Clinical Trial of the Potassium Channel Activator Diazoxide for Major Depressive Disorder Halted Due to Intolerability.

BACKGROUND: Some glutamatergic modulators have demonstrated rapid and relatively sustained antidepressant properties in patients with major depressive disorder. Because the potassium channel activator diazoxide increases glutamate uptake via potassium channel activation, we hypothesized that it might exert antidepressant effects by increasing the removal of glutamate from the synaptic cleft, thereby reducing excessive glutamate transmission. METHODS: This randomized, double-blind, placebo-controlled, crossover, single-site inpatient clinical study was conducted at the National Institute of Mental Health to assess the efficacy and safety of a 3-week course of diazoxide (200-400 mg daily, twice a day) versus a 3-week course of placebo in 6 participants with treatment-refractory major depressive disorder. The primary clinical outcome measure was change in Montgomery-Asberg Depression Rating Scale score from baseline to posttreatment. Quantitative insulin sensitivity check index, as well as concomitant imaging measures (electroencephalography, proton magnetic resonance spectroscopy, magnetoencephalography), were used as potential surrogate markers of target (KATP channel) engagement. RESULTS: The study was halted due to severe adverse effects. Given the small sample size, statistical evaluation of the effect of diazoxide on Montgomery-Asberg Depression Rating Scale scores or the imaging measures was not pursued. Visual inspection of the quantitative insulin sensitivity check index test revealed no evidence of target engagement. CONCLUSIONS: Although the results are negative, they are an important addition to the literature in this rapidly changing field.

Synaptic potentiation onto habenula neurons in the learned helplessness model of depression.

The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.

31P RINEPT MRSI and VBM reveal alterations in brain aging associated with major depression.

PURPOSE: Phosphomono- and diesters, the major components of the choline peak in (1) H magnetic resonance spectroscopy, are associated with membrane anabolic and catabolic mechanisms. With the refocused insensitive nuclei-enhanced polarization transfer technique, these phospholipids are edited and enhanced in the (31) P MR spectrum. In depressed patients, alterations of the choline peak and cerebral volume have been found, indicating a possible relation. Thus, combining MR phosphorous spectroscopy and volumetry in depressed patients seems to be a promising approach to detect underlying pathomechanisms. METHODS: Depressed in-patients were either treated with antidepressive medication or with electroconvulsive therapy and compared to matched healthy controls. (31) P magnetic resonance spectroscopy imaging was conducted before and after the treatment phases. A 3D MRI dataset for volumetry was acquired in a dedicated (1) H head coil. RESULTS: Phosphocholine and phosphoethanolamine were increased in depressed patients. Though patients responded to the treatments, phospholipids were not significantly altered. An increased age-related gray matter loss in fronto-limbic regions along with an altered relation of phosphomonoesters/phosphodiesters with age were found in depressed patients. DISCUSSION: The findings of increased phosphomonoesthers and an age*group interaction for gray matter volumes need further research to define the role of phospholipids in major depression and possible associations to gray matter loss.

Synaptic abnormalities in the infralimbic cortex of a model of congenital depression.

Multiple lines of evidence suggest that disturbances in excitatory transmission contribute to depression. Whether these defects involve the number, size, or composition of glutamatergic contacts is unclear. This study used recently introduced procedures for fluorescence deconvolution tomography in a well-studied rat model of congenital depression to characterize excitatory synapses in layer I of infralimbic cortex, a region involved in mood disorders, and of primary somatosensory cortex. Three groups were studied: (1) rats bred for learned helplessness (cLH); (2) rats resistant to learned helplessness (cNLH); and (3) control Sprague Dawley rats. In fields within infralimbic cortex, cLH rats had the same numerical density of synapses, immunolabeled for either the postsynaptic density (PSD) marker PSD95 or the presynaptic protein synaptophysin, as controls. However, PSD95 immunolabeling intensities were substantially lower in cLH rats, as were numerical densities of synapse-sized clusters of the AMPA receptor subunit GluA1. Similar but less pronounced differences (comparable numerical densities but reduced immunolabeling intensity for PSD95) were found in the somatosensory cortex. In contrast, non-helpless rats had 25% more PSDs than either cLH or control rats without any increase in synaptophysin-labeled terminal frequency. Compared with controls, both cLH and cNLH rats had fewer GABAergic contacts. These results indicate that congenital tendencies that increase or decrease depression-like behavior differentially affect excitatory synapses.

Simultaneous assessment of rodent behavior and neurochemistry using a miniature positron emission tomograph.

Positron emission tomography (PET) neuroimaging and behavioral assays in rodents are widely used in neuroscience. PET gives insights into the molecular processes of neuronal communication, and behavioral methods analyze the actions that are associated with such processes. These methods have not been directly integrated, because PET studies in animals have until now required general anesthesia to immobilize the subject, which precludes behavioral studies. We present a method for imaging awake, behaving rats with PET that allows the simultaneous study of behavior. Key components include the 'rat conscious animal PET' or RatCAP, a miniature portable PET scanner that is mounted on the rat's head, a mobility system that allows considerable freedom of movement, radiotracer administration techniques and methods for quantifying behavior and correlating the two data sets. The simultaneity of the PET and behavioral data provides a multidimensional tool for studying the functions of different brain regions and their molecular constituents.

Selective breeding for helplessness in rats alters the metabolic profile of the hippocampus and frontal cortex: a 1H-MRS study at 9.4 T.

In humans metabolic changes, particularly in frontal areas of the brain, accompany depressive disorders, but few studies were conducted in animal models of depression. We used hydrogen-1 magnetic resonance spectroscopy at 9.4 T to measure the metabolic profiles of the hippocampus and frontal cortex in congenital learned helpless (cLH) and wild-type (WT) rats. The learned helplessness model of depression exposes animals to uncontrollable stress to induce changes in emotion, cognition and behaviour, but cLH rats were selectively bred to show changes in behaviour even without exposure to uncontrollable stress. Experimentally naive male 8- to 10-wk-old cLH (n = 10) and WT rats (n = 22) underwent spectroscopy and were exposed to uncontrollable stress 1 wk after the scan. We found that cLH compared to WT rats had lower levels of glutamate in the hippocampus and lower levels of choline-containing compounds in the hippocampus and frontal cortex, but higher levels of taurine and phosphocreatine in these regions, pointing to compensatory efforts of the brain to reduce excitotoxic potential and to increase neuroprotection and energy, possibly as a result of cellular stress and damage. The reduction in choline-containing phospholipids might represent a source or correlate of such stress. Overall, the results indicate that metabolic abnormalities are present in animals with a predisposition to helplessness even without exposure to explicit stress and may help identify non-invasive biomarkers in individuals who are prone to depression.

Changes in concentrations of NMDA receptor subunit GluN2B, Arc and syntaxin-1 in dorsal hippocampus Schaffer collateral synapses in a rat learned helplessness model of depression.

Major depressive disorder involves changes in synaptic structure and function, but the molecular underpinnings of these changes are still not established. In an initial pilot experiment, whole-brain synaptosome screening with quantitative western blotting was performed to identify synaptic proteins that may show concentration changes in a congenital rat learned helplessness model of depression. We found that the N-methyl-d-aspartate receptor (NMDAR) subunits GluN2A/GluN2B, activity-regulated cytoskeleton-associated protein (Arc) and syntaxin-1 showed significant concentration differences between congenitally learned helpless (LH) and nonlearned helpless (NLH) rats. Having identified these three proteins, we then performed more elaborate quantitative immunogold electron microscopic analyses of the proteins in a specific synapse type in the dorsal hippocampus: the Schaffer collateral synapse in the CA1 region. We expanded the setup to include also unstressed wild-type (WT) rats. The concentrations of the proteins in the LH and NLH groups were compared to WT animals. In this specific synapse, we found that the concentration of NMDARs was increased in postsynaptic spines in both LH and NLH rats. The concentration of Arc was significantly increased in postsynaptic densities in LH animals as well as in presynaptic cytoplasm of NLH rats. The concentration of syntaxin-1 was significantly increased in both presynaptic terminals and postsynaptic spines in LH animals, while pre- and postsynaptic syntaxin-1 concentrations were significantly decreased in NLH animals. These protein changes suggest pathways by which synaptic plasticity may be increased in dorsal hippocampal Schaffer collateral synapses during depression, corresponding to decreased synaptic stability.

Cognitive aspects of congenital learned helplessness and its reversal by the monoamine oxidase (MAO)-B inhibitor deprenyl.

Cognitive processes are assumed to change with learned helplessness, an animal model of depression, but little is known about such deficits. Here we investigated the role of cognitive and related functions in selectively bred helpless (cLH, n=10), non-helpless (cNLH, n=12) and wild type (WT, n=8) Sprague Dawley rats. The animals were exposed to an open field for 10min on each of two test days. On the third day, an object exploration paradigm was carried out. The animals were later tested for helplessness. Both cLH and cNLH rats were more active than WTs on the first day in the open field. Over trials, cNLH and WT rats lowered their activity less than cLH rats. This resistance-to-habituation co-varied with a resistance to develop helplessness. In cLH rats, higher 'anxiety' or less time spent in the center of the open field co-varied with severe helplessness. In WTs, a greater reactivity to novel objects and to a spatially relocated object predicted lower levels of helplessness. In cLH rats (n=4-5 per group), chronic treatment with a high dose of the monoamine oxidase (MAO)-B inhibitor deprenyl (10mg/kg; i.p.), an anti-Parkinson, nootropic and antidepressant drug, attenuated helplessness. Remarkably, helplessness reversal required the experience of repeated test trials, reminiscent of a learning process. Chronic deprenyl (10mg/kg; i.p.) did not alter locomotion/exploration or 'anxiety' in the open field. In conclusion, helplessness may be related to altered mechanisms of reinforcement learning and working memory, and to abnormalities in MAO-A and/or MAO-B functioning.

Aging and depression vulnerability interaction results in decreased serotonin innervation associated with reduced BDNF levels in hippocampus of rats bred for learned helplessness.

Epidemiological studies have revealed a strong genetic contribution to the risk for depression. Both reduced hippocampal serotonin neurotransmission and brain-derived neurotrophic factor (BDNF) levels have been associated with increased depression vulnerability and are also regulated during aging. Brains from young (5 months old) and old (13 months old) congenital Learned Helplessness rats (cLH), and congenital Non Learned Helplessness rats (cNLH) were immunohistochemically stained for the serotonin transporter and subsequently stereologically quantified for estimating hippocampal serotonin fiber density. Hippocampal BDNF protein levels were measured by ELISA. An exacerbated age-related loss of serotonin fiber density specific for the CA1 area was observed in the cLH animals, whereas reduced hippocampal BDNF levels were seen in young and old cLH when compared with age-matched cNLH controls. These observations indicate that aging should be taken into account when studying the neurobiological factors behind the vulnerability for depression and that understanding the effect of aging on genetically predisposed individuals may contribute to a better understanding of the pathophysiology behind depression, particularly in the elderly.

Gene expression of NMDA receptor subunits in the cerebellum of elderly patients with schizophrenia.

To determine if NMDA receptor alterations are present in the cerebellum in schizophrenia, we measured NMDA receptor binding and gene expression of the NMDA receptor subunits in a post-mortem study of elderly patients with schizophrenia and non-affected subjects. Furthermore, we assessed influence of genetic variation in the candidate gene neuregulin-1 (NRG1) on the expression of the NMDA receptor in an exploratory study. Post-mortem samples from the cerebellar cortex of ten schizophrenic patients were compared with nine normal subjects. We investigated NMDA receptor binding by receptor autoradiography and gene expression of the NMDA receptor subunits NR1, NR2A, NR2B, NR2C and NR2D by in situ hybridization. For the genetic study, we genotyped the NRG1 polymorphism rs35753505 (SNP8NRG221533). Additionally, we treated rats with the antipsychotics haloperidol or clozapine and assessed cerebellar NMDA receptor binding and gene expression of subunits to examine the effects of antipsychotic treatment. Gene expression of the NR2D subunit was increased in the right cerebellum of schizophrenic patients compared to controls. Individuals carrying at least one C allele of rs35753505 (SNP8NRG221533) showed decreased expression of the NR2C subunit in the right cerebellum, compared to individuals homozygous for the T allele. Correlation with medication parameters and the animal model revealed no treatment effects. In conclusion, increased NR2D expression results in a hyperexcitable NMDA receptor suggesting an adaptive effect due to receptor hypofunction. The decreased NR2C expression in NRG1 risk variant may cause a deficit in NMDA receptor function. This supports the hypothesis of an abnormal glutamatergic neurotransmission in the right cerebellum in the pathophysiology of schizophrenia.

Brain monoamine oxidase A activity predicts trait aggression.

The genetic deletion of monoamine oxidase A (MAO A), an enzyme that breaks down the monoamine neurotransmitters norepinephrine, serotonin, and dopamine, produces aggressive phenotypes across species. Therefore, a common polymorphism in the MAO A gene (MAOA, Mendelian Inheritance in Men database number 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes. These studies provide evidence linking the low MAOA genotype and violent behavior but only through interaction with severe environmental stressors during childhood. Here, we hypothesized that in healthy adult males the gene product of MAO A in the brain, rather than the gene per se, would be associated with regulating the concentration of brain amines involved in trait aggression. Brain MAO A activity was measured in vivo in healthy nonsmoking men with positron emission tomography using a radioligand specific for MAO A (clorgyline labeled with carbon 11). Trait aggression was measured with the multidimensional personality questionnaire (MPQ). Here we report for the first time that brain MAO A correlates inversely with the MPQ trait measure of aggression (but not with other personality traits) such that the lower the MAO A activity in cortical and subcortical brain regions, the higher the self-reported aggression (in both MAOA genotype groups) contributing to more than one-third of the variability. Because trait aggression is a measure used to predict antisocial behavior, these results underscore the relevance of MAO A as a neurochemical substrate of aberrant aggression.

Increased D-amino acid oxidase expression in the bilateral hippocampal CA4 of schizophrenic patients: a post-mortem study.

An important risk gene in schizophrenia is D-: amino acid oxidase (DAAO). To establish if expression of DAAO is altered in cortical, hippocampal or thalamic regions of schizophrenia patients, we measured gene expression of DAAO in a post-mortem study of elderly patients with schizophrenia and non-affected controls in both hemispheres differentiating between gray and white matter. We compared cerebral post-mortem samples (granular frontal cortex BA9, middle frontal cortex BA46, superior temporal cortex BA22, entorhinal cortex BA28, sensoric cortex BA1-3, hippocampus (CA4), mediodorsal nucleus of the thalamus) from 10 schizophrenia patients to 13 normal subjects investigating gene expression of DAAO in the gray and white matter of both hemispheres of the above-mentioned brain regions by in situ-hybridization. We found increased expression of DAAO-mRNA in the hippocampal CA4 of schizophrenic patients. Compared to the control group, both hemispheres of the hippocampus of schizophrenic patients showed an increased expression of 46% (right, P = 0.013) and 54% (left, P = 0.019), respectively. None of the other regions examined showed statistically significant differences in DAAO expression. This post-mortem study demonstrated increased gene expression of DAAO in the left and right hippocampus of schizophrenia patients. This increased expression could be responsible for a decrease in local D-: serine levels leading to a NMDA-receptor hypofunction that is hypothesized to play a major role in the pathophysiology of schizophrenia. However, our study group was small and results should be verified using larger samples.

Early and differential diagnosis of dementia and mild cognitive impairment: design and cohort baseline characteristics of the German Dementia Competence Network.

BACKGROUND: The German Dementia Competence Network (DCN) has established procedures for standardized multicenter acquisition of clinical, biological and imaging data, for centralized data management, and for the evaluation of new treatments. METHODS: A longitudinal cohort study was set up for patients with mild cognitive impairment (MCI), patients with mild dementia and control subjects. The aims were to establish the diagnostic, differential diagnostic and prognostic power of a range of clinical, laboratory and imaging methods. Furthermore, 2 clinical trials were conducted with patients suffering from MCI and mild to moderate Alzheimer's Disease (AD). These trials aimed at evaluating the efficacy and safety of the combination of galantamine and memantine versus galantamine alone. RESULTS: Here, we report on the scope and projects of the DCN, the methods that were employed, the composition and flow within the diverse groups of patients and control persons and on the clinical and neuropsychological baseline characteristics of the group of 2,113 subjects who participated in the observational and clinical trials. CONCLUSION: These data have an impact on the procedures for the early and differential clinical diagnosis of dementias, the current standard treatment of AD as well as on future clinical trials in AD.

Neuregulin 1 ICE-single nucleotide polymorphism in first episode schizophrenia correlates with cerebral activation in fronto-temporal areas.

The Neuregulin (NRG1) gene has been associated with schizophrenia, but its functional implications are largely unknown. Our aim was to assess differential brain activation between patients carrying an at-risk allele on the Neuregulin 1 gene and patients without this genetic risk. Neural signal changes between 14 first episode schizophrenia patients with the at risk allele (SNP8NRG221533) from the Icelandic core haplotype and 14 without were measured with fMRI during a working memory task. Patients without the at risk allele showed greater activations (P < 0.05; corrected) in the left hippocampus, precuneus and cerebellum, as well as the right anterior cingulate. Brain regions previously associated with the pathology of Schizophrenia are differentially affected in those with a genetic at risk status in the NRG1 gene. Heterogeneity of structural and functional measures within patients characterized by clinical phenotypes may be in part due to this genetic variation.

Cognitive impairment in 873 patients with idiopathic Parkinson's disease. Results from the German Study on Epidemiology of Parkinson's Disease with Dementia (GEPAD).

BACKGROUND: Parkinson's disease (PD) is often accompanied by non-motor complications, such as dementia, depression, and psychotic symptoms, which worsen the prognosis and increase the personal and socioeconomic burden of disease. Prevalence estimates of these complications are quite variable and are lacking for the outpatient care sector. METHODS: As part of a larger, nationwide, cross-sectional epidemiological study in n = 315 neurological outpatient settings in Germany, this paper estimates the frequency of dementia and cognitive impairment in n = 873 outpatients meeting the UK Brain Bank criteria for idiopathic PD. Assessments were based on a clinical interview and neuropsychological assessments, including the Hoehn & Yahr rating and Unified Parkinson's Disease Rating Scale (UPDRS). Cognitive impairment was assessed by the Mini-Mental State Exam (MMSE), Clock Drawing Test (CDT) and the Parkinson Neuropsychometric Dementia Assessment (PANDA) and the clinician's diagnosis of dementia was based on the diagnostic criteria of DSMIV. RESULTS: Using standardized cutoff scores, the prevalence of cognitive impairment in the study sample as measured by various methods was 17.5% by MMSE (< or = 24), 41.8% by CDT (> or = 3), 43.6% by PANDA (< or = 14), and 28.6% met the DSM-IV criteria for dementia. All estimates increased with age and PD severity. Gender was an inconsistent contributor while illness duration had no significant impact on cognition. Multiple regression analyses revealed PD severity to be the strongest predictor of dementia risk (OR = 4.3; 95% CI: 2.1-9.1), while neuropsychiatric syndromes had independent, although modest additional contributions (OR = 2.5, 95% CI: 1.6-3.8). CONCLUSION: Estimates of cognitive impairment and dementia in PD patients are largely dependent on the diagnostic measure used. Using established clinical diagnostic standards for dementia the overall rate on routine outpatient neurological care is 28.6%, but using more sensitive neuropsychological measures, rates for cognitive impairment might be up to 2-fold higher. The MMSE revealed strikingly low sensitivity. Neuropsychiatric syndromes, in addition to PD severity and age, have an independent--although modest--additional contribution to patients' risk for cognitive impairment and dementia.

Tissue-sparing effect of x-ray microplanar beams particularly in the CNS: is a bystander effect involved?

OBJECTIVE: Normal tissues, including the central nervous system, tolerate single exposures to narrow planes of synchrotron-generated x-rays (microplanar beams; microbeams) up to several hundred Gy. The repairs apparently involve the microvasculature and the glial system. We evaluate a hypothesis on the involvement of bystander effects in these repairs. METHODS: Confluent cultures of bovine aortic endothelial cells were irradiated with three parallel 27-microm microbeams at 24 Gy. Rats' spinal cords were transaxially irradiated with a single microplanar beam, 270 microm thick, at 750 Gy; the dose distribution in tissue was calculated. RESULTS: Within 6 hours following irradiation of the cell culture the hit cells died, apparently by apoptosis, were lost, and the confluency was maintained. The spinal cord study revealed a loss of oligodendrocytes, astrocytes, and myelin in 2 weeks, but by 3 months repopulation and remyelination was nearly complete. Monte Carlo simulations showed that the microbeam dose fell from the peak's 80% to 20% in 9 microm. CONCLUSIONS: In both studies the repair processes could have involved "beneficial" bystander effects leading to tissue restoration, most likely through the release of growth factors, such as cytokines, and the initiation of cell-signaling cascades. In cell culture these events could have promoted fast disappearance of the hit cells and fast structural response of the surviving neighboring cells, while in the spinal cord study similar events could have been promoting angiogenesis to replace damaged capillary blood vessels, and proliferation, migration, and differentiation of the progenitor glial cells to produce new, mature, and functional glial cells.

Neural correlates of working memory dysfunction in first-episode schizophrenia patients: an fMRI multi-center study.

Working memory dysfunction is a prominent impairment in patients with schizophrenia. Our aim was to determine cerebral dysfunctions by means of functional magnetic resonance imaging (fMRI) in a large sample of first-episode schizophrenia patients during a working memory task. 75 first-episode schizophrenia patients and 81 control subjects, recruited within a multi-center study, performed 2- and 0-back tasks while brain activation was measured with fMRI. In order to guarantee comparability between data quality from different scanners, we developed and adopted a standardized, fully automated quality assurance of scanner hard- and software as well as a measure for in vivo data quality. After these quality-control measures had been implemented, 48 patients and 57 controls were included in the final analysis. During attention-related processes, even when the performance between patients and controls was comparable, there was a recognizable emergence of cerebral dysfunctions with hypoactivations in the ventrolateral prefrontal cortex (VLPFC), in the superior temporal cortex and in the thalamus. During working memory performance, parietal hypoactivations, especially in the precuneus, were prominent and were accompanied by poorer performance in patients. A hyperfrontality emerged in the ventrolateral prefrontal cortex. Hence, results point to a dysfunctional ventrolateral prefrontal-parietal network during working memory in patients, suggesting impairments in basic functions such as retrieval, storage and maintenance. The brain activation pattern of this large and significant sample of first-episode schizophrenia patients indicates an imbalanced system failing to adjust the amount of brain activity required in the cerebral network involved in attention and working memory.

Elevated spectroscopic glutamate/gamma-amino butyric acid in rats bred for learned helplessness.

The theory of depression is dominated by the monoamine hypothesis but there is increasing evidence that beyond monoamines, glutamate (Glu) and gamma-aminobutyric acid (GABA) play an essential role in the pathogenesis of depression. In this study, the effect of alterations of GABA and Glu were investigated in the congenital learned helplessness paradigm. Proton magnetic resonance spectroscopy is an important monitoring tool to bridge the findings in clinical and preclinical studies. We found increased Glu/GABA ratios in the hippocampus and prefrontal cortex of placebo-treated (saline intraperitoneally) congenital learned helplessness rats versus wild-type rats, and a treatment-induced (desipramine 10 mg/kg intraperitoneally or electroconvulsive shock) decrease of this monoamine ratio in both brain regions. Our results corroborate previous findings of an amino-acid influence on the pathomechanisms of mood disorders.

Reduced expression of complexins I and II in rats bred for learned helplessness.

Disturbed synaptic transmission contributes to the pathophysiology of mood disorders. Post mortem studies reported reduced expression of the synaptic vesicle protein (SVP) complexins I and II in depression. Antidepressants were found to induce the expression of these genes. Since animals with congenital susceptibility to learned helplessness provide a valid animal model of depression, we investigated the expression of different SVPs in this system by semiquantitative in situ hybridization. Rats bred for congenital learned helpless behavior (cLH, N=6) failed to interrupt foot shock currents by lever pressing (mean 12.3 failures out of 15 trials). These animals showed significantly lower expression of complexins I and II mRNA in hippocampal, limbic and cortical brain areas compared to not helpless animals (cNLH, N=6) with a mean failure rate of 0.83 out of 15 trials. Expression levels of complexins I and II significantly correlated with the failure rate in the test paradigm. In contrast, the expressions of synaptotagmin I and synaptophysin were found unchanged. This investigation provides a further validation of the LH model of depression. The experimental data fit well into current pathogenetic concepts of mood disorders and support the hypothesis, that complexins are pivotal players in the pathophysiology of depression and tentative targets of antidepressants.

Diffusion weighted MRI in the early phase after electroconvulsive therapy.

Although cognitive side effects may occur after electroconvulsive therapy (ECT), no structural brain abnormalities have been detected after ECT with conventional magnetic resonance imaging (MRI). Transient disturbances of memory function are common findings after ECT indicating functional compromise. Diffusion weighted imaging (DWI) has been shown to be sensitive to focal tissue changes associated with compromise of energy metabolism in cerebral ischemia and after prolonged ictal activity. We used conventional MRI and DWI in an exploratory study examining ten patients after treatment with ECT, eight of whom experienced short-lasting memory disturbances. MRI and DWI showed no definite signal abnormalities on qualitative and quantitative analysis. In three patients, equivocal marginal DWI hyperintensity was noted in the hippocampal formation. These findings are in line with previous negative studies using conventional MRI. Higher resolution DWI and serial imaging may be necessary to visualize possible minimal signal changes after ECT.