Pharmacologic interventions for antidepressant-induced sexual dysfunction: a systematic review and network meta-analysis of trials using the Arizona sexual experience scale.

BACKGROUND: Despite the prevalence of antidepressant-related sexual side effects, comparisons of treatments for these problematic side effects are lacking. METHODS: To address this, we performed a systematic review and Bayesian network meta-analysis to compare interventions for antidepressant-induced sexual dysfunction in adults. Using PubMed and clinicaltrials.gov, we identified published and unpublished prospective treatment trials from 1985 to September 2020 (primary outcome: the Arizona sexual experience scale [ASEX] score). The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation framework. RESULTS: We identified 57 citations (27 randomized controlled trials, 66 treatment arms, 27 open-label trials, and 3 crossover trials) that evaluated 33 interventions (3108 patients). In the systematic review, 44% (25/57) of trials reported successful interventions; this was more common in open-label (70%, 19/27) compared to placebo-controlled studies (22%, 6/27). In the meta-analysis of placebo-controlled studies that used the ASEX (N = 8), pycnogenol was superior to placebo (standardized mean difference: -1.8, 95% credible interval [CrI]: [-3.7 to 0.0]) and there was evidence that, at a 6% threshold, sildenafil improved sexual dysfunction (standardized mean difference: -1.2, 95% CrI [-2.5 to 0.1]). In the meta-analysis including single-arm studies (15 studies), treatment response was more common with sildenafil, tianeptine, maca, tiagabine, and mirtazapine compared to placebo, but these differences failed to reach statistical significance. CONCLUSIONS: While heterogeneity across randomized controlled trials complicates identifying the single best intervention, multiple trials suggest that sildenafil ameliorates antidepressant-induced sexual dysfunction. More randomized controlled trials are needed to examine the putative efficacy of other interventions.

Bridging Anxiety and Depression: A Network Approach in Anxious Adolescents.

BACKGROUND: The phenomenology and neurobiology of depressive symptoms in anxious youth is poorly understood. METHODS: Association networks of anxiety and depressive symptoms were developed in adolescents with generalized anxiety disorder (GAD; N=52, mean age: 15.4±1.6 years) who had not yet developed major depressive disorder. Community analyses were used to create consensus clusters of depressive and anxiety symptoms and to identify "bridge" symptoms between the clusters. In a subset of this sample (n=39), correlations between cortical thickness and depressive symptom severity was examined. RESULTS: Ten symptoms clustered into an anxious community, 5 clustered into a depressive community and 5 bridged the two communities: impaired schoolwork, excessive weeping, low self-esteem, disturbed appetite, and physical symptoms of depression. Patients with more depressive cluster burden had altered cortical thickness in prefrontal, inferior and medial parietal (e.g., precuneus, supramarginal) regions and had decreases in cortical thickness-age relationships in prefrontal, temporal and parietal cortices. LIMITATIONS: Data are cross-sectional and observational. Limited sample size precluded secondary analysis of comorbidities and demographics. CONCLUSIONS: In youth with GAD, a sub-set of symptoms not directly related to anxiety bridge anxiety and depression. Youth with greater depressive cluster burden had altered cortical thickness in cortical structures within the default mode and central executive networks. These alternations in cortical thickness may represent a distinct neurostructural fingerprint in anxious youth with early depressive symptoms. Finally, youth with GAD and high depressive symptoms had reduced age-cortical thickness correlations. The emergence of depressive symptoms in early GAD and cortical development may have bidirectional, neurobiological relationships.

Efficacy and Tolerability of Pharmacotherapy for Pediatric Anxiety Disorders: A Network Meta-Analysis.

OBJECTIVE: To evaluate the efficacy and tolerability of pharmacotherapy in pediatric anxiety disorders using network meta-analysis. DATA SOURCES: PubMed, Cochrane Database, Web of Science, PsycNET, and ClinicalTrials.gov were searched for double-blind, controlled pharmacotherapy trials in youth with anxiety disorders from 1966 to September 2017. DATA SELECTION: All double-blind, placebo-controlled trials of pharmacotherapy in the treatment of pediatric patients with generalized, social, and/or separation anxiety disorders were included. DATA EXTRACTION: We extracted demographic, symptom severity, global improvement, discontinuation, and suicidality data. Risk of bias was assessed with the Cochrane risk-of-bias tool, and a network meta-analysis comparing the efficacy and tolerability of medications and medication classes was performed using the gemtc package (R). RESULTS: We identified 20 citations (22 RCTs, 24 treatment arms) with 2,623 patients. Selective serotonin reuptake inhibitors (SSRIs) were the only class that was superior in reducing anxiety (standardized mean difference: 5.2; credible interval [CrI]: [2.8 to 8.8]) and in likelihood of treatment response compared to placebo (odds ratio [OR]: 4.6; CrI: [3.1 to 7.5]). Serotonin-norepinephrine reuptake inhibitor (SNRI) and α2 agonist treatment were associated with more frequent treatment response compared to placebo. The likelihood of treatment response was greater for SSRIs compared to SNRIs (OR: 1.9; CrI: [1.1 to 3.5]). All-cause discontinuation and treatment-emergent suicidality significantly differed among medications but not medication class. CONCLUSIONS: Although multiple medications reduce anxiety in children and adolescents, treatment response, tolerability, and treatment-emergent suicidality differ among these medications and medication classes. Determining whether efficacy and tolerability differences represent true differences (or reflect differences in trial design) requires additional head-to-head medication trials and-to exclude the impact of missing treatment interventions-requires trials of medications that successfully treat anxiety in adults but that have not been evaluated in youth.

Suicidality in psychiatrically hospitalized children and adolescents: Demographics, treatment, and outcome.

BACKGROUND: Despite the high prevalence of suicidality in psychiatrically hospitalized youth, its risk factors and impact on inpatient psychopharmacologic treatment are unknown. We identified characteristics associated with suicidality in psychiatrically hospitalized youth and determined the association of suicidality with subsequent psychopharmacologic interventions. METHODS: Medical records from consecutive psychiatric admissions to a large, acute care, urban, pediatric hospital were analyzed retrospectively (N = 1,309). Demographic, clinical, and treatment-related features of suicidal and nonsuicidal youth were characterized. Logistic regression identified predictors of suicidality, and multiple comparison analyses evaluated the association between suicidality and changes to antidepressant prescribing during inpatient course. RESULTS: Compared with nonsuicidal patients, inpatients who were suicidal were more likely to have a mood disorder or posttraumatic stress disorder, as well as Cannabis and alcohol use, were more commonly girls, and at least 13 years of age (all P ≤ .05). Hospitalization was shorter for suicidal patients, was more likely to be associated with antidepressant treatment (P ≤ .001), and among suicidal patients prescribed antidepressants at the time of admission, was associated with a greater likelihood of changing antidepressant treatment compared with nonsuicidal inpatients (P ≤ .05). CONCLUSIONS: These findings reveal differences between suicidal and nonsuicidal psychiatrically hospitalized youth and suggest that suicidality is associated with specific pharmacologic treatment approaches within this population.

Placebo Response in Pediatric Anxiety Disorders: Results from the Child/Adolescent Anxiety Multimodal Study.

OBJECTIVES: The aim of this study is to identify predictors of pill placebo response and to characterize the temporal course of pill placebo response in anxious youth. METHODS: Data from placebo-treated patients (N = 76) in the Child/Adolescent Anxiety Multimodal Study (CAMS), a multisite, randomized controlled trial that examined the efficacy of cognitive-behavioral therapy, sertraline, their combination, and placebo for the treatment of separation, generalized, and social anxiety disorders, were evaluated. Multiple linear regression models identified features associated with placebo response and models were confirmed with leave-one-out cross-validation. The likelihood of improvement in patients receiving pill placebo-over time-relative to improvement associated with active treatment was determined using probabilistic Bayesian analyses. RESULTS: Based on a categorical definition of response (Clinical Global Impressions-Improvement Scale score ≤2), nonresponders (n = 48), and pill placebo responders (n = 18) did not differ in age (p = 0.217), sex (p = 0.980), race (p = 0.743), or primary diagnosis (all ps > 0.659). In terms of change in anxiety symptoms, separation anxiety disorder and treatment expectation were associated with the degree of pill placebo response. Greater probability of placebo-related anxiety symptom improvement was observed early in the course of treatment (baseline to week 4, p < 0.0001). No significant change in the probability of placebo-related improvement was observed after week 4 (weeks 4-8, p = 0.07; weeks 8-12, p = 0.85), whereas the probability of improvement, in general, significantly increased week over week with active treatment. CONCLUSIONS: Pill placebo-related improvement occurs early in the course of treatment and both clinical factors and expectation predict this improvement. Additionally, probabilistic approaches may refine our understanding and prediction of pill placebo response.

Primary Pediatric Care Psychopharmacology: Focus on Medications for ADHD, Depression, and Anxiety.

The evidence base for psychopharmacologic interventions in youth with depressive and anxiety disorders as well as attention/deficit hyperactivity disorder (ADHD) has dramatically increased over the past two decades. Psychopharmacologic interventions commonly utilized in the pediatric primary care setting-selective serotonin (norepinephrine) reuptake inhibitors (SSRIs/SSNRIs), stimulants and α2 agonists-are reviewed. General pharmacologic principles are summarized along with class-related side effects and tolerability concerns (e.g., suicidality and activation in antidepressant-treated youth as well as insomnia, irritability, anorexia in stimulant-treated pediatric patients). Selected landmark trials of antidepressant medications in youth with depressive disorders [Treatment of Adolescent Depression Study (TADS) and the Treatment of SSRI-Resistant Depression Study (TADS)] and anxiety disorders [Child/Adolescent Anxiety Multimodal Study (CAMS) and Child/Adolescent Anxiety Multimodal Extended Long-term Study (CAMELS)] are described in addition to the Multimodal Treatment of ADHD Study. Finally, available data are presented that are related to prediction of treatment outcomes in youth with depressive disorders, anxiety disorders, and ADHD.

Pharmacologic Treatment of Pediatric Anxiety Disorders.

The last decade has seen considerable advances in the treatment of anxiety disorders in children and adolescents and a considerable expansion of the evidence base for psychopharmacologic in this population. The extant data suggest that, for fear-based anxiety disorders (e.g., generalized anxiety disorder, social phobia/social anxiety disorder, and separation anxiety disorder), selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors (SSNRIs) are well tolerated and offer considerable benefit. However, the salutary effects of SSRIs and SSNRIs in pediatric anxiety disorders are consistently amplified by the addition of psychotherapy, particularly in individuals with social anxiety disorder. Additionally, several key demographic and clinical factors, including male sex, non-minority status, and better family functioning and younger age predict greater symptomatic improvement in youth with fear-based anxiety disorders. Thus, current data suggest that in addition to several forms of psychotherapy, including cognitive-behavioral therapy (CBT), SSRIs and SSNRIs are efficacious in the treatment of these conditions in youth and that CBT + an SSRI may be associated with greater improvement than would be expected with either treatment as monotherapy. Finally, given that some children and adolescents may exhibit partial response to current pharmacotherapies, benzodiazepines, anti-histamines and other agents may have adjunctive roles, despite a lack of data in terms of large, randomized controlled trials.

Placebo Response in Pediatric Anxiety Disorders: Implications for Clinical Trial Design and Interpretation.

OBJECTIVES: The characterization and prediction of placebo response in clinical trials of youth with anxiety disorders have received little attention, despite the critical effects of placebo response rate on the success or failure of clinical trials. With this in mind, we sought to examine the factors that predict or influence placebo response in randomized controlled trials of youth with anxiety disorders. METHODS: Prospective, randomized, parallel-group controlled trials of psychopharmacologic interventions in pediatric patients with anxiety disorders were identified using a search of PubMed/Medline (1966-2015). Weighted least squares regression models and z-tests were utilized to examine the impact of continuous and categorical variables, respectively, on placebo response. These variables included demographic (e.g., age, percent white, percent female), clinical (e.g., baseline symptom severity), and trial characteristics (sample size, duration, funding). Finally, the relationship between the class of comparator medication and placebo response rate was examined using a multiple comparison for proportions test. RESULTS: The analyses of data from 14 trials involving 2230 patients and 9 medications reveal that higher placebo response rates were associated with a greater number of study sites (p = 0.013) and fewer patients per site (p < 0.008), while placebo dropout rates increased with more recent publication (p = 0.01) and were positively associated with the number of study visits (p < 0.02). Lower placebo response rates were associated with federally funded studies (z = -4.61, p < 0.001), studies conducted in the United States (z = 1.81, p < 0.035), and with an increased likelihood of detecting a significant effect on the primary outcome (z = 4.58, p < 0.0001). Additionally, studies, in which the majority of patients (>60%) had a diagnosis of social anxiety disorder, exhibited lower placebo response rates (p < 0.001). Finally, for trials, effect size has decreased over time (p = 0.004). CONCLUSIONS: Important trial-specific factors affect placebo response and placebo dropout in youth with anxiety disorders and have pragmatic implications for the conduct and design of clinical trials and raise the possibility that limiting the number of sites while maximizing the number of patients per site could enhance the ability to detect medication-placebo differences.

Pharmacotherapy for Pediatric Generalized Anxiety Disorder: A Systematic Evaluation of Efficacy, Safety and Tolerability.

BACKGROUND: Randomized controlled trials consistently support the efficacy of antidepressants in treating youth with generalized anxiety disorder (GAD), although integrated examinations of efficacy, safety, and tolerability of psychotropic medications in GAD, specifically, are rare. With this in mind, we sought to describe the efficacy, safety, and tolerability of psychopharmacologic interventions in pediatric patients with GAD. METHODS: Randomized, double-blind, placebo-controlled, prospective trials of psychopharmacologic interventions in youth with GAD were identified through a PubMed/Medline (1966-2015) search. Both authors manually reviewed trials and, to evaluate comparative efficacy and tolerability across medications, numbers needed to treat (NNT) [based on Pediatric Anxiety Rating Scale (PARS) remission criteria (PARS ≤8)] and number needed to harm (NNH) for selected treatment-emergent adverse events (TEAEs) were calculated. Finally, treatment-emergent suicidality and taper-emergent/post-study adverse events are reported descriptively. RESULTS: Five trials that involved 1186 patients and evaluated four medications were reviewed and efficacy data were extracted with regard to dimensional measures of anxiety. Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) demonstrated efficacy in the reduction of anxiety symptoms with NNTs ranging from 2.8 to 9.3. TEAEs varied considerably between studies but tended to be mild and generally did not lead to discontinuation. CONCLUSIONS: Data from five trials of SSRI/SNRI in youth with GAD, many of whom had co-occurring separation and social anxiety disorders, suggest superiority to placebo and favorable tolerability profiles.

Programming pH-triggered self-assembly transitions via isomerization of peptide sequence.

While the ordering of amino acids in proteins and peptide-based materials is known to affect their folding patterns and supramolecular architectures, tailoring self-assembly behavior in stimuli responsive peptides by isomerizing a peptide sequence has not been extensively explored. Here, we show that changing the position of a single hydrophobic amino acid in short amphiphilic peptides can dramatically alter their pH-triggered self-assembly transitions. Using palmitoyl-IAAAEEEE-NH2 and palmitoyl-IAAAEEEEK(DO3A:Gd)-NH2 as controls, moving the Isoleucine away from the palmitoyl tail preferentially induces nanofiber formation over spherical micelles. Shifting the Isoleucine one residue away makes the transition pH more basic by 2 units. When in the third or fourth position, nanofibers are formed exclusively above 10 µM. We propose that moving the Isoleucine away from the tail enhances its ability to promote ß-sheet formation instead of folding back into the palmitoyl core. These findings reveal a novel strategy for programming pH-triggered self-assembly by isomerizing a peptide sequence.

Mechanism of the pH-Controlled Self-Assembly of Nanofibers from Peptide Amphiphiles.

Stimuli-responsive, self-assembling nanomaterials hold a great promise to revolutionize medicine and technology. However, current discovery is slow and often serendipitous. Here we report a multiscale modeling study to elucidate the pH-controlled self-assembly of nanofibers from the peptide amphiphiles, palmitoyl-I-A3E4-NH2. The coarse-grained simulations revealed the formation of random-coil based spherical micelles at strong electrostatic repulsion. However, at weak or no electrostatic repulsion, the micelles merge into a nanofiber driven by the ß-sheet formation between the peptide segments. The all-atom constant pH molecular dynamics revealed a cooperative transition between random coil and ß-sheet in the pH range 6-7, matching the CD data. Interestingly, although the bulk pKa is more than one unit below the transition pH, consistent with the titration data, the highest pKa's coincide with the transition pH, suggesting that the latter may be tuned by modulating the pKa's of a few solvent-buried Glu side chains. Together, these data offer, to our best knowledge, the first multiresolution and quantitative view of the pH-dependent self-assembly of nanofibers. The novel protocols and insights gained are expected to advance the computer-aided design and discovery of pH-responsive nanomaterials.