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ScienceDirect Comprehensive Psychiatry xx (2014) xxx – xxx www.elsevier.com/locate/comppsych
Relationships between IGF-1, schizophrenia, and treatment of metabolic syndrome Aysegul Demirel⁎, Omer Faruk Demirel, Murat Emül, Alaattin Duran, Mufit Uğur Department of Psychiatry, Cerrahpaşa Faculty of Medicine, Istanbul University, Turkey
Abstract Objectives: The use of atypical antipsychotic drugs in patients with psychiatric illness may result in dyslipidemia, hypertension, glucose intolerance, and abdominal obesity, which are together referred to as metabolic syndrome (MS). To investigate any correlations among insulin-like growth factor-1 (IGF-1), schizophrenia, and MS, we examined the metabolic profiles of patients with schizophrenia taking atypical antipsychotics. Design: Patients with schizophrenia, their siblings, and controls participated in this study (N = 50 in each group). The Structured Clinical Interview for DSM-IV Axis 1 Disorders (SCID I) and the Brief Psychiatric Rating Scale (BPRS) were administered to patients, and SCID I was administered to patients' siblings. We drew blood to measure IGF-1 levels and to determine the metabolic profiles of all participants; we also conducted anthropometric measurements. Results: There were no significant differences in IGF-1 levels between groups. By comparing IGF-1 levels with MS-related parameters, we found that IGF-1 levels were negatively correlated with triglyceride levels in the control group, and positively correlated with HDL levels in the patient group (Pearson's correlation: r = −0.291, P = 0.04, and r = 0.328, P = 0.02, respectively). Compared to their siblings, patients with schizophrenia had a significantly different body mass index, waist circumference, and insulin resistance, and showed a trend toward a difference in glucose levels (ANOVA: P = 0.004, P b 0.0001, P = 0.004, P = 0.072, respectively). Conclusion: A correlation between IGF-1 and MS may significantly influence future therapeutic strategies for MS. In order to determine the role of IGF-1 in schizophrenia, comprehensive longitudinal studies with first-episode drug-naive patients are needed. © 2014 Elsevier Inc. All rights reserved.
1. Introduction The use of atypical antipsychotic medication in patients with psychiatric illnesses may result in dyslipidemia, hypertension, glucose intolerance, and abdominal obesity, collectively referred to as metabolic syndrome (MS) [1]. Compared with the general population, life expectancy in patients with schizophrenia is decreased by 10–20%. The primary reasons for this disparity are thought to be cardiovascular disease and diabetes, which are closely related to MS [2,3]. Recent research on insulin-like growth factor-1 (IGF-1) has suggested a relationship with schizophrenia [4,5]. IGF-1, a growth hormone (GH) mediator, is found in all tissues and organs throughout life, and plays a particularly important ⁎ Corresponding author. Tel.: +90 530 2433777; fax: +90 212 4143128. E-mail address: [email protected] (A. Demirel). http://dx.doi.org/10.1016/j.comppsych.2014.04.008 0010-440X/© 2014 Elsevier Inc. All rights reserved.
role in the central nervous system [6,7]. In vivo studies have shown that IGF-1 stimulates mitosis in sympathetic neuroblasts, plays a role in the survival of embryonic sensory, sympathetic, cortical, and motor neurons, and causes differentiation of oligodendrocytes [8]. Cognitive deficits related to low levels of IGF-1, resulting from GH insufficiency and aging, illustrate the importance of the neuroprotective and anti-apoptotic effects of IGF-1 [9]. Genetic sensitivity and environmental factors play a role in the etiology of schizophrenia. Delay in fetal development, long-term hunger during pregnancy, birth complications, maternal infections, and childhood meningitis increase the risk of schizophrenia. Disruptions of the GH–IGF-I axis likely lead to schizophrenia by causing deficits in early stages of neurodevelopment, and low IGF-1 levels are related to pre/postnatal growth and schizophrenia. Indeed, low birth weight, leanness, and short stature are related to low IGF-1 levels and are associated with an increased risk of
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schizophrenia. For example, infants weighing less than 2.5 kg at birth have a two-fold increase in risk for developing schizophrenia [10]. In a previous study, it was hypothesized that subcutaneous administration of IGF-1 to improve oligodendrocytic function could be used as a potential treatment for patients with schizophrenia [11]. Recently, Palomino et al. found that IGF-1 levels at the time of the first psychotic episode in patients with schizophrenia are correlated with negative symptoms. This finding suggests that alterations in IGF-1 signaling may contribute to the pathophysiology of schizophrenia, and that elevated levels of IGF-1 might represent a compensatory response to attenuate a structural defect in schizophrenia [12]. Prospective studies have shown a relationship between low IGF-1 levels and insulin resistance. For example, in a controlled study of 44 patients with schizophrenia, who had not previously taken antipsychotic drugs, IGF-1 levels were found to be lower in the patients compared to controls, whereas serum insulin levels were found to be higher than average, and these two parameters were found to be negatively correlated [13]. In addition, type 2 diabetes occurs at a rate of 19–31% in families of patients with schizophrenia [14]. It is proposed that the comorbidities of insulin resistance and psychosis are both associated with low IGF-1 levels [5]. In patients with schizophrenia and their first-degree relatives, the incidence of cancer was found to be low. These data might be associated with the protective effects of low IGF-1 levels on prostate, breast, colorectal, and lung cancer [15]. However, that the negative relationship between schizophrenia and cancer is possibly secondary to low IGF-1 levels [10]. Unfortunately, patients with schizophrenia who also have MS develop severe medical conditions. The two main goals of MS treatment are to prevent diabetes and cardiovascular diseases, and eliminating insulin resistance is reported to be a key factor for this [16]. As IGF-1 has anti-diabetogenic and lipolytic roles, IGF-1 treatment has been effective for treating GH insufficiency, type 2 diabetes, insulin resistance, obesity, and hyperlipidemia [17]. The effect of IGF-1 on glucose metabolism was thought to be either on striated muscles, via direct interaction with its own receptors [19], or by inhibiting GH [18]. In a prospective study on healthy individuals with normal glucose levels, a high IGF-1 level in circulation was found to decrease the risk of glucose intolerance and diabetes [20]. A comprehensive study that included patients with type 2 diabetes, showed that in patients with low serum IGF-1 levels, infusion of intravenous IGF-1 decreased the need for insulin [21]. Furthermore, IGF-1 infusion results in a decrease of serum lipid levels in the healthy population. Long-term treatment with IGF-1, in contrast to insulintherapy, decreased the body adipose mass via lipolysis [22]. IGF-1 possibly reduces lipogenesis by inhibiting insulin secretion [22,23]. Apart from its known vasodilatory effects,
IGF-1 can lower blood pressure owing to its positive effects on insulin sensitivity and glycemic control. IGF-1 also shows antihypertensive effects by inhibiting the local renin angiotensin system and by regulating angiotensin type 1 receptors [23]. In the current study, we investigated the incidence of MS and the prevalence of its parameters in relation to antipsychotic drug use in patients with schizophrenia, and compared these data with data obtained from the patients' siblings and a control group. The relationships between schizophrenia, IGF1, and MS parameters were examined. The presence of a possible correlation between the IGF-1 levels of the patients and those of their siblings, but not those of the control group, mimicking a genetic load, was investigated.
2. Methods and materials Fifty patients with chronic schizophrenia, aged 16–60 years, were recruited for this study from the psychosis outpatient clinic of the Department of Psychiatry, Istanbul University, Cerrahpasa Faculty of Medicine, between June and October 2009. The patients were taking atypical antipsychotic drugs either as monotherapy or as part of a combination therapy. The control group (N = 50) and the patients' siblings (N = 50) were aged 16–60 years, and had not been diagnosed as having any axis 1 disorder according to the SCID-I. Any disorders resulting in impaired general medical condition, mental retardation and/or organic brain syndrome were also exclusion criteria. After being informed about the aim and method of the study, oral and written consent were given by each individual. We received approval for our study from the Cerrahpasa Faculty of Medicine Ethical Committee, and the Istanbul University Research Projects Unit financially supported the biochemical tests. 2.1. Data collection tools In the study, a semi-structured interview schedule was used to determine patients' socio-demographic characteristics. Data on age of disease onset, number of hospitalizations, family history of schizophrenia, treatment procedures, and treatment responses were collected. Patients' siblings and the control group's socio-demographic characteristics were also recorded using the same interview schedule. 2.2. Structured clinical interview for DSM-IV axis 1 disorders (SCID I) The structured clinical interview for DSM-IV axis 1 disorders (SCID I) is a semi-structured interview scale used for the diagnosis of major DSM-IV axis 1 disorders. This test was designed by adapting the DSM III-R diagnosis criteria, and revised by the American Psychiatry Association according to DSM-IV diagnostic criteria. The questionnaire begins with socio-demographic data guidelines and includes
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seven diagnosis groups. Turkish adaptation and validity studies were carried out by Çorapcioglu et al. [24]. 2.3. Brief psychiatric rating scale The brief psychiatric rating scale (BPRS) is a 7-point Likert scale, created by Overall and Gorham for evaluating depressive, psychotic, negative symptoms, as well as cognitive functions such as attention and orientation in patients with psychosis [25]. There were 16 items in the original version, but the current scale was expanded to include 18 items. Each item is rated from 0 to 6 according to the severity of the symptoms. The result is calculated by summing the points from each item: 15–30 points indicate a minor syndrome, whereas N30 points indicate a major syndrome.
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Insulin levels were measured using the Abbott C-2000i device, and glucose and lipid levels were measured using the Abbott C 8000 device. The estimation methods used were as follows: for glucose, the oxygen rate method using the oxygen electrode; for triglycerides, the timed-endpoint method; for HDL, the direct method, and for IGF-I and insulin, the radioimmunoassay method. The intra- and interassay CV values for IGF-1 were 4.76% and 5.06%, respectively. The inter-assay CV values were as follows: for glucose (o1.7%), for cholesterol (o1.7%), for LDLcholesterol (o1.03%), for HDL-cholesterol (o1.3%), and for triglycerides (o1.8%). We had no financial or personal relationships with people or organizations that could have inappropriately influenced our study.
2.4. Evaluation of MS
2.6. Statistical analysis
The presence of MS was assessed using the National Cholesterol Education Program Adult Treatment Panel III-A (NCEP ATP III-A) criteria, which specifies the presence of any three of the following five criteria for a diagnosis:
All statistical analyses were conducted with the Statistical Package for Social Sciences for Windows (SPSS) version 16.0. Demographic information was analyzed using descriptive statistics, and the distribution of the data was determined using the Shapiro-Wilk test. For normally distributed data, one-way analysis of variance (ANOVA) and Tukey's honest significant difference (HSD) post hoc test were used, with Bonferroni correction. Categorical variables were compared using the chi-square test. Correlation analysis was performed using Pearson's correlation. Results with a P b 0.05 were considered statistically significant.
• Fasting triglycerides (TG): ≥150 mg/dL • High-density lipoprotein (HDL): Men b40 mg/dL, Women b50 mg/dL • Blood pressure (Systolic BP/Diastolic BP): ≥130/ 85 mm Hg, or use of antihypertensive medication • Fasting glucose (FBS): ≥100 mg/dL, or use of insulin or hypoglycemic medication • Waist circumference: (WC) N102 cm in men and N88 cm in women [26]. 2.5. Method After the clinical interviews, we selected patients who were appropriate for the study and conducted the BPRS and SCID I. Blood samples after one night of fasting were drawn from the patients and controls to evaluate serum levels for the IGF-1 and MS parameters. Blood pressure, waist circumference, height, and weight were then measured. Blood samples were drawn from the patients' siblings who met the inclusion criteria to determine IGF-1, glucose, and insulin levels. Waist circumference, height, and weight were also measured. Blood samples were drawn in the morning at around 8 A.M. from the participant's forearm vein, following an overnight fasting period of at least 8 h. Tubes with 5 mL capacity and containing ethylene diaminetetraacetic acid (EDTA) were used to collect the blood samples. The blood was then carefully and immediately (within a few seconds) transferred from these tubes to centrifuge tubes containing aprotinin (0.6 TIU/mL of blood). The first tube was stored on ice immediately. Before centrifugation, the tubes were gently mixed several times to inhibit the activity of the proteinases. After centrifugation at 1600 × g for 15 min at 41 °C, the plasma was obtained and stored at −80 °C until the time of assay.
3. Results There was no statistically significant difference between the three groups for gender, age or duration of education (χ 2 = 1.860, P = 0.395; F = 0.112, P = 0.894, and F = 1.567, P = 0.212, respectively). Socio-demographic data for each group are provided in Table 1, and clinical data for the patients are shown in Table 2. The average age of disease onset was 24.6 ± 6.6 years and the average disease duration was 11.8 ± 9.7 years. The average number of hospitalizations was 3.8 ± 4.7 for patients with schizophrenia. There was a complete drug response in 18%, partial drug response in 80%, and drug resistance in 2% of the patients. In 11 (22%) of the patients, family history for schizophrenia was positive and in 4 (8%) patients, history of hypertension (N = 2), hyperlipidemia (N = 2), and/or diabetes mellitus (N = 2) was positive. Based on the NCEP ATP III-A criteria, MS was found in 21 (42%) of the patients and 10 (20%) of the control group, and this difference was statistically significant (χ 2 = 5.657, P = 0.017). The frequency of MS parameters in the control and the patient groups was as follows: WC (36% vs. 58%), FBS (8% vs. 16%), TG (18% vs. 52%), HDL (70% vs. 78%), and hypertension (16% vs. 34%). Hypertriglyceridemia, abdominal obesity, and hypertension frequencies were significantly higher in the patient compared with the control
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Table 1 Socio-demographic data of each groups.
Age Gender (n) • Male/female Marital status • Married • Single • Widowed Education (year) Children (n) Employee • Working • Non-working Smoking • Smoker • Non-smoker
p1
Schizophrenia
Siblings
Controls
36.46 ± 11.20
35,66 ± 11,12
35.54 ± 9.20
37/13
31/19
32/18
χ 2 = 1.86; p = 0.395
10 34 6 8.94 ± 3.2 0.5 ± 0.99
27 23 0 10.1 ± 3.5 0.4 ± 0.75
33 15 2 9.8 ± 3.5 1.34 ± 1.4
χ 2 = 26.78; p b 0.0001⁎⁎⁎
13 37
30 20
47 3
χ 2 = 48.16; p b 0.0001⁎⁎⁎
32 18
18 32
22 28
χ 2 = 8.33; p = 0.016⁎
1.000
0.29 1.000
p2 1.000
1.000 b0.0001⁎⁎⁎
p3 1.000
0.53 0.001⁎⁎
One Way ANOVA post hoc Tukey HSD test after Bonferroni correction. p 1, schizophrenia vs. siblings; p 2, siblings vs. controls; p 3, schizophrenia vs. control. ⁎ p b 0.05. ⁎⁎ p b 0.01. ⁎⁎⁎ p b 0.0001.
group (χ 2 = 12.70, P b 0.001; χ 2 = 4.857, P = 0.028; χ 2 = 4.320, P = 0.038, respectively). For the between groups analyses of glucose, insulin, insulin resistance (HOMA-IR), IGF-1, BMI, and WC, statistically significant results were found only for average BMI and WC (F = 9.625, P b 0.0001, and F = 9.970, P b 0.0001, respectively), while mean IGF-1 levels did not differ between groups (F = 0.003, P = 0.997). When schizophrenia vs. siblings and schizophrenia vs. control groups were compared on the same parameters, significant results were found for BMI (P = 0.004 for schizophrenia vs. sibling, P b 0.0001 schizophrenia vs. controls) and WC (P b 0.0001 for schizophrenia vs. sibling, P = 0.001 schizophrenia vs. controls). The mean HOMA-IR score in patients with schizophrenia was significantly higher than that of their siblings (P = 0.004), but was comparable to that of healthy controls (P = 0.433). Strikingly, there were no
Table 2 The summary of clinical data of patients with schizophrenia.
BPRS asymptomatic BPRS minor BPRS major Duration of illness (years) Age of onset Number of hospitalization Family history for schizophrenia Other medical conditions • Diabetes mellitus • Hypertension • Hyperlipidemia
n
Mean ± SD
5 28 17
9.20 20.92 40.05 11.8 24.6 3.8
4 (%8) 4 2 2 2
± ± ± ± ± ±
3.11 2.89 8.81 9.7 6.6 4.7
differences between siblings and healthy controls for the abovementioned parameters (Table 3). We found that IGF-1 levels negatively correlated with only one MS parameter, triglyceride levels in the control group (r = −0.291, P = 0.04). We did not find a correlation between IGF-1 and other parameters (BPRS, HDL, TG, and FBS). However, a positive correlation was found between levels of serum HDL and IGF-1 in the patient group (r = 0.328, P = 0.02). The patients included in this study were being treated with clozapine, olanzapine, risperidone, quetiapine, or aripiprazole monotherapy (88%), or with combined antipsychotic therapy (12%). The most frequently used drugs were clozapine (19%) and olanzapine (15%). There were no significant differences between these groups in terms of MS frequency (40.9% vs. 50%). In addition, no significant differences were observed in the MS occurrence among patients using different atypical antipsychotic drugs. Schizophrenia in the patients who were diagnosed with MS was mostly paranoid (52.4%) or residual (33.3%) type, but the difference in MS prevalence according to schizophrenia subtypes was not significant (χ 2 = 3.004, P = 0.223). Among patients diagnosed with MS, partial recovery was observed in 85.7% of the patients, and 14.3% showed complete recovery. For those without a diagnosis of MS, the ratios were 75.9% and 20.7%, respectively, but the difference in frequency of MS for a complete compared to a partial response to treatment was not significant (χ 2 = 0.408, P = 0.523). There was no significant difference between MSpositive and negative patients with schizophrenia in terms of disease duration or number of hospitalizations and MS frequency (Student t-test, P = 0.068, P = 0.073, respectively). When the levels of IGF-1 were analyzed based on schizophrenia subtypes, low IGF-1 levels were detected mostly in
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Table 3 Comparison ¥ of glucose parameters, IGF-1 and anthropometric measurements between each group.
BMI (kg/m 2) Waist (cm) Glucose (mg/dl) Insulin (pmol/L) IGF-1 (ng/ml) HOMA-IR
Schizophrenia
Sibling
29.77 102.42 82.64 10.86 176.06 2.21
26.62 93.22 76,94 8,30 175,04 1,61
± ± ± ± ± ±
5.38 12.18 15.84 5.56 81.65 1.19
Control ± ± ± ± ± ±
4.46 11.10 8,817 6,63 72,14 1,48
25.74 93.62 80.22 8.76 175.04 1.89
± ± ± ± ± ±
4.56 11.87 11.87 10.15 64.01 2.66
p1
p2
p3
0.004⁎⁎ b0.0001⁎⁎⁎ 0.072 0.296 1.000 0.004⁎⁎
1.000 1.000 0.574 1.000 1.000 0,999
b0.00001⁎⁎⁎ 0.001⁎⁎ 1.000 0.524 1.000 0.433
p 1, schizophrenia vs. siblings; p 2, siblings vs. controls; p 3, schizophrenia vs. control. ¥ One Way ANOVA post Hoc Tukey HSD test after Bonferroni correction. ⁎⁎ p b 0.01. ⁎⁎⁎ p b 0.0001.
patients with residual (54.5%) and paranoid types (37.5%). However, differences in the means for low serum IGF-1 levels and low IGF-1 that were detected in schizophrenia subtypes were not statistically significant (Pearson's chi-square: P = 0.565, ANOVA: P = 0.139, respectively).
4. Discussion The aim of this study was to determine the prevalence of MS in patients with schizophrenia, to assess a range of parameters that may emerge during the use of atypical antipsychotic drugs in this cohort, and to determine if there is a relationship between schizophrenia, MS prevalence, and serum IGF-1 levels. We also aimed to evaluate the possible effects of MS on the clinical course of the disease. Both genetic sensitivity and environmental factors have a strong impact on the etiology of schizophrenia and disruption of the GH–IGF-1 axis might cause schizophrenia due to deficits in the early stages of neurodevelopment [10]. Gunnel and Holly established an “IGF-1 deficiency hypothesis” in schizophrenia pathogenesis [10]; however, our findings did not support this hypothesis. In our study, serum IGF-1 levels were comparable across all groups. Moreover, there was no difference in the prevalence of low IGF-1 levels across the three groups, adding to the few reports of low IGF-1 levels in patients with schizophrenia. However, as the patients in our study were being treated with atypical antipsychotic drugs, the use of typical antipsychotic drugs used in a combination treatment regimen in patients with schizophrenia should now be studied. Venkatasubramanian et al. examined the effect of serum IGF-1 in schizophrenia pathogenesis and showed that serum IGF-1 levels in patients with schizophrenia were lower when compared with a control group. In addition, they reported an inverse relationship between serum IGF-1 levels and patients' positive symptom scores. These results suggest that IGF-1 is potentially involved in the pathogenesis of schizophrenia [13]. Consistent with this, Yang et al. demonstrated that the children of patients with schizophrenia had significantly lower IGF-1 levels relative to control groups [27]. Moreover, patients with schizophrenia under a
clozapine treatment regimen were compared with obese individuals and healthy controls, and serum IGF-1 levels were found to be lower in the schizophrenia group than in the other two groups [28]. Furthermore, patients with schizophrenia had above-normal levels of serum IGF-2, which is related to atherogenic lipoproteins in these patients [29]. However, by investigating whether plasma IGF-1 levels were altered at the onset of psychiatric disorders such as schizophrenia or bipolar disorder, Palomino et al. found no difference in IGF-1 levels between patients and controls [12]. Single nucleotide polymorphism studies also support the hypothesis that the IGF-1 gene is not involved in schizophrenia [30,31]. Serum IGF-1 levels can also vary with age. That increased insulin resistance restricts IGF-1-mediated glucose uptake into muscle cells suggests that this is directly dependent on aging. As plasma IGF-1 levels show a decrease of at least 50% due to aging [32], diminished GH secretion after the age of 30 is a likely cause. In our study, there is a possibility that the IGF-1 levels were higher than expected since on average, our subjects were relatively young (patients, 36.4 ± 11.2, siblings, 35.6 ± 11.1, and controls, 35.5 ± 9 years old, respectively). In addition, GH, thyroid and parathyroid hormones, insulin, estrogens, androgens, inflammatory cytokines, BMI, a protein-rich diet, and exercise can all impact serum IGF-1 levels [33]. In our study, one or more of these factors may have been a confounding variable. The non-significant difference of IGF-1 levels between groups might also be explained by the cross-sectional nature of our study and the limited sample size. We found that IGF-1 levels were negatively correlated only with triglyceride levels in the control group, but positively correlated only with HDL levels in the patient group. As a result, IGF-1 was only correlated with the dyslipidemia component of MS in the patient and control groups. Our data are concordant with the idea that long-term IGF-1 therapy leads to a decrease in body lipid mass and lipolysis [22]. In a cross-sectional study on the relationship between coronary artery risk factors, IGF-1, and IGFBP-3, Colangelo et al. evaluated 544 Black and 747 White males (age range 20–34). After testing the males in their second, seventh and tenth years, they observed a negative correlation
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between serum IGF-1 and serum lipid levels, especially in white males [21]. Apart from the lipolytic effects of IGF-1, its role in the treatment of hypertension and diabetes has also been reported, which lends support to its predicted role in MS treatment [17,21,23]. In an attempt to understand MS, several studies on its prevalence in schizophrenia and similar psychotic diseases have been performed. In a recent meta-analysis, it was found that half of the patients with schizophrenia were obese, onefifth were hyperglycemic, and at least two-fifths had lipid anomalies [34]. Interestingly, MS prevalence is 20–60% in patients with schizophrenia, which is twice that of the general population [1]. In our study, MS was found in 20% of the control group and in 42% of the patients (P = 0.01), and the latter value was higher than that reported in certain general population-based Turkish and American studies [35–38]. This result emphasizes the view that compared to the healthy population, MS and related metabolic disorders are seen in a higher ratio in patients prescribed antipsychotics. As schizophrenia and diabetes may be comorbid diseases, independent of antipsychotic drug therapy [14], patients with first episode drug-naive schizophrenia and their first-degree relatives were found to have glucose intolerance rates of 10.5% and 18.2%, respectively [39]. In our study, 4% of the patients had a history of diabetes and 16% of patients had impaired fasting glucose, yet none of the siblings had diabetes or impaired fasting glucose. Comparisons of serum glucose, insulin, and insulin resistance between all groups did not yield any statistically significant differences. However, when schizophrenia/siblings and schizophrenia/ control groups were compared based on the same parameters, there was a significant difference in insulin resistance in the schizophrenia/siblings group, and a trend for a difference between glucose levels. Thus, in agreement with previous work [39], our data suggests that both patients with schizophrenia and their siblings have a tendency to develop insulin resistance and diabetes mellitus. Consistent with previous studies, we did not find any significant difference in the occurrence of MS between mono- and combined atypical therapy [40], and between patients using different atypical antipsychotics [41,42]. In addition, while it has been proposed that a long disease duration and advanced age are important risk factors for MS [43], we did not find any link between MS and disease duration or number of hospitalizations. Although there are similar data in the literature [41,44], a meta-analysis by Mitchell et al. revealed that advanced age has a modest effect on MS prevalence, but disease duration is the most pertinent factor [34]. We also found no significant differences in disease subtypes, treatment response, and MS.
5. Conclusion Since we did not find any significant difference between groups in terms of IGF-1 levels, our findings do not support
the hypothesis that low IGF-1 levels play a role in the etiopathogenesis of schizophrenia. IGF-1 levels negatively correlated with triglyceride levels in the control group, and positively correlated with HDL levels in the patient group. Thus, our findings suggest a lipolytic effect of IGF-1. Since there are reports on the therapeutic effects of IGF-1 on other components of MS and in related metabolic disorders, IGF-1 is a promising candidate for treating patients with schizophrenia who are exposed to greater risk of MS than healthy individuals are. In order to determine the possible role of IGF-1 in the etiopathogenesis of schizophrenia and in MS treatment, comprehensive prospective studies, including first-episode drug-naive patients with schizophrenia, might provide more conclusive results.
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ScienceDirect Comprehensive Psychiatry xx (2014) xxx – xxx www.elsevier.com/locate/comppsych
Relationships between IGF-1, schizophrenia, and treatment of metabolic syndrome Aysegul Demirel⁎, Omer Faruk Demirel, Murat Emül, Alaattin Duran, Mufit Uğur Department of Psychiatry, Cerrahpaşa Faculty of Medicine, Istanbul University, Turkey
Abstract Objectives: The use of atypical antipsychotic drugs in patients with psychiatric illness may result in dyslipidemia, hypertension, glucose intolerance, and abdominal obesity, which are together referred to as metabolic syndrome (MS). To investigate any correlations among insulin-like growth factor-1 (IGF-1), schizophrenia, and MS, we examined the metabolic profiles of patients with schizophrenia taking atypical antipsychotics. Design: Patients with schizophrenia, their siblings, and controls participated in this study (N = 50 in each group). The Structured Clinical Interview for DSM-IV Axis 1 Disorders (SCID I) and the Brief Psychiatric Rating Scale (BPRS) were administered to patients, and SCID I was administered to patients' siblings. We drew blood to measure IGF-1 levels and to determine the metabolic profiles of all participants; we also conducted anthropometric measurements. Results: There were no significant differences in IGF-1 levels between groups. By comparing IGF-1 levels with MS-related parameters, we found that IGF-1 levels were negatively correlated with triglyceride levels in the control group, and positively correlated with HDL levels in the patient group (Pearson's correlation: r = −0.291, P = 0.04, and r = 0.328, P = 0.02, respectively). Compared to their siblings, patients with schizophrenia had a significantly different body mass index, waist circumference, and insulin resistance, and showed a trend toward a difference in glucose levels (ANOVA: P = 0.004, P b 0.0001, P = 0.004, P = 0.072, respectively). Conclusion: A correlation between IGF-1 and MS may significantly influence future therapeutic strategies for MS. In order to determine the role of IGF-1 in schizophrenia, comprehensive longitudinal studies with first-episode drug-naive patients are needed. © 2014 Elsevier Inc. All rights reserved.
1. Introduction The use of atypical antipsychotic medication in patients with psychiatric illnesses may result in dyslipidemia, hypertension, glucose intolerance, and abdominal obesity, collectively referred to as metabolic syndrome (MS) [1]. Compared with the general population, life expectancy in patients with schizophrenia is decreased by 10–20%. The primary reasons for this disparity are thought to be cardiovascular disease and diabetes, which are closely related to MS [2,3]. Recent research on insulin-like growth factor-1 (IGF-1) has suggested a relationship with schizophrenia [4,5]. IGF-1, a growth hormone (GH) mediator, is found in all tissues and organs throughout life, and plays a particularly important ⁎ Corresponding author. Tel.: +90 530 2433777; fax: +90 212 4143128. E-mail address: [email protected] (A. Demirel). http://dx.doi.org/10.1016/j.comppsych.2014.04.008 0010-440X/© 2014 Elsevier Inc. All rights reserved.
role in the central nervous system [6,7]. In vivo studies have shown that IGF-1 stimulates mitosis in sympathetic neuroblasts, plays a role in the survival of embryonic sensory, sympathetic, cortical, and motor neurons, and causes differentiation of oligodendrocytes [8]. Cognitive deficits related to low levels of IGF-1, resulting from GH insufficiency and aging, illustrate the importance of the neuroprotective and anti-apoptotic effects of IGF-1 [9]. Genetic sensitivity and environmental factors play a role in the etiology of schizophrenia. Delay in fetal development, long-term hunger during pregnancy, birth complications, maternal infections, and childhood meningitis increase the risk of schizophrenia. Disruptions of the GH–IGF-I axis likely lead to schizophrenia by causing deficits in early stages of neurodevelopment, and low IGF-1 levels are related to pre/postnatal growth and schizophrenia. Indeed, low birth weight, leanness, and short stature are related to low IGF-1 levels and are associated with an increased risk of
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schizophrenia. For example, infants weighing less than 2.5 kg at birth have a two-fold increase in risk for developing schizophrenia [10]. In a previous study, it was hypothesized that subcutaneous administration of IGF-1 to improve oligodendrocytic function could be used as a potential treatment for patients with schizophrenia [11]. Recently, Palomino et al. found that IGF-1 levels at the time of the first psychotic episode in patients with schizophrenia are correlated with negative symptoms. This finding suggests that alterations in IGF-1 signaling may contribute to the pathophysiology of schizophrenia, and that elevated levels of IGF-1 might represent a compensatory response to attenuate a structural defect in schizophrenia [12]. Prospective studies have shown a relationship between low IGF-1 levels and insulin resistance. For example, in a controlled study of 44 patients with schizophrenia, who had not previously taken antipsychotic drugs, IGF-1 levels were found to be lower in the patients compared to controls, whereas serum insulin levels were found to be higher than average, and these two parameters were found to be negatively correlated [13]. In addition, type 2 diabetes occurs at a rate of 19–31% in families of patients with schizophrenia [14]. It is proposed that the comorbidities of insulin resistance and psychosis are both associated with low IGF-1 levels [5]. In patients with schizophrenia and their first-degree relatives, the incidence of cancer was found to be low. These data might be associated with the protective effects of low IGF-1 levels on prostate, breast, colorectal, and lung cancer [15]. However, that the negative relationship between schizophrenia and cancer is possibly secondary to low IGF-1 levels [10]. Unfortunately, patients with schizophrenia who also have MS develop severe medical conditions. The two main goals of MS treatment are to prevent diabetes and cardiovascular diseases, and eliminating insulin resistance is reported to be a key factor for this [16]. As IGF-1 has anti-diabetogenic and lipolytic roles, IGF-1 treatment has been effective for treating GH insufficiency, type 2 diabetes, insulin resistance, obesity, and hyperlipidemia [17]. The effect of IGF-1 on glucose metabolism was thought to be either on striated muscles, via direct interaction with its own receptors [19], or by inhibiting GH [18]. In a prospective study on healthy individuals with normal glucose levels, a high IGF-1 level in circulation was found to decrease the risk of glucose intolerance and diabetes [20]. A comprehensive study that included patients with type 2 diabetes, showed that in patients with low serum IGF-1 levels, infusion of intravenous IGF-1 decreased the need for insulin [21]. Furthermore, IGF-1 infusion results in a decrease of serum lipid levels in the healthy population. Long-term treatment with IGF-1, in contrast to insulintherapy, decreased the body adipose mass via lipolysis [22]. IGF-1 possibly reduces lipogenesis by inhibiting insulin secretion [22,23]. Apart from its known vasodilatory effects,
IGF-1 can lower blood pressure owing to its positive effects on insulin sensitivity and glycemic control. IGF-1 also shows antihypertensive effects by inhibiting the local renin angiotensin system and by regulating angiotensin type 1 receptors [23]. In the current study, we investigated the incidence of MS and the prevalence of its parameters in relation to antipsychotic drug use in patients with schizophrenia, and compared these data with data obtained from the patients' siblings and a control group. The relationships between schizophrenia, IGF1, and MS parameters were examined. The presence of a possible correlation between the IGF-1 levels of the patients and those of their siblings, but not those of the control group, mimicking a genetic load, was investigated.
2. Methods and materials Fifty patients with chronic schizophrenia, aged 16–60 years, were recruited for this study from the psychosis outpatient clinic of the Department of Psychiatry, Istanbul University, Cerrahpasa Faculty of Medicine, between June and October 2009. The patients were taking atypical antipsychotic drugs either as monotherapy or as part of a combination therapy. The control group (N = 50) and the patients' siblings (N = 50) were aged 16–60 years, and had not been diagnosed as having any axis 1 disorder according to the SCID-I. Any disorders resulting in impaired general medical condition, mental retardation and/or organic brain syndrome were also exclusion criteria. After being informed about the aim and method of the study, oral and written consent were given by each individual. We received approval for our study from the Cerrahpasa Faculty of Medicine Ethical Committee, and the Istanbul University Research Projects Unit financially supported the biochemical tests. 2.1. Data collection tools In the study, a semi-structured interview schedule was used to determine patients' socio-demographic characteristics. Data on age of disease onset, number of hospitalizations, family history of schizophrenia, treatment procedures, and treatment responses were collected. Patients' siblings and the control group's socio-demographic characteristics were also recorded using the same interview schedule. 2.2. Structured clinical interview for DSM-IV axis 1 disorders (SCID I) The structured clinical interview for DSM-IV axis 1 disorders (SCID I) is a semi-structured interview scale used for the diagnosis of major DSM-IV axis 1 disorders. This test was designed by adapting the DSM III-R diagnosis criteria, and revised by the American Psychiatry Association according to DSM-IV diagnostic criteria. The questionnaire begins with socio-demographic data guidelines and includes
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seven diagnosis groups. Turkish adaptation and validity studies were carried out by Çorapcioglu et al. [24]. 2.3. Brief psychiatric rating scale The brief psychiatric rating scale (BPRS) is a 7-point Likert scale, created by Overall and Gorham for evaluating depressive, psychotic, negative symptoms, as well as cognitive functions such as attention and orientation in patients with psychosis [25]. There were 16 items in the original version, but the current scale was expanded to include 18 items. Each item is rated from 0 to 6 according to the severity of the symptoms. The result is calculated by summing the points from each item: 15–30 points indicate a minor syndrome, whereas N30 points indicate a major syndrome.
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Insulin levels were measured using the Abbott C-2000i device, and glucose and lipid levels were measured using the Abbott C 8000 device. The estimation methods used were as follows: for glucose, the oxygen rate method using the oxygen electrode; for triglycerides, the timed-endpoint method; for HDL, the direct method, and for IGF-I and insulin, the radioimmunoassay method. The intra- and interassay CV values for IGF-1 were 4.76% and 5.06%, respectively. The inter-assay CV values were as follows: for glucose (o1.7%), for cholesterol (o1.7%), for LDLcholesterol (o1.03%), for HDL-cholesterol (o1.3%), and for triglycerides (o1.8%). We had no financial or personal relationships with people or organizations that could have inappropriately influenced our study.
2.4. Evaluation of MS
2.6. Statistical analysis
The presence of MS was assessed using the National Cholesterol Education Program Adult Treatment Panel III-A (NCEP ATP III-A) criteria, which specifies the presence of any three of the following five criteria for a diagnosis:
All statistical analyses were conducted with the Statistical Package for Social Sciences for Windows (SPSS) version 16.0. Demographic information was analyzed using descriptive statistics, and the distribution of the data was determined using the Shapiro-Wilk test. For normally distributed data, one-way analysis of variance (ANOVA) and Tukey's honest significant difference (HSD) post hoc test were used, with Bonferroni correction. Categorical variables were compared using the chi-square test. Correlation analysis was performed using Pearson's correlation. Results with a P b 0.05 were considered statistically significant.
• Fasting triglycerides (TG): ≥150 mg/dL • High-density lipoprotein (HDL): Men b40 mg/dL, Women b50 mg/dL • Blood pressure (Systolic BP/Diastolic BP): ≥130/ 85 mm Hg, or use of antihypertensive medication • Fasting glucose (FBS): ≥100 mg/dL, or use of insulin or hypoglycemic medication • Waist circumference: (WC) N102 cm in men and N88 cm in women [26]. 2.5. Method After the clinical interviews, we selected patients who were appropriate for the study and conducted the BPRS and SCID I. Blood samples after one night of fasting were drawn from the patients and controls to evaluate serum levels for the IGF-1 and MS parameters. Blood pressure, waist circumference, height, and weight were then measured. Blood samples were drawn from the patients' siblings who met the inclusion criteria to determine IGF-1, glucose, and insulin levels. Waist circumference, height, and weight were also measured. Blood samples were drawn in the morning at around 8 A.M. from the participant's forearm vein, following an overnight fasting period of at least 8 h. Tubes with 5 mL capacity and containing ethylene diaminetetraacetic acid (EDTA) were used to collect the blood samples. The blood was then carefully and immediately (within a few seconds) transferred from these tubes to centrifuge tubes containing aprotinin (0.6 TIU/mL of blood). The first tube was stored on ice immediately. Before centrifugation, the tubes were gently mixed several times to inhibit the activity of the proteinases. After centrifugation at 1600 × g for 15 min at 41 °C, the plasma was obtained and stored at −80 °C until the time of assay.
3. Results There was no statistically significant difference between the three groups for gender, age or duration of education (χ 2 = 1.860, P = 0.395; F = 0.112, P = 0.894, and F = 1.567, P = 0.212, respectively). Socio-demographic data for each group are provided in Table 1, and clinical data for the patients are shown in Table 2. The average age of disease onset was 24.6 ± 6.6 years and the average disease duration was 11.8 ± 9.7 years. The average number of hospitalizations was 3.8 ± 4.7 for patients with schizophrenia. There was a complete drug response in 18%, partial drug response in 80%, and drug resistance in 2% of the patients. In 11 (22%) of the patients, family history for schizophrenia was positive and in 4 (8%) patients, history of hypertension (N = 2), hyperlipidemia (N = 2), and/or diabetes mellitus (N = 2) was positive. Based on the NCEP ATP III-A criteria, MS was found in 21 (42%) of the patients and 10 (20%) of the control group, and this difference was statistically significant (χ 2 = 5.657, P = 0.017). The frequency of MS parameters in the control and the patient groups was as follows: WC (36% vs. 58%), FBS (8% vs. 16%), TG (18% vs. 52%), HDL (70% vs. 78%), and hypertension (16% vs. 34%). Hypertriglyceridemia, abdominal obesity, and hypertension frequencies were significantly higher in the patient compared with the control
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Table 1 Socio-demographic data of each groups.
Age Gender (n) • Male/female Marital status • Married • Single • Widowed Education (year) Children (n) Employee • Working • Non-working Smoking • Smoker • Non-smoker
p1
Schizophrenia
Siblings
Controls
36.46 ± 11.20
35,66 ± 11,12
35.54 ± 9.20
37/13
31/19
32/18
χ 2 = 1.86; p = 0.395
10 34 6 8.94 ± 3.2 0.5 ± 0.99
27 23 0 10.1 ± 3.5 0.4 ± 0.75
33 15 2 9.8 ± 3.5 1.34 ± 1.4
χ 2 = 26.78; p b 0.0001⁎⁎⁎
13 37
30 20
47 3
χ 2 = 48.16; p b 0.0001⁎⁎⁎
32 18
18 32
22 28
χ 2 = 8.33; p = 0.016⁎
1.000
0.29 1.000
p2 1.000
1.000 b0.0001⁎⁎⁎
p3 1.000
0.53 0.001⁎⁎
One Way ANOVA post hoc Tukey HSD test after Bonferroni correction. p 1, schizophrenia vs. siblings; p 2, siblings vs. controls; p 3, schizophrenia vs. control. ⁎ p b 0.05. ⁎⁎ p b 0.01. ⁎⁎⁎ p b 0.0001.
group (χ 2 = 12.70, P b 0.001; χ 2 = 4.857, P = 0.028; χ 2 = 4.320, P = 0.038, respectively). For the between groups analyses of glucose, insulin, insulin resistance (HOMA-IR), IGF-1, BMI, and WC, statistically significant results were found only for average BMI and WC (F = 9.625, P b 0.0001, and F = 9.970, P b 0.0001, respectively), while mean IGF-1 levels did not differ between groups (F = 0.003, P = 0.997). When schizophrenia vs. siblings and schizophrenia vs. control groups were compared on the same parameters, significant results were found for BMI (P = 0.004 for schizophrenia vs. sibling, P b 0.0001 schizophrenia vs. controls) and WC (P b 0.0001 for schizophrenia vs. sibling, P = 0.001 schizophrenia vs. controls). The mean HOMA-IR score in patients with schizophrenia was significantly higher than that of their siblings (P = 0.004), but was comparable to that of healthy controls (P = 0.433). Strikingly, there were no
Table 2 The summary of clinical data of patients with schizophrenia.
BPRS asymptomatic BPRS minor BPRS major Duration of illness (years) Age of onset Number of hospitalization Family history for schizophrenia Other medical conditions • Diabetes mellitus • Hypertension • Hyperlipidemia
n
Mean ± SD
5 28 17
9.20 20.92 40.05 11.8 24.6 3.8
4 (%8) 4 2 2 2
± ± ± ± ± ±
3.11 2.89 8.81 9.7 6.6 4.7
differences between siblings and healthy controls for the abovementioned parameters (Table 3). We found that IGF-1 levels negatively correlated with only one MS parameter, triglyceride levels in the control group (r = −0.291, P = 0.04). We did not find a correlation between IGF-1 and other parameters (BPRS, HDL, TG, and FBS). However, a positive correlation was found between levels of serum HDL and IGF-1 in the patient group (r = 0.328, P = 0.02). The patients included in this study were being treated with clozapine, olanzapine, risperidone, quetiapine, or aripiprazole monotherapy (88%), or with combined antipsychotic therapy (12%). The most frequently used drugs were clozapine (19%) and olanzapine (15%). There were no significant differences between these groups in terms of MS frequency (40.9% vs. 50%). In addition, no significant differences were observed in the MS occurrence among patients using different atypical antipsychotic drugs. Schizophrenia in the patients who were diagnosed with MS was mostly paranoid (52.4%) or residual (33.3%) type, but the difference in MS prevalence according to schizophrenia subtypes was not significant (χ 2 = 3.004, P = 0.223). Among patients diagnosed with MS, partial recovery was observed in 85.7% of the patients, and 14.3% showed complete recovery. For those without a diagnosis of MS, the ratios were 75.9% and 20.7%, respectively, but the difference in frequency of MS for a complete compared to a partial response to treatment was not significant (χ 2 = 0.408, P = 0.523). There was no significant difference between MSpositive and negative patients with schizophrenia in terms of disease duration or number of hospitalizations and MS frequency (Student t-test, P = 0.068, P = 0.073, respectively). When the levels of IGF-1 were analyzed based on schizophrenia subtypes, low IGF-1 levels were detected mostly in
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Table 3 Comparison ¥ of glucose parameters, IGF-1 and anthropometric measurements between each group.
BMI (kg/m 2) Waist (cm) Glucose (mg/dl) Insulin (pmol/L) IGF-1 (ng/ml) HOMA-IR
Schizophrenia
Sibling
29.77 102.42 82.64 10.86 176.06 2.21
26.62 93.22 76,94 8,30 175,04 1,61
± ± ± ± ± ±
5.38 12.18 15.84 5.56 81.65 1.19
Control ± ± ± ± ± ±
4.46 11.10 8,817 6,63 72,14 1,48
25.74 93.62 80.22 8.76 175.04 1.89
± ± ± ± ± ±
4.56 11.87 11.87 10.15 64.01 2.66
p1
p2
p3
0.004⁎⁎ b0.0001⁎⁎⁎ 0.072 0.296 1.000 0.004⁎⁎
1.000 1.000 0.574 1.000 1.000 0,999
b0.00001⁎⁎⁎ 0.001⁎⁎ 1.000 0.524 1.000 0.433
p 1, schizophrenia vs. siblings; p 2, siblings vs. controls; p 3, schizophrenia vs. control. ¥ One Way ANOVA post Hoc Tukey HSD test after Bonferroni correction. ⁎⁎ p b 0.01. ⁎⁎⁎ p b 0.0001.
patients with residual (54.5%) and paranoid types (37.5%). However, differences in the means for low serum IGF-1 levels and low IGF-1 that were detected in schizophrenia subtypes were not statistically significant (Pearson's chi-square: P = 0.565, ANOVA: P = 0.139, respectively).
4. Discussion The aim of this study was to determine the prevalence of MS in patients with schizophrenia, to assess a range of parameters that may emerge during the use of atypical antipsychotic drugs in this cohort, and to determine if there is a relationship between schizophrenia, MS prevalence, and serum IGF-1 levels. We also aimed to evaluate the possible effects of MS on the clinical course of the disease. Both genetic sensitivity and environmental factors have a strong impact on the etiology of schizophrenia and disruption of the GH–IGF-1 axis might cause schizophrenia due to deficits in the early stages of neurodevelopment [10]. Gunnel and Holly established an “IGF-1 deficiency hypothesis” in schizophrenia pathogenesis [10]; however, our findings did not support this hypothesis. In our study, serum IGF-1 levels were comparable across all groups. Moreover, there was no difference in the prevalence of low IGF-1 levels across the three groups, adding to the few reports of low IGF-1 levels in patients with schizophrenia. However, as the patients in our study were being treated with atypical antipsychotic drugs, the use of typical antipsychotic drugs used in a combination treatment regimen in patients with schizophrenia should now be studied. Venkatasubramanian et al. examined the effect of serum IGF-1 in schizophrenia pathogenesis and showed that serum IGF-1 levels in patients with schizophrenia were lower when compared with a control group. In addition, they reported an inverse relationship between serum IGF-1 levels and patients' positive symptom scores. These results suggest that IGF-1 is potentially involved in the pathogenesis of schizophrenia [13]. Consistent with this, Yang et al. demonstrated that the children of patients with schizophrenia had significantly lower IGF-1 levels relative to control groups [27]. Moreover, patients with schizophrenia under a
clozapine treatment regimen were compared with obese individuals and healthy controls, and serum IGF-1 levels were found to be lower in the schizophrenia group than in the other two groups [28]. Furthermore, patients with schizophrenia had above-normal levels of serum IGF-2, which is related to atherogenic lipoproteins in these patients [29]. However, by investigating whether plasma IGF-1 levels were altered at the onset of psychiatric disorders such as schizophrenia or bipolar disorder, Palomino et al. found no difference in IGF-1 levels between patients and controls [12]. Single nucleotide polymorphism studies also support the hypothesis that the IGF-1 gene is not involved in schizophrenia [30,31]. Serum IGF-1 levels can also vary with age. That increased insulin resistance restricts IGF-1-mediated glucose uptake into muscle cells suggests that this is directly dependent on aging. As plasma IGF-1 levels show a decrease of at least 50% due to aging [32], diminished GH secretion after the age of 30 is a likely cause. In our study, there is a possibility that the IGF-1 levels were higher than expected since on average, our subjects were relatively young (patients, 36.4 ± 11.2, siblings, 35.6 ± 11.1, and controls, 35.5 ± 9 years old, respectively). In addition, GH, thyroid and parathyroid hormones, insulin, estrogens, androgens, inflammatory cytokines, BMI, a protein-rich diet, and exercise can all impact serum IGF-1 levels [33]. In our study, one or more of these factors may have been a confounding variable. The non-significant difference of IGF-1 levels between groups might also be explained by the cross-sectional nature of our study and the limited sample size. We found that IGF-1 levels were negatively correlated only with triglyceride levels in the control group, but positively correlated only with HDL levels in the patient group. As a result, IGF-1 was only correlated with the dyslipidemia component of MS in the patient and control groups. Our data are concordant with the idea that long-term IGF-1 therapy leads to a decrease in body lipid mass and lipolysis [22]. In a cross-sectional study on the relationship between coronary artery risk factors, IGF-1, and IGFBP-3, Colangelo et al. evaluated 544 Black and 747 White males (age range 20–34). After testing the males in their second, seventh and tenth years, they observed a negative correlation
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between serum IGF-1 and serum lipid levels, especially in white males [21]. Apart from the lipolytic effects of IGF-1, its role in the treatment of hypertension and diabetes has also been reported, which lends support to its predicted role in MS treatment [17,21,23]. In an attempt to understand MS, several studies on its prevalence in schizophrenia and similar psychotic diseases have been performed. In a recent meta-analysis, it was found that half of the patients with schizophrenia were obese, onefifth were hyperglycemic, and at least two-fifths had lipid anomalies [34]. Interestingly, MS prevalence is 20–60% in patients with schizophrenia, which is twice that of the general population [1]. In our study, MS was found in 20% of the control group and in 42% of the patients (P = 0.01), and the latter value was higher than that reported in certain general population-based Turkish and American studies [35–38]. This result emphasizes the view that compared to the healthy population, MS and related metabolic disorders are seen in a higher ratio in patients prescribed antipsychotics. As schizophrenia and diabetes may be comorbid diseases, independent of antipsychotic drug therapy [14], patients with first episode drug-naive schizophrenia and their first-degree relatives were found to have glucose intolerance rates of 10.5% and 18.2%, respectively [39]. In our study, 4% of the patients had a history of diabetes and 16% of patients had impaired fasting glucose, yet none of the siblings had diabetes or impaired fasting glucose. Comparisons of serum glucose, insulin, and insulin resistance between all groups did not yield any statistically significant differences. However, when schizophrenia/siblings and schizophrenia/ control groups were compared based on the same parameters, there was a significant difference in insulin resistance in the schizophrenia/siblings group, and a trend for a difference between glucose levels. Thus, in agreement with previous work [39], our data suggests that both patients with schizophrenia and their siblings have a tendency to develop insulin resistance and diabetes mellitus. Consistent with previous studies, we did not find any significant difference in the occurrence of MS between mono- and combined atypical therapy [40], and between patients using different atypical antipsychotics [41,42]. In addition, while it has been proposed that a long disease duration and advanced age are important risk factors for MS [43], we did not find any link between MS and disease duration or number of hospitalizations. Although there are similar data in the literature [41,44], a meta-analysis by Mitchell et al. revealed that advanced age has a modest effect on MS prevalence, but disease duration is the most pertinent factor [34]. We also found no significant differences in disease subtypes, treatment response, and MS.
5. Conclusion Since we did not find any significant difference between groups in terms of IGF-1 levels, our findings do not support
the hypothesis that low IGF-1 levels play a role in the etiopathogenesis of schizophrenia. IGF-1 levels negatively correlated with triglyceride levels in the control group, and positively correlated with HDL levels in the patient group. Thus, our findings suggest a lipolytic effect of IGF-1. Since there are reports on the therapeutic effects of IGF-1 on other components of MS and in related metabolic disorders, IGF-1 is a promising candidate for treating patients with schizophrenia who are exposed to greater risk of MS than healthy individuals are. In order to determine the possible role of IGF-1 in the etiopathogenesis of schizophrenia and in MS treatment, comprehensive prospective studies, including first-episode drug-naive patients with schizophrenia, might provide more conclusive results.
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