Evolution of BDNF Full-Length/Truncated Receptor Ratio and Cognitive/General Functioning After a First Episode of Psychosis

Abstract Background Dysregulation of epigenetic processes might account for alterations of the hypothalamic-pituitary-adrenal axis observed in patients with schizophrenia. Therefore, in this study, we aimed to investigate methylation of the glucocorticoid receptor (NR3C1) gene in patients with schizophrenia-spectrum disorders, individuals at familial high risk of schizophrenia (FHR-P) and healthy controls (HCs) with respect to clinical manifestation and a history of psychosocial stressors. Methods We recruited 40 first-episode psychosis (FEP) patients, 45 acutely relapsed schizophrenia (SCZ-AR) patients, 39 FHR-P individuals and 56 HCs. The level of methylation at nine CpG sites of the NR3C1 gene was determined using pyrosequencing. Results The level of NR3C1 methylation was significantly lower in FEP patients and significantly higher in SCZ-AR patients compared to other subgroups of participants. Individuals with FHR-P and HCs had similar levels of NR3C1 methylation. A history of adverse childhood experiences (ACEs) was associated with significantly lower NR3C1 methylation in all subgroups of participants. Higher methylation of the NR3C1 gene was related to worse performance of attention and immediate memory as well as lower level of general functioning in patients with psychosis. Conclusions Patients with schizophrenia-spectrum disorders show altered levels of NR3C1 methylation that is significantly lower in FEP patients and significantly higher in SCZ-AR patients. Higher methylation of the NR3C1 gene might be related to cognitive impairment observed in this clinical population. The association between a history of ACEs and lower NR3C1 methylation is not specific to patients with psychosis. Longitudinal studies are needed to establish causal mechanisms underlying these observations.

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Longitudinal follow-up in acute and transient psychotic disorders and schizophrenia

The British Journal of Psychiatry ◽

10.1192/bjp.187.3.286 ◽

2005 ◽

Vol 187 (3) ◽

pp. 286-287 ◽

Cited By ~ 37

Author(s):

Frank Pillmann ◽

Andreas Marneros

Keyword(s):

Psychotic Disorders ◽

First Episode ◽

Control Group ◽

Level Of Functioning ◽

General Functioning ◽

And Gender ◽

High Level ◽

Observation Period

SummaryWe prospectively studied the long-term course of individuals with acute and transient psychotic disorders and a control group with positive schizophrenia matched for age and gender. Follow-up investigations using standardised instruments were performed at three time-points covering 7 years after the index episode or 12 years after the first episode. During follow-up, those with positive schizophrenia experienced a deterioration in their general functioning whereas those with acute and transient psychotic disorders retained their high level of functioning. At the end of the observation period, 12 out of 39 (31%) of those with acute and transient psychotic disorders were functioning well without medication compared with 0 out of 38 with positive schizophrenia.

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CNR2 GENE AND CANNABIS USE INTERPLAY MODULATES MANIPULATIVE ABILITIES IN FIRST-EPISODE OF PSYCHOSIS

10.17579/sepd2021o003 ◽

2021 ◽

Author(s):

Maitane Oscoz Irurozqui ◽

Maria Guardiola-Ripoll ◽

Carmen Almodóvar-Payá ◽

Amalia Guerrero-Pedraza ◽

Edith Pomarol-Clotet ◽

...

Keyword(s):

Cannabinoid Receptor ◽

Clinical Symptoms ◽

Endocannabinoid System ◽

Cognitive Outcomes ◽

Cannabis Use ◽

Psychotic Symptoms ◽

First Episode ◽

The Matrix ◽

General Functioning ◽

Matrix Reasoning

1. Objectives: While endocannabinoid system seems to be involved in processes underlying psychosis, research about Cannabinoid Receptor 2 gene (CNR2) is scarce and inconclusive. Some few reports indicate that CNR2 plays a role in psychiatric conditions, including depression or drug addiction (Onaivi et al., 2009). We aimed to evaluate the role of CNR2 and its interplay with cannabis on cognition and clinical symptoms in patients with a first-episode of psychosis (FEP). 2. Materials and Methods: the sample comprised 50 Caucasian individuals with a FEP (mean age(sd)=26.14(6.55) years, 76% males, 58% cannabis users). There were no differences in age, sex, premorbid IQ and antipsychotic dose between cannabis users (CU) and non-users (CNU). Neuropsychological (premorbid IQ - TAP-E, current IQ - WAIS, memory - WMS, executive function - BADS) and clinical (psychotic symptoms - PANSS, general functioning - GAF) scales were administered. Genetic variability was assessed by genotyping one Single Nucleotide Polymorphism (SNP) in CNR2 gene (rs2501431) (qPCR, TaqMan). 3. Results and conclusions: genotypic frequencies did not differ between cannabis users and non-users. CNR2 was not associated with PANSS scores.; however, it showed a differential effect on the performance IQ (measured by the matrix reasoning test - WAIS), conditional to the cannabis use (beta=0.73, p=0.02),. In particular, cannabis non-users with the AA genotype (23.53%) showed higher scores (mean(sd)=10.25 (1.87)) than those with at least one copy of the G allele (76.47%, mean(sd)=6.05(0.99); while cannabis users showed scores in the opposite direction (AA (42.31%): 8.21(1.09) and GG/GA (57.69%): 10.28(0.92)). Our results align with previous studies reporting the association of the CNR2 gene with psychiatric diseases (Ishiguro et al. 2007; Onaivi et al., 2008) adding evidence on the interplay of this gene with cannabis use on cognitive outcomes in first-episode psychosis. However, evidence is still scant, and further investigation in larger samples is needed.

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Quetiapinev.lithium in the maintenance phase following a first episode of mania: Randomised controlled trial

The British Journal of Psychiatry ◽

10.1192/bjp.bp.116.186833 ◽

2017 ◽

Vol 210 (6) ◽

pp. 413-421 ◽

Cited By ~ 29

Author(s):

Michael Berk ◽

Rothanthi Daglas ◽

Orwa Dandash ◽

Murat Yücel ◽

Lisa Henry ◽

...

Keyword(s):

Repeated Measures ◽

Mixed Model ◽

Lithium Treatment ◽

Controlled Trial ◽

Maintenance Phase ◽

Psychotic Symptoms ◽

First Episode ◽

General Functioning ◽

Randomised Controlled ◽

Clinical Trials Registry

BackgroundLithium and quetiapine are considered standard maintenance agents for bipolar disorder yet it is unclear how their efficacy compares with each other.AimsTo investigate the differential effect of lithium and quetiapine on symptoms of depression, mania, general functioning, global illness severity and quality of life in patients with recently stabilised first-episode mania.MethodMaintenance trial of patients with first-episode mania stabilised on a combination of lithium and quetiapine, subsequently randomised to lithium or quetiapine monotherapy (up to 800 mg/day) and followed up for 1 year. (Trial registration: Australian and New Zealand Clinical Trials Registry – ACTRN12607000639426.)ResultsIn total, 61 individuals were randomised. Within mixed-model repeated measures analyses, significant omnibus treatment × visit interactions were observed for measures of overall psychopathology, psychotic symptoms and functioning. Planned andpost hoccomparisons further demonstrated the superiority of lithium treatment over quetiapine.ConclusionsIn people with first-episode mania treated with a combination of lithium and quetiapine, continuation treatment with lithium rather than quetiapine is superior in terms of mean levels of symptoms during a 1-year evolution.

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General Functioning in Patients With First-Episode Psychosis After the First 18 Months of Treatment

Journal of Clinical Psychopharmacology ◽

10.1097/jcp.0000000000001224 ◽

2020 ◽

Vol 40 (4) ◽

pp. 366-372

Author(s):

Martina Rojnic Kuzman ◽

Porin Makaric ◽

Dina Bosnjak Kuharic ◽

Ivana Kekin ◽

Zoran Madzarac ◽

...

Keyword(s):

First Episode Psychosis ◽

First Episode ◽

Episode Psychosis ◽

General Functioning

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How Could Affect Stress, PEP and Sex in Working Memory?

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.304 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S98-S98

Author(s):

C.-R. Maria Isabel ◽

C.-R. Manuel ◽

M. Andrea ◽

R.-V. Miguel

Keyword(s):

Working Memory ◽

Social Cognition ◽

Cognitive Processes ◽

Cognitive Abilities ◽

Visual Memory ◽

Motor Coordination ◽

First Episode ◽

Control Group ◽

General Functioning ◽

Competing Interest

BackgroundThe first episode of psychosis is a crucial period when early intervention can alter the trajectory of the young person's ongoing mental health and general functioning. Cognitive abilities are nuclear for the social recovery. Stress impairs higher cognitive processes, dependent on the prefrontal cortex (PFC) and that involve maintenance and integration of information over extended periods, including working memory and attention. Different mechanism are involved such as HPA-Axis hyperactivity, affecting PFC. Recently, investigations show the different evolution of cognitive abilities between different sex in WM.MethodsA sample of 41 FEPs and 39 healthy subjects were evaluated. The variables assessed were verbal and visual memory, attention, working memory, processing speed, mental flexibility, verbal fluency, motor coordination, planning ability and intelligence.ResultsWe found an interaction between age (< 16 years and > 16 years) and group (psychosis vs. controls) in working memory (P = 0.04). There were no difference in men < 16 years old control group and men with same age plus psychosis (5.87 ± 1.57 vs. 5.83 ± 1; P = 0.1) in WM. However, this work was found to be significantly different in the univariant analysis of working memory in the group < 16 years old women control (7.30 ± 1.56) and women psychosis group (5.61 ± 1.91).ConclusionSocial cognition and stress seem to be directly relation. Some studies show that stress enhance cognition performance in men while impairing it in women. Stress affect a variety of cognitive processes such attention and working memory. Deficit in social cognition are present in the prodromal phases of psychosis.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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The first cysteine-rich domain of the receptor GFRα1 stabilizes the binding of GDNF

Biochemical Journal ◽

10.1042/bj20041257 ◽

2005 ◽

Vol 387 (3) ◽

pp. 817-824 ◽

Cited By ~ 10

Author(s):

Heidi VIRTANEN ◽

Jianmin YANG ◽

Maxim M. BESPALOV ◽

Jukka O. HILTUNEN ◽

Veli-Matti LEPPÄNEN ◽

...

Keyword(s):

Binding Capacity ◽

Full Length ◽

Tyrosine Kinase Receptor ◽

Soluble Receptors ◽

Truncated Receptor ◽

Rich Domain ◽

Low Concentrations ◽

Optimal Function ◽

High Concentrations ◽

Cysteine Rich Domain

The GDNF (glial cell line-derived neurotrophic factor)-binding receptor GFRα1 (GDNF family receptor α1) is attached to the membrane by a GPI (glycosylphosphatidylinositol) anchor and consists of three cysteine-rich domains. The region corresponding to the second and third domains has been shown previously to participate in ligand binding, and to interact with the transmembrane tyrosine kinase receptor RET. No function has so far been found for the N-terminal, first domain (D1). Here we show that the GPI-anchored full-length receptor binds 125I-GDNF two times more tightly than does a GPI-anchored truncated receptor lacking D1. Scintillation proximity assays with purified receptor proteins also show that the GDNF-binding capacity of the soluble full-length GFRα1 is two times higher than the GDNF-binding capacity of the soluble D1-truncated GFRα1. As RET stabilizes the binding of GDNF equally well to the full-length and truncated receptors, D1 seems not to be involved in the interaction between GFRα1 and RET. Moreover, soluble full-length GFRα1 mediates GDNF-promoted neurite outgrowth in PC6-3 cells more efficiently than the soluble truncated GFRα1 protein. At low concentrations, the soluble fulllength receptor mediates the phosphorylation of RET more efficiently than the soluble truncated receptor. However, when the receptors are overexpressed on the cell surface as GPI-anchored proteins, or added to the growth medium at high concentrations as soluble proteins, full-length and truncated GFRα1 are indistinguishable in GDNF-dependent RET-phosphorylation assays. High levels of the receptors can thus mask a slightly impaired function in the phosphorylation assay. Based on assays with both GPI-anchored and soluble receptors, we therefore conclude that D1 contributes to the optimal function of GFRα1 by stabilizing the interaction between GFRα1 and GDNF.

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T38. POSTER PRESENTATION: HAMLETT: HANDLING ANTIPSYCHOTIC MEDICATION, A LONGTERM EVALUATION OF TARGETED TREATMENT A PRAGMATIC SINGLE-BLIND RANDOMISED CONTROLLED TRIAL OF CONTINUATION VERSUS DISCONTINUATION OF PSYCHOTIC MEDICATION

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa029.598 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S246-S246

Author(s):

Erna van‘t Hag

Keyword(s):

Antipsychotic Medication ◽

Controlled Trial ◽

Well Being ◽

First Episode ◽

Psychotic Episode ◽

Subjective Well Being ◽

First Psychotic Episode ◽

Episode Psychosis ◽

General Functioning

Abstract Background When achieving remission after a first psychotic episode using antipsychotic medication, international guidelines generally recommend continuation of use for >1 year. However, patients often have a strong wish to stop earlier due to side-effects, affecting everyday functioning. Recently, guidelines have been questioned as one Dutch study found that more patients achieved long-term functional remission after early discontinuation. Yet, this finding has not yet been replicated. Psychiatrists, patients and family are unsure which regime to follow: to continue or not to continue? Methods In total 512 participants will be included who achieved remission after first-episode psychosis and use antipsychotic medication. Recruitment takes place at 24 Dutch sites. HAMLETT is a multicenter pragmatic single-blind randomized controlled trial with two conditions (1:1): maintenance treatment versus discontinuation/dose reduction of antipsychotic medication. Main research question: Is long-term general functioning better if patients reduce/discontinue antipsychotic medication at an early stage (3–6 months after remission of their first psychotic episode), than when they continue medication >1 year? General functioning is measured in two ways: with the WHO-DAS interview and with Ecological Momentary Assessments (EMA). EMA is a structured diary method in which individuals are asked in daily life to report on their current thoughts, feelings and symptoms, as well as the context (e.g. location, company, activity) and the appraisal of the context (e.g. stress). Diaries are completed via a smartphone diary app maximally 10 times daily at semi-random moments, over eight consecutive days. Momentary positive/negative affect, self-esteem, subjective well-being, paranoia, hallucinations, sleep, and frequency, type and appraisal of social company and activities are assessed on a 1–7 scale. At baseline and after 6 months, 1, 2, 3 and 4 years follow-up, patients of both arms will perform EMA. This results in an intensive time series of psychopathology, subjective well-being and social functioning in relation to antipsychotic medication and a range of contextual influences. Results The study is active and currently recruiting patients (since September 2017), At present 194 patients have been included, 20% participated in EMA measurements. Results of the interim analysis and preliminary of EMA data will be presented. Discussion The HAMLETT study investigates the effects of maintenance treatment versus discontinuation/dose reduction of antipsychotic medication after remission of first episode psychosis on personal and social functioning, psychotic symptom severity, health-related quality of life and cognitive functioning. The HAMLETT study will offer evidence to guide patients and clinicians when evaluating optimal treatment duration for psychotic disorders. Using different types of outcome measures will provide a more in-depth analysis of effects of continuation/ discontinuation on functioning.

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First bipolar episode and functionality: Relation with depressive symptoms and inflammation levels

European Psychiatry ◽

10.1016/j.eurpsy.2016.01.154 ◽

2016 ◽

Vol 33 (S1) ◽

pp. S122-S123 ◽

Cited By ~ 1

Author(s):

M. Martinez-cengotitabengoa ◽

C. Bermudez-ampudia ◽

M.P. Lopez ◽

A. Garcia-alocen ◽

I. Gonzalez-ortega ◽

...

Keyword(s):

Oxidative Stress ◽

Depressive Symptoms ◽

Manic Episode ◽

Inflammatory Factors ◽

First Episode ◽

Illness Onset ◽

Inflammatory Parameters ◽

General Functioning ◽

Competing Interest ◽

One Year

IntroductionIt is important to make an early and effective intervention from the first bipolar episode. The presence of depressive symptoms in the course of a manic episode could influence negatively the evolution and the prognosis of the patient. Inflammation and oxidative stress are also related with functionality.ObjectivesTo explore the relationship between depressive symptoms during a first episode of mania, inflammatory parameters and patient functionality during the follow-up.MethodWe included in the study 92 are patients with a first manic episode and 92 matched healthy controls. We compared 13 inflammatory/oxidative stress parameters measured at baseline (TFNα, IL6, PGE2, MCP1, TBARS, NO2, SOD, CAT, GSHTOT, GSSG, GSHfree, GPx, TAS) between both groups. Between patients, 46 presented pure mania (PM) (no depressive symptoms) and 46 mixed mania (MM) (with depressive symptoms). We explored the influence of inflammatory factors in functionality, exploring differences between PM and MM. To measure patients’ general functioning one year after illness onset, we used the Functional Assessment Short Test (FAST).ResultsWe found significant differences in TFNα, MCP1 and TBARS (higher in patients) and in SOD, GSHtot, GSSG, GSHfree, GPx and TAS levels (lower in patients). Only In MM group, there was a significant influence of SOD and GSHfree in FAST scores suggesting that a higher antioxidant levels at baseline the patient functionality improves one year after.ConclusionsSome parameters of oxidative stress at baseline are related with patient's functionality one year after the first episode of mania, but only when mania debuts with depressive symptons simultaneously.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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