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A Four-Step Approach for Developing Diagnostic Tests in Psychiatry

N. N. Boutros and C. L. Arfken

ABSTRACT

A four-step approach for developing diagnostic tests in psychiatry is proposed. Step 1, a biological variable is observed to be deviant from healthy controls in a particular patient population. The demonstration of test retest reliability of the finding using blinding procedures is an essential component of this early step. Step 2, is the demonstration of potential clinical usefulness of the specific finding. The two most important objectives at this step are demonstration of difference between the target patient population and appropriate control groups (these should be groups of patients with diagnoses that commonly appear on the differential diagnostic lists of the target disorder). Estimation of the effect size of the finding could be a reasonable guide to which findings should be considered good candidates for Step 3 studies. During Step 3 the performance characteristics of the test should be established. Specifically, the sensitivity, specificity, positive and negative predictive values of the biological marker should be examined. Step 4 defines the clinical application of the test and helps standardize the technique used in large and multicenter clinical trials. Multicenter trials should pave the road towards standardization of laboratory procedures used to conduct the test, as well as providing data regarding cost effectiveness and impact on both short-term and long-term clinical outcomes.

Challenge Tests of Monoaminergic Systems: Neurophysiological Aspects

Christine Norra

ABSTRACT

Monoaminergic challenge tests allow investigating central nervous changes in humans under acute depletion of specific neurotransmitters (5-HT, DA, NE). Along with studies using alpha-methyl-para-tyrosine test (AMPT) and phenylalanine/tyrosine depletion test (APTD), the tryptophan depletion test (ATDT) represents the currently most established human challenge tool for the assessment of brain serotonin functioning. Neurophysiological studies in healthy and clinical samples may contribute to the search for a non-invasive and reliable biological marker of monoaminergic vulnerability or dysfunction. In the design of these studies, various biochemical and methodological aspects have to be taken into account. This article focuses on electrophysiological methodology and results of monoamine depletion studies (i.e., electroencephalography, magnetoencephalography, polysomnography, auditory evoked potentials and startle response).

Prediction of Clinical Response to Antidepressants in Patients With Depression: Neurophysiology in Clinical Practice

Oliver Pogarell, Georg Juckel, Christine Norra, Gregor Leicht, Susanne Karch, Nadine Schaaff, Malte Folkerts, Ahmad Ibrahim, Christoph Mulert and Ulrich Hegerl

ABSTRACT

Brain monoaminergic neurotransmission is involved in the pathophysiology of various psychiatric disorders including depression. Reliable indicators of central monoaminergic activity might be helpful to specifically identify and differentiate dysfunctions in individual patients in order to selectively adjust medication and predict clinical response.

In patients with depression, predictors of treatment response to serotonergic versus non-serotonergic (e.g., noradrenergic) antidepressants could be of considerable clinical relevance by avoiding unfavorable factors such as a prolonged duration of the disorder, risk of suicidality and therapy-resistance. Consequently, these tools might help to decrease direct and indirect costs of treatment.

The loudness dependence of the N1/P2 component of auditory evoked potentials (LD) has been proposed as a noninvasive neurophysiological indicator of central serotonergic function. This review focuses on recent studies providing evidence for the validity of LD as an indirect serotonergic marker and highlights data on the clinical application in terms of prediction of treatment response in patients with depression.

Rostral Anterior Cingulate Cortex Activity in the Theta Band Predicts Response to Antidepressive Medication

Christoph Mulert, Georg Juckel, Michael Brunnmeier, Susanne Karch Gregor Leicht, Roland Mergl, Hans-Jürgen Möller, Ulrich Hegerl and Oliver Pogarell

ABSTRACT

During the last 10 years the knowledge about rostral anterior cingulate cortex (ACC) activity in major depression has substantially increased. Several groups have independently described a relationship between resting activity in this area and response to antidepressant treatment.

We have recently confirmed a relationship between resting activity of rostral ACC activity and response in a group of 20 patients with major depression using resting theta activity. In this earlier study regions of interest (ROI) were defined in order to establish regional specificity. Differences between responders and nonresponders were only found in the ACC-ROI, but not in the posterior cingulate region. We have now reanalyzed our data using a whole brain voxelwise approach, in order not to miss any other relevant functional differences. In addition to major differences between responders and nonresponders in the rostral ACC, we have identified a nearby region in the midline orbito-frontal region.

Hand-Motor Dysfunction in Depression: Characteristics and Pharmacological Effects

Roland Mergl, Oliver Pogarell, Georg Juckel, Julian Rihl, Verena Henkel, Thomas Frodl, Florian Müller-Siecheneder, Max Karner, Peter Tigges, Andreas Schröter and Ulrich Hegerl

ABSTRACT

Motor retardation is a relevant aspect of depression. Kinematic analysis of movements can be applied to explore which type of motor dysfunction is associated with depression and to examine motor side effects of antidepressants. Using this tool, we aimed to investigate fine motor performance in patients suffering from depression and to compare a selective noradrenaline re-uptake inhibitor (NARI) (reboxetine) and a selective serotonin reuptake inhibitor (SSRI) (citalopram) regarding motor side effects after 4 weeks of treatment.

In the first study (I), we examined 37 depressed patients and 37 healthy subjects using a digitizing graphic tablet and kinematic analysis of handwriting and rapid drawing movements. Both groups were comparable regarding age, gender distribution, handedness (preponderance of right-handers) and educational level. In the second study (II), we examined different types of hand movements in 16 depressed patients receiving citalopram (flexible dosage) and 12 depressed patients treated with reboxetine (varying dosage) using the afore-mentioned methods. Both groups were comparable regarding age, gender, handedness and the baseline Hamilton Depression Rating Scale total score.

I: Depressed patients performed drawing with significantly less regular velocity than controls (p < 0.001), but normal velocity. Handwriting of depressed patients was abnormally slow (p = 0.04). II: Reboxetine led to a significant improvement of repetitive drawing movements in depression. In contrast, citalopram had no pronounced effects on hand movements in depressed patients.

I: Irregular patterns of velocity peaks in depressed patients point to basal ganglia dysfunction and/or deficient activity of the sensorimotor cortex and the supplementary motor area as possible substrates of hand-motor disturbances in depression. II: Computer-aided analysis of hand movements is a sensitive tool for the registration of differential pharmaceutical effects on hand-motor function in depression.

Influence of Anxiety on Electrophysiological Correlates of Response Inhibition Capacities in Alcoholism

Susanne Karch, Christian Graz, Lorenz Jager, Evangelos Karamatskos, Andreas Stammel Wilhelm Flatz, Jürgen Lutz, Bettina Holtschmidt-Taschner, Just Genius, Gregor Leicht Maximilian Reiser, Hans-Jürgen Möller, Ulrich Hegerl, Michael Soyka and Christoph Mulert

ABSTRACT

Anxiety disorders are highly prevalent in patients with alcohol use disorder. The purpose of the present study was to examine the neural correlates of behavioral inhibition in alcohol-dependent patients (ICD-10: F 10.2), and in healthy controls and to determine the influence of anxiety on these processes. Therefore, behavioral responses (reaction times; error rates) and event-related potentials of 16 patients with alcohol dependence syndrome and 16 age- and gender-matched healthy controls were recorded while the participants performed an auditory go/no-go task. The patient group was stratified according to their self-rated trait anxiety (STAI) with scores above and below median. We hypothesized that patients suffering from alcohol dependence would show reduced no-go P3 amplitudes involved in response inhibition compared to healthy subjects. In patients with alcoholism and high trait anxiety the decline of no-go P3 amplitudes was expected to be less distinct.

The estimation of effect size based on the reaction times of patients with high and low anxiety ratings revealed a cohen’s d of 0.61 indicating a small effect. High trait anxiety ratings were also associated with slightly enhanced no-go P3 amplitudes in central brain regions (Mean no-go P3 amplitude at Cz: 10.43 µV) compared to patients with low anxiety scores (Mean 8.98 µV). The effect size (cohen’s d) revealed a small effect. Using the Mann-Whitney-U-test for independent samples of the comparison of high- and low-anxious patients, however, did not reveal any significant differences concerning no-go P3 amplitudes. Patients with alcohol use disorder and healthy controls did not differ significantly with regard to reaction time, error rate and no-go P3 amplitudes.

This study suggests that no-go P3 amplitudes in patients with alcohol use disorder might be affected to some degree by habitual anxiety. The results emphasize the importance of monitoring trait anxiety in studies regarding cognitive functions in subjects with alcohol use disorder.

Induced Gamma Activity and Event-Related Coherence in Schizophrenia

P. Bucci, A. Mucci, E. Merlotti, U. Volpe and S. Galderisi

ABSTRACT

Evidence has been provided that high frequency oscillations within the gamma band reflect mechanisms of cortical integration. In the light of recently proposed pathophysiological models of schizophrenia, suggesting a disturbance of the functional connectivity within distributed neural networks, it has been hypothesized that abnormalities in the gamma band underlie perceptual and cognitive dysfunctions in patients with schizophrenia.

In the present study we investigated evoked and induced 40-Hz gamma power as well as frontoparietal and frontotemporal event-related coherence in patients with deficit and nondeficit schizophrenia and in matched healthy controls. In patients, correlations between gamma oscillations and psychopathological dimensions were also investigated.

A reduction of both induced gamma power and event-related coherence was observed in patients with nondeficit schizophrenia, but not in those with deficit schizophrenia.

Our findings support the hypothesis that deficit and nondeficit schizophrenia represent separate disease entities, suggesting the presence of a poor integration of the neuronal activity within distributed neural network only in the subgroup of schizophrenic patients without primary and persistent negative symptoms.

Associations between an excess of gamma oscillations and psychopathological dimensions were observed, suggesting that abnormal thoughts, behaviors and perceptions might be related to the formation of inappropriate neural connections.

Transcranial and Deep Brain Stimulation Approaches as Treatment for Depression

Anne Rau, Nicola Großheinrich, Ulrich Palm, Oliver Pogarell and Frank Padberg

ABSTRACT

Given that a considerable portion of depressed patients does not respond to or remit during pharmacotherapy, there is increasing interest in non-pharmacological strategies to treat depressive disorders. Several brain stimulation approaches are currently being investigated as novel therapeutic interventions beside electroconvulsive therapy (ECT), a prototypic method in this field with proven effectiveness. These neurostimulation methods include repetitive transcranial magnetic stimulation (rTMS), magnetic seizure therapy (MST), vagus nerve stimulation (VNS), deep brain stimulation (DBS) and transcranial direct current stimulation (tDCS). It is via different neuroanatomically defined “windows” that the various approaches access the neuronal networks showing an altered function in depression. Also, the methods vary regarding their degree of invasiveness. One or the other method may finally achieve antidepressant effectiveness with minimized side effects and constitute a new effective treatment for major depression.

Antiepileptic Drugs and Mood Stability

Benedikt Amann, Heinz Grunze, Eduard Vieta and Michael Trimble

ABSTRACT

This paper will discuss different definitions of the term “mood stabilizer” and highlight in detail the antiepileptic drugs carbamazepine, valproate and lamotrigine with respect to their relative strengths in stabilizing mood in bipolar patients. These drugs are heterogeneous in their mechanisms of action and in their efficacy to stabilize patients with epilepsy and the various mood states in bipolar disorder. Lamotrigine has obtained approval in several countries for the indication of preventing bipolar depressive episodes, which raises the question of differential efficacy of other antiepileptic drugs as mood stabilizers in the prevention of either depressive or hypo-/manic episodes. A Medline Search to 2006 was conducted for controlled acute and maintenance studies of the three scientifically and clinically most established antiepileptic drugs carbamazepine, valproate and lamotrigine. The medications discussed in this review only partly fulfill definitions of a mood stabilizer, and we suggest that future research should  focus on combined treatment strategies.