There is encouraging evidence of an association between low total cholesterol and aggression towards others as well as suicidality in schizophrenia; association was strongest for low total cholesterol

How do lipids influence risk of violence, self-harm and suicidality in people with psychosis? A systematic review. Piyal Sen et al. Australian & New Zealand Journal of Psychiatry, July 9, 2021. https://doi.org/10.1177/00048674211025608

Abstract

Objectives: Low cholesterol has been linked with violent and suicidal behaviour in people with schizophrenia. This association, if consistently present, may be a promising biological marker that could assist clinicians in decision making regarding risk and treatment. We conducted a systematic review to assess whether there is a reliable association between lipid profile (total cholesterol, high- and low-density lipoprotein cholesterol, and triglycerides) and aggression, self-harm or suicide in people with schizophrenia, and whether effects are similar in males and females.

Method: Relevant databases were searched to identify primary research studies (up to November 2020) that (1) involved adults (some samples also included 16- to 18-year olds) with a confirmed diagnosis of schizophrenia, schizoaffective disorder or psychosis; and (2) included a standardised assessment of verbal aggression, physical aggression against objects, physical aggression against self (including suicide) or others. The search yielded 23 studies eligible for inclusion following a quality appraisal.

Results: Suicidality was the most commonly assessed subtype of aggression (20 studies). For suicidality, about half the studies, including the study with the largest sample size, found a link with total cholesterol. An association between low total cholesterol and violence towards others was found in six of nine studies that investigated this. The evidence for a link with violence was the strongest for total cholesterol, followed by low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, and the weakest for triglycerides. Only a few studies investigated sex differences and yielded mixed evidence. Studies focussed on self-harm as well as involving females in forensic settings were lacking.

Conclusion: There is encouraging evidence of an association between low total cholesterol and aggression towards others as well as suicidality in schizophrenia. Future studies should systematically explore this association in people with schizophrenia who have a significant history of violence, suicidality and self-harm, both inpatients and community, and also investigate underlying mechanisms.

Keywords: Cholesterol, aggression, suicide, schizophrenia, sex

Discussion

There were three main findings in relation to the primary objectives of this systematic review.

First, there were many more studies which reported on a link between low cholesterol and violence to others than those which did not find a link. All researchers investigating forensic samples found such a relationship. However, the relationship was not only with low TC but also with other parameters of the lipid profile, such as low LDL and low HDL. It is thus important not just to collect data on TC, but LDL and HDL as well. The evidence was weaker for the link between TG and violence, with only two studies finding a link, but one with high TG, the other with low TG. It is to be noted that the study with the largest sample size failed to find a link (Hjell et al., 2020). However, one of the issues in this study was the relatively low rate of baseline violence in the study population, thus offering some indication that the link is likely to be more valid in groups where there is a greater prevalence of violence (i.e. forensic populations).

The biological mechanism behind cholesterol–violence association has been hypothesised to involve serotonin. Animal studies have found an increase in violent behaviour in monkeys assigned to a low-cholesterol diet (Kaplan et al., 1991, 1994). Kaplan et al. (1991) suggested that low cholesterol may reduce cell viscosity and reduce serotonergic receptor activity. This may lead to a depressive state (Marcinko et al., 2005), increased impulsivity (Carver and Miller, 2006; Paaver et al., 2007) and aggressive behaviour (Chakrabarti et al., 2004). This finding was observed in Kaplan et al. (1994), where monkeys with experimentally lowered cholesterol had higher concentrations of serotonin metabolites than monkeys given high-cholesterol diets. However, the exact biological mechanism underlying cholesterol–violence (towards self/others) association in humans is still unclear.

Second, there was mixed evidence for a link between low cholesterol and suicidality in schizophrenia, with almost equal number of studies in favour and against such a link. The majority of studies used suicide as the method of assessing aggression. Eight studies found a statistically significant association between low cholesterol and suicide attempts, two of which only found this association in females (Misiak et al., 2015; Shrivastava et al., 2017). Seven studies failed to find a link. However, the study with the largest sample size (Sankaranarayan et al., 2020) did find a link, thus suggesting that methodological flaws, particularly low power, might have contributed to the variation in findings.

The evidence for a specific relationship between lipid profile and violent suicidal attempts was even more mixed. Ruljancic et al. (2007) found a significant association between low cholesterol and non-violent suicide attempts, in contrast to two other studies (Marcinko et al., 2005; Tripodianakis et al., 2002), reporting an association between low cholesterol and violent suicide attempts. While the two studies showing a positive association had smaller sample sizes, such findings are supported by other literature (Garland et al., 2000; Vevera et al., 2003). A meta-analysis found 50% more violent deaths in males with relatively low cholesterol than in participants with higher levels of cholesterol (Jacobs et al., 1992). This meta-analysis also found a higher prevalence of depressive symptoms in males with low serum cholesterol.

An association between low cholesterol and depression has frequently been observed (Grussu et al., 2007; Ploeckinger et al., 1996; Troisi et al., 2002). It is plausible that the causal pathway from low cholesterol to suicidality in schizophrenia patients involves depression. Kunugi et al. (1997) did not find a significant difference in cholesterol level between suicidal and non-suicidal inpatients with schizophrenia spectrum disorders. However, significantly lower cholesterol levels were found in suicide attempters with mood disorders compared with controls. Similarly, Modai et al. (1994) found a significant association between lower cholesterol and suicidality in patients with depression, but not in schizophrenia patients. Around 40% of people with schizophrenia have depression, with depression being the most significant factor in completed suicide (Upthegrove et al., 2016). People with schizophrenia and comorbid depression also have a significantly increased risk of violence and suicidality (Conley et al., 2007) and poorer clinical outcomes (Gardsjord et al., 2016; Upthegrove et al., 2009). The studies included in this systematic review did not control for depressive symptoms in schizophrenia patients. Although findings of low cholesterol and depression are inconsistent, with a number of researchers not finding a significant association (Cepeda et al., 2020; Van Dam et al., 1999), it is plausible that suicidality seen in schizophrenia patients with low cholesterol may be a consequence of depressive symptoms.

Third, most of the studies had similar findings for males and females. However, low HDL was seen in two studies to be a better predictor of violence than low TC for males (Eriksen et al., 2017, 2018). Another study found female sex and low TC levels could be used, in part, as predictors of violence in patients with schizophrenia (Chen et al., 2015). One study found higher TC and LDL levels to be associated with suicidality in females but not males with first-episode schizophrenia, thus suggesting that the link between lipids and violence is somewhat complex (Misiak et al., 2015). Future studies need to be designed to explore the nature of the link separately for females and males. All studies (Chakrabarti et al., 2004; Marcinko et al., 2005, 2007, 2008; Repo-Tiihonen et al., 2002) investigating only male schizophrenia patients found a significant association between low cholesterol and suicidality, except one group (Turkoglu et al., 2009) who did not report a significant association. On the contrary, three study authors observed an association only in female participants: two for suicidality (Misiak et al., 2015; Shrivastava et al., 2017) and one for violence towards others in patients with schizophrenia (Chen et al., 2015). However, one study (Eriksen et al., 2017) did not find this specific correlation in female participants.

Thus, it can be concluded that cholesterol levels could be used, in part, as predictors of violence in patients with schizophrenia. The evidence for a clear link with sex remains inconclusive. This is an important area for further work given that rates of violence in psychiatric patients following discharge tend to be higher in men than in women (Robbins et al., 2003). In addition, the neurobiology of violence, factors like body mass index (BMI), incidence of metabolic syndrome following antipsychotic medication and the effects of cholesterol are different between men and women, suggesting that discrete effects may occur in each sex (Golomb, 1998).

Limitations

There were several limitations regarding the studies reviewed. First, in many of the studies reviewed, the main focus was on suicide and physical aggression to others. As a result, most patients observed were clinically ill enough to warrant inpatient treatment. Few studies evaluated aggression as physical against property and verbal, potentially deemed less severe and more likely to be seen in community or outpatient-based studies. A representative view of schizophrenia patients of all severities, including inpatients and outpatients, was therefore not specifically assessed in this review. Second, confounding factors, including sex, medication and age, may have affected the findings of this review. According to the Gender Paradox in Suicide, men are more likely to die by suicide than women, while women are more likely to engage in suicidal behaviour and deliberate self-harm (Canetto and Sakinofsky, 1998). However, self-harm was not frequently assessed in these studies. There is some indication of a link between low TC, HDL, LDL and impulsivity, which could translate into risk of self-harm, but this link needs to be explored through studies in populations with higher self-harming behaviours, like inpatient female wards. Medication, such as certain antipsychotics like risperidone, stimulate serotonergic output in cortical and subcortical areas more than other antipsychotics (Amato, 2015), and this may contribute to changes in aggressive behaviour independent of cholesterol level. In addition, with age comes a natural variance in cholesterol level, with a tendency of increased serum cholesterol with increasing age (Morgan et al., 2016). Aggressive behaviour may be independent of low cholesterol in younger participants as they, typically, would have a lower cholesterol level when compared to older patients. The effects of age as well as medication were not accounted for in a number of studies. Finally, the lack of statistical analysis using a 95% confidence interval in a number of studies (see Table 4) limited the review by making it difficult to assess precision and risk in data obtained.

In addition, there are limitations to the review itself. First, the review may have been limited by only allowing diagnosis of schizophrenia by a variant of DSM or ICD classifications. This excluded foreign classifications such as T-SCL-90-R. Second, selection bias arose when only considering studies reported in English. The inclusion and exclusion criteria stated that participants must be adults only, unless unavoidable. As a result, three included studies (Chen et al., 2015; Repo-Tiihonen et al., 2002; Ruljancic et al., 2007) had some participants below the age of 18, leading to wide variations in the age range of the study participants.