Emanuel Bubl

Increased Prefrontal and Hippocampal Glutamate Concentration in Schizophrenia: Evidence from a Magnetic Resonance Spectroscopy Study

BACKGROUND Glutamatergic dysfunction has been implicated in the pathophysiology of schizophrenia. However, so far there is limited direct evidence of altered in vivo glutamate concentrations in the brains of patients with schizophrenia. To test the hypothesis that altered glutamatergic neurotransmission might play a role in the pathogenesis of schizophrenia, we measured glutamate and glutamine concentrations in the prefrontal cortex and the hippocampus of patients with chronic schizophrenia using high-field magnetic resonance spectroscopy. METHODS Twenty-one patients with schizophrenia and 32 healthy volunteers were examined clinically and by means of short echo time single voxel magnetic resonance spectroscopy of the dorsolateral prefrontal cortex and the hippocampus. Absolute concentrations of neurometabolites were calculated. RESULTS Absolute concentrations of glutamate were significantly higher in the prefrontal cortex and the hippocampus in the patient group. Factorial analysis of variance (ANOVA) revealed no significant interactions between duration of schizophrenia, number of hospitalizations, or type of antipsychotic medication and glutamate concentrations. Increased prefrontal glutamate concentrations were associated with poorer global mental functioning. CONCLUSIONS This is the first study that reports increased levels of glutamate in prefrontal and limbic areas in patients with schizophrenia. Our data support the hypothesis of glutamatergic dysfunction in schizophrenia.

Seeing Gray When Feeling Blue? Depression Can Be Measured in the Eye of the Diseased

BACKGROUND Everyday language relates depressed mood to visual phenomena. Previous studies point to a reduced sensitivity of subjective contrast perception in depressed patients. One way to assess visual contrast perception in an objective way at the level of the retina is to measure the pattern electroretinogram (PERG). To find an objective correlate of reduced contrast perception, we measured the PERG in healthy control subjects and unmedicated and medicated patients with depression. METHODS Forty patients with a diagnosis of major depression (20 with and 20 without medication) and 40 matched healthy subjects were studied. Visual PERGs were recorded from both eyes. RESULTS Unmedicated and medicated depressed patients displayed dramatically lower retinal contrast gain. We found a strong and significant correlation between contrast gain and severity of depression. This marker distinguishes most patients on a single-case basis from control subjects. A receiver operating characteristic analysis revealed a specificity of 92.5% and a sensitivity of 77.5% for classifying the participants correctly. CONCLUSIONS Because PERG recording does not depend on subjective ratings, this marker may be an objective correlate of depression in human beings. If replicated, PERG may be helpful in further animal and human research in depression.

Spectroscopic findings in attention-deficit/hyperactivity disorder: Review and meta-analysis

Objectives. The last decade has seen an increasing interest in the method of magnet resonance spectroscopy (MRS) since this is the only research tool that allows a non-invasive in vivo assessment of neurochemical aspects of ADHD without employing ionising radiation. In this paper we review published MRS results with respect to childhood, adolescence and adult ADHD. Method. We searched the Medline (Pub Med) database using the key words ADHD, attention-deficit/hyperactivity disorder, magnet resonance spectroscopy, MRS and spectroscopy. Citations of identified articles were also searched for relevant studies. Meta-analyses were performed for the measured metabolites and regions of assessment. Results. Sixteen studies could be identified that used MRS to investigate the neurobiology of ADHD. Two regions could be identified as the focus of spectroscopic investigations – the frontal lobe including anterior cingulate cortex and parts of prefrontal cortex and the basal ganglia, mostly striatum, alongside the fronto-striato-thalamo-frontal circuits. As for metabolites, in the majority of studies the ratios to creatine and not absolute concentrations of metabolites were estimated. Choline compounds, N-acetyl-aspartate and glutamate/glutamine (to creatine ratios) could be identified as being altered in several studies in ADHD. The meta-analysis showed increased choline compounds in several researched regions. Discussion. MRS is a promising tool for the non-invasive in vivo assessment of the cerebral neurochemistry in ADHD. More regions of interest (ROI) like amygdala, hippocampus, thalamus and cerebellum should be assessed in future studies. Further methodological improvements of MRS are desirable in order to assess the absolute metabolite concentration of several ROIs at the same time. Such developments will open novel perspectives in spectroscopic investigations of ADHD.

Vision in depressive disorder

Background. Reduced dopaminergic transmission has been implicated in the pathophysiology of major depression. Furthermore, dopaminergic neurotransmission plays an important role in the physiology of visual contrast sensitivity (CS). To test the hypothesis that altered dopaminergic neurotransmission plays a role in major depression we measured contrast sensitivity in patients with major depression and in healthy control subjects. Methods. Twenty-eight patients diagnosed with major depressive disorder were compared to 21 age-matched control subjects on their ability to detect a Gabor target with slightly elevated luminance contrast embedded in seven equi-contrast distracters. Results. Contrast discrimination thresholds were significantly elevated in unmedicated and medicated patients with major depression compared to control subjects, at all pedestal contrast levels tested. Conclusions. Contrast discrimination performance is reduced in depressive patients and might reflect a state of altered dopaminergic neurotransmission.

Aripiprazole in patients with Tourette syndrome

The treatment of the Gilles de la Tourette syndrome (GTS) is often challenging. One reason for this is the high neuropsychiatric cormorbidity in terms of ADHD or obsessive-compulsive symptoms. Dopaminergic modulation e.g. with antidopaminergic medication is an important part of the medical therapy aimed at motor and vocal tics. We report recent experiences with treatment with aripiprazole, a novel antipsychotic agent, which not only improved motor and vocal tics but also ameliorated some behavioural symptoms of the GTS cluster. Furthermore, we discuss possible pharmacological mechanisms for the observed effects.

Effect of antidepressive therapy on retinal contrast processing in depressive disorder.

BACKGROUND Recently, we reported a reduced retinal contrast gain in unmedicated and medicated patients with major depression. AIMS To analyse whether the contrast gain normalises after successful antidepressive therapy by recording the pattern electroretinogram (PERG) in healthy controls and patients with depression before and after antidepressive therapy. METHOD Fourteen patients diagnosed with major depression were repeatedly scanned and the results compared with that from 40 matched controls. RESULTS The retinal contrast gain was lower at baseline in patients with depression, was normalised with remission and correlated with the severity of depression. Patients who did not achieve remission retained significantly lower contrast gain at follow-up. CONCLUSIONS The study provides evidence for a state-dependent modulation of retinal contrast gain in patients with major depression. Reduced contrast gain normalised after therapy. A PERG-based contrast gain could serve as a state marker of depression.

Serum creatine kinase elevation as a possible complication of therapy with olanzapine

A 33-year-old white German (Caucasian) man with schizoaffective disorder according to ICD-10 criteria had been treated with olanzapine for 7 weeks when he suddenly developed extremely high elevated serum CK concentrations (assessed by chance in a routine testing) with peak values of about 28,000 IU/l (normal: <174). Careful analysis revealed that this increased CK concentration was due to the skeletal muscle isoenzyme CK-MM. There was also an elevated serum myoglobin concentration of more then 2,500 ng/ml (normal: <90) and a moderate increase in two liver enzymes (AST, ALT). The cardiac muscle isoenzyme CK-MB as well as all other haematological, electrolyte, renal and inflammation parameters were essentially normal. There were no prior clinical symptoms of a flu-like or other inflammatory nature or of muscle pain or weakness. Previous controls of the serum CK-levels had been normal. The only other drug the patient had taken for months was amitriptylineoxid and, to date, there has been no report in the literature on this agent causing CK elevation or rhabdomyolysis. There were no symptoms or signs of malignant neuroleptic syndrome (MNS)-like myopathy, muscle rigidity or febrile temperatures. The patient followed his normal behavioural routine 2 weeks prior to the incidence without being extremely active with respect to sports or suffering muscle injuries. Thus, muscle trauma could be excluded as a possible cause of the elevated CK concentrations. Immediate discontinuation of olanzapine and forced alkaline diuresis resulted in normalisation of the serum CK and myoglobin levels within 14 days for CK and 7 days for myoglobin. In summary, we found extremely high elevated CK and myoglobin concentrations by chance in a schizoaffective patient treated with olanzapine and amitriptylineoxid being otherwise completely asymptomatic for neuromuscular disorders. A possible first assumption would be that the patient suffered from an oligosymptomatic MNS. However, the absence of any clinical symptom or sign for MNS does not support this assumption. The fact that all laboratory parameters normalised within 2 weeks of discontinuation of the drugs supports the assumption of an olanzapine-induced CK and myoglobin elevation.

Retinal contrast transfer functions in adults with and without ADHD.

In previous studies, we found a strong reduction in contrast perception and retinal contrast gain in patients with major depression, which normalized after remission of depression. We also identified a possible role of the dopaminergic system in this effect, because visual contrast perception depends on dopaminergic neurotransmission. Dopamine is also known to play an important role in the pathogenesis of attention deficit hyperactivity disorder (ADHD). Therefore, in order to explore the specificity of retinal contrast gain as a marker of depression in comparison with other psychiatric diseases, we recorded the pattern electroretinogram (PERG) in patients with ADHD. Twenty patients diagnosed with ADHD and 20 matched healthy subjects were studied. Visual pattern electroretinograms were recorded from both eyes. The contrast gain of the patients with attention deficit disorder (ADD) did not differ from the control group, nor did the contrast gain of any ADHD subgroup (predominantly inattentive or combined patients). In the healthy subjects, a significant correlation between depression score and contrast gain was found. As the contrast gain in an earlier study clearly separated the patients with depression from the controls, we assume that retinal contrast gain might be a specific marker in depression.

Neuropsychological and cerebral morphometric aspects of negative symptoms in schizophrenia: negative symptomatology is associated with specific mnestic deficits in schizophrenic patients

BackgroundThe prevalence of negative symptoms in schizophrenic patients seems to be an important indicator for treatment response and prognosis. Although negative symptoms have often been attributed to frontal lobe anomalies, neuropsychological and anatomical findings do not explicitly support this assumption. Since knowledge about the cerebral correlate of negative symptoms in schizophrenia might have a strong impact on therapeutic and psychopharmacological interventions, we aimed to answer this question by investigating the relationship between negative symptoms, neuropsychological functioning and cerebral volumes in schizophrenic patients.MethodsTwenty schizophrenic patients and 32 healthy controls were examined using a neuropsychological test battery for the assessment of temporal (mnestic) and frontal (executive) faculties. Volumetric measurements of temporal (hippocampus and amygdala) and frontal (orbitofrontal, dorsolateral prefrontal, and anterior cingulate area) brain areas were performed. Negative symptoms were assessed using the Scale for the Assessment of Negative Symptoms (SANS).ResultsSchizophrenic patients performed worse than healthy controls in tests assessing verbal and visuospatial learning and memory functions and on the Stroop interference task. After dividing the schizophrenic group in patients with high and low SANS scores almost all of these deficits were restricted to the former group. There were no overall group differences regarding cerebral subarea volumes. Overall negative symptoms were significantly correlated with verbal memory functions but not with frontal lobe faculties.ConclusionsNegative symptoms in schizophrenia could specifically associated with verbal memory deficits.

Elevated background noise in adult attention deficit hyperactivity disorder is associated with inattention.

Background Inattention and distractibility are core symptoms of attention deficit hyperactivity disorder (ADHD). Still the neuronal organization is largely unknown. Previously we studied the electrophysiological activity of a distinct neuronal network—the retina—and found no change in stimulus-driven neural activity in patients with ADHD. However there is growing evidence for an elevated non stimulus-driven neural activity, or neuronal background noise, as underlying pathophysiological correlate. To further examine the biological bases that might underlie ADHD and problems with inattention, we performed a new analysis to test the hypothesis of an elevated background noise as underlying neuronal correlate for ADHD and problems with inattention in humans. A direct measure of background noise in patients with ADHD has not been described yet. Methods The retinal background noise was assessed based on pattern electroretinogram (PERG) data in 20 unmedicated ADHD patients and 20 healthy controls. The PERG is an electrophysiological measure for retinal ganglion cell function. ADHD severity was assessed by interview and questionnaire. Results Noise amplitude was significantly higher (138%) in patients with ADHD compared to the control group (p = 0.0047). Noise amplitude correlated significantly with psychometric measures for ADHD (CAARS) especially inattention (r = 0.44, p = 0.004). Conclusions The data provide evidence that an elevated background noise is associated with symptoms of inattention in ADHD and support the use of therapeutic interventions that reduce noise and distraction in patients with ADHD.