Treating depression with botulinum toxin: a pooled analysis of randomized controlled trials.

INTRODUCTION: Botulinum toxin A (BTA) injection into the glabellar region is currently being studied as a treatment for major depressive disorder (MDD). Here we explore efficacy data of this novel approach in a pooled analysis. METHODS: A literature search revealed 3 RCTs on this topic. Individual patient data and clinical end points shared by these 3 trials were pooled and analyzed as one study (n=134) using multiple regression models with random effects. RESULTS: In the pooled sample, the BTA (n=59) and the placebo group (n=75) did not differ in the baseline variables. Efficacy outcomes revealed BTA superiority over placebo: Improvement in the Hamilton Depression Rating Scale or Montgomery-Asberg Depression Rating Scale 6 weeks after baseline was 45.7% for BTA vs. 14.6% for placebo (p<0.0001), corresponding to a BTA response rate of 54.2% (vs. 10.7%) and a BTA remission rate of 30.5% (vs. 6.7%). DISCUSSION: Equalling the status of a meta-analysis, this study increases evidence that a single treatment of BTA into the glabellar region can reduce symptoms of MDD. Further studies are needed to better understand how BTA exerts its mood-lifting effect.

Botulinum toxin therapy of bipolar depression: A case series.

We and others have recently found that botulinum toxin injected into the brow muscles has significant antidepressant properties as compared to placebo in randomized controlled trials in patients with major depressive disorder. However, data for the treatment of bipolar depression with botulinum toxin is lacking. We report here six patients with bipolar disorder experiencing moderate to severe depressive episodes who were treated on a compassionate basis with botulinum toxin given their persistent depressive symptoms and adverse side effects from medications. Four of six patients with bipolar depression experienced a remission following treatment with botulinum toxin, and the other two patients experienced a reduction of depressive symptoms. When the effect of botulinum toxin on the frown muscles began to wear off, depressive symptoms returned and retreatment with botulinum toxin provided successful relief of depressive symptoms again.

In vitro-staining specificity of the antibody 5-D-4 for microglia but not for monocytes and macrophages indicates that microglia are a unique subgroup of the myelomonocytic lineage.

We have previously shown that (i) the ramified phenotype and (ii) the microglia-specific pattern of membrane currents are induced not only in microglia, but also in monocytes and macrophages if they are cultured in the presence of astrocytes. These findings indicated that microglia are not a separate type of cell of the myelomonocytic lineage, but are induced to take on their unique characteristics by astrocytes. Recently, it was discovered that the antibody 5-D-4 selectively stains ramified microglia in situ. We therefore studied the influence of astrocytes and other epithelial cells on the expression of the keratan sulfate epitope recognized by 5-D-4 in microglia and other myelomonocytic cells. Our findings show that this antigen is exclusively expressed in microglia only if they are induced to ramify by coculture with either astrocytes or epithelial cells. By contrast monocytes and macrophages, even if induced to take on the ramified phenotype do not stain positive with 5-D-4. These findings indicate (i) that 5-D-4 is a specific marker for ramified microglia in vitro, and (ii) that microglia are a separate class of myelomonocytic cells, distinct from monocytes and macrophages.

ATP and adenosine induce ramification of microglia in vitro.

Microglial cells in the healthy adult brain possess a characteristic ramified morphology with multiple branched processes, small somata and down-regulated inflammatory properties. In contrast, microglial cells isolated from new-born rat brain inevitably show a non-ramified amoeboid phenotype, which is observed in vivo after pathologic activation or during development. To identify factors that control microglial morphology we investigated the effects of purines alone or in combination with astrocyte-conditioned medium (ACM). Under optimized culture conditions postnatal rat microglial cells developed an amoeboid to ovoid phenotype. Addition of 0.6-1 mM ATP or adenosine induced the outgrowth of numerous processes after 2-3 days that could be observed also in the presence of ACM as previously reported. Culture in ACM plus ATP or adenosine yielded an optimized ramified phenotype. ATP or adenosine, but not ACM alone, also prevented the formation of a flat, amoeboid morphology induced by lipopolysaccharide (LPS); however, at 0.6-1 mM they did not reduce the initial LPS-induced activation of the transcription factor NF-kappaB. By using specific agonists or antagonists the morphological transformations could not be confined to a distinct purinoreceptor subtype, but appeared to be mediated by long-term presence of adenosine in the medium to which phosphorylated purines were rapidly hydrolyzed by microglial cells. Since ACM did not contain sufficient concentrations of ATP or adenosine, purines are not the only ramification-inducing factors present in ACM; however, they are a valuable tool to induce microglial ramification in vitro.

Increased cystatin C in astrocytes of transgenic mice expressing the K670N-M671L mutation of the amyloid precursor protein and deposition in brain amyloid plaques.

Cystatin C is an essential secretory cofactor for neurogenesis with potent protease inhibitor activities. Polymorphisms of cystatin C are genetically associated with Alzheimer's disease (AD), and the L68Q mutation causes hereditary cerebral hemorrhage with amyloidosis of the Icelandic type, in which cystatin C and beta-amyloid are colocalized in cortical blood vessels. To determine whether cystatin C and beta-amyloid also colocalize in brain amyloid plaques, we analyzed transgenic mice expressing the Swedish APP (SweAPP) mutation. We found high levels of cystatin C in astrocytes surrounding beta-amyloid plaques, and discrete layers of cystatin C attached to amyloid plaque cores covered by a layer of beta-amyloid. In addition, cystatin C accumulated in reactive astrocytes throughout the brain, independently of, and before the onset of, amyloid plaque formation. These results show that expression of SweAPP is associated with increased cystatin C in reactive astrocytes, and they suggest an early role of cystatin C in appositional amyloid plaque growth.

Saitohin gene is not associated with Alzheimer's disease.

BACKGROUND: The deposition of tau protein in neurofibrillary tangles constitutes an important feature of many neurodegenerative disorders, including Alzheimer's disease. A polymorphic gene, saitohin (STH), nested within the tau gene (microtubule associated protein tau, MAPT), was recently identified and an association of a non-synonymous polymorphism in STH with increased risk for Alzheimer's disease was suggested. OBJECTIVE AND METHODS: To test the above hypothesis in a case-control association study of two independent white populations within Switzerland and Greece, comparing genotype and allele frequencies from 225 Alzheimer's disease patients and 144 healthy control subjects. RESULTS: No differences in allelic or genotypic distributions between Alzheimer's disease patients and controls was found in the individual samples (Swiss/Greek) or in the combined sample. Stratification for the presence of apolipoprotein E (APOE) epsilon 4 allele, sex, or age did not show significant effects in the populations studied, nor was there an effect on the age of onset. CONCLUSIONS: No evidence was found for an association of the non-synonymous polymorphism (Q7R) in STH and Alzheimer's disease. This finding is in line with earlier studies showing no association between MAPT and Alzheimer's disease.

Genetic association of acyl-coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer's disease.

A common polymorphism of the gene encoding acyl-coenzyme A: cholesterol acyltransferase 1 (SOAT1), which is involved in the regulation of beta-amyloid peptide generation, is associated with low brain amyloid load (P=0.03) and with low cerebrospinal fluid levels of cholesterol (P=0.005). This polymorphism of SOAT1 is also associated with reduced risk for Alzheimer's disease in ethnically distinct populations (P=0.0001, odds ratio: 0.6, 95% confidence interval 0.4-0.8).