Antipsychotic treatment is associated with inflammatory and metabolic biomarkers alterations among first-episode psychosis patients: A 7-month follow-up study.

AIM: Second-generation antipsychotics are commonly used to treat schizophrenia, but may cause metabolic syndrome (MetS) in a subset of patients. The mechanisms of antipsychotic-related metabolic changes remain to be established, especially in first-episode psychosis (FEP) patients. METHODS: In the present study, we used a chip technology to measure metabolic (C-peptide, insulin, leptin, adiponectin and resistin) and inflammatory biomarkers (ferritin, interleukin-6, interleukin-1α, tumour necrosis factor-α and plasminogen activator inhibitor-1) in the serum samples of a population of FEP patients before and after 7 months of antipsychotic drug treatment, compared to control subjects (CS). RESULTS: The comparison of these markers in antipsychotic-naïve FEP patients (N = 38) and CS (N = 37) revealed significantly higher levels of ferritin (P = .004), and resistin (P = .03) and lower level of leptin (P = .03) among FEP patients group. Seven months of antipsychotic drug treatment in patients (N = 36) ameliorated clinical symptoms, but increased significantly body mass index (BMI; P = .002) and these changes were accompanied by increased levels of C-peptide (P = .03) and leptin (P = .02), as well as decreased level of adiponectin (P = .01). CONCLUSIONS: Seven months of antipsychotic drug treatment suppressed the clinical symptoms of psychosis whereas caused imbalance in metabolic biomarkers and increased BMI. These findings provide insight into antipsychotic-induced MetS and refer to problems in insulin processing already present in the early stage of the chronic psychotic disorder.

Antipsychotic Treatment Reduces Indices of Oxidative Stress in First-Episode Psychosis Patients.

38 first-episode psychosis (FEP) patients and 37 control subjects were recruited for the study of indices of oxidative stress (OxS). The main purpose of the study was to compare the OxS statuses (serum total antioxidant capacity (TAC), total level of peroxides (TPX), oxidative stress index (OSI), and ratio oxidized methionine (Met-SO) to methionine (Met)) between antipsychotic-naïve FEP patients and individuals without a history of psychiatric disorders. Subsequently, the impact of 7-month antipsychotic treatment was evaluated on the OxS status in FEP patients. An attempt was made to assess links between OxS signature and inflammation markers. The oxidative stress indices remained generally unchanged in antipsychotic-naïve FEP patients compared to control subjects. Despite that, there was a significant correlation between the levels of TPX and EGF (endothelial growth factor) in FEP patients. This correlation disappeared after antipsychotic treatment of FEP patients. Moreover, antipsychotic treatment was associated with a significant reduction in OxS indices, including TPX, OSI, and ratio between Met-SO and Met. By contrast, in chronic SCZ patients we established a significant high-grade OxS. In conclusion, the markers of total antioxidative capacity, lipid peroxidation, and protein oxidation revealed no high-grade OxS in FEP patients. Nevertheless, antipsychotic treatment induced a considerable anti-inflammatory effect. OxS levels were also significantly decreased if compared in FEP patients before and after antipsychotic treatment.

Antipsychotic treatment reduces psychotic symptoms and markers of low-grade inflammation in first episode psychosis patients, but increases their body mass index.

OBJECTIVE: The main goal of the present study was to analyze levels of cytokines of the interleukin family (IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8 and IL-10), interferon-gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP1), tumor necrosis factor-alpha (TNF-α), and vascular endothelial and endothelial growth factors (VEGF and EGF), in the blood samples of first-episode psychosis (FEP) patients before and seven months after the start of antipsychotic medication use. METHOD: 38 anti-psychotic medication-naïve FEP patients and 37 healthy controls (HC) were recruited. Biochip array technology was used to measure cytokines and growth factors. RESULTS: The comparison of these markers in FEP patients and HC revealed significantly higher levels of EGF, IL-4 and IL-6 and significantly lower level of IL-1ß in FEP patients before the antipsychotic treatment. Multiple regression analysis demonstrated significant correlations between FEP and EGF, IL-1ß and smoking. Treatment with antipsychotic drugs resulted in a statistically significant amelioration of the symptoms of psychosis, but caused a significant increase in the body mass index (BMI) of patients. Levels of EGF, IL-2, VEGF, IL-6, IFN-γ, IL-4, IL-8 and IL-1α were significantly lower in treated FEP patients compared to premedication levels. CONCLUSIONS: According to the present study, EGF and IL-1ß are markers of FEP. Antipsychotic drug treatment resulted in a significant clinical improvement of FEP patients and the suppression of positive symptoms was correlated with the decreased levels of EGF, IL-2 and IL-4. EGF was the strongest marker of FEP and treatment efficiency among the measured cytokines and growth factors.

Polymorphisms of IKBKE gene are associated with major depressive disorder and panic disorder.

BACKGROUND: The immune system has been increasingly implicated in the development of mood and anxiety disorders. Inhibitor of kappa light polypeptide gene enhancer in B cells, kinase epsilon (IKBKE) gene encodes IKKε protein that is involved in innate immunity, predominantly antiviral response generation. It also bears pro-inflammatory properties that could affect psychiatric outcomes. In order to investigate the possible role of IKBKE gene in major depressive disorder (MDD) and panic disorder (PD), we conducted a case-control genetic association study concerning these disorders. METHODS: In all, 14 SNPs of IKBKE gene were genotyped in groups of 391 patients with MDD and 190 patients with PD together with respective 389 and 371 healthy control individuals. The given groups were further divided by gender for additional analyses. RESULTS: Substantial genetic associations were revealed between IKBKE SNPs and MDD (multiple testing adjusted P < 0.05) and suggestive associations in case of PD (P(adj) > 0.05). In addition, two SNPs that were only associated with PD among males, also displayed significantly different allele frequencies compared to PD females. This may indicate a specific role of these SNPs in male PD, but caution should be applied here due to the small size of the studied PD males group. CONCLUSIONS: The results of this study confirm our initial findings and indicate a possible role of IKBKE gene in mood and anxiety disorders.

Associations between polymorphisms of LSAMP gene and schizophrenia.

The purpose of this study was to explore relationships between single-nucleotide polymorphisms (SNPs) in the limbic system-associated membrane protein (LSAMP) gene and schizophrenia. Twenty-two SNPs were analysed in 127 unrelated schizophrenic patients and in 171 healthy controls. The results showed significant allelic and haplotypic associations between LSAMP gene and schizophrenia.

A survey of parentally reported sleep health disorders in Estonian 8-9 year old children.

BACKGROUND: Pediatric sleep research is rather new in Estonia. There has not been a comprehensive study of age specific sleep disorders in Estonian children. The aim of this study was to investigate sleep disorders in a sample of Estonian second grade children.We hypothesized that:: Children with low BMI are as susceptible to SDB as are children with high BMI. Under weight children are susceptible to residual SDB after adenotonsillectomy. Parasomnias present with SDB in children.• Excessive day time sleepiness is a significant symptom which leads parents to suspect sleep disorders in their child. METHODS: A retrospective questionnaire based survey was used to analyze factors influencing sleep, parasomnias, daytime sleepiness, and sleep disordered breathing (SDB). 1065 Pediatric Sleep Questionnaire (PSQ) packets were distributed by post to randomly selected parents of second grade students; 703 (66%) subjects were included in the study group; each parent/guardian participant had one second grade child. Descriptive statistics were used to compare characteristics of SDB symptomatic and healthy children. We used logistic regression to analyze factors influencing sleep and parasomnias in relation to SDB severity. Odds ratios (OR) and 95% CI were used to estimate relative risk. RESULTS: Parents of children with SDB complaints seem to pay attention to sleep disorders especially when a child is suffering from excessive day time sleepiness. Parasomnias are present simultaneously with SDB and tend to worsen in relation to more severe SDB complaints. Many underweight children have SDB symptoms after adenotonsillectomy. CONCLUSION: SDB symptoms are found in both overweight and underweight children. Both groups should be observed, especially in terms of the current focus on overweight children. Careful follow up after SDB treatment is necessary in case of under and overweight children. Parental suspicions regarding SDB are noticeably higher in cases of excessive daytime sleepiness in their children.

Whole-exome sequencing identifies a polymorphism in the BMP5 gene associated with SSRI treatment response in major depression.

Although antidepressants are widely used in the pharmacotherapy of major depressive disorder (MDD), their efficacy is still insufficient as approximately one-third of the patients do not fully recover even after several treatment trials. Inter-individual genetic differences are thought to contribute to the variability in antidepressant response; however, current findings from pharmacogenetic studies are uncertain or not clearly replicated. Here we report the first application of full exome sequencing for the analysis of pharmacogenomics on antidepressant treatment. After 12 weeks of treatment with the selective serotonin re-uptake inhibitor escitalopram, we selected five clear responders and five clear non-responders for exome sequencing. By comparing the allele counts of previously known single nucleotide polymorphisms and novel polymorphisms we selected 38 markers for further genotyping in two independent patient samples treated with escitalopram (n=116 and n=394). The A allele, carried by approximately 30% of the patients with MDD, of rs41271330 in the bone morphogenetic protein (BMP5) gene showed strong association with worse treatment response in both sample sets (p=0.001), indicating that this is an promising pharmacogenetic marker for prediction of antidepressant therapeutic outcome.

Help-seeking for emotional problems in major depression : findings of the 2006 Estonian health survey.

To study help-seeking among the general population and people with major depression. 12-month help-seeking for emotional problems was assessed in a cross-sectional 2006 Estonian Health Survey. Non-institutionalized individuals aged 18-84 years (n = 6,105) were interviewed. A major depressive episode was assessed using the Mini-International Neuropsychiatric Interview. The factors associated with help-seeking, received help, and health service use were analyzed. The prevalence of 12-month help-seeking for emotional symptoms was 4.8%. The rate of 12-month help-seeking in the depressed sample was 34.1%. Depressed people used non-mental health services 1.5-3 times more than non-depressed persons even when adjusted for the chronic somatic disorder. Only one third of depressed persons sought help, which was most of all associated with severity of depression. Underdiagnosis and undertreatment of depression leads to an increased use of expensive but non-specific health services by depressed persons.

The effect of 6-week treatment with escitalopram on CCK-4 challenge: a placebo-controlled study in CCK-4-sensitive healthy volunteers.

Cholecystokinin-tetrapeptide (CCK-4)-induced panic attacks are reportedly attenuated by effective treatment with antipanic antidepressants in patients with panic disorder, but in healthy volunteers such effects are not well studied. The aim of this study was to assess the effect of 6-week treatment with an SSRI escitalopram on CCK-4-induced symptoms in healthy volunteers, who previously responded with a panic attack to CCK-4 challenge. A total of 18 healthy subjects (10 males and eight females, mean age 22.5 ± 5.8) received a 6-week treatment with escitalopram (10 mg/day) and placebo followed by CCK-4 challenge (50 µg) in a double-blind crossover design. The panic rate was 67% after treatment with escitalopram and 56% after treatment with placebo (p = 0.7). Thus, the results showed a significant reduction in CCK-4-induced panic rates without significant differences between escitalopram and placebo conditions. There were no significant effects of either treatment on any other variable of anxiety or cardiovascular indices. Secondary analysis showed no effect of gender or 5-HTTLPR polymorphism on response to CCK-4 challenge. This study demonstrated that in contrast to the findings in patients with panic disorder, in CCK-4-sensitive healthy volunteers the treatment with an antipanic SSRI did not cause a reduction of CCK-4-induced panic attacks beyond the effect of placebo. The mechanisms behind this discrepancy and the reasons of the decrease in sensitivity to CCK-4 challenge on repeated administration remain to be clarified in future studies.

Diagnostic stability over 2 years in patients with acute and transient psychotic disorders.

OBJECTIVE: The nosological entity of acute and transient psychotic disorders (ATPD) as an independent diagnostic category has become a subject of controversial opinions. The present study aimed to follow-up the diagnostic stability of index episode of ATPD and to examine the influence of clinical and socio-demographic factors on the ATPD prognosis. METHOD: A sample of 153 (60.1% females; mean age 27.8 ± 8.2) first-admitted patients with ATPD was followed over 2 years. The clinical manifestations, global functioning and quality of life were regularly evaluated during follow-up period. RESULTS: At the end of follow-up, the overall stability rate of ATPD, excluding the cases not readmitted until last assessment, reached 34%. The diagnostic transition was observed in 35.9% of the patients, mostly to schizophrenia and schizoaffective disorders. There was a significant deterioration in several clinical and social indicators among the patients who developed schizophrenia, compared with those with stable ATPD, whereas no reliable predictors were found for diagnostic transition to schizophrenia, except younger age, unmarried status and period of the first hospitalization. CONCLUSION: A sizeable proportion of the patients with initial diagnosis of ATPD is likely to represent early manifestations of schizophrenia-related disorders. In agreement with some previous observations, our study indicates a lack of strong rationale for separating ATPD from other psychotic disorders within the ICD-10 F2 category.

Gender differences in brain serotonin transporter availability in panic disorder.

The role of the serotonin (5-HT) system in the neurobiology and treatment of panic disorder (PD) remains unproven. Previously we detected lower brain 5-HT transporter (SERT) availability in PD, but the findings were preliminary and mainly limited to female patients. The aim of this study was to assess non-displaceable brain SERT binding potential (BP (ND)) in male and female patients with PD. The SERT BP (ND) was measured in groups of patients with PD (five males and six females) and matched healthy control subjects (12 males and 12 females) using positron emission tomography (PET) and [¹¹C]MADAM tracer. SERT BP (ND) were significantly higher in 13 of 20 studied brain regions, including several cortical and raphe areas, but lower in the hippocampus in males with PD as compared with healthy males. No significant differences in SERT BP (ND) were observed between female patients and controls. The results suggest gender-dependent regional differences in brain SERT availability and converge with previous PET findings of reduced 5-HT(1A) receptor binding in similar brain areas in PD. Distinctive functioning of the 5-HT system in males and females may underlie certain gender-dependent differences in expressions of PD.

Associations between personality traits and CCK-4-induced panic attacks in healthy volunteers.

In this study we examined how personality disposition may affect the response to cholecystokinin tetrapeptide (CCK-4; 50 microg) challenge in healthy volunteers (n=105). Personality traits were assessed with the Swedish universities Scales of Personality (SSP). Statistical methods employed were correlation analysis and logistic regression. The results showed that the occurrence of CCK-4-induced panic attacks was best predicted by baseline diastolic blood pressure, preceding anxiety and SSP-defined traits of lack of assertiveness, detachment, embitterment and verbal aggression. Significant interactions were noted between the above mentioned variables, modifying their individual effects. For different subsets of CCK-4-induced symptoms, the traits of physical aggression, irritability, somatic anxiety and stress susceptibility also appeared related to panic manifestations. These findings suggest that some personality traits and their interactions may influence vulnerability to CCK-4-induced panic attacks in healthy volunteers.

Obstructive sleep apnea syndrome (OSAS): Pathophysiology in Estonians.

The aim of the study was to clarify the roles of age, obesity, smoking, alcohol, pathoanatomy and -physiology in Estonian's OSAS. For this 164 randomly chosen such patients were selected in different regions of Estonia. They underwent naso-oropharyngeal examination, physical examination of craniofacial abnormalities, and polysomnography. They also completed a self-reported questionnaire about smoking, alcohol use, excessive daytime sleepiness, hypertension, cardiac disorders, headaches, concentration disorders, and recurrent upper-airway diseases. The patients (129 men; 35 women) aged between 19 and 75 years (mean 47+/-12), BMI between 21 and 49 (mean 30.5+/-5.15), AHI between 5 and 105 (33+/-22). The results showed that there was a high percentage of naso-oropharyngeal disorders, such as: recurrent upper-airway diseases (54.2%), nasal breathing disorders (63.5%), and hypertrophy of tonsils (57%). There was also a high percentage of general characteristics, such as alcohol use (64%), excessive daytime sleepiness (85.5%), overweight (63%), and hypertension (51.2%). The regression summary for the dependent variable AHI if p-level=0.0042 (R=0.63347013) included age, BMI, hypertension, cardiac disorders, headaches, nasal obstruction, hypertrophy of pharyngeal muscles, tongue level, submental fat and slow-wave sleep (S3+S4%). In conclusion recurrent upper-airway diseases, nasal obstruction, and hypertrophy of tonsils in combination with smoking and alcohol caused the changes in the pharyngeal and lingual muscles. The latter gives rise to such sleep apnea-related problems as heart complaints, hypertension, headache and shortage of slow-wave sleep (SWS).

Thyroid autoimmunity and treatment response to escitalopram in major depression.

BACKGROUND: There is evidence that immune alterations play an important part in the pathogenesis of major depression. Thyroid autoimmunity has been found in association with major depression in several studies. AIM: 1) to examine whether the prevalence of anti-thyroid peroxidase autoantibodies (anti-TPO) in depressive patients differs from that in healthy controls; 2) to investigate the possible relationship between thyroid autoimmunity, total T3, free T3, free T4, thyroid-stimulating hormone (TSH), clinical status and treatment outcome in depression. METHOD: The study group consisted of 129 outpatients (69.8% female; mean age 31.7+/-12.0 years) with major depressive disorder with a Montgomery-Azsberg Depression Rating Scale total score of 22 or higher and 72 healthy controls (62.5% female; mean age 31.7+/-13.1 years). The patients were treated with escitalopram 10-20 mg/day for 12 weeks using open-label placebo non-controlled design. Anti-TPO, total T3, free T3, free T4 and TSH were measured before the treatment. RESULTS: The anti-TPO was found in eight (8.9%) depressive and two (4.8%) healthy females without statistical difference between these groups. Since anti-TPO was not seen in males, all further statistical analyses were carried out in females. At the end of week 12 of the treatment, 60 female patients (66.7%) were defined as responders and 30 depressive females (33.3%) showed insufficient response to treatment. Although there were no significant differences in the measurements between responders and non-responders, the last group showed a trend for a higher prevalence of anti-TPO compared with responders. CONCLUSION: Thyroid autoimmunity might be a factor predicting treatment response to antidepressants in depressive patients.

Evaluation of personality traits in panic disorder using Swedish universities Scales of Personality.

Personality factors may interact with development and expressions of panic disorder (PD). This study sought to identify differences in personality traits between patients with PD and healthy individuals and explore the relationships between personality domains and various demographic and clinical variables of PD. Personality traits were evaluated in 193 patients and 314 matched healthy subjects using the Swedish universities Scales of Personality (SSP). All SSP traits, except for detachment and physical trait aggression, were significantly deviated in PD group, as compared to healthy subjects. The SSP factors of neuroticism and aggressiveness, but not extraversion, were significantly higher in PD group than in controls. More pronounced aberrations in personality traits were observed in PD with affective comorbidity. Only few demographic and clinical variables were associated with SSP scores in PD group. These results add to the evidence of maladaptive personality disposition in patients with PD, particularly high neuroticism and manifest somatic trait anxiety. Use of SSP proved to add clinically relevant information on personality traits in patients with PD.

Interleukin 10 family gene polymorphisms are not associated with major depressive disorder and panic disorder phenotypes.

Genetic regulation of immune system and inflammatory response may be related to the pathogenesis and manifestations of mood and anxiety disorders. In the present study we examined a range of single-nucleotide polymorphisms (SNP) in chromosomal region 1q32, the locus of interleukin 10 (IL10) gene, in patients with major depressive disorder (n=312) and panic disorder (n=210), and matched healthy controls (n=356). We found no significant associations of the SNPs in IL10 family genes with either diagnostic group. Haplotype analysis revealed seven haplotype blocks, but their frequencies did not differ between patients and controls. Significant associations were detected for SNP rs1539243 in IKBKE (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon) gene showing different allelic and genotypic distributions in the total as well as in separate diagnostic groups as compared to controls. IKBKE emerged as a candidate for further studies of genetic factors associated with panic disorder and major depressive disorder.

Peripheral gene expression profiling of CCK-4-induced panic in healthy subjects.

Progress in understanding the genetic basis of panic attacks may extend current knowledge on susceptibility to panic and pathogenesis of panic disorder. In the present study we applied the microarray Illumina platform for whole genome expression profiling in healthy subjects participating in the CCK-4-induced panic test. The study sample consisted of 31 male and female healthy volunteers, who were categorized according to predefined criteria as "panickers" or "non-panickers" to a CCK-4 challenge. The gene expression profiles were measured on peripheral blood cells at baseline and at 120 min post-CCK-4 injection using Illumina Human-6 v2 BeadChips. The fold change was used to demonstrate rate of changes in average gene expressions between studied groups. Statistical analyses were performed using the false discovery rate (FDR). Gene expression profiling 2 hr post-CCK-4 challenge showed changes in transcriptional levels of 226 genes. A total of 61 genes were differentially expressed between panickers and non-panickers with most of them related to immune, enzymatic or stress regulation systems. Other distinctive mRNA transcripts were from the genes known to be related to phenotypes associated with increased occurrence of panic attacks, such as asthma, diabetes, or myocardial ischemia. Our findings provide preliminary evidence for genetic substrates of panic attacks on the transcriptional level and indicate potential biological proximity between acute panicogenesis and several somatic conditions.

The role of IL-2 and soluble IL-2R in depression and antidepressant response.

Cytokines are widely studied in the context of the pathogenesis and treatment of major depression. This review focuses on the potential importance of IL-2 and soluble IL-2R in major depression, as well as on their role in the mediation of the effects of antidepressant treatment. In general, there has been no consistent pattern in the associations observed between cytokine concentration, or changes thereof, and clinical indices of major depression. One intriguing question is whether pretreatment levels of immune system markers, such as IL-2R alpha, can be used to predict responses to antidepressant treatment. Based on the currently available data, this issue remains unresolved. This review also highlights certain methodological problems pertaining to the measurement of IL-2 and IL-2R in the context of depression and presents ideas for further research in this field.