Case report: Avoiding intolerance to antipsychotics through a personalized treatment approach based on pharmacogenetics.

Introduction: The standard approach to treatment in psychiatry is known as "treatment as usual" (TAU), in which the same types of treatment are administered to a group of patients. TAU often requires numerous dose adjustments and medication changes due to ineffectiveness and/or the occurrence of adverse drug reactions (ADRs). This process is not only time-consuming but also costly. Antipsychotic medications are commonly used to treat various psychiatric disorders such as schizophrenia and mood disorders. Some of the inter-individual differences in efficacy and ADRs observed in psychopharmacotherapy can be explained by genetic variability in the pharmacokinetics and pharmacodynamics of antipsychotics. A better understanding of (in)efficacy and possible ADRs can be achieved by pharmacogenetic analysis of genes involved in the metabolism of antipsychotics. Most psychotropic drugs are metabolized by genetically variable CYP2D6, CYP1A2, CYP3A4, and CYP2C19 enzymes. To demonstrate the utility of pharmacogenetic testing for tailoring antipsychotic treatment, in this paper, we present the case of a patient in whom a pharmacogenetic approach remarkably altered an otherwise intolerant or ineffective conventional TAU with antipsychotics. Methods: In this case report, we present a 60-year-old patient with psychotic symptoms who suffered from severe extrapyramidal symptoms and a malignant neuroleptic syndrome during treatment with risperidone, fluphenazine, aripiprazole, brexpiprazole, and olanzapine. Therefore, we performed a pharmacogenetic analysis by genotyping common functional variants in genes involved in the pharmacokinetic pathways of prescribed antipsychotics, namely, CYP2D6, CYP3A4, CYP3A5, CYP1A2, ABCB1, and ABCG2. Treatment recommendations for drug-gene pairs were made according to available evidence-based pharmacogenetic recommendations from the Dutch Pharmacogenetics Working Group (DPWG) or Clinical Pharmacogenetics Implementation Consortium (CPIC). Results: Pharmacogenetic testing revealed a specific metabolic profile and pharmacokinetic phenotype of the patient, which in retrospect provided possible explanations for the observed ADRs. Based on the pharmacogenetic results, the choice of an effective and safe medication proved to be much easier. The psychotic symptoms disappeared after treatment, while the negative symptoms persisted to a lesser extent. Conclusion: With the case presented, we have shown that taking into account the pharmacogenetic characteristics of the patient can explain the response to antipsychotic treatment and associated side effects. In addition, pharmacogenetic testing enabled an informed choice of the most appropriate drug and optimal dose adjustment. This approach makes it possible to avoid or minimize potentially serious dose-related ADRs and treatment ineffectiveness. However, due to the complexity of psychopathology and the polypharmacy used in this field, it is of great importance to conduct further pharmacokinetic and pharmacogenetic studies to better assess gene-drug and gene-gene-drug interactions.

What is it like to do a visuo-spatial working memory task: A qualitative phenomenological study of the visual span task.

Working memory is typically measured with specifically designed psychological tasks. When evaluating the validity of working memory tasks, we commonly focus on the reliability of the outcome measurements. Only rarely do we focus on how participants experience these tasks. Accounting for lived experience of working memory task may help us better understand variability in working memory performance and conscious experience in general. We replicated recently established protocols for the phenomenological investigation of working memory using the visual span task. We collected subjective reports from eighteen healthy participants (10 women) aged 21 to 35 years. We observed that working memory can be phenomenologically characterized at three different time scales: background feelings, strategies, and tactics. On the level of tactics, we identified transmodality (i.e., how one modality of lived experience can be transformed into another one) as the central phenomenological dynamic at play during working memory task performance.

Dense attention network identifies EEG abnormalities during working memory performance of patients with schizophrenia.

Introduction: Patients with schizophrenia typically exhibit deficits in working memory (WM) associated with abnormalities in brain activity. Alterations in the encoding, maintenance and retrieval phases of sequential WM tasks are well established. However, due to the heterogeneity of symptoms and complexity of its neurophysiological underpinnings, differential diagnosis remains a challenge. We conducted an electroencephalographic (EEG) study during a visual WM task in fifteen schizophrenia patients and fifteen healthy controls. We hypothesized that EEG abnormalities during the task could be identified, and patients successfully classified by an interpretable machine learning algorithm. Methods: We tested a custom dense attention network (DAN) machine learning model to discriminate patients from control subjects and compared its performance with simpler and more commonly used machine learning models. Additionally, we analyzed behavioral performance, event-related EEG potentials, and time-frequency representations of the evoked responses to further characterize abnormalities in patients during WM. Results: The DAN model was significantly accurate in discriminating patients from healthy controls, ACC = 0.69, SD = 0.05. There were no significant differences between groups, conditions, or their interaction in behavioral performance or event-related potentials. However, patients showed significantly lower alpha suppression in the task preparation, memory encoding, maintenance, and retrieval phases F(1,28) = 5.93, p = 0.022, η2 = 0.149. Further analysis revealed that the two highest peaks in the attention value vector of the DAN model overlapped in time with the preparation and memory retrieval phases, as well as with two of the four significant time-frequency ROIs. Discussion: These results highlight the potential utility of interpretable machine learning algorithms as an aid in diagnosis of schizophrenia and other psychiatric disorders presenting oscillatory abnormalities.

DNA Methylation Patterns in Relation to Acute Severity and Duration of Anxiety and Depression.

Depression and anxiety are common mental disorders that often occur together. Stress is an important risk factor for both disorders, affecting pathophysiological processes through epigenetic changes that mediate gene-environment interactions. In this study, we explored two proposed models about the dynamic nature of DNA methylation in anxiety and depression: a stable change, in which DNA methylation accumulates over time as a function of the duration of clinical symptoms of anxiety and depression, or a flexible change, in which DNA methylation correlates with the acute severity of clinical symptoms. Symptom severity was assessed using clinical questionnaires for anxiety and depression (BDI-II, IDS-C, and HAM-A), and the current episode and the total lifetime symptom duration was obtained from patients' medical records. Peripheral blood DNA methylation levels were determined for the BDNF, COMT, and SLC6A4 genes. We found a significant negative correlation between COMT_1 amplicon methylation and acute symptom scores, with BDI-II (R(22) = 0.190, p = 0.033), IDS-C (R(22) = 0.199, p = 0.029), and HAM-A (R(22) = 0.231, p = 0.018) all showing a similar degree of correlation. Our results suggest that DNA methylation follows flexible dynamics, with methylation levels closely associated with acute clinical presentation rather than with the duration of anxiety and depression. These results provide important insights into the dynamic nature of DNA methylation in anxiety and affective disorders and contribute to our understanding of the complex interplay between stress, epigenetics, and individual phenotype.

Case report: application of pharmacogenetics in the personalized treatment of an elderly patient with a major depressive episode.

Background: Pharmacogenetic analyses can predict interpersonal differences in response to psychopharmacotherapy, which greatly facilitates the selection of the most effective medication at optimal doses. By personalizing therapy in this way, we can minimize adverse drug reactions (ADR) and prevent polypharmacy. Most psychotropic medications are metabolized by the cytochrome P450 enzymes CYP2D6, CYP2C19, and CYPA3A4, which influence drug metabolism and concentration, affecting both efficacy and the occurrence of ADR. The relationships between genetic variations and enzymatic activity allow pharmacogenetic analysis to provide important data for optimal drug selection. The following case report illustrates the impact of pharmacogenetic analysis on the course of pharmacologic treatment in an elderly patient with a major depressive episode. Methods: We present a case of a 79-year-old patient treated for severe depression with psychotic symptoms. We collected data on treatment selection and response to treatment before and after pharmacogenetic analysis. For pharmacogenetic analysis, common functional variants in CYP1A2, CYP3A4, CYP2B6, CYP2C19, and CYP2D6 were genotyped, and corresponding evidence-based treatment recommendations were prepared. Results: The patient suffered from lack of efficacy and serious ADR of several medications, resulting in worsening depression and treatment resistance over the course of several months of treatment. Pharmacogenetic analysis provided important insights into the patient's pharmacokinetic phenotype and allowed us to personalize treatment and achieve remission of the depressive episode. Conclusion: In the case presented, we have shown how consideration of pharmacogenetic characteristics in an individual patient can improve treatment outcome and patient well-being. Knowledge of the patient's pharmacogenetic characteristics helped us to personalize treatment, resulting in complete remission of psychopathology. Due to the complexity of psychiatric disorders, the efficacy of combinations of different medications, which are often required in individual patients, cannot be clearly explained. Therefore, it is of great importance to conduct further pharmacokinetic and pharmacogenetic studies to better assess gene-drug interactions in psychopharmacotherapy.

The Diversity of Strategies Used in Working Memory for Colors, Orientations, and Positions: A Quantitative Approach to a First-Person Inquiry.

The study of individual experience during the performance of a psychological task using a phenomenological approach is a relatively new area of research. The aim of this paper was to combine first- and third-person approaches to investigate whether the strategies individuals use during a working memory task are associated with specific task conditions, whether the strategies combine to form stable patterns, and whether the use of specific strategies is related to task accuracy. Thirty-one participants took part in an experiment in which they were instructed to remember colors, orientations, or positions of stimuli presented in a change detection task. After every 7th-15th trial, participants took part in an in-depth phenomenological interview in which they described their experiences during the trial that immediately preceded the interview. Qualitative analysis revealed a set of 18 strategies that participants used while performing the task, which we divided into active and passive strategies of encoding, maintenance, and retrieval. Quantitative analysis revealed that while many strategies were used in all task conditions, some strategies and their combinations may be better suited to the specific task demands, while others are more general in nature. The results also suggest a distinction between strategies for encoding object identity and spatial features. Finally, our results did not provide robust evidence for a relationship between specific strategies and task accuracy.

Detecting Subtle Cognitive Impairment in Patients with Parkinson's Disease and Normal Cognition: A Novel Cognitive Control Challenge Task (C3T).

Patients with Parkinson's disease (PD) often show early deficits in cognitive control, with primary difficulties in flexibility and relatively intact stable representations. The aim of our study was to assess executive function using an ecologically valid approach that combines measures of stability and flexibility. Fourteen patients without cognitive deficits and sixteen comparable control subjects completed a standardized neuropsychological test battery and a newly developed cognitive control challenge task (C3T). We found that the accuracy of C3T performance decreased with age in healthy participants and remained impaired in PD patients regardless of age. In addition, PD patients showed significantly lower overall performance for cognitive control tasks than healthy controls, even when they scored in the normal range on standardized neuropsychological tests. PD Patients responded significantly faster than healthy control subjects regarding flexible cognitive control tasks due to their impulsivity. Correlations showed that the C3T task targets multiple cognitive systems, including working memory, inhibition, and task switching, providing a reliable measure of complex cognitive control. C3T could be a valuable tool for characterizing cognitive deficits associated with PD and appears to be a more sensitive measure than standardized neuropsychological tests. A different assessment approach could potentially detect early signs of the disease and identify opportunities for early intervention with neuroprotective therapies.

Effects of Mindfulness-Based Therapy on Clinical Symptoms and DNA Methylation in Patients with Polycystic Ovary Syndrome and High Metabolic Risk.

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder affecting women of reproductive age. Research has shown that epigenetic alterations such as DNA methylation may play a role in the development and progression of abnormal ovarian function and metabolic disorders in PCOS. Studies have identified specific genes (related with insulin signaling and steroid hormone metabolism) that are methylated in women with PCOS. DNA methylation appears to respond to various interventions aimed at altering health and lifestyle factors. We tested the efficacy of a mindfulness-based stress reduction program (MBSR) in PCOS patients. We examined its effects on anthropometric measurements, mental health and wellbeing, and alterations in DNA methylation in peripheral blood. MBSR was associated with a reduction in body mass index, waist circumference and blood glucose level, an improvement in subjectively perceived general health, emotional role limitation, and levels of pain, as well as mindfulness-like traits. MBSR reduced the expression of anxious symptomatology and subjectively perceived stress. Methylation changes were observed in four genes: COMT, FST, FKBP51, and MAOA. We conclude that MBSR may be a useful supplementary therapy to mitigate the deleterious effects of PCOS on mental health.

Age related changes and sex related differences of functional brain networks in childhood: A high-density EEG study.

OBJECTIVE: The aim of this study was to explore functional network age-related changes and sex-related differences during the early lifespan with a high-density resting state electroencephalography (rs-EEG). METHODS: We analyzed two data sets of high-density rs-EEG in healthy children and adolescents. We recorded a 64-channel EEG and calculated functional connectomes in 27 participants aged 5-18 years. To validate our results, we used publicly available data and calculated functional connectomes in another 86 participants aged 6-18 years from a 128-channel rs-EEG. We were primarily interested in alpha frequency band, but we also analyzed theta and beta frequency bands. RESULTS: We observed age-related increase of characteristic path, clustering coefficient and interhemispheric strength in the alpha frequency band of both data sets and in the beta frequency band of the larger validation data set. Age-related increase of global efficiency was seen in the theta band of the validation data set and in the alpha band of the test data set. Increase in small worldness was observed only in the alpha frequency band of the test data set. We also observed an increase of individual peak alpha frequency with age in both data sets. Sex-related differences were only observed in the beta frequency band of the larger validation data set, with females having higher values than same aged males. CONCLUSIONS: Functional brain networks show indices of higher segregation, but also increasing global integration with maturation. Age-related changes are most prominent in the alpha frequency band. SIGNIFICANCE: To the best of our knowledge, our study was the first to analyze maturation related changes and sex-related differences of functional brain networks with a high-density EEG and to compare functional connectomes generated from two diverse high-density EEG data sets. Understanding the age-related changes and sex-related differences of functional brain networks in healthy children and adolescents is crucial for identifying network abnormalities in different neurologic and psychiatric conditions, with the aim to identify possible markers for prognosis and treatment.

Facilitated lexical processing accuracy and reaction times following repetitive Transcranial Magnetic Stimulation in dementia of the Alzheimer type: a case study.

We investigated the potential effects of high-frequency (10 Hz) repetitive Transcranial Magnetic Stimulation (rTMS) of the bilateral Dorsolateral Prefrontal Cortex (DLPFC) (30-sessions; 2-sessions/day) on improving lexical processing in one participant with mild - Alzheimer's disease (hereafter dementia of the Alzheimer type-DAT). Increased accuracy and faster reaction times (RTs) were reported in a lexical-decision task (LDT) up to 2-months post-intervention. The current findings indicate that high-frequency stimulation of the DLPFC might be a potential therapeutic tool to improve lexical processing in mild-DAT.

The effects of grammatical gender on the processing of occupational role names in Slovene: An event-related potential study.

The event-related potential method has proven to be a useful tool for studying the effects of gender information in language. Studies have shown that mismatch between the antecedent and the following referent triggers two ERP components, N400 and P600. In the present study, we investigated how grammatical gender affects the mental representation of the grammatical subject. A match-mismatch paradigm was used to investigate how masculine grammatical gender and gender-balanced forms (the explicit mention of masculine and feminine forms as word pairs) as role nouns affect the processing of the referent in Slovenian. The morphological complexity of Slovenian language required the use of anaphoric verbs instead of nouns/pronouns, on which previous research was based. The results showed that following both the gender-balanced and the masculine generic forms, P600 (but not N400) was observed in response to the feminine verb but not to the masculine verb. The P600 amplitude was smaller in the case of the gender-balanced form than in the case of the masculine generic form only. We have concluded that gender-balanced forms are more open to feminine continuations than masculine generic forms. This is the first ERP study in Slovenian to address the effects of processing grammatical gender, thus contributing to existing research on languages with grammatical gender. The great strength of the study is that it is one of the first ERP studies to test the mental inclusivity of gender-balanced forms.

Quantitative EEG and cholinergic basal forebrain atrophy in Parkinson's disease and mild cognitive impairment.

Cholinergic degeneration is a key feature of dementia in neurodegenerative conditions including Alzheimer's disease (AD) and Parkinson's disease (PD). Quantitative electro-encephalography (EEG) metrics are altered in both conditions from early stages, and recent research in people with Lewy body and AD dementia suggests these changes may be associated with atrophy in cholinergic basal forebrain nuclei (cBF). To determine if these relationships exist in predementia stages of neurodegenerative conditions, we studied resting-state EEG and in vivo cBF volumes in 31 people with PD (without dementia), 21 people with mild cognitive impairment (MCI), and 21 age-matched controls. People with PD showed increased power in slower frequencies and reduced alpha reactivity compared to controls. Volumes of cholinergic cell clusters corresponding to the medial septum and vertical and horizontal limb of the diagonal band, and the posterior nucleus basalis of Meynert, correlated positively with; alpha reactivity in people with PD (p< 0.01); and pre-alpha power in people with MCI (p< 0.05). These results suggest that alpha reactivity and pre-alpha power are related to changes in cBF volumes in MCI and PD without dementia.

Similar effect of intermittent theta burst and sham stimulation on corticospinal excitability: A 5-day repeated sessions study.

Despite accumulating evidence of inter and intraindividual variability in response to theta burst stimulation, it is widely believed that in therapeutic applications, repeated sessions can have a "build-up" effect that increases the response over and above that seen in a single session. However, strong evidence for this is lacking. Therefore, we examined whether daily administration of intermittent theta burst stimulation (iTBS) over the primary motor cortex induces cumulative changes in transcranial magnetic stimulation measures of cortical excitability, above the changes induced by sham stimulation. Over five consecutive days, 20 healthy participants received either active iTBS or sham stimulation. Each day, baseline measures of cortical excitability were assessed before and up to 30 min after the intervention. There was no significant difference in the rate of response between iTBS and sham stimulation on any of the 5 days. There was no iTBS specific cumulative increase of corticospinal excitability. The likelihood that an individual would remain a responder from day-to-day was low in both groups, implying high within-subject variability of both active and sham iTBS after-effects. In contrast, we found a high within-subject repeatability of resting and active motor threshold, and baseline motor-evoked potential amplitude. In summary, sham stimulation has similar effect to active iTBS on corticospinal excitability, even when applied repeatedly for 5 days. Our results might be relevant to research and clinical applications of theta burst stimulation protocols.