Dorota Frydecka

Homocysteine levels in schizophrenia and affective disorders—focus on cognition

Although homocysteine (Hcy) has been widely implicated in the etiology of various physical health impairments, especially cardiovascular diseases, overwhelming evidence indicates that Hcy is also involved in the pathophysiology of schizophrenia and affective disorders. There are several mechanisms linking Hcy to biological underpinnings of psychiatric disorders. It has been found that Hcy interacts with NMDA receptors, initiates oxidative stress, induces apoptosis, triggers mitochondrial dysfunction and leads to vascular damage. Elevated Hcy levels might also contribute to cognitive impairment that is widely observed among patients with affective disorders and schizophrenia. Supplementation of vitamins B and folic acid has been proved to be effective in lowering Hcy levels. There are also studies showing that this supplementation strategy might be beneficial for schizophrenia patients with respect to alleviating negative symptoms. However, there are no studies addressing the influence of add-on therapies with folate and vitamins B on cognitive performance of patients with schizophrenia and affective disorders. In this article, we provide an overview of Hcy metabolism in psychiatric disorders focusing on cognitive correlates and indicating future directions and perspectives.

Interleukin-6: the missing element of the neurocognitive deterioration in schizophrenia? The focus on genetic underpinnings, cognitive impairment and clinical manifestation.

The influence of the immune system deregulation on the risk of schizophrenia is increasingly recognized. The aim of this study was to assess the influence of serum interleukin-6 (IL-6) level together with the polymorphism in its gene (IL6 -174G/C) and high sensitivity C-reactive protein (hsCRP) levels on clinical manifestation and cognition in schizophrenia patients. We recruited 151 patients with schizophrenia and 194 healthy control subjects. Psychopathology was evaluated using Operational Criteria for Psychotic Illness checklist, Positive and Negative Syndrome Scale (PANSS) and Scales for Assessment of Positive and Negative Symptoms. Cognitive performance in schizophrenia patients was assessed using following tests: Rey Auditory Verbal Learning Test, Trail Making Test, Verbal Fluency Tests, Stroop and subscales from Wechsler Adults Intelligence Scale-R-Pl (Similarities, Digit Symbol Coding, Digit Span Forward and Backward). Serum IL-6 and hsCRP levels were significantly higher in schizophrenia patients in comparison with healthy controls. Both hsCRP and IL-6 levels were associated with insidious psychosis onset, duration of illness and chronic schizophrenia course with deterioration. After adjustment for age, education level, number of years of completed education, illness duration, total PANSS score, depression severity and chlorpromazine equivalent, there was still a positive association between IL-6 and hsCRP levels and worse cognitive performance. The IL6 -174G/C polymorphism did not influence IL-6 level, but it was associated with the severity of positive symptoms. Our results suggest that elevated IL-6 levels may play the role in cognitive impairment and serve as potential inflammatory biomarker of deterioration in schizophrenia.

Estimating the burden of early onset dementia; systematic review of disease prevalence.

Dementia is more common in older age but a number of people develop symptoms at a younger age and are said to have early onset dementia (EOD). Those with EOD face different challenges to those with onset later in life. It has been difficult to quantify this disease burden. This is a systematic review of papers reporting on the prevalence of EOD. A search of Medline and Embase was performed. This was followed by a hand search of the references of these papers. Eleven suitable studies were included. All of the data was from more economically developed countries. The studies were heterogeneous in their design hindering direct comparison. The majority of the papers looked at all types of dementia although many gave a breakdown of the prevalence of different subgroups. A variety of diagnostic criteria was employed. Figures of 38 to 260 per 100 000 are quoted by papers looking at various different types of dementia together with an onset of between 30 and 64 or up to 420 per 100 000 for those aged 55–64. Prevalence rises as age approaches 65. Epidemiological data for prevalence rates for EOD are sparse. EOD remains a rare condition with low case numbers. Assimilation and comparison of results from existing studies is difficult due to methodological heterogeneity. Cross‐national standardization of methodology should be a priority for future research in this area.

Elevated homocysteine level in first-episode schizophrenia patients—the relevance of family history of schizophrenia and lifetime diagnosis of cannabis abuse

Accumulating evidence indicates that elevated homocysteine (Hcy) level occurs in first-episode schizophrenia (FES) patients. We included 56 FES patients and 53 healthy controls (HC). Plasma level of Hcy was significantly higher in FES patients than HC (p = 0.044). In addition, plasma levels of high-density lipoproteins (HDL) and folate were significantly lower in FES than in HC (p < 0.001). Positive family history of schizophrenia was associated with lower plasma HDL (p = 0.041) and vitamin B12 (p = 0.017), as well as higher level of Hcy (p = 0.017). Patients with FES, who abused cannabis, had higher levels of Hcy (p = 0.017), as well as lower levels of vitamin B12 (p = 0.017) and HDL (p = 0.041). Plasma Hcy negatively correlated with duration of untreated psychosis (r = −0.272, p = 0.042). There was a positive correlation between Hcy level and the severity of negative symptoms (r = 0.363, p = 0.006) and general psychopathology (r = 0.349, p = 0.008) assessed using Positive and Negative Syndrome Scale (PANSS). Vitamin B12 level was negatively associated with the severity of negative symptoms (r = −0.406, p = 0.002), while folate level negatively correlated with general psychopathology score (r = −0.365, p = 0.006) in PANSS. These results indicate that the severity of one-carbon metabolism alterations and HDL deficiency might be associated with family history of schizophrenia and cannabis abuse. Lower vitamin B12 and folate along with elevated Hcy may influence the severity of FES psychopathology.

Cytokines and C-reactive protein alterations with respect to cognitive impairment in schizophrenia and bipolar disorder: A systematic review

BACKGROUND The aim of this article was to perform a systematic review of studies investigating the association between peripheral levels of cytokines and C-reactive protein (CRP), cytokine gene polymorphisms and cognition in patients with schizophrenia and bipolar disorder (BD). METHODS The following databases: PubMed, CINAHL Complete, Academic Search Complete, ERIC and Health Source: Nursing/Academic Edition databases were searched according to the PRISMA guidelines. We included studies that investigated the association between peripheral levels of CRP and cytokines, cytokine gene polymorphisms and cognitive performance in schizophrenia and/or BD patients. Subsequently, quality assessment of eligible publications was performed. Results were synthesized by discussing main findings around correlations between inflammatory markers and cognition. RESULTS Most consistent results indicate worse cognitive performance in schizophrenia patients with higher CRP levels. Less consistent evidence suggests better cognitive functioning of schizophrenia patients with higher levels of tumour necrosis factor-α (TNF-α). Evidence for the involvement of other cytokines in cognitive impairment in patients with schizophrenia is less convincing due to discordant results or scarcity of studies. Due to low number of studies, it is difficult to draw conclusions on the involvement of CRP and cytokine alterations in the development of cognitive deficits in BD. Single studies suggest the role of CRP, interleukin(IL)-1 receptor antagonist, IL-6 and TNF-α with its receptors in the development of cognitive impairment in BD. CONCLUSIONS Peripheral inflammation might be related to cognitive deficits in schizophrenia and BD. Unequivocal conclusions cannot be made due to methodological heterogeneity and low number of studies investigating particular cytokines.

European studies on the prevalence of dementia in the elderly: time for a step towards a methodological consensus

The aim of this study was to discuss methodological limitations in studies on the prevalence of dementia across European countries with particular attention to post‐EURODEM studies.

The multidimensional nature of metabolic syndrome in schizophrenia: lessons from studies of one-carbon metabolism and DNA methylation

Large data sets indicate that the prevalence of metabolic syndrome (MetS) is significantly higher in patients with schizophrenia in comparison with the general population. Given that interactions between genes and the environment may underlie the etiology of MetS in subjects with schizophrenia, it is feasible that epigenetic phenomena can serve as the etiological consensus between genetic and environmental factors. However, there is still a striking scarcity of studies aimed at investigating the role of aberrant DNA methylation in the development of MetS in this group of patients. This article provides an update on the epigenetics of schizophrenia and reviews studies on the role of one-carbon metabolism and aberrant DNA methylation in the development of MetS.

Metabolic dysregulation in first-episode schizophrenia patients with respect to genetic variation in one-carbon metabolism.

The aim of this study was to investigate the prevalence of metabolic disturbances in patients with first-episode schizophrenia (FES) and test the hypothesis that genetic variation in one-carbon metabolism may account for metabolic dysregulation in early psychosis. We measured fasting glucose, lipid profile parameters, homocysteine, folate and vitamin B12 in 135 patients with FES and 146 healthy controls (HCs). Polymorphisms in the following genes were determined: MTHFR (C677T and A1298C), MTHFD1 (G1958A), MTRR (A66G) and BHMT (G742A). Serum levels of folate and high-density lipoproteins (HDL) were significantly lower in patients with FES compared to HCs. In turn, serum levels of homocysteine and triglycerides were significantly higher in patients with FES than in HCs. Prevalence of hyperhomocysteinemia, low folate and HDL levels together with dyslipidemia was significantly higher in patients with FES compared to HCs. Higher homocysteine levels, lower vitamin B12 levels and the presence of metabolic syndrome were associated with higher severity of negative symptoms. None of studied polymorphisms was associated with schizophrenia risk. Several associations between studied polymorphisms and cardio-metabolic parameters were found. None of them remained significant after Bonferroni correction. Our results indicate that metabolic dysregulation in patients with FES is not associated with genetic variation in one-carbon metabolism.

Some dopaminergic genes polymorphisms are not associated with response to antipsychotic drugs in schizophrenic patients.

BACKGROUND Therapeutic effects of all clinically used antipsychotics are related to the reduction of dopaminergic transmission in the limbic system. The aim of present study was two-fold. First, efficacy of atypical drugs (ziprasidone and olanzapine) against schizophrenia symptoms was compared to that offered by a typical antipsychotic medication, perazine. Second, associations between some dopaminergic genes polymorphisms and therapeutic response to antipsychotics were assessed in the same group of schizophrenia patients. METHODS One hundred ninety one Caucasian patients admitted with exacerbation of paranoid schizophrenia were genotyped for polymorphisms of the DRD2 [the ins/del -141C (rs1799732) and exon 8 (rs 71653615)], DRD2/ANKK1 Taq IA(rs 1800497), DAT1 (the 40 bp VNTR), COMT (rs 4680), and MAOA gene (the 30 bp VNTR in promoter). The patients were randomly assigned to the treatment with perazine, olanzapine or ziprasidone given as monotherapy for 3 months. Treatment efficacy was measured from baseline (T0) to T1 (14 days) and T2 (3 months). A retention rate was also assessed at T1 and T2. RESULTS The three antipsychotics did not differ in terms of reduction of the PANSS score or retention rate at the follow-up. There was no interaction between the investigated polymorphisms and response to the antipsychotic treatment. CONCLUSIONS The present results suggest that: i) there are no major differences in short-term efficacy or effectiveness of atypical (olanzapine, ziprasidone) and typical (perazine) antipsychotic drugs; ii) the studied polymorphisms are not primarily involved in treatment response to antipsychotics in schizophrenia patients.

Toward a unified theory of childhood trauma and psychosis: A comprehensive review of epidemiological, clinical, neuropsychological and biological findings

HIGHLIGHTSChildhood traumatic events increase a risk of psychosis.Childhood trauma might be associated with a specific psychosis manifestation.Childhood adversities trigger specific biological alterations in psychosis.Childhood trauma might predict poor prognosis in psychotic disorders.Psychosis with positive history of childhood trauma might be a distinct phenotype. ABSTRACT There is a growing body of research focused on the relationship between childhood trauma and the risk of developing psychosis. Numerous studies, including many large‐scale population‐based studies, controlling for possible mediating variables, provide persuasive evidence of a dose‐response association and are indicative of a causal relationship. Existing evidence supports the specificity model, showing differential associations between particular adversities and clinical symptoms, with cumulative adversity causing less favorable clinical and functional outcomes in psychotic patients. To date, several psychological and biological models have been proposed to search for underlying developmental trajectories leading to the onset of psychosis, influencing psychopathological manifestation and negative functional outcomes due to a history of childhood trauma. In this article, we provide a unified review on the relationship between childhood trauma and psychosis by integrating results of epidemiological, clinical, neuropsychological and biological studies. The question whether psychosis with a positive history of childhood trauma should be considered as a new psychotic phenotype, requiring specific therapeutic interventions, warrants further investigation.