Gaze-based attention refocusing training in virtual reality for adult attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is characterized by substantial interindividual heterogeneity that challenges the systematic assessment and treatment. Considering mixed evidence from previous neurofeedback research, we present a novel feedback system that relies on gaze behavior to detect signs of inattention while performing a neuropsychological attention task in a virtual seminar room. More specifically, an audiovisual feedback was given whenever participants averted their gaze from the given task. METHODS: Eighteen adults with ADHD and 18 healthy controls performed a continuous performance task (CPT) in virtual reality under three counterbalanced conditions in which either gaze-based feedback, sham feedback, or no feedback was provided. In all conditions, phases of high and low virtual distraction alternated. CPT errors and reaction times, proportions of gaze dwell times (e.g., task focus or distraction focus), saccade characteristics, EEG theta/beta ratios, head movements, and an experience sampling of ADHD symptoms were analyzed. RESULTS: While patients can be discriminated well from healthy controls in that they showed more omission errors, higher reaction times, higher distraction-related dwell times, and more head movements, the feedback did not immediately improve task performance. It was also indicated that sham feedback was rather associated with an aggravation of symptoms in patients. CONCLUSIONS: Our findings demonstrate sufficient suitability and specificity for this holistic ADHD symptom assessment. Regarding the feedback, a single-session training was insufficient to achieve learning effects based on the proposed metacognitive strategies. Future longitudinal, multi-session trials should conclusively examine the therapeutic efficacy of gaze-based virtual reality attention training in ADHD. TRIAL REGISTRATION: drks.de (identifier: DRKS00022370).

[Attention deficit hyperactivity disorder and substance use in adulthood-Guideline-conform diagnostics and treatment]. / Aufmerksamkeitsdefizit­/Hyperaktivitätsstörung und Substanzkonsum im Erwachsenenalter ­ leitliniengerechte Diagnostik und Behandlung.

Attention deficit hyperactivity disorder (ADHD) is the most frequent developmental disorder in childhood, adolescence and adulthood. Substance use disorders are a frequent comorbidity in ADHD. The many different forms and severities of these comorbidities necessitate individual strategies in the diagnostics and treatment. Principally, ADHD and addictive disorders should be treated together whenever possible. The more acute or severe the dependence disorder is, the less priority can be given to the topic of ADHD and the lower are the chances of carrying out valid diagnostics and simultaneous treatment at the beginning of the treatment of the addictive disorder. The less severe and acute the addictive disorder is, the quicker the diagnostics and, if necessary, treatment of ADHD can be initiated. In this continuing education article, the customary means for diagnostics and pharmacotherapy as well as the special features that must be considered with respect to comorbidities of both disorders are presented.

Lower fractional anisotropy of the corticothalamic tract and increased response time variability in adult patients with ADHD.

BACKGROUND: Intraindividual intertrial variability has been suggested as an endophenotype of attention-deficit/hyperactivity disorder (ADHD). It is usually evaluated as response time variability (RTV) in reaction time tasks, and RTV has emerged as a robust and stable feature of ADHD. Among attempts to elucidate the neurobiological underpinnings of RTV, it has been suggested that alterations in white matter microstructure may explain RTV. METHODS: We used diffusion tensor imaging (DTI) in a group of 53 adults with ADHD and 50 healthy controls. We obtained RTV parameters from a simple reaction-time task, in which participants were asked to respond to the appearance of white crosses on a screen using button presses. RESULTS: We observed significant between-group differences for the ex-Gaussian parameter τ, indicating that the mean of extremely slow responses was greater for adults with ADHD than controls. Fractional anisotropy (FA) derived from DTI was significantly different between groups in 2 clusters of the corticothalamic tract. In the ADHD group, relatively decreased FA values were significantly associated with the parameter τ, such that lower FA values in the corticothalamic tract predicted greater τ as an index of RTV. We did not observe this association in healthy controls. LIMITATIONS: For comparison with previous studies, we used FA as a dependent variable of interest. However, although this metric is sensitive to white matter structural properties, there are ambiguities in its interpretation. CONCLUSION: Even in a simple reaction-time task, RTV proved again to be a stable feature of ADHD. It was associated with altered white matter structural properties of the corticothalamic tract in adults with ADHD.

Glucose modulates food-related salience coding of midbrain neurons in humans.

Although early rat studies demonstrated that administration of glucose diminishes dopaminergic midbrain activity, evidence in humans has been lacking so far. In the present functional magnetic resonance imaging study, glucose was intravenously infused in healthy human male participants while seeing images depicting low-caloric food (LC), high-caloric food (HC), and non-food (NF) during a food/NF discrimination task. Analysis of brain activation focused on the ventral tegmental area (VTA) as the origin of the mesolimbic system involved in salience coding. Under unmodulated fasting baseline conditions, VTA activation was greater during HC compared with LC food cues. Subsequent to infusion of glucose, this difference in VTA activation as a function of caloric load leveled off and even reversed. In a control group not receiving glucose, VTA activation during HC relative to LC cues remained stable throughout the course of the experiment. Similar treatment-specific patterns of brain activation were observed for the hypothalamus. The present findings show for the first time in humans that glucose infusion modulates salience coding mediated by the VTA. Hum Brain Mapp 37:4376-4384, 2016. © 2016 Wiley Periodicals, Inc.

[Feasibility of a screening instrument for adult attention-deficit/hyperactivity disorder (ASRS-5) in general practice: A qualitative study]. / Anwendbarkeit eines Screening-Instruments für die Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung bei Erwachsenen (ASRS-5) in der Hausarztpraxis ­ eine qualitative Studie.

OBJECTIVES: The aim of the study was to explore the subjective views of general practitioners on the applicability of the Adult ADHD Self-Report Screening Scale for DSM-5 (ASRS-5) as a screening tool for attention-deficit/hyperactivity disorder (ADHD) in adults in general practice. METHOD: Eleven general practitioners, who had participated in the validation study of the German version of the ASRS-5, were interviewed. For this purpose, a semi-structured interview guide was designed using the Consolidated Framework for Implementation Research (CFIR). The interviews were audio-recorded, transcribed, and analyzed using qualitative content analysis according to Kuckartz. RESULTS: The ASRS-5 seems to work well in general medical practice. But there is evidence for a lack of knowledge about ADHD in adults among general practitioners and a demand for further training in this area. Moreover, insufficient possibilities for subsequent treatment after a positive ADHD screening were claimed. DISCUSSION: In general medicine, the introduction of a screening using ASRS-5 in cases of clinical suspicion could be the first step towards improving the management of adult patients with ADHD. CONCLUSION: Optimizing the management of adults with ADHD requires additional information and training initiatives to support early diagnosis especially in the primary care setting, and to reveal treatment options and care concepts for adults with ADHD.

Methylphenidate Differentially Affects Intrinsic Functional Connectivity of the Salience Network in Adult ADHD Treatment Responders and Non-Responders.

Positron emission tomography (PET) studies have shown involvement of the striatum when treating adult attention-deficit/hyperactivity disorder (ADHD) with methylphenidate (MPH). Results from resting-state functional magnetic resonance imaging (rs-fMRI) for the same issue were less unequivocal. Here, a new analytical framework was set up to investigate medication effects using seed-based rs-fMRI analysis to infer brain regions with alterations in intrinsic functional connectivity (IFC) corresponding with ADHD symptom reduction. In a within-subjects study design, 53 stimulant-naïve adult ADHD patients were investigated before and after 6 weeks of MPH treatment, using two major clinical symptom scales and rs-fMRI. The same data were acquired in a sample of 50 age- and sex-matched healthy controls at baseline. A consensual atlas provided seeds for five predefined major resting-state networks. In order to avoid biasing of medication effects due to putative treatment failure, the entire ADHD sample was first categorized into treatment Responders (N = 36) and Non-Responders (N = 17) using machine learning-based classification with the clinical scales as primary data. Imaging data revealed medication effects only in Responders. In that group, IFC of bilateral putamen changed significantly with medication and approached almost normal levels of IFC. Present results align well with results from previous PET studies, with seed-based rs-fMRI as an entirely different neuroimaging method.

Evaluation of the German Version of the Adult Attention-Deficit/Hyperactivity Disorder Self-Report Screening Scale for DSM-5 as a Screening Tool for Adult Attention-Deficit/Hyperactivity Disorder in Primary Care.

Adult attention-deficit/hyperactivity disorder (ADHD) is common, but often undiagnosed. A valid and time-efficient screening tool for primary care is needed. Objective of this study is to evaluate the German version of the Adult ADHD Self-Report Scale for DSM-5 (ASRS-5) and its feasibility, acceptability, and reliability as a screening tool for adult ADHD in primary care. A multi-centered prospective, diagnostic study was performed. We recruited 262 patients in primary care practices and at an ADHD Outpatient Service of a department of psychiatry in Germany. Patients from 18 to 65 years with suspected or diagnosed ADHD were included by medical doctors, as well as non-ADHD patients as "negative controls." Participants filled in the ASRS-5 and a sociodemographic questionnaire. The Integrated Diagnosis of Adult ADHD, revised version (IDA-R) performed by trained interviewers was used for validation. Feasibility, acceptability, and credibility in primary care practices were examined through a semi-structured interview. The German version of the ASRS-5 showed comparable psychometric properties to the English original version (sensitivity 95.6% and specificity 72.3%). For factor structure, a parallel analysis suggested one latent dimension. Performing confirmatory factor analysis, the best fit was achieved for a general factor with one correlated error. Internal consistency results in Raykovs Omega = 0.86 and Cronbach's α = 0.88. The ASRS-5 was assessed positively in terms of feasibility, acceptability, and credibility by interviewed general practitioners. Potential problems were raised for "treatment options," "stigmatization," and "knowledge gaps." In conclusion, the German version of the ASRS-5 offers a promising tool to improve adult ADHD patients' diagnosis and healthcare.

Development of Obsessive-Compulsive Symptoms Following Abrupt Discontinuation of Venlafaxine.

Withdrawal symptoms after discontinuation of antidepressants are common and have long been known. Typical symptoms after dose reduction or discontinuation of antidepressants are dizziness, drowsiness, headache, flu-like symptoms, hyperarousal, imbalance, insomnia, irritability, and nausea. Rebound, relapse, or recurrence associated with the underlying mental disorder may also occur. The occurrence of obsessive-compulsive symptoms (OCS) following abrupt discontinuation of antidepressants have not yet been reported. Here we report the development of OCS (obsessional suicidal thoughts) in a patient with major depressive disorder and absence of a previous obsessive-compulsive disorder following abrupt discontinuation of venlafaxine. Treatment with escitalopram facilitated remission of OCS. We discuss a possible causal link between abrupt discontinuation of venlafaxine and development of OCS under consideration of pathophysiologic aspects regarding obsessive compulsive disorders, the chronological sequence of symptoms in the present case, and pharmacodynamic and -kinetic aspects. Our case report suggests the possibility of the occurrence of obsessive-compulsive symptoms following abrupt discontinuation of venlafaxine.

Abuse of methylphenidate in Germany: data from spontaneous reports of adverse drug reactions.

To retrieve insights into abuse/dependence of methylphenidate (MPH) in Germany, a query of a pharmacovigilance database was performed (observation interval: 1993 until 2012). From 1190 reports of any ADR related to MPH, n=23 (2%) cases of MPH abuse were identified (mean age 29 years; male sex 78%; mean daily MPH-dosage 111 ± 126.6 mg). As oral application was predominant (70%), the majority of reported cases of MPH abuse might be due to pharmacologic neuroenhancement.

Rapid relapse in depression following initialization of oral contraception with ethinyl estradiol and chlormadinone acetate.

OBJECTIVE: Female sexual hormones (estrogens and gestagens) may affect neurocognitive functioning and mood. Thus, the use of oral hormonal contraceptives (OHC) bears the risk of psychiatric adverse drug reactions such as depression and psychosis. However, the available empiric evidence regarding this connection is conflicting, and, moreover, female sex hormones seem to feature also mood-stabilizing and antidepressive effects. Hence, individual susceptibility factors and preparation-specific pharmacologic properties might play a pivotal role in the development of mood disturbances related to OHC. Single case reports provide empiric data for further systematic approaches. METHODS: A clinical case is presented and discussed. RESULTS: A 36-year-old female patient with recurrent major depressive disorder developed rapid relapse in depression after initialization of OHC with ethinyl estradiol 30 µg/chlormadinone acetate 2 mg. This OHC combination was described to particularly feature positive effects on depressive mood. CONCLUSIONS: OHC may induce serious mood disturbances and should be administered with care, particularly in patients with affective disorders.

Concerns about pregabalin: further experience with its potential of causing addictive behaviors.

Pregabalin (PRG) is approved for the treatment of neuropathic pain, partial seizures, and generalized anxiety disorder in many countries. Supported by case reports and a few studies there is an ongoing debate on PRG's potential to cause addictive behaviors. Considering that PRG is currently under investigation for the treatment of benzodiazepine dependence and withdrawal as well as relapse prevention in alcohol dependence, assessment of PRG's abuse and dependence potential is indispensable. We report the case of a 38-year-old female patient with borderline personality disorder and past alcohol abuse who developed PRG abuse. The patient took up to 800 mg PRG per day, initially administered to treat unspecific anxiety, and experienced euphoric feelings after PRG intake. In the further course, she increased the daily PRG dosage and consulted other physicians to receive additional PRG prescriptions. During reduction of PRG, the patient developed a moderate withdrawal syndrome with vegetative symptoms. Because of the early detection of the developing PRG abuse (4 months after first application of PRG), the development of PRG dependence was prevented. This case illustrates the possibility of PRG to trigger the development of addictive behaviors and should encourage physicians to be very careful when administering PRG to patients with current or past substance-related disorders.

Intoxications with the monoamine oxidase inhibitor tranylcypromine: an analysis of fatal and non-fatal events.

Tranylcypromine (TCP) is a non-selective and irreversible monoamine oxidase inhibitor and an effective agent in the treatment of major depression. It features a complex pharmacologic profile and overdoses might induce severe intoxications. To identify typical clinical presentations of TCP-intoxications, range of associated TCP-dosages and possible differences between fatal and non-fatal intoxications a systematic review of all previously published cases of TCP-intoxications was conducted. We detected n=20 reports of TCP-intoxications in the literature (fatalities n=10). Mean age was 36.7 years (median 37); the majority of patients were female (60%). Frequent findings in patients with TCP-intoxications were disturbance of consciousness/cognitive dysfunction (90%), cardio-vascular symptoms (55%), hyperthermia (50%), respiratory distress (45%), delirium (45%), muscular rigidity (30%) and renal failure (20%). Suicidal intent was present in n=18 (90%) patients. First clinical symptoms related to TCP-intoxication developed on average in less than 1 day. The average dosage related to TCP-intoxication was 677 mg. The highest survived TCP-dosage was 4000 mg and the lowest fatal dosage was 170 mg. Patients with fatal intoxications were on average older (40.5 vs. 32.8 years) and developed a more rapid onset of symptoms (0.2 vs. 0.8 days). Death occurred after a mean time of 0.6 days; symptom relief in patients with non-fatal intoxications developed on average after 3.2 days. Considering the large dose spectrum between survived and lethal TCP-dosages individual susceptibility factors might play a role regarding the severity of clinical symptoms independently of the ingested dosage.

Electroconvulsive therapy in patients with diagnoses other than major depression and/or difficult characteristics: a combined psychiatric-anesthesiological approach based on a retrospective chart analysis.

Though electroconvulsive therapy (ECT) requires a close cooperation between anesthesiology and psychiatry, literature lacks of approaches that consider both disciplines in parallel. Special problems might be posed by patients with complicated features or ECT-indications other than treatment-refractory depression (TRD). Considering these patients there is a particular paucity of data, especially regarding anesthesiological aspects. Therefore, we sought (1) to discuss special issues of the peri-interventional management of non-TRD-cases from a combined psychiatric-anesthesiological point of view and (2) to assess the efficacy of ECT in the classical indication of TRD as compared to cases undergoing ECT for other indications or under difficult conditions (non-TRD) by means of Clinical Global Impression-Improvement (CGI-I) scale scores. A retrospective chart analysis of patients treated with ECT between the years 2009 and 2011 at the University of Ulm, Department of Psychiatry, was conducted. Special anesthesiological efforts were necessary in cohort non-TRD. There was no difference in the clinical outcome between cohort non-TRD (n=7) and TRD (n=22) with a median CGI-I score of 2 ("much improved") in both groups. Close cooperation between psychiatry and anesthesiology is indispensable in non-TRD patients. Our results provide preliminary evidence that ECT is equally effective in the standard indication of TRD compared to other indications.

Self-mutilation induced by psychotropic substances: a systematic review.

Self-mutilation (SM) not only occurs among patients with schizophrenia, personality disorders or transsexuality but also as a phenomenon induced by psychotropic substances (PS). We intended to find characteristics of patients at risk to perform SM induced by PS (SMIPS), frequent PS within this phenomenon and typical presentations of SMIPS. A systematic review of the literature (including Medline, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials and Scopus) was conducted. On October 2011 we identified 26 cases (23 publications) of SM related to PS. Majority of patients (85%) was male, mean age was 30 years (median 41 years). Seventy-three percent of patients developed SM subsequent to the use of one PS, 27% presented SM after the use of more than one PS. Alcohol (25%), hallucinogens (25%) and amphetamines (22%) were found most frequently among the reported substances. Major impairment was present in 80%. Our findings suggest male sex, young age, a previous history of abuse of PS and the current use of alcohol, hallucinogens or amphetamines to favour SMIPS.

Successful treatment of schizophrenia with melperone augmentation in a patient with phenotypic CYP2D6 ultrarapid metabolization: a case report.

INTRODUCTION: There are limited treatment options for people with schizophrenia with cytochrome P450 2D6 ultrarapid metabolizer status who do not respond to amisulpride.Furthermore, the literature does not provide evidence-based guidelines for this particular constellation. CASE PRESENTATION: We report the case of a 50-year-old Caucasian female patient with schizophrenia and cytochrome P450 2D6 ultrarapid metabolizer status who experienced an insufficient antipsychotic effect with amisulpride. She was successfully treated with melperone-augmented haloperidol. CONCLUSION: This report yields melperone-augmented haloperidol as a possible pharmacological strategy in the described situation. In addition, our observations support the available evidence for the potential of melperone to act as an inhibitor of cytochrome P450 2D6.

Paliperidone extended-release: does it have a place in antipsychotic therapy?

Paliperidone (9-hydroxy-risperidone), the active metabolite of risperidone, was approved for treating schizophrenia worldwide in 2006 as paliperidone extended-release (PER), and became the first second-generation antipsychotic specifically licensed for treating schizoaffective disorder in 2009. However, at the same time, its comparatively high cost gave rise to concerns about the cost-effectiveness of PER as compared with its precursor, risperidone. This paper reviews the existing knowledge of the pharmacology, kinetics, efficacy, tolerability, and fields of application of PER, and compares PER with risperidone in order to determine whether it has a place in antipsychotic therapy. An independent assessment of all relevant publications on PER published until July 2010 was undertaken. PER has a unique pharmacological profile, including single dosing, predominantly renal excretion, low drug-drug interaction risk, and differs from risperidone in terms of mode of action and pharmacokinetics. High-level evidence suggests that PER is efficacious and safe in schizophrenia, schizoaffective disorder, and acute manic episodes. There is a striking lack of published head-to-head comparisons between PER and risperidone, irrespective of indication. Low-level evidence shows a lower risk for hyperprolactinemia and higher patient satisfaction with PER than with risperidone. PER adds to the still limited arsenal of second-generation antipsychotics. In the absence of direct comparisons with risperidone, it remains difficult to come to a final verdict on the potential additional therapeutic benefits of PER which would justify its substantially higher costs as compared with risperidone. However, in terms of pharmacology, the available evidence cautiously suggests a place for PER in modern antipsychotic therapy.

Delusional infestation: neural correlates and antipsychotic therapy investigated by multimodal neuroimaging.

INTRODUCTION: In delusional infestation (DI), as with other non-schizophrenic psychotic disorders, little is known about the neural basis and the mechanisms of antipsychotic treatment. We aimed at investigating the brain circuitry involved in DI and the role of postsynaptic D2 receptors in mediating the effects of antipsychotics by means of multimodal neuroimaging. METHODS: In Case 1, a patient with DI (initially drug-induced), cerebral glucose metabolism and dopaminergic neurotransmission were studied in the untreated state (FDG-PET, FDOPA-PET, 123I-FP-CIT-SPECT, and IBZM-SPECT) and after effective aripiprazole treatment (FDG-PET and IBZM-SPECT), with negative drug screenings at both imaging sessions. In Case 2 (DI secondary to mild vascular encephalopathy) cerebral perfusion and gray matter volume changes were investigated in the untreated state and compared to N=8 [corrected] age-matched healthy controls (MRI-based CASL and VBM). RESULTS: In Case 1, before treatment, glucose metabolism was left-dominant in the thalamus and the putamen. Pre- and postsynaptic dopaminergic neurotransmissions were altered in the striatum, again mainly the left putamen. Full remission to aripiprazole was associated with 63 to 78% striatal D2 receptor occupancy and glucose metabolism changes in the bilateral thalamus. In Case 2, significant perfusion and GMV changes were observed in the bilateral putamen, frontal and parietal somatosensory cortices as compared to controls. Symptoms partially remitted to ziprasidone therapy. DISCUSSION/CONCLUSION: Six imaging techniques were first used to study the neural basis of DI and mechanisms of antipsychotic therapy. The study provides first low-level evidence in vivo evidence of fronto-striato-thalamo-parietal network to mediate core symptoms of DI, i.e. a priori brain regions involved in judgment (frontal cortex), sensory gating (thalamus) and body perception (dorsal striatum, thalamus and somatic cortices). This is also the first report of effective treatment with aripiprazole in drug-induced DI and with ziprasidone in organic DI, adding to existing limited evidence that SGAs are helpful in various forms of DI. Effective antipsychotic treatment seems to depend on blocking striatal D2 receptors with similar occupancy rates as in schizophrenia. Larger samples are needed to confirm our preliminary findings and further evaluate their relevance for the different forms of DI.