BackgroundKetamine and its enantiomers are widely researched and increasingly used to treat mental disorders, especially treatment-resistant depression. The phenomenology of ketamine-induced... Show moreBackgroundKetamine and its enantiomers are widely researched and increasingly used to treat mental disorders, especially treatment-resistant depression. The phenomenology of ketamine-induced experiences and their relation to its psychotherapeutic potential have not yet been systematically investigated.AimsTo describe the phenomenology of patient experiences during oral esketamine treatment for treatment-resistant depression (TRD) and to explore the potential therapeutic relevance of these experiences.MethodsIn-depth interviews were conducted with 17 patients after a 6-week, twice-weekly ‘off label’ generic oral esketamine (0.5–3.0mg/kg) treatment program. Interviews explored participants’ perspectives, expectations, and experiences with oral esketamine treatment. Audio interviews were transcribed and analyzed using an Interpretative Phenomenological Analysis (IPA) framework.ResultsThe effects of ketamine were highly variable, and psychological distress was common in most patients. Key themes included (a) perceptual effects (auditory, visual, proprioceptive), (b) detachment (from body, self, emotions, and the world), (c) stillness and openness, (d) mystical-type effects (transcendence, relativeness, spirituality), and (e) fear and anxiety. Key themes related to post-session reports included (a) feeling hungover and fatigued, and (b) lifting the blanket: neutralizing mood effects.ConclusionPatients reported several esketamine effects with psychotherapeutic potential, such as increased openness, detachment, an interruption of negativity, and mystical-type experiences. These experiences deserve to be explored further to enhance treatment outcomes in patients with TRD. Given the frequency and severity of the perceived distress, we identify a need for additional support in all stages of esketamine treatment. Show less
Background: Ketamine and its enantiomer esketamine represent promising new treatments for treatment-resistant depression (TRD). Esketamine induces acute, transient psychoactive effects. How... Show moreBackground: Ketamine and its enantiomer esketamine represent promising new treatments for treatment-resistant depression (TRD). Esketamine induces acute, transient psychoactive effects. How patients perceive esketamine treatment, and which conditions facilitate optimal outcomes, remains poorly understood. Understanding patient perspectives on these phenomena is important to identify unmet needs, which can be used to improve (es)ketamine treatments. Aims: To explore the perspectives of TRD patients participating in "off label" oral esketamine treatment. Materials and methods: In-depth interviews were conducted with 17 patients (11 women) after a six-week, twice-weekly esketamine treatment program, and subsequently after six months of at-home use. Interviews explored participants' perspectives, expectations, and experiences with esketamine treatment. Audio interviews were transcribed verbatim and analysed following an Interpretative Phenomenological Analysis (IPA) framework. Results: Key themes included overwhelming experiences; inadequate preparation; letting go of control; mood states influencing session experiences; presence and emotional support, and supportive settings. Patients' attempts to let go and give into vs. attempts to maintain control over occasionally overwhelming experiences was a central theme. Multiple factors influenced patients' ability to give into the experience and appeared to impact their mood and anxiety about future sessions, including level of preparation and education, physical and emotional support, and setting during the session. Conclusion: Better preparation beforehand, an optimized treatment setting, and emotional and psychological support during (es)ketamine sessions can help patients to "let go" and may lead to better quality of care and outcomes. Recommendations to improve quality of patient care in (es)ketamine treatment are provided, including suggestions for the training of nurses and other support staff. Show less
Amsterdam, J. van; Blanken, P.; Spijkerman, R.; Brink, W. van den; Hendriks, V. 2022
Short Summary: This systematic review shows that 10 out of 19 RCTs (53%) demonstrated an added value of combined therapy for alcohol use disorders (psychotherapy + pharmacotherapy) compared to... Show moreShort Summary: This systematic review shows that 10 out of 19 RCTs (53%) demonstrated an added value of combined therapy for alcohol use disorders (psychotherapy + pharmacotherapy) compared to psychotherapy only, whereas only three out of nine RCTs (33%) showed a possible added value for combined therapy compared to pharmacotherapy.Aim To explore whether combined interventions i.e. psychotherapeutic plus psychosocial interventions are more effective than monotherapies in the treatment of alcohol use disorders. Methods Systematic review of the results of randomized controlled trials that compared combined therapies with monotherapies (either pharmacotherapy or psychotherapy). Results The search resulted in 28 eligible studies. Data from these RCTs showed that 10 out of 19 RCTs (53%) demonstrated an added value of combined therapy (psychotherapy + pharmacotherapy) compared to psychotherapy only, whereas only three out of nine RCTs (33%) comparing combined therapy with pharmacotherapy showed a possible added value for combined therapy. Conclusions Pharmacotherapy is effective to treat AUD with or without psychotherapy and that psychotherapy can best be offered in combination with pharmacotherapy. Show less
Breeksema, J.J.; Kuin, B.W.; Kamphuis, J.; Brink, W. van den; Vermetten, E.; Schoevers, R.A. 2022
Introduction: Small-scale clinical studies with psychedelic drugs have shown promising results for the treatment of several mental disorders. Before psychedelics become registered medicines, it is... Show moreIntroduction: Small-scale clinical studies with psychedelic drugs have shown promising results for the treatment of several mental disorders. Before psychedelics become registered medicines, it is important to know the full range of adverse events (AEs) for making balanced treatment decisions. Objective: To systematically review the presence of AEs during and after administration of serotonergic psychedelics and 3,4-methyenedioxymethamphetamine (MDMA) in clinical studies. Methods: We systematically searched PubMed, PsycINFO, Embase, and ClinicalTrials.gov for clinical trials with psychedelics since 2000 describing the results of quantitative and qualitative studies. Results: We included 44 articles (34 quantitative + 10 qualitative), describing treatments with MDMA and serotonergic psychedelics (psilocybin, lysergic acid diethylamide, and ayahuasca) in 598 unique patients. In many studies, AEs were not systematically assessed. Despite this limitation, treatments seemed to be overall well tolerated. Nausea, headaches, and anxiety were commonly reported acute AEs across diagnoses and compounds. Late AEs included headaches (psilocybin, MDMA), fatigue, low mood, and anxiety (MDMA). One serious AE occurred during MDMA administration (increase in premature ventricular contractions requiring brief hospitalization); no other AEs required medical intervention. Qualitative studies suggested that psychologically challenging experiences may also be therapeutically beneficial. Except for ayahuasca, a large proportion of patients had prior experience with psychedelic drugs before entering studies. Conclusions: AEs are poorly defined in the context of psychedelic treatments and are probably underreported in the literature due to study design (lack of systematic assessment of AEs) and sample selection. Acute challenging experiences may be therapeutically meaningful, but a better understanding of AEs in the context of psychedelic treatments requires systematic and detailed reporting. Show less
Ozgen, H.; Spijkerman, R.; Noack, M.; Holtmann, M.; Schellekens, A.; Dalsgaard, S.; ... ; Hendriks, V. 2021
Childhood attention-deficit/hyperactivity disorder (ADHD) is a risk factor for the development of substance abuse and substance use disorders (SUD) in adolescence and (early) adulthood. ADHD and... Show moreChildhood attention-deficit/hyperactivity disorder (ADHD) is a risk factor for the development of substance abuse and substance use disorders (SUD) in adolescence and (early) adulthood. ADHD and SUD also frequently co-occur in treatment-seeking adolescents, which complicates diagnosis and treatment, and is associated with poor treatment outcomes. In this study, we provide a systematic review of controlled studies on the effectiveness of pharmacological, psychosocial, and complementary treatments of ADHD in adolescents with and without comorbid SUD. In addition, we review the longitudinal association between pharmacotherapy for childhood ADHD and the development of SUD in adolescence and early adulthood. We conducted a systematic review of the research literature published since 2000 using Medline, PsycINFO, and the Cochrane Database of Systematic Reviews databases to select randomized clinical trials, observational studies, and meta-analyses. The quality of the evidence from each study was rated using the SIGN grading system. Based on the limited evidence available, strong clinical recommendations are not justified, but provisionally, we conclude that stimulant treatment in children with ADHD may prevent the development of SUD in adolescence or young adulthood, that high-dose stimulant treatment could be an effective treatment for adolescents with ADHD and SUD comorbidity, that cognitive behavior therapy might have a small beneficial effect in these patients, and that alternative treatments are probably not effective. More studies are needed to draw definitive conclusions that will allow for strong clinical recommendations. Show less
Ozgen, H.; Spijkerman, R.; Noack, M.; Holtmann, M.; Schellekens, A.S.A.; Glind, G. van de; ... ; Hendriks, V. 2020
Background:Childhood attention-deficit/hyperactivity disorder (ADHD) is a risk factor for substance misuse and substance use disorder (SUD) in adolescence and (early) adulthood. ADHD and SUD also... Show moreBackground:Childhood attention-deficit/hyperactivity disorder (ADHD) is a risk factor for substance misuse and substance use disorder (SUD) in adolescence and (early) adulthood. ADHD and SUD also frequently co-occur in treatment-seeking adolescents, which complicates diagnosis and treatment and is associated with poor treatment outcomes. Research on the effect of treatment of childhood ADHD on the prevention of adolescent SUD is inconclusive, and studies on the diagnosis and treatment of adolescents with ADHD and SUD are scarce. Thus, the available evidence is generally not sufficient to justify robust treatment recommendations.Objective:The aim of the study was to obtain a consensus statement based on a combination of scientific data and clinical experience.Method:A modified Delphi study to reach consensus based upon the combination of scientific data and clinical experience with a multidisciplinary group of 55 experts from 17 countries. The experts were asked to rate a set of statements on the effect of treatment of childhood ADHD on adolescent SUD and on the screening, diagnosis, and treatment of adolescents with comorbid ADHD and SUD.Results:After 3 iterative rounds of rating and adapting 37 statements, consensus was reached on 36 of these statements representing 6 domains: general (n= 4), risk of developing SUD (n= 3), screening and diagnosis (n= 7), psychosocial treatment (n= 5), pharmacological treatment (n= 11), and complementary treatments (n= 7). Routine screening is recommended for ADHD in adolescent patients in substance abuse treatment and for SUD in adolescent patients with ADHD in mental healthcare settings. Long-acting stimulants are recommended as the first-line treatment of ADHD in adolescents with concurrent ADHD and SUD, and pharmacotherapy should preferably be embedded in psychosocial treatment. The only remaining no-consensus statement concerned the requirement of abstinence before starting pharmacological treatment in adolescents with ADHD and concurrent SUD. In contrast to the majority, some experts required full abstinence before starting any pharmacological treatment, some were against the use of stimulants in the treatment of these patients (independent of abstinence), while some were against the alternative use of bupropion.Conclusion:This international consensus statement can be used by clinicians and patients together in a shared decision-making process to select the best interventions and to reach optimal outcomes in adolescent patients with concurrent ADHD and SUD. Show less
Özgen, H.; Spijkerman, R.; Noack, M.; Holtmann, M.; Schellekens, A.S.A.; Glind, G. van de; ... ; Hendriks, V. 2020
Impaired cognitive–motivational functioning is present in many psychiatric disorders, including alcohol use disorder (AUD). Emotion regulation is a key intermediate factor, relating to the ... Show moreImpaired cognitive–motivational functioning is present in many psychiatric disorders, including alcohol use disorder (AUD). Emotion regulation is a key intermediate factor, relating to the (cognitive) regulation of emotional and motivational states, such as in regulation of craving or negative emotions that may lead to relapse in alcohol use. These cognitive–motivational functions, including emotion regulation, are a target in cognitive behavioral therapy and may possibly be improved by neurostimulation techniques. The present between-subjects, single-blind study assesses the effects of sham-controlled high-frequency neuronavigated repetitive transcranial magnetic stimulation (10 Hz) of the right dorsolateral prefrontal cortex (dlPFC) on several aspects relevant for emotion regulation (emotion processing and reappraisal abilities) and related brain activity, as well as self-reported craving in a sample of alcohol use disorder patients (AUD; n = 39) and healthy controls (HC; n = 36). During the emotion reappraisal task, participants were instructed to either attend or reappraise their emotions related to the negative, positive, neutral, and alcohol-related images, after which they rated their experienced emotions. We found that repetitive transcranial magnetic stimulation (rTMS) reduces self-reported experienced emotions in response to positive and negative images in AUD patients, whereas experienced emotions were increased in response to neutral and positive images in HCs. In the functional magnetic resonance imaging (fMRI) analyses, we found that rTMS reduces right dlPFC activity during appraisal of affective images relative to sham stimulation only in AUD patients. We could not confirm our hypotheses regarding the effect of rTMS craving levels, or on reappraisal related brain function, since no significant effects of rTMS on craving or reappraisal related brain function were found. These findings imply that rTMS can reduce the emotional impact of images as reflected in blood oxygenation level-dependent (BOLD) response, especially in AUD patients. Future studies should replicate and expand the current study, for instance, by assessing the effect of multiple stimulation sessions on both explicit and implicit emotion regulation paradigms and craving, and assess the effect of rTMS within subgroups with specific addiction-relevant image preferences.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02557815. Show less
Luigjes, J.; Lorenzetti, V.; Haan, S. de; Youssef, G.J.; Murawski, C.; Sjoerds, Z.; ... ; Yücel, M. 2019
Compulsive tendencies are a central feature of problematic human behavior and thereby are of great interest to the scientific and clinical community. However, no consensus exists about the precise... Show moreCompulsive tendencies are a central feature of problematic human behavior and thereby are of great interest to the scientific and clinical community. However, no consensus exists about the precise meaning of ‘compulsivity,’ creating confusion in the field and hampering comparison across psychiatric disorders. A vague conceptualization makes compulsivity a moving target encompassing a fluctuating variety of behaviors, which is unlikely to improve the new dimension-based psychiatric or psychopathology approach. This article aims to help progress the definition of what constitutes compulsive behavior, cross-diagnostically, by analyzing different definitions in the psychiatric literature. We searched PubMed for articles in human psychiatric research with ‘compulsive behavior’ or ‘compulsivity’ in the title that focused on the broader concept of compulsivity—returning 28 articles with nine original definitions. Within the definitions, we separated three types of descriptive elements: phenomenological, observational and explanatory. The elements most applicable, cross-diagnostically, resulted in this definition: Compulsive behavior consists of repetitive acts that are characterized by the feeling that one ‘has to’ perform them while one is aware that these acts are not in line with one’s overall goal. Having a more unified definition for compulsive behavior will make its meaning precise and explicit, and therefore more transferable and testable across clinical and non-clinical populations. Show less
Jansen, J.M.; Heuvel, O.A. van den; Werf, Y.D. van der; Wit, S.J. de; Veltman, D.J.; Brink, W. van den; Goudriaan, A.E. 2019
AbstractBackgroundNeuroimaging studies have demonstrated gray matter (GM) volume abnormalities in substance users. While the majority of substance users are polysubstance users, very little is... Show moreAbstractBackgroundNeuroimaging studies have demonstrated gray matter (GM) volume abnormalities in substance users. While the majority of substance users are polysubstance users, very little is known about the relation between GM volume abnormalities and polysubstance use.MethodsIn this study we assessed the relation between GM volume, and the use of alcohol, tobacco, cocaine and cannabis as well as the total number of substances used, in a sample of 169 males: 15 non-substance users, 89 moderate drinkers, 27 moderate drinkers who also smoke tobacco, 13 moderate drinkers who also smoke tobacco and use cocaine, 10 heavy drinkers who smoke tobacco and use cocaine and 15 heavy drinkers who smoke tobacco, cannabis and use cocaine.ResultsRegression analyses showed that there was a negative relation between the number of substances used and volume of the dorsal medial prefrontal cortex (mPFC) and the ventral mPFC. Without controlling for the use of other substances, the volume of the dorsal mPFC was negatively associated with the use of alcohol, tobacco, and cocaine. After controlling for the use of other substances, a negative relation was found between tobacco and cocaine and volume of the thalami and ventrolateral PFC, respectively.ConclusionThese findings indicate that mPFC alterations may not be substance-specific, but rather related to the number of substances used, whereas, thalamic and ventrolateral PFC pathology is specifically associated with tobacco and cocaine use, respectively. These findings are important, as the differential alterations in GM volume may underlie different cognitive deficits associated with substance use disorders. Show less
Schluter, R.S.; Jansen, J.M.; Holst, R.J. van; Brink, W. van den; Goudriaan, A.E. 2018
Structural Magnetic Resonance Imaging studies have reported volume reductions in several brain regions implicated in social cognition and emotion recognition in juvenile antisocial populations.... Show moreStructural Magnetic Resonance Imaging studies have reported volume reductions in several brain regions implicated in social cognition and emotion recognition in juvenile antisocial populations. However, it is unclear whether these structural abnormalities are specifically related to antisocial features, or to co-occurring callous-unemotional (CU) traits. The present study employed voxel-based morphometry to assess both grey matter volume (GMV) and grey matter concentration (GMC) in a large representative at-risk sample of adolescents (n=134; mean age 17.7yr), characterized by a broad range of CU trait and conduct disorder (CD) symptom scores. There was a significant interaction between CD symptom and CU trait scores in the prediction of GMV in the anterior insula, with a significant positive association between CU traits and GMV in youth low on CD symptoms only. In addition, we found a significant unique positive association between CD symptoms and GMC in the amygdala, and unique negative associations between CU traits and GMC in the amygdala and insula. These findings are in line with accumulating evidence of distinct associations of CD symptoms and CU traits with amygdala and insula GMC in juvenile antisocial populations. Show less
Cohn, M.D.; Lith, K. van; Kindt, M.; Pape, L.E.; Doreleijers, T.A.H.; Brink, W. van den; ... ; Popma, A. 2016
Alcohol dependence (AD) is characterized by corticostriatal impairments in individual brain areas such as the striatum. As yet however, complex brain network topology in AD and its association with... Show moreAlcohol dependence (AD) is characterized by corticostriatal impairments in individual brain areas such as the striatum. As yet however, complex brain network topology in AD and its association with disease progression are unknown. We applied graph theory to resting‐state functional magnetic resonance imaging (RS‐fMRI) to examine weighted global efficiency and local (clustering coefficient, degree and eigenvector centrality) network topology and the functional role of the striatum in 24 AD patients compared with 20 matched healthy controls (HCs), and their association with dependence characteristics. Graph analyses were performed based on Pearson's correlations between RS‐fMRI time series, while correcting for age, gender and head motion. We found no significant group differences between AD patients and HCs in network topology. Notably, within the patient group, but not in HCs, the whole‐brain network showed reduced average cluster coefficient with more severe alcohol use, whereas longer AD duration within the patient group was associated with a global decrease in efficiency, degree and clustering coefficient. Additionally, within four a‐priori chosen bilateral striatal nodes, alcohol use severity was associated with lower clustering coefficient in the left caudate. Longer AD duration was associated with reduced clustering coefficient in caudate and putamen, and reduced degree in bilateral caudate, but with increased eigenvector centrality in left posterior putamen. Especially changes in global network topology and clustering coefficient in anterior striatum remained strikingly robust after exploratory variations in network weight. Our results show adverse effects of AD on overall network integration and possibly on striatal efficiency, putatively contributing to the increasing behavioral impairments seen in chronically addicted patients. Show less
Cohn, M.D.; Veltman, D.J.; Pape, L.E.; Lith, K. van; Vermeiren, R.R.J.M.; Brink, W. van den; ... ; Popma, A. 2015
