A posterior-alpha ageing network is differentially associated with antidepressant effects of venlafaxine and rTMS.

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, but chances for remission largely decrease with each failed treatment attempt. It is therefore desirable to assign a given patient to the most promising individual treatment option as early as possible. We used a polygenic score (PGS) informed electroencephalography (EEG) data-driven approach to identify potential predictors for MDD treatment outcome. Post-hoc we conducted exploratory analyses in order to understand the results in depth. First, an EEG independent component analysis produced 54 functional brain networks in a large heterogeneous cohort of psychiatric patients (n = 4,045; 5-84 yrs.). Next, the network that was associated to PGS for antidepressant-response (PRS-AR) in an independent sample (n = 722) was selected: an age-related posterior alpha network that explained >60 % of EEG variance, and was highly stable over recording time. Translational analyses were performed in two other independent datasets to examine if the network was predictive of psychopharmacotherapy (n = 535) and/or repetitive transcranial magnetic stimulation (rTMS) and concomitant psychotherapy (PT; n = 186) outcome. The network predicted remission to venlafaxine (p = 0.015), resulting in a normalized positive predicted value (nPPV) of 138 %, and rTMS + PT - but in opposite direction for women (p = 0.002) relative to men (p = 0.018) - yielding a nPPV of 131 %. Blinded out-of-sample validations for venlafaxine (n = 29) and rTMS + PT (n = 36) confirmed the findings for venlafaxine, while results for rTMS + PT could not be replicated. These data suggest the existence of a relatively stable EEG posterior alpha aging network related to PGS-AR that has potential as MDD treatment predictor.

Associations between psychotropic drugs and rsEEG connectivity and network characteristics: a cross-sectional study in hospital-admitted psychiatric patients.

Introduction: Resting-state EEG (rsEEG) characteristics, such as functional connectivity and network topology, are studied as potential biomarkers in psychiatric research. However, the presence of psychopharmacological treatment in study participants poses a potential confounding factor in biomarker research. To address this concern, our study aims to explore the impact of both single and multi-class psychotropic treatments on aforementioned rsEEG characteristics in a psychiatric population. Methods: RsEEG was analyzed in a real-world cross-sectional sample of 900 hospital-admitted psychiatric patients. Patients were clustered into eight psychopharmacological groups: unmedicated, single-class treatment with antipsychotics (AP), antidepressants (AD) or benzodiazepines (BDZ), and multi-class combinations of these treatments. To assess the associations between psychotropic treatments and the macroscale rsEEG characteristics mentioned above, we employed a general linear model with post-hoc tests. Additionally, Spearman's rank correlation analyses were performed to explore potential dosage effects. Results: Compared to unmedicated patients, single-class use of AD was associated with lower functional connectivity in the delta band, while AP was associated with lower functional connectivity in both the delta and alpha bands. Single-class use of BDZ was associated with widespread rsEEG differences, including lower functional connectivity across frequency bands and a different network topology within the beta band relative to unmedicated patients. All of the multi-class groups showed associations with functional connectivity or topology measures, but effects were most pronounced for concomitant use of all three classes of psychotropics. Differences were not only observed in comparison with unmedicated patients, but were also evident in comparisons between single-class, multi-class, and single/multi-class groups. Importantly, multi-class associations with rsEEG characteristics were found even in the absence of single-class associations, suggesting potential cumulative or interaction effects of different classes of psychotropics. Dosage correlations were only found for antipsychotics. Conclusion: Our exploratory, cross-sectional study suggests small but significant associations between single and multi-class use of antidepressants, antipsychotics and benzodiazepines and macroscale rsEEG functional connectivity and network topology characteristics. These findings highlight the importance of considering the effects of specific psychotropics, as well as their interactions, when investigating rsEEG biomarkers in a medicated psychiatric population.

A polygenic-informed approach to a predictive EEG signature empowers antidepressant treatment prediction: A proof-of-concept study.

The treatment of major depressive disorder (MDD) is hampered by low chances of treatment response in each treatment step, which is partly due to a lack of firmly established outcome-predictive biomarkers. Here, we hypothesize that polygenic-informed EEG signatures may help predict antidepressant treatment response. Using a polygenic-informed electroencephalography (EEG) data-driven, data-reduction approach, we identify a brain network in a large cohort (N=1,123), and discover it is sex-specifically (male patients, N=617) associated with polygenic risk score (PRS) of antidepressant response. Subsequently, we demonstrate in three independent datasets the utility of the network in predicting response to antidepressant medication (male, N=232) as well as repetitive transcranial magnetic stimulation (rTMS) and concurrent psychotherapy (male, N=95). This network significantly improves a treatment response prediction model with age and baseline severity data (area under the curve, AUC=0.623 for medicaton; AUC=0.719 for rTMS). A predictive model for MDD patients, aimed at increasing the likelihood of being a responder to antidepressants or rTMS and concurrent psychotherapy based on only this network, yields a positive predictive value (PPV) of 69% for medication and 77% for rTMS. Finally, blinded out-of-sample validation of the network as predictor for psychotherapy response in another independent dataset (male, N=50) results in a within-subsample response rate of 50% (improvement of 56%). Overall, the findings provide a first proof-of-concept of a combined genetic and neurophysiological approach in the search for clinically-relevant biomarkers in psychiatric disorders, and should encourage researchers to incorporate genetic information, such as PRS, in their search for clinically relevant neuroimaging biomarkers.

Event-related potentials and use of psychotropic medication in major psychiatric disorders.

BACKGROUND: Attention deficits measured using event-related potentials (ERPs) have been frequently reported in several major psychiatric disorders, e.g. mood disorder (MD), psychotic disorder (PD) and substance use disorder (SUD). However, comparisons between these specific categories are lacking. Here we investigated if electrophysiological parameters of basic information processing are associated with the above-mentioned categories of psychiatric disorders, or instead were associated with general psychopathology. METHODS: 579 subjects with MD, PD or SUD and healthy controls (HC) were included. Participants were tested in a passive auditory and an active visual oddball paradigm to assess mismatch negativity (MMN), P3A and P3B amplitudes. Additionally, we examined associations between these measures and psychoactive medication treatments. RESULTS: All patients had significantly lower P3B amplitudes compared to healthy controls, while only SUD patients had lower P3A amplitudes than MD, PD and HC. PD patients also produced significantly less MMN than both MD and SUD patients. Additionally, we found significantly higher P3B amplitude in HC compared to patients without psychopharmacological treatment and patients treated with two or more psychoactive compounds (polypharmacy), but no significant associations with medication on P3A and MMN amplitudes. CONCLUSIONS: Our results add to the theory that P3B deficits are associated with general psychopathology, whereas P3A and MMN deficits appear to be associated with substance abuse and psychotic disorders respectively.

Raloxifene augmentation in men and women with a schizophrenia spectrum disorder: A study protocol.

Although acute psychotic symptoms are often reduced by antipsychotic treatment, many patients with schizophrenia are impaired in daily functioning due to the persistence of negative and cognitive symptoms. Raloxifene, a Selective Estrogen Receptor Modulator (SERM) has been shown to be an effective adjunctive treatment in schizophrenia. Yet, there is a paucity in evidence for raloxifene efficacy in men and premenopausal women. We report the design of a study that aims to replicate earlier findings concerning the efficacy of raloxifene augmentation in reducing persisting symptoms and cognitive impairment in postmenopausal women, and to extend these findings to a male and peri/premenopausal population of patients with schizophrenia. The study is a multisite, placebo-controlled, double-blind, randomised clinical trial in approximately 110 adult men and women with schizophrenia. Participants are randomised 1:1 to adjunctive raloxifene 120 mg or placebo daily during 12 weeks. The treatment phase includes measurements at three time points (week 0, 6 and 12), followed by a follow-up period of two years. The primary outcome measure is change in symptom severity, as measured with the Positive and Negative Syndrome Scale (PANSS), and cognition, as measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Secondary outcome measures include social functioning and quality of life. Genetic, hormonal and inflammatory biomarkers are measured to assess potential associations with treatment effects. If it becomes apparent that raloxifene reduces psychotic symptoms and/or improves cognition, social functioning and/or quality of life as compared to placebo, implementation of raloxifene in clinical psychiatric practice can be considered.

Risky Decision-Making but Not Delay Discounting Improves during Inpatient Treatment of Polysubstance Dependent Alcoholics.

BACKGROUND: High levels of impulsivity, characteristics of addicted patients, are known to be important predictors of relapse. However, so far, little is known about the stability or variability of two main components of impulsivity (delay discounting and decision-making). The present study examined the changes in impulsivity during the first week of an abstinence based, behavioral orientated inpatient treatment program. METHOD: Thirty-seven polysubstance dependent alcoholics completed the Delay Discounting Task (DDT), and the Iowa Gambling Task (IGT) using the original version with decks A'B'C'D', and an alternative version with decks K'L'M'N', for measuring decision-making, after 2 and 6 weeks of active treatment. RESULTS: It was found that performances on the IGT changed during treatment while performances on the DDT did not (test-retest period: 4 weeks). CONCLUSION: The results provide preliminary evidence that improvements in decision-making might be related to treatment effects. All patients followed a highly structured cognitive-behavioral treatment program, which might have enhanced their executive functioning (coping skills training).

Affective decision-making is predictive of three-month relapse in polysubstance-dependent alcoholics.

BACKGROUND/AIMS: Common and long-lasting deficits in decision-making in polysubstance-dependent alcoholics (PSA) reflect neurobiological alterations that define the chronic nature of addiction. These deficits affect goal-directed behavior and might be critical risk factors predicting relapse in PSA. METHODS: The Delay Discounting Task (DDT) and the Iowa Gambling Task (IGT) assessed the delay-discounting and decision-making skills among 37 abstinent PSA. RESULTS: The findings indicated that IGT but not DDT performances were associated with 3-month abstinence, irrespective of the influence of personality traits and coexistent medications. CONCLUSION: The results show that the IGT, which assesses processes that are important in the latter stages of addiction, is ecologically more valid compared to the DDT, which assesses processes important in the early stages. They underline the importance of using neurocognitive measures to identify high relapse risk patients and emphasize the relevance of promoting new treatments.

Relapse in pathological gamblers: A pilot study on the predictive value of different impulsivity measures.

Backgrounds and aims Pathological gambling, a common psychiatric disorder, has many similarities with substance use disorders. Relapse, an important element in addictive disorders, however, has seldom been studied in pathological gambling. Hence, in analogy with previous research studies examining the role of self-report and neurocognitive measures on relapse in substance dependent patients, the present pilot study was executed. Methods Twenty-two pathological gamblers and 31 healthy controls took part in this research. They filled in self-report questionnaires measuring impulsive personality (Barratt Impulsiveness Scale, Sensitivity to Punishment and Sensitivity to Reward Questionnaires) and performed neurocognitive tasks measuring impulsivity, decision-making and attentional bias (Iowa Gambling Task, Delay Discounting Task, Stroop Gambling Task). Twelve months later gambling activity was re-examined. Results Analyses showed that PGs who relapsed (n = 13) did not differ on self-report and neurocognitive measures of impulsivity with PGs who did not relapse (n = 9). However, both groups did differ in age at onset. Finally, healthy controls and PGs differed in some (Barratt Impulsiveness Scale, Stroop Gambling Task), but not all impulsivity measures (Delay Discounting Task, Iowa Gambling Task, Sensitivity to Punishment and Sensitivity to Reward Questionnaires). Conclusions One-year relapse in pathological gamblers is not predicted by self-report and or neurocognitive measures of impulsivity and decision-making. The similarities in performances between pathological gamblers and healthy controls illustrate the relative health of the examined pathological gamblers. This last finding supports the idea that subtypes of pathological gamblers exist so that different treatment strategies might be necessary.

Motor functioning and alcohol dependence.

BACKGROUND: Autopsy and neuroimaging research in stably abstinent alcoholics illuminated structural and functional abnormalities in brain areas that organize and coordinate motor functioning. Researchers that used behavioural tasks to measure motor functioning found that abstinent alcoholics perform worse than healthy controls. These researchers however did not analyze timed responses into their cognitive and motor components. They thus were unable to decide which aspects of information processing are impaired. We here used a Fitts' task to examine differences in cognitive and motor components between abstinent alcoholics and healthy controls. METHODS: Fifty-two abstinent alcoholics and 52 healthy controls participated in this research design. Fine motor functioning was assessed by means of the Fitts' task. RESULTS: Abstinent alcoholics needed more time to perform timed responses than healthy controls. As both reaction and movement times were higher in abstinent alcoholics, both cognitive and motor processes seem to be impaired. When the task became more difficult (small targets instead of large targets) abstinent alcoholics needed proportionally more time to give the correct response than healthy controls. This phenomenon solely applied to movement times. CONCLUSIONS: These research data indicate that abstinent alcoholics are somewhat impaired on a behavioral level. The execution of timed responses indeed was lengthier in abstinent alcoholics than in healthy controls. As both cognitive and motor processes were impaired, we here assume that both central and peripheral processes are affected by progressive alcohol intake. Abstinent alcoholics also have more difficulties to adapt their motor responses to changing task conditions.

Traumatic experiences and posttraumatic stress disorders: differences between treatment-seeking early- and late-onset alcoholic patients.

Childhood traumatic experiences have been suggested to relate to early-onset alcoholism and to negatively influence the severity and course of alcohol use disorders. Early-onset alcoholic (n = 54) and late-onset alcoholic (n = 65) inpatients were compared as to the severity of their childhood traumatic experiences, prevalence of current and lifetime posttraumatic stress disorder (PTSD), and depressive symptoms. The early-onset alcoholic patients had a higher number and more severe childhood traumatic experiences compared with the late-onset alcoholic patients. More female than male alcohol-dependent patients had lifetime PTSD diagnosis. Finally, specifically within the female alcoholic patients the severity of early childhood experiences was positively associated with the severity of current substance use and related problems. Within early-onset alcoholic treatment-seeking populations, active screening for childhood traumatic experiences and current PTSD is advised in view of treatment planning.

Decision-making deficits in alcohol-dependent patients with and without comorbid personality disorder.

BACKGROUND: Impairments in decision making are a consistent finding in substance use disorder (SUD) populations. However, decision-making deficits are not specific for SUDs and are also reported in the context of other psychiatric disorders such as antisocial and borderline personality disorders (PDs). Given the frequent comorbidity between SUD and cluster B PD, it might be questioned whether the decision-making impairments typically reported in SUD populations reflect the addictive disorder, the cluster B PD, or a combination of the 2. METHODS: In the current study, we compare the decision-making performance of non-substance-abusing controls (n=53) on the Iowa Gambling Task (IGT) with the decision-making performance of 3 abstinent alcohol-dependent samples, i.e., alcoholic patients without any PD (n=38), alcoholic patients with a cluster A or C PD (n=19), and alcoholic patients with a cluster B PD (n=23). RESULTS: Overall, all 3 alcohol-dependent subsamples performed inferior compared with controls. Between alcoholic subsamples, the alcoholic patients with a cluster A or C PD had the highest IGT score, followed by the alcoholic patients without a PD, while the cluster B alcoholic patients were the most impaired. CONCLUSION: These findings suggest that impairments in decision making underlie both alcohol dependence and cluster B PD, and alcoholic patients with a comorbid cluster B PD are particularly impaired in their decision making. These deficits may underlie the severe problems that characterize cluster B alcoholic patients specifically in inappropriate behaviors (e.g., poly substance abuse, legal, and professional dysfunction).

Behavioural aspects of impulsivity in alcoholics with and without a cluster-B personality disorder.

AIMS: Studies have shown that alcoholics with a cluster-B personality disorder (cluster-B PD) are characterized by high levels of impulsivity. However, impulsivity has mainly been studied as a broad concept without its different aspects being considered. The present study compared abstinent alcoholic inpatients without any personality disorder (PD) and abstinent alcoholics with cluster-B PD on different aspects of impulsivity, i.e. self-reported impulsivity and neuropsychological indicators such as behavioural control and delay of gratification. METHODS: Forty alcohol-dependent inpatients without PD and 22 alcohol-dependent inpatients with a cluster-B PD were compared on two self-report impulsivity questionnaires (Barratt impulsiveness scale; sensation-seeking scales) and three behavioural impulsivity tasks [Go/No-Go task; delay discounting task (DDT); Stroop colour word test]. Tests were administered after stable abstinence of at least 3 weeks. RESULTS: Self-report measures of impulsivity were higher in cluster-B alcoholics than in alcoholics without PD. Behavioural tasks revealed a more differentiated pattern of impairments. On the Go/No-Go task, cluster-B alcoholics were impaired in inhibitory control but not in reaction time compared with alcoholics without PD. In contrast, no significant differences on the DDT and the Stroop were observed. CONCLUSION: Alcohol-dependent patients with and without a cluster-B PD differ in terms of behavioural inhibition but not in terms of activation or the ability to delay gratification. This finding may partly account for their impulsive and (self-) destructive behaviours. Treatment planning should pay specific attention to these impairments in behavioural control.