Thomas Wobrock

Hippocampal plasticity in response to exercise in schizophrenia.

CONTEXT Hippocampal volume is lower than expected in patients with schizophrenia; however, whether this represents a fixed deficit is uncertain. Exercise is a stimulus to hippocampal plasticity. OBJECTIVE To determine whether hippocampal volume would increase with exercise in humans and whether this effect would be related to improved aerobic fitness. DESIGN Randomized controlled study. SETTING Patients attending a day hospital program or an outpatient clinic. PATIENTS OR OTHER PARTICIPANTS Male patients with chronic schizophrenia and matched healthy subjects. INTERVENTIONS Aerobic exercise training (cycling) and playing table football (control group) for a period of 3 months. MAIN OUTCOME MEASURES Magnetic resonance imaging of the hippocampus. Secondary outcome measures were magnetic resonance spectroscopy, neuropsychological (Rey Auditory Verbal Learning Test, Corsi block-tapping test), and clinical (Positive and Negative Syndrome Scale) features. RESULTS Following exercise training, relative hippocampal volume increased significantly in patients (12%) and healthy subjects (16%), with no change in the nonexercise group of patients (-1%). Changes in hippocampal volume in the exercise group were correlated with improvements in aerobic fitness measured by change in maximum oxygen consumption (r = 0.71; P = .003). In the schizophrenia exercise group (but not the controls), change in hippocampal volume was associated with a 35% increase in the N-acetylaspartate to creatine ratio in the hippocampus. Finally, improvement in test scores for short-term memory in the combined exercise and nonexercise schizophrenia group was correlated with change in hippocampal volume (r = 0.51; P < .05). CONCLUSION These results indicate that in both healthy subjects and patients with schizophrenia hippocampal volume is plastic in response to aerobic exercise.

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, Part 2: Long-term treatment of schizophrenia

These guidelines for the biological treatment of schizophrenia were developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). The goal during the development of these guidelines was to review systematically all available evidence pertaining to the treatment of schizophrenia, and to reach a consensus on a series of practice recommendations that are clinically and scientifically meaningful based on the available evidence. These guidelines are intended for use by all physicians seeing and treating people with schizophrenia. The data used for developing these guidelines have been extracted primarily from various national treatment guidelines and panels for schizophrenia, as well as from meta-analyses, reviews and randomised clinical trials on the efficacy of pharmacological and other biological treatment interventions identified by a search of the MEDLINE database and Cochrane Library. The identified literature was evaluated with respect to the strength of evidence for its efficacy and then categorised into four levels of evidence (A–D). This second part of the guidelines covers the long-term treatment as well as the management of relevant side effects. These guidelines are primarily concerned with the biological treatment (including antipsychotic medication, other pharmacological treatment options, electroconvulsive therapy, adjunctive and novel therapeutic strategies) of adults suffering from schizophrenia.

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, Part 1: Update 2012 on the acute treatment of schizophrenia and the management of treatment resistance

Abstract These updated guidelines are based on a first edition of the World Federation of Societies of Biological Psychiatry Guidelines for Biological Treatment of Schizophrenia published in 2005. For this 2012 revision, all available publications pertaining to the biological treatment of schizophrenia were reviewed systematically to allow for an evidence-based update. These guidelines provide evidence-based practice recommendations that are clinically and scientifically meaningful and these guidelines are intended to be used by all physicians diagnosing and treating people suffering from schizophrenia. Based on the first version of these guidelines, a systematic review of the MEDLINE/PUBMED database and the Cochrane Library, in addition to data extraction from national treatment guidelines, has been performed for this update. The identified literature was evaluated with respect to the strength of evidence for its efficacy and then categorised into six levels of evidence (A–F; Bandelow et al. 2008b, World J Biol Psychiatry 9:242). This first part of the updated guidelines covers the general descriptions of antipsychotics and their side effects, the biological treatment of acute schizophrenia and the management of treatment-resistant schizophrenia.

World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 2: update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects.

Abstract These updated guidelines are based on a first edition of the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia published in 2006. For this 2012 revision, all available publications pertaining to the biological treatment of schizophrenia were reviewed systematically to allow for an evidence-based update. These guidelines provide evidence-based practice recommendations that are clinically and scientifically meaningful. They are intended to be used by all physicians diagnosing and treating people suffering from schizophrenia. Based on the first version of these guidelines, a systematic review of the MEDLINE/PUBMED database and the Cochrane Library, in addition to data extraction from national treatment guidelines, has been performed for this update. The identified literature was evaluated with respect to the strength of evidence for its efficacy and then categorised into six levels of evidence (A–F) and five levels of recommendation (1–5) (22,b, World J Biol Psychiatry 9:242, see Table I). This second part of the updated guidelines covers long-term treatment as well as the management of relevant side effects. These guidelines are primarily concerned with the biological treatment (including antipsychotic medication and other pharmacological treatment options) of adults suffering from schizophrenia.

Proteome analysis of the thalamus and cerebrospinal fluid reveals glycolysis dysfunction and potential biomarkers candidates for schizophrenia

Schizophrenia (SCZ) is the result of DNA alterations and environmental factors, which together lead to differential protein expression and ultimately to the development of the illness. The diagnosis is based on clinical symptoms, and the molecular background of SCZ is not completely understood. The thalamus, whose dysfunction has been associated with SCZ based in diverse lines of evidences, plays for instance a pivotal role in the central nervous system as a relay center by re-distributing auditory and visual stimuli from diverse brain regions to the cerebral cortex. We analyzed the proteome of postmortem mediodorsal thalamus (MDT) samples from 11 SCZ patients and 8 non-SCZ individuals by using quantitative shotgun-mass spectrometry and two-dimensional gel electrophoresis. Our analyses identified 551 proteins, 50 of which showed significant differential expression. The main pathways affected by the differentially expressed proteins include energy metabolism, oligodendrocyte metabolism, and cytoskeleton assembly. The potential protein biomarkers candidates myelin basic protein and myelin oligodendrocyte protein were validated by Western blot in the MDT samples and also in cerebrospinal fluid from a separate set of samples of 17 first-episode SCZ patients and 10 healthy controls. The differential expression of μ-crystallin, protein kinase C-gamma, and glial fibrillary acidic protein were confirmed in MDT. Because we found several glycolysis enzymes to be differentially expressed, we measured the levels of pyruvate and NADPH and found them to be altered in MDT. The protein changes described here corroborate the importance of myelin/oligodendrocyte and energy metabolism in SCZ and highlight new potential biomarkers candidates that may contribute to the understanding of the pathogenesis of this complex disease.

Dysfunctional long-term potentiation-like plasticity in schizophrenia revealed by transcranial direct current stimulation

Neural and cortical plasticity represent the ability of the brain to reorganize its function in response to a challenge. Plasticity involves changing synaptic activity and connectivity. Long-term-potentiation is one important mechanism underlying these synaptic changes. Disturbed neuronal plasticity is considered to be part of the pathophysiology of schizophrenia and has been linked to the different clinical features of this severe illness. The aim of the present study was to investigate nonfocal cortical plasticity and cortical excitability in recent-onset and multi-episode schizophrenia compared with healthy subjects. Nonfocal cortical plasticity can be induced in the motor cortex of healthy subjects with anodal transcranial direct current stimulation. Animal and human research indicates that this long-term-potentiation-like plasticity is glutamate-dependent and that these plasticity shifts can last for several hours. Transcranial direct current stimulation-induced plasticity was monitored by transcranial magnetic stimulation-generated motor evoked potentials. Well-characterized transcranial magnetic stimulation protocols were applied to determine the physiological basis of plasticity changes. Multi-episode schizophrenia patients showed significantly reduced long-term-potentiation-like plasticity compared to recent-onset schizophrenia patients and healthy controls. All schizophrenia patients demonstrated reduced cortical inhibition. Our results indicate that the long-term-potentiation-like plasticity deficit in schizophrenia patients is related to the disease course. Disturbances of N-methyl-d-aspartate, gamma-aminobutyric acid and dopamine receptors may account for this plasticity deficit. LTP-like plasticity deficits might be related to disturbed information processing in schizophrenia patients.

Praxisleitlinien in Psychiatrie und Psychotherapie

Zusammenfassung: Eine starkere Orientierung der arztlichen diagnostisch-therapeutischen Entscheidungsfindung an vorliegenden Leitlinien kann grundsatzlich einen entscheidenden Beitrag zur Erschliesung von Optimierungspotenzialen in Psychiatrie und Psychotherapie leisten. Studien verweisen jedoch auf vielfach noch unzureichende Leitlinienkonformitat und auf Varianzen in der Behandlungsqualitat. Vor diesem Hintergrund werden zunachst Konzept und Methodik der Leitlinienentwicklung durch eine Fachgesellschaft am Beispiel der DGPPN vorgestellt. Anhand einer Reihe von Projekten aus den Kompetenznetzen Depression und Schizophrenie werden zudem aktuelle Befunde zu erfolgreichen Strategien der Dissemination und Implementation von Leitlinien diskutiert. Vorliegende erste positive Evaluationsergebnisse aus diesen Projekten verdeutlichen das Potenzial hinsichtlich Prozessqualitat und Outcome der Behandlung, das von einer Verbesserung der Leitlinienkonformitat auch unter Alltagsbedingungen zu erwarten ist.

Reduced cortical inhibition in first-episode schizophrenia

Disturbances in cortico-cortical and cortico-subcortical circuits in schizophrenia have been described by previous neuroimaging and electrophysiological studies. Transcranial magnetic stimulation (TMS) provides a neurophysiological technique for the measurement of cortical excitability, especially of the motoneural system. Previous studies using paired-pulse TMS to investigate short-interval cortical inhibition (SICI) and intracortical facilitation (ICF), mainly involving chronic schizophrenia patients, have been inconsistent and only one study in first-episode patients has been conducted so far. We assessed SICI (interstimulus interval, ISI, 3 milliseconds, ms) and ICF (ISI 7 ms) in 29 first-episode schizophrenia patients (FE-SZ) with limited exposure to antipsychotic treatment against measures of 28 healthy controls (HC). Amplitudes of motor evoked potentials (MEPs) were measured from the left and right first dorsal interosseus muscle (FDI). The conditioning stimulus was set at 80% intensity of resting motor threshold (RMT) and the test stimulus (TS) was set at an intensity that produced an MEP amplitude of about 1 mV. For SICI conditions, FE-SZ demonstrated significantly higher MEP amplitudes from left motor cortex (right FDI) compared to HC, and for MEPs from right motor cortex (left FDI) a similar trend was observable (FE-SZ 41% vs. HC 21% of TS, p=0.017 for left motor cortex, and FE-SZ 59% vs. HC 31% of TS, p=0.059 for right motor cortex; Mann-Whitney U-test). No significant difference in MEPs could be detected for ICF on either hemisphere. In addition, there was no difference in left and right RMT comparing patients and control subjects. Our result of a reduced SICI in a large sample of well characterized first-episode schizophrenia patients suggests that a GABAergic deficit may be involved in schizophrenic pathophysiology, already early in the disease course, supporting the intracortical dysconnectivity hypothesis.

Cognitive impairment of executive function as a core symptom of schizophrenia

Cognitive dysfunction is a common finding in schizophrenia. Nevertheless the specific pattern of neuropsychological impairment in schizophrenia compared to other severe mental illnesses has not been intensively studied. Twenty-four patients with schizophrenia belonging to different stages of the disease (11 first-episode patients, 13 patients with multiple episodes), 18 patients with bipolar disorder and 23 healthy control subjects underwent standardized neuropsychological assessment. Statistical analysis of covariance (ANCOVA) demonstrated that, compared to control subjects, patients with schizophrenia performed significantly worse in the trail-making test (P = 0.012), verbal fluency (category letter, P = 0.004), verbal learning/memory (P = 0.005), and the Wisconsin Card Sorting Test (WCST) (P = 0.004 for administered trials; P = 0.025 for perseverative responses, T value) indicating significant deficits in attention and psychomotor performance, and in particular in verbal working memory and cognitive flexibility for schizophrenic patients. A significant difference between schizophrenic and bipolar patients was found only in the WCST. Schizophrenic patients made significantly more perseverative responses (P = 0.002, ANCOVA), indicating a more pronounced and specific deficit in cognitive flexibility and frontally based executive function. In conclusion, these results may suggest a cognitive endophenotype in schizophrenia and underline the role of the prefrontal cortex in schizophrenic pathophysiology.

Motor cortical excitability assessed by transcranial magnetic stimulation in psychiatric disorders: a systematic review.

BACKGROUND Transcranial magnetic stimulation (TMS) is a popular neurostimulation technique suitable for the investigation of inhibitory and facilitatory networks in the human motor system. In the last 20 years, several studies have used TMS to investigate cortical excitability in various psychiatric disorders, leading to a consequent improvement in pathophysiological understanding. However, little is known about the overlap and specificity of these findings across these conditions. OBJECTIVE To provide a systematic review of TMS studies (1985-2013) focusing on motor cortical excitability in dementia, schizophrenia, affective disorders (major depression and bipolar), attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), Tourette Syndrome (TS), substance abuse (alcohol, cocaine, cannabis, nicotine) and other disorders (borderline personality disorder, posttraumatic stress disorder (PTSD)). METHODS Systematic literature-based review. RESULTS Across disorders, patients displayed a general pattern of cortical disinhibition, while the most consistent results of reduced short-interval intracortical inhibition could be found in schizophrenia, OCD and Tourette Syndrome. In dementia, the most frequently reported finding was reduced short-latency afferent inhibition as a marker of cholinergic dysfunction. CONCLUSIONS The results of this systematic review indicate a general alteration in motor cortical inhibition in mental illness, rather than disease-specific changes. Changes in motor cortical excitability provide insight that can advance understanding of the pathophysiology underlying various psychiatric disorders. Further investigations are needed to improve the diagnostic application of these parameters.