Antipsychotic Injectable Medications Deplete Neurotrophic Factor In Schizophrenia Patients
Overview
Schizophrenia (SCZ) and schizoaffective disorder (SAD) are severe psychiatric conditions influenced by both genetic and environmental factors. Serum brain-derived neurotrophic factor (BDNF) has been identified as a potential biomarker for these disorders, though its temporal changes remain unclear. This study analyzes data from the Longitudinal Assessment of BDNF in Sardinian Psychotic Patients (LABSP) to examine the effects of antipsychotic treatments, particularly long-acting injectable (LAI) antipsychotics, on serum BDNF levels, and to assess the role of BDNF genetic variants.
Patients in the LABSP study were evaluated every six months for two years, with blood samples collected consistently in the morning to measure BDNF levels using an ELISA Kit. Four single nucleotide polymorphisms (SNPs) in the BDNF gene (rs1519480, rs11030104, rs6265 [Val66Met], and rs7934165) were analyzed using polymerase chain reaction (PCR). Mixed-effects linear regression models (MLRMs) were employed to analyze the data.
Out of 105 patients, 24 (22.9%) received LAI antipsychotic treatment. MLRM analysis revealed that LAI therapy significantly increased serum BDNF levels (Z = 2.2, p = 0.02), whereas oral antipsychotics had no significant impact on BDNF levels (Z = 0.15, p = 0.9). BDNF genetic variants did not moderate this effect.
The findings indicate a significant increase in serum BDNF levels in SCZ and SAD patients treated with LAI antipsychotics, suggesting a moderate to large effect. These results highlight the potential of LAI antipsychotics to influence BDNF levels and suggest that further research with larger sample sizes is needed to confirm these findings and explore their clinical implications.
Introduction
Schizophrenia (SCZ) is a severe, chronic mental illness characterized by significant clinical and functional impairment. The disorder is marked by positive symptoms, such as delusions and hallucinations, negative symptoms like impaired motivation and social withdrawal, and cognitive deficits. Schizoaffective disorder (SAD), on the other hand, combines these symptoms with significant mood disturbances, either depressive or manic. Both SCZ and SAD are closely related and influenced by a combination of genetic and environmental factors. Genetic studies have shown substantial hereditary contributions to the risk of both disorders, with numerous genetic loci associated with SCZ identified through genome-wide analyses.
Precision psychiatry aims to predict illness progression and outcomes by using algorithms that analyze multimodal data, including biomarkers. Brain-derived neurotrophic factor (BDNF) is a key biomarker of interest due to its involvement in neurogenesis, synaptic plasticity, and dopaminergic neuron function. Dysregulation of BDNF signaling is linked to various psychiatric conditions, including SCZ. While there is general agreement that serum BDNF levels are lower in SCZ patients compared to healthy controls, the pattern of this decline over time is debated. BDNF levels may either decrease steadily or fluctuate with the illness’s acute phases. Meta-analyses indicate a significant reduction in BDNF levels associated with disease activity.
Pharmacological treatments, particularly antipsychotics, can influence BDNF levels. Antipsychotics, including long-acting injectable (LAI) formulations, are known to impact BDNF levels and potentially improve clinical outcomes. LAIs are effective in reducing treatment non-adherence and lowering mortality rates in SCZ patients, and they have been associated with decreased symptom severity and reduced hospitalizations. However, the relationship between LAI treatment and BDNF levels remains under-researched.
The Longitudinal Assessment of BDNF in Sardinian Psychotic patients (LABSP) study investigates the effects of antipsychotic therapy on serum BDNF levels over 24 months. This secondary analysis focuses on the impact of LAI antipsychotics on BDNF levels and examines whether genetic variations in the BDNF gene influence this relationship.
Method
The LABSP study, conducted at the community mental health center associated with the University of Cagliari and its Health Agency in Italy, investigated patients with schizophrenia (SCZ) and social anxiety disorder (SAD). The study, approved by the Ethics Committee of the University of Cagliari Health Agency and compliant with the Declaration of Helsinki, involved participants who provided written informed consent. Diagnosis was confirmed using the Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Patient Edition (SCID-I/P) administered by trained professionals.
Inclusion criteria for the LABSP study were: age between 18 and 65 years, a diagnosis of SCZ or SAD based on DSM-IV-TR, and stability over the six months prior to recruitment. Exclusion criteria included refusal to consent, acute psychopathological symptoms, severe cognitive impairment affecting cooperation, major unstable medical conditions, severe mental retardation, significant neurological disorders or prior head injury, and current substance dependence. The patient cohort was not drug-naïve and was undergoing treatment primarily with antipsychotics.
Assessment involved collecting blood samples at baseline (T0) and at four subsequent time points: 6 months (T1), 12 months (T2), 18 months (T3), and 24 months (T4). Detailed pharmacological treatment data was collected through direct assessment and medical record review. Brain-derived neurotrophic factor (BDNF) serum levels were measured using a BDNF ELISA Kit, with samples processed according to standardized procedures and analyzed using a microplate reader and associated software.
Genetic analysis focused on tag single nucleotide polymorphisms (SNPs) using the Tagger tool in Haploview, selecting SNPs with r2 ≥ 0.8 and a minor allele frequency of 0.01. Genotyping of BDNF SNPs (rs1519480, rs11030104, rs6265 (Val66Met), and rs7934165) was performed using Taq-Man probes on a StepOne Plus instrument.
Data analysis employed mixed-effects linear regression models (MLRMs) to examine longitudinal changes in BDNF levels, regressing independent variables, including antipsychotic therapy and BDNF SNPs, on BDNF serum levels while controlling for age and sex. ANOVA was used to compare BDNF levels among different long-acting injectable (LAI) antipsychotic groups. The analysis utilized R packages “lme4” for modeling, “na.action” for handling missing data, “multcomp” for statistical significance, and “sJPlot” and “sjmisc” for graphical representation.
Result
The study analyzed a sample of 105 patients, including 64 with schizophrenia (SCZ) and 41 with schizoaffective disorder (SAD). At the time of recruitment, 98% of the participants were on oral antipsychotic medications, with 22.9% also receiving long-acting injectable (LAI) antipsychotics. Among the oral antipsychotics, haloperidol (19.3%), amisulpride (6.4%), aripiprazole (12.9%), chlorpromazine (3.2%), clozapine (25.8%), olanzapine (20.4%), paliperidone (1.0%), quetiapine (6.4%), and risperidone (4.3%) were commonly used. For LAI antipsychotics, haloperidol (47.3%), paliperidone (26.3%), risperidone (10.4%), aripiprazole (10.5%), and zuclopenthixol (5.2%) were most prevalent. During the study, no changes were observed in concomitant psychotherapies or other non-pharmacological treatments.
The longitudinal analysis using mixed linear regression models (MLRM) revealed no significant impact of oral antipsychotic treatment on serum BDNF (brain-derived neurotrophic factor) levels over time (Model 1: Z = 0.15, p = 0.9; Model 2 with covariates: Z = -0.04, p = 0.9). However, a trend towards increased serum BDNF levels was noted in patients receiving LAI therapy, with a significant association emerging when age and sex were included as covariates (Z = 2.2, p = 0.02). No significant differences in BDNF levels were found between different LAI medication groups (ANOVA: F = 0.703, p = 0.6).
Additionally, the study assessed whether variations in the BDNF gene influenced the effect of LAI therapy on serum BDNF levels. Analysis of four polymorphisms in the BDNF gene showed no significant moderating effects on the relationship between LAI therapy and BDNF levels.
Conclusion
This secondary analysis of LABSP data revealed that long-acting injectable (LAI) antipsychotics, unlike oral antipsychotics, significantly influenced the longitudinal changes in serum brain-derived neurotrophic factor (BDNF) levels. Specifically, the 24 patients receiving LAI antipsychotics exhibited a consistent increase in serum BDNF levels over time. This finding aligns with both preclinical and clinical research indicating that certain antipsychotics, particularly second-generation ones, positively impact BDNF levels.
Preclinical studies, such as those by Park et al., have shown that chronic administration of quetiapine can counteract BDNF reduction in animal models subjected to stress. Additionally, research suggests that while second-generation antipsychotics like aripiprazole and olanzapine restore BDNF levels, first-generation antipsychotics like haloperidol may not. Similarly, findings from Pillai, Terry, and Mahadik support the notion that switching from haloperidol to second-generation antipsychotics can restore BDNF levels.
Our analysis also highlighted the differential effects of oral versus LAI antipsychotics on BDNF levels. LAI antipsychotics might be more effective due to their improved adherence rates and more stable pharmacokinetics, which contribute to consistent drug levels and potentially more significant physiological effects. Preclinical studies indicate that continuous administration of LAI antipsychotics, such as risperidone, is associated with increased BDNF levels, further supporting our findings.
Moreover, our study did not find evidence that genetic variants within the BDNF gene significantly moderated the effects of LAI therapy on serum BDNF levels. This is consistent with previous research showing that the Val66Met polymorphism in the BDNF gene does not notably influence BDNF serum levels.
The study’s limitations include the small sample size of the LAI antipsychotic group, which restricted the ability to perform more detailed secondary analyses. Despite this, the observed association between LAI treatment and increased serum BDNF levels suggests a potentially significant effect that warrants further investigation in larger, prospective studies. Additionally, changes in serum BDNF may not fully reflect changes at the brain level, but identifying peripheral biomarkers like serum BDNF could offer valuable prognostic insights.
In summary, this study identified a notable increase in serum BDNF levels among patients treated with LAI antipsychotics. This effect, observed despite the small sample size, suggests a moderate to large magnitude impact that should be explored in future research to better understand the relationship between LAI antipsychotic treatment and BDNF levels.
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