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BACKGROUND: Electroconvulsive therapy (ECT) is the most effective treatment option for major depressive disorder, so understanding whether its clinical effect relates to structural brain changes is vital for current and future antidepressant research. OBJECTIVE: To determine whether clinical response to ECT is related to structural volumetric changes in the brain as measured by structural magnetic resonance imaging (MRI) and, if so, which regions are related to this clinical effect. We also determine whether a similar model can be used to identify regions associated with electrode placement (unilateral versus bilateral ECT). METHODS: Longitudinal MRI and clinical data (Hamilton Depression Rating Scale) was collected from 10 sites as part of the Global ECT-MRI research collaboration (GEMRIC). From 192 subjects, relative changes in 80 (sub)cortical areas were used as potential features for classifying treatment response. We used recursive feature elimination to extract relevant features, which were subsequently used to train a linear classifier. As a validation, the same was done for electrode placement. We report accuracy as well as the structural coefficients of regions included in the discriminative spatial patterns obtained. RESULTS: A pattern of structural changes in cortical midline, striatal and lateral prefrontal areas discriminates responders from non-responders (75% accuracy, p

Objective To investigate the role of hippocampal plasticity in the antidepressant effect of electroconvulsive therapy (ECT). Method We used magnetic resonance (MR) imaging including diffusion tensor imaging (DTI) and proton MR spectroscopy (1H-MRS) to investigate hippocampal volume, diffusivity, and metabolite changes in 19 patients receiving ECT for severe depression. Other regions of interest included the amygdala, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex, and hypothalamus. Patients received a 3T MR scan before ECT (TP1), 1 week (TP2), and 4 weeks (TP3) after ECT. Results Hippocampal and amygdala volume increased significantly at TP2 and continued to be increased at TP3. DLPFC exhibited a transient volume reduction at TP2. DTI revealed a reduced anisotropy and diffusivity of the hippocampus at TP2. We found no significant post-ECT changes in brain metabolite concentrations, and we were unable to identify a spectral signature at ≈1.30 ppm previously suggested to reflect neurogenesis induced by ECT. None of the brain imaging measures correlated to the clinical response. Conclusion Our findings show that ECT causes a remodeling of brain structures involved in affective regulation, but due to their lack of correlation with the antidepressant effect, this remodeling does not appear to be directly underlying the antidepressant action of ECT.

Background: Depression has been associated with increased oxidative stress and hypothesized to accelerate aging. Nucleic acid damage from oxidation is a critical part of the aging process, and a suggested early event in age-related somatic morbidities that are also prevalent in depression, such as dementia and type 2 diabetes. We hypothesized that increased severity of depression is associated with increased systemic oxidatively generated DNA and RNA damage, and that this increase is attenuated by an effective antidepressant treatment. Methods: The urinary excretion of markers of systemic oxidatively generated DNA and RNA damage, 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), respectively, were determined in healthy controls (N ¼ 28), moderately depressed, non-medicated patients (N ¼ 26) and severely depressed patients eligible for electroconvulsive therapy (ECT) (N¼ 29). In the severely depressed patient group, samples were also obtained 1 week after the completion of ECT. Results: Systemic RNA damage from oxidation, as measured by 8-oxoGuo excretion, was higher with increasing severity of depression (controlsomoderately depressedo severely depressed) (P for trend ¼ 0.004). The 8-oxoGuo excretion was further increased after clinically effective ECT compared with pre-ECT values (P¼0.006). There were no differences in 8-oxodG excretion between the groups or pre- vs. post-ECT. Limitations: Small sample size and the inclusion of both unipolar and bipolar patients in the severely depressed group. Conclusions: Severe depression is associated with increased systemic oxidatively generated RNA damage, which may be an additional factor underlying the somatic morbidity and neurodegenerative features associated with depression. Due to the lack of normalization by clinically effective ECT, the phenomenon does not appear to be causally linked to the depressive state per se.

Objective To investigate the role of hippocampal plasticity in the antidepressant effect of electroconvulsive therapy (ECT). Method We used magnetic resonance (MR) imaging including diffusion tensor imaging (DTI) and proton MR spectroscopy (1H-MRS) to investigate hippocampal volume, diffusivity, and metabolite changes in 19 patients receiving ECT for severe depression. Other regions of interest included the amygdala, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex, and hypothalamus. Patients received a 3T MR scan before ECT (TP1), 1 week (TP2), and 4 weeks (TP3) after ECT. Results Hippocampal and amygdala volume increased significantly at TP2 and continued to be increased at TP3. DLPFC exhibited a transient volume reduction at TP2. DTI revealed a reduced anisotropy and diffusivity of the hippocampus at TP2. We found no significant post-ECT changes in brain metabolite concentrations, and we were unable to identify a spectral signature at ≈1.30 ppm previously suggested to reflect neurogenesis induced by ECT. None of the brain imaging measures correlated to the clinical response. Conclusion Our findings show that ECT causes a remodeling of brain structures involved in affective regulation, but due to their lack of correlation with the antidepressant effect, this remodeling does not appear to be directly underlying the antidepressant action of ECT.

Objective: This research sought neurobiological features common to psychotic states displayed by patients with different clinical diagnoses. Method: Cluster analysis with quantitative electroencephalographic (QEEG) variables was used to subtype drug-naive, non-medicated, and medicated schizophrenic, depressed and alcoholic patients with psychotic symptoms, from the USA and Germany. QEEG source localization brain images were computed for each cluster. Results: Psychotic patients with schizophrenia, depression and alcoholism, and drug- naive schizophrenic patients, were distributed among six clusters. QEEG images revealed one set of brain regions differentially upregulated in each cluster and another group of structures downregulated in the same way in every cluster. Conclusion: Subtypes previously found among 94 schizophrenic patients were replicated in a sample of 390 non-schizophrenic as well as schizophrenic psychotics, and displayed common neurobiological abnormalities. Collaborative longitudinal studies using these economical methods might improve differential understanding and treatment of patients based upon these features rather than clinical symptoms.

Objective: To evaluate current hypothesis regarding the pathophysiology of obsessive–compulsive disorder (OCD) by studying the serotonin receptor binding in patients with OCD using single photon emission computerized tomography (SPECT). Method: We studied nine patients (four men and five women, age range 21–56 years) fulfilling the DMS-III-R criteria for OCD using SPECT and the serotonin transporter (SERT) tracer 123I-β-CIT. SERT binding potential (BP2) was determined by Logan plot derived from seven scans obtained during 10–400 min. Results: The binding of 123I-β-CIT in midbrain-pons was reduced in OCD patients when compared with controls (BP2 0.97 ± 0.07 vs. 0.84 ± 0.12, P = 0.011). There was no correlation between BP2 and any of the clinical variables (age at onset, disease duration, and Yale-Brown Obsessive–Compulsive Scale score). Conclusion: This study suggests a reduced serotonergic input into the fronto-subcortical circuits in OCD, thereby diminishing the inhibitory regulation of serotonin on these circuits.

BACKGROUND: Recent studies have indicated that the 11-item Psychotic Depression Assessment Scale (PDAS), consisting of the 6-item melancholia subscale (HAM-D6) of the Hamilton Depression Rating Scale and 5 psychosis items from the Brief Psychiatric Rating Scale (BPRS), is a valid measure for the severity of psychotic depression. The aim of this study was to subject the PDAS, and its depression (HAM-D6) and psychosis (BPRS5) subscales to further validation.METHODS: Patients diagnosed with psychotic depression at Danish psychiatric hospitals participated in semi-structured interviews. Video recordings of these interviews were assessed by two experienced psychiatrists (global severity rating of psychotic depression, depressive symptoms and psychotic symptoms) and by two young physicians (rating on 27 symptom items, including the 11 PDAS items). The clinical validity and responsiveness of the PDAS and its subscales was investigated by Spearman correlation analysis of the global severity ratings and the PDAS, HAM-D6, and BPRS5 total scores. The unidimensionality of the scales was tested by item response theory analysis (Mokken).RESULTS: Ratings from 39 participants with unipolar psychotic depression and nine participants with bipolar psychotic depression were included in the analysis. The Spearman correlation analysis indicated that the PDAS, HAM-D6 and BPRS5 were clinically valid (correlation coefficients from 0.78 to 0.85, pCONCLUSIONS: The clinical validity, responsiveness and unidimensionality of the PDAS and its subscales were confirmed in an independent sample of patients with psychotic depression.

Objective: We describe a case of deep venous thrombosis (DVT) and pulmonary embolism (PE) following the use of physical restraint in a patient with a diagnosis of acute delusional psychotic disorder. Method: A new case report of DVT and PE associated with prolonged physical restraint is presented. The literature on physical restraint, DVT, and PE was reviewed using a search of Medline and Psychinfo from 1966 to the present. Results: Four other reported cases of DVT and PE were found in association with physically restrained patients. Conclusion: Risk of DVT and PE in association with immobilization during physical restraint may occur in spite of no pre-existing risk factors. Medical guidelines for the prevention of thrombosis following physical restraint are presented. Despite the absence of controlled trials of treatment effectiveness, the catastrophic outcome of DVT and PE warrants early and vigorous intervention in patients undergoing physical restraint.

Individuals with obsessive-compulsive disorder (OCD) display frontal lobe deficits, but there are inconsistencies between various tests of frontal lobe functions and between the results from different studies. The objective of this work was to characterize frontal lobe dysfunctions in OCD patients. Fifteen patients and 17 control subjects matched for age, sex and intelligence were tested on classic tests of frontal lobe functions [Wisconsin Card Sorting Test (WCST) and tests of fluency], a smell identification test and one computerized test: the Intra/Extra Dimension test. The Intra/Extra Dimension test showed a significant difference between the two groups in reversal of response. The test of Figural fluency showed a significant difference between the two groups in numbers of produced figures. There were no differences on the WCST, verbal fluency and the smell identification test.

Repeated maternal separation of rat pups during the early postnatal period may affect brain-derived neurotrophic factor (BDNF) or neurons in brain areas that are compromised by chronic stress. In the present study, a highly significant increase in hippocampal BDNF protein concentration was found in adult rats that as neonates had been subjected to 180 min of daily separation compared with handled rats separated for 15 min daily. BDNF protein was unchanged in the frontal cortex and hypothalamus/paraventricular nucleus. Expression of BDNF mRNA in the CA1, CA3, or dentate gyrus of the hippocampus or in the paraventricular hypothalamic nucleus was not affected by maternal separation. All animals displayed similar behavioral patterns in a forced-swim paradigm, which did not affect BDNF protein concentration in the hippocampus or hypothalamus. Repeated administration of bromodeoxyuridine revealed equal numbers of surviving, newly generated granule cells in the dentate gyrus of adult rats from the 15 min or 180 min groups. The age-dependent decline in neurogenesis from 3 months to 7 months of age did not differ between the groups. Insofar as BDNF can stimulate neurogenesis and repair, we propose that the elevated hippocampal protein concentration found in maternally deprived rats might be a compensatory reaction to separation during the neonatal period, maintaining adult neurogenesis at levels equal to those of the handled rats.

Tardive dyskinesia (TD) from long-term neuroleptic treatment may be irreversible; therefore prevention has become a major concern. A controversial issue with regard to the clinical use of neuroleptic drugs is the possible influence on the development of TD of drug holidays. The major characteristics of kindling, theories of TD and the role of multiplicity in the development of TD are described. Some clinical studies point to interruption of neuroleptic therapy being a risk factor for development of irreversible TD. Induction of dyskinesia in non-human primates has been demonstrated after repeated administration of haloperidol. Rodent studies have not been conclusive. Several experimental results link TD with kindling: both conditions involve repeated stimulations, both seem to involve increased receptor responsiveness and in both conditions does depression in GABA transmission in SNR (substantia nigra; pars reticulata) play an important role. It is concluded that the kindling hypothesis is relevant to the investigation of TD.

Repeated electroconvulsive stimulations and other seizure modalities produce an increase in neuropeptide Y synthesis and local release in the rat hippocampus, and perhaps as a consequence, a change in the concentration of neuropeptide Y binding sites in the same region. The aim of the present study was to determine possible changes in the expression of neuropeptide Y receptor subtypes affected by repeated stimulations in the hippocampus. Rats were exposed to 14 daily stimulations, and the brains were removed 24h after the last stimulation. For in vitro receptor autoradiography and in situ hybridisation histochemistry, the brains were frozen, sectioned, and levels of neuropeptide Y binding sites and messenger RNA expressions were determined quantitatively on sections from the same animals. In order to determine the contribution of different neuropeptide Y receptor subtypes, serial sections were incubated with either 125I-labelled peptide YY alone or the same radio-labelled peptide mixed with an excess of a number of displacing compounds with affinity for either neuropeptide Y receptor subtype Y1, Y2, or both. Binding studies revealed that the majority of peptide YY binding sites was represented by Y2, and that electroconvulsive stimulations reduced the binding capacity or the concentration of this receptor. A prominent reduction of Y1-preferring binding sites was determined in the dentate gyrus, and to a lesser extent in the CA1 and CA3 regions. Similarly, the treatment produced a significant reduction of Y2-preferring binding sites in the CA1 and CA3 region, but not in the granular cell layer of the dentate gyrus. Using semi-quantitative in situ hybridization, Y1 receptor messenger RNA level in the granular cell layer of the dentate increased by the stimulations. In the same region, Y2 receptor messenger RNA was expressed in low to undetectable amounts, but after the repeated stimulations, this transcript was found in moderate to high levels. These data suggest that the neuropeptide Yergic system in the dentate gyrus and the pyramidal cell layer are affected by the treatment, and that this includes both Y1 and Y2 receptor subtypes. Because levels of messenger RNA and binding are distinctly regulated, the turnover of both Y1 and Y2 molecules is strongly increased under electroconvulsive stimulations, suggesting that the intrahippocampal neuropeptide Yergic neurotransmission is also increased under the stimulations.

A review of efficacy studies on psychotherapy of depression is made. Based on the available literature, there is evidence of effectiveness of cognitive and interpersonal therapy in the treatment of mild to moderate depression. To a lesser degree, the effect of psychoanalytically oriented and behavioural therapy has been documented. The effectiveness of psychotherapy among in-patients and patients with severe depression has not been documented. No studies have documented a preventive effect of psychotherapy on future recurrent depressive episodes. In recurrently depressive patients who respond to a combination of imipramine and interpersonal psychotherapy, maintenance treatment with interpersonal psychotherapy may prevent new episodes, but not as effectively as maintenance therapy with imipramine.

This article reviews 3 current theories of electroconvulsive therapy (ECT). One theory points to generalized seizures as essential for the therapeutic efficacy of ECT. Another theory highlights the normalization of neuroendocrine dysfunction in melancholic depression as a result of ECT. A third theory is based on recent findings of increased hippocampal neurogenesis and synaptogenesis in experimental animals given electroconvulsive seizures. Presently, the endocrine theory has the strongest foundation to explain the working mechanism of ECT.

The results of two-dimensional cerebral blood flow (CBF) studies in depression and the results of measurements of regional CBF (rCBF) using single photon emission computerized tomography (SPECT) are briefly reviewed. A technical outline of both types of method is described. The majority of SPECT studies point to a decreased CBF in untreated patients with a tendency towards normalization, but other studies suggest that, following treatment, there is an increase above normal either from a decreased or an abnormally high initial level. One study has pointed to unipolar patients having lower flow in the right temporal and parietal lobes relative to normals, whereas non-endogenous patients did not differ significantly from normal controls. Bipolar depressives have been found to have higher flow values than normals in the parietal and temporal lobes in the left hemispheres. This relevant aspect or a possible relationship between type of depression and hemispheric asymmetry needs further study for full classification. Thus, most investigations designed to determine which brain structures might be involved in regulating affect have not been very successful, which may be a consequence of the biological heterogeneity of these disorders or of the limited spatial resolution of the techniques used for investigation. Even if some of these technical difficulties can be overcome with measurements of receptor kinetics supplemented, other biological variables that have proved valuable in psychiatry (such as rapid eye movement latency and biogenic amines) should be studied to find more precise biological markers for depressive illness.

To identify whether a genetic variation (rs1800857; IVS1-5TC) in the neuropeptide cholecystokinin-A receptor (CCKAR) gene is a risk factor in the pathogenesis of schizophrenia.The variation was analysed in a case-control design comprising 508 patients with schizophrenia and 1619 control subjects. A possible functional impact of this variant on CCKAR protein synthesis through alterations in splicing was analysed in an exon-trapping assay.In males only, the risk variant, IVS1-5C, was associated with a significantly increased risk of schizophrenia. Carrying one risk allele was associated with an increased risk of 1.74 (Odds Ratio, OR) and homozygosity (CC) was associated with an OR of 3.19. The variation had no impact on protein synthesis of CCKAR.This is the first report associating the CCKAR gene variant with schizophrenia specifically in men. Our study strengthens the conclusion that a CCKAR dysfunction could be involved in the aetiology of schizophrenia.

Objective: To demonstrate the utility of three-dimensional source localization of the scalp-recorded electroencephalogram (EEG) for the identification of the most probable underlying brain dysfunction in patients with obsessive–compulsive disorder (OCD). Method: Eyes-closed resting EEG data was recorded from the scalp locations of the International 10/20 System. Variable resolution electromagnetic tomography (VARETA) was applied to artifact-free EEG data. This mathematical algorithm estimates the source generators of EEG recorded from the scalp. Results: An excess in the alpha range was found with sources in the corpus striatum, in the orbito-frontal and temporo-frontal regions in untreated OCD patients. This abnormality was seen to decrease following successful treatment with paroxetine. Conclusion: The VARETA findings of an activation/deactivation pattern in cortical and subcortical structures in paroxetine-responsive patients are in good accordance with data obtained in previously published positron emission tomography studies related to current hypotheses of a thalamo-striatal-frontal feedback loop being relevant for understanding the pathophysiology of OCD.

Objective: To elucidate the relationship between the effects of electroconvulsive therapy (ECT) on hippocampal anatomy and function in the therapy of melancholic depression and preclinical observations of increased neurogenesis in the hippocampus of experimental animals receiving electroconvulsive seizures (ECS). We emphasize the role of hypercortisolaemia in melancholic depression and in experimental hippocampal neurogenesis. Method: Our statements are based on a variety of studies pointing to i) ECT being superior to all other treatment modalities in the therapy of melancholia, ii) melancholia being associated with hypercortisolaemia and iii) evidence of hippocampal neurogenesis being relevant for understanding both melancholia and ECT. Results: The increased neurogenesis found in animal studies shows stronger effect of seizures than of antidepressant drugs. The onset of effect is not only faster but is also sustained. Newborn cells are found to be functional. Suppression of neurogenesis by chronic treatment with corticosterone is associated with depression-like biology and behaviour making comparison with human depression and its response to ECT relevant. Conclusion: We hypothesize that the superior antimelancholic effect of induced seizures may be understood in the light of the powerful control of neural plasticity exerted by the regulation of the hypothalamic-pituitary-adrenal axis and, perhaps, other regulatory factors.

Objective: A polymorphism in the promoter region of the NPY gene at position −399 C>T was recently reported to be associated with schizophrenia in a Japanese population and with treatment refractory unipolar depression in a Swedish population. The objective of this study was to investigate potential associations between the polymorphism and three psychiatric disorders in a Danish population. Method: We investigated the occurrence of the polymorphism in patients with schizophrenia (n = 291), unipolar depression (n = 256) and panic disorder (n = 142) compared with controls (n = 716). Results: We detected the polymorphism −399 C>T at a frequency of 48% in controls. No significant differences were found between genotype or allele frequencies in controls vs. the patient groups. Conclusion: The lack of association between the −399 C>T polymorphism and schizophrenia, unipolar depression or panic disorder, respectively, suggests that the polymorphism is not involved in the etiology of these disorders in the Danish population.

Maternal separation (MS) is an animal model of early adverse experience, which is known to affect hypothalamic-pituitary-adrenal (HPA) axis function and various aspects of emotional behaviour. Sexual dysfunction is a prominent symptom in depression and in the present study we investigated the effects of maternal separation on copulatory behaviour and partner preference in adult male rats and paced mating in adult female rats. It has been suggested that corticotropin releasing factor (CRF) inhibits copulatory behaviour in male rats and we therefore examined if changes in male sexual behaviour were accompanied by changes in hypothalamic corticotropin releasing factor protein content. We found changed copulatory behaviour reflected in decreased mount latency, intromission latency, and post-ejaculatory interval in rats subjected to 180 min daily separation compared to handled rats, separated for 15 min daily on postnatal days (PNDs) 2-14. Ejaculation latency was not affected and there were no changes in partner preference in male rats. Paced mating behaviour of adult maternally separated female rats was unaffected. The concentration of corticotropin releasing factor-like immunoreactivity was lower in the hypothalamus of male rats separated for 180 min compared to male handled rats. We therefore suggest that 180 min of maternal separation generates a male phenotype with increased sexual motivation possibly due to inadequate levels of corticotropin releasing factor in the hypothalamus.

The generation of new neurons in the adult mammalian brain has been documented in numerous recent reports. Studies undertaken so far indicate that adult hippocampal neurogenesis is related in a number of ways to hippocampal function. Here, we report that subjecting adult rats to fractionated brain irradiation blocked the formation of new neurons in the dentate gyrus of the hippocampus. At different time points after the termination of the irradiation procedure, the animals were tested in two tests of short-term memory that differ with respect to their dependence on hippocampal function. Eight and 21 days after irradiation, the animals with blocked neurogenesis performed poorer than controls in a hippocampus-dependent place-recognition task, indicating that the presence of newly generated neurons may be necessary for the normal function of this brain area. The animals were never impaired in a hippocampus-independent object-recognition task. These results are in line with other reports documenting the functional significance of newly generated neurons in this region. As our irradiation procedure models prophylactic cranial irradiation used in the treatment of different cancers, we suggest that blocked neurogenesis contributes to the reported deleterious side effects of this treatment, consisting of memory impairment, dysphoria and lethargy.

To investigate the temporal relationships between a range of neurological diseases and affective disorders.Data derived from linkage of the Danish Psychiatric Central Register and the Danish National Hospital Register. Seven cohorts with neurological index diagnoses and two control group diagnoses were followed for up to 21 years. The incidences of affective disorders in the different groups were compared with the control groups, using competing risks to consider the risk of affective disorder and the risk of death in the same analysis.We found an increased incidence of affective disorders in dementia, Parkinson's disease, epilepsy, stroke and intracerebral haemorrhage compared with control groups. The association was found to be the strongest for dementia and Parkinson's disease. In hospitalized patients, with incident multiple sclerosis, the incidence of affective disorder was lower than the incidence in the control groups.In neurological diseases there seems to be an increased incidence of affective disorders. The elevated incidence was found to be particularly high for dementia and Parkinson's disease (neurodegenerative diseases).

Several neuroimaging studies of patients with OCD have pointed to basal ganglia and the frontal cortical regions being relevant for an understanding of the pathophysiology and therapy of OCD. In a search for the neural substrate underlying the therapeutic action of paroxetine in the therapy of OCD we measured regional glucose metabolism in a PET study of 20 OCD patients before and after at least 3 months of treatment. We used 18-fluoro-deoxyglucose PET-scanning to measure regional cerebral glucose metabolic rate (rCMRglc) in 20 non-depressed patients fulfilling DSM-IV criteria for OCD. Patients were studied before and after 12-20 wk of treatment with the serotonin re-uptake inhibitor paroxetine. Clinical assessment rating with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) was performed before the first and after the second study. The PET data was analysed regionally using statistical parametric mapping (SPM-96). A clinical improvement was indicated by a mean decrease of 55% in the Y-BOCS score. There was no difference in global cerebral metabolism before and after treatment whereas a post-treatment reduction in normalized rCMRglc was found in the right caudate nucleus. This finding also showed a significant positive correlation with symptom severity. Our results support hypotheses regarding a malfunction of the cortico-striato-thalamic system in the pathophysiology of OCD and particularly point to the caudate nucleus playing an important role for the therapeutic action of paroxetine in the treatment of OCD.

Rationale: Dividing cells can be detected in the live brain by positron emission tomography or optical imaging. Here we apply proton magnetic resonance spectroscopy ((HMRS)-H-1) and a widely used spectral fitting algorithm to characterize the effect of increased neurogenesis after electroconvulsive shock in the live rodent brain via spectral signatures representing mobile lipids resonating at similar to 1.30 ppm. In addition, we also apply the same (HMRS)-H-1 methodology to metabolically profile glioblastomas with actively dividing cells growing in RCAS-PDGF mice. Methods: (HMRS)-H-1 metabolic profiles were acquired on a 9.4T MRI instrument in combination with LCModel spectral analysis of: 1) rat brains before and after ECS or sham treatments and 2) RCAS-PDGF mice with glioblastomas and wild-type controls. Quantified (HMRS)-H-1 data were compared to post-mortem histology. Results: Dividing cells in the rat hippocampus increased similar to 3-fold after ECS compared to sham treatment. Quantification of hippocampal metabolites revealed significant decreases in N-acetyl-aspartate but no evidence of an elevated signal at similar to 1.3 ppm (Lip13a+Lip13b) in the ECS compared to the sham group. In RCAS-PDGF mice a high density (22%) of dividing cells characterized glioblastomas. Nile Red staining revealed a small fraction (3%) of dying cells with intracellular lipid droplets in the tumors of RCAS-PDGF mice. Concentrations of NAA were lower, whereas lactate and Lip13a+Lip13b were found to be significantly higher in glioblastomas of RCAS-PDGF mice, when compared to normal brain tissue in the control mice. Conclusions: Metabolic profiling using (HMRS)-H-1 in combination with LCModel analysis did not reveal correlation between Lip13a+Lip13b spectral signatures and an increase in neurogenesis in adult rat hippocampus after ECS. However, increases in Lip13a+Lip13b were evident in glioblastomas suggesting that a higher density of actively dividing cells and/or the presence of lipid droplets is necessary for LCModel to reveal mobile lipids.

To investigate whether patients with a diagnosis of affective disorder are at an increased risk of developing Parkinson's disease compared with medically ill control groups.By linkage of public hospital registers from 1977 to 1993, three study cohorts were identified: patients with affective disorder episodes (mania or depression) and patients with osteoarthritis or diabetes. Time to the first diagnosis of Parkinson's disease was estimated with the use of survival analysis.A total of 164 385 patients entered the study base. The risk of being given a diagnosis of Parkinson's disease was significantly increased for patients with affective disorder, odds ratio 2.2 (CI 95% 1.7-2.8) compared with osteoarthritis, and depressive disorders, odds ratio 2.2 (CI 95% 1.7-2.9) compared with osteoarthritis.This study supports the hypothesis of a common aetiology for major affective disorder and Parkinson's disease.

In recent years, studies of the risk of recurrence in affective disorder in relation to the number of prior episodes have given contradictory results. Survival analysis was used to calculate the rate of recurrence after successive episodes in a case register study including all hospital admissions with primary affective disorder in Denmark during 1971-1993. Totally, 20,350 first-admission patients were discharged with a diagnosis of affective disorder, depressive or manic/circular type. The rate of recurrence increased with the number of previous episodes in both unipolar and bipolar disorder. Initially, the two types of disorders followed markedly different courses, but later in the course of the illness the rate of recurrence was the same for the two disorders. The course of severe unipolar and bipolar disorder seems to be progressive in nature despite the effect of treatment.

Gamma-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain. A deficiency of GABAergic inhibition mediated via the GABAA receptor complex has for a long time been suspected to be a central factor in epileptogenesis. Status epilepticus is a condition of sustained and prolonged excitation of neuronal circuits, as detected by epileptiform discharges in the electroencephalogram (EEG). Reduction of GABAA receptor-mediated hippocampal inhibition has been implicated in the development of status epilepticus. The present study provides direct evidence of a link between the GABAA receptor and epilepsy. We show that selective inhibition of the expression of the GABAA receptor gamma2 subunit in the rat hippocampus by means of antisense oligonucleotides leads to spontaneous electrographic seizures that evolve into profound limbic status epilepticus, ultimately resulting in severe neurodegenerative changes. Concurrent treatment with diazepam prevents the development of status epilepticus and markedly reduces neuronal cell loss. These findings strongly support the hypothesis that the GABAA receptor is critically involved in the pathogenesis of seizures and status epilepticus.

BackgroundIn recent years, studies of the risk of recurrence in affective disorder in relation to the number of prior episodes have given contradictory results.MethodSurvival analysis was used to calculate the rate of recurrence after successive episodes in a case register study including all hospital admissions with primary affective disorder in Denmark during 1971–1993. A total of 20 350 first-admission patients were discharged with a diagnosis of affective disorder, depressive or manic/cyclic type.ResultsThe rate of recurrence increased with the number of previous episodes in both unipolar and bipolar disorder. Initially, the two types of disorders followed markedly different courses, but later in the course of the illness the rate of recurrence was the same for the two disorders.ConclusionsThe course of severe unipolar and bipolar disorder seems to be progressive in nature despite the effect of treatment.

The observation of a progressive recurrence in affective disorder has been interpreted as a process of sensitisation. The clinical applicability of such a theoretical model was investigated using the Danish case register, which includes all hospital admissions with primary affective disorder in Denmark from 1971 to 1993. A total of 8,737 patients admitted to a psychiatric hospital at least twice constituted the study sample. Information on treatment intervention was not available. Measures describing the initial course of admission episodes were defined in three different ways: 1) a short period between initial episodes 2) decreasing intervals between initial episodes or 3) a combination of 1) and 2). Socio-demographic variables such as gender, age at onset and marital status differentiated between the three types of measures and the measures also demonstrated different effects in predicting the risk of further recurrence. In unipolar disorder, patients with a decreasing interval between episodes had the greatest risk of further recurrence, whereas for bipolar patients, a short period between episodes played a more important role than the sequence of episodes in itself.

Clinically derived measures of the initial course of episodes might reflect a process of sensitisation in affective disorder. However, the clinical consequences of such measures have not been investigated. The predictive effect of measures of the initial course of episodes was investigated in relation to the subsequent risk of alcoholism, dementia, death and suicidal attempts/suicide in a case register study including all hospital admissions with primary affective disorder in Denmark from 1971 to 1993. A total of 8737 patients with more than one episode were included in the analyses. A short period between initial episodes of the illness, reflecting a great intensity of illness, predicted increased risk of subsequent development of dementia, and for unipolar patients, decreased risk of subsequent alcoholism. Surprisingly, a progressive course, with decreasing intervals between initial episodes of the illness, had no predictive effect. Similarly, no predictive effects on the risk of death or suicidal acts could be demonstrated with any measure of the initial course of episodes.

Forty-five patients with schizophrenia or schizophreniform disorder admitted to hospital for the first time had a neurological examination, including integrative sensory and complex motor acts, by a trained neurologist. The patients were studied by CT and regional cerebral blood flow as well. A control group of 24 healthy volunteers was included. The patients had significantly more neurological abnormalities (NA) than the healthy volunteers. Medication did not explain the discrepancy. The NA were associated with sulcal enlargement and smaller brains as visualized by CT but not with ventricular enlargement. There was no association between the regional flow values and NA.

The aim of the study was to examine the occurrence of psychiatric disorders in epilepsy patients who had received surgical treatment, especially amygdalohippocampectomy (AHE), for the relief of medically intractable seizures. Forty-seven subjects, treated during the period 1987-1991 in the Danish epilepsy surgery programme (EPIKIR), entered a retrospective interview study. Of these, 37 had undergone AHE. Preoperative psychiatric morbidity was assessed through interview and available case notes, including a routine psychiatric interview. Postoperative psychiatric morbidity was assessed by the use of the Present State Examination. A total of six subjects (five AHE subjects) developed depressive disorders of various duration and severity after operation. In three subjects this occurred "de novo". No paranoid-hallucinatory psychoses developed within the follow-up period (a minimum of one year), and the presence of psychiatric disorders could not be associated with either lateralization of cerebral dominance of histopathological findings. Thus, depression appears to be the most frequent psychiatric problem following epilepsy surgery. Although the present study mainly deals with AHE, this finding is in accordance with the results of recent findings concerning anterior temporal lobe resection.

A 27-year-old man positive for human immunodeficiency virus (HIV) presented with severe depressive stupor, peripheral neuropathy, and myelopathy. The onset of psychiatric symptoms, closely followed by neurological symptoms, without other possible somatic etiology suggests that HIV itself might precipitate psychosis. The patient was treated successfully with electroconvulsive therapy. The advantages and risks are discussed.

Research in psychiatry with computed tomography, magnetic resonance, single photon emission computed tomography and positron emission tomography has until recently focused on schizophrenia. Results from the latest years suggest some of the same cerebral changes in affective disorder. Structural changes with enlargement of the lateral and third ventricles and broader sulci on the brain surface are frequently found in both patient groups compared to healthy volunteers. Areas with subcortical hyperintensity in the deep white matter and periventricular regions are frequently seen, especially in affective disorder bipolar patients, but seldom in schizophrenics. Functionally, the reduced activity in the prefrontal cortex in the depressive state is the most common finding together with hypoactivity in the left hemisphere. The aetiology and pathophysiological meaning of these brain changes remain unsolved.