In this study, we evaluated the probable benefits of dietary dose of omega-3 fatty acids on some traditional and non-traditional cardiovascular risk factors, when added at the beginning of SGAs and mood stabilizers before the establishment of the metabolic side effects.
In this study, we did not observe a change in BP. Fish oil (containing omega-3) supplementation for a median duration of eight weeks has been shown to lower systolic and diastolic blood pressures. BP reduction pattern of fish oils is also shown to be linear at dietary doses (EPA plus DHA <1 g/day) and reaches plateaus at higher than the dietary doses. This effect is also claimed to be less pronounced in healthy adults younger than 45 years-old[9, 16] and may take a longer time to take place. Thus, the unchanged BP in this study may be attributed to the younger age of the participants and the short duration of trial.
Omega-3 fatty acids did not favorably affect LDL and TC levels in our study; however, a trend toward lower TC increment in the omega-3 group (15.6 mg/dl) than that in placebo group (28.43 mg/dl) may suggest that omega-3 may prevent increases in TC levels. Studies have shown that omega-3 fatty acids can decrease small dense LDL, a highly atherogenic form of LDL. Thus, it is suggested to measure this form of LDL when studying effects of omega-3 on cholesterol levels.
With regard to HDL, McKenney and Sica reported that omega-3 fatty acids can only modestly increase this factor. This may partly explain the observed unchanged values of HDL in our study. Contrary to our expectations, HDL levels were increased significantly in the placebo group that may be related to the fact that our sample size was not sufficient to detect more pronounced effects for some of the outcome variables including HDL.
Despite our hypothesis, omega-3 fatty acids did not reduce TG levels in our study. Some studies have shown that TG lowering effects of omega-3 fatty acids occur within months to years and with a greater effect in patients with higher baseline TG levels[16, 17]. In addition, effect of omega-3 on lowering TG concentration appears to be linear; omega-3 in doses of 3-4 g/day have greater effect compared with doses <1g/day. Therefore, the reason that TG levels were not reduced in our study may be due to the fact that psychiatric patients without important medical problems were included, lower EPA and DHA doses were utilized, baseline TG levels were not considered in the high range and this trial was performed in a relatively short duration of time.
Current guidelines identify non-HDL-C as a secondary target of therapy in patients with TG ≥ 200 mg/dl after achieving LDL goals. Non-HDL-C increased significantly in each study group; however, no difference was noted between the two groups. Interestingly, when evaluating patients whose TG levels were above 200 mg/dl at the end of the present trial, increase in non-HDL-C, requiring treatment, was identified in 2.4% of participants in the omega-3 group versus 14.6% in the placebo group. This is while, at the beginning of the study, we excluded patients with non-HDL-C levels requiring treatment according to NCEP ATP III guidelines, from entering the study. Thus, the above finding may suggest a promising role for dietary doses of omega-3 to prevent increases of non-HDL-C concentrations above target levels in patients receiving psychiatric medications with metabolic side effects.
Along with elevated LDL cholesterol, elevated Lp(a) is considered to promote atherosclerosis. Lp(a) serum levels are primarily, genetically controlled, however, its levels may also be affected by some exogenous factors. Long term treatment with anti-epileptic drugs, specifically VPA is shown to increase Lp(a) levels in patients with epilepsy[20–23]. Currently, medication effects on Lp(a) are limited. According to the results of our study, omega-3 supplementation prevented Lp(a) elevation due to therapy. In line with our results, a favorable effect of omega-3 on decreasing Lp(a) serum levels was previously demonstrated in hypertensive and coronary artery disease patients[24, 25].
MetS is a procoagulant state with elevated fibrinogen level as a contributor. Elevated fibrinogen has been observed in patients with obesity. Additionally, increased fibrinogen plasma levels are considered a risk factor for major CVDs including coronary heart disease and stroke. Baptista and his colleagues hypothesized that olanzapine increases fibrinogen levels, leading to a procoagulant state. Another study demonstrated elevated levels of fibrinogen after 12 weeks of olanzapine administration in patients with schizophrenia. In contrast to olanzapine, VPA has reported to reduce fibrinogen levels[23, 29, 30], indicating impaired hepatic synthetic function. The above studies did not assess the relevance of decreased fibrinogen levels to CVD risk. However, VPA may still lead to atherosclerosis and thrombosis despite decreased fibrinogen levels. In our study fibrinogen plasma levels did not change in the group assigned to placebo. Even although the effects of most of the other medications on this parameter is yet unclear, the above finding may reflect a probable combined effect of olanzapine and valproate on fibrinogen plasma levels. Interestingly, in the group assigned to omega-3, fibrinogen levels decreased significantly by 38.15 mg/dl (from 321.95 mg/dl to 283.80 mg/dl). The normal range of fibrinogen level is 200-400 mg/dl. Whether this decrease in fibrinogen level corresponds to CVD reduction, remains to be elucidated.
Evidence supports inflammatory processes contributing to atherogenesis. Centers for Disease Control and Prevention and the American Heart Association have defined values of CRP-hs <1, 1-3 and > 3 mg/dl as low, average and high risks to develop CVD, respectively. It should be noted that elevated levels of CRP has been observed in patients with BD and schizophrenia which may suggest an inflammatory component in these psychiatric illnesses[33, 34]. At baseline we observed CRP-hs values of 4.33 and 3.1 mg/dl in the omega-3 and placebo groups, respectively; these values remained elevated throughout the study period. The above observation suggests an inflammatory process occurring in psychiatric patients and remaining beyond the acute phase of the involved illnesses. This is consistent with Dickerson et al. report on elevated levels of CRP in outpatients with a relatively long duration of BD. Our results also showed that omega-3 fatty acids did not have any significant effect on CRP-hs levels. In general, controlled trials have not detected significant effects of omega-3 supplementation on CRP-hs levels.
Despite the suggested protective role of omega-3 against abdominal obesity, this supplement could not lessen increases in weight and WC in our study patients. After 6 weeks, our participants significantly gained a mean of 4.35 kg in the omega-3 group and 4.07 kg in the placebo group. Few studies have reported the extent to which each specific combination therapies of Li or VPA plus olanzapine increase weight. This study was not designed to assess weight changes related to various combination therapies or to any of these agents alone. However, our results were similar to those reported by Kim et al. who reported weight gain of 3.8 ± 2.9 kg with olanzapine plus VPA and 3.3 ± 3.1 kg with olanzapine plus Li. Kim et al. also found that olanzapine monotherapy resulted in 1.6 ± 3.5 kg increase in weight after 4 weeks in patients with BD.
It should be emphasized that the short duration of our study set limit to observe more profound effects. Additionally, even though the assessment of omega-3 effects was aimed to be accomplished in a realistic setting, receiving combination of olanzapine with a mood stabilizer by patients might have influenced the results of the present study. Another limitation that could influence our study was the fact that even though patients were asked not to change their regular diet during the study, they were not strictly controlled for their diet calories taken and activity levels.
In conclusion the addition of dietary doses of omega-3 fatty acid supplements per day at the commencement of olanzapine combination with either Li or VPA may not prevent or modulate early anthropometric and lipid profile deterioration. However, this study noted that Lp(a) level was not elevated and fibrinogen level was decreased in patients receiving omega-3 fatty acids for six weeks. A trend toward smaller increases in TC levels and the ability to prevent non-HDL-C exceeding its target in patients with TG levels above 200 mg/dl supports some cardiovascular benefit of low dose omega-3.