Metabolic status and resistin in chronic schizophrenia over a 2-year period with continuous atypical antipsychotics

Abstract

Background:

Common adverse effects of atypical antipsychotic treatments for schizophrenia are weight gain and lipid metabolism abnormality. We aimed to identify the signs of metabolic problems with continuous atypical antipsychotic treatment for schizophrenia over a 2-year period.

Methods:

The participants were 68 schizophrenic patients (29 males, 39 females; ages 53.4 ± 13.5 years old). Changes in carbohydrate metabolism and changes in physical characteristics were studied over a 2-year period. In addition, functional single nucleotide polymorphisms in the transcriptional regulatory region of the resistin gene were examined.

Results:

We found no changes in the mental state of the participants over a 2-year period. Patients did show a significant decrease in total cholesterol and hemoglobin A1c levels, although physical changes such as body mass index and abdominal girth, were not observed. The amount of resistin may not be associated with mental states and physical parameters.

Conclusions:

We could not find physical factors related to metabolic changes of antipsychotics in this 2-year study. However, several psychological factors, such as health-related thoughts and behaviors, should be studied in the future.

Keywords

antipsychotics diabetes metabolic syndrome resistin schizophrenia

Introduction

Schizophrenic patients need to take antipsychotic agents throughout most of their later lifetime. Nowadays, atypical antipsychotic agents are most commonly used to treat schizophrenia. Metabolic problems that have been linked to atypical antipsychotic agents are abnormalities of glucose metabolism such as insulin resistance, hyperglycemia, new onset diabetes mellitus (DM) and dyslipidemia. Schizophrenic patients with atypical antipsychotic treatments sometimes have metabolic syndrome (MetS) such as weight gain and lipid metabolism abnormalities as adverse effects. The risk of metabolic complications differs with different atypical antipsychotic agents. Aripiprazole and ziprasidone have a smaller metabolic burden compared with the rest of the atypical antipsychotic agents [Meyer et al. 2008]. Clozapine and olanzapine appear to be mostly associated with metabolic side effects, followed by quetiapine and risperidone, with ziprasidone and aripiprazole causing fewer side effects [Tschoner et al. 2009; Leucht et al. 2013].

The prevalence of DM in schizophrenic patients is several times higher than that of the general population [Holt et al. 2004]. DM is a particularly strong risk factor for cardiovascular morbidity, being a risk equivalent of myocardial infarction [Haffner et al. 1998]. The weight gain induced by antipsychotic agents is known as a mechanism of the risk for insulin resistance, hyperglycemia and dyslipidemia. However, the mechanisms responsible for metabolic effects have not been well characterized. One of several hypotheses is that atypical antipsychotic agents may cause a dysregulation of hormones that control appetite and food intake, such as insulin, leptin, adiponectin, and ghrelin [Sentissi et al. 2008]. Resistin, which antagonizes insulin action, is an adipokine secreted from adipocytes [Steppan et al. 2001; Steppan and Lanzar, 2004]. The relationship between serum resistin, insulin resistance, type 2 diabetes (T2D) and adiposity in humans is controversial [Lazar, 2007]. Carvalho and colleagues reported that resistin serum levels are significantly lower among major depressive disorder (MDD) in humans [Carvalho et al. 2014]. However, it is reported that the resistin level in patients with the first episode of psychosis treated with antipsychotics was not significantly changed [Perez-Iglesias et al. 2008]. To date, the change of resistin has not been studied as an outcome in using atypical antipsychotic agents among only schizophrenia. We hypothesized that amounts in serum resistin and other metabolic parameters would be changed by continuous atypical antipsychotic treatment.

In this study, we aimed to identify changes in physical characteristics, carbohydrate and lipid metabolism, and resistin levels with continuous atypical antipsychotic treatment for schizophrenia over a 2-year period.

Methods

Study design and participants

This study was conducted in the outpatient and inpatient psychiatric units of Horie Hospital, located in Ehime prefecture, in the western part of Japan. Patients recruited into this study were evaluated at the beginning and end of a 2-year period from August 2011 to August 2013 who met the following criteria: (1) fulfilled the Diagnostic and Statistical Manual of Mental Disorders IV Text Revision (DSM-IV-TR) criteria for schizophrenia; (2) understood the nature of the study and signed an informed consent; and (3) had been using a single atypical antipsychotic agent for more than 90 days. Those patients were medically assessed using the Brief Psychiatric Rating Scale (BPRS) and their prescribed dose of various antipsychotics was converted to the chlorpromazine equivalent dose (CP), using the calculation table which is routinely adopted in Japan [Inagaki and Inada, 2008]. The prevalence of MetS according to the recommendations of the International Diabetes Federation (IDF) was examined. The bodyweight and height of all subjects were measured and the body mass index (BMI) was calculated. Anticholinergic, mood stabilizers and antipsychotic agents were permitted if clinically needed. The study’s outcome measured changes in carbohydrate metabolism (resistin, lipid metabolism) and in physical characteristics (BMI, abdominal girth, the number of MetS conditions) over a 2-year period. Furthermore, functional single nucleotide polymorphisms (SNPs) in the transcriptional regulatory region of the resistin gene (rs1862513 and rs3219175) were examined. All measurements were obtained at 8–10 o’clock in fasting conditions.

This study was a prospective cohort study. For genetic studies, we obtained genomic DNA samples from the participants. The study protocol was approved by the ethics committee of Ehime University Hospital (IRB approval number: 1306002). Written informed consent was obtained from all the participants after a complete description of the study was provided.

Measurement of plasma resistin

Fasting plasma resistin was determined using a human resistin ELISA kit (EMD Millipore Corporation Billerica, MA USA), according to the manufacturer’s protocol [Osawa et al. 2004]. The assay was linear below 0.16 ng/ml. Inter- and intra-assay coefficients of variation (CVs) were 6.9 and 1.7% (low levels) and 7.2 and 8.1% (high levels), respectively.

Genotyping

Genotyping of SNPs (rs1862513 and rs3219175) was conducted using the TaqMan 5′-exonuclease allelic discrimination assay (Assay ID: rs1862513; C_1394112_10 and rs3219175; C__27472440_10, respectively, Applied Biosystems, Foster City, CA) using a StepOnePlus real-time polymerase chain reaction (PCR) system (Applied Biosystems, Foster City, CA). Genotyping call rates were 100% (rs1862513) and 100% (rs3219175). No deviation from the Hardy–Weinberg equilibrium (HWE) in each examined SNP was detected in the patients with schizophrenia (p > 0.05).

Statistical analysis

All statistical analyses were performed using SPSS Statistics for Windows (Version 22.0; IBM Corp, Armonk, NY, USA). Descriptive data are presented as mean ± standard deviation (SD) unless otherwise specified. Differences in baseline characteristics were assessed by analysis of variance (ANOVA). A paired t-test was used to investigate if there were statistically significant changes in the outcome after 2 years from the beginning of this study. Pearson’s correlations were used to investigate relationships between plasma resistin concentration and physical parameters. Statistical significance was defined as a p < 0.05.

Results

Demographic data

Subjects included 68 schizophrenic patients being stably treated with olanzapine (n = 21), risperidone (n = 15), aripiprazole (n = 15), blonanserin (n = 11) or quetiapine (n = 6) participated at the starting point. All subjects were of Japanese origin. The age range was between 23 and 77 years old, with an average age of 53.4 ± 13.5 years old (Table 1). Patient illness duration was 25.1 ± 12.6 years. The prevalence of MetS was 39.7% (n = 27; male: 44.8%, n = 13; female: 35.9%, n = 14) at the beginning of this study. No significant difference in biochemical parameters were observed among any medications (Table 2). CP for patients treated with quetiapine was significantly higher than those with other antipsychotics. Insulin and C-peptide showed a strong correlation with BMI, both at baseline (r = 0.60; p < 0.001) (r = 0.56; p < 0.001). Resistin was not correlated with BMI (r = −0.035; p = 0.78).

Table 1.

Demographic and clinical characteristics of study population (n = 68).

	Mean (standard deviation)
Age, years	53.4 ± 13.5
Sex	Male: 29; 42.6%
	Female: 39; 57.4%
Schizophrenia duration, years	25.1 ± 12.6
BPRS	35.6 ± 11.5
DIEPSS	1.9 ± 3.2
CP, mg/day	553.6 ± 246.8
Starting weight, kg	62.2 ± 14.9
Starting BMI, kg/m²	24.4 ± 4.9
Abdominal girth, cm	89 ± 13.9
In or out patient status	In-patients: 28; 41.2%
	Out-patients: 40; 58.8%
Marital status	Married: 23; 33.8%
	Not married: 45; 66.2%
Living with family	Yes: 46; 67.6%
	No: 22; 32.4%
Smoking	Yes: 20; 41.2%
	No: 48; 58.8%

Values are mean ± standard deviation or n (%).

BMI, body mass index; BPRS, Brief Psychiatric Rating Scale; CP, chlorpromazine equivalent; DIEPSS, Drug-Induced Extrapyramidal Symptoms Scale.

Table 2.

Clinical characteristics of each antipsychotic agent.

	Olanzapine	Risperidone	Aripiprazole	Blonanserin	Quetiapine
Number	21	15	15	11	6
Age	52.6 ± 13.0	60.0 ± 15.4	47.5 ± 13.8	53.9 ± 6.7	53.7 ± 15.9
BPRS	35.6 ± 8.8	33.9 ± 10.6	35.3 ± 13.3	36.8 ± 15.6	38.3 ± 11.9
DIEPSS	1.9 ± 3.9	1.5 ± 1.9	1.8 ± 3.0	2.6 ± 4.4	1.5 ± 1.5
Dose, mg/day	16.5 ± 4.5	4.3 ± 2.9	19.1 ± 7.0	17.1 ± 4.0	608.3 ± 120.1
Dose, range	10 – 20	1 – 10	6 – 30	12 – 24	400 – 750
CP, mg/day	659.1 ± 180.1	426.7 ± 291.5	478.3 ± 174.5	427.3 ± 100.9	921.7 ± 181.9
Weight, kg	63.7 ± 13.4	61.7 ± 8.9	61.1 ± 21.2	64.9 ± 16.1	56.4 ± 13.5
BMI, kg/m²	25.8 ± 5.3	24.5 ± 3.0	23.6 ± 5.7	23.9 ± 4.9	22.6 ± 5.4
Abdominal girth, cm	93.8 ± 14.0	88.2 ± 11.0	82.5 ± 17.3	90.5 ± 12.0	87.4 ± 10.2
GOT, IU/l	22.4 ± 8.4	21.8 ± 8.1	34.5 ± 34.8	21.0 ± 4.9	22.7 ± 6.8
GPT, IU/l	28.5 ± 24.2	22.9 ± 11.3	39.7 ± 54.9	17.4 ± 6.5	23.8 ± 20.2
T-cho, mg/dl	216.9 ± 46.1	207.9 ± 48.6	175.6 ± 39.8	210.6 ± 39.3	199.2 ± 57.4
TG, mg/dl	127.1 ± 43.9	121.5 ± 63.7	102.9 ± 62.8	124.5 ± 67.1	89.7 ± 60.9
HDL-cho, mg/dl	52.6 ± 14.2	53.7 ± 16.8	51.3 ± 10.7	52.0 ± 13.9	61.8 ± 21.5
FBG, mg/dl	93.0 ± 12.0	106.8 ± 34.9	93.1 ± 23.1	90.5 ± 13.8	88.8 ± 17.6
HbA1c,%	5.3 ± 0.4	5.9 ± 1.1	5.7 ± 1.0	5.4 ± 0.5	5.2 ± 0.5
FFA, mmol/l	0.57 ± 0.3	0.57 ± 0.3	0.60 ± 0.4	0.53 ± 0.2	0.34 ± 0.2
Resistin, ng/ml	6.7 ± 4.1	6.3 ± 4.9	7.6 ± 2.8	6.7 ± 4.2	6.7 ± 3.1
Insulin, μIU/l	11.5 ± 10.2	9.5 ± 4.9	8.6 ± 6.2	7.6 ± 3.9	7.7 ± 5.0
HOMA-IR	2.6 ± 2.2	2.5 ± 1.5	2.2 ± 2.3	1.8 ± 1.1	1.8 ± 1.4
C-peptide, ng/ml	1.9 ± 1.5	1.8 ± 0.5	1.7 ± 0.9	1.6 ± 0.8	1.3 ± 0.7

Values are mean ± standard deviation.

Differences in characteristics are assessed by analysis of variance (ANOVA).

BPRS, Brief Psychiatric Rating Scale; CP, chlorpromazine equivalent; DIEPSS, Drug-Induced Extrapyramidal Symptoms Scale; FBG, fasting blood glucose; FFA, free fatty acids; GOT, glutamic oxaloacetic transaminase; GPT, glutamic pyruvic transaminase; HbA1c, glycated haemoglobin; HDL-cho, high density lipoprotein cholesterol; HOMA-IR, homeostatic model assessment and insulin resistance; IU, international unit; T-cho, total cholesterol; TG, triglyceride.

A total of 42 schizophrenic patients completed this study (Figure 1). At the endpoint, 34 patients received monotherapy with olanzapine (n = 11), risperidone (n = 8), aripiprazole (n = 5), blonanserin (n = 7) or quetiapine (n = 3). The other 8 patients were treated with polypharmacy (n = 7) or no antipsychotics (n = 1). The prevalence of MetS was 34.9% (n = 15; male: 40.9%, n = 9; female: 27.3%, n = 6) at the endpoint. As shown in Table 3, mental states and physical characteristics did not change after 2 years of treatment. There were statistically signiﬁcant decreases in the mean values of total cholesterol (T-cho) and hemoglobin A1c levels (HbA1c) after 2 years. There was no change in the value of resistin after 2 years. Resistin may not be associated with mental states and physical parameters (Table 4). Resistin was highest in subjects with SNP-420 (rs1862513) G/G and SNP-358 (rs3219175) A/A genotypes (Table 5).

Figure 1.

Flow diagram of participants.

Table 3.

Changes in mental state, physical and biochemistry parameters of patients who completed 2-year study (n = 42; 22 males and 20 females).

	Baseline mean (SD)	Mean after 2 years (SD)	Change	t	p
BPRS	35.9 ± 11.8	35.3 ± 11.1	−0.6	1.687	0.099
DIEPSS	1.9 ± 3.1	1.9 ± 2.5	0	0.067	0.947
CP, mg/day	605.9 ± 225.8	646.5 ± 376.3	40.6	−0.874	0.387
Weight, kg	63.4 ± 15	62.6 ±14.5	−0.8	0.997	0.325
BMI, kg/m²	24.1 ± 4.5	23.7 ± 4.5	−0.4	0.926	0.36
Abdominal girth, cm	90.1 ± 12.5	90.5 ± 11.5	0.4	−0.349	0.729
GOT, IU/l	23.5 ± 11.2	23.7 ± 10	0.2	−0.194	0.847
GPT, IU/l	25.4 ± 20.3	25 ± 20.9	−0.4	0.125	0.901
T-cho, mg/dl	198.4 ± 43.0	188.1 ± 33.9	−10.3	2.191	0.034*
TG, mg/dl	117.9 ± 63.1	119.4 ± 58.2	1.5	−0.307	0.761
HDL-cho, mg/dl	51.6 ± 14.3	50.6 ± 14.2	−1	0.799	0.429
FBG, mg/dl	94.0 ± 19.3	91.6 ± 12.8	−2.4	1.171	0.249
HbA1c,%	5.6 ± 0.9	5.4 ± 0.6	−0.2	2.384	0.022*
FFA, mmol/l	0.56 ± 0.3	0.56 ± 0.3	0	−0.045	0.964
Resistin, ng/ml	6.9 ± 3.8	7.4 ± 4.7	0.5	−1.282	0.207

Values are mean ± SD.

Changes in the outcome after 2 years from the beginning are assessed by a paired t-test.

BPRS, Brief Psychiatric Rating Scale; CP, chlorpromazine equivalent; DIEPSS, Drug-Induced Extrapyramidal Symptoms Scale; FBG, fasting blood glucose; FFA, free fatty acids; GOT, glutamic oxaloacetic transaminase; GPT, glutamic pyruvic transaminase; HbA1c, glycated haemoglobin; HDL-cho, high density lipoprotein cholesterol; IU, international unit; SD, standard deviation; T-cho, total cholesterol; TG, triglyceride.

Table 4.

Correlations between serum resistin concentration and physical parameters.

Resistin	r	p
Age	−0.47	0.766
BPRS	−0.144	0.364
DIEPSS	0.79	0.621
CP	−0.93	0.556
Weight	0.293	0.06
BMI	0.08	0.613
Abdominal girth	0.074	0.641

Relationships between serum resistin concentration and physical parameters are assessed by Pearson’s correlations.

BMI, body mass index; BPRS, Brief Psychiatric Rating Scale; CP, chlorpromazine equivalent; DIEPSS, Drug-Induced Extrapyramidal Symptoms Scale.

Table 5.

Resistin (ng/ml) in subjects with each combination of the resistin gene: SNP-420 and SNP-358 genotypes (n = 40).

	SNP-358
		G/G	G/A	A/A
SNP-420	C/C	5.5 ± 2.0 (15)	N/A (0)	N/A (0)
	C/G	5.6 ± 1.7 (5)	10.6 ± 6.4 (11)	N/A (0)
	G/G	4.5 ± 0.2 (2)	7.7 ± 2.7 (6)	20.2 (1)

Resistin, mean ± standard deviation is shown for each combination of SNP-420 and SNP-358 genotypes.

The number of subjects is shown in parenthesis.

Discussion

In previous studies, a high prevalence of MetS has been reported in schizophrenic patients. According to the IDF, the prevalence of MetS in Japanese schizophrenia patients is 25.4% [Sugawara et al. 2010], and is 17.0% in Japanese male workers [Miyaki et al. 2006]. In our study, a high prevalence of MetS were found in schizophrenic patients (34.9% even after 2-years’ study). It is important that MetS is carefully monitored in schizophrenic patients. Parsons and colleagues examined bodyweight changes during short- and long-term treatments of patients, and found that there were substantial differences among antipsychotics in their effects on bodyweight [Parsons et al. 2009]. In our study, we could not find significant differences in BMI and metabolic parameter among any antipsychotics. One major side effect of many atypical antipsychotic drugs is weight gain, which many studies have documented in the early stage of starting the drugs [Allison et al. 1999]. It seems that weight gain might reach a plateau after a certain period, which is why we did not see any significant changes in our study.

In this pilot study, we investigated the factors of metabolic side effect in schizophrenia during 2 years using atypical antipsychotic agents and observed changes in some parameters. Several candidate genes including HTR2C, leptin, DRD2, TNF, SNAP-25 and MC4R have been reported [Lett et al. 2012]. In this study, plasma resistin was not changed during the study period and there was no relationship between mental states and physical parameters in schizophrenia patients. The resistin gene has been associated with T2D susceptibility [Osawa et al. 2004]. In the general Japanese population, A at −358 is required for G at −420 to confer the highest plasma resistin [Onuma et al. 2010]. Associations between plasma resistin and these genotypes were also comparable in our schizophrenic patients. Although the relationship between the genes related to metabolism and schizophrenia is still unknown, genetic analyses of them, such as the resistin gene, in schizophrenia would be needed in further studies.

Previous studies have shown that subsequent long-term weight loss is difficult to achieve, either through behavioral or pharmacologic interventions [Marder et al. 2004]. Although schizophrenic patients with continuous antipsychotic treatment commonly tend to gradually increase in some metabolic markers, patients in this study had no changes in physical parameters, but did show significant decreases in T-cho and HbA1c levels after 2 years. There may be unknown factors that improve their healthiness, such as health-related behavioral changes. In the future, we plan to compare some parameters between patients with and without weight gain, and to study metabolic markers in combination with psychological and behavioral questionnaires. Clinicians should focus on not only metabolic markers but also patients’ behaviors.

The findings of this study have to be interpreted within its limitations. One of the main limitations of this study is the small sample size. Other limitations include lack of randomized treatment assignment and lack of a control group. This study did not examine individual antipsychotic agents separately. It is important to note the duration of the study. Our 2-year study might be too short to evaluate the possible effects of antipsychotic treatment, as chronic schizophrenia patients often take antipsychotics throughout their lifetime.

Conclusion

There was a significant reduction of total cholesterol and HbA1c in 2-year follow up of schizophrenia patients treated with any atypical antipsychotics. However, we did not find any factors related to those changes. Further studies including psychological parameters may be needed to find factors related to metabolic changes in the chronic treatment of antipsychotics.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare no conflicts of interest in preparing this article.

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