Sex-controlled differences in sertraline and citalopram efficacies in major depressive disorder: a randomized, double-blind trial.

To investigate the response to antidepressants while controlling for sex, which has been controversial, 92 outpatient males and females with major depressive disorder were assigned to sertraline (100 mg/day) or citalopram (40 mg/day) in two strata and were assessed using Hamilton depression rating scale (HDRS) scores and brain-derived neurotrophic factor (BDNF), interleukin (IL)-6 and cortisol serum levels in this 8-week, randomized, parallel-group, double-blind clinical trial. Data of 40 sertraline and 40 citalopram recipients with equal representation of males and females assigned to each medication were analyzed, while their baseline characteristics were not statistically different (P > 0.05). There were no significant differences between sertraline and citalopram recipients in outcome changes (P > 0.05), all of which indicated improvement, but a significant time-treatment-sex interaction effect in BDNF levels was observed (P = 0.035). Regarding this, subgroup analyses illustrated a significantly greater increase in male BDNF levels following sertraline treatment (P = 0.020) with a moderate to large effect size (Cohen's d = 0.76 and ). Significant associations were observed between percentage changes in IL-6 levels and BDNF levels in sertraline recipients (P = 0.033) and HDRS scores in citalopram recipients (P < 0.001). Sex was an effect modifier in BDNF alterations following sertraline and citalopram administration. Further large-scale, high-quality, long-term studies are recommended.

Emerging drugs for the treatment of irritability associated with autism spectrum disorder.

INTRODUCTION: Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million. Irritability is a challenging behavior associated with ASD, for which medication development has lagged. More specifically, pharmacotherapy effectiveness may be limited against high adverse effects (considering side effect profiles and patient medication sensitivity); thus, the possible benefits of pharmacological interventions must be balanced against potential adverse events in each patient. AREAS COVERED: After reviewing the neuropathophysiology of ASD-associated irritability, the benefits and tolerability of emerging medications in its treatment based on randomized controlled trials were detailed in light of mechanisms and targets of action. EXPERT OPINION: Succeeding risperidone and aripiprazole, monotherapy with memantine may be beneficial. In addition, N-acetylcysteine, galantamine, sulforaphane, celecoxib, palmitoylethanolamide, pentoxifylline, simvastatin, minocycline, amantadine, pregnenolone, prednisolone, riluzole, propentofylline, pioglitazone, and topiramate, all adjunct to risperidone, and clonidine and methylphenidate outperformed placebo. These effects were through glutamatergic, γ-aminobutyric acidergic, inflammatory, oxidative, cholinergic, dopaminergic, and serotonergic systems. All medications were reported to be safe and tolerable. Considering sample size, follow-up, and effect size, further studies are necessary. Along with drug development, repositioning and combining existing drugs supported by the mechanism of action is recommended.

Outcomes of the Pin and Plate Technique in Complex Fractures and Nonunions of Distal Humerus.

Objectives: This study investigates outcomes and complications of the pin and plate fixation technique, which was suggested for distal humerus fractures. It also reports the results of its application in nonunions for the first time. Methods: Forty-nine fracture and 17 nonunion cases who underwent surgery using the technique and were followed for at least 18 months were assessed through the range of motion (ROM), Quick Disabilities of the Arm, Shoulder, and Hand Score (Quick-DASH), Mayo Elbow Performance Score (MEPS), four-category verbal rating scale (VRS-4), and complications. Results: At the last follow-up, the mean scores of flexion, extension deficit, supination, and pronation ranges in fracture cases were 116.7, 22.9, 90.0, and 90.0 degrees, respectively. These values in nonunion cases were 112.2, 26.4, 86.7, and 85.5 degrees, respectively. The average ROM in fracture cases was 93.8, while it was 85.8 degrees in nonunion cases. The mean Quick-DASH in fracture and nonunion patients were 25.2 and 31.1, respectively. According to the MEPS, 77.5% of fracture and 64.7% of nonunion patients had excellent and good results. In fracture cases, the mean scores of VRS-4 at rest, light activity, and hard activity were 1.3, 1.8, and 2.3, respectively. These values in nonunion cases were 1.8, 2.2, and 2.5, respectively. The most common complications were device prominence and ulnar neuropathy. Conclusion: An acceptable union rate and proper elbow function can be expected by using this technique. Owing to the promising results of this study, further high-quality studies are recommended. Hereby this technique is called Persian Fixation.

Reboxetine Combination Therapy With Fluoxetine in Moderate to Severe Obsessive-Compulsive Disorder: A Placebo-Controlled, Double-Blind, Randomized Trial.

OBJECTIVES: Reboxetine is a potent and selective norepinephrine reuptake inhibitor that was effective in combination with citalopram for resistant obsessive-compulsive disorder (OCD). This study aims to assess its effectiveness and tolerability in combination with fluoxetine in treating OCD. METHODS: In this 2-center, placebo-controlled, and double-blind, randomized clinical trial, 76 patients with OCD were assigned into 2 parallel groups to receive fluoxetine (up to 80 mg/d) plus placebo (F + P) or fluoxetine (up to 80 mg/d) plus reboxetine (F + R) (10 mg twice daily) for 10 weeks. Participants were assessed with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline and weeks 5 and 10. RESULTS: A total of 76 patients completed the trial. There was no significant difference between the 2 groups in baseline Y-BOCS scores. General linear model repeated-measures showed significant effects on time × treatment interaction on total Y-BOCS ( F = 6.33, df = 1.42, P = 0.006) and obsession subscale scores ( F = 10.39, df = 1.48, P < 0.001), and insignificance on compulsion subscale scores ( F = 1.86, df = 1.24, P = 0.173). Reboxetine combination therapy demonstrated a higher partial and complete treatment response rate ( P < 0.01) according to the Y-BOCS total scores. There was no significant difference between the 2 groups in the frequency of adverse effects. CONCLUSIONS: Reboxetine combination therapy with fluoxetine can effectively improve symptoms in patients with OCD in a short period of treatment. However, further studies with larger sample sizes and longer follow-up periods are needed to confirm these findings.This trial was registered with the Iranian Registry of Clinical Trials ( www.irct.ir ; No IRCT20090117001556N129).

L-Theanine adjunct to risperidone in the treatment of chronic schizophrenia inpatients: a randomized, double-blind, placebo-controlled clinical trial.

RATIONALE: Inadequate responses to current schizophrenia treatments have accelerated research into novel therapeutic approaches. OBJECTIVES: This study investigated the efficacy and tolerability of adjunctive L-theanine, an ingredient with neuroimmunomodulatory and neuroprotective properties, for chronic schizophrenia. METHODS: Eighty chronic schizophrenia inpatients were equally assigned to receive risperidone (6 mg/day) plus either L-theanine (400 mg/day) or matched placebo in this 8-week, randomized, parallel-group, double-blind, placebo-controlled trial. The participants were assessed using the Positive and Negative Syndrome Scale (PANSS) by recording the results of subscales at baseline and weeks 4 and 8 to measure treatment efficacy. Additionally, the participants were assessed for the Hamilton Depression Rating Scale (HDRS) and adverse events, including the Extrapyramidal Symptom Rating Scale (ESRS). RESULTS: Sixty patients, 30 in each group, were included in the analyses. All baseline demographic and clinical characteristics were comparable between the groups (p-values > 0.05). The reduction rates from baseline to endpoint in negative, general psychopathology, and total scores of PANSS were greater in the L-theanine group (p-values = 0.03, 0.01, and 0.04, respectively). Regarding general psychopathology scores, the reduction in the L-theanine group was also greater until week 4 (p-value < 0.01). The time × treatment interaction effect was significant on negative (p-value = 0.03), general psychopathology (p-value < 0.01), and total (p-value = 0.04) scores of PANSS, indicating additional improvements in the L-theanine group. The HDRS and side effects were comparable between the groups (p-values > 0.05). CONCLUSIONS: L-Theanine adjunct to risperidone safely and tolerably outperformed adjunctive placebo for schizophrenia, and promising evidence indicated its effects on primary negative symptoms, which need to be scrutinized in further studies. TRIAL REGISTRATION: The study protocol was registered and published prospectively in the Iranian Registry of Clinical Trials ( http://www.irct.ir ; registration number: IRCT20090117001556N133) on 2020-12-12.

Suicidality risk after using cannabis and cannabinoids: An umbrella review.

The increasing prevalence and burden of suicide have led to numerous studies to identify its risk factors. Cannabis is the most common illicit substance detected in suicide victims' toxicology tests. This study aims to identify and appraise systematic reviews investigating suicidality after using cannabis and cannabinoids. Seven databases and two registries were searched without restrictions for systematic reviews investigating cannabis effects on suicidality. AMSTAR-2 was used for quality assessment and corrected covered area and citation matrix were used to determine overlap. Twenty-five studies were included, of which 24 were on recreational use and one was on therapeutic use. Only three of the studies on recreational use reported no effect or inconsistent results. Evidence generally showed a positive association between cannabis use and suicidal ideation and attempt among the general population, military veterans, and bipolar or major depression patients. A bidirectional causal association between cannabis and suicidal ideation was also mentioned. Moreover, a younger age of initiation, long-term use, and heavy consumption were reported to be associated with even worse suicidal outcomes. On the contrary, current evidence indicates that the therapeutic cannabis is safe. In conclusion, the literature supports the cannabis-suicidality association in recreational use but considers cannabidiol safe for treatment. Further studies with quantitative and interventional approaches are recommended.

Neuroimaging Correlates of Treatment Response to Transcranial Magnetic Stimulation in Bipolar Depression: A Systematic Review.

Transcranial magnetic stimulation (TMS) has become a promising strategy for bipolar disorder (BD). This study reviews neuroimaging findings, indicating functional, structural, and metabolic brain changes associated with TMS in BD. Web of Science, Embase, Medline, and Google Scholar were searched without any restrictions for studies investigating neuroimaging biomarkers, through structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), functional MRI (fMRI), magnetic resonance spectroscopy (MRS), positron emission tomography (PET), and single photon emission computed tomography (SPECT), in association with response to TMS in patients with BD. Eleven studies were included (fMRI = 4, MRI = 1, PET = 3, SPECT = 2, and MRS = 1). Important fMRI predictors of response to repetitive TMS (rTMS) included higher connectivity of emotion regulation and executive control regions. Prominent MRI predictors included lower ventromedial prefrontal cortex connectivity and lower superior frontal and caudal middle frontal volumes. SPECT studies found hypoconnectivity of the uncus/parahippocampal cortex and right thalamus in non-responders. The post-rTMS changes using fMRI mostly showed increased connectivity among the areas neighboring the coil. Increased blood perfusion was reported post-rTMS in PET and SPECT studies. Treatment response comparison between unipolar depression and BD revealed almost equal responses. Neuroimaging evidence suggests various correlates of response to rTMS in BD, which needs to be further replicated in future studies.

l-theanine adjunct to sertraline for major depressive disorder: A randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Unsatisfactory responses to major depressive disorder (MDD) therapeutics available necessitated up-to-date treatment approaches. This study sought to investigate the efficacy and tolerability of adjunctive l-theanine, a green tea constituent with neuropsychotropic effects, for MDD. METHODS: Sixty MDD (DSM-5) patients were equally assigned to receive sertraline (100 mg/d) plus either l-theanine (200 mg/d) or matched placebo in a six-week randomized, parallel-group, double-blind, placebo-controlled study. The participants were assessed using the Hamilton depression rating scale (HDRS) at baseline and weeks 2, 4, and 6. Changes in scores, early improvement, response and remission rates, and adverse events were compared between the groups. RESULTS: Twenty-five participants in each group, a total of 50 patients, completed the study. All baseline characteristics were similar between the groups. The general linear model repeated-measures analysis demonstrated a significant time-treatment interaction effect for HDRS during the trial (p-value = 0.014), indicating more remarkable symptom improvement in the l-theanine group. A greater reduction in HDRS scores was observed in the l-theanine group from baseline to weeks 2, 4, and 6 (p-values = 0.02, 0.03, and 0.01, respectively). All patients responded to sertraline plus l-theanine until week 6. l-theanine was superior to placebo regarding response to treatment and remission rates at week 6 (p-values = 0.05 and 0.02, respectively). The frequency of side effects was comparable between the groups. LIMITATIONS: The small sample size and short study period were the limitations. CONCLUSIONS: l-theanine adjunct to sertraline outperforms placebo in treating MDD in a safe manner. Further long-term, large-scale studies are recommended to confirm this evidence.

Efficacy and tolerability of Lavandula angustifolia in treating patients with the diagnosis of depression: a systematic review of randomized controlled trials.

Pharmacotherapy is the conventional treatment for depression, with only half of the patients responding to the first trial of monotherapy with first-line medicines. One way to overcome this resistance is to use complementary and alternative medicine. The antidepressant effects of Lavandula angustifolia, which is commonly called lavender, have been investigated in previous studies. This study aims to provide the first systematic review of lavender in treating patients with depression diagnosis. ISI Web of Science, Scopus, PubMed, Embase, PsycINFO, Google Scholar, and three trial registries were searched until May 2020 to find randomized controlled trials on lavender for depressed patients. The primary outcome was difference between the intervention and control groups in changing depression scores from baseline to endpoint. The included studies were assessed for effect size and methodological quality. Seven clinical trials were identified, in which 852 patients were studied. In six trials, the effectiveness of lavender in treating depression was reported, as being more pronounced adjunct to a typical antidepressant in one study. Significant reported side effects include headaches and eructation. Lavender is beneficial, tolerable, and safe in treating depression. Despite obtaining promising results, they are not enough to recommend prescribing lavender to depressed patients. Further high-quality, large-scale studies for rectifying the shortcomings of existing studies are recommended.

ODSS vs. ABSIS and PDAI oral parts in pemphigus vulgaris: inter-rater reliability and testing times.

OBJECTIVES: The existence of standard methods for diagnosis and measuring the severity of diseases leads to a more accurate severity assessment, the possibility of following up, and the possibility of comparing the results of studies. This study aimed to compare different pemphigus vulgaris (PV) assessment methods regarding inter-observer reliability and testing times-focusing on oral parts. MATERIALS AND METHODS: Two dermatologists evaluated orally involved PV patients by oral parts of Autoimmune Bullous Skin Disorder Intensity Score (ABSIS), Pemphigus Disease Area Index (PDAI), and Oral Disease Severity Score (ODSS). RESULTS: Seventy patients completed the study. The intraclass correlation coefficient showed the evaluators' agreements on ABSIS, PDAI, and ODSS with 0.98, 0.94, and 0.95, respectively. Reliability analyses showed near-perfect relationships between each scoring methods pairs. There was no association between lesion sites and disease severity. The PDAI scoring duration was significantly shorter, and the ABSIS scoring duration was significantly longer. CONCLUSION: ODSS is valid for evaluating oral involvement in patients with PV and relates to ABSIS and PDAI almost perfectly. Besides, it was shown that the evaluation of patients' oral involvement based on PDAI and ODSS is done in about 1 min, which seems clinically reasonable.

Ketamine and Other Glutamate Receptor Modulating Agents for Treatment-Resistant Depression: A Systematic Review of Randomized Controlled Trials.

Objective: Available treatments of depression have limited efficacy and unsatisfactory remission rates. This study aims to review randomized controlled trials (RCTs) investigating effects of glutamate receptor modulators in treating patients with resistant depression. Method : The study protocol was registered in PROSPERO (CRD42021225516). Scopus, ISI Web of Science, Embase, Cochrane Library, Google Scholar, and three trial registries were searched up to September 2020 to find RCTs evaluating glutamate receptor modulators for resistant depression. The difference between intervention and control groups in changing depression scores from baseline to endpoint was considered the primary outcome. Version 2 of the Cochrane risk-of-bias tool for randomized trials was used to assess the quality of the RCTs. No funding was received. Results: Thirty-eight RCTs were included. Based on the included studies, compelling evidence was found for ketamine (with or without electroconvulsive therapy, intravenous or other forms), nitrous oxide, amantadine, and rislenemdaz (MK-0657); the results for MK-0657, amantadine, and nitrous oxide were only based on one study for each. Lithium, lanicemine, D-cycloserine, and decoglurant showed mixed results for efficacy, and, riluzole, and 7-chlorokynurenic acid were mostly comparable to placebo. A limited number of studies were available that addressed drugs other than ketamine. Conclusion: The study cannot determine the difference between statistical and clinical significance between the agents and placebo due to high heterogeneity among the RCTs. Nevertheless, ketamine could be used as an efficacious drug in TRD; still, additional studies are needed to delineate the optimum dosage, duration of efficacy, and intervals. Further studies are also recommended on the effectiveness of glutamatergic system modulators other than ketamine on treatment-resistant depression.

The neuropsychotropic effects of Crocus sativus L. (saffron): an overview of systematic reviews and meta-analyses investigating its clinical efficacy in psychiatric and neurological disorders.

Objective: Saffron is a spice derived from the Crocus sativus L. with antioxidant, anti-inflammatory, and neuroprotective effects. This study aims to systematically review the systematic reviews (SRs) investigating the clinical neuropsychotropic effects of saffron. Materials and Methods: The protocol of this SR was registered in PROSPERO (CRD42021268446). Scopus, ISI Web of Science, Embase, MEDLINE, PubMed, CINAHL, Cochrane Library, Google Scholar, and PROSPERO were searched up to June 6, 2021, to find SRs investigating the neuropsychotropic effects of saffron. The primary outcome was a report on whether or not saffron was effective in each study. AMSTAR was checked for the included reviews. Results: Twenty-three studies were reviewed with a mean AMSTAR score of 6.08 (ranging from 1 to 10). Thirteen SRs investigated the effects of saffron on depression. Six of the SRs studied its impact on sexual dysfunction. Each of the anxiety and cognitive disorders was discussed in three distinct reviews. Furthermore, possible effects of saffron on some other disorders, like premenstrual syndrome, postpartum depression, sleep disorders, and snacking behavior, have been reported. Conclusion: Saffron is beneficial, safe, and tolerable in treating the mentioned neurological and psychiatric disorders. Further high-quality, large-scale studies are recommended to rectify the shortcomings.

Crocus sativus (saffron) in the treatment of female sexual dysfunction: a three-center, double-blind, randomized, and placebo-controlled clinical trial.

Objective: One of the traditional aphrodisiacs used in various cultures is Crocus sativus, commonly called saffron. Previous studies have pointed to the possible applicability of saffron for sexual dysfunction in both men and women. This study investigates the effects of saffron capsules on female sexual dysfunction. Materials and Methods: This study was a parallel-group, double-blind, randomized, placebo-controlled clinical trial. Participants, who were married women between 18 and 55 years of age suffering from severe sexual dysfunction, were randomized to receive either 15 mg Crocus sativus capsules twice daily or placebo. The treatment continued for 6 weeks, and patients were evaluated every 2 weeks. The primary outcome was the change in the female sexual function index score. Other outcomes included the female sexual function index sub-domains. Results: Seventy -four patients were equally randomized to each group, and 34 in each group completed the trial. Participants in both groups experienced improved total scores at each visit. However, a repeated-measures ANOVA revealed that time treatment differed between groups in favor of the saffron group (p=0.050). During the 6th week follow-up, the saffron group had a 62% score improvement from baseline. Desire, lubrication, and satisfaction were female sexual function index domains in which saffron demonstrated superiority over placebo. The adverse event profile was similar for the groups, and no participant discontinued treatment. Conclusion: Findings of this study suggest that saffron might be a safe and effective option to ameliorate female sexual dysfunction. Further robust research is warranted.

The Perioperative Management of Antiplatelet and Anticoagulant Drugs in Hip Fractures: Do the Surgery as Early as Possible.

Hip fractures are among the most common fractures operated by orthopedic surgeons. Many elderly patients, who account for a significant percentage of hip fractures, suffer from medical conditions requiring antiplatelet and anticoagulant administration. Meanwhile, considerable evidence recommends early surgery within 48b hours of admission. We aim to review the existing evidence regarding the perioperative management of antiplatelet and anticoagulant drugs in hip fractures. It was concluded that surgery for hip fractures in patients with antiplatelet drug consumption should not be delayed unless a clear contraindication exists. Active reversal strategies are indicated for patients with hip fractures and warfarin therapy. However, evidence for the safety of these agents in pregnancy, breastfeeding state, and adolescence has not yet been established. Little data exists about perioperative management of direct-acting oral anticoagulants in hip fractures. Early surgery after 12-24 hours of drug cessation has been suggested in studies; however, it should be employed cautiously. Despite extensive research, the importance of the issue necessitates additional higher-quality studies.

Topiramate and other kainate receptor antagonists for depression: A systematic review of randomized controlled trials.

BACKGROUND: Depression is a common disorder that affects patients' quality of life and incurs health system costs. Due to the resistance to treat depression, better understanding of neurophysiology was considered; one of the implications is the glutamatergic system. This study aims to systematically review clinical trials investigating the antidepressant effects of kainate receptor antagonists. METHODS: The study protocol was registered in PROSPERO (CRD42021213912). Scopus, ISI, Embase, PubMed, Cochrane Library, Google Scholar, and two trial registries were searched for randomized controlled trials on the effectiveness of topiramate, phenobarbital, and other ten barbiturates in depression. The difference with control groups in terms of changing depressive symptoms was the primary outcome. RESULTS: Nine trials were identified, in which 784 patients were studied. The efficacy of thiopental was comparable to that of imipramine, with fewer side effects. When administered with electroconvulsive therapy, it had fewer to similar effects and fewer side effects than ketamine. Both monotherapy and adjunctive therapy with topiramate were effective and tolerable in treating depressed patients. Phenobarbital had therapeutic effects compared to imipramine and amitriptyline with fewer side effects. CONCLUSION: Regarding the glutamatergic hypothesis of depression and obtained promising results, further studies of kainate receptor antagonists in high-quality trials are recommended. Given the high prevalence of depression in epileptic patients, more problems with its treatment, and the fact that the studied agents were anticonvulsants, it is recommended that future studies prioritize depressed-epileptic patients.

Clinical, radiological, pedobarographic, and quality of life outcomes of the Ponseti treatment for clubfoot: a prospective study.

BACKGROUND: Talipes equinovarus, also known as clubfoot, is a congenital anomaly that affects one newborn per 1000 live births. Its standard treatment strategy is Ponseti casting management. This study aims to report the long-term outcomes of the Ponseti treatment in Iran. METHODS: A prospective cohort study was enrolled to evaluate clinical outcomes, radiological results, pedobarographic measurements, and quality of life after the Ponseti treatment in patients with clubfoot who were followed for at least five years. RESULTS: In this study, 25 clubfeet of 18 patients were included. Significant reductions in Pirani, Dimeglio, and CAP scores, improved ankle dorsiflexion, and acceptable pedobarographic indices were observed in this study. From the radiological evaluation indices, the calcaneal pitch and lateral talus-first metatarsal angles were significantly reduced. After five years of treatment, patients' quality of life was favorable, which was better in females. This study showed that the results of the Ponseti treatment remained acceptable after five years. CONCLUSIONS: The Ponseti management for clubfoot in the long term appears to maintain significant improvements. However, the recurrence rate - albeit without disruption to daily activities - cannot be ignored.

Erratum to 'Total Knee Arthroplasty and Atypical Cartilaginous Tumor/Enchondroma of the Distal Femur' [Arthroplasty Today 6 (2020) 521-525].

[This corrects the article DOI: 10.1016/j.artd.2020.06.005.].