Efficacy of repetitive transcranial magnetic stimulation in depression: A review of the evidence

Repetitive transcranial magnetic stimulation (rTMS) is a novel treatment in psychiatry. We reviewed all published evidence on the efficacy of this treatment option in depressive disorders. An extensive electronic and manual search for eligible research reports identified only 12 studies that met the predetermined criteria for inclusion. rTMS was administered differently in most studies, and patient characteristics varied widely. A formal meta-analysis of the studies was thus not possible. Instead, we conducted a qualitative evaluation of the included studies. The antidepressive efficacy was not consistent, and where efficacy was demonstrated, it was modest in most studies. Some patients had good but transient responses to rTMS. Treatment gains were not maintained beyond the treatment period. Comparisons with electroconvulsive therapy (ECT) indicated the superiority of ECT. More, larger and more carefully designed studies are needed to demonstrate convincingly a clinically relevant effect of rTMS. We conclude that there is insufficient evidence for rTMS as a valid treatment for depression at present.     

Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion

Mutations in SUCLA2, encoding the ß-subunit of succinyl-CoA synthetase of Krebs cycle, are one cause of mitochondrial DNA depletion syndrome. Patients have been reported to have severe progressive childhood-onset encephalomyopathy, and methylmalonic aciduria, often leading to death in childhood. We studied two families, with children manifesting with slowly progressive mitochondrial encephalomyopathy, hearing impairment and transient methylmalonic aciduria, without mtDNA depletion. The other family also showed dominant inheritance of bilateral retinoblastoma, which coexisted with mitochondrial encephalomyopathy in one patient. We found a variant in SUCLA2 leading to Asp333Gly change, homozygous in one patient and compound heterozygous in one. The latter patient also carried a deletion of 13q14 of the other allele, discovered with molecular karyotyping. The deletion spanned both SUCLA2 and RB1 gene regions, leading to manifestation of both mitochondrial disease and retinoblastoma. We made a homology model for human succinyl-CoA synthetase and used it for structure–function analysis of all reported pathogenic mutations in SUCLA2. On the basis of our model, all previously described mutations were predicted to result in decreased amounts of incorrectly assembled protein or disruption of ADP phosphorylation, explaining the severe early lethal manifestations. However, the Asp333Gly change was predicted to reduce the activity of the otherwise functional enzyme. On the basis of our findings, SUCLA2 mutations should be analyzed in patients with slowly progressive encephalomyopathy, even in the absence of methylmalonic aciduria or mitochondrial DNA depletion. In addition, an encephalomyopathy in a patient with retinoblastoma suggests mutations affecting SUCLA2.Mitochondrial diseases are caused by genetic defects in nuclear or mitochondrial DNA (mtDNA) that disrupt function of the respiratory chain, compromising the synthesis of ATP. Most childhood-onset phenotypes are caused by autosomal recessive mutations in nuclear-encoded mitochondrial proteins. Mitochondrial diseases can manifest at any age, with almost any symptom, in almost any tissue, although the tissues with the largest dependence on oxidative energy supply, such as the central nervous system, sensory organs and skeletal muscle,¹ are most commonly affected. The wide clinical and genetic heterogeneity with overlapping phenotypes makes the diagnostics of mitochondrial diseases challenging.²mtDNA depletion syndrome is associated with many clinical phenotypes and has a variable genetic background. It can be caused by several nuclear genes, which typically impair mtDNA replication, repair or nucleotide synthesis.³ One of these genes is SUCLA2, encoding the β-subunit of the Krebs cycle enzyme ADP-forming succinyl-CoA synthetase (SCS-A). SCS catalyzes the reversible conversion of succinyl-CoA to succinate, accompanied by substrate-level phosphorylation of ADP or GDP.⁴ The enzyme is a heterodimer composed of a catalytic α-subunit, encoded by SUCLG1 and a β-subunit that determines the enzymes'' substrate specificity for either ADP (SUCLA2) or GDP (SUCLG2). SCS is widely expressed in mammalian tissues, with predominance of either the ADP- or GDP-forming form in each tissue. SUCLG1 is ubiquitously expressed, whereas expression of SUCLA2 dominates in catabolic tissues, in which the main source of energy is ATP, such as the brain, and is induced in heart and skeletal muscle.^{4, 5} Patients with SUCLA2 mutations typically have progressive childhood-onset Leigh-like encephalomyopathy associated with dystonia, hypotonia, sensorineural hearing deficit, lesions of the basal ganglia, depletion of mtDNA and methylmalonic aciduria.^{3, 6} Over 20 patients and five different mutations in SUCLA2 have been described.^{6, 7, 8, 9, 10}We report here molecular basis of mitochondrial encephalomyopathy, also combined with bilateral retinoblastoma, in patients with clinical symptoms or signs previously described in association with SUCLA2 mutations: encephalomyopathy with hearing deficit and methylmalonic aciduria.     

Depressive disorder as a predictor of physical disability in old age

OBJECTIVES: To determine whether the occurrence of depression predicts physical disability in older people. DESIGN: A longitudinal epidemiological study with a follow-up of 5 years. SETTING: A comparison between depressed and nondepressed participants. PARTICIPANTS: The series consisted of the persons who participated in the longitudinal epidemiological study on depression in old age performed in Ahtari, Finland. The first round of interviews and examinations was performed in 1984/1985 and the second round in 1989/1990. The study series (N = 786) was composed of persons functionally independent in activities of daily living (ADLs) during the first round and alive and participating in both rounds. MEASUREMENTS: Depression was determined according to DSM-III criteria. Physical functional abilities were measured with self-assessments of ability to manage ADLs. RESULTS: In bivariate analyses, depression at the baseline did not predict lowering of functional abilities during follow-up, but the occurrence of depression with a long-term or relapsing course during follow-up and the onset of depression during follow-up in persons not depressed at the baseline predicted lowering of functional abilities during follow-up. The logistic regression analyses showed the presence of the following variables measured during the first round--older age, low basic education, poor self-perceived health, and occurrence of a physical disease--and the onset of the following diseases during follow-up--any physical disease, neurological disease, cerebrovascular disease, or depressive symptoms (in persons nondepressed at the baseline)--predicted lowered functional abilities after a follow-up of 5 years. CONCLUSION: Depression that developed during the follow-up in previously nondepressed persons was associated with an increased risk for lowering of functional abilities, even when controlling for age, sociodemographic factors, physical diseases, and baseline disabilities. Depressed older people are at high risk for physical disability, and an individually planned program to maintain their functional abilities by training in ADLs and instrumental activities of daily living (IADLs) and physical exercise should be included in their treatment.     

Time to change the glomerular filtration rate estimating formula in primary care?

BackgroundThe most commonly used equation for estimated glomerular filtration rate (eGFR) is nowadays the four-variable Modification of Diet in Renal Disease (MDRD) equation. This formula was derived from patients with non-diabetic chronic kidney disease (CKD) with mean GFR 40 ml/min.MethodsWe compared the MDRD study equation and the recently developed Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation by applying the two formulas in 1747 middle-aged cardiovascular risk persons in primary care.ResultsThe prevalence of renal insufficiency defined as eGFR < 60 ml/min was 6.7% (95% CI 5.6–8.0) according to the MDRD formula, and 3.6% (95% CI 2.8–4.6) according to the CKD-EPI formula. The subjects who were classified as having CKD according to the MDRD equation, but no-CKD according to the CKD-EPI formula, were mostly women (86%) and slightly younger than the subjects having CKD according to both formulas.ConclusionThe characteristics of the subjects commonly treated in primary care resemble more closely the population from which the CKD-EPI than the MDRD study equation was derived from. Thus, we suppose that in general practice, the CKD-EPI equation is more suitable for estimating renal function than the MDRD equation.