Sequencing of the insulin receptor (INSR) gene reveals association between gene variants in exon and intron 13 and schizoaffective disorder.

OBJECTIVES: From the hypothesis that an impaired insulin and insulin-like growth factor cellular signalling in brain and body might result in the development of schizophrenia or related psychoses, I in this study chose to thoroughly investigate the insulin receptor gene in patients with schizophrenia or schizoaffective disorder and controls. METHODS: For identification of single nucleotide polymorphisms (SNPs) of interest in the insulin receptor gene, targeted whole gene sequencing of DNA using the SOLiD technology was first carried out in two subgroups of the study population: 1) 49 schizophrenia or schizoaffective disorder patients with heredity for schizophrenia or related psychoses, and 2) 25 controls. Ten possible SNPs of interest were identified and these were then typed by standard methods in the whole study population consisting of 105 patients with schizophrenia or schizoaffective disorder and 60 controls. RESULTS: In comparisons between schizophrenia patients, schizoaffective disorder patients and controls, overall significant differences were found in genotype distribution and allele frequency for SNP rs2229431 in exon 13, and tendencies towards overall significant differences were found for SNP rs12610022 in intron 13, but not for the other 8 possible SNPs investigated. It was the patients with schizoaffective disorder who differed in genotype distributions and allele frequencies compared to both the patients with schizophrenia and the controls, whereas between the patients with schizophrenia and the controls, no significant differences were found. CONCLUSION: The results of this study show that two gene variants in exon and intron 13 of the insulin receptor gene confer risk specifically for schizoaffective disorder.

Signs of impaired blood-brain barrier function and lower IgG synthesis within the central nervous system in patients with schizophrenia or related psychosis, compared to that in controls.

OBJECTIVES: Evidence has accumulated that an inflammatory, possibly autoimmune-mediated, process in the central nervous system (CNS), and by way of an aberrant immune system, may underlie the development of schizophrenia. Therefore, the aim of this study was to evaluate patients with schizophrenia or related psychosis for blood-brain barrier (BBB) function and immunoglobulin (Ig)G synthesis within the CNS. METHODS: Fifteen patients with schizophrenia or schizoaffective disorder and 12 controls were investigated using lumbar puncture and blood sampling. Cerebrospinal fluid (CSF) and serum/plasma (S/P) were analysed for albumin and IgG by standard laboratory methods, and the ratio of CSF-albumin to P-albumin (marker of BBB function) and the IgG index (marker of CNS IgG synthesis) were calculated. Additionally, the patients were assessed for clinical symptoms with the Positive and Negative Syndrome Scale for schizophrenia. RESULTS: The ratio of CSF-albumin to P-albumin was higher and the IgG index was lower in patients than in controls (p=0.045 and p=0.001, respectively). Moreover, subgroup analyses showed that patients in partial symptom remission had higher ratios of CSF-albumin to P-albumin than patients in full symptom remission, and that patients with heredity for schizophrenia or related psychosis had lower IgG indices than patients without heredity. CONCLUSIONS: In this study we show that patients with schizophrenia or related psychosis have impaired BBB function and lower IgG synthesis within the CNS, compared to controls. These findings support the view that a pathological process within the CNS, combined with an aberrant immune system, may underlie the development of schizophrenia.

Early-onset inguinal hernia as risk factor for schizophrenia or related psychosis: a nationwide register-based cohort study.

OBJECTIVES: In an earlier interview study, we found that more men with familial schizophrenia had undergone inguinal hernia operation, than men with sporadic schizophrenia. However, there are no other studies published specifically on inguinal hernia and schizophrenia. Therefore, the aim of this study was to carry out a Swedish register-based cohort study on the association between inguinal hernia and schizophrenia or related psychosis. METHODS: Data from the Total Population- and Medical Birth-Registers were used to create a cohort of all individuals born in Sweden 1987-1999 (n=1 406 168). The cohort individuals were linked with the In- and Out-patient Registers and followed from birth to 2015 to identify onset of schizophrenia, schizoaffective disorder and inguinal hernia. Cox proportional hazards regression models were used to assess the association between inguinal hernia before age 13 and risk of developing schizophrenia or schizoaffective disorder during a follow-up from age 13. RESULTS: Inguinal hernia before age 13 was identified in 21 095 individuals, and during the follow-up in total 1314 individuals developed schizophrenia or schizoaffective disorder. The risk of schizophrenia or schizoaffective disorder was higher among individuals with inguinal hernia before age 13, than among individuals without such a diagnosis, especially among the men [adjusted hazard ratio (95% confidence interval); all: 1.44 (1.01-2.06), p=0.0452, men: 1.46 (1.01-2.12), p=0.0460, women: 0.56 (0.14-2.27), p=0.4173]. CONCLUSIONS: This study shows that early-onset inguinal hernia is associated with increased risk of developing schizophrenia or schizoaffective disorder, especially in men. Such an association may point to a common biological basis for the development of inguinal hernia and schizophrenia or related psychosis.

Higher serum concentrations of tyrosine and glutamate in schizophrenia patients treated with clozapine, compared to in those treated with conventional antipsychotics.

RATIONALE: The effect of long-term treatment with the atypical antipsychotic clozapine on the serum amino acid profile in schizophrenia patients has not previously been studied. OBJECTIVES: The aim of this study was to compare serum amino acid patterns in patients on long-term clozapine treatment with long-term conventional antipsychotic treatment, and their relationships to insulin resistance and antipsychotic serum concentrations. METHODS: Thirty-three patients with schizophrenia or schizoaffective disorder on long-term treatment (mean 8.3 years) with clozapine (n=20) or conventional antipsychotics (n=13) were studied. Amino acids were quantified in fasting serum samples by ion exchange chromatography and markers of insulin resistance and antipsychotic drug concentrations were determined by standard methods. RESULTS: Several amino acids, most notably tyrosine and glutamic acid, were elevated above the reference range in several patients receiving clozapine. Additionally, significantly higher mean values of tyrosine (1.5-fold, p=0.001), glutamic acid (2-fold, p=0.0005) and six other amino acids were observed in the clozapine group than in the conventional antipsychotic group. Several amino acids were related to insulin resistance in both treatment groups. CONCLUSIONS: In this study, we show that serum tyrosine and glutamic acid concentrations are markedly elevated in patients on long-term clozapine treatment, compared to patients on long-term conventional antipsychotic treatment. These findings are of importance since these two amino acids have been implicated in the pathophysiology of schizophrenia.

Case report of a patient with schizophrenia and a mutation in the insulin receptor substrate-4 gene.

This report deals with a female patient with schizophrenia who was found to have a mutation in the insulin receptor substrate-4 gene that is located on chromosome Xq22.3. Since this mutation is expected to change amino acid coding from histidine to tyrosine and cause an altered insulin receptor substrate-4 protein, and the insulin receptor substrate-4 protein may be involved in neuronal growth and function in the brain, it is possible that it is this insulin receptor substrate-4 gene mutation that underlies this patient's schizophrenia development.

Higher concentration in serum of insulin autoantibodies in patients with schizophrenia or related psychosis, compared to in control subjects.

OBJECTIVES: In a recent study, we found increased antibody reactivity against the insulin receptor-A and insulin-like growth factor 1 receptor and their ligands in patients with schizophrenia or related psychosis, indicating that an autoimmune-mediated process may underlie development of schizophrenia. The aim of this study was to supplement our previous study with analysing additional neuronal- and diabetes-associated autoantibodies of potential interest for schizophrenia in the same patients and controls as in the foregoing study. MATERIAL AND METHODS: Analyses of neuronal (NMDAR, VGKC, AMPAR, GABABR, DPPX, GAD)- and voltage-gated calcium channel (VGCC) autoantibodies in cerebrospinal fluid (12 patients, 11 controls) and of diabetes-associated (GAD, IA-2, ZnT8, insulin)- and VGCC autoantibodies in serum (17 patients, 11 controls) were done by standard methods. Additionally, patients (n = 16) were accessed for clinical symptoms with the Positive and Negative Syndrome Scale (PANSS) for schizophrenia. RESULTS: Concentrations in cerebrospinal fluid of NMDAR-, VGKC-, AMPAR-, GABABR-, DPPX-, GAD- and VGCC autoantibodies were below detection limits in all patients and controls. Concentration in serum of insulin autoantibodies was significantly higher in patients than in controls (p = 0.001), whereas no significant differences were found in concentrations in serum of GAD-, IA-2-, ZnT8- or VGCC autoantibodies between patients and controls. Patients' serum concentrations of insulin autoantibodies tended to inversely correlate to their PANSS scores. CONCLUSION: In this study, we show higher concentration in serum of insulin autoantibodies in patients with schizophrenia. This finding is of importance since autoantibodies against insulin may be implicated in the autoimmune-mediated process underlying development of schizophrenia.

Associations between heredity, height, BMI, diabetes mellitus type 1 or 2 and gene variants in the insulin receptor (INSR) gene in patients with schizophrenia.

OBJECTIVES: Schizophrenia is a psychotic disorder with high heritability. There are also indications that an autoimmune-mediated process in the brain underlies development of schizophrenia, and that the insulin receptor A may constitute a main antigen target. Therefore, as the insulin receptor gene hitherto has been little studied in schizophrenia, this study was undertaken to investigate this gene in schizophrenia susceptibility. MATERIALS AND METHODS: To identify gene variants of possible interest, the whole insulin receptor gene was first DNA-sequenced in all or subgroups of patients with schizophrenia and controls, using the Sanger method and the SOLiD technology. Then, association analyses of total 50 identified gene variants were carried out in the whole study population, consisting of 94 patients and 60 controls. RESULTS: No significant differences in genotype- and allele frequencies for the 50 gene variants were found between all patients and controls. However, in subgroup analyses, rs2229431 and rs747721248 tended to associate with heredity for schizophrenia, rs2229431 associated with height, rs41505247 with body mass index, rs59765738 and rs57476618 with diabetes mellitus (DM) type 1 and/ or heredity for DM type 1, and rs2962, rs2352954, rs2352955 and rs2252673 with DM type 2 and/ or heredity for DM type 2 in patients. CONCLUSIONS: In this study, we show associations between heredity, height, body mass index, DM type 1, or DM type 2 and gene variants in the insulin receptor gene in patients with schizophrenia. Taken together, these findings clearly point to that the insulin receptor gene is involved in schizophrenia susceptibility.

Metabolic parameters and long-term antipsychotic treatment: a comparison between patients treated with clozapine or olanzapine.

OBJECTIVES: This study was undertaken to examine if patients exhibit more pronounced metabolic abnormalities after 8-year treatment with clozapine or olanzapine than before, and also to investigate whether there exist any differences between long-term clozapine and olanzapine therapies regarding metabolic side- effects. METHODS: Fifty psychiatric outpatients diagnosed with schizophrenia or schizoaffective disorder and on treatment with clozapine or olanzapine were studied during 8 years. Fasting blood or serum samples for glucose, lipids, prolactin and antipsychotic drug concentrations were analyzed. In addition, body mass index was calculated. RESULTS: More patients treated with olanzapine compared with those treated with clozapine ended with their medication, in most cases because of diabetes mellitus and/or hyperlipidemia, during the 8-year follow-up. Also more patients treated with olanzapine compared with those treated with clozapine developed manifest diabetes mellitus during the 8-year period. Prolactin levels were higher in the patients treated with olanzapine compared with in those treated with clozapine at study start, but there were no differences in the other parameters between the treatment groups at study start. In the patients remaining on their medication all 8 years, the glucose level increased over time in the clozapine group, but not in the olanzapine group, whereas body mass index and lipids were unchanged over time in both treatment groups. CONCLUSIONS: Our findings point to that both olanzapine and clozapine long-term treatments cause development of hyperglycemia and/or hyperlipidemia. Furthermore, olanzapine long-term treatment seems to more often lead to development of manifest diabetes mellitus than long-term treatment with clozapine.

Evidence for a negative association between schizophrenia and a polymorphism in the insulin receptor substrate-3 (IRS-3) gene.

OBJECTIVES: Since there are clear indications that schizophrenia is a systemic disorder, we sought for a common molecular basis for schizophrenia abnormalities in brain and body. Our hypothesis was that an impaired insulin and insulin-like growth factor signalling in cells might underlie changes in both brain and body in schizophrenia. In this regard, the insulin receptor substrates 1-4, linking both the insulin and insulin-like growth factor-1 receptors with intracellular pathways, might be of interest to study genetically. In the present study, we chose to study the insulin receptor substrate-3 (IRS-3) gene as a candidate gene in schizophrenia. METHODS: The IRS-3 gene of 93 patients with the diagnosis of schizophrenia according to DSM-IV criteria and 57 healthy control subjects was screened for DNA sequence variations, followed by case-control analyses of total 10 detected polymorphisms. RESULTS: The A/G genotype of the single nucleotide polymorphism (SNP) rs117078492 in the IRS-3 gene occurred in 5.3% of the control subjects compared with in 0% of the patients (p=0.05). Similarly, the haplotypes 5 and 3X, constructed from polymorphisms in the IRS-3 gene and including the A allele of this A/G SNP, occurred only in the control subjects and not in the patients (5.3% vs 0%, p=0.05). CONCLUSION: Our findings suggest that individuals carrying the A allele of this A/G SNP in the IRS-3 gene as well as the estimated haplotypes 5 or 3X including this A allele, have a protection against schizophrenia development.

Association between single nucleotide polymorphisms in non-coding regions of the insulin (INS) gene and schizophrenia.

OBJECTIVES: Schizophrenia is a psychotic disorder with high heritability. There are also indications that impaired cellular signalling via the insulin receptor-A and the insulin-like growth factor 1 receptor may play a role in its pathogenesis. Insulin, and possibly also C-peptide, are ligands to these receptors. The insulin gene, coding both insulin and C-peptide, has however not been genetically studied in schizophrenia. Therefore, this study was undertaken to investigate the involvement of this gene in schizophrenia susceptibility. MATERIAL AND METHODS: For identification of single nucleotide polymorphisms (SNPs) of interest, the whole insulin gene and parts of its promoter region were first DNA sequenced in two subgroups of the study population (37 schizophrenia patients with heredity for schizophrenia or related psychosis, and 25 controls), and mapped to the reference sequence. Then, 7 identified SNPs of potential interest were typed by TaqMan® SNP Genotyping Assays in the whole study population, consisting of 94 patients with schizophrenia and 60 controls. RESULTS: Allele frequencies tended to differ between patients and controls for two of the 7 SNPs, rs5505 and rs3842749 (p=0.077 and p=0.078, respectively), whereas subgroup analyses of diabetes mellitus (type 1 or 2) and/ or heredity for diabetes mellitus (type 1 or 2) in patients and controls showed overall significant differences in genotype/ allele frequencies solely for rs5505 (p=0.021/ 0.023). CONCLUSION: These findings are of interest, as the two SNPs - rs5505 and rs3842749 - may have regulatory function on the coding of insulin and C-peptide, against which increased antibody reactivity has been previously reported in schizophrenia.

Association between body mass index and insulin receptor substrate-4 (IRS-4) gene polymorphisms in patients with schizophrenia.

OBJECTIVES: The insulin receptor substrate-4 (IRS-4) protein is highly expressed in the hypothalamus that plays a main role in the regulation of body weight. Therefore, as overweight and obesity are more frequent in patients with schizophrenia compared to the general population, this study was undertaken to investigate potential associations between body mass index (BMI) or height and polymorphisms in the IRS-4 gene in schizophrenia patients and healthy controls. METHODS: The IRS-4 gene of 93 patients and 59 controls was screened for DNA sequence variations, and then 10 detected single nucleotide polymorphisms (SNPs) were investigated in relation to BMI and height of patients and controls. RESULTS: Mean BMI was higher in patients than in controls, whereas there was no difference regarding height. Significant associations were found between patients' BMI and genotypes of six SNPs (rs1801164, rs80131334, rs41307415, rs73253702, rs1801162, rs2073114) or a haplotype including these six SNPs. In contrast, no associations were found between BMI or height of controls, or height of patients, and the genotypes or haplotypes. CONCLUSION: This study clearly demonstrates associations between BMI and IRS-4 variants in schizophrenia patients, but not in healthy controls, pointing to a possible involvement of IRS-4 in the control of body weight in schizophrenia.

Effect of antipsychotic-induced hyperprolactinemia on anthropometric measures, insulin sensitivity and lipid profile in patients with schizophrenia or related psychoses.

OBJECTIVES: This study consisting of two subprojects was undertaken to evaluate the effects of hyperprolactinemia on cardiovascular disease (CVD) risk parameters such as anthropometric measures, insulin sensitivity and blood lipids in patients with schizophrenia or related psychoses on long term treatment with antipsychotics. METHODS: In subproject Ι, 45 patients receiving the 2nd generation antipsychotics risperidone, clozapine or olanzapine were compared regarding prolactin (PRL), body mass index (BMI), insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and blood lipids. In subproject Π, 24 patients receiving 1st or 2nd generation antipsychotics were investigated with diurnal profile of PRL and oral glucose tolerance test (OGTT). RESULTS: Elevated PRL levels were found in about 45% of the patients and occurred more often in patients receiving risperidone or haloperidol, compared to patients receiving clozapine or olanzapine. In contrast, in subproject Ι, insulin and HOMA-IR were higher and high density lipoprotein cholesterol was lower in patients receiving clozapine or olanzapine, compared with patients receiving risperidone. However, PRL levels did not correlate to BMI, insulin, HOMA-IR or lipids in any of these three treatment groups. In subproject Π, OGTT showed impaired glucose tolerance in 25% and new-onset diabetes in 4% of the 24 patients investigated. Additionally, the PRL (median 24 h) levels correlated positively to the 2 h glucose level at OGTT (rs=0.42, p=0.04). CONCLUSIONS: Our findings point to that hyperprolactinemia due to 1st and 2nd generation antipsychotics may decrease insulin sensitivity, whereas other mechanisms probably underlie insulin resistance induced by PRL-sparing antipsychotics such as clozapine and olanzapine.

The insulin receptor substrate-4 (IRS-4) gene and schizophrenia: no evidence for a main genetic factor, however one report of a single schizophrenia patient with a mutation.

OBJECTIVES: Since there are clear indications that schizophrenia is a systemic disorder, we sought for a common molecular basis for schizophrenia abnormalities in brain and body. Our hypothesis was that an impaired insulin/ insulin-like growth factor signalling in cells might underlie both structural and functional brain changes and peripheral abnormalities in schizophrenia. No associations between polymorphisms in the genes for insulin-like growth factor 1 or its receptor and schizophrenia have been reported. However, the insulin receptor substrates 1-4 linking both the insulin and insulin-like growth factor 1 receptors with intracellular pathways have not been extensively studied in schizophrenia. In this study, we therefore chose to study the insulin receptor substrate-4 (IRS-4) gene as a candidate gene in schizophrenia. METHODS: The IRS-4 gene of 93 patients and 59 control subjects was screened for DNA sequence variations, followed by case-control analyses of 10 detected single nucleotide polymorphisms. RESULTS: No significant genotype, allele or haplotype associations were found with the schizophrenia illness. However, one female patient with paranoid schizophrenia had an IRS-4 gene mutation at position 107863596, resulting in a change in amino acid coding from histidine to tyrosine at position 879. CONCLUSIONS: Although this study supports the view that the IRS-4 gene is not of major importance for the aetiology of the vast majority of schizophrenia cases, our finding of this single patient with schizophrenia and a mutation in the IRS-4 gene may point to that the insulin/ insulin-like growth factor signalling system in cells is still of interest in the future search for schizophrenia genes.

Increased antibody reactivity against insulin receptor-A and insulin like growth factor 1 receptor and their ligands in cerebrospinal fluid and serum of patients with schizophrenia or related psychosis.

OBJECTIVES: Evidence has accumulated that an autoimmune-mediated process in the central nervous system may underlie the development of schizophrenia. Various antibodies have also previously been detected in serum of patients with schizophrenia. Therefore, the aim of this study was to analyze antibody reactivity against proteins, selected based on potential schizophrenia disease relevance, in both cerebrospinal fluid and serum of patients with schizophrenia. MATERIAL AND METHODS: Cerebrospinal fluid and serum from 17 patients with schizophrenia or related psychosis and 12 controls were analyzed regarding antibody reactivity, using bead-based antigen arrays of protein fragments or peptides of 21 selected proteins. Additionally, the patients were accessed for clinical symptoms with the Positive and Negative Syndrome Scale (PANSS) for schizophrenia. RESULTS: Increased antibody reactivity was found in patients compared to controls against the insulin receptor (INSR), PAGE2B;2;5 and heat shock proteins (HSPs) in both cerebrospinal fluid and serum, and against the insulin like growth factor 1 receptor (IGF1R), insulin (INS), insulin like growth factor 1 (IGF1), cadherin 5 (CDH5), nerve growth factor (NGF) and vascular endothelial growth factor A (VEGFA) in serum alone. Moreover, patients' antibody reactivity in serum against PAGE2B;2;5, IGF1R or NGF correlated positively to their PANSS scores. CONCLUSIONS: Taken together, these results point to that an autoimmune-mediated process underlies the development of a core group of schizophrenia cases and that the INSR and IGF1R, their ligands (INS and IGF1) and related inter- and intracellular proteins (CDH5, PAGE2B;2;5, HSPs, NGF and VEGFA) may constitute antigen targets.

Impact of serotonin receptor 2A gene haplotypes on C-peptide levels in clozapine- and olanzapine-treated patients.

OBJECTIVE: Antagonism at the serotonin receptor 2A by the atypical antipsychotics clozapine and olanzapine has been suggested to be linked to these drugs' adverse effects on glucose-insulin homeostasis. Therefore, the aim of this study was to evaluate the impact of haplotypes based on the main functionally characterized polymorphisms of the serotonin receptor 2A (HTR2A) gene on parameters related to the glucose metabolism in clozapine- and olanzapine-treated patients. METHODS: Forty-nine patients, with schizophrenia or schizoaffective disorder and treated with clozapine (n = 22) or olanzapine (n = 27), were evaluated for fasting levels of C-peptide, insulin and blood glucose, homeostasis model assessment index for insulin resistance (HOMA-IR) and body mass index (BMI), and genotyped for the -1438A/G, -783A/G, 102T/C, and His452Tyr polymorphisms of the HTR2A gene. RESULTS: About 50% of the patients had elevated levels of C-peptide (>0.68 nmol/L) and insulin (>or=79 pmol/L). However, patients carrying the haplotype [-1438A, -783A, 102T, 452Tyr] had significantly lower C-peptide levels compared with patients not carrying this haplotype (p = 0.039), despite no differences in blood glucose, HOMA-IR or BMI between the patient groups. CONCLUSION: Our results indicate that patients with the HTR2A haplotype [-1438A, -783A, 102T, 452Tyr] are less likely to develop metabolic abnormalities like C-peptide and insulin elevations during clozapine and olanzapine treatment.

Schizophrenia- or schizoaffective disorder diagnosis and the risk for subsequent type 1- or type 2 diabetes mellitus: a Swedish nationwide register-based cohort study.

OBJECTIVES: The aim of this study was to examine the effect of schizophrenia or schizoaffective disorder on the risk of developing subsequent type 1 (T1)- or type 2 (T2) diabetes mellitus (DM), by carrying out a Swedish register study. MATERIAL & METHODS: Data from the Total Population- and Medical Birth- Registers were used to create a cohort of all individuals born in Sweden 1987-2004. The cohort individuals were linked with the Inpatient- and Outpatient-Registers and followed from birth to 2018 to identify onset of schizophrenia, schizoaffective disorder and DM. Cox proportional hazard models were applied to assess the associations between schizophrenia or schizoaffective disorder and risk for T1DM or T2DM during a follow-up from age 13. RESULTS: The study population included 1 736 281 individuals and the length of follow-up was maximally 19.0 (median 10.6) years. The risk of developing T1DM was significantly higher among individuals with, than without, schizophrenia [adjusted hazard ratio (HR) (95% confidence interval (CI)): 2.84 (1.18-6.82), p=0.0195], whereas among individuals with or without schizoaffective disorder, the risk of developing T1DM did not differ [adjusted HR (95% CI): 1.23 (0.17-8.74), p=0.8377]. The risk of developing T2DM was significantly higher both among individuals with schizophrenia and schizoaffective disorder, than among those without such diagnoses [adjusted HR (95% CI): 13.98 (8.70-22.46), p<0.0001 and 14.27 (7.36-27.70), p<0.0001, respectively]. CONCLUSIONS: This study shows that schizophrenia is associated with increased risk for subsequent T1DM. It also shows that both schizophrenia and schizoaffective disorder are associated with increased risk for subsequent T2DM.

Association between HTR2C and HTR2A polymorphisms and metabolic abnormalities in patients treated with olanzapine or clozapine.

Serotonin 2C and 2A receptor (5-HT2C and 5-HT2A) antagonisms are hypothesized to play a role in the metabolic adverse effects induced by olanzapine and clozapine. Associations between polymorphisms in 5-HT2C and 5-HT2A receptor coding genes, HTR2C and HTR2A, with antipsychotic-induced weight gain have been reported. The impact of HTR2C and HTR2A polymorphisms on body mass index (BMI), glucose-insulin homeostasis, and blood lipid levels was evaluated in 46 patients with schizophrenia or schizoaffective disorder and treated with olanzapine (n = 28) or clozapine (n = 18) for at least 6 months. Olanzapine-treated patients with HTR2C haplotype C (-759C, -697C, and 23Ser) had higher BMI (P = 0.029) and C peptide levels (P = 0.029) compared with patients with haplotype B (-759T, -697C, and 23Cys). The frequency of patients homozygous for the HTR2C haplotype A (-759C, -697G, and 23Cys) was significantly higher among clozapine-treated patients with obesity (BMI >/= 30 kg/m) compared with nonobese patients (P = 0.015; odds ratio, 28; 95% confidence interval, 2-380). Patients carrying the HTR2A haplotype 2 (-1438A, 102T, and 452His) had significantly higher C peptide levels compared with haplotype 3 (-1438A, 102T, and 452Tyr) carriers in the olanzapine group (P = 0.034) and in the overall study population (P = 0.019). None of the haplotypes were associated with serum levels of insulin, triglycerides, and cholesterol or with homeostasis model assessment index for insulin resistance. In conclusion, both HTR2C and HTR2A gene polymorphisms seem to be associated with the occurrence of metabolic abnormalities in patients treated with olanzapine or clozapine.

Serotonin receptor 2A gene polymorphisms and schizophrenia: association with family history, diagnostic subtype and height in patients.

OBJECTIVES: The 102T/C single nucleotide polymorphism (SNP) in the 5-hydroxytryptamine receptor 2A (HTR2A) gene has been reported to be associated with schizophrenia. However, SNPs of the HTR2A gene other than the 102T/C have attracted only limited studies in relation to schizophrenia, and also on the whole SNPs of the HTR2A gene have been little studied in relation to clinical parameters in patients. Therefore, the aim of this study was to evaluate the impact of main functionally characterized SNPs of the HTR2A gene on both the schizophrenia and clinical parameters. METHODS: Ninety-four patients with schizophrenia and 57 control subjects were genotyped for the -1438A/G, -783A/G, 102T/C and His452Tyr SNPs of the HTR2A gene. The four SNPs were then investigated in relation to the schizophrenia and clinical parameters. RESULTS: No differences were found in genotype-, allele- or haplotype frequencies between schizophrenia patients and control subjects. However, the 452Tyr variant of the His452Tyr polymorphism occurred more often in patients with a family history of schizophrenia compared with patients without heredity (p=0.028). The 452Tyr variant was also more common in female patients with paranoid schizophrenia than in those with non-paranoid schizophrenia (p=0.018). Moreover, the male patients carrying the A/A or T/T genotypes of the -1438A/G and 102T/C polymorphisms were shorter than those carrying the G/A or C/T genotypes (p=0.007; p=0.006). CONCLUSION: The present findings bring further support to the view that the -1438A/G, 102T/C and His452Tyr polymorphisms of the HTR2A gene are connected with a constitutive cellular change that causes susceptibility to schizophrenia.

Type 1 diabetes mellitus and the risk for schizophrenia or schizoaffective disorder: a Swedish nationwide register-based cohort study.

OBJECTIVES: Type 1 diabetes mellitus (T1DM), resulting from an immune-associated destruction of insulin-secreting pancreatic ß-cells, has been reported in a few earlier studies to be inversely associated with schizophrenia, but not with schizophrenia-like psychoses. The aim of this study was to verify this finding by carrying out a Swedish register study. METHODS: Data from the Total Population- and Medical Birth-Registers were used to create a cohort of all individuals born in Sweden 1987-2004. The cohort individuals were linked with the Inpatient- and Outpatient-Registers and followed from birth to 2017 to identify onset of T1DM, schizophrenia and schizoaffective disorder. Cox proportional hazard regression models were used to assess the association between T1DM and risk of developing schizophrenia or schizoaffective disorder during a follow-up from age 13. RESULTS: The study population included 1 745 977 individuals and the length of follow-up was maximally 18.0 (median 9.7) years. During the follow-up, 1 280 individuals developed schizophrenia and 649 individuals schizoaffective disorder. The risk of developing schizophrenia was significantly lower among individuals with, than among individuals without, a diagnosis of T1DM, whereas the risk of developing schizoaffective disorder did not differ among individuals with or without a T1DM diagnosis [adjusted hazard ratio (95% confidence interval); schizophrenia: 0.29 (0.09-0.91), p=0.0338, schizoaffective disorder: 1.50 (0.71-3.16), p=0.2909]. CONCLUSIONS: This study, in line with previous studies, shows that a diagnosis of T1DM is associated with a decreased risk of schizophrenia. This finding of an inverse association between T1DM and schizophrenia may bring an interesting piece, related to autoimmunity, into the schizophrenia-aetiology puzzle.

Effects of the atypical antipsychotic clozapine on insulin release in vitro.

OBJECTIVES: Treatment with the atypical antipsychotic clozapine is frequently associated with metabolic side-effects such as weight gain, lipid abnormalities and diabetes mellitus. Since insulin is a hormone that is involved in both the regulation of body weight, as well as in lipid metabolism and glucose regulation, an effect of clozapine on insulin secretion and/or on insulin action - at least in part - might explain its capability to induce these side-effects. The aim of this study was therefore to examine the influence of clozapine on insulin release in vitro. METHODS: The effect of clozapine in three different concentrations, 10(-6), 10(-5) and 10(-4) M, was investigated on both basal (i.e. 3.3 mM glucose) and glucose-stimulated (i.e. 16.7 mM glucose) insulin release, using isolated rat islets of Langerhans. RESULTS: The presence of clozapine in the concentrations of 10(-6), 10(-5) and 10(4 )M significantly increased basal insulin release compared to the control after 4 h (but not after 1 h) of incubation. As regards the glucose-stimulated insulin release, the presence of clozapine in the concentrations of 10(-5) and 10(-4) M, but not in that of 10(-6) M, significantly inhibited the glucose-stimulated insulin release compared to the control after both 1 and 4 h of incubation. CONCLUSION: This study demonstrates that the atypical antipsychotic clozapine exerts dual effects on insulin release in vitro, through stimulating basal insulin release and inhibiting glucose-stimulated insulin release. Both these effects of clozapine on insulin release may contribute to its disadvantage inducing metabolic side-effects.