Brain stimulation-induced neuroplasticity underlying therapeutic response in phantom sounds.

Noninvasive brain stimulation can modify phantom sounds for longer periods by modulating neural activity and putatively inducing regional neuroplastic changes. However, treatment response is limited and there are no good demographic or clinical predictors for treatment outcome. We used state-of-the-art voxel-based morphometry (VBM) to investigate whether transcranial magnetic stimulation-induced neuroplasticity determines therapeutic outcome. Sixty subjects chronically experiencing phantom sounds (i.e., tinnitus) received repetitive transcranial magnetic stimulation (rTMS) of left dorsolateral prefrontal and temporal cortex according to a protocol that has been shown to yield a significantly higher number of treatment responders than sham stimulation and previous stimulation protocols. Structural magnetic resonance imaging was performed before and after rTMS. In VBM whole-brain analyses (P < 0.05, FWE corrected), we assessed longitudinal gray matter changes as well as structural connectivity between the ensuing regions. We observed longitudinal mesoscopic gray matter changes of left dorsolateral prefontal (DLPFC), left operculo-insular, and right inferior temporal cortex (ITC) in responders (N = 22) but not nonresponders (N = 38), as indicated by a group × time interaction and post-hoc tests. These results were neither influenced by age, sex, hearing loss nor by tinnitus laterality, duration, and severity at baseline. Furthermore, we found robust DLPFC-insula and insula-ITC connectivity in responders, while only relatively weak DLPFC-insula connectivity and no insula-ITC connectivity could be demonstrated in nonresponders. Our results reinforce the implication of nonauditory brain regions in phantom sounds and suggest the dependence of therapeutic response on their neuroplastic capabilities. The latter in turn may depend on (differences in) their individual structural connectivity. Hum Brain Mapp 39:554-562, 2018. © 2017 Wiley Periodicals, Inc.

[Circadian rhythms and depression]. / Störung zirkadianer Rhythmen im Kontext depressiver Erkrankungen.

Depressive disorders are associated with various neurobiological alterations like hyperactivity of the hypothalamic-pituitary-adrenal axis, altered neuroplasticity and altered circadian rhythms. Relating to the circadian symptoms, a process is adopted in which individual genetic factors together with social, psychological and physical stressors may lead to a decompensation of the circadian system. The causal connections between depressive disorders and disturbed circadian rhythms have not been completely clarified. Chronobiological therapy is based on these disturbed processes. For the treatment of the circadian symptoms, various scientifically tested chronotherapeutics are available with however different effectiveness and evidence like light therapy or sleep deprivation. The successful treatment of depression also frequently leads to a improvement in altered circadian rhythm.

Changes in motor cortex excitability associated with temporal repetitive transcranial magnetic stimulation in tinnitus: hints for cross-modal plasticity?

BACKGROUND: Motor cortex excitability was found to be changed after repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex highlighting the occurrence of cross-modal plasticity in non-invasive brain stimulation. Here, we investigated the effects of temporal low-frequency rTMS on motor cortex plasticity in a large sample of tinnitus patients. In 116 patients with chronic tinnitus different parameters of cortical excitability were assessed before and after ten rTMS treatment sessions. Patients received one of three different protocols all including 1 Hz rTMS over the left temporal cortex. Treatment response was defined as improvement by at least five points in the tinnitus questionnaire (TQ). Variables of interest were resting motor threshold (RMT), short-interval intra-cortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP). RESULTS: After rTMS treatment RMT was decreased by about 1% of stimulator output near-significantly in the whole group of patients. SICI was associated with significant changes with respect to treatment response. The group of treatment responders showed a decrease of SICI over the course of treatment, the group of non-responders the reverse pattern. CONCLUSIONS: Minor RMT changes during rTMS treatment do not necessarily suggest the need for systematic re-examination of the RMT for safety and efficacy issues. Treatment response to rTMS was shown to be related to changes in SICI that might reflect modulation of GABAergic mechanisms directly or indirectly related to rTMS treatment effects.

Amygdalohippocampal neuroplastic changes following neuroleptic treatment with quetiapine in first-episode schizophrenia.

Schizophrenia is a severe, debilitating, chronic disease that is accompanied by morphologic changes within the brain. However, it is unclear to what extent alterations of grey and white matter in schizophrenia are linked to the disease itself, or whether they are a consequence of neuroleptic treatment. Typical and atypical antipsychotics exert differential effects on brain structure. Moreover, atypical antipsychotics may have distinct profiles with respect to grey matter in schizophrenic patients. Findings on drug-induced grey matter changes are heterogeneous due to variation in stage of illness, duration of treatment and use of multiple antipsychotics. Using voxel-based morphometry applied to high-resolution magnetic resonance images, we show that monotherapy with the atypical agent quetiapine (mean daily dose = 445 mg ± 200 s.d.) may induce structural brain changes in first-episode schizophrenia patients (N = 20) within 21 d of treatment. Specifically, we demonstrate longitudinal macroscopic changes (i.e. grey matter increases) in the left amygdalohippocampal region that were predicted by drug plasma levels but not daily doses. These structural alterations were accompanied by a clinical improvement of schizophrenic symptoms. Comparison with healthy controls (n = 30) showed that grey matter amount in the respective amygdalar region was significantly reduced in unmedicated first-episode schizophrenia patients. These findings suggest that drug-induced neuroplastic changes in schizophrenia can occur quickly and are dependent on pharmacokinetics.

Which tinnitus-related aspects are relevant for quality of life and depression: results from a large international multicentre sample.

BACKGROUND: The aim of the present study was to investigate, which aspects of tinnitus are most relevant for impairment of quality of life. For this purpose we analysed how responses to the Tinnitus Handicap Inventory (THI) and to the question "How much of a problem is your tinnitus at present" correlate with the different aspects of quality of life and depression. METHODS: 1274 patients of the Tinnitus Research Initiative database were eligible for analysis. The Tinnitus Research Initiative database is composed of eight study centres from five countries. We assessed to which extent the Tinnitus Handicap Inventory (THI) and its subscales and single items as well as the tinnitus severity correlate with Beck Depression Inventory (BDI) score and different domains of the short version of the WHO-Quality of Life questionnaire (WHO-QoL Bref) by means of simple and multiple linear regression models. RESULTS: The THI explained considerable portions of the variance of the WHO-QoL Physical Health (R2 = 0.39) and Psychological Health (R2 = 0.40) and the BDI (R2 = 0.46). Furthermore, multiple linear regression models which included each THI item separately explained an additional 5% of the variance compared to the THI total score. The items feeling confused from tinnitus, the trouble of falling asleep at night, the interference with job or household responsibilities, getting upset from tinnitus, and the feeling of being depressed were those with the highest influence on quality of life and depression. The single question with regard to tinnitus severity explained 18%, 16%, and 20% of the variance of Physical Health, Psychological Health, and BDI respectively. CONCLUSIONS: In the context of a cross-sectional correlation analysis, our findings confirmed the strong and consistent relationships between self-reported tinnitus burden and both quality of life, and depression. The single question "How much of a problem is your tinnitus" reflects tinnitus-related impairment in quality of life and can thus be recommended for use in clinical routine.

Trauma-associated tinnitus.

BACKGROUND: Up to 53% of individuals suffering from traumatic brain injuries develop tinnitus. OBJECTIVE: To review the current literature on trauma-associated tinnitus in order to provide orientation for the clinical management of patients with trauma-associated tinnitus. MATERIALS: A systematic literature search has been conducted in PubMed database applying the search terms posttraumatic tinnitus and trauma-associated tinnitus. Results have been complemented by related studies, book chapters, and the authors' clinical experience. RESULTS: Not only mechanical, pressure-related, or noise-related head traumata but also neck injuries and emotional trauma can cause tinnitus. Exact diagnosis is essential. Disorders such as ossicular chain disruption, traumatic eardrum perforation, or perilymphatic fistula can be surgically treated. It should also be considered that pulsatile tinnitus can be a sign of life-threatening disorders such as carotid cavernous fistulas, arteriovenous malformations, and carotid dissections. Also, posttraumatic stress disorder should be taken into consideration as a potential contributing factor. CONCLUSIONS: There is an evident mismatch between the high incidence of trauma-associated tinnitus and scarce literature on the topic. A consistent and-at best-standardized assessment of tinnitus- and hearing-related sequelae of trauma is recommended both for the improvement of clinical care and for a deeper understanding of the various pathophysiological mechanisms of trauma-associated tinnitus.

Structural brain changes following left temporal low-frequency rTMS in patients with subjective tinnitus.

Repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has been used to treat patients with subjective tinnitus. While rTMS is known to induce morphological changes in healthy subjects, no study has investigated yet whether rTMS treatment induces grey matter (GM) changes in tinnitus patients as well, whether these changes are correlated with treatment success, and whether GM at baseline is a useful predictor for treatment outcome. Therefore, we examined magnetic resonance images of 77 tinnitus patients who were treated with rTMS of the left temporal cortex (10 days, 2000 stimuli/day, 1 Hz). At baseline and after the last treatment session high-resolution structural images of the brain were acquired and tinnitus severity was assessed. For a subgroup of 41 patients, additional brain scans were done after a follow-up period of 90 days. GM changes were analysed by means of voxel based morphometry. Transient GM decreases were detectable in several brain regions, especially in the insula and the inferior frontal cortex. These changes were not related to treatment outcome though. Baseline images correlated with change in tinnitus severity in the frontal cortex and the lingual gyrus, suggesting that GM at baseline might hold potential as a possible predictor for treatment outcome.

Assessing the impact of sex on high-frequency repetitive transcranial magnetic stimulation´s clinical response in schizophrenia - results from a secondary analysis.

BACKGROUND: The evidence for repetitive transcranial magnetic stimulation (rTMS) to treat negative symptoms in schizophrenia (SCZ) is increasing, although variable response rates remain a challenge. Subject´s sex critically influences rTMS´ treatment outcomes. Females with major depressive disorder are more likely to respond to rTMS, while SCZ data is scarce. METHODS: Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we assessed the impact of sex on rTMS´ clinical response rate from screening up to 105 days after intervention among SCZ patients. The impact of resting motor threshold (RMT) on response rates was also assessed. RESULTS: 157 patients received either active or sham rTMS treatment. No significant group differences were observed. Linear mixed model showed no effects on response rates (all p > 0.519). Apart from a significant sex*time interaction for the positive subscale of the positive and negative syndrome scale (PANSS) scores (p = 0.032), no other significant effects of sex on continuous PANSS scores were observed. RMT had no effect on response rate. CONCLUSION: In the largest rTMS trial on the treatment of SCZ negative symptoms we did not observe any significant effect of sex on treatment outcomes. Better assessments of sex-related differences could improve treatment individualisation.

Enhanced resting-state oscillations in schizophrenia are associated with decreased synchronization during inattentional blindness.

Patients suffering from schizophrenia have been characterized by an apparent lack of theta (around 6 Hz) and gamma (>40 Hz) brain oscillatory activity during task execution. The neurocognitive reasons for these abnormal synchronization patterns, however, remain elusive. Recording the electroencephalogramm (EEG) during a selective visual attention task, the current study investigates whether abnormal brain oscillatory resting-state activity in the theta band might account for a lack of task-related brain oscillatory activity in schizophrenia. EEGs were recorded from 26 patients with schizophrenia and 26 healthy matched controls during rest and during the execution of a selective visual attention task, in which an unexpected object (monkey) appeared on the screen. On a behavioral level, patients were less likely to report perceiving the unexpected event than controls. Controls showed a stronger increase in task-related theta power than patients in prefrontal, parietal, and occipital brain regions. Task-related theta power change differed between patients who perceived, and patients who did not perceive the unexpected event. Moreover, patients showed higher levels of theta power during rest than controls, whereas the absolute theta power values during the selective attention task did not differ between groups. These results suggest that the failure to increase oscillatory activity during a cognitive task can be accounted for by abnormally high oscillatory activity in a resting state. This finding has important implications for future studies examining abnormal brain oscillatory activity in schizophrenia, which usually treat resting-state activity as a baseline for task-related activity.

Neural correlates of tinnitus duration and distress: a positron emission tomography study.

Cerebral (18)F-deoxyglucose positron emission tomography (FDG-PET) has shown altered auditory pathway activity in tinnitus. However, the corresponding studies involved only small samples and analyses were restricted to the auditory cortex in most studies. Evidence is growing that also limbic, frontal, and parietal areas are involved in the pathophysiology of chronic tinnitus. These regions are considered to mediate perceptual, attentional, and emotional processes. Thus, the aim of the present study was the systematic evaluation of metabolic brain activity in a large sample of tinnitus patients. Ninety one patients with chronic tinnitus underwent FDG-PET. The effects of tinnitus severity (assessed by a tinnitus questionnaire score), duration and laterality were evaluated with statistical parametric mapping (SPM) in whole brain analyses. In addition, region of interest analyses were performed for primary auditory areas. Tinnitus duration correlated positively with brain metabolism in right inferior frontal, right ventro-medial prefrontal, and right posterior cingulate cortex. Tinnitus distress correlated positively with activation of left and right posterior inferior temporal gyrus as well as left and right posterior parahippocampal-hippocampal interface. Region of interest analysis demonstrated an overactivation of left in contrast to right Heschl's gyrus independently from tinnitus laterality and anatomical hemispheric differences. Tinnitus duration and distress were associated with areas involved in attentional and emotional processing. This is in line with recent findings indicating the relevance of higher order areas in the pathophysiology of tinnitus. Earlier results of asymmetric activation of the auditory cortices in tinnitus were confirmed, i.e., left-sided overactivation was found independently from tinnitus laterality.

Multisite rTMS for the treatment of chronic tinnitus: stimulation of the cortical tinnitus network--a pilot study.

Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the auditory cortex has been shown to significantly reduce tinnitus severity in some patients. There is growing evidence that a neural network of both auditory and non-auditory cortical areas is involved in the pathophysiology of chronic subjective tinnitus. Targeting several core regions of this network by rTMS might constitute a promising strategy to enhance treatment effects. This study intends to test the effects of a multisite rTMS protocol on tinnitus severity. 45 patients with chronic tinnitus were treated with multisite stimulation (left dorsolateral prefrontal, 2,000 stimuli, 20 Hz; left temporoparietal, 1,000 stimuli, 1 Hz; right temporoparietal, 1,000 stimuli, 1 Hz). Results were compared with a historical control group consisting of 29 patients who received left temporal stimulation (2,000 stimuli, 1 Hz). Both groups were treated on ten consecutive working days. Tinnitus severity was assessed at three time points: at baseline, after the last treatment session (day 12) and after a follow-up period of 90 days. A change of tinnitus severity over time was tested using repeated measures ANOVA with the between-subjects factor treatment group. Both groups improved similarly from baseline to day 12. However, there was a difference on day 90: the multisite stimulation group showed an overall improvement whereas patients receiving temporal stimulation returned to their baseline level of tinnitus severity. These pilot data suggest that multisite rTMS is superior to temporal rTMS and represents a promising strategy for enhancing treatment effects of rTMS in tinnitus. Future studies should explore this new protocol with respect to clinical and neurobiological effects in more detail.

Cognitive remediation improves cognition and good cognitive performance increases time to relapse--results of a 5 year catamnestic study in schizophrenia patients.

BACKGROUND: Cognitive deficits are stable features of schizophrenia that are linked to functional outcome. Cognitive remediation approaches have been proven successful in ameliorating these deficits, although effect sizes vary considerably. Whether cognitive deficits are serious predictors of clinical outcome is less clear. METHODS: Sixty patients suffering from schizophrenia were included in our sample, thirty of them received computer-assisted cognitive training, and thirty received occupational therapy. For a subsample of 55 patients, who could be traced over a period of five years after the end of the cognitive remediation intervention, time until first relapse and time in psychosis were determined retrospectively from their medical records. RESULTS: Cognitive remediation significantly improved problem solving, memory and attention with high effect sizes. Employment status, a post test verbal memory performance measure and a measure of executive functioning outperformed all other measures in the prediction of time to relapse, while allocation to treatment group outperformed all other variables in the prediction of both cognitive measures. CONCLUSIONS: Cognitive remediation of neurocognitive deficits thus makes sense in a twofold fashion: It enhances cognition directly and positively acts on clinical course indirectly via improved neurocognition. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00004880.

Repetitive transcranial magnetic stimulation for the treatment of chronic tinnitus after traumatic brain injury: a case study.

Tinnitus is a frequent symptom of traumatic brain injury, which is difficult to treat. Repetitive transcranial magnetic stimulation has shown beneficial effects in some forms of tinnitus. However, traumatic brain injury in the past has been considered as a relative contraindication for repetitive transcranial magnetic stimulation because of the increased risk of seizures. Here we present the case of a 53-year-old male patient suffering from severe tinnitus after traumatic brain injury with comorbid depression and alcohol abuse, who received 5 treatment series of repetitive transcranial magnetic stimulation (1 Hz stimulation protocol over left primary auditory cortex, 10 sessions of 2000 stimuli each, stimulation intensity 110% resting motor threshold). Repetitive transcranial magnetic stimulation was tolerated without any side effects and tinnitus complaints (measured by a validated tinnitus questionnaire and numeric rating scales) were improved in a replicable way throughout 5 courses of transcranial magnetic stimulation up to now.

Supporting return to work after psychiatric hospitalization-A cluster randomized study (RETURN-study).

BACKGROUND: If people with episodic mental-health conditions lose their job due to an episode of their mental illness, they often experience personal negative consequences. Therefore, reintegration after sick leave is critical to avoid unfavorable courses of disease, longer inability to work, long payment of sickness benefits, and unemployment. Existing return-to-work (RTW) programs have mainly focused on "common mental disorders" and often used very elaborate and costly interventions without yielding convincing effects. It was the aim of the RETURN study to evaluate an easy-to-implement RTW intervention specifically addressing persons with mental illnesses being so severe that they require inpatient treatment. METHODS: The RETURN study was a multi-center, cluster-randomized controlled trial in acute psychiatric wards addressing inpatients suffering from a psychiatric disorder. In intervention wards, case managers (RTW experts) were introduced who supported patients in their RTW process, while in control wards treatment, as usual, was continued. RESULTS: A total of 268 patients were recruited for the trial. Patients in the intervention group had more often returned to their workplace at 6 and 12 months, which was also mirrored in more days at work. These group differences were statistically significant at 6 months. However, for the main outcome (days at work at 12 months), differences were no longer statistically significant (p = 0.14). Intervention patients returned to their workplace earlier than patients in the control group (p = 0.040). CONCLUSIONS: The RETURN intervention has shown the potential of case-management interventions when addressing RTW. Further analyses, especially the qualitative ones, may help to better understand limitations and potential areas for improvement.

Tinnitus assessment by means of standardized self-report questionnaires: psychometric properties of the Tinnitus Questionnaire (TQ), the Tinnitus Handicap Inventory (THI), and their short versions in an international and multi-lingual sample.

BACKGROUND: Tinnitus research in an international context requires standardized and validated questionnaires in different languages. The aim of the present set of analyses was the reassessment of basic psychometric properties according to classical test theory of self-report instruments that are being used within the multicentre Tinnitus Research Initiative (TRI) database project. METHODS: 1318 patients of the TRI Database were eligible for the analyses. The basic psychometric properties reliability, validity, and sensitivity of Tinnitus Handicap Inventory (THI), Tinnitus Questionnaire (TQ) and Tinnitus Beeinträchtigungs Fragebogen (i.e., Tinnitus Impairment Questionnaire, TBF-12) were assessed by the use of Cronbach's alpha, corrected item-total correlations, correlation coefficients and standardized response means. RESULTS: Throughout the languages, all questionnaires showed high internal consistencies (Cronbach's alpha > 0.79) and solid item-total correlations, as well as high correlations among themselves (around 0.8) and in combination with the self-reported tinnitus severity. However, some paradoxical correlations between individual items of the TBF-12, constructed as a shortform of the THI, and the corresponding THI-items were seen. Standardized Response Means (SRM) were low if tinnitus did not change, and between 0.3 and 1.09 for improved or worsened tinnitus complaints, indicating the sensitivity of the measures. CONCLUSIONS: All investigated instruments have high internal consistency, high convergence and discriminant validity and good change sensitivity in an unselected large multinational clinical sample and thus appear appropriate to evaluate the effects of tinnitus treatments in a cross-cultural context.

Linking the Tinnitus Questionnaire and the subjective Clinical Global Impression: which differences are clinically important?

BACKGROUND: Development of new tinnitus treatments requires prospective placebo-controlled randomized trials to prove their efficacy. The Tinnitus Questionnaire (TQ) is a validated and commonly used instrument for assessment of tinnitus severity and has been used in many clinical studies. Defining the Minimal Clinically Important Difference (MCID) for TQ changes is an important step to a better interpretation of the clinical relevance of changes observed in clinical trials. In this study we aimed to estimate the minimum change of the TQ score that could be considered clinically relevant. METHODS: 757 patients with chronic tinnitus were pooled from the TRI database and the RESET study. An anchor-based approach using the Clinical Global Impression (CGI) scale and distributional approaches were used to estimate MCID. Receiver Operating Characteristic (ROC) curves were calculated to define optimal TQ change cutoffs discriminating between minimally changed and unchanged subjects. RESULTS: The relationship between TQ change scores and CGI ratings of change was good (r = 0.52, p < 0.05). Mean change scores associated with minimally better and minimally worse CGI categories were -6.65 and +2.72 respectively. According to the ROC method MCID for improvement was -5 points and for deterioration +1 points. CONCLUSION: Distribution and anchor-based methods yielded comparable results in identifying MCIDs. ΔTQ scores of -5 and +1 points were identified as the minimal clinically relevant change for improvement and worsening respectively. The asymmetry of the MCIDs for improvement and worsening may be related to expectation effects.

Reduction of tinnitus severity by the centrally acting muscle relaxant cyclobenzaprine: an open-label pilot study.

Tinnitus, the phantom perception of sounds, is a highly prevalent disorder. Although a wide variety of drugs have been investigated off label for the treatment of tinnitus, there is no approved pharmacotherapy. We report an open-label exploratory pilot study to assess the effect of muscle relaxants acting on the central nervous system on tinnitus patients. Cyclobenzaprine at high (30 mg) and low doses (10 mg), orphenadrine (100 mg), tizanidine (24 mg) and eperisone (50 mg) were administered to a maximum of 20 patients per group over a 12-week period. High-dose cyclobenzaprine resulted in a significant reduction in the Tinnitus Handicap Inventory (THI) score between baseline and week 12 in the intention-to-treat sample. On the other hand, other treatments were not effective. These results were confirmed in an explorative analysis where baseline corrected THI and Clinical Global Impression scores at week 12 were compared between groups. The present open trial presents a new promising pharmacotherapy for tinnitus that should be validated in placebo-controlled double-blind trials.

Mindfulness-and body-psychotherapy-based group treatment of chronic tinnitus: a randomized controlled pilot study.

BACKGROUND: Tinnitus, the perception of sound in absence of an external acoustic source, impairs the quality of life in 2% of the population. Since in most cases causal treatment is not possible, the majority of therapeutic attempts aim at developing and strengthening individual coping and habituation strategies. Therapeutic interventions that incorporate training in mindfulness meditation have become increasingly popular in the treatment of stress-related disorders. Here we conducted a randomized, controlled clinical study to investigate the efficacy of a specific mindfulness- and body-psychotherapy based program in patients suffering from chronic tinnitus. METHODS: Thirty-six patients were enrolled in this pilot study. The treatment was specifically developed for tinnitus patients and is based on mindfulness and body psychotherapy. Treatment was performed as group therapy at two training weekends that were separated by an interval of 7 weeks (eleven hours/weekend) and in four further two-hour sessions (week 2, 9, 18 and 22). Patients were randomized to receive treatment either immediately or after waiting time, which served as a control condition. The primary study outcome was the change in tinnitus complaints as measured by the German Version of the Tinnitus Questionnaire (TQ). RESULTS: ANOVA testing for the primary outcome showed a significant interaction effect time by group (F = 7.4; df = 1,33; p = 0.010). Post hoc t-tests indicated an amelioration of TQ scores from baseline to week 9 in both groups (intervention group: t = 6.2; df = 17; p < 0.001; control group: t = 2.5; df = 16; p = 0.023), but the intervention group improved more than the control group. Groups differed at week 7 and 9, but not at week 24 as far as the TQ score was concerned. CONCLUSIONS: Our results suggest that this mindfulness- and body-psychotherapy-based approach is feasible in the treatment of tinnitus and merits further evaluation in clinical studies with larger sample sizes.The study is registered with clinicaltrials.gov (NCT01540357).

Disentangling dyskinesia from parkinsonism in motor structures of patients with schizophrenia.

Patients with schizophrenia frequently suffer from motor abnormalities, but underlying alterations in neuroarchitecture remain unclear. Here, we aimed to disentangle dyskinesia from parkinsonism in motor structures of patients with schizophrenia and to assess associated molecular architecture. We measured grey matter of motor regions and correlated volumetric estimates with dyskinesia and parkinsonism severity. Associations with molecular architecture were identified by cross-modal spatial correlations between ensuing maps of abnormality-related volume alterations and neurotransmitter maps from healthy populations. Both phenomena were linked to (specific) striatal and basal forebrain reductions as well as to D1 receptor density. Dyskinesia also manifested in cerebellar decrease, while parkinsonism was associated with less motor cortex volume. The parkinsonism-related brain pattern was additionally associated with 5-HT1A/2A and µ-opioid receptors distribution. Findings suggest the need to develop psychopharmacological compounds that display not only selectivity for receptor subtypes but also anatomical selectivity for alleviating dyskinesia without worsening parkinsonism and vice versa.

Changing the Antipsychotic in Early Nonimprovers to Amisulpride or Olanzapine: Randomized, Double-Blind Trial in Patients With Schizophrenia.

BACKGROUND AND HYPOTHESIS: Meta-analyses have shown that the majority of patients with schizophrenia who have not improved after 2 weeks of treatment with an antipsychotic drug are unlikely to fully respond later. We hypothesized that switching to another antipsychotic with a different receptor binding profile is an effective strategy in such a situation. STUDY DESIGN: In total, 327 inpatients with an acute exacerbation of schizophrenia were randomized to double-blind treatment with either olanzapine (5-20 mg/day) or amisulpride (200-800 mg/day). Those patients who had not reached at least 25% Positive-and-Negative-Syndrome-Scale (PANSS) total score reduction from baseline after 2 weeks (the "non-improvers") were rerandomized double-blind to either staying on the same compound ("stayers") or to switching to the other antipsychotic ("switchers") for another 6 weeks. The primary outcome was the difference in the number of patients in symptomatic remission between the combined "switchers" and the "stayers" after 8 weeks of treatment, analyzed by logistic regression. STUDY RESULTS: A total of 142 nonimprovers were rerandomized at week two. 25 (45.5 %) of the 'stayers' compared to 41 (68.3 %) of the "switchers" reached remission at endpoint (p = .006). Differences in secondary efficacy outcomes were not significant, except for the PANSS negative subscore and the Clinical-Global-Impression-Scale. "Switchers" and "stayers" did not differ in safety outcomes. CONCLUSIONS: Switching "non-improvers" from amisulpride to olanzapine or vice-versa increased remission rates and was safe. The superiority in the primary outcome was, however, not paralleled by significant differences in most secondary efficacy outcomes and the effect was only apparent at the last visit making replications of longer duration necessary.