drug-free patients of schizophrenia

Accepted Manuscript Title: Lipids, Aggression, Suicidality and Impulsivity in drug-na¨ıve/drug-free patients of Schizophrenia Author: Anjana Rao Kavoor Sayantanava Mitra Sudhir Kumar Anil Kr. Sisodia Rakesh Jain PII: DOI: Reference:

S1876-2018(16)30604-9 http://dx.doi.org/doi:10.1016/j.ajp.2017.03.002 AJP 1082

To appear in: Received date: Revised date: Accepted date:

18-12-2016 13-2-2017 1-3-2017

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Lipids, Aggression, Suicidality and Impulsivity in drug-naïve/drug-free patients of Schizophrenia

Anjana Rao Kavoor

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Consultant Psychiatrist, Fortis Hospital, Bengaluru, India Sayantanava Mitra

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Post-Doctoral fellow, Department of Psychiatry, NIMHANS, Bengaluru, India

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Sudhir Kumar

Director, Institute of Mental Health and Hospital, Agra, Uttar Pradesh, India

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Anil Kr. Sisodia

Assistant Professor of Psychiatry, Institute of Mental Health and Hospital, Agra, Uttar Pradesh, India

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Rakesh Jain

Corresponding Author:

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Sayantanava Mitra

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Senior Clinical Psychologist, Institute of Mental Health and Hospital, Agra, Uttar Pradesh, India

Post-Doctoral fellow, Department of Psychiatry, NIMHANS, Bengaluru, India [email protected]

Conflict of Interest: None to declare Acknowledgements: None

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Abstract Aim: Present study aimed at determining lipid profiles in acutely symptomatic drug-

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naïve/drug-free patients of Schizophrenia, comparing them with healthy controls and exploring relationships between various lipid fractions, aggression, suicidality and

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impulsivity in this population.

Materials and Methods: This was a cross-sectional hospital-based study, comparing patients

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with Schizophrenia (M=46,F=14; mean age 32.40±6.6 years; 48 drug-free for 10.50±9.2

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weeks) with 60 age-sex matched healthy controls. Upon recruitment, fasting venous blood samples of all subjects were analysed for Total Cholesterol, HDL, LDL, VLDL and TG

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levels; and patients were rated on PANSS for symptom severity, Modified Overt Aggression Scale for aggression, Impulsivity Rating Scale for impulsivity and Scale for Suicide Ideation

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for suicidality.

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Results: The socio-demographic characteristics of the patients were comparable to controls. In patients, Total Cholesterol, HDL and LDL levels were found to be significantly lower

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(p<0.01) than the control group. When explored further in patients, lower total cholesterol and LDL levels showed significant negative correlations with scores on impulsivity (p<0.01) and suicidality (p<0.05); and TG level showed a negative correlation with impulsivity (p<0.05).

Conclusions: This study adds to a growing literature on a complex relationship between lipid fractions and impulsivity, suicidality and aggression in Schizophrenia; providing interesting insights into the biochemical basis of human behaviour and confirming these in a developingworld population. The implications are many, including a need to review judiciously the promotion of weight loss and cholesterol reduction programs in constitutionally vulnerable population; at least during their acutely-symptomatic states.

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Lipid;

Cholesterol;

Impulsivity;

Schizophrenia

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Keywords:

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Introduction Suicide accounts for a substantial proportion of excess mortality in patients with

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schizophrenia (White et al., 2009; Inskip et al., 1998; Palmer et al., 2005), with increased lethality, violence, an intent to die and multiple attempts (Volavka and Citrome, 2008).

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Similarly, this population is four times as likely to be engaged in violent acts (Lewis et al., 2009), a part of which is explained through heightened impulsivity (Volavka and Citrome,

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2011). Impulsivity also contributes to suicidality (Dervaux et al., 2010; Gut-Fayand et al.,

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2001; Perroud et al., 2001; Kaladjian et al., 2011), and therefore might be an important construct for further investigation (Volavka and Citrome, 2008; McGirr et al., 2007).

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Reduced cerebrospinal fluid (CSF) 5-hydroxy-indole-acetic acid (5-HIAA) levels in suicide attempters had been demonstrated in the past (Nordstrom et al., 1994), and receptor

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studies have confirmed reduced serotonergic (5-HT) signalling in the brains of suicide

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victims (Mann and Currier, 2009, 1999; Mann et al., 2000). Studies have found an inverse relationship between brain serotonergic functions, violent attacks (Tobena, 2009) and an

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increase in impulsivity (Soubrie, 1986; Homberg et al., 2007; Dalley et al., 2002; Cardinal, 2006), and numerous other studies have supported these evidences (Walderhaug et al., 2007; Dougherty et al., 2007; Crockett et al., 2009; Robinson et al., 2012; Schweighofer et al., 2008). However, the data remains heterogenous (Winstanleyet al., 2004; Crean et al., 2002), though a picture of some link between impulsivity, aggression and suicidality, influenced by alterations in 5-HT neurotransmission (Mann and Currier, 2009; Zouk et al., 2007) seems to emerge. Interestingly, altered lipid homeostasis in humans could particularly affect the serotonergic system (Muldoon et al., 1990; Muldoon et al., 2001, Engelberg, 1992; Diebold et al., 1998; Kaplan et al., 1994; Papakostas et al., 2003; Sjogren et al., 2006; Singh et al.,

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2007) via cholesterol’s effects on lipid raft micro-domains on the cell membranes (Gil et al., 2006). Lipid profiles could, therefore, reflect central serotonergic function (Kavoor et al., 2014) and their clinical manifestations as impulsivity, suicidality and violence (Buydens-

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Branchey et al., 2000; Chakrabarti et al., 2004; Pozzi et al., 2003; Conklin and Stanford, 2008). While some reported higher levels of cholesterol to be associated with increased

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suicidality (Chang et al., 2012; Jee et al., 2011), majority confirmed an inverse relationship between the two (Sarchiapone et al., 2001; Atmaca et al., 2002; Sullivan et al., 1994; Golier

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et al., 1995). Similarly, both Vevera and colleagues (2003) and Troisi (2011) found low

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serum cholesterol in patients to increase aggression and impulsivity; as Lalovic and colleagues (2007) reported lower frontal grey-matter cholesterol content in post-mortem

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samples of violent suicide victims. Lifetime suicide rates were found to be higher in those with lower cholesterol levels (Fiedorowicz, 2007), although the role of cholesterol level in

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suicidality continued to be questioned by some (Almeida-Montes et al., 2000; Tsai et al.,

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2002).

Since impulsivity remains one of the most prominent mediators of both aggression

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and suicide in patients with schizophrenia (Courtney et al., 2012; Dervaux et al., 2010); and since serum lipid levels might influence manifestations of all three construct via their influences on serotonergic transmissions in brain; probing these complex interactions between lipids, serotonin, impulsivity, aggression and suicidality is needed in this patient population. Studies in this regard are sparse (Park et al., 2013; John et al., 2014; Ainiyet and Rybakowski, 2014), heterogenous (Atmaca et al., 2003; Marcinko et al., 2005; Ainiyet and Rybakowski, 2014; Chen et al., 2015) and are from the developed-world population. Data from India, in this regard, is far from clear (Sanyal et al., 1998; Singh et al., 2003; Margoob et al., 2004). Finally, medication-effects on these construct cannot be teased out from the past reports.

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Therefore, explorations regarding the relationships between lipids, impulsivity, suicidality and aggression in a representative Indian population of schizophrenia patients, keeping in mind the methodological shortcomings of past researches seem warranted.

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Materials and Methods The study was conducted at a tertiary-level referral centre and a post graduate

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teaching hospital in western Uttar Pradesh. Study protocol was approved by institute’s ethical and scientific committees. This was a cross sectional, hospital based study, in which sixty

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consecutive patients with schizophrenia, diagnosed as per International Classification of

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Diseases-10 Diagnostic Criteria for Research (ICD-10 DCR; World Health Organization, 1993), who were antipsychotic-drug naïve or antipsychotic-drug free [for at least 4 weeks

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(oral medication) or for 8 weeks (depot medication)], educated at least up to class 5th were recruited after an informed consent had been obtained. The consent was obtained in a pre-

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designed and approved bi-lingual consent form, after explaining the whole procedure and

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their risks/benefits to the patients/their legal guardians. Patients’ legal guardians were approached for obtaining consent if the patients themselves were not competent for the same.

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We further recruited 60 age, sex and ethnicity matched healthy controls [General Health Questionnaire-12 (Goldberg and William, 1998) score < 3] from the accompaniments of the patients and ward staff at the hospital, to compare socio-demographic characteristics and serum lipid values with that of the patients. Participation as a control subject was voluntary, and consent was obtained from them for the purpose. No monetary incentive was advanced to the participants in either group. Subjects, who had a simultaneous diagnosis of substance dependence as per ICD-10 DCR, other psychiatric or eating disorders, comorbid neurological disorder or medical conditions such as diabetes mellitus, liver disease, renal disease, hypertension and thyroid dysfunction etc., and those taking oral contraceptives and beta blockers, were excluded.

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Socio-demographic and clinical data were collected. Psychopathology was measured on Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987). Modified Overt Aggression scale (MOAS; Sorgi et al., 1991), Impulsivity Rating Scale (IRS, Lecrubier et al.,

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1995), and Scale for suicide ideation (BSI; Beck et al., 1997) were used to quantify impulsivity, aggression and suicidality, respectively, in patients. MOAS measures four types

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of aggression (verbal, physical against objects, physical against self, physical against others), with a rating of zero when aggression is absent, and of four when aggression is severe. Items

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are thus scored on a 5-point scale, and sores range from 0 to 40, with higher scores indicating

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more aggression. There is an additional measure of frequency to each of the behaviours that occurred during the period of observation (past week). IRS is a 7-item scale, and real life

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examples are used to assess the underlying constructs during the most recent period (last week). IRS takes into account the heterogeneity of impulsivity and different common

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behaviors involved in impulsivity. The existence of a difficulty to delay, a poor control of

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behavior, and quick responses without evaluation of consequences, irritability and aggressiveness are the most commonly cited characteristics of impulsive subjects. The Scale

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for Suicide Ideation (BSI) is a 19-item rating scale, administered by interviewer, that measures the current intensity of patients’ specific thoughts, behaviors, and plans to commit suicide at the time of the interview. Each item is graded according to the intensity on a 3point likert scale ranging from 0 to 2. The ratings for the items yield a total score from 0 to 38. The first five items on the scale are screening items. First three items assess the wish to live or the wish to die and two items assess active and passive suicidal desire. In case the subject reports any active or passive desire to commit suicide or wish to die, then 14 additional items are administered. Rest of the individual items assess suicidal risk factors such as the duration and frequency of ideation, control over acting-out suicidal wish, number of deterrents, and amount of actual preparation for a contemplated attempt.

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All the assessments were done by the first author (ARK), who did not have access to the lipid profile details at the time of doing such assessments. Height was measured with the subject standing erect in a relaxed manner, looking

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straight ahead, and with feet shoulder-width apart. Weight was measured in 12-hour fasting state on an analogue weighing scale with zero error. Body mass index (BMI) were calculated

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for each subject using the formula BMI = [(Weight in KG)/((Height in m)2)]. Venous blood samples (5ml) were drawn on weekdays between 7 and 9 am after the participants had fasted

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for at least 12 hours. Samples were immediately delivered to the hospital laboratory and

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analysed for TC, HDL, LDL, VLDL and TGs using enzymatic auto-analyser. The control subjects were rated on GHQ-12 at their recruitment.

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Statistical Package for Social Sciences (SPSS for Windows, version 20) was used to analyse the data. After tabulation of all variables; descriptive statistics in form of frequency

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count was used to describe categorical variables and mean-standard deviation measurements

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were done for continuous variables, respectively. Patients and controls were compared using Chi-square/Fisher’s exact tests for categorical variables and using independent sample t-tests

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for continuous variables. In patients, relationships among measures of impulsivity, suicidality, aggression, various lipid fractions and body-mass index were explored using Pearson’s correlation analysis. Results

The study recruited 60 patients and 60 healthy controls. Twenty two of the patients

(36.7%) had a diagnosis of paranoid schizophrenia, and 38(63.3%) had a diagnosis of undifferentiated schizophrenia. Of the 60 patients, 48 (80%) were drug free for at least 2 weeks, and the rest 12 (20%) were drug naïve. The mean duration of illness was 91.96±69.5 months, and 48 patients were drug free for a mean duration of 10.50±9.2 weeks. Table 1 compares the two groups in terms of their socio-demographic characteristics. There were nil

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significant differences between the two groups on these variables, except for a significantly higher (p<0.01) mean years of education in the control group. Table 2 describe the results of the comparison of lipid profiles between patients and

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healthy controls. The mean value of TC in patient group was 130.33±12.0 mg/dl, and control group was 140.55±17.5 mg/dl which showed a significant difference between the two

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(p=0.000). Similarly, mean HDL levels in patient group were 40.50±4.4 mg/dl which was significantly lower than control group (42.70±3.9 mg/dl). Mean LDL level in patients was

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72.83±9.9 mg/dl which was significantly lower (p=0.009) than controls (78.62±13.6mg/dl).

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Finally, the serum triglyceride level (p=0.068), and the VLDL levels (p=0.119) were not significantly different. As seen in figures 1-3; a greater proportion of patients had their TC,

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LDL and HDL levels in the lower range, compared to controls. Interestingly, when we separately analysed lipid levels among the male subjects (N=46 in each group), similar trends

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group.

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prevailed, with an additional finding of a significantly (p=0.025) lower TG level in the patient

Table 3 describes the psychological profiles of the patients. Table 4 describe

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correlations between lipid profile, BMI and measures of psychopathology, impulsivity, aggression and suicidality in the patients. No significant correlation was found between psychopathology scores measured on PANSS, BMI and various lipid fractions. There was a significant negative correlation between total cholesterol and impulsivity, as measured on Impulsivity Rating Scale (IRS; r=-0.517). LDL levels showed a significant negative correlation with IRS scores in this population (r=-0.387), as did serum triglyceride level (r=0.282). Though a negative trend was observed between the TC, triglyceride, LDL and VLDL levels and MOAS score, these trends did not reach statistical significance. Pearson’s correlation analysis of relationship between scores on Beck Scale for suicidal ideation (BSI) and various lipid fractions in the patients’ sample showed a significant negative correlation

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between total cholesterol and BSI scores (r=-0.303), and serum LDL levels also showed a significant negative correlation with BSI scores (r=-0.257). Though a negative trend between BSI score and TG was observed (r=-0.060), this did not reach statistical significance.

negative, general or total scores, and the scores on IRS, MOAS and BSI.

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Discussion

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Finally, we did not find any significant correlations between PANSS positive,

We included cases of schizophrenia, diagnosed as per ICD-10 DCR (World Health

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Organization, 1993), without any comorbid psychiatric diagnoses, substance dependence or

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eating disorders. Our homogenously selected patients’ sample diminished the likelihood of contamination, an issue which had plagued the interpretation of many past reports (Sanyal et

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al., 1998; Singh et al., 2003; Park et al., 2013; Liao et al., 2012). At intake, 12 patients were drug-naïve and 48 were antipsychotic-drug free for a mean duration of 10.50±9.2 weeks. It is

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well documented that dopaminergic, serotonergic and other neurotransmitter systems are

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involved in impulsivity (Pattij and Vanderschuren, 2008; Dursun et al., 2000; Spivak et al., 1997), and are extensively affected by antipsychotic medications. Clozapine in suicidality is a

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case in point (Liao et al., 2012). Further, these drugs variously influence lipid levels in schizophrenia (Meyer and Koro, 2004), and therefore drug status could be an important confounder. A long drug-free status of our patients ensured that these extraneous influences on variables of interest were kept to the minimum (cf. Ainiyet and Rybakowski, 2014). The use of self-report measures had been a limitation in past (Kavoor et al., 2014;

Troisi, 2011), especially since it may be argued that acute symptoms in these patients might have reduced the reliability of self-reports and confounded the results. We used well validated scales to measure these constructs, and collected data from the caregivers (IRS and MOAS) to reduce such contamination. A lack of correlation between PANSS scores and IRS, MOAS and BSI values in our data reduces the possibility of these measures being state

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markers of the illness (cf. Park et a., 2013; Ainiyet and Rybakowski, 2014; Marcinko et al., 2005; Liao et al., 2012). A well matched control group from the same general population was an improvement over the study by John et al (2014) and is in line with several other authors

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(Park et al., 2013; Atmaca et al., 2003; Olié et al., 2011; Jokinen et al., 2010). The sex distribution and other socio-demographic data in present study are similar to others with the

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same patient profile (Grover et al., 2014; Sawant et al., 2010; Srinivasan et al., 2005, Mahintamani et al. 2015; Rabinowitz et al., 2002).

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The mean Body Mass Index (BMI) of the sample was 19.72±2.8 kg/m², in line with

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the literature on Indian population (Verma et al., 2013; Bajaj et al., 2013; Grover et al., 2015). In past, majority of the Indian studies assessing cholesterol levels in patients with

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schizophrenia intended to explore metabolic syndrome in this group and had recruited patients on long term medications (Bajaj et al., 2013; Grover et al., 2015), and those reporting

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cholesterol levels in drug naïve or drug free patients with schizophrenia are lacking.

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The mean TC value showed a significant difference between patients and controls (p<0.001). Similarly, mean HDL level in patient group was significantly lower than control

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group, as was LDL level. Lower cholesterol levels have been reported in an unselected sample of psychiatric patients in India (Sanyal et al., 1998). Wu et al. (2013) reported significantly lower TC and HDL levels in 70 drug naïve patients of schizophrenia. Ainiyet and Ribakowsky (2014) found lower TG values in schizophrenia patients with suicidal thoughts, though they did not use a matched control group. In our study, both serum triglyceride and VLDL levels were lower in the patient group, though this did not reach statistical significance (p=0.068 and 0.119, respectively). The absence of a significant difference in TG levels between patients and controls in our study might either reflect an advantage of using healthy and properly matched control group in present study to clarify

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relationships further, or the influences of differing lifestyle and food habits between Indian and Scandinavian population. Within the patient population, a significant positive correlation was found between the

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scores on IRS, BSI and MOAS; probably indicating the inter-relatedness of these constructs (McGirr et al., 2007; Baca-Garcia et al., 2005; Hull-Blanks et al., 2004; Dougherty et al.,

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2004; Dumais et al., 2005; Conner et al., 2009). No significant correlations were found between PANSS subscale scores and various lipid fractions. This, in agreement with

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available literature, hints at the independence of PANSS constructs from the interactions

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between various lipid components and consequent changes in central neurotransmission. Our study found a significant negative correlation between TC and LDL levels with IRS and BSI

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scores (p<0.01). TG levels also negatively correlated with IRS (p<0.05). Pozzi et al. (2003) found that subjects with low serum cholesterol showed greater impulsivity. Conklin and

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Stanford (2008) had found that low concentrations of TC and LDL were associated with

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increased impulsivity in their subjects of substance use disorder. Troisi (2011), using a mixed sample of 301 patients found that attentional impulsivity was inversely related to TC levels,

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as was also noted by Kavoor et al. (2014) in mania patients. Lower TC levels have been implicated in increasing suicidality by several authors (Sarchiapone et al., 2001; Atmaca et al., 2002; Sullivan et al., 1994; Olié et al., 2011), especially in the male gender (Golier et al., 1995). Gallerani et al. (1995) found lower TC in 331 cases of parasuicides, compared to healthy controls. Sullivan et al. (1994) found a significant relationship between lower TC levels and increased suicidality. Vevera et al. (2003) found low levels of TC in patients with increased tendency for impulsivity and aggression, both of which could lead to a violent pattern of suicidal behaviour. Atmaca et al. (2003) found that suicide attempters had significantly lower TC and leptin levels; those with violent attempts having even lower levels. Fiedorowicz (2007) had also demonstrated that lower TC levels were associated with

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lifetime suicide attempts. Chakrabarti et al. (2004) had found decreased levels of TC and LDL in patients with a history of violent crimes, compared to those without, in an Indian sample.

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Our study found a significant negative correlation between serum TG levels and IRS scores (p<0.05). Liao et al. (2012) reported significant relationship between violent behaviour

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and serum TG levels in psychiatric patients with violent behaviour. The authors had not used specific measures of impulsivity, and assessed violence historically. But it is possible that the

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violent behaviour could be the manifestation of a propensity to act impulsively in these

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patients (Chakrabarti et al., 2004). Park and colleagues (2013) did not find any significant relationship between cholesterol levels and suicide in Korea though, probably because of

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intrinsic characteristics of the study population. Ainiyet and Rybakowski (2014) reported lower TC, TG and LDL levels in those with suicidal thoughts in a Polish population, and

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Chen and colleagues (2015) demonstrated falling TG levels to predict increasing violence in

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patients with schizophrenia spectrum disorders. In present study, we found a lower TG level in patients compared to healthy group, which failed to reach 95% significance level

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(p=0.068) overall, but which was significantly lower when only the male participants were compared. A significant negative correlation of TG levels with IRS scores in patients is in agreement of past literature, and warrants a further characterization of the relationships. Interestingly, we found no significant correlation between HDL levels and

impulsivity, aggression or suicidality in patients with schizophrenia. Some studies showed lower HDL levels to be associated with increased suicide attempts in women (Jokinen et al., 2010; Zhang et al., 2005; Marcinko et al., 2007) but others did not (Conklin and Stanford, 2008). Buydens-Branchey et al. (2000) implicated low HDL levels in personality disorderassociated aggression. However, the sample had a number of potential confounders as substance abuse, nutritional status, and use of historical indices of violence.

Thus,

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inconclusive data on relationship between HDL levels and suicidality, violence and impulsivity warrants further clarification in future studies. We also failed to find a significant impact of BMI on IRS, MOAS or BSI scores. While some report (Gao et al., 2013) an inverse

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linear relationship between BMI and suicidality in depressed suicide attempters (majority BMI ranged between 25.0-29.9 Kg/m2) or with impulsivity in mania (Kavoor et al., 2014),

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others suggest increasing impulsivity with BMI (Murphy et al., 2014; mean BMI 22.78 Kg/m2) and aggression (Pinhey, 2002; Gallup and Wilson, 2009). The influences of BMI on

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these constructs, thus, appear to be complex and are better established at extremes of a range

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(Gao et al., 2013; Kavoor et al., 2014). Our patients, with a mean BMI of 19.72±2.8 Kg/m2, are placed in between these values; and at this level BMI does not appear to influences any of

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these behaviours.

In summary, our findings suggest that patients with schizophrenia, at least during an

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actively symptomatic phase, have serum lipid profiles significantly different from their

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healthy counterparts. They have lower TC, LDL and HDL cholesterol levels compared to matched controls, and these alterations appear to be independent of the effects of

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psychotropic medications used for their treatment. Further, lower TC and LDL levels appear to increase the propensity of these patients towards acting impulsively and indulging in selfharming/suicidal behaviours. Similarly, lower TG values also appear to have a negative impact on impulsivity during symptomatic phase of the illness. These findings provide us with important insights into the biochemical basis of human

behaviour, specifically in terms of the interactions between lipid fractions and serotonergic neurotransmission. Most of the studies investigating these aspects have been done in the west. The western diet differs significantly from average Indian food habit, and a greater proportion of their population follows sedentary lifestyle compared to India. Present study appears to fill in a gap in scientific literature in this regard, in being from a representative

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Indian population and recruiting subjects from predominantly rural background. The fact that the findings from western studies have been replicated in our population reaffirms the universal biological factors determining human behaviour, and strengthens the proposals that

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serum lipid levels could indeed act as surrogate markers for impulsivity, suicidality and a variety of related constructs (Olié et al., 2011; Jokinen et al., 2010) in patients with

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schizophrenia. Since impulsivity and suicidality are factors detrimental for the prognosis of many psychiatric disorders in general and Schizophrenia in particular, the findings warrant

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caution on part of the treating physician. They call for a careful monitoring and pragmatic

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anticipation of untoward incidents in Schizophrenia patients with lipid levels on the lower side of normal. These also suggest careful use of lipid lowering agents and dietary

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modifications in this patient group, at least when they are actively symptomatic. Present study had several limitations. The sample size was modest (N=60), had an

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underrepresentation of female, urban and more affluent subjects; and some variables like

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exact diet and levels of physical activity were not considered. We used rating scales to assess impulsivity, aggression and suicidality; which might have been subject to recall biases and

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reporting errors. Further, since our study was a cross-sectional, conclusions on directionality could not be drawn from the data. Finally, we recruited patients from a tertiary-level hospital, and therefore they might have been severely symptomatic at the time of recruitment. These patients, thus, might not be representative of community-based samples. For future studies in this regard, we suggest larger, randomly drawn population-based samples; a prospective evaluation of patients from recruitment; and a balanced representation from the two genders, thus allowing between-gender comparisons. We also suggest detailed evaluations of factors as dietary habits and physical activity levels, to assess lifestyle factors comprehensively while assessing lipid levels.

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Buydens-Branchey L, Branchey M, Hudson J, Fergeson P. Low HDL cholesterol, aggression and altered central serotonergic activity. Journal of Psychiatric Research 2000;93:93-102. Cardinal RN. Neural systems implicated in delayed and probabilistic reinforcement. Neural Networks 2006;19:1277-1301. Chakrabarti N, Sinha VK, Sinha BNP. A study of lipid profile and apolipoproteins A1 and B: their relationship to aggression and psychopathology in male patients with psychosis. Journal of Forensic Psychiatry and Psychology 2004;15:314-324. Chang SS, Wen CP, Tsai MK, Lawlor DA, Yang YC, Gunnell D. Adiposity, its related biologic risk factors, and suicide: a cohort study of 542,088 Taiwanese adults. American Journal of Epidemiology 2012;175:804-815. Chen SC, Chu NH, Hwu HG, Chen WJ. Trajectory classes of violent behavior and their relationship to lipid levels in schizophrenia inpatients. Journal of Psychiatry Research 2015;66-67:105-111. Conklin SM, Stanford MS. Premeditated aggression is associated with serum cholesterol in abstinent drug and alcohol dependent men. Psychiatry Research 2008;15:283- 287.

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Tables: Table 1: Comparison of the socio-demographic variables between patients and healthy controls Chi Sq./ § Fisher’s p exact

Family Habitat

Groups

Controls N=60 Mean ± SD 32.42±6.7

7.87±4.3

19.72±2.8

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Age(years) Years of Education (years) Body-Mass Index (Kg/m2) *p<0.05, **p<0.01

Patients N=60 Mean ± SD 32.40±6.6

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Variables

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1.000

0.585

§

0.120

0.142

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Marital Status

Male Female Hindu Others Unmarried Married Widowed Separated Urban Sub urban Rural

Controls N=60(%) 46 (23.3) 14 (76.7) 56 (93.3) 4 (6.7) 27 (45) 32 (53.3) 1(1.7) 0 (0) 10 (16.7) 18 (30) 32 (53.3)

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Religion

Patients N=60 (%) 46 (23.3) 14 (76.7) 51 (85) 9 (15) 21 (35) 37 (61.7) 1 (1.7) 1 (1.7) 3 (5) 18 (30) 39 (65)

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Sex

Class

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Groups Variables

4.459

0.391

0.108

t-test for equality of means t

p

-0.014

0.989

11.92±4.8

-4.789

<0.001**

20.46±2.6

-1.463

0.146

Table 2: Comparison of lipid profiles between patients and healthy controls

Variables

Total Cholesterol (mg/dl) Triglyceride (mg/dl) HDL (mg/dl) LDL (mg/dl) VLDL(mg/dl) *p<0.05,** p<0.01;

Groups Patients N=60 Mean ± SD

t-test for equality of means Controls N=60 Mean ± SD

t

p

130.33±12.0

140.55±17.5

-3.720

<0.001**

89.09±22.6

97.38±26.7

-1.841

0.068

40.50±4.4 72.83±9.9 17.70±4.5 HDL=High Density

42.70±3.9 -2.880 78.62±13.6 -2.644 19.13±5.3 -1.571 Lipoproteins; LDL=Low Density

0.005** 0.009** 0.119 Lipoproteins; 24 Page 24 of 28

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Table 3: Psychological profiles of patients (N=60) Variables Mean ± SD 20.95±6.0 PANSS Positive 12.50±6.9 PANSS Negative 27.87±6.6 PANSS General 61.31±13.1 PANSS Total 9.53±4.4 Impulsivity Rating Scale Score 7.90±9.1 Modified Overt Aggression Score 2.73±3.6 Beck Scale for suicidal Ideation Score PANSS=Positive and Negative Syndrome Scale in Schizophrenia

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VLDL=Very Low Density Lipoproteins

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Table 4: Correlation between Lipid profile, BMI and measures of Psychopathology, Impulsivity, Aggression and Suicidality PANSS PANSS PANSS PANSS Variables IRS MOAS BSI Positive Negative General Total Total -0.193 -0.119 -0.149 -0.227 -0.517** -0.183 -0.303* Cholesterol 0.021 0.056 0.047 -0.282* -0.102 -0.060 Triglycerides 0.015 -0.227 -0.196 -0.018 -0.218 -0.248 0.021 -0.080 HDL -0.224 0.006 -0.050 -0.126 -0.387** -0.092 -0.257* LDL -0.016 0.062 0.022 0.037 -0.192 -0.103 -0.082 VLDL 0.139 -0.200 -0.105 -0.094 -0.173 -0.124 -0.247 BMI *p<0.05; **p<0.01; PANSS=Positive and Negative Syndrome Scale for Schizophrenia; IRS=Impulsivity Rating Scale; MOAS=Modified Overt Aggression Scale; BSI=Beck Scale for suicide ideation; HDL=High Density Lipoproteins; LDL=Low Density Lipoproteins; VLDL=Very Low Density Lipoproteins; BMI=Body-Mass index

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Figures:

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Figure 1: Distribution of Total Cholesterol levels between Patients and Controls

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Figure 2: Distribution of HDL levels between Patients and Controls

Figure 3: Distribution of LDL levels between Patients and Controls

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Highlights: 1. An altered lipid homeostasis in patients with schizophrenia could particularly affect the serotonergic system; and thus aggression, impulsivity and suicidality

2. Present study found lower, total Cholesterol, HDL and LDL levels in patients with

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schizophrenia

3. Lower total cholesterol and LDL levels correlated negatively with impulsivity and

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suicidality; while TG level showed a negative correlation with impulsivity in this group

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