Structural changes induced by electroconvulsive therapy are associated with clinical outcome.

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 < 0.001) while left-sided mediotemporal changes discriminate unilateral from bilateral electrode placement (81% accuracy, p < 0.001). CONCLUSIONS: The identification of a multivariate discriminative pattern shows that structural change is relevant for clinical response to ECT, but this pattern does not include mediotemporal regions that have been the focus of electroconvulsive therapy research so far.

Clinical and psychometric validation of the psychotic depression assessment scale.

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, p<0.001) and responsive (correlation coefficients from 0.72 to 0.86, p<0.001) measures of psychotic depression. According to the Mokken analysis, all three scales were unidimensional. CONCLUSIONS: The clinical validity, responsiveness and unidimensionality of the PDAS and its subscales were confirmed in an independent sample of patients with psychotic depression.

Metabolic profiling of dividing cells in live rodent brain by proton magnetic resonance spectroscopy (1HMRS) and LCModel analysis.

RATIONALE: Dividing cells can be detected in the live brain by positron emission tomography or optical imaging. Here we apply proton magnetic resonance spectroscopy (1HMRS) 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 ∼1.30 ppm. In addition, we also apply the same 1HMRS methodology to metabolically profile glioblastomas with actively dividing cells growing in RCAS-PDGF mice. METHODS: 1HMRS 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 1HMRS data were compared to post-mortem histology. RESULTS: Dividing cells in the rat hippocampus increased ∼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 ∼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 1HMRS 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.

Neuroimaging and electroconvulsive therapy: a review.

BACKGROUND: Since the 1970s, a number of neuroimaging studies of electroconvulsive therapy (ECT) have been conducted to elucidate the working action of this highly efficacious treatment modality. The technologies used are single photon emission tomography, positron emission tomography, magnetic resonance imaging, magnetic resonance spectroscopy, and quantitative electroencephalography. METHODS: A PubMed literature search with focus on clinical studies was made from the inception of the database until December 2013 using the search terms electroconvulsive therapy and neuroimaging. RESULTS: Early methods allowing only identification of global changes of cerebral blood flow and cerebral metabolism show considerable ictal increases of these measures, which normalize during the postictal period. Later methodological developments have given access to measurements of minute activity changes in localized cortical and subcortical areas of the brain and have revealed differences in neurophysiology and metabolism between the hyperactive ictal state and the restorative interictal/postictal periods. Recent magnetic resonance imaging studies seem to pave way for new insights into ECT's effects on increased connectivity in the brain during depression. CONCLUSION: The existing data reveal considerable variations among studies and therefore do not yet allow the formulation of a unified hypothesis for the mechanism of ECT. The rapid developments in imaging technology, however, hold promises for further elucidation of the mode of action of ECT.

Electroconvulsive therapy, hypertensive surge, blood-brain barrier breach, and amnesia: exploring the evidence for a connection.

Preclinical and clinical evidence show that electroconvulsive therapy (ECT)-induced intraictal surge in blood pressure may result in a small, transient breach in the blood-brain barrier, leading to mild cerebral edema and a possible leach of noxious substances from blood into brain tissues. These changes may impair neuronal functioning and contribute to the mechanisms underlying ECT-induced cognitive deficits. Some but not all clinical data on the subject suggest that blood pressure changes during ECT correlate with indices of cognitive impairment. In animal models, pharmacological manipulations of blood pressure during electroconvulsive shocks attenuate electroconvulsive shock-induced amnestic changes; however, the evidence suggests that antihypertensive mechanisms may not necessarily be involved. Clinical studies involving pre-ECT administration of antihypertensive medications do not provide convincing evidence of benefits. It is concluded that there is insufficient support, at present, for the hypothesis that the hypertensive surge during ECT and the resultant blood-brain barrier breach contribute meaningfully to ECT-induced cognitive deficits. Future research should address the subset of patients who experience pronounced hypertensive changes during ECT, and clinically relevant outcome measures, such as autobiographical memory impairment, should be examined.

Systemic oxidatively generated DNA/RNA damage in clinical depression: associations to symptom severity and response to electroconvulsive therapy.

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=28), moderately depressed, non-medicated patients (N=26) and severely depressed patients eligible for electroconvulsive therapy (ECT) (N=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 (controls

Association of the leucine-7 to proline-7 variation in the signal sequence of neuropeptide Y with major depression.

OBJECTIVE: There is clear evidence of a genetic component in major depression, and several studies indicate that neuropeptide Y (NPY) could play an important role in the pathophysiology of the disease. A well-known polymorphism encoding the substitution of leucine to proline in the signal peptide sequence of NPY (Leu7Pro variation) was previously found to protect against depression. Our study aimed at replicating this association in a large Danish population with major depression. METHOD: Leu7Pro was studied in a sample of depressed patients and ethnically matched controls, as well as psychiatric disease controls with schizophrenia. Possible functional consequences of Leu7Pro were explored in vitro. RESULTS: In contrast to previous studies, Pro7 appeared to be a risk allele for depression, being significantly more frequent in the depression sample (5.5%, n = 593; p = 0.009; odds ratio, OR: 1.46) as compared to ethnically matched controls (3.8%, n = 2912), while schizophrenia patients (4.1%, n = 503) did not differ. In vitro, the Pro7 substitution appeared to be associated with reduced levels of NPY without affecting its mRNA level. CONCLUSION: The Leu7Pro variation may increase the risk of major depression, possibly by affecting the biosynthesis of NPY.

How does electroconvulsive therapy work? Theories on its mechanism.

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.

Gene variations in the cholecystokinin system in patients with panic disorder.

OBJECTIVES: Panic disorder (PD) is a common psychiatric disease occurring more frequently in women than men. Multiple common and/or rare variants in the genome contribute to the complex etiology of the disorder. The neuropeptide cholecystokinin (CCK) and its receptors (the CCK system) have been suggested to be involved in the pathogenesis of PD. METHODS: We examined the promoter, exon, and exon-intron boundaries of the genes encoding CCK and its receptors (CCKAR and CCKBR) for variations in 187 patients with PD and 277 screened control individuals. Up to 1342 additional healthy population controls were examined for some of the variations. One CCK gene intron variation was analyzed for alternative splicing using an exon-trapping assay. RESULTS: The promoter variant (-36C > T; rs1799923) and an intron 1 polymorphism (IVS1-7C > G; rs754635) in the CCK gene were found to protect against PD (P<0.05). The intron 1 variation did not seem to alter the splicing of the gene. None of the other variations found were associated with PD, but a 2-marker haplotype (rs1800855/rs1800857) in the CCKAR gene protected women against PD (P=0.004). In addition, we found two novel rare missense variations in the CCKBR gene (Lys329Asn and Pro446Leu) in two and one patient, respectively. CONCLUSION: The results suggest that the CCK system may play a role in the pathogenesis of PD, with susceptibility alleles both protecting and contributing to the disease. Both common and rare variants seem to be involved. The involvement of the CCK system may also contribute to the increased prevalence of PD in women.

Electrotherapy for melancholia: the pioneering contributions of Benjamin Franklin and Giovanni Aldini.

The electrical induction of seizures with a therapeutic aim began in 1938, but the history of electric currents to relieve mental illness began 2 centuries earlier with the pioneering work of the Italian Giovanni Aldini and the American Benjamin Franklin.These early experiments are described demonstrating that the electrical force encouraged hopeful applications. This history emphasizes the unique contribution in the induction of grand mal seizures as the therapeutic basis rather than the role of electricity alone.

Gene-environment interaction affects substance P and neurokinin A in the entorhinal cortex and periaqueductal grey in a genetic animal model of depression: implications for the pathophysiology of depression.

Evidence implies a role for corticotropin-releasing hormone (CRH) and tachykinins, e.g. substance P (SP) and neurokinin A (NKA) in the pathophysiology of depression. We have previously shown that SP- and NKA-like immunoreactivity (-LI) concentrations were altered in the frontal cortex and striatum of the congenitally 'depressed' Flinders Sensitive Line (FSL) compared to the Flinders Resistant Line (FRL) control rats. It is also known that environmental stress may affect brain levels of tachykinins. In view of these results we decided to superimpose maternal deprivation, an early life environmental stressor, onto the genetically predisposed 'depressed' FSL rats and the FRL control rats and use this paradigm as a model of gene-environment interaction. The adult animals were sacrificed, adrenal glands and brains dissected out and SP-, NKA- and CRH-LI levels were determined in ten discrete brain regions. Maternal deprivation led to a marked increase in SP-LI and NKA-LI levels in the periaqueductal grey (PAG) and entorhinal cortex of the 'depressed' FSL strain while it had no significant effect in the FRL controls. Furthermore, specific strain differences in peptide-LI content were confirmed. No difference was found in relative adrenal gland weight, which is consistent with the finding that CRH-LI levels in the hypothalamus were similar across strains, and insensitive to stress in either strain. Taken together, these data are in line with behavioural experiments showing ameliorating effects of NK1 and NK2 receptor antagonists against anxiety and depression-like symptoms in rodents, and therefore further implicate the tachykinin systems in the pathophysiology of depression and adult life psychopathology.

[Electroconvulsive therapy in treatment of depression]. / Elektrokonvulsiv terapi ved behandling af depression.

ECT is the most powerful treatment of severe melancholic/ psychotic depression. A treatment series consists of 8-12 sessions, given 3 times a week under anaesthesia, muscle relaxation and artificial ventilation with 100% oxygen. EEG, EMG, EKG and pulse oximetry are monitored. Benzodiazepines, anticonvulsants and lithium salts should be avoided during treatment with ECT. Ambulatory single ECT sessions with an interval of 3-4 weeks (maintenance-ECT) is recommended in drug-resistant depression. In Denmark, 5% of all patients admitted to psychiatric departments were treated with ECT; 18% of patients diagnosed with depression were given ECT. ECT is a safe and sometimes life-saving treatment.