postmenopausal female ratio between normal controls ( 5 : 6 : 17) and subjects with major depression (5 : 11 : 20) (x2=0.7, df=2, NS). In the total study group, there were no significant correlations between age and serum cholesterol (r=O.ll, NS), triglycerides (r=-0.13, NS), HDL-C (r=0.01, NS), LDL-C (r=O.14, NS), vitamin E (r=0.12, NS) and HDL-Ckholesterol ratio (r=-0.01, NS) (results of Pearson’s correlation analyses pooled over normal controls and depressed subjects). No significant associations between age and any of the above variables could be found in either normal controls or subjects with major depression. Table 1 shows the measurements of serum lipids and vitamin E in pre- and postmenopausal females and in male

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Maes et al.

Table 1. Serum cholesterol, triglycerides, HDL-C, LDL-C and vitamin E in men and pre- and postmenopausal women'

Category Cholesterol Triglycerides HDL-C LDL-C Vitamin E HDL-C/cholesterol x 100

Premenopausal women 190(39) 102(44) 58(18) 111(35) 0.80(0.24) 31 6(11.1) Postmenopausal women 212133) 1 OE(50) 52114) 138(30)** 0.90(0.26) 24.6(5.5)"** Men 215(42) 117(51) 43112)" 146(41)** 0.94(0.23) 21.0(7.0)**'

ANCOVAsb F-value 1.9 0.6 7.5 3.2 1 1 8.2 df 2/57 2/56 2/56 2/56 2/53 2/56 Pvalue NS NS < 0.01 < 0.05 NS <0.001

a All results are expressed as mean values (as mg dl-'), with SD in parentheses. All results of analyses of variance with diagnostic classification as second factor. Significantly different from pre- and postmenopausal women (t=3.56. P=O 001, Dunn test).

** Significantly different from premenopausal women ( t= 2.48, P=O.Ol, Dunn test). *** Significantly different from premenopausal women (t=3.79, P =0.0006. Dunn test).

subjects. Serum HDL-C levels were significantly lower in men than in women; serum LDL-C levels were significantly higher in postmenopausal females and in males than in premenopausal females. The HDL-Ckholesterol ratio was significantly lower in postmenopausal females and in males than in premenopausal females. In order to adjust for possible age, gender and menopausal effects, we have controlled subsequent statistical analyses for these variables by entering them as additional explanatory variables or covariates in multivariate analyses.

Serum cholesterol concentration was significantly and positively correlated with triglycerides (r=0.39, P<O.Ol) and LDL-C (r=0.93, P<O.Ol), but not with HDL-C (r=-0.16, NS). HDL-C was significantly and negatively correlated with triglycerides (r=-0.33, P < O . O l ) and LDL-C (r=-0.36, P<O.Ol). Serum vitamin E levels were significantly and positively correlated with serum cholesterol (r=0.46, P<O.Ool) and triglyceride levels (r=0.53, P<O.OOl) (all results of correlation analyses which were pooled over the normal control and major depression groups).

Serum HDL-C, other lipid variables and depression

Table 2 shows the measurements of serum cholesterol, triglycerides, HDL-C, LDL-C and vitamin E and the HDL-Ckholesterol ratio. Serum cholesterol, HDL-C and the HDL-C/cholesterol ratio were significantly lower in subjects with major depression than in normal controls. Using a cut-off value of HDL-C of <35 mg dl-', it was found that 38.2% of subjects with major depression had decreased serum HDL-C values with a specificity

area under the ROC curve=78.4%). It was also found that 22.7% of the variance in serum HDL- C could be explained by diagnostic classification.

of 100% (PV+=lOO%; ~=0.36 , t=3.18, P<O.Ol;

In the combined study group consisting of men and postmenopausal women, we found significantly lower serum HDL-C levels (F=27.4, df=1/48, P<O.OOl) and HDL-Ckholesterol ratio (F=7.3, df=1/48, P<O.Ol) in subjects with major depression than in normal control subjects (all results of ANCOVAs with age and gender as covariates).

Table 2 lists the levels of serum lipids and vitamin E in patients with major depression, categorized according to melancholic features and TRD. ANCOVAs revealed no significant differences in any of the serum lipids or vitamin E between these depressive subgroups. There were no significant correlations between staging of depression based on the severity of treatment resistance and serum total cholesterol (r=0.14, NS), triglycerides

(r=0.13, NS), vitamin E (r=0.03, NS) and the HDL-Ckholesterol ratio (r=-0.21, NS).

There were no significant correlations between the HDRS score and serum cholesterol (r= -0.22, NS), triglycerides (r=-0.09, NS), HDL-C (r=0.07, NS), LDL-C (r=-0.24, NS) and vitamin E (r=-0.02, NS), nor was there any significant association between any of the serum lipids or vitamin E and age at onset of depression, duration of illness, number of previous depressive episodes or duration of the actual depressive episode.

(r=0.19, NS), HDL-C (rz-0.21, NS), LDL-C

Effects of antidepressive treatments

Table 3 shows the measurements of serum lipids and vitamin E before and after treatment with trazodone 100 mg daily, trazodone 100 mg daily+pindolol 7.5 mg daily, or trazodone 100 mg daily+fluoxetine 20 mg daily over a 5-week period. Repeated-measures ANOVA with type of medication as factor revealed no significant effects of subchronic treatment on any of the lipid variables. The time x type of treatment interaction was not significant in any of these

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Table 2. Serum cholesterol, triglycerides, HDL-C, LDL-C and vitamin E in 28 normal controls (NC) and 36 subjects with major depression (MD), subdivided into those with lMD+M) and without (MD -MI melancholia, and those with (TRD) and without (non-TRD) treatment-resistant depression”

Categov Cholesterol Triglycerides HOL-C LDL-C Vitamin E HDL-C/cholesterol x 100

NC MD

M D - M M D + M

Non-TRD TRD

NC vs. MDb f-value df f-value

221136) 201141)

197(46) 207133)

205(43) 200(41)

4.3 1/58

<0.05

105(44) 118(w

1 17158) 119145)

120161) 117(51)

0.8 1/57 NS

55(14) 41(12)

421 1 3) 41(9)

43(15) 41(11)

20 8 1/57

t0.001

142(34) 13343)

132(49) 141(32)

138140) 134145)

0 6 1/57 NS

0.84(0.21) 0.9q0.26)

0 9310.26) I .00(0.26)

l.OO(O.29) 0.94(0.25)

2.9 1/54 NS

25.617.2) 22.0(8.9)

23.0(10.2) 20.316 0)

22.3(10.1) 21.2(8.4)

4.5 1/57

4 0 5

a All results are expressed as mean values (as mg dl-’1, with SD in parentheses. ’ All results of analyses of covariance with age, gender and pre- vs postmenopausal status as covariates.

Table 3. Serum cholesterol. triglycerides. HDL-C. LDL-C and vitamin E in 24 normal controls (NC) and in subjects with major depression (MD). both before and after treatment with antidepressants (TRY

Category Cholesterol Triglycerides HDL-C LDL-C Vitamin E HDL-C/cholesterol x 100

NC MD before TR MD after TR

Before vs. after TRb f-va I u e df f-value

221136) 105(44) 551 1 4) 142134) 0.84(0.21) 25.6172) 194(33) 11 5(57) 42(10) 12333) 0.94(0.28) 23.2(8.8) 193(44) 124(70) 41(7) 124137) 0.9410.25) 22.616.1)

0.0 2.0 0.0 0.1 0.4 1/21 1/21 1/19 1/19 1/17 NS NS NS NS NS

0.0 1/19 NS

ND vs. after TR“ f-value 6.1 0.6 32.1 2.3 1.9 6.2 df 1/47 1/46 1/46 1/46 1/40 1/46 P-value <0.05 NS <0.001 NS NS <0.01

a All results are expressed as mean values (as mg dl-’), wi th SD in parentheses. All results of repeated-measures analyses of variance with type of antidepressant as factor All results of analyses of covariance with age, gender and pre- vs. postmenopausal status as covariates.

repeated-measures ANOVAs. There were highly significant and positive correlations between the pre- and post-treatment serum levels of cholesterol (r=0.61, P<O.Ol), triglycerides (r=0.84, P<O.OOl) and LDL-C (r=0.64, P<0.001), but not of HDL-C (r=0.38, NS) or vitamin E (r=0.36, NS). Table 3 shows that the post-treatment serum cholesterol and HDL-C levels and the HDL-Ckholesterol ratio were significantly lower in subjects with major depression than in normal controls (all results of ANCOVAs with age, gender and menopausal state as covariates). In patients for whom lipids and vitamin E were assayed before and after treatment, repeated-measures ANOVA showed that the post-treatment HDRS score (median=11.5; q25=6; q75 =20) was significantly lower than the baseline HDRS values (F=120, df=1/25, P<O.OOl). There were no significant correlations between the

changes in HDRS score during treatment (i.e. the difference between pre- and post-treatment values) and the values of Acholesterol (r=-0.09, NS), Atriglyceride (r=0.10, NS), AHDL-C (r=0.21, NS), ALDL-C (r=-0.18, NS) or Avitamin E (r=-0.33, NS). No significant differences in pre- or post- treatment serum lipid or vitamin E levels could be found between subjects who responded to treatment and non-responders.

Other relevant relationships

Spearman correlation analyses revealed no sigmfi- cant associations between the HDRS items ‘anorexia’ or ‘weight loss’ and any of the lipid variables. There were no significant correlations between the HDRS item ‘suicide’ and either serum HDL-C (r=0.07, NS) or total cholesterol (r=0.12, NS),

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triglycerides (r=0.18, NS), LDL-C (r=0.10, NS) and vitamin E (r=0.22, NS). Among the male patients, 8 subjects had at some time made serious suicide attempts (12 subjects had no history of suicidal behaviour). One woman had made a serious suicide attempt, seven women had made half-hearted attempts, and eight had no history of suicidal behaviour. Mean HDL-C (f SD) levels were significantly lower (F=4.9, df= 1/17, P<0.05) (32.8f7.3 mg dl-l) in men with major depression who had at some time made a serious suicidal attempt than in those who had no history of suicide attempts (40.7k8.1 mg dl-l) (results of ANCOVA with age as covariate). Among women, no significant differences in HDL-C levels were found between subjects with and without a history of suicide attempts (F=0.1, df=1/11, NS) (results of ANCOVA with age as covariate). ANCOVAs revealed no significant differences in serum cholesterol, LDL-C, triglycerides, vitamin E or the HDL- C/cholesterol ratio between subjects who had attempted suicide and those who had not.

There were no significant differences in the ratio of non-smokers to moderate smokers (<15 cigarettes daily) to heavy smokers (>15 cigarettes daily) between normal controls (19/6/3) and subjects with major depression (24/9/3) (x2=0.2, df=2, NS). Furthermore, there were no significant differences between non-smokers, moderate smokers and heavy smokers in serum HDL-C (F=2.3, df=2/ 53, NS), total cholesterol (F=0.3, df=2/54, NS), triglycerides (F=0.6, df=2/53, NS), LDL-C (F=O.l, df=2/53, NS), vitamin E (F=0.1, df=2/50, NS) or the HDL-C/cholesterol ratio (F=2.1, df=2/53, NS) (all results of ANCOVAs with age, gender and menopausal state as covariates and diagnostic classification as second factor). The differences in serum cholesterol and HDL-C levels and HDL-C/cholesterol ratio remained significant after adjusting for smoking behaviour (entered as two dummy variables in ANCOVAS).

ANCOVA with age, gender and menopausal state as covariates showed that the mean (CD4+/ CD8+) T-cell ratio (kSD) was significantly (F=4.3, df=1/36, PcO.05) higher in subjects with major depression (2.55f1.18) than in normal controls (1.78f0.79). Figure 1 shows that there is a significant inverse correlation between the (CD4+/ CD8+) T-cell ratio and HDL-C levels (r=-0.47, P < O . O l ; semi-partial correlation after adjusting HDL-C for age, gender and menopausal state). ANCOVA showed that serum Alb was significantly lower (F=17.5, df=1/56, P<O.OOl) in subjects with major depression (41.4k4.3 mg dl-l) than in normal controls (46.0k4.5 mg dl-*). The semi-partial correlation coefficient between serum Alb and HDL- C was significant (r=0.36, P<O.Ol; adjusted for age,

gender and menopausal state). Serum Zn levels were significantly (F=26.0, df= 1/35, P<O.OOl) lower in subjects with major depression (94f12 pg dl-') than in normal controls (115+12 pg dl-I). The semi- partial correlation coefficient between serum Zn and HDL-C was significant (r=0.35, P<0.05; adjusted for age, gender and menopausal state).

Discussion

This study revealed significantly lower serum HDL-C levels in subjects with major depression than in normal controls. Lower HDL-C levels were found to be a hallmark of major depression per se, and not of subgroups such as major depression with or without melancholia or TRD vs. non-TRD. These results extend the findings of Glueck et al. (7). We also found lower serum total cholesterol levels in subjects with major depression, although the differences were less significant. A significant association between lower serum total cholesterol levels and major depression has also been reported by Glueck et al. (7) and Morgan et al. (6). The finding in the present study that the HDL-C/ cholesterol ratio is significantly lower in subjects with major depression than in normal controls suggests that the most important change in serum lipid composition occurs in serum HDL-C rather than in serum total cholesterol.

In fact, the results of the present study support those of our previous report, which showed a significant decrease in esterified cholesterol, but not in total or free cholesterol levels in depression (4). Indeed, LCAT is responsible for the esterification of plasma free cholesterol, and it reacts preferentially with the free cholesterol of the HDL particles (13, 14). It is important to note that the esterification of free cholesterol on the HDL particles is important in the transport of cholesterol to the liver, where it is catabolized (13, 14). Thus our findings suggest that there is impairment of this reverse cholesterol transport from the body tissues to the liver.

The second major finding of this study is that serum HDL-C levels are significantly lowered in depressed men who have at some time made a medically serious suicide attempt. We were unable to find any significant association between suicidal behaviour or ideation and serum total cholesterol, LDL-C or triglyceride levels. These results are in conflict with previous reports of an inverse correlation between serum total cholesterol levels and suicidality (19, 20).

The third major finding of the present study is that subchronic treatment with antidepressants does not significantly alter serum HDL-C or total cholesterol levels, or the HDL-C/cholesterol ratio.

218


80 l A 70

60

50

40

30

A A A

I A A A A

A

A

20 ' -0.5 0 0.5 1 .o 1.5 2.0

In CD4+/CD8+ratio Fig. I. Regression of serum HDL-C (A) on the CD4+/CD8+ T-cell ratio (in In transformation); r=-0.47, P<0.02.

Moreover, there were no significant differences in baseline or post-treatment HDL-C levels or in the HDL-C/cholesterol ratio between patients who responded to treatment and non-responders. No significant effects of subchronic antidepressant treatment over a period of 5 weeks could be found on serum LDL-C, triglycerides or vitamin E. On the other hand, Pollock et al. found a significant effect of antidepressant treatment on triglycerides (36). These differences may be explained by the fact that the tricyclic antidepressant nortriptyline was used in the study by Pollack, whereas we used trazodone, either alone or in combination with pindolol or fluoxetine.

The findings of this and our previous studies (4, 5) have important consequences for understanding of the relationships between lipid metabolism and the monoamine and immunehflammatory pathophysiology of major depression. First, Engelberg has postulated that a reduction in serum cholesterol levels may lead to a decrease in membrane lipid viscosity, and hence to a reduction in 5-HT uptake from the blood and, consequently, decreased 5-HT levels in the brain (17). However, as has been argued by Elliott (44), the 5-HT site affected by lowering of cholesterol levels (45) is more likely to be a 5-HT1 receptor than the 5-HT uptake site. In fact, our findings of lower esterified cholesterol (4) and HDL-C levels could suggest that cells and membranes are endowed with larger amounts of free cholesterol. It has been shown that

the addition of cholesterol reduces 5-HT uptake (4), a phenomenon which is consistemt with the 5-HT hypothesis of major depression (21).

Secondly, the findings of our present study, as well as previous ones (4,5), are also in agreement with the expected changes in lipid metabolism during an immune or AP response, i.e. lowered serum HDL-C, esterified cholesterol and total cholesterol levels (27, 29). The hypothesis that lower serum HDL-C levels are related to the AP response in major depression is substantiated by our finding that serum HDL-C is significantly related to immune/inflammatory markers, such as the (CD4+/CD8+) T-cell ratio (negative correlation) and serum Zn and Alb (both positive correlations).

Lower serum HDL-C levels in major depression provide another explanation for the increased risk of major cardiac events in patients with major depression (30). As has been pointed out by Hibbeln and Salem (2), the robust positive correlation between depression and coronary heart disease is in contrast to the proposed association of low serum total cholesterol levels and increased incidence of depression or suicide. However, lower HDL-C levels constitute another risk factor for developing cardiovascular disease in both men and women (34,35). We found that up to 38.2% of the subjects with major depression had HDL-C values lower than 35 mg dl-', whereas none of the normal controls had such low values. A serum HDL-C

21 9

Maes et al.

concentration of less than 35 mg dl-' is regarded as a significant risk factor for increased likelihood of cardiovascular disease (34, 35).

In this study, we have either controlled or may disregard the putative effects of other variables that may affect serum HDL-C and cholesterol levels, e.g. age, gender, menopausal state, smoking, psychological stress, depression-related anorexia and weight loss (46). First, in the present study, no significant associations were detected between age and serum HDL-C or total cholesterol levels (or any of the other lipid variables). The review by Young reports an increase, decrease or no effects of age on serum HDL-C and total cholesterol levels (46). Secondly, we found lower HDL-C levels in men than in women. Young stated that various studies were unable to find gender-related differences in serum cholesterol levels, while some studies reported higher or lower values in women (46). In any case, our results were statistically controlled for putative effects of gender and menopausal state. Young also reported that most studies were unable to detect significant changes in serum HDL-C levels during the menstrual cycle (46). In our study, the decrease in HDL-C levels or in the HDL-Ckholesterol ratio was also observed when the study groups of men and postmenopausal women were combined. Thirdly, the present study was unable to detect any effects of smoking behaviour on serum HDL-C levels or any of the other lipid variables. The review by Young shows no consistent effects of smoking on HDL-C or total cholesterol levels (46). Fourthly, our finding of lower serum HDL-C levels is probably not the result of psychological stress. Indeed, it has been reported that psychological stress may increase, rather than decrease, serum HDL-C and total cholesterol levels in humans (46). Finally, we were unable to detect significant correlations between serum HDL-C levels and anorexia or weight loss. Young stated that the effects of fasting and weight loss on serum HDL-C and total cholesterol levels are not very consistent (46). The results of our previous study on fatty acid composition in subjects with depression (5) did not in any way indicate the specific changes in serum cholesteryl esters and phospholipids that could have been induced by weight loss (47).

Acknowledgements

The research described in this paper was supported in part by the National Funds for Scientific Research, Belgium (NFWO), the Clinical Research Center for Mental Health (CRC-MH), Antwerp, Belgium, and Continental-Pharma Searle and Eli-Lilly, Belgium. We also acknowledge the receipt of the Staglin Investigator Award by M.M., grants USPHS MH 41684 and GCRC MOlRR00080, and grants from the Elisabeth

Severance Prentiss and John Pascal Sawyer Foundations. H.Y.M. is the recipient of a USPHS Research Career Scientist Award (MH 47808). The secretarial assistance of Mrs M. Maes is gratefully acknowledged.

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