Glabellar Botulinum Toxin Injections in Major Depressive Disorder: A Critical Review.

OBJECTIVE: To provide a critical appraisal of the primary clinical trials exploring the use of glabellar botulinum toxin type A (BTA) injections in the treatment of major depressive disorder (MDD) and propose future directions for research on this topic. DATA SOURCES: A search in PubMed, Scopus, and Google Scholar databases was performed in September 2017. Search terms included ("botulinum" OR "botox" OR "abobotulinumtoxin" OR "onabotulinum" OR "onabotulinumtoxin" OR "botulinumtoxin") AND ("antidepressant" OR "depression" OR "depressive" OR "depressed"). No other search parameters were utilized. STUDY SELECTION: Studies were selected for review if they were found to be a primary clinical trial on the use of BTA for the treatment of MDD. DATA EXTRACTION: Six studies were identified and scored by the authors using a 5-point Jadad scoring system. RESULTS: Three of the 6 studies were found to be of high quality with a Jadad score ≥ 3. The remainder had Jadad scores of 1. CONCLUSIONS: In general, the results from the reviewed studies suggest that BTA may be a promising treatment for MDD. However, these findings need to be interpreted with caution due to several limitations of the reviewed studies such as lack of a priori hypotheses, limited sample sizes, large gender bias, and significant difficulty in ensuring blinding.

Lyn tyrosine kinase regulates androgen receptor expression and activity in castrate-resistant prostate cancer.

Castrate-resistant prostate cancer (CRPC) progression is a complex process by which prostate cells acquire the ability to survive and proliferate in the absence or under very low levels of androgens. Most CRPC tumors continue to express the androgen receptor (AR) as well as androgen-responsive genes owing to reactivation of AR. Protein tyrosine kinases have been implicated in supporting AR activation under castrate conditions. Here we report that Lyn tyrosine kinase expression is upregulated in CRPC human specimens compared with hormone naive or normal tissue. Lyn overexpression enhanced AR transcriptional activity both in vitro and in vivo and accelerated CRPC. Reciprocally, specific targeting of Lyn resulted in a decrease of AR transcriptional activity in vitro and in vivo and prolonged time to castration. Mechanistically, we found that targeting Lyn kinase induces AR dissociation from the molecular chaperone Hsp90, leading to its ubiquitination and proteasomal degradation. This work indicates a novel mechanism of regulation of AR stability and transcriptional activity by Lyn and justifies further investigation of the Lyn tyrosine kinase as a therapeutic target for the treatment of CRPC.Oncogenesis (2014) 3, e115; doi:10.1038/oncsis.2014.30; published online 18 August 2014.

Androgen deprivation therapy in advanced prostate cancer: is intermittent therapy the new standard of care?

PURPOSE: Intermittent androgen deprivation is increasingly used as an alternative to continuous life-long androgen deprivation therapy for men with advanced or recurrent prostate cancer. RECENT FINDINGS: Two recent phase iii trials have clarified the benefits of intermittent therapy. The Canadian-led pr.7 trial in men with nonmetastatic disease and prostate-specific antigen recurrence after definitive local therapy showed that intermittent therapy resulted in survival equivalent to that with continuous therapy, with significant improvements in quality of life. Patients on intermittent therapy experienced improved bone health, fewer metabolic and hematologic disturbances, fewer hot flashes, and improved sexual function. In men with metastatic disease, the data are less clear. The long-awaited results of the Southwest Oncology Group 9346 trial, comparing intermittent with continuous therapy in metastatic disease, showed no difference in overall survival. Post hoc stratification analysis showed a worse outcome in patients with "minimal" metastatic disease, and no difference in those with widespread bone metastases. The significance of that observation is in dispute. The present review also addresses practical issues in the use of intermittent therapy, including patient selection, follow-up, and therapy cycling. SUMMARY: The recent results of randomized clinical trials now establish that intermittent androgen deprivation therapy is an approach that should be considered the standard of care in most patients with nonmetastatic prostate cancer requiring hormonal therapy and in selected patients with metastatic disease. KEY POINTS: Level i evidence supports the oncologic equivalence of intermittent compared with continuous androgen blockade in men with biochemical failure.Compared with continuous androgen deprivation, intermittent therapy demonstrates improved quality of life and fewer side effects.Patient selection for intermittent therapy is important to maintain good oncologic results.Monitoring of prostate-specific androgen response and duration of off-treatment intervals allow for stratification of patients by risk of progression.

Behavioral effects of agents active at the gamma-aminobutyric acid receptor complex in the staircase paradigm.

This study examined the behavioral effects of agents active at the gamma-aminobutyric acid (GABA(A)) receptor complex in the mouse staircase paradigm. The neuroactivesteroids dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) were compared with the benzodiazepine agonist clonazepam, the non-benzodiazepine hypnotic compound zopiclone, and the antiepileptic agent gabapentin. Clonazepam, zopiclone and gabapentin reduced rearing activity at doses that did not affect climbing. The rearing-suppression effect of clonazepam and zopiclone, but not of gabapentin, was blocked by the benzodiazepine antagonist flumazenil, suggesting that the added effect of gabapentin is not mediated by the benzodiazepine receptor on the GABA complex. DHEA suppressed rearing behavior at doses that did not reduce climbing, but analysis with the Bonferroni post hoc test yielded no statistically significant difference. This inhibitory effect was attenuated by flumazenil. By contrast, DHEA-S suppressed, in a dose-dependent manner, both rearing and climbing behavior to the same extent. The findings support the potential value of the mouse staircase paradigm for demonstrating behaviorally relevant anxiolysis of test compounds shown to interact in vitro with the GABA(A) receptor complex.

Case series: brief parent-child group therapy for childhood anxiety disorders using a manual-based cognitive-behavioral technique.

OBJECTIVE: To report on a brief parent-child group therapy program for children with anxiety disorders. METHOD: Twenty-four children with an anxiety disorder and their parents participated in a 10-session treatment. Children were evaluated at pretreatment (T1), posttreatment (T2), 12-month follow-up (T3), and 36-month follow-up (T4). Ten children were also assessed on entering a waiting period (T0). RESULTS: There were no significant symptomatic changes between T0 and T1. Anxiety symptoms decreased significantly during the treatment and follow-up periods. Depressive symptoms changed only during the follow-up period. The percentage of children with no current anxiety disorder was 71% at T2 and 91% at T4. Children of mothers with an anxiety disorder improved more than children of nonanxious mothers, whereas the anxiety level of anxious mothers remained stable. CONCLUSIONS: Brief parent-child group psychotherapy may serve as a time-limited, cost-effective, and efficient intervention.

Neurocognitive correlates of anxiety disorders in children: a preliminary report.

Children with anxiety disorders have been suggested to possess a specific cognitive scheme that underscores negative information and leads to the formation of a negative view of themselves and of the world. The aim of the present study was to assess the neuropsychological processes of children and adolescents with anxiety disorders, as compared to healthy matched controls. Nineteen children (6-18 years) with anxiety disorders and 14 age-matched healthy controls participated in the study. Both groups scored within normal range on the Wechsler Intelligence Scale for Children-Revised (WISC-R). All children underwent neuropsychological assessment with the California Verbal Learning Test (CVLT) (Verbal Processing), the Rey-Osterrieth Complex Figure test (ROCF) (Nonverbal Processing), and the Wisconsin Card Sorting Test (WCST) (Executive Functions). The anxiety group scored lower than the control group on all measures of the CVLT and had a significantly greater number of errors, perseverative responses, and incorrect answers after negative feedback on the WCST. No differences were detected for the ROCF. We conclude that in children and adolescents, anxiety disorders may be associated with lowered linguistic abilities and cognitive flexibility, as measured by neuropsychological paradigms. Anxiety does not appear to be associated with nonverbal processes.

The effects of target and distractor familiarity on visual search in anxious children: latent inhibition and novel pop-out.

Children and adolescents (ages 6-17 years) diagnosed as having an anxiety disorder were compared to matched controls on a two-stage serial visual search task in which they identified presence or absence of a unique shape presented with homogeneous distractors. Response time was examined as a function of prior experience with either target, distractor, or both, allowing for a within-subject assessment of latent inhibition (LI: slower responding to a target that was formerly a distractor against a background of distractors that were formerly targets as compared to a novel target with distractors that were formerly targets) and novel pop-out effects (NPO: faster responding to a novel target against a background of familiar former targets as compared to the condition in which both the target and distractors were novel). There were robust LI and NPO effects for both anxious and control children. However, the predicted interaction between diagnosis and LI condition was not obtained. In general, the results suggest that children with diagnosed anxiety disorder do not differ from controls on basic information processing as assessed by this visual search task.

Image control from childhood to adolescence.

Despite the recognized importance of imagery use by children as well as the developmental relevance for maturity and health of imagery properties such as vividness and control, only a few studies have investigated imagery of children. The aim of the present study was to examine the development of control of mental images in a sample of boys and girls aged 7 to 17 years. Children were assessed on two aspects of mental imagery, vividness and control, and teachers were asked to rate the children's intellectual and socioemotional performance. Analysis showed that the capacity for image control increased in adolescence and that children characterized by vivid and uncontrolled imagery received the lowest ratings from teachers, whereas those with nonvivid and controlled imagery received the highest ratings. The implications of these results were discussed in relation to normal and abnormal development as well as suggestions for research.

Image control and symptom expression in posttraumatic stress disorder.

Despite the devastating impact of affective dysregulation in posttraumatic stress disorder (PTSD), there has been little research on how trauma relates to affect regulation. This study examines the relationship between the cognitive capacity to control mental images and symptoms of individuals with (N = 23) and without (N = 23) PTSD after exposure to SCUD missile attacks during the Gulf War. The capacity to control mental images, symptoms of posttrauma, anxiety, and anger were assessed. PTSD subjects with a high image control reported a higher capacity to control anger, lower levels of anger state and expression, and lower levels of intrusive symptoms compared with PTSD subjects with low image control. In individuals without PTSD, results show that the better the image control, the lower the control of anger and the higher the expression of anger. Image control seems to play different functions in the emotional regulation of normal subjects (facilitatory) and PTSD patients (protective).

Ondansetron treatment in patients with Tourette's syndrome.

Ondansetron, a selective 5-HT3 antagonist, may lower mesolimbic dopaminergic hyperactivity. The present open-label pilot study evaluated the effect of ondansetron in Tourette's syndrome. Six Tourette's syndrome men aged 14-48 years resistant to haloperidol participated in the study. Assessments included the Yale Global Tic Severity Scale (YGTSS), Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and Tourette's syndrome-Clinical Global Impression (TS-CGI) scale. The maximal ondansetron dosage (8-16 mg per day) was given for 3 weeks. Ondansetron treatment was associated with a significant decrease in the severity of tics. Two patients showed a definite response (score improvement of 40% or more), and two showed a probable response (> 25%). Two patients did not improve. Side-effects were transient and included abdominal pain (n = 5) and constipation (n = 2). Ondansetron may possess anti-tic effects in some Tourette's syndrome patients.

Image vividness as a psychophysiological regulator in Posttraumatic Stress Disorder.

This study examined the relationship between image vividness and psychophysiological responses to trauma-related stimuli in participants with Posttraumatic Stress Disorder (PTSD). An auditory stimulus related to a shared trauma was presented to participants with and without PTSD and physiological parameters (heart rate and blood pressure) were measured concurrently. A negative correlation was noted in the PTSD group between image vividness and the level of physiological response. When the PTSD group was divided into high and low vividness, the physiological response was higher than that of the non-PTSD controls only when image vividness was low. The results are discussed in the context of Lang' s theoretical model, emphasizing the role of image vividness in the mediation and regulation of psychophysiology.

The prevalence of mitral valve prolapse in children with anxiety disorders.

Studies in adults have suggested a comorbidity of mitral valve prolapse and anxiety disorders, especially panic disorder. The nature of the association between these disorders is yet unclear. In the last years, case studies have appeared, reporting on the comorbidity of anxiety disorders and mitral valve prolapse in children. The present study evaluated the prevalence of mitral valve prolapse in children with anxiety disorders as compared to normal controls. The study group consisted of 52 children, 6-18 years old, with a diagnosis of panic disorder (9.6%), separation anxiety disorder (65.4%) and/or overanxious disorder (61.5%). Fifty-one normal age- and gender-matched healthy children served as controls. All participants were evaluated for the presence of mitral valve prolapse by cardiac auscultation and echocardiography. None of the 52 children with anxiety disorder and one of the 51 control children (1.96%) had mitral valve prolapse. There appears to be no association between childhood anxiety disorders and mitral valve prolapse. Whether children with panic disorder proper show a greater prevalence of mitral valve prolapse remains an open question. Implications to the association of mitral valve prolapse and panic disorder are discussed.

Pathological laughter: common vs. unusual aetiology and presentation.

Pathological laughter and crying is a well known clinical phenomenon which in most cases appears in association with diverse neurological and psychiatric symptoms and signs. It is not a disturbance of affectivity but rather of the motor concomitant of affective expression. Its main clinical characteristics are: absence of voluntary control and absence of the corresponding change in mood. It is not accompanied by the emotional lability of the organic brain syndromes, it does not present the inappropriate jocularity of the patients with frontal lobe disturbance, it is not due to the intoxicating effect of alcohol or addictive drugs and there are no typical symptoms of manic syndromes (such as grandiose self-esteem, flight of ideas, hyperactivity, etc.). In this paper three cases of pathological laughter are presented, two of these associated with organic brain conditions. The discussion will deal in particular with aetiological considerations and psychopathology of the third case which was unusual because it was a monosymptomatic condition and seemed to be the expression of a posttraumatic stress disorder.

Disposition and metabolism of rifapentine, a rifamycin antibiotic, in mice, rats, and monkeys.

Rifapentine is a cyclopentyl derivative of rifampin under development for the treatment of Mycobacterium tuberculosis and Mycobacterium avium complex infections. These studies were designed to investigate the disposition and biotransformation of single iv and oral doses of 14C-rifapentine in mice, bile duct-cannulated and uncannulated rats, and monkeys. Mass balance studies included 14C analyses of urine, feces, bile, cage wash, carcasses, and cage air collected for up to 120 hr postdose. Separation of radioactive compounds extracted from urine, bile, and feces was conducted using high-performance liquid chromatography and radioisotope detection. The mass spectra of selected chromatographic peaks were obtained. Disposition results were similar for all three species. Less than 5% of the radioactive dose of 14C-rifapentine was recovered in urine, indicating that renal excretion is a minor route of elimination in these species. The major route of elimination of radioactivity was into the feces, where more than 75% of the radioactivity was recovered. Biliary excretion was the major route of elimination of radioactivity in bile duct-cannulated rats dosed either po or IV. Radiochromatograms were similar for fecal samples from animals dosed by IV or orally. Ten regions of radioactivity were observed in mouse and rat fecal sample radiochromatograms, and seven regions of radioactivity were observed in monkey fecal sample radiochromatograms. The most abundant compound identified in feces was usually intact rifapentine (27%-41% of dose in mouse, 3%-35% of dose in rat, and 17%-29% of dose in monkey). Other peaks identified or characterized in feces based on liquid chromatography/ultraviolet/14C and/or liquid chromatography/mass spectrometry methods included 25-desacetyl-rifapentine, 3-formyl-25-desacetyl-rifapentine, and 3-formyl-rifapentine. The compounds rifapentine, 25-desacetyl-rifapentine, and 3-formyl-rifapentine were present in rat bile samples. These studies show that the metabolism and disposition of rifapentine in mice, rats, and monkeys were similar.

Disposition and metabolism of 14C-rifapentine in healthy volunteers.

Rifapentine is a long-acting cyclopentyl-derivative of rifampin. This study was designed to investigate the mass balance and biotransformation of 14C-rifapentine in humans. Four healthy male volunteers received a single 600-mg oral dose of 14C-rifapentine in a hydroalcoholic solution. Whole blood, urine, and fecal samples were collected before and at frequent intervals after drug administration. Amount of radioactivity recovered in urine and feces was assessed for up to 18 days postdose. Metabolite characterization in urine and feces was conducted using high-performance liquid chromatography with radiometric detection and liquid chromatography/mass spectroscopy. The total recovery of radioactive dose was 86.8%, with the majority of the radioactive dose recovered in feces (70.2%). Urine was a minor pathway for excretion (16.6% of the dose recovered). More than 90% of the excreted radioactivity was profiled as 14C chromatographic peaks and 50% was structurally characterized. These characterized compounds found in feces and urine were rifapentine, 25-desacetyl-rifapentine, 3-formyl-rifapentine, and 3-formyl-25-desacetyl-rifapentine. The 25-desacetyl metabolite, formed by esterase enzymes found in blood, liver, and other tissues, was the most abundant compound in feces and urine, contributing 22% to the profiled radioactivity in feces and 54% in urine. The 3-formyl derivatives of rifapentine and 25-desacetyl-rifapentine, formed by nonenzymatic hydrolysis, were also prominent in feces and, to a lesser extent, in urine. In contrast to the feces and urine, rifapentine and 25-desacetyl-rifapentine accounted for essentially all of the plasma radioactivity (99% of the 14C area under the concentration-time curve), indicating that 25-desacetyl-rifapentine is the primary metabolite in plasma. It appears, therefore, that the nonenzymatic hydrolysis of rifapentine to 3-formyl byproducts occurs primarily in the gut and the acidic environment of the urine.

Cholesteryl hydroperoxyoctadecadienoate from oxidized low density lipoprotein inactivates platelet-derived growth factor.

Both oxidized low density lipoprotein (ox-LDL) and platelet-derived growth factor (PDGF) have been implicated in the genesis of various inflammatory responses, including atherosclerosis. We demonstrate here a novel interaction between specific oxidized lipids derived from ox-LDL and PDGF. The lipid moieties of ox-LDL caused concentration-dependent inactivation of PDGF as measured by loss of its mitogenic activity and its binding to high affinity receptors. Reverse-phase and normal-phase HPLC were used to purify the inactivating component in the lipid mixture. By fast atom bombardment mass spectrometry and infrared spectroscopy, we identified the inactivating lipids as the 9- and 13-hydroperoxy derivatives of cholesteryl linoleate, cholesteryl hydroperoxyoctadecadienoate. When a series of cholesteryl esters were subjected to oxidizing conditions, only those containing two or more double bonds caused inactivation of PDGF; the extent of inactivation increased with increased levels of oxidation. Exposing PDGF to cumene hydroperoxide, t-butyl hydroperoxide, or hydrogen peroxide did not affect the activity of the mitogen. The oxidized lipid had no effect on the mitogenic activity of epidermal growth factor but did abolish the mitogenic activity of basic fibroblast growth factor and the antiproliferative activity of transforming growth factor beta1. The inactivation of PDGF and other cytokines by lipid hydroperoxides may occur in such processes as vascular disease, inflammation, and wound healing.

Use of atypical neuroleptics in child and adolescent psychiatry.

BACKGROUND: This article reviews the published clinical experience with atypical neuroleptics in children and adolescents. METHOD: A computerized literature search was conducted (MEDLINE, 1974-1998) to retrieve all reports on the use of atypical neuroleptics in children and adolescents. A hand search was performed as well. All relevant clinical data were collated by type of drug. RESULTS: We found 5 blind placebo-controlled clinical trials (105 patients), 24 open-label clinical trials (387 patients), and 33 case series (115 patients) describing the use of the atypical neuroleptics clozapine, risperidone, olanzapine, sulpiride, tiapride, amisulpride, remoxipride, and clothiapine in children and adolescents. Some of these agents, especially clozapine, risperidone, and olanzapine, were found to be efficacious in the treatment of schizophrenia, bipolar disorders, and pervasive developmental disorders. The role of atypical neuroleptics as augmenters of serotonin reuptake inhibitors in obsessive-compulsive disorder is unclear. Risperidone appears to possess anti-tic properties in patients with Tourette's disorder. CONCLUSION: The most convincing evidence of the efficacy of atypical neuroleptics in children and adolescents concerns clozapine in the treatment of schizophrenia. Data on other atypical neuroleptics in other disorders are still sparse, and further research is needed. Some of the atypical neuroleptics may become the first-line treatment for childhood schizophrenia and pervasive developmental disorders.

Lack of effect of methylphenidate on serum growth hormone (GH), GH-binding protein, and insulin-like growth factor I.

The aim of this study was to assess the growth hormone (GH) axis in methylphenidate (MPH)-treated and untreated boys with attention-deficit and hyperactivity disorder (ADHD), by evaluating serum GH, GH-binding protein (GHBP) activity, and insulin-like growth factor I (IGF-I) levels as compared to age-matched normal controls. Blood samples were taken from 42 boys (aged 6-16 years) diagnosed as having ADHD according to DSM-III-R criteria and confirmed by using the Schedule for Affective Disorder and Schizophrenia for school-age children (K[Kiddle]-SADS). A total of 21 patients were treated with MPH (5-20 mg/day; 0.15-0.77 mg/kg/day), on a drug holiday protocol, for 1-36 months, and 21 were drug naive. A total of 46 age-matched normal boys at height and weight within normal range served as controls. No significant differences were detected between the MPH-treated ADHD children, the untreated ADHD children, and the control children on fasting serum GH levels, GHBP activity, or IGF-I levels. Active treatment with MPH, in ADHD children on a drug holiday protocol, does not cause changes in GH axis as manifested by normal values of GH, GHBP, and IGF-I.

An open trial of clozapine in neuroleptic-resistant childhood-onset schizophrenia.

BACKGROUND: Studies performed with schizophrenic adults who were resistant to classical neuroleptics showed improvement in 30% of the patients when treated with clozapine. Very early onset schizophrenic patients benefit only partially from conventional antipsychotics and are at increased risk of developing extrapyramidal symptoms; clozapine may offer an alternative treatment for these patients. METHODS: Eleven neuroleptic-resistant children (< 13 years) with schizophrenia were treated with clozapine. Improvement was monitored during the first 16 weeks using the Brief Psychiatric Rating Scale, Positive and Negative Syndrome Scale and Clinical Global Impression. The mean clozapine dosage was 227.3 (s.d. 34.4 mg/day at the end of the 16 weeks. RESULTS: There was an overall statistically significant reduction in all parameters, especially positive symptoms, implying a favourable outcome. Most of the improvement occurred during the first 6 to 8 weeks. The major side-effects were somnolence and drooling (no agranulocytosis). CONCLUSION: Clozapine may be a promising drug for the treatment of resistant childhood-onset schizophrenia.