Pharmacotherapy Trials Research Articles

Predicting Medication Nonadherence in Older Adults With Difficult-to-Treat Depression in the IRL-GRey Randomized Controlled Trial

Nonadherence to antidepressants interferes with optimal treatment of late-life depression. This analysis examines clinical and treatment factors predicting medication nonadherence in difficult-to-treat late-life depression. Secondary analysis of data from a clinical trial of antidepressant pharmacotherapy for Major Depressive Disorder in 468 adults aged 60+ years. All participants received venlafaxine XR for 12 weeks. Nonremitters were randomized to augmentation with either aripiprazole or placebo for 12 additional weeks. Medication adherence was assessed 14 times over 24 weeks. The analyses examined sociodemographic, clinical, and treatment factors that may predict antidepressant nonadherence during early (weeks 1-6), late (weeks 7-12), and augmentation (weeks 13--24) treatment. Poor cognitive function and early response were predictive of early nonadherence. Poor cognitive function and prior nonadherence were predictive of late nonadherence. Living alone was associated with nonadherence both late and during augmentation treatment. Future studies should consider the role of early response and cognitive function to improve antidepressant adherence, particularly among older adults who live alone.

Pharmacotherapy for post traumatic stress disorder (PTSD).

Posttraumatic stress disorder (PTSD) is a prevalent and disabling disorder. Evidence that PTSD is characterised by specific psychobiological dysfunctions has contributed to a growing interest in the use of medication in its treatment. To assess the effects of medication for reducing PTSD symptoms in adults with PTSD. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 11, November 2020); MEDLINE (1946-), Embase (1974-), PsycINFO (1967-) and PTSDPubs (all available years) either directly or via the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR). We also searched international trial registers. The date of the latest search was 13 November 2020. All randomised controlled trials (RCTs) of pharmacotherapy for adults with PTSD. Three review authors (TW, JI, and NP) independently assessed RCTs for inclusion in the review, collated trial data, and assessed trial quality. We contacted investigators to obtain missing data. We stratified summary statistics by medication class, and by medication agent for all medications. We calculated dichotomous and continuous measures using a random-effects model, and assessed heterogeneity. We include 66 RCTs in the review (range: 13 days to 28 weeks; 7442 participants; age range 18 to 85 years) and 54 in the meta-analysis. For the primary outcome of treatment response, we found evidence of beneficial effect for selective serotonin reuptake inhibitors (SSRIs) compared with placebo (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.59 to 0.74; 8 studies, 1078 participants), which improved PTSD symptoms in 58% of SSRI participants compared with 35% of placebo participants, based on moderate-certainty evidence. For this outcome we also found evidence of beneficial effect for the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine: (RR 0.45, 95% CI 0.22 to 0.94; 1 study, 26 participants) in 65% of people on mirtazapine compared with 22% of placebo participants, and for the tricyclic antidepressant (TCA) amitriptyline (RR 0.60, 95% CI 0.38 to 0.96; 1 study, 40 participants) in 50% of amitriptyline participants compared with 17% of placebo participants, which improved PTSD symptoms. These outcomes are based on low-certainty evidence. There was however no evidence of beneficial effect for the number of participants who improved with the antipsychotics (RR 0.51, 95% CI 0.16 to 1.67; 2 studies, 43 participants) compared to placebo, based on very low-certainty evidence. For the outcome of treatment withdrawal, we found evidence of a harm for the individual SSRI agents compared with placebo (RR 1.41, 95% CI 1.07 to 1.87; 14 studies, 2399 participants). Withdrawals were also higher for the separate SSRI paroxetine group compared to the placebo group (RR 1.55, 95% CI 1.05 to 2.29; 5 studies, 1101 participants). Nonetheless, the absolute proportion of individuals dropping out from treatment due to adverse events in the SSRI groups was low (9%), based on moderate-certainty evidence. For the rest of the medications compared to placebo, we did not find evidence of harm for individuals dropping out from treatment due to adverse events. The findings of this review support the conclusion that SSRIs improve PTSD symptoms; they are first-line agents for the pharmacotherapy of PTSD, based on moderate-certainty evidence. The NaSSA mirtazapine and the TCA amitriptyline may also improve PTSD symptoms, but this is based on low-certainty evidence. In addition, we found no evidence of benefit for the number of participants who improved following treatment with the antipsychotic group compared to placebo, based on very low-certainty evidence. There remain important gaps in the evidence base, and a continued need for more effective agents in the management of PTSD.

A Meta-Regression of Trial Features Predicting the Effects of Alcohol Use Disorder Pharmacotherapies on Drinking Outcomes in Randomized Clinical Trials: A Secondary Data Analysis.

To test whether two critical design features, inclusion criteria of required pre-trial abstinence and pre-trial alcohol use disorder (AUD) diagnosis, predict the likelihood of detecting treatment effects in AUD pharmacotherapy trials. This secondary data analysis used data collected from a literature review to identify randomized controlled pharmacotherapy trials for AUD. Treatment outcomes were selected into abstinence and no heavy drinking. Target effect sizes were calculated for each outcome and a meta-regression was conducted to test the effects of required pre-trial abstinence, required pre-trial AUD diagnosis, and their interaction on effect sizes. A sub-analysis was conducted on trials, which included FDA-approved medications for AUD. In total, 118 studies testing 19 medications representing 21,032 treated participants were included in the meta-regression analysis. There was no significant effect of either predictor on abstinence or no heavy drinking outcomes in the full analysis or in the sub-study of FDA-approved medications. By examining these design features in a quantitative, rather than qualitative, fashion the present study advances the literature and shows that requiring AUD diagnosis or requiring pre-trial abstinence do not impact the likelihood of a significant medication effect in the trial.

Are study populations in trials of antidepressants and psychotherapy comparable? A retrospective case study of two parallel running trials for multi- organ functional somatic disorder

This study retrospectively compares two previous parallel running, randomized, controlled trials of pharmacotherapy (imipramine) and psychotherapy (acceptance and commitment therapy) for multi-organ functional somatic disorder (FSD). Differences in demographics, psychiatric comorbidity, illness severity, and illness duration associated with eligibility for the two trials and patients' willingness to participate are explored using linear or binary regression models. 418 patients with multi-organ FSD was included. We found that 377 (95%) were eligible for psychotherapy and 257 patients (61%) for pharmacotherapy. Patients eligible for pharmacotherapy were less severely impaired, less often received disability pension, reported shorter illness duration and experienced less psychological distress than patients eligible for psychotherapy. Whilst exclusion criteria for both trials differed markedly, it was not possible to clearly identify patient or illness characteristics associated with patients' willingness to participate. The study showed that trial-specific exclusion criteria led to the selection of less complex and less severely impaired patients in the pharmacological trial in this sample of multi-organ FSD. Our findings have important implications for the interpretation and comparability of RCT results of different treatments in multi-organ FSD and may point to some common flaws in study design and interpretation of pharmacological vs. psychotherapeutic intervention trials in psychiatry.

The efficacy of psychotherapies and pharmacotherapies for mental disorders in adults: an umbrella review and meta-analytic evaluation of recent meta-analyses.

Mental disorders represent a worldwide public health concern. Psychotherapies and pharmacotherapies are recommended as first line treatments. However, evidence has emerged that their efficacy may be overestimated, due to a variety of shortcomings in clinical trials (e.g., publication bias, weak control conditions such as waiting list). We performed an umbrella review of recent meta-analyses of randomized controlled trials (RCTs) of psychotherapies and pharmacotherapies for the main mental disorders in adults. We selected meta-analyses that formally assessed risk of bias or quality of studies, excluded weak comparators, and used effect sizes for target symptoms as primary outcome. We searched PubMed and PsycINFO and individual records of the Cochrane Library for meta-analyses published between January 2014 and March 2021 comparing psychotherapies or pharmacotherapies with placebo or treatment-as-usual (TAU), or psychotherapies vs. pharmacotherapies head-to-head, or the combination of psychotherapy with pharmacotherapy to either monotherapy. One hundred and two meta-analyses, encompassing 3,782 RCTs and 650,514 patients, were included, covering depressive disorders, anxiety disorders, post-traumatic stress disorder, obsessive-compulsive disorder, somatoform disorders, eating disorders, attention-deficit/hyperactivity disorder, substance use disorders, insomnia, schizophrenia spectrum disorders, and bipolar disorder. Across disorders and treatments, the majority of effect sizes for target symptoms were small. A random effect meta-analytic evaluation of the effect sizes reported by the largest meta-analyses per disorder yielded a standardized mean difference (SMD) of 0.34 (95% CI: 0.26-0.42) for psychotherapies and 0.36 (95% CI: 0.32-0.41) for pharmacotherapies compared with placebo or TAU. The SMD for head-to-head comparisons of psychotherapies vs. pharmacotherapies was 0.11 (95% CI: -0.05 to 0.26). The SMD for the combined treatment compared with either monotherapy was 0.31 (95% CI: 0.19-0.44). Risk of bias was often high. After more than half a century of research, thousands of RCTs and millions of invested funds, the effect sizes of psychotherapies and pharmacotherapies for mental disorders are limited, suggesting a ceiling effect for treatment research as presently conducted. A paradigm shift in research seems to be required to achieve further progress.

Systematic review and meta-analysis of the placebo effect in panic disorder: Implications for research and clinical practice.

This review aimed to measure the degree of placebo response in panic disorder. We searched major databases up to 31 January 2021, for randomized pharmacotherapy trials published in English. A total of 43 studies met inclusion criteria to be in the analysis (with 174 separate outcome measurements). Changes in outcome measures from baseline in the placebo group were used to estimate modified Cohen's d effect size. A total of 43 trials (2392 subjects, 174 outcomes using 27 rating scales) were included in the meta-analysis. Overall placebo effect size was 0.57 (95% confidence interval = [0.50, 0.64]), heterogeneity (I2: 96.3%). Higher placebo effect size was observed among clinician-rated scales compared to patient reports (0.75 vs 0.35) and among general symptom and anxiety scales compared to panic symptoms and depression scales (0.92 and 0.64 vs 0.56 and 0.54, respectively). There was an upward trend in effect size over the publication period (r = 0.02, p = 0.002) that was only significant among clinician-rated scales (r = 0.02, p = 0.011). There was no significant publication bias, Egger's test (p = 0.08). We observed a substantial placebo effect size in panic disorder. This effect was more prominent for some aspects of panic disorder psychopathology than for others and was correlated with the source of the assessment and publication year. This finding has implications both for research design, to address the heterogeneity and diversity in placebo responses, and for clinical practice to ensure optimal quality of care. PROSPERO, CRD42019125979.

Temporal trends in the inclusion of patient-reported outcomes in heart failure randomized trials published in high-impact medical journals: a systematic bibliometric review

Abstract Background Patient reported outcomes (PROs) are important measures of health, particularly in symptomatic conditions such as heart failure (HF), and regulatory agencies have encouraged their collection in randomized controlled trials (RCTs). Purpose To assess temporal trends in the inclusion of patient-reported outcomes (PROs) in heart failure (HF) randomized controlled trials (RCTs) published in high-impact medical journals, explore trial characteristics associated with inclusion of PROs, and describe the quality of PRO reporting in HF RCTs. Methods We searched MEDLINE, EMBASE and CINAHL for studies published between January 1, 2000 and July 17, 2020. We included RCTs published in journals with impact factor ≥10. We assessed temporal trends using the Jonckheere-Terpstra test and conducted multivariable logistic regression analysis to explore trial characteristics independently associated with inclusion of PROs. We assessed the quality of PRO reporting using the Consolidated Standards for Trial Reporting PRO extension statement. Results We identified 12,342 articles, of which 417 RCTs met inclusion criteria. PROs were included in 224 RCTs (53.7%, 95% confidence interval [CI]: 48.8%-58.6%), of which 44 (19.6%) reported PRO as primary or co-primary endpoint. The proportion of RCTs with PROs increased significantly between 2000–2003 (37.4%) and 2016–2020 (65.1%) (p<0.001). PROs had higher odds of inclusion in RCTs that were multicenter (odds ratio [OR]: 1.95; 95% CI: 1.05–3.64; p=0.036); medium-sized (n=51–250) (OR: 2.29; 95% CI: 1.24–4.23; p=0.008); coordinated in in Central and South America (OR: 6.79; 95% CI: 1.34–34.36; p=0.021); and assessed health services (OR: 4.21; 1.97–8.98; p<0.001), device / surgical (OR: 6.24; 95% CI 3.05–12.80; p<0.001), or exercise and rehabilitation interventions (OR: 3.98; 95% CI 1.59–9.97; p=0.003). A majority (54.9%) of the 224 RCTs reported four or less of the eleven CONSORT-PRO items. The median number of CONSORT-PRO items reported was 4 (interquartile range [IQR] 3–6 items per trial), with improved reporting in trials with PRO as primary or co-primary endpoint. Conclusions PROs are included in in just over half of HF RCTs, with an increased reporting of PROs between 2000 and 2020. Large, pharmacotherapy trials conducted in North America and Europe were less likely to include PROs. The quality of PRO reporting in HF RCTs was modest, with trials most often reporting four of eleven CONSORT-PRO items. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Canadian Institutes of Health Research

Meta-analyses of the efficacy of pharmacotherapies and sublingual allergy immunotherapy tablets for allergic rhinitis in adults and children.

Treatment options for seasonal and perennial allergic rhinitis (SAR/PAR) include pharmacotherapies and allergy immunotherapy. These meta-analyses evaluated the efficacy of pharmacotherapies and sublingual immunotherapy tablets (SLIT-tablets) versus placebo on nasal symptoms associated with SAR and PAR. Randomized, double-blind, placebo-controlled trials were identified from systematic PubMED/EMBASE searches through 7/18/2019 (PROSPERO protocol CRD42018105632). The primary outcome was mean numerical difference in total nasal symptom score (TNSS; 0-12) between active treatment and placebo at the end of the assessment period. Random-effects meta-analyses estimated the mean difference for each medication group weighted by the inverse of the trial variance. Publication bias assessments and sensitivity analyses were conducted. Rescue symptom-relieving pharmacotherapy was prohibited in most pharmacotherapy trials but was allowed in all SLIT-tablet trials. For adult/adolescent SAR, the mean numerical difference (95% CI) in TNSS versus placebo was: intranasal corticosteroids (INCS)=1.38 (1.18, 1.58; 39 trials); combination intranasal antihistamine/INCS=1.34 (1.15, 1.54; 4 trials); intranasal antihistamines=0.72 (0.56, 0.89; 13 trials); oral antihistamine=0.62 (0.35, 0.90; 18 trials); SLIT-tablets=0.57 (0.41, 0.73; 4 trials); and montelukast=0.48 (0.36, 0.60; 10 trials). For adult/adolescent PAR, mean difference in TNSS versus placebo (95% CI) was: INCS=0.82 (0.66, 0.97; 14 trials); SLIT-tablets=0.65 (0.42, 0.88; 3 trials); and oral antihistamine=0.27 (0.11, 0.42; 3 trials). The number of eligible trials limited meta-analyses for pediatric SAR/PAR. All treatments significantly improved nasal symptoms versus placebo. SLIT-tablets provided improvement in TNSS despite access to rescue symptom-relieving pharmacotherapy. Extensive trial heterogeneity and strong indications of publication bias preclude the comparison of treatment effects among treatment classes.

The relationship of frequency of cocaine use to substance and psychiatric disorders in the U.S. general population

BackgroundIn clinical trials of pharmacotherapy for substance use, abstinence is the primary endpoint accepted by regulatory agencies. However, this endpoint could be overly restrictive, impeding efforts to identify effective medications for cocaine use disorder. To examine non-abstinent gradations in cocaine use as potential indicators of improvement, we investigated the relationship of frequency of cocaine use to clinical correlates in national survey data. MethodsLifetime cocaine users (n = 2501) were interviewed in the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) in 2001−2002 and re-interviewed in 2004–2005. Adjusted odds ratios (aORs) indicated associations between heaviest frequency of cocaine use and use of other substances, DSM-IV substance use disorders, psychiatric disorders, and change between 2001−2002 and 2004–2005. The reference category for all aORs was non-users. ResultsGreater lifetime cocaine use frequency was associated with lifetime cocaine, alcohol, and cannabis dependence (aOR for a linear trend = 2.80, 1.22, 1.22, respectively) and past-year cocaine, alcohol, and cannabis dependence (aOR = 1.78, 1.13, 1.16, respectively). Greater lifetime cocaine use frequency was associated with past-year depressive, panic, and generalized anxiety disorders (aOR = 1.07, 1.09, 1.12, respectively). Among cocaine users in 2001−2002, compared to the reference group using less than monthly, use ≥1x/week and use 1−3 times a month was associated with cocaine use disorder in 2004–2005 (aOR = 2.13 and aOR = 1.67, respectively). ConclusionGradations in risk for dependence on cocaine, other substances and psychiatric disorders by frequency of cocaine use indicates a promising direction for more sensitive outcome measures of treatment effects on cocaine outcomes than binary indicators (e.g., any use vs. none). Study results add to findings suggesting that non-abstinent measures might be useful indicators of treatment efficacy in clinical trials.

Patterns of reduced use and abstinence in multi-site randomized controlled trials of pharmacotherapies for cocaine and methamphetamine use disorders

BackgroundMany individuals with cocaine or methamphetamine use disorders who enter treatment do not achieve abstinence but reduce their use of the target drug. We aimed to compare change in pattern of drug use (i.e., achieving “abstinence”, “reduced use” or no reduction in use) among participants in randomized controlled trials (RCTs) of treatment of cocaine and methamphetamine use disorder, irrespective of the type of treatment. MethodsThe data were drawn from 10 multi-site pharmacotherapy RCTs of cocaine (n = 1,134) and methamphetamine (n = 555) use disorders. The outcome patterns and their sociodemographic and clinical correlates were compared in cocaine and methamphetamine RCTs, using multinomial logistic regression models. Analyses were adjusted for missing data, clustering within RCTs, socio-demographic and baseline clinical characteristics, and treatment arms. ResultsThose in cocaine RCTs were more likely to experience reduced use compared to participants in methamphetamine RCTs (20.6% vs. 13.2%, respectively), but less likely to experience “abstinence” (7.6% vs. 20.3%; Chi-squared = 14.20, df = 2, P < 0.001). Differences in “abstinence” persisted after adjustment for baseline covariates. Association of sociodemographic and clinical correlates with outcomes differed in cocaine and methamphetamine RCTs. ConclusionA sizeable proportion of individuals in RCTs of pharmacological treatment for stimulant use disorder who do not attain “abstinence” nevertheless reduce their use. The outcome patterns of drug use are different for cocaine and methamphetamine use disorders and reliance on abstinence as the sole outcome may obscure these differences.

World Health Organization risk drinking levels as a treatment outcome measure in topiramate trials.

Although abstinence has traditionally been considered the only suitable outcome for alcohol treatment, reduced drinking is also associated with improved functioning and medical and psychiatric outcomes. The World Health Organization (WHO) risk drinking levels (RDLs) have been shown to be valid outcome measures in treatment trials for alcohol use disorder (AUD). We conducted a secondary analysis of two 12-week, randomized controlled trials (RCTs), in which a total of 308 individuals with problematic alcohol use received topiramate or placebo treatment. We compared the utility of the WHO RDLs with other treatment outcomes, including self-reported measures of alcohol consumption, alcohol-related problems, and quality of life, and the biomarker gamma-glutamyltransferase. Topiramate treatment was associated with small effect sizes for both a 1-level (d=0.26) and a 2-level (d=0.19) reduction in WHO RDL, effects that were not significant after correction for multiple comparisons. No heavy drinking days, one of the outcome measures recommended by the US Food and Drug Administration for alcohol medication registration trials, also exhibited a small effect (0.21), while an effect size for abstinence could not be calculated. There were medium effects of topiramate on continuous measures of percent heavy drinking days (d=0.49) and alcohol-related problems (d=0.41). Topiramate is an efficacious pharmacotherapy for AUD. Although continuous measures of drinking and alcohol-related problems yielded larger effect sizes than the WHO RDLs, the latter nonetheless provide a categorical alternative for use in both clinical care and pharmacotherapy trials.

Subgroup analyses in randomized clinical trials: value and limitations. Review #3 on important aspects of randomized clinical trials in cardiovascular pharmacotherapy.

Subgroup analyses in randomized clinical trials: value and limitations. Review #3 on important aspects of randomized clinical trials in cardiovascular pharmacotherapy.

Impact of rescue medication in placebo-controlled trials of pharmacotherapy for neuropathic pain and low back pain.

Rescue medication (RM) consumption is commonly used as a secondary outcome in placebo-controlled trials of chronic pain, but its validity has yet to be established. If participants randomized to placebo take more RM than those randomized to an active drug, the difference in pain between the 2 groups may be reduced, potentially masking effects of the active drug. This study assessed proportional RM consumption in the placebo and active groups according to results of 42 randomized controlled trials of neuropathic pain (NeP), and 29 trials of low back pain, which were included in 2 systematic reviews and meta-analyses. Trial results were assessed based on effect size, statistical significance, and whether the drug was recommended as first-line treatment by the systematic reviews. In trials indicating effect of the investigational drug, RM consumption was generally higher in the placebo groups than in the active groups. In trials reporting a small or a medium effect size of the investigational drug, subjects receiving placebo consumed 17% to 30% more RM than subjects receiving active drug, potentially leading to underestimation of the effects of the investigational drugs. Few trials reported a large effect size. Differences in RM consumption between participants receiving placebo and those receiving active drug were seldom taken in account by the individual trials and not at all by the systemic reviews when making treatment recommendations for NeP or low back pain. Elaboration on analytical methods to assess treatment effects in chronic pain trials using RM is warranted.

Lipids and peripheral neuropathy.

Hyperlipidaemia is associated with the development of neuropathy. Indeed, a mechanistic link between altered lipid metabolism and peripheral nerve dysfunction has been demonstrated in a number of experimental and clinical studies. Furthermore, post hoc analyses of clinical trials of cholesterol and triglyceride-lowering pharmacotherapy have shown reduced rates of progression of diabetic neuropathy. Given, there are currently no FDA approved disease-modifying therapies for diabetic neuropathy, modulation of lipids may represent a key therapeutic target for the treatment of diabetic nerve damage. This review summarizes the current evidence base on the role of hyperlipidaemia and lipid lowering therapy on the development and progression of peripheral neuropathy. A body of literature supports a detrimental effect of dyslipidaemia on nerve fibres resulting in somatic and autonomic neuropathy. The case for an important modulating role of hypertriglyceridemia is stronger than for low-density lipoprotein cholesterol (LDL-C) in relation to peripheral neuropathy. This is reflected in the outcomes of clinical trials with the different therapeutic agents targeting hyperlipidaemia reporting beneficial or neutral effects with statins and fibrates. The potential concern with the association between proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy and cognitive decline raised the possibility that extreme LDL-C lowering may result in neurodegeneration. However, studies in murine models and data from small observational studies indicate an association between increased circulating PCSK9 levels and small nerve fibre damage with a protective effect of PCSK9i therapy against small fibre neuropathy. Additionally, weight loss with bariatric surgery leads to an improvement in peripheral neuropathy and regeneration of small nerve fibres measured with corneal confocal microscopy in people with obesity with or without type 2 diabetes. These improvements correlate inversely with changes in triglyceride levels. Hyperlipidaemia, particularly hypertriglyceridemia, is associated with the development and progression of neuropathy. Lipid modifying agents may represent a potential therapeutic option for peripheral neuropathy. Post hoc analyses indicate that lipid-lowering therapies may halt the progression of neuropathy or even lead to regeneration of nerve fibres. Well designed randomized controlled trials are needed to establish if intensive targeted lipid lowering therapy as a part of holistic metabolic control leads to nerve fibre regeneration and improvement in neuropathy symptoms.

Cognitive insight, medication adherence and methamphetamine cessation in people enrolled in a pharmacotherapy trial for methamphetamine use

BackgroundThe current study examined correlates of cognitive insight in people enrolled in a methamphetamine pharmacotherapy trial; whether cognitive insight at the start of the trial predicted medication adherence and reductions in methamphetamine use during the trial; and, whether insight would remain stable over the trial or improve with reductions in methamphetamine use. MethodsA subset of people enrolled in a 12-week randomised placebo-controlled pharmacotherapy trial for methamphetamine dependence completed the Beck Cognitive Insight Scale, comprising subscales for Self-Reflection and Self-Certainty, at baseline (n = 152) and at week 12 (n = 79). Medication adherence was expressed as the percentage of non-missed doses measured using eCAP™ technology. Methamphetamine use days were assessed using the Timeline Followback. ResultsAt baseline, greater Self-Reflection was correlated with more severe methamphetamine withdrawal, and hostility, whereas Self-Certainty was correlated with less education and longer duration of methamphetamine use. No relationship was found between BCIS subscales at baseline and medication adherence (Self-Reflection b[SE] = −0.73 [0.43] p = .09; Self-Certainty b[SE] = −0.31 [0.48] p = .52,). Neither BCIS subscale was predictive of reduced methamphetamine use at 12 weeks (Self-Reflection b[SE] = 0.001 [0.01] p = .95 Self-Certainty b[SE] = −0.003 [0.01], p = .74). Self-Reflection decreased over the trial (t = 3.42, p = .001) but this was unrelated to change in methamphetamine use (Self-Reflection, b[SE] = −1.68 [1.16] p = .15) Change in methamphetamine use was found to be a significant predictor of Self-Certainty at 12 weeks (b [SE] = −2.71 [1.16] p = .02). ConclusionsWe found no evidence that cognitive insight predicted medication adherence or methamphetamine reduction in people engaged in this trial. Ongoing or increased methamphetamine use predicted increased Self-Certainty at 12 weeks.

Beyond ECT – Neuromodulation and Interventional Psychiatry for Treatment Resistant Depression in Later Life

There is a paucity of research, in general, on TRD-LL and on novel approaches and interventional methods for older adults suffering with TRD-LL. Most of the lack of data stems from limited studies on these interventions in older adults since most pharmacotherapy and neuromodulation trials specifically exclude older adults or those with comorbid medical or psychiatric conditions. Broadly, approaches can be divided into those that are FDA approved for depression (but not specifically for TRD-LL) and those that are available and empirically supported but not FDA approved. Among the FDA approved treatments of transcranial magnetic stimulation (all forms of rTMS and dTMS), vagus nerve stimulation (VNS), deep brain stimulation (DBS), and now intranasal ketamine, TMS has been most extensively studied for treatment of late life depression. Newer forms of TMS are also being evaluated in older adults. Though there are extensive data on the use of VNS in TRD, there are no studies in older adults specifically, although a multicenter trial supported by the US Center of Medicare and Medicaid Services, which will recruit adults aged 65 and above, will soon be underway. Published studies in DBS have included older adults but not in appreciable numbers for separate analyses. Studies thus far suggest some benefit in TRD but no specific data for TRD-LL. Most of the published studies of IV ketamine, which is not FDA approved for depression, are limited to case reports which tend to support its use and tolerability in TRD-LL when used as monotherapy or in combination with other interventions. Use of intranasal ketamine, which was recently FDA approved earlier in 2019, in TRD-LL remains anecdotal. Among other approaches with empirical support, but not necessarily FDA approved specific indications, are behavioral interventions (exercise, stress reduction activities), bright light therapy, combination pharmacotherapy (lithium, T3/T4, atypical antipsychotics, psychostimulants, D3 agonists, and opioid analogs), and combination pharmacotherapy and psychotherapy. After briefly reviewing the above interventions, discussion will focus on the clinical assessment of TRD-LL and possible treatment algorithms.

Consecutive Controlled Case Series on Effectiveness of Opipramol in Severe Sleep Bruxism Management-Preliminary Study on New Therapeutic Path.

Background: Sleep bruxism (SB) management aims to reduce the number and magnitude of bruxism episodes per hour of a patient’s sleep and, therefore, reduce the potentially negative clinical consequences. Opipramol belongs to the group of tricyclic antidepressants (TCAs) and is considered as an atypical TCA, as it acts primarily as a sigma receptor agonist. This study aimed to preliminarily determine the effectiveness of opipramol in the management of severe SB. Methods: A total of 19 otherwise healthy participants with severe SB diagnosed during stage I video polysomnography (vPSG) were subjected to an 8-week pharmacotherapy trial with a 100 mg bedtime daily dose of opipramol and were then analyzed by control stage II vPSG. Results: The participants included 14 females and 5 males, aged 20–47 years (mean ± standard deviation: 32.32 ± 8.12). A comparison of stage I and II vPSG recordings showed a decrease in all the studied SB parameters in 78.85% of participants. Only in a small group of participants (15.53%) was a non-significant increase of SB parameters observed. Conclusions: A single 100 mg dose of opipramol at bedtime seems to positively affect the reduction of SB in otherwise healthy individuals diagnosed with severe SB. However, the subject requires further research on a larger population including a control group.

Pharmacological interventions for self-harm in adults.

Self-harm (SH; intentional self-poisoning or self-injury regardless of degree of suicidal intent or other types of motivation) is a growing problem in most countries, often repeated, and associated with suicide. Evidence assessing the effectiveness of pharmacological agents and/or natural products in the treatment of SH is lacking, especially when compared with the evidence for psychosocial interventions. This review therefore updates a previous Cochrane Review (last published in 2015) on the role of pharmacological interventions for SH in adults. To assess the effects of pharmacological agents or natural products for SH compared to comparison types of treatment (e.g. placebo or alternative pharmacological treatment) for adults (aged 18 years or older) who engage in SH. We searched the Cochrane Common Mental Disorders Specialised Register, the Cochrane Library (Central Register of Controlled Trials [CENTRAL] and Cochrane Database of Systematic Reviews [CDSR]), together with MEDLINE. Ovid Embase and PsycINFO (to 4 July 2020). We included all randomised controlled trials (RCTs) comparing pharmacological agents or natural products with placebo/alternative pharmacological treatment in individuals with a recent (within six months of trial entry) episode of SH resulting in presentation to hospital or clinical services. The primary outcome was the occurrence of a repeated episode of SH over a maximum follow-up period of two years. Secondary outcomes included treatment acceptability, treatment adherence, depression, hopelessness, general functioning, social functioning, suicidal ideation, and suicide. We independently selected trials, extracted data, and appraised trial quality. For binary outcomes, we calculated odds ratios (ORs) and their 95% confidence internals (CIs). For continuous outcomes we calculated the mean difference (MD) or standardised mean difference (SMD) and 95% CI. The overall certainty of evidence for the primary outcome (i.e. repetition of SH at post-intervention) was appraised for each intervention using the GRADE approach. We included data from seven trials with a total of 574 participants. Participants in these trials were predominately female (63.5%) with a mean age of 35.3 years (standard deviation (SD) 3.1 years). It is uncertain if newer generation antidepressants reduce repetition of SH compared to placebo (OR 0.59, 95% CI 0.29 to 1.19; N = 129; k = 2; very low-certainty evidence). There may be a lower rate of SH repetition for antipsychotics (21%) as compared to placebo (75%) (OR 0.09, 95% CI 0.02 to 0.50; N = 30; k = 1; low-certainty evidence). However, there was no evidence of a difference between antipsychotics compared to another comparator drug/dose for repetition of SH (OR 1.51, 95% CI 0.50 to 4.58; N = 53; k = 1; low-certainty evidence). There was also no evidence of a difference for mood stabilisers compared to placebo for repetition of SH (OR 0.99, 95% CI 0.33 to 2.95; N = 167; k = 1; very low-certainty evidence), or for natural products compared to placebo for repetition of SH (OR 1.33, 95% CI 0.38 to 4.62; N = 49; k = 1; lo- certainty) evidence. Given the low or very low quality of the available evidence, and the small number of trials identified, there is only uncertain evidence regarding pharmacological interventions in patients who engage in SH. More and larger trials of pharmacotherapy are required, preferably using newer agents. These might include evaluation of newer atypical antipsychotics. Further work should also include evaluation of adverse effects of pharmacological agents. Other research could include evaluation of combined pharmacotherapy and psychological treatment.

An Open Trial of Metacognitive Remediation Therapy and Pharmacotherapy to Promote Smoking Cessation among Individuals with Psychotic-Spectrum Disorders.

Introduction Individuals with psychotic-spectrum disorders may smoke due to the ameliorating effect of nicotine on the cognitive deficits that accompany these illnesses. Metacognitive remediation therapy (MCR) has been shown to produce improvements in cognitive functioning among individuals with psychotic-spectrum disorders and provides a foundation for a novel smoking cessation intervention for this population. Aims To complete an open investigation of pharmacotherapy and a modified version of MCR [MCR to Quit (MCR-Q)] in promoting smoking cessation among individuals with psychotic-spectrum disorders. Methods Forty-nine individuals with a psychotic-spectrum disorder and who currently smoke cigarettes participated in MCR-Q while also receiving evidence-based smoking cessation pharmacotherapy. Tobacco use was assessed as follows: (i) prior to MCR-Q, (ii) immediately after completing MCR-Q, and (iii) six weeks after completion of MCR-Q. Results/Findings. During participation in MCR-Q, nearly 80% of participants made a 24-hour quit attempt. Following the completion of MCR-Q, participants experienced reductions in level of nicotine dependency and exhaled carbon monoxide, with reductions in nicotine dependency sustained six weeks after completion of MCR-Q. Over the course of their participation in MCR-Q, participants reported strong therapeutic alliance with their MCR-Q therapist and high levels of intrinsic motivation with regard to completing MCR-Q exercises. Conclusions The results from the current study suggest cautious optimism with regard to the use of MCR-Q in combination with medication for individuals with psychotic-spectrum disorders who want to quit smoking.

Neurodevelopmental disorders in children and the possibilities of their pharmacotherapy

Neurodevelopmental disorders (NDD) are characterized by disturbances of the formation of cognitive functions, communication skills, behavior characteristics and/or motor skills, which are caused by abnormalities in the course of the processes of neuroontogenesis. In the clinical practice of a pediatric neurologist and pediatrician, a significant part consists of patients with NDD without a general decrease in intelligence, primarily with speech development disorders, attention deficit hyperactivity disorder (ADHD), specific learning disorders (dyslexia, dysgraphia, dyscalculia). NDD represent a heterogeneous group of diseases, having multifactorial origin and a neurobiological nature, which are caused by genetic mechanisms and early (perinatal) brain damage. Among children with NDD, there is a higher occurrence of anxiety disorders compared to their peers. With NDD, early intervention is indicated, and its positive effect is possible during the period when the brain is most plastic and capable of changes. The published results of multicenter, double-blind, placebo-controlled, randomized clinical trials of pharmacotherapy with the medication "Tenoten for children" for ADHD, specific learning disorders, anxiety disorders and the consequences of perinatal damage to the central nervous system are reviewed.