Hildegard Janouschek

Brain and Plasma Pharmacokinetics of Aripiprazole in Patients With Schizophrenia: An [ 18 F]Fallypride PET Study

OBJECTIVE Aripiprazole at clinically effective doses occupies some 90% of striatal dopamine 2 and 3 (D(2)/D(3)) receptors. In order to further characterize its extrastriatal and time-dependent binding characteristics, the authors conducted positron emission tomography (PET) studies with the D(2)/D(3) antagonist [(18)F]fallypride at varying time points after the last aripiprazole administration in patients with schizophrenia. METHOD Sixteen inpatients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder receiving treatment with aripiprazole underwent an [(18)F]fallypride PET scan. Receptor occupancy was calculated as the percentage reduction in binding potential relative to unblocked values measured in eight age-matched, medication-free patients with schizophrenia. In addition, aripiprazole serum concentrations were determined as part of a routine therapeutic drug monitoring program in a large group of patients (N=128) treated with aripiprazole. RESULTS Mean dopamine D(2)/D(3) receptor occupancy was high in all brain regions investigated, with no binding difference across brain regions. Nonlinear regression analysis revealed maximum attainable receptor occupancy (E(max)) values close to saturation. The values for serum concentration predicted to provide 50% of E(max) (EC(50)) were in the range of 5-10 ng/ml in all brain regions. The D(2)/D(3) receptors were completely saturated when serum aripiprazole concentration exceeded 100-150 ng/ml. The mean concentration in the large clinical patient sample was 228 ng/ml (SD=142). CONCLUSIONS Because of its high affinity for D(2)/D(3) receptors and its long elimination half-life, aripiprazole at clinical doses occupies a high fraction of its target receptor everywhere in the brain. Its dissociation from those receptors is very slow, such that the authors calculate from the results that in patients with serum aripiprazole concentrations in the range typical for clinical practice, D(2)/D(3) receptors must remain nearly saturated for as long as 1 week after the last dose.

From psychosurgery to neuromodulation: deep brain stimulation for intractable Tourette syndrome.

Tourette syndrome is a neuropsychiatric disorder characterized by motor and vocal tics. It is often associated with depression, obsessive-compulsive symptoms, self-injurious behaviour and attention deficit-hyperactivity disorder (ADHD). In intractable patients, neuromodulation using deep brain stimulation (DBS) has widely replaced psychosurgery. Three different key structures are defined for DBS, the medial portion of the thalamus, the globus pallidus internus and the anterior limb of the internal capsule/nucleus accumbens. This is a comprehensive overview on the effect of DBS on motor and non-motor symptoms using different case series and two larger studies.

In vivo evidence of deep brain stimulation-induced dopaminergic modulation in Tourette's syndrome

To the Editor: D ue to its large effect size, deep brain stimulation (DBS) is progressively considered in the treatment of medicationresistant Tourette’s syndrome (TS) (1). Nevertheless, the underlying beneficial mechanisms of DBS in TS are still a matter of debate (2,3). Treatment strategies (D2-receptor antagonists) as well as previous research results point to a dysfunction of basal gangliarelated circuits and hyperactive dopaminergic innervations (4 – 8). It might thus be hypothesized that DBS acts via modulation of dopamine transmission; however, corresponding in vivo evidence is lacking, except for one positive single-patient [F]fallypride-positron emission tomography (FP) investigation (9). In fact, FP allows for quantification of D2/3-receptor availability in striatal and extrasriatal regions within a single positron emission tomography (PET) can but requires more than 3 hours of acquisition time. Because TS atients suffer from heavy motor tics, a long-term anesthesia was ecessary during the PET scan. Encouraged by the observation of elevant FP-binding changes within the pilot-investigation, we proeeded to enlarge the number of such investigations. This investigation was approved by the local ethics committee nd the German drug safety and radiation safety authorities. Three atients (two men, one woman) (Table 1) suffering from medicaion-resistant TS were investigated. The two male patients underent prior bilateral thalamic DBS in the pallidal and nigral input egions of the thalamus (Th). The female patient (Patient 3) underent a left-sided unilateral thalamic stimulation, because the leftided intraoperative test-stimulation revealed already-complete tic uppression (detailed electrode positions) (Table 2). They all responded with substantial improvements in the Yale Global Tic Severity Scale (YGTSS) (reductions of 30%– 80%) (Table 1). The PET scans were scheduled 6 months after the surgery. For an orientating comparison with stimulation-free conditions we used FP-PET results of eight age-matched healthy subjects (seven men/ one woman; age: 19 –29 years; mean SD: 23.6 3.8). The FP-radiosynthesis has been described previously (10). Each patient experienced two PET scans (first: “stimulator-on”; second: “stimulator-off”) under general propofol/remifentanil anesthesia of 4 –5 hours in duration (3 hours: FP-scan; 1 hour: anesthesia preparation; 1 hour: latency between stimulation deactivation and ligand injection [second scan]). Control subjects were scanned without

Dopamine D2/3 receptor occupancy by quetiapine in striatal and extrastriatal areas.

Quetiapine is next to clozapine an antipsychotic agent that exerts hardly any extrapyramidal side-effects at clinical efficacious doses. Some previous receptor occupancy studies reported preferential extrastriatal D2/3 receptor (D2/3R)-binding properties of second-generation antipsychotics and suggested this as possible reason for improved tolerability. This positron emission tomography (PET) investigation was designed to compare the occupancy of dopamine D2/3Rs by quetiapine in striatal and extrastriatal brain regions. Therefore, a cohort of 16 quetiapine-treated psychotic patients underwent an [18F]fallypride (FP) PET scan. Due to the high affinity of FP and its comparatively long half-life, striatal and extrastriatal binding potentials could be determined in one single scan. Receptor occupancy was calculated as percent reduction in binding potential relative to age-matched medication-free patients suffering from schizophrenia. Quetiapine occupied 44+/-18% in the temporal cortex and 26+/-17% in the putamen, a difference significant at the level of p=0.005 (Students t test). Quetiapine showed a mean occupancy of 36+/-16% and in the thalamus. In the caudate nucleus there was an occupancy of 29+/-16% (p=0.0072). Individual occupancy levels did not exceed 59% in any of the striatal volumes of interest. The time-interval between scan and last drug ingestion did not influence the relationship between plasma concentration and central D2/3R occupancy. Taken together, quetiapine shows preferential extrastriatal binding at D2/3Rs; the extent of this difference is comparable to that previously described for clozapine. Both antipsychotics show very low affinity for D2/3Rs.

Fine motor skills in adult Tourette patients are task-dependent.

BackgroundTourette syndrome is a neuropsychiatric disorder characterized by motor and phonic tics. Deficient motor inhibition underlying tics is one of the main hypotheses in its pathophysiology. Therefore the question arises whether this supposed deficient motor inhibition affects also voluntary movements. Despite severe motor tics, different personalities who suffer from Tourette perform successfully as neurosurgeon, pilot or professional basketball player.MethodsFor the investigation of fine motor skills we conducted a motor performance test battery in an adult Tourette sample and an age matched group of healthy controls.ResultsThe Tourette patients showed a significant lower performance in the categories steadiness of both hands and aiming of the right hand in comparison to the healthy controls. A comparison of patients’ subgroup without comorbidities or medication and healthy controls revealed a significant difference in the category steadiness of the right hand.ConclusionsOur results show that steadiness and visuomotor integration of fine motor skills are altered in our adult sample but not precision and speed of movements. This alteration pattern might be the clinical vignette of complex adaptations in the excitability of the motor system on the basis of altered cortical and subcortical components. The structurally and functionally altered neuronal components could encompass orbitofrontal, ventrolateral prefrontal and parietal cortices, the anterior cingulate, amygdala, primary motor and sensorimotor areas including altered corticospinal projections, the corpus callosum and the basal ganglia.

Comparison of methohexital and etomidate as anesthetic agents for electroconvulsive therapy in affective and psychotic disorders

BACKGROUND ECT is a well-established treatment for severe depression. The available data on psychosis are limited, but reliable. Its therapeutic potential relies on the induction of a generalized seizure. Besides other narcotics, methohexital and etomidate are used for general anesthesia in ECT. Since prolonged seizures have been reported following the use of etomidate, it can be deduced that the substances might differ in their anticonvulsant properties, resulting in a lower increase in stimulus intensity during the course of treatment under etomidate. Besides this hypothesis, we aimed to investigate the differential effects of etomidate and methohexital on clinical features, ECT parameters and side effects of the treatment. METHODS We performed a retrospective analysis of treatment data of patients with affective and psychotic diagnosis who received general anesthesia for ECT either with etomidate or with methohexital. RESULTS ECT with etomidate and methohexital was equally effective. During the course of therapies the administered electric charge increased significantly and equally in both treatment groups. In the methohexital group, but not in the etomidate group, electroencephalographic seizure duration had a declining trend during the course of therapies. We observed more side effects during and immediately after ECT in the methohexital group than in the etomidate group. LIMITATIONS The limitations of this study are that the patients received various psychotropic co-medications, which influence ictal parameters differently, and, secondly, the study is based on a retrospective analysis. CONCLUSION The results of our analysis suggest that etomidate and methohexital affect ictal parameters to different extents. Longer seizure duration and fewer side effects are in favor of etomidate.

Acute and chronic effects of bithalamic deep brain stimulation on dopaminergic transmission

Deep brain stimulation (DBS) in Tourettes syndrome (GTS) is one of the few accepted surgical treatment options in psychiatry. However, the choice of target areas and stimulation parameters are principally based on empirical knowledge because the underlying physiological principles of DBS are not entirely understood, yet. To this end, we performed an [18F]fallypride positron-emission tomography investigation (FP-PET) in order to elucidate DBS-effects on dopamine transmission. Two patients suffering from treatment resistant GTS (age: both 22 years) underwent bithalamical (mediodorsal nuclei) DBS approximately 6 months before the PET-scans. Both of the patients improved significantly in their symptomatology. We performed two PET scan using the high-affinity D2/3-receptor ligand [18F]fallypride (FP): the first scan under stimulator-“on”, the second scan under “off”-conditions (electrodes turned off 1 h before tracer injection). The scans necessarily had to be performed under anesthesia (propofol/remifentanil) in order to avoid tics during the 4 h of acquisition. Time–activity curves have been obtained after anatomical coregistration and normalization using our standard VOI-template. BP(nd) calculation was performed according to the simplified reference tissue (SRTM) model using the cerebellum as reference region. In both patients we found region-specific reductions of FP-BP(nd): in the medial thalamus VOI, BP(nd)reductions ranged from 6 to 16% indicating an increased dopaminergic transmission during “off”-conditions. Conversely, in the putamen the BP(nd) increased from “on” to “off” conditions in a range from 4 to 6%. In other regions we found only little or inconsistent changes in BP(nd)s. Interestingly, the receptor availability under both conditions was much higher than in a group of age-matched control subjects (+80 and +94% in the thalamus). The binding equilibrium was reached in all scans for all regions within the 3 h of acquisition. The region-specific reduction of BP(nd) values during “off” conditions suggests a strong increase of dopamine release. This, inversely, points to an inhibition of thalamic dopamine transmission by DBS. Due to the highly experimental therapeutic approach, we have not been able to investigate a suitable number of patients for statistical analysis. The much higher FP-BP(nd) values in DBS-GTS patients suggests an upregulation of central D2/3-receptor as a counterregulative effect after prolonged DBS. That might explain the slow process of recurrence of symptoms after DBS-surgery.

Wirkungsmechanismen der EKT

Die Elektrokonvulsionstherapie (EKT) wirkt bei klinisch heterogenen Syndromen: Neben antidepressiven, antimanischen, antipsychotischen, antikonvulsiven, antisuizidalen, stimmungsstabilisierenden und antikatatonen Eigenschaften wurden positive Effekte auf motorische Symptome des Morbus Parkinson beschrieben. Eine umfassende Theorie des Wirkmechanismus existiert bislang noch nicht. In human- und tierexperimentellen Studien mit EKT bzw. ECS, dem Tiermodell der EKT, konnten jedoch Veranderungen verschiedener potenziell antidepressiv wirksamer Hormone, Neurotransmitter und ihrer Rezeptoren, verschiedener Neuropeptide und neurotropher Faktoren festgestellt werden. Zudem konnten eine EKT-bedingte kurzzeitige Offnung der Blut-Hirn-Schranke und eine Zunahme des zerebralen Blutflusses nachgewiesen werden. Mittels Bildgebung konnten eine teilweise Normalisierung von Fasertraktanomalien sowie eine Normalisierung der funktionellen Konnektivitat depressiver Patienten durch EKT gezeigt werden.

The role of striatal dopamine D 2/3 receptors in cognitive performance in drug-free patients with schizophrenia

ObjectiveA considerable body of research links cognitive function to dopaminergic transmission in the prefrontal cortex, but less is known about cognition in relation to striatal dopamine D2/3 receptors in unmedicated patients with psychosis.MethodsWe investigated this association by obtaining PET recordings with the high-affinity D2/3 antagonist ligand [18F] fallypride in 15 medication-free patients with schizophrenia and 11 healthy controls. On the day of PET scanning, we undertook comprehensive neuropsychological testing and assessment of psychopathology using the Positive and Negative Syndrome Scale (PANSS).ResultsThe patients’ performance in cognitive tests was significantly impaired in almost all domains. Irrespective of medication history, the mean [18F] fallypride binding potential (BPND) in the patient group tended to be globally 5–10% higher than that of the control group, but without reaching significance in any brain region. There were significant positive correlations between individual patient performance in the Trail Making Test (TMT(A) and TMT(B)) and Digit-Symbol-Substitution-Test with regional [18F] fallypride BPND, which remained significant after Bonferroni correction for the TMT(A) in caudate nucleus (CN) and for the TMT(B) in CN and putamen. No such correlations were evident in the control group.DiscussionThe association between better cognitive performance and greater BPND in schizophrenia patients may imply that relatively lower receptor occupancy by endogenous dopamine favors better sparing of cognitive function. Absence of comparable correlations in healthy controls could indicate a greater involvement of signaling at dopamine D2/3 receptors in certain cognitive functions in schizophrenia patients than in healthy controls.

Using coordinate-based meta-analyses to explore structural imaging genetics

Imaging genetics has become a highly popular approach in the field of schizophrenia research. A frequently reported finding is that effects from common genetic variation are associated with a schizophrenia-related structural endophenotype. Genetic contributions to a structural endophenotype may be easier to delineate, when referring to biological rather than diagnostic criteria. We used coordinate-based meta-analyses, namely the anatomical likelihood estimation (ALE) algorithm on 30 schizophrenia-related imaging genetics studies, representing 44 single-nucleotide polymorphisms at 26 gene loci investigated in 4682 subjects. To test whether analyses based on biological information would improve the convergence of results, gene ontology (GO) terms were used to group the findings from the published studies. We did not find any significant results for the main contrast. However, our analysis enrolling studies on genotype × diagnosis interaction yielded two clusters in the left temporal lobe and the medial orbitofrontal cortex. All other subanalyses did not yield any significant results. To gain insight into possible biological relationships between the genes implicated by these clusters, we mapped five of them to GO terms of the category “biological process” (AKT1, CNNM2, DISC1, DTNBP1, VAV3), then five to “cellular component” terms (AKT1, CNNM2, DISC1, DTNBP1, VAV3), and three to “molecular function” terms (AKT1, VAV3, ZNF804A). A subsequent cluster analysis identified representative, non-redundant subsets of semantically similar terms that aided a further interpretation. We regard this approach as a new option to systematically explore the richness of the literature in imaging genetics.