Meta-Analysis of Placebo Response in Adult Antidepressant Trials Abstract Background Roughly 80% of the symptom improvement experienced on antidepressants in clinical trials is also observed in the placebo comparison group. Understanding the correlates of placebo improvement and response is important to designing efficient and successful trials of future antidepressants. Objective The objective of this meta-analysis was to investigate the magnitude of placebo symptom improvement and placebo response rates in second-generation antidepressant trials of depression, anxiety, and obsessive-compulsive disorder. Methods We searched PubMed on 10 June, 2016, with no date or language limits, to identify randomized placebo-controlled trials of second-generation antidepressants in adults with depression, anxiety, or obsessive-compulsive disorder. We used a random-effects meta-analysis to examine the magnitude of placebo symptom improvement using standardized mean difference and placebo response rate. Stratified subgroup analysis and meta-regression were utilized to examine the effect of diagnostic indication and correlates of placebo symptom improvement. Results The meta-analysis included 164 trials involving 19,591 participants. Magnitude of placebo improvement and placebo response rates varied significantly between diagnostic indications. The magnitude of placebo improvement was much lower in obsessive-compulsive disorder (standardized mean difference = 0.58, 95% confidence interval 0.36–0.79) than in depression (standardized mean difference = 1.22, 95% confidence interval 1.12–1.32) or anxiety (standardized mean difference = 1.01, 95% confidence interval 0.90–1.12) trials. There was a large amount of heterogeneity in placebo improvement between studies (Q = 899, df = 110, p < 0.001, I2 = 88%). A greater number of study sites and a later publication year were associated with a greater magnitude of placebo improvement and response rate. Presence of a placebo lead-in and absence of non-US sites were associated with a reduced magnitude of placebo improvement. Trial duration was positively associated with the magnitude of placebo improvement in depression trials but negatively associated with the magnitude of placebo improvement in anxiety and obsessive-compulsive disorder trials. Conclusions Magnitude of placebo symptom improvement differed significantly based on diagnostic indication with improvement being significantly less in obsessive-compulsive disorder than anxiety and depression. Some trial characteristics were associated with a greater magnitude of placebo improvement in trials across disorders but others were disorder specific.

Opioid-Induced Tolerance and Hyperalgesia Abstract Opioids are very potent and efficacious drugs, traditionally used for both acute and chronic pain conditions. However, the use of opioids is frequently associated with the occurrence of adverse effects or clinical problems. Other than adverse effects and dependence, the development of tolerance is a significant problem, as it requires increased opioid drug doses to achieve the same effect. Mechanisms of opioid tolerance include drug-induced adaptations or allostatic changes at the cellular, circuitry, and system levels. Dose escalation in long-term opioid therapy might cause opioid-induced hyperalgesia (OIH), which is a state of hypersensitivity to painful stimuli associated with opioid therapy, resulting in exacerbation of pain sensation rather than relief of pain. Various strategies may provide extra-opioid analgesia. There are drugs that may produce independent analgesic effects. A tailored treatment provided by skilled personnel, in accordance with the individual condition, is mandatory. Any treatment aimed at reducing opioid consumption may be indicated in these circumstances. Interventional techniques able to decrease the pain input may allow a decrease in the opioid dose, thus reverting the mechanisms producing tolerance of OIH. Intrathecal therapy with local anesthetics and a sympathetic block are the most common techniques utilized in these circumstances.

Do Vaccines Trigger Neurological Diseases? Epidemiological Evaluation of Vaccination and Neurological Diseases Using Examples of Multiple Sclerosis, Guillain–Barré Syndrome and Narcolepsy Abstract This article evaluates the epidemiological evidence for a relationship between vaccination and neurological disease, specifically multiple sclerosis, Guillain–Barré syndrome and narcolepsy. The statistical methods used to test vaccine safety hypotheses are described and the merits of different study designs evaluated; these include the cohort, case-control, case-coverage and the self-controlled case-series methods. For multiple sclerosis, the evidence does not support the hypothesized relationship with hepatitis B vaccine. For Guillain−Barré syndrome, the evidence suggests a small elevated risk after influenza vaccines, though considerably lower than after natural influenza infection, with no elevated risk after human papilloma virus vaccine. For narcolepsy, there is strong evidence of a causal association with one adjuvanted vaccine used in the 2009/10 influenza pandemic. Rapid investigation of vaccine safety concerns, however biologically implausible, is essential to maintain public and professional confidence in vaccination programmes.

Recent Advances in Pharmacotherapy for Episodic Migraine Abstract In 2018, three calcitonin gene-related peptide (CGRP) pathway monoclonal antibodies, erenumab, fremanezumab and galcanezumab, were approved in various parts of the world, including Europe and the US, and another, eptinezumab, is pending, for the prevention of migraine. In this article, episodic migraine treatment is reviewed, although these medicines are approved and are just as effective for chronic migraine. These new medicines usher a new phase in the preventive management of migraine with migraine-specific treatments. Data from phase III trials of CGRP pathway monoclonal antibodies have shown they are efficacious, with adverse effect rates comparable to placebo. The combination of clear efficacy and excellent tolerability will be welcome in an area where poor adherence to current preventives is common. Rimegepant, ubrogepant and lasmiditan are migraine-specific acute therapies yet to be approved by regulators. Phase III data for the respective CGRP receptor antagonists, the gepants, and the serotonin 5-HT1F receptor agonist, the ditan, have been positive and free of cardiovascular adverse effects. These medicines are not vasoconstrictors. When approved, they could meet the acute therapy demand of patients with cardiovascular risk factors where triptans are contraindicated. Beyond this, gepants will see the most disruptive development in migraine management in generations with medicines that can have both acute and preventive effects, the latter evidenced by data from the discontinued drug telcagepant and the early-phase drug atogepant. Moreover, one can expect no risk of medication overuse syndromes with gepants since the more patients take, the less migraines they have. During the next years, as experience with monoclonal antibodies grows in clinical practice, we can expect an evolution in migraine management to take shape. Clinicians will be able to offer treatment patients want rather than trying to fit migraineurs into therapeutic boxes for their management. Despite pessimistic susurrations of a largely addlepated form, many patients, and physicians, will welcome new options, and the challenges of new treatment paradigms, with optimism.

Targeting Iron Dyshomeostasis for Treatment of Neurodegenerative Disorders Abstract While iron has an important role in the normal functioning of the brain owing to its involvement in several physiological processes, dyshomeostasis has been found in many neurodegenerative disorders, as evidenced by both histopathological and imaging studies. Although the exact causes have remained elusive, the fact that altered iron levels have been found in disparate diseases suggests that iron may contribute to their development and/or progression. As such, the processes involved in iron dyshomeostasis may represent novel therapeutic targets. There are, however, many questions about the exact interplay between neurodegeneration and altered iron homeostasis. Some insight can be gained by considering the parallels with respect to what occurs in healthy aging, which is also characterized by increased iron throughout many regions in the brain along with progressive neurodegeneration. Nevertheless, the exact mechanisms of iron-mediated damage are likely disease specific to a certain degree, given that iron plays a crucial role in many disparate biological processes, which are not always affected in the same way across different neurodegenerative disorders. Moreover, it is not even entirely clear yet whether iron actually has a causative role in all of the diseases where altered iron levels have been noted. For example, there is strong evidence of iron dyshomeostasis leading to neurodegeneration in Parkinson’s disease, but there is still some question as to whether changes in iron levels are merely an epiphenomenon in multiple sclerosis. Recent advances in neuroimaging now offer the possibility to detect and monitor iron levels in vivo, which allows for an improved understanding of both the temporal and spatial dynamics of iron changes and associated neurodegeneration compared to post-mortem studies. In this regard, iron-based imaging will likely play an important role in the development of therapeutic approaches aimed at addressing altered iron dynamics in neurodegenerative diseases. Currently, the bulk of such therapies have focused on chelating excess iron. Although there is some evidence that these treatment options may yield some benefit, they are not without their own limitations. They are generally effective at reducing brain iron levels, as assessed by imaging, but clinical benefits are more modest. New drugs that specifically target iron-related pathological processes may offer the possibility to prevent, or at the least, slow down irreversible neurodegeneration, which represents an unmet therapeutic target.

Emergency Department Initiation of Buprenorphine for Opioid Use Disorder: Current Status, and Future Potential Abstract Patients experiencing the consequences of opioid use often present to the emergency department (ED) at times of crisis, such as following overdose or when in withdrawal. This highlights the important role of the ED in recognizing opioid use disorder and engaging these patients into ongoing treatment. Given the limited ability of the healthcare system to provide timely addiction treatment, initiation of therapy in the ED, with referral to long-term care, is associated with improved outcomes. The primary evidence-based treatment used in EDs for this indication is buprenorphine. Although clinicians may find the initiation of buprenorphine therapy daunting, it is straightforward and well-tolerated, and many of the barriers are surmountable. This article addresses these barriers, which include stigma, complicated pharmacology, and confusing regulations, and provides a basis for the use of buprenorphine in acute care clinical practice.

Potential of Cannabinoid Receptor Ligands as Treatment for Substance Use Disorders Abstract Substance use disorder (SUD) is a major public health crisis worldwide, and effective treatment options are limited. During the past 2 decades, researchers have investigated the impact of a variety of pharmacological approaches to treat SUD, one of which is the use of medical cannabis or cannabinoids. Significant progress was made with the discovery of rimonabant, a selective CB1 receptor (CB1R) antagonist (also an inverse agonist), as a promising therapeutic for SUDs and obesity. However, serious adverse effects such as depression and suicidality led to the withdrawal of rimonabant (and almost all other CB1R antagonists/inverse agonists) from clinical trials worldwide in 2008. Since then, much research interest has shifted to other cannabinoid-based strategies, such as peripheral CB1R antagonists/inverse agonists, neutral CB1R antagonists, allosteric CB1R modulators, CB2R agonists, fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MAGL) inhibitors, fatty acid binding protein (FABP) inhibitors, or nonaddictive phytocannabinoids with CB1R or CB2R-binding profiles, as new therapeutics for SUDs. In this article, we first review recent progress in research regarding the endocannabinoid systems, cannabis reward versus aversion, and the underlying receptor mechanisms. We then review recent progress in cannabinoid-based medication development for the treatment of SUDs. As evidence continues to accumulate, neutral CB1R antagonists (such as AM4113), CB2R agonists (JWH133, Xie2-64), and nonselective phytocannabinoids (cannabidiol, β-caryophyllene, ∆9-tetrahydrocannabivarin) have shown great therapeutic potential for SUDs, as shown in experimental animals. Several cannabinoid-based medications (e.g., dronabinol, nabilone, PF-04457845) that entered clinical trials have shown promising results in reducing withdrawal symptoms in cannabis and opioid users.

An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials Abstract Background Treatment with nusinersen has demonstrated significant and clinically meaningful benefits in clinical trials in infants and children with spinal muscular atrophy (SMA). Objective The objective of this analysis was to characterize the safety of nusinersen across the clinical trial program in infants and children with symptomatic SMA. Methods An integrated safety analysis evaluated end of study data from seven completed clinical trials that enrolled infants and children with symptomatic SMA who were treated with intrathecal nusinersen or underwent sham procedures. Two of the studies were conducted in symptomatic infants with infantile-onset SMA (most likely to develop SMA type I or II) and the remaining five in symptomatic children and adolescents with later-onset SMA (have or are most likely to develop SMA type II or III). Safety assessments included incidence of adverse events (AEs), physical and neurological examinations, vital signs, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and electrocardiograms. Results Data were analyzed from 323 infants and children, including 240 treated with nusinersen (100 with infantile-onset SMA and 140 with later-onset SMA) and 83 who underwent sham procedures (41 infantile-onset, 42 later-onset). Median (range) exposure to nusinersen was 449.0 (6–1538) days (375.9 participant-years). The most common AEs with nusinersen were pyrexia, upper respiratory tract infection, nasopharyngitis, vomiting, headache, and constipation. The incidence of serious AEs was lower with nusinersen than with the sham procedure (41% vs. 61%). The overall incidence of respiratory, thoracic, and mediastinal AEs was higher in participants with symptomatic infantile-onset SMA than those with symptomatic later-onset SMA and similar in nusinersen- versus sham procedure–treated participants. Rates of post–lumbar puncture syndrome and related events were higher with nusinersen versus sham procedure in later-onset SMA participants. No abnormal patterns or trends in laboratory test results were observed. Conclusions Nusinersen demonstrated a favorable safety profile in children with symptomatic infantile- and later-onset SMA. Most reported AEs and serious AEs were consistent with the nature and frequency of events typically seen with SMA or in the context of lumbar puncture procedures. Registration NCT01494701, NCT01703988, NCT01839656, NCT02193074, NCT02292537, NCT01780246, NCT02052791.

Current Drug Treatment of Acute Ischemic Stroke: Challenges and Opportunities Abstract Patient-level health outcomes for acute ischemic stroke have significantly improved in the last decade primarily because of superior overall case management, availability of tailored drug interventions, and advances in endovascular procedures. Nevertheless, disease registries show a “quality gap” across social determinants of health and between in-hospital and community-onset strokes. Several factors, including financing and infrastructure constraints, limited expertise, and clinical uncertainty, still prevent adherence to evidence-based clinical guidelines and optimal care pathways. This paper critically appraises existing evidence on the use of drug therapies in acute ischemic stroke, in an attempt to resolve physician-related subjective barriers for effective acute management of the disease. We conclude that intravenous administration of rt-PA (recombinant tissue-type plasminogen activator, alteplase) is an essential component of acute-phase pharmacologic treatment and a driver for the improvement of overall ischemic stroke health outcomes. The safety profile of alteplase and similar treatments are well within the patient benefit zone of eligible patients when compared to non-treatment alternatives. Monomodal neuroprotective drugs with single or pleiotropic mechanisms of action have failed to support long-term sustainable results. Drugs with complex mechanisms of action that promote neurorecovery, such as cerebrolysin, are valid options for adjunctive treatment of acute ischemic stroke. Recent years have shown clear improvements in the methodology and design of clinical trials, with an increase in overall internal and external validity. A better understanding of study limitations has not hindered, but enhanced their potential to contribute, together with sometimes superior data sources, to health decision making.

Subjective Versus Objective Outcomes of Antipsychotics for the Treatment of Neuropsychiatric Symptoms Associated with Dementia Abstract Background Knowledge about treatment status can influence effects measured in trials when subjective scales are used. Objective The aim of this study was to compare subjective outcomes with objective outcomes of conventional and atypical antipsychotics for neuropsychiatric symptoms (NPS) in dementia. Methods We performed a meta-epidemiological study of 38 randomized, placebo-controlled trials. For effectiveness, we used change in NPS and response rate as subjective outcomes, while overall dropout and additional psychotropic use were used as objective outcomes. For side effects, extrapyramidal symptoms (EPS) and somnolence were used as subjective outcomes, while dropout due to adverse events, medication use for EPS, and participants falling were used as objective outcomes. Results Conventional antipsychotics reduced NPS more than placebo (standardized mean difference [SMD] − 0.36, 95% confidence interval [CI] − 0.49 to − 0.23), as did atypical antipsychotics (SMD − 0.14, 95% CI − 0.19 to − 0.08). Response rates in the drug groups were also higher. Overall dropout did not differ between conventional antipsychotics and placebo (odds ratio [OR] 1.03, 95% CI 0.77–1.37) or atypical antipsychotics and placebo (OR 1.01, 95% CI 0.89–1.14). Furthermore, additional psychotropic use did not differ. The risk of EPS was higher for conventional (OR 2.93, 95% CI 2.04–4.22) and atypical antipsychotics (OR 1.52, 95% CI 1.23–1.88) versus placebo, as was the risk of somnolence and dropout due to adverse events, but medication use for EPS, as well as risk of falls, was not. Conclusions The effectiveness of antipsychotics for NPS in dementia based on subjective scales was not confirmed using objective outcomes, in contrast to the increased risk of side effects.