INTRODUCTION

The main features of conduct disorder (CD) are the persistent and repetitive assault on the fundamental rights of others and the infringement of age-appropriate societal norms and rules. While behavioral problems exist in a wide variety of settings, significant functional impairments occur in the home, school, or work environment. The presence of a set of behaviors that define CD in number, severity, and persistence for at least 12 months is required for diagnosis. Behavioral symptoms of CD fall into four categories: aggression towards people and animals, smashing things, cheating or stealing, and breaking rules.

CD is one of the important mental health problems for many reasons. CD primarily affects the individual, family and society negatively. Although it is a disorder causing a significant expenditure on the fields of education, justice and mental health systems, studies related to CD are limited in Turkey [1].

A substantial proportion of those with CD have Attention-Deficit/Hyperactivity Disorder (ADHD) [2, 3]. A study was conducted in Turkey in 2018 showing the association between ADHD and impaired lipid profile in boys. In this study, mean total cholesterol, low-density lipoprotein (LDL-C) and high-density lipoprotein (HDL-C) levels were found to be significantly lower in boys with ADHD [4].

According to studies, about 40% of those diagnosed with CD develop antisocial personality disorder (APD) [5]. If the age of onset of CD is below 10, it is classified as “childhood-onset subtype”, and if above 10, classified as “adolescent-onset subtype”. The subtype starting in childhood has a higher risk of APD in adulthood [6]. APD is characterized by severe homicidal and delinquent behavioral symptoms towards people [7]. In a study conducted in Turkey, serum triglyceride levels of patients with homicidal behaviors were found to be significantly lower than of those without homicidal behaviors and the control group [8]. Lower blood cholesterol levels have been demonstrated in men with APD [9], chronic violent behaviors [10], ADHD with comorbid CD [11]. A study showed that low total cholesterol levels in adulthood were associated with childhood-onset conduct disorder. In addition, low cholesterol levels were found to be associated with early death in violence-related perpetrators, especially in those who died of unnatural causes [12]. In a study conducted in 2003, violent suicide attempters had significantly lower serum cholesterol levels compared to non-violent suicide attempters and controls. Low serum cholesterol may be associated with low lipid microviscosity in brain cell membranes, and low microviscosity may reduce the expression of serotonin receptors on the membrane surface, resulting in decreased serotoninergic receptor functions and suppression of serotonin neurotransmission. This may lead to the inability to suppress impulsivity or aggressive behaviors and to a depressive mood that triggers a violent pattern in sensitive individuals [13]. Cholesterol is important for central nervous system development, synaptogenesis and myelinization. Cholesterol is also a precursor of steroid hormones. Therefore, possible impairments on cholesterol synthesis indirectly affect all these processes in a negative way [14–17]. Given the functions of cholesterol in the central nervous system, dysfunctions in cholesterol metabolism may predispose to neuropsychiatric manifestations.

There are some studies indicating a relationship between cholesterol and ADHD, which can be defined as a precursor of CD. The associations between APD, which is often preceded by CD, have also been demonstrated. However, there is only one study from 30 years before in the literature examining the relationship between children’s aggressive behaviors and serum cholesterol levels [18]. To our knowledge, the current study is the first to examine the relationship between cholesterol levels and conduct disorder as a diagnosis.

MATERIALS AND METHODS

Since very few patients applied to the outpatient clinic in 2020 due to the pandemic of Coronavirus disease, the files of the patients who were examined between December 2017 and December 2019 were scrutinized for this study to determine patients with CD. In this clinic all of the patients is assessed at the first application with a semi-structured diagnostic interview called “Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime Version (K-SADS-PL)” and the psychiatric examination information is written in the patients’ files. The cases were diagnosed by child and adolescent psychiatrists via the K-SADS-PL according to DSM-V criteria. The DSM-5 diagnostic criteria for conduct disorder are first of all, a repetitive and persistent pattern of behavior in which the basic rights of others or major ageappropriate societal norms or rules are violated, as manifested by the presence of at least three of the following 15 criteria in the past 12 months from any of the categories below, with at least one criterion present in the past 6 months. These categories consists of aggression to people and animals, destruction of property, deceitfulness or theft and serious violations of rules. The diagnostic criteria under the category “aggression to people and animals” are often bullies, threatens, or intimidates others; often initiates physical fights; has used a weapon that can cause serious physical harm to others (e.g., a bat, brick, broken bottle, knife, gun); has been physically cruel to people; has been physically cruel to animals; has stolen while confronting a victim (e.g., mugging, purse snatching, extortion, armed robbery); has forced someone into sexual activity. The criteria continues with the “destruction of property”, includes, one has deliberately engaged in fire setting with the intention of causing serious damage and/or has deliberately destroyed others’ property (other than by fire setting). Under the category “deceitfulness or theft” we investigate if the patient has broken into someone else’s house, building, or car; often lies to obtain goods or favors or to avoid obligations (i.e., “cons” others); has stolen items of nontrivial value without confronting a victim (e.g., shoplifting, but without breaking and entering; forgery). The last category is “serious violations of rules”, here we obtain information on if the patient often stays out at night despite parental prohibitions, beginning before age 13 years; has run away from home overnight at least twice while living in the parental or parental surrogate home, or once without returning for a lengthy period; is often truant from school, beginning before age 13 years. To diagnose conduct disorder the disturbance in behavior must cause clinically significant impairment in social, academic, or occupational functioning. The patient group in our study were determined according to these criteria. There were 45 patients diagnosed with CD, which were aged 12–17 years and had no comorbid diseases. Furthermore, while some studies indicate that there is a relationship between serum cholesterol and ADHD, we did not include patients diagnosed with ADHD previous to the diagnose of CD, in order to determine the relationship between CD and blood lipid levels clearly. [4] Before the drug treatment, total cholesterol, LDL-C, HDL-C and triglyceride(TG) values of these 45 patients with CD were determined. With their complete data(K-SADS-PL, WISC-R and Turgay ADHD-RS-IV) age- and gender-matched 45 healthy children and adolescents whose examination and evaluation data were complete in the files were compared with the patient group. Healthy children and adolescents applied to the outpatient clinic for counseling, were determined as healthy and gave blood for routine periodic examination. Ethics committee approval was obtained from Manisa Celal Bayar University (date: 24.02.2021, decision no: 20.478.486/765). The study was not pre-registered. No randomization was performed to allocate subjects in the study. Neither blinding nor sample calculation was performed.

The kiddie schedule for affective disorders and schizophrenia—present and lifetime version (K-SADS-PL). K-SADS-PL is a semi-structured interview, which was developed by Kauffman et al. according to DSM-IV diagnostic criteria to screen mental disorders in children/adolescents aged 6–18 years [19]. The validity and reliability study of the interview form for Turkish language was conducted in 2004 [20].

Wechsler intelligence scale for children—revised version (WISC-R). WISC-R consists of two parts, which are verbal and performance intelligence parts. The total intelligence score is calculated using the verbal and performance intelligence scores. The standardization study of WISC-R for Turkish children was carried out by Savaşır and Şahin with the 6–16 aged [21, 22].

Turgay ADHD rating scale—IV(ADHD-RS-IV). In this scale developed according to DSM-IV, inattention is questioned with 9 items, hyperactivity with 6 items, impulsivity with 3 items, oppositional-defiant disorder with 8 items and conduct disorder with 15 items. Validity and reliability study was conducted by Ercan et al. [23]. Symptom severity of the cases diagnosed with CD was evaluated with total CD subscale score of ADHD-RS-IV.

The serum lipid levels and BMI reference intervals were determined with reference to the US National Heart, Lung, and Blood Institute (2012) for childhood (0–9 years) and adolescence (10–19 years) [24].

Statistical analysis. 20th version of SPSS (the Statistical Package for the Social Sciences) software was used for the statistical analysis. Descriptive statistics of the data were calculated as values of mean, standard deviation, minimum, maximum and percentage. To compare categorical variables, chi-square test was performed. Mann–Whitney U test analysis was conducted in the groups that could not fulfill the parametric assumption for continuous variables. Considering the distribution of variables, the correlation among quantitative measures was evaluated with the Spearman test. Statistical significance level was set as p ≤ 0.05.

RESULTS

The demographic characteristics of adolescents with CD and the control group were compared (Table 1). No statistically significant difference was determined between the groups regarding age, sex, socioeconomic status of the family from the perspective of the adolescent, age of the adolescents’ mothers, mothers’ education and fathers’ education. Furthermore, parental marital status and living together with grandparents caused no statistically significant difference. Nevertheless, school attendance rate was significantly higher in healthy controls compared to the CD group (p = 0.014).

Table 1. Sociodemographic data of the adolescents with CD and healthy controls
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The metabolic parameters of the adolescents with CD and healthy controls are demonstrated in Table 2. No association was found between the conduct disorder and BMI, diastolic blood pressure, plasma HDL-C and triglyceride levels. On the other hand, systolic blood pressure; plasma glucose, total cholesterol and LDL-C levels were significantly different between the groups. Adolescents with CD had higher plasma glucose levels; less plasma cholesterol and less LDL-C levels (p = <.001). In addition, CD group had significantly higher systolic blood pressure (p = 0.013). Compared with the average metabolic parameters at this age, both groups had normal systolic blood pressure; plasma glucose, cholesterol and LDL-C levels.

Table 2. Metabolic parameters of the adolescents with CD and healthy controls
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There was no significant correlation between total cholesterol, LDL-C, TG, and HDL-C levels with the ADHD-RS-IV scores (p > 0.05).

DISCUSSION

In our study, cholesterol and LDL-C levels were found to be significantly lower in the CD group compared to the control group, however no significant correlates were found between LDL-C levels and the severity of CD. TG and HDL-C levels in the cases with CD were found to be similar to the healthy group.

In the literature, there are studies reporting a relationship between low cholesterol levels and psychiatric disorders and symptoms such as depression, suicidal attempt, criminal behavior and aggression [25–27]. It has been suggested that low cholesterol levels cause a decrease in serotonergic function through decreased lipid microviscosity of the serotonin receptor on the neuronal membrane. As a result, decreased serotonergic function causes impulsive and aggressive behaviors, such as suicide [28]. The brain accounts for 2% of our body weight but contains 25% of the cholesterol in the body [29]. Cholesterol is important for brain functions and neurotransmission because neuroactive steroids (NASs) are synthesized from cholesterol and they modulate brain processes and interact with γ‑aminobutyric acid, N-methyl-D-aspartate and serotonin receptors (all of which are implicated in psychiatric disorders) as well as neurotrophins such as nerve growth factor. NASs are involved in mood regulation and cognition and regulate synaptic plasticity, apoptosis and neuroprotection. For the brain to function normally, NASs must be maintained in normal levels, because low levels of NASs may lead to adverse consequences, such as depression, neuroinflammation, epilepsy, multiple sclerosis and psychosis [30]. In a study of 4444 consecutive patients, it was found out that those with low total cholesterol levels had higher scores of anxiety, phobia, psychoticism and aggressive hostility. [31] Low cholesterol has been proposed as a biomarker for mood dysregulation, depression, and suicidality, as well as a predictor of the depression severity and increased suicide risk [32, 33]. At lower levels, it appears to be associated with depression, suicide, violence, anxiety, schizophrenia, and severe personality disorders. (including antisocial personality disorder and borderline personality disorder) [34]. As it is known, aggressive behaviors and impulsivity can be seen in CD. It has been reported that those who were diagnosed with CD in their childhood were more likely to be diagnosed with APD in adulthood [5]. Considering the results of our study, low total cholesterol levels of patients with CD support this information.

It is noteworthy that cholesterol and lipid levels of the patients with ADHD were investigated in child and adolescent age groups. However, the results of the studies were inconsistent. In a study conducted with children aged 6–12 years with ADHD, it was discovered that the cholesterol and HDL-C levels of ADHD subjects were significantly higher, TG levels were significantly lower than healthy controls, whereas there were no differences in terms of LDL-C levels between ADHD and control groups [31]. In a study conducted with 32 ADHD children and 29 healthy boys, it was determined that total cholesterol, LDL-C and HDL-C levels of ADHD cases were significantly lower than controls and there was no significant difference between the groups in terms of TG levels [35]. As it is known, ADHD often accompanies CD [2, 3]. However no study in which blood cholesterol and lipid levels are examined in patients with CD exists in the literature. Similar to Avcıl's study, in our study total cholesterol and LDL-C levels were found to be significantly lower in the group diagnosed with CD. It has been reported that, low serum cholesterol in patients increases aggression and impulsivity [4, 36]. It is an undeniable fact that, impulsivity and aggression are symptoms in common in CD as well as the two presentations of ADHD, which are predominantly hyperactive/impulsive ADHD and the combined presentation. Perhaps low cholesterol levels in children with ADHD is the reason of the presence of impulsivity and aggression in those children.

To our knowledge our study is the first study to investigate the serum cholesterol and lipid levels of children and adolescents with CD, and to compare them with healthy controls. If we examine the strengths of our study, it is noteworthy that, in our study, children and adolescents with CD without any comorbid psychiatric disorder and without medication and healthy controls were compared in terms of serum cholesterol and lipid levels. Several factors including age, gender, diet, and socio-economic status are known to affect lipid profile [13]. In our study, gender, socioeconomic levels and BMI were similar in the case and control groups. Our study has also some limitations that should be noted. Blood lipid levels were checked only once before medication. Whereas 44.4% of the patient group consists of females, the percentage of the females in healthy controls were 24.4%. Female groups couldn’t be compared separately, due to the fact that the sample size was small. While this study was a cross-sectional retrospective study, the levels of sex hormones in male and female groups were not separately examined and the timing of puberty in these adolescents could not be determined. As far as we are concerned, long-term prospective studies consisting of separate female and male groups with larger sample sizes are required. Nevertheless, this study is significant, due to the fact that it is the first one to examine the relationship between blood lipid levels and conduct disorder as a diagnosis in children and adolescents’ groups.

CONCLUSIONS

To conclude, in our study, serum total cholesterol and LDL-C levels were found to be lower in children and adolescents with a diagnosis of CD, but no correlation was found between cholesterol levels and symptom severity. The results of our study emphasize that serum cholesterol and lipid levels may play a role in the etiopathogenesis of CD. It seems that more studies examining biochemical markers in this field are necessary to develop more appropriate treatment approaches regarding CD. It is thought that our study will shed light on new research on the etiology of CD, which is an important childhood psychiatric disorder.