CONCLUSIONS: Two dietary interventions that successfully lowered serum cholesterol levels had no adverse effect on mood. There was some evidence for a relative impairment in cognitive function in the treated groups in one of four cognitive tests, but additional studies will be required to determine the relevance of this finding.

RESULTS: Total serum cholesterol levels fell significantly more in the intervention groups (8.2% reduction) than in the control group (P <0.001). All three groups showed a modest improvement in psychological well-being during the 12-week treatment period, but there were no differences among the groups. There were no between-group differences on three measures of cognitive function, but for a fourth measure, which involved the task with the greatest processing load, the two intervention groups did significantly worse (P <0.001) than the control group. The change in performance was correlated with the change in total serum cholesterol level (r = 0.21, P = 0.01).

Cholesterol lowering is central to the prevention of coronary heart disease (). There has, however, been concern that cholesterol lowering could have adverse effects on aspects of psychological functioning, particularly by increasing depression or aggression (). A meta-analysis suggested that the reduction in coronary deaths following cholesterol-lowering treatments in low-risk patients might be counterbalanced by an increase in deaths from external causes, especially suicide and other violent deaths ().

Most of the studies of the association between low cholesterol levels and psychological function have been observational, limiting inferences about causation (). One study showed higher levels of depression in older men with low cholesterol levels (), and there have been sporadic reports of hypocholesterolemia among depressed and suicidal patients (). However, many community studies have either failed to detect any association between low cholesterol levels and depression () or have found that adjusting for physical functioning diminished the effect (). The situation is similar for studies of aggression and hostility: hypocholesterolemia appears to be overrepresented in violent () and antisocial () patients, but neither hostility nor aggressiveness are associated with low cholesterol levels in the general population (). Studies of the effects of cholesterol-lowering drugs on mood have generally had negative results (). However, two experiments in monkeys found that animals placed on cholesterol-lowering diets exhibited significantly more aggression and had less affiliative behavior than did controls (). Two human studies that assessed the association between cholesterol levels and cognitive function found some evidence that high serum cholesterol levels are associated with better cognitive function (), but no studies of cholesterol lowering in humans have been reported.

To ensure that reducing serum cholesterol to the recommended levels does not lead to unwanted outcomes, there is a need to identify any adverse psychological effects of cholesterol-lowering interventions. This is especially true for dietary interventions, because pharmacological treatments are usually restricted to patients at greatest cardiovascular risk, in whom benefits are likely to outweigh risks, whereas low-fat diets are recommended for patients with moderately raised serum cholesterol levels, and even for the general population. The present study was designed to evaluate the effects of cholesterol-lowering dietary treatments on mood and cognitive functioning in adults with raised serum cholesterol levels.

Statistical analysis was carried out with SPSS, release 6.1. Repeated measures analysis of variance was used to evaluate changes in the primary outcome variables (lipid levels, mood, and cognitive function). Correlational analyses were used to establish associations between changes in fat intake and serum cholesterol levels, and between cholesterol reduction and changes in mood. With sample sizes of about 50 per group, the trial had 80% power to detect a 0.5 standard deviation increase in depression (Beck Depression Inventory) score (one-sided, alpha = 0.05). A one-sided test was used because the study was designed to detect adverse effects of treatment. Two-sided P values are reported in the results.

Cognitive function was assessed with a battery of computer-based tests that included assessment of verbal immediate free recall, tapping speed (two-finger tapping), choice reaction time (a modification of the Erikson and Erikson task), and a sustained-attention task (adapted from the Bakan vigilance paradigm) in which subjects watched single-digit numbers displayed briefly with no interstimulus intervals and had to respond if they saw sequences of three odd or even numbers. Cognitive testing was carried out at baseline, 6 weeks, and 12 weeks.

Depression was measured with the Beck Depression Inventory () and the depression subscale of the Profile of Mood States (); higher scores indicate greater depression. Personal history of depression was assessed by interview. Anger was assessed with the State-Trait Anger inventory () and the anger subscale of the Profile of Mood States, with higher scores indicating greater anger. General psychological well-being was assessed with the 28-item version of the General Health Questionnaire () and stress levels with the Perceived Stress Scale (). For both of these scales, a higher score denoted poorer well-being. In addition to the patient’s own ratings, where possible, a partner or a close friend completed the Profile of Mood States about his or her perception of the patient’s mood.

Assessments were carried out at baseline, 6 weeks, and 12 weeks, and included measures of physical health status (fasting serum lipid levels, weight, waist-hip ratio, and blood pressure), social functioning, mood, and cognitive function. Weight was measured on a beam balance. Waist and hip girth were measured using standard procedures (). Lipid levels were measured in fasting venous samples.

The dietary treatments were delivered in eight sessions during a 12-week period using a combination of individual and group sessions with a dietitian and a psychologist. This format provided education about the recommended dietary changes and a cognitive-behavioral intervention that was concerned with implementing changes in eating behavior. The recommendations for participants in the low-fat diet group were to shift away from foods containing saturated fats, with a target to reduce energy from fats to <20%, largely polyunsaturates. The recommendations for the Mediterranean diet were for an increase in fruit and vegetables, an increase in oily fish, and a reduction in fat to 30% of energy, with substitution of predominantly monounsaturated fats for saturated fats. All participants received individualized advice on implementing the dietary changes based on their lifestyle and food preferences, and group support in maintaining changes. They were also given free-spreading fats and oils that were high in polyunsaturated fat (low-fat diet) or monounsaturated fat (Mediterranean diet) to encourage compliance. (Fats and oils were donated by Van den Berghs, Crawley, United Kingdom.) Waiting-list control patients were told that it was necessary to wait for treatment but that they would be seen at 6-week intervals. They were not given specific dietary advice, but were not discouraged from making dietary changes; some patients elected to do so.

At the end of the first assessment session, subjects were randomly assigned to one of two lipid-lowering dietary treatments—a low-fat diet (n = 59) or a Mediterranean diet (n = 61)—or to a waiting-list control condition (n = 56). Random allocation was by sealed opaque envelopes that were produced by members of the research team who were not in contact with the subjects. Nutritional, medical, and psychological assessments were completed before treatment, after 6 weeks (midtreatment), and at 12 weeks (posttreatment). Subjects assigned to the control condition were offered treatment at the end of their waiting-list period. For each participant, assessments were completed by a member of the research team who was not involved in their treatment and was, in most cases, blind to the treatment condition.

Adults with mildly or moderately raised serum cholesterol levels were referred by hospital dietetic clinics, hospital physicians, and general practitioners in London and Southeast England. Participants were required to have a serum cholesterol level >5.2 mM (198 mg/dL); no serious illness (except cardiovascular disease, for which cholesterol lowering was indicated); no current or previous (within 3 months) use of lipid-lowering medication; and physician’s permission to participate. In addition, they could not be pregnant, lactating, or planning to become pregnant, and they were required to provide informed consent. If the patient’s serum cholesterol level was >7.8 mM (296 mg/dL), the physician was asked if he or she wished to withdraw the patient from the trial to begin pharmacological treatment. Participants were asked to complete and return a 7-day dietary diary before the first assessment. We sent brief details of the diets and the expected time commitments, as well as a dietary diary, to 260 people meeting the inclusion criteria. Diaries were returned and the first assessment session was attended by 176 subjects.

There were no significant differences among the groups in the motor speed, memory, or choice reaction time at either 6 or 12 weeks. However, results on the sustained-attention task (the Bakan task) did differ (P <0.001, Figure 2 ). Posthoc tests indicated that although the waiting-list group improved their hit rate (number of correct responses) during the study, which was the expected pattern, there was no improvement in either of the diet groups. The change in the average hit rate from before to after the intervention was significantly correlated with the change in total cholesterol level (r = 0.21, P = 0.01), indicating greater declines in performance for those with greater reductions in cholesterol level. Adjusting for weight loss, either in a repeated measures analysis or in a multivariate linear regression model, had little effect.

All three groups had stable or improved psychological well-being during the study, with no significant differences among the three groups ( Table 4 ). Depression (Beck Depression Inventory and Profile of Mood States), anxiety (Profile of Mood States), and perceived stress all declined significantly. Partner-completed Profile of Mood States were available for 111 participants at follow-up. The profile of change was similar for the partner assessments, although the decrease was less. State anger, anger expression, and the total General Health Questionnaire scores were stable, with no between-group differences. The vigor, confusion, and fatigue scales of the Profile of Mood States also showed no between-group differences. The correlations between the reduction in serum cholesterol levels and change in depression scores were not statistically significant. There was no evidence that the effects of the interventions on change in Beck Depression Inventory scores differed among the 18 participants who had a personal or family history of depression as compared with the remaining subjects.

Total energy intake was reduced significantly during treatment in all groups ( Table 3 ). Total fat intake was significantly reduced in both treatment groups, and more so than in the control group (P <0.001). In the entire sample, the reduction in saturated fat intake was associated with the reduction in total serum cholesterol (r = 0.24, P <0.01), and low-density lipoprotein cholesterol (r = 0.20, P <0.05) levels.

At 6 weeks, both the low-fat and the Mediterranean diet groups had significant reductions in mean total cholesterol levels (low-fat: 5.1% reduction; Mediterranean: 10% reduction; average 8.2% reduction [P <0.001 compared with control]) and in low-density lipoprotein cholesterol levels (average 8.3% reduction as compared with baseline, P <0.05 [ Table 2 ]). These reductions were maintained at 12 weeks. The control group did not change at 6 weeks, but showed a 3.3% reduction in mean total cholesterol level at 12 weeks. Repeated measures analysis of variance confirmed that the differences between each diet group and the control group were statistically significant. Participants in the two intervention groups lost similar and substantial amounts of weight during the 12-week period, whereas the control group did not have a significant weight loss.

There were significant differences (P <0.005) in the changes from baseline between each of the intervention groups (low-fat diet and Mediterranean diet) and control.

† There were significant differences (P <0.005) in the changes from baseline between each of the intervention groups (low-fat diet and Mediterranean diet) and control.

There were significant differences (P <0.005) in the changes from baseline between each of the intervention groups (low-fat diet and Mediterranean diet) and control.

† There were significant differences (P <0.005) in the changes from baseline between each of the intervention groups (low-fat diet and Mediterranean diet) and control.

There were significant differences (P <0.005) in the changes from baseline between each of the intervention groups (low-fat diet and Mediterranean diet) and control.

† There were significant differences (P <0.005) in the changes from baseline between each of the intervention groups (low-fat diet and Mediterranean diet) and control.

There were significant differences (P <0.005) in the changes from baseline between each of the intervention groups (low-fat diet and Mediterranean diet) and control.

† There were significant differences (P <0.005) in the changes from baseline between each of the intervention groups (low-fat diet and Mediterranean diet) and control.

There were significant differences (P <0.005) in the changes from baseline between each of the intervention groups (low-fat diet and Mediterranean diet) and control.

† There were significant differences (P <0.005) in the changes from baseline between each of the intervention groups (low-fat diet and Mediterranean diet) and control.

There were significant differences (P <0.005) in the changes from baseline between each of the intervention groups (low-fat diet and Mediterranean diet) and control.

† There were significant differences (P <0.005) in the changes from baseline between each of the intervention groups (low-fat diet and Mediterranean diet) and control.

Similar numbers of patients withdrew before the end of treatment in each treatment group (7 from the low-fat diet, 8 from the Mediterranean diet, and 6 from the control group), largely because of difficulty in attendance. No patients reported specific adverse effects of treatment. At baseline, the noncompleters had lower mean (±SD) total cholesterol levels (6.2 ± 1.1 mM versus 7.1 ± 1.1 mM, P <0.001), and higher scores on the General Health Questionnaire (20.8 ± 8.0 versus 17.0 ± 7.4, P <0.05), but were otherwise similar to the participants who completed the study. Subsequent analyses include only those who completed the study.

Of the 176 participants who began treatment, 155 completed the posttreatment assessment and had attended at least four treatment sessions ( Figure 1 ). Participants were generally middle-aged and somewhat overweight ( Table 1 ). Nutrient analyses from the 7-day diaries showed that reported energy intakes were reasonable for adults of this age, as were levels of depression, anxiety, and aggression. There were no significant differences among the three treatment groups in any of the baseline characteristics.

Discussion

The participants in this study were adults with at least mild hypercholesterolemia by UK criteria. As volunteers who agreed to participate in a relatively demanding study, participants were probably more highly motivated than the population at large, but that is true in most clinical trials. Many of the participants were already following a low-fat diet, and the recorded fat intake at baseline (32% of energy) was lower than the UK average of 39%. The dropout rate was low, partly because extensive information was given at recruitment to ensure that participants knew what to expect and because of intensive efforts to sustain participation during the program. The reasons for withdrawing from the trial were often practical (eg, moving or taking a new job) or related to difficulty in finding time to attend treatment sessions. Nevertheless, the noncompleters had lower serum cholesterol levels (and therefore may have viewed their risk as lower) and higher General Health Questionnaire scores, reflecting poorer psychological well-being, at the start of the trial.

30 Schaefer E.J

Lamon-Fava S

Ausman L.M

et al. Individual variability in lipoprotein cholesterol response to National Cholesterol Education Program Step 2 diets. 31 Howell W.H

McNamara D.J

Tosca M.A

et al. Plasma lipid and lipoprotein responses to dietary fat and cholesterol a meta-analysis. 32 Tang J.L

Armitage J.M

Lancaster T

et al. Systematic review of dietary intervention trials to lower blood total cholesterol in free-living subjects. Both dietary interventions in this study were successful in changing lipid levels, with an average 8.2% reduction in the total serum cholesterol level and an 8.3% reduction in the low-density lipoprotein cholesterol level. This reduction is smaller than has been achieved using the US National Cholesterol Education Program Step II Diet in which all diet foods are supplied to the participants (), but somewhat larger than the 5.6% to 7.7% reductions that were estimated in meta-analyses of studies of Step II cholesterol-lowering diets ().

17 Downs J.R

Oster G

Santanello N.C Air Force Coronary Atherosclerosis Prevention Study Research Group

HMG CoA reductase inhibitors, and quality of life. 18 Lines C Hazards of reducing cholesterol. 19 Wardle J

Armitage J

Collins R

et al. Randomised placebo controlled trial of effect on mood of lowering cholesterol concentration. 33 Santanello N.C

Barber B.L

Applegate W.B

et al. Effect of pharmacologic lipid lowering on health-related quality of life in older persons results from cholesterol reduction in seniors program (CRISP) pilot study. As the cholesterol reduction was similar to that expected as a result of clinical interventions, we were able to test whether mood or cognitive function was adversely affected by compliance with cholesterol-lowering dietary advice. Reassuringly, there was no evidence that cholesterol lowering had any adverse effects on mood or well-being, whether rated by the patients or their partners, nor did we find that patients with a history of depressive illness were especially vulnerable. Indeed, most participants were in better emotional shape after the program than before, probably because of the attention and support. The absence of any effect on mood or well-being is consistent with the results of drug treatment studies, which have also failed to detect emotional impairments in treated patients, despite substantially larger decreases in cholesterol levels (). Although psychological treatments cannot blind patients to treatment allocation, it seems unlikely that the absence of blinding would explain the lack of between-group differences.

22 Benton D Do low cholesterol levels slow mental processing?. 23 Muldoon M.F

Ryan C.M

Matthews K.A

Manuck S.B Serum cholesterol and intellectual performance. 33 Santanello N.C

Barber B.L

Applegate W.B

et al. Effect of pharmacologic lipid lowering on health-related quality of life in older persons results from cholesterol reduction in seniors program (CRISP) pilot study. 34 Genko F

Cwudzinski D

Kinkel P

et al. Effects of treatment with Lovastatin and Pravastatin on daytime cognitive performance. 35 Rogers P.J

Green M.W Dieting, dietary restraint and cognitive performance. 36 Wing R.R

Vazquez J.A

Ryan C.M Cognitive effects of ketogenic weight-reducing diets. There was some evidence of an adverse effect on cognitive function, although this was seen for only one of four tasks. Both intervention groups showed impairment compared with controls on the task with the greatest processing load, and impairment was greatest among those who had the largest decrease in cholesterol level, consistent with the possibility that the cholesterol reduction may have contributed to the effect. Two recent studies have also reported associations between serum cholesterol level and intellectual performance, although both were cross-sectional and therefore examined serum cholesterol levels rather than cholesterol reduction (). In contrast, several studies of cholesterol-lowering drugs have failed to show effects on the WAIS Digit symbol test () or on most tests of cognitive function among a small sample of participants in a crossover trial of various statins (). One possible explanation for the difference that we observed from results of the drug studies is the time scale. In most drug studies, assessments were carried out after only 4 weeks of medication, whereas in the present study, the effect did not emerge until the 12-week assessment. Alternatively, any intellectual impairment may be related not to the reduction in serum cholesterol levels, but to energy deprivation or weight loss, a side effect of diet interventions (). Adjusting for weight loss in the present study, however, did not diminish the effect.

The general conclusions from this study are broadly reassuring and in line with research on pharmaceutical interventions. Patients can be reassured that neither cholesterol-lowering diets nor cholesterol-lowering drugs have an adverse effect on mood. The finding of a single adverse effect on cognitive function may be due to chance, and should be evaluated again in future studies. If the effect proves to be robust, its explanation will need to be determined. We did not measure participants’ perceptions of change in cognitive function, nor whether they had observed any changes in everyday life; these might be important questions for future studies. Because low-fat diets are recommended to healthy adults as a preventive measure against future disease, public acceptance depends upon confidence that all possible adverse effects are investigated thoroughly and that benefits are weighed against costs and risks.