The role of metformin in treatment of weight gain associated with atypical antipsychotic treatment in children and adolescents: A systematic review and meta-analysis of randomized controlled trials.

Introduction: Second-generation antipsychotics are associated with significant weight gain. The aim of this systematic review and meta-analysis was to determine the efficacy and safety of metformin for the treatment of weight gain in children and young adults treated with second-generation antipsychotics. Methods: We followed PRISMA guidelines to evaluated studies published before March 2020 in Medline, Google Scholar, PubMed, Cochrane library database, annual scientific sessions of the American Psychiatric Association, American Academy of Child and Adolescent, Psychiatry, and American Society of Clinical Psychopharmacology. Studies included compared metformin with the placebo for management of weight gain in children and adolescents taking atypical antipsychotics. Non-randomized studies, animal experiment studies, editorials, and review studies were excluded. Multiple parameters, including change in anthropometric-biochemical parameters, drug discontinuation rate, and side effects among the groups were assessed. The random-effects method was used for meta-analysis. Results: Four studies with were included in the final analysis (213 patients; metformin: 106; control: 107). After pooled analysis, 12-16 weeks of metformin therapy was associated with a significant reduction in weight [(mean difference (MD): -4.53 lbs, confidence interval (CI): -6.19 to -2.87, p-value < 0.001)], and BMI z score [MD, -0.09, CI: -0.16, -0.03, p-value: 0.004] compared to control. Metformin was also associated with a significant reduction in insulin resistance [MD: -1.38, CI: -2.26 to -0.51, p-value: 0.002]. There were higher odds of nausea-vomiting [OR: 4.07, CI: 1.32-12.54, p-value: 0.02] and diarrhea [OR: 2.93, CI: 1.50-5.71, p-value: 0.002] in the metformin group. However, there was no difference in drug discontinuation rate [OR: 1.45, CI: 0.41-5.06, p-value: 0.56]. Conclusion: Metformin may prove beneficial in the treatment of weight gain in children treated with second-generation antipsychotics. The pooled treatment effect showed a significant reduction in BMI Z-score and weight in just 12-16 weeks. The limitations include small sample size, variation in metformin dose, and duration of treatment. This meta-analysis should be interpreted as promising, and further larger studies are warranted before drawing a conclusion.

A Plausible Explanation of Increased Suicidal Behaviors Among Transgender Youth Based on the Interpersonal Theory of Suicide (IPTS): Case Series and Literature Review.

BACKGROUND: Growing data on suicidal behavior among members of the lesbian, gay, bisexual, transgender, queer, questioning, and other sexual/gender minority (LGBTQ+) communities, particularly in the transgender subgroup, demonstrate that there is a stark elevation in suicidality compared with rates in their cisgender counterparts. Among the available theories of suicide, the interpersonal theory of suicide (IPTS) is a plausible explanation for the increased suicidal behaviors among transgender youths. OBJECTIVE: The objective of this study was to examine the pathologic basis of treatment-resistant suicidality in transgender youth despite favorable environments using the theoretical framework of the IPTS, supported by a literature review and case series. METHODS: We conducted a literature review using PubMed and PsycInfo with key words suicidal ideation, suicidality, transgender, transgender youth, gender dysphoria, and interpersonal theory of suicide. Seventy-eight articles were retrieved, which were then narrowed down to 30 articles after non-English articles and irrelevant topics were excluded. The clinical presentations of 5 transgender youths, 11 to 17 years of age, were found to be correlated with relevant reports in the research literature, implying a plausible rationale for elevated rates of suicide. All patients and families supplied verbal consent for these case reports to be published. RESULTS: Reasons for suicidal behavior among the patients included thwarted belongingness and perceived burdensomeness leading to perpetual suicidal behavior. The presence in these cases of the following contributing factors in the IPTS-thwarted belongingness, perceived burdensomeness, and acquired capability for suicide-suggests that such a basis exists. Perceived burdensomeness appears to have a greater correlation with developing suicidal behavior than thwarted belongingness alone, but the presence of both demonstrates the highest risk of suicidality in transgender youth. Transgender children and adolescents are at extremely high risk of suicidal behavior, but little research has been devoted to the etiology and plausible explanations for this elevated risk, despite growing awareness of and support for the problem. This review suggests further research is required on the triadic factor interactions of the IPTS model that could help us to better understand and intervene with this high-risk population.

Substance Use Disorders (SUD) and Suicidal Behaviors in Adolescents: Insights From Cross-Sectional Inpatient Study.

Objectives To determine the demographic predictors of suicidal behaviors and measure the association between the spectrum of substance use disorders (SUD) and hospitalization for suicidal behaviors in the adolescent population. Methods We conducted a cross-sectional study using the nationwide inpatient sample and included 466,244 adolescent inpatients with psychiatric illnesses. The study sample was sub-grouped into suicidal (N = 182,454) and non-suicidal (N = 283,790) cohorts. The odds ratio (OR) of association for demographic characteristics and comorbid SUD in the suicidal group was evaluated using a logistic regression model witha P-value < 0.01. Results Our study population included 466,244 adolescent inpatients. Females had higher odds of suicidal behaviors (OR 1.45; 95% CI 1.431-1.470) compared to males. The most prevalent comorbid SUD among suicidal inpatients was cannabis (15.3%) but had a statistically non-significant association with suicidal behaviors (OR 0.98; 95% CI 0.95-0.99). Inpatients with alcohol use disorders had significantly increased odds of association with suicidal behaviors (OR 1.18; CI: 1.142-1.209) compare to other SUD. Among other substances (cannabis and stimulants), there existed a statistically non-significant association with hospitalization for suicidal behaviors. Conclusion Adolescent inpatients with comorbid alcohol use disorders were at 18% higher odds of hospitalization for suicidal behaviors. Our study provides a basis for more research while also suggesting potential avenues for early identification and intervention efforts for comorbid SUD in adolescents requiring psychiatric care to improve their prognosis and quality of life.

Efficacy and Safety of Quetiapine for Pediatric Bipolar Depression: A Systematic Review of Randomized Clinical Trials.

Quetiapine is a second-generation antipsychotic (SGA) approved by the Food and Drug Administration (FDA) for the treatment of schizophrenia, mania, and aggression in children and adolescents. It is also commonly used as an off-label medication to treat children and adolescents with bipolar depression, although the FDA has not approved quetiapine for this purpose. We conducted a systematic review of randomized clinical trials (RCTs) using the MEDLINE database and included two studies that met our inclusion criteria. Both RCTs were eight-week short-term studies that involved patients of 10-18 years of age with a Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) diagnosis of bipolar disorder, depressed type. The mean difference in the Children's Depression Rating Scale-Revised (CDRS-R) score and the response and remission rates in the quetiapine group were not statistically significant when compared to the placebo group. A high placebo response rate proved that quetiapine was no better than the placebo in treating pediatric bipolar depression. Quetiapine proved to be a relatively safe drug with the most common side effects being headache, somnolence, gastric upset, and weight gain. There was a significant increase in triglyceride levels, but no other metabolic effects were reported. This calls for future studies with larger sample sizes and improved methodology to explore the efficacy of quetiapine and other SGAs for the management of pediatric bipolar depression.

Is Cannabis Use Associated With the Worst Inpatient Outcomes in Attention Deficit Hyperactivity Disorder Adolescents?

Objective To determine the impact of cannabis use disorder (CUD) on the inpatient outcomes of attention deficit hyperactivity disorder (ADHD) in adolescents Background Previous studies have evaluated the impact of CUD on the health-related quality of life in ADHD patients. Methods We used the nationwide inpatient sample (NIS) from the Healthcare Cost and Utilization Project (HCUP) from years 2010--2014. We identified ADHD and cannabis use (CU) as the primary and the other diagnosis, respectively, using validated International Classification of Diseases, 9th Revision, and Clinical Modification (ICD-9--CM) codes. We used the binomial logistic regression model to generate adjusted odds ratios (aOR). Results We analyzed a total of 11,232 ADHD adolescent hospital admissions from years 2010-2014; of these, 1.79% had CUD. The mean age of adolescents was 14.1 years (SD = 1.79). The prevalence of CUD was highest in ADHD adolescents of 15-18 years (73%) and common in the white race (71%). A higher proportion of ADHD with CUD was transferred to acute care hospitals and skilled/other nursing facilities (5.4% and 7.4% vs. 1.1% and 2.6%, respectively, p-value < 0.001). CUD increases the risk of inpatient charges > $12,247 (median) by 0.6 times (aOR = 1.835; p-value = 0.002) and increases the risk of inpatient stay > 5 days (median) by 0.7 times (aOR = 2.099; p-value < 0.001). The utilization of psychotropic medications was reduced by 0.8 times in ADHD with CUD adolescents by 0.8 times (aOR = 0.448; p-value = 0.017), and the implication of behavioral therapy in the management of ADHD with CUD adolescents was reduced by 0.9 times (aOR = 0.412; p-value = 0.048). Also, there is a 2.8 times higher risk of comorbid alcohol abuse in ADHD with CUD adolescents (aOR = 17.141; p-value < 0.001). Conclusion The increased risk of substance use is a long-term implication of ADHD in adolescents. It has been determined that comorbid CUD in patients with ADHD not only increases the risk of acute inpatient care but also prolongs the inpatient stay, thus increasing the healthcare cost. Surprisingly, comorbid CUD decreases the utilization of psychotropic medications and behavioral therapy in ADHD. Another major issue is the higher risk of comorbid alcohol abuse in ADHD with CUD adolescents. Further exploration with randomized controlled studies would be required to support and highlight the growing issue of cannabis use among adolescents with ADHD.

Role of Repetitive Transcranial Magnetic Stimulation (rTMS) in Treatment of Addiction and Related Disorders: A Systematic Review.

BACKGROUND: Addiction and related disorders are devastating with their tremendous social, psychological, and physical consequences for which development of optimally effective treatments is long overdue. Repetitive Transcranial Magnetic Stimulation (rTMS) is relatively safe and is becoming an emerging therapeutic tool for these conditions. METHODS: This systematic review was conducted using PubMed, PsycINFO, PsychiatryOnline and Cochrane Library ranging from year 2001 to 2017. RESULTS: Our search selected 70 related articles of which, based on the Strength of Recommendation Taxonomy (SORT) guidelines, 11 indicated Level-1 study quality and class-B strength of recommendation for rTMS in nicotine addiction (effective in 218/289 subjects who received rTMS as found in 11 studies). Level-2/Class-B evidence was found for alcohol and cocaine addictions (Alcohol: effective in 126/193 subjects who received rTMS as found in 8 studies; Cocaine: effective in 86/128 subjects, as found in 5 studies). For food cravings, Level-3/Class-B evidence was noted (effective in 134/169, found in 7 studies). However, the evidence was limited to Level-3/Class-C for heroin (10/20 subjects received active rTMS, effective in 1 study), methamphetamine (33/48 subjects received active rTMS, effective in 2 studies), cannabis (18/18 subjects received active rTMS, effective in 1 study), and pathological gambling (31/31 subjects received active rTMS, effective in 2 studies). CONCLUSION: rTMS may serve as an emerging therapeutic option for addiction and related disorders. The major lacunae include important methodological limitations and dearth of knowledge about precise mechanism of action that need to be addressed in the future studies.

Impact of Depression on Hospitalization and Related Outcomes for Parkinson's Disease Patients: A Nationwide Inpatient Sample-Based Retrospective Study.

Background Major Depressive Disorder (MDD) is a common comorbidity that significantly affects the quality of life and disease outcomes in Parkinson's disease (PD) patients. No studies have been conducted to our knowledge to address the health care utilization and its outcomes in these patients. The aim of this study is to analyze and discern the differences in the hospitalization outcomes, comorbid conditions, and utilization of procedures in PD patients versus patients with comorbid MDD. Methods We used the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project from year's 2010-2014. We identified PD and MDD as a primary and secondary diagnosis respectively using validated International Classification of Diseases, 9th Revision, and Clinical Modification codes. Pearson's chi-square test and independent sample T-test were used for categorical data and continuous data, respectively. All statistical analysis was done by SPSS 22.0 in this study. Results Extensive analysis was performed on 63,912 patients with PD and 1445 patients with PD having MDD. Patients with comorbid depression had three times greater chances of disposition to acute care hospital (3.1% vs. 1.1%, p < 0.001). Median length of hospitalization was higher in Parkinson's patients with depression (5.85 vs. 4.08 days; p < 0.001) though the median cost of hospitalization was low ($ 31,039 vs. $ 39,464; p < 0.001). This could be because therapeutic procedures performed during the hospitalization were lower in Parkinson's patients with depression (0.53 vs. 0.89, p < 0.001). Utilization of Deep Brain Stimulation (DBS) was lower in Parkinson's patients with depression (9.4% vs. 25.6%, p < 0.001). In--hospital mortality was significantly higher in Parkinson's patients with depression (1.4% vs. 1.1%; p < 0.001). Conclusion Our study establishes the negative impact of depression in PD with regards to hospitalization-related outcomes including the illness severity, comorbid conditions, risk of mortality, utilization of diagnostic and therapeutic procedures, the length of stay and disposition as compared to PD without depression.

Nonconventional interventions for chronic post-traumatic stress disorder: Ketamine, repetitive trans-cranial magnetic stimulation (rTMS), and alternative approaches.

It is alarming that only 59% of those who have post-traumatic stress disorder (PTSD) respond to selective serotonin reuptake inhibitors. Many existing treatments, both pharmacological and nonpharmacological, do not directly target trauma memories that lay at the core of the PTSD pathogenesis. Notable exceptions are medications like ketamine and propranolol and trauma-focused psychotherapies like eye-movement desensitization and reprocessing therapy (developed by Shapiro) and Trauma Interventions using Mindfulness Based Extinction and Reconsolidation (TIMBER) for trauma memories (developed by Pradhan). Although the antidepressant effects of ketamine are no longer news, ketamine's effects on treatment refractory PTSD (TR-PTSD) is a recent concept. As TR-PTSD has a marked public health burden and significant limitations in terms of treatment interventions, a thorough assessment of current strategies is required. Research to bring clarity to the underlying pathophysiology and neurobiology of TR-PTSD delineating the chemical, structural, and circuitry abnormalities will take time. In the interim, in the absence of a 1-size-fits-all therapeutic approach, pragmatically parallel lines of research can be pursued using the pharmacological and nonpharmacological treatments that have a strong theoretical rationale for efficacy. This article aims to review the current literature on interventions for PTSD, most notably ketamine, trans-cranial magnetic stimulation treatment, yoga and mindfulness interventions, and TIMBER. We present an outline for their future use, alone as well as in combination, with a hope of providing additional insights as well as advocating for developing more effective therapeutic intervention for this treatment-resistant and debilitating condition.

Ketamine, Transcranial Magnetic Stimulation, and Depression Specific Yoga and Mindfulness Based Cognitive Therapy in Management of Treatment Resistant Depression: Review and Some Data on Efficacy.

Depression affects about 121 million people worldwide and prevalence of major depressive disorder (MDD) in US adults is 6.4%. Treatment resistant depression (TRD) accounts for approximately 12-20% of all depression patients and costs $29-$48 billion annually. Ketamine and repetitive transcranial magnetic stimulation (rTMS) have useful roles in TRD, but their utility in long term is unknown. As per the latest literature, the interventions using Yoga and meditation including the mindfulness based cognitive therapy (MBCT) have been useful in treatment of depression and relapse prevention. We present a review of rTMS, ketamine, and MBCT and also report efficacy of a depression specific, innovative, and translational model of Yoga and mindfulness based cognitive therapy (DepS Y-MBCT), developed by the first author. DepS Y-MBCT as an adjunctive treatment successfully ameliorated TRD symptoms in 27/32 patients in an open label pilot trial in TRD patients. Considering the limitations of existing treatment options, including those of ketamine and rTMS when used as the sole modality of treatment, we suggest a "tiered approach for TRD" by combining ketamine and rTMS (alone or along with antidepressants) for rapid remission of acute depression symptoms and to use DepS Y-MBCT for maintaining remission and preventing relapse.

Elevation of 1-hour plasma glucose during oral glucose tolerance testing is associated with worse pulmonary function in cystic fibrosis.

OBJECTIVE: Cystic fibrosis (CF)-related diabetes (CFRD) is associated with declining pulmonary function and increased mortality. During oral glucose tolerance testing (OGTT), CFRD is defined by 2-h plasma glucose (PG2). We hypothesized PG elevations during OGTT resolving by 2 h, not meeting CFRD criteria, influence pulmonary function in CF. Thus we investigated the frequency of elevated 1-h OGTT PG (PG1) and its relationship with pulmonary function. RESEARCH DESIGN AND METHODS: Retrospective review of OGTTs was performed between August 2005 (annual screening initiation) and June 2008 at Children's Hospital of Philadelphia CF Center. First-time, well state OGTTs (PG0, PG1, PG2) were analyzed. Additional data collected were: percent predicted forced expiratory volume in 1 s (FEV(1)), BMI percentile, lung bacterial colonization, age, and sex. OGTTs were categorized as normal (PG2 <140 mg/dL), impaired glucose tolerance (IGT) (PG2 140-199 mg/dL), CFRD (PG2 ≥ 200 mg/dL), and indeterminate glycemia (INDET) (PG1 ≥ 200 mg/dL and PG2 <140 mg/dL). Frequency of PG1 ≥ 140 but <200 mg/dL was also noted. Multivariable linear regression was used to assess associations between percent predicted FEV(1), BMI percentile, and OGTT PG. RESULTS: OGTTs (101) were available (59 male/42 female; age 5.8-22 years, percent predicted FEV(1) = 94.5 ± 18%, BMI percentile = 52 ± 25%). With the use of PG2, 91 OGTT were normal, eight were IGT, and two were CFRD. With the use of PG1 (n = 89), 39 OGTT were normal, 36 were PG1 ≥ 140 <200 mg/dL, and 14 were PG1 ≥ 200 mg/dL. PG1 was negatively associated with percent predicted FEV(1), adjusting for BMI percentile (P = 0.009, R(2) 0.13). Percent predicted FEV(1) was not associated with PG0, PG2, age, sex, or lung bacterial colonization. CONCLUSIONS: PG elevations at nontraditional OGTT times are common in CF. The association of increasing PG1 with worse pulmonary function suggests early PG abnormalities may be deleterious or an early marker for worsening disease and will be missed if CFRD diagnosis focuses on PG2.