Comparing the efficacy of benzodiazepines and serotonergic anti-depressants for adults with generalized anxiety disorder: a meta-analytic review

Introduction: Generalized anxiety disorder (GAD) is a common form of anxiety disorder. Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and benzodiazepines (BZs) are the most commonly prescribed medications for GAD, but little is known about the relative efficacy of these pharmacological treatments.

Areas covered: This study provides a meta-analytic review of the efficacy of these medications in the treatment of adults with GAD. A comprehensive literature search yielded 54 articles reporting 56 unique studies with 12,655 participants treated with either pill placebo (6,191 participants), SSRIs (16 trials, 2,712 participants), SNRIs (17 trials, 2,603 participants), or BZs (23 trials, 1,149 participants). The overall combined effect size was modest to moderate (Hedges’ g = 0.37, p < 0.0001). Effect sizes decreased significantly over time. SSRIs (Hedges’ g = 0.33) and SNRIs (Hedges’ g = 0.36) demonstrated significantly lower effect sizes than BZs (Hedges’ g = 0.50). These findings were not due to differences in treatment length or publication year.

Expert opinion: The results of this study suggest that the most common forms of pharmacotherapy for adult GAD are moderately effective, with BZs being the most effective drug.     

Agomelatine for the treatment of generalized anxiety disorder

Introduction: Agomelatine is a melatonergic antidepressant, approved for the treatment of Major Depressive Disorder (MDD) in Europe and Australia, but not in the United States. This compound seems to be promising in the short-term and maintenance treatment of Generalized Anxiety Disorder (GAD).

Areas covered: This paper presents an evaluation of the available data about the clinical efficacy and tolerability of agomelatine in the treatment of GAD.

Expert opinion: First-line GAD treatments are limited by high rates of lack of clinical response. Preliminary data would indicate agomelatine as a safe compound, and with a higher rate of clinical response in the short-term and an earlier improvement of symptoms with respect to Selective Serotonine Reuptake Inhibitors (SSRIs) and Selective Serotonin Noradrenaline Reuptake Inhibitors (SNRIs). In addition, agomelatine has not been associated with potential risk of abuse as in case of pregabalin and with long-term metabolic side effects similar to quetiapine. The major limitation of the results presented is that little data has come from long-term or comparative trials. Furthermore, some caution should be reserved in case of liver impairment (e.g. in subjects with alcohol abuse).     

Risks and benefits of medications for panic disorder: a comparison of SSRIs and benzodiazepines

Introduction: Panic disorder (PD) is a prevalent and disabling anxiety disorder that can be treated effectively. Selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines are among the most frequently prescribed drugs for PD. In this article, the authors review the current evidence on efficacy, adverse events, and limitations of these two treatment options.

Areas covered: MEDLINE/Pubmed and Web of Science databases were searched for open or placebo-controlled trials on SSRIs and/or benzodiazepines in PD treatment.

Expert opinion: The literature search yielded 4,957 articles related to the theme. Of these, 24 articles were included in this review. Despite their usefulness in PD, SSRIs are associated with a delay of several weeks in onset of therapeutic effect and have the potential to exacerbate anxiety and panic early in the treatment course. Benzodiazepines present rapid onset of action, but can cause tolerance and dependence. Despite strong evidence of the effectiveness of SSRIs and benzodiazepines in the treatment of PD, few trials have performed head-to-head comparisons of these two drug classes. Future studies on the pharmacological treatment of PD should make direct comparisons of risks, benefits, and limitations of each group. This could help improve the evidence-based pharmacotherapy of PD.     

Are there advances in pharmacotherapy for panic disorder? A systematic review of the past five years

Introduction: Several effective medications are available for treating panic disorder (PD). However, outcomes are unsatisfactory in a number of patients, suggesting the usefulness of expanding the array of antipanic drugs and improving the quality of response to current recommended treatments.

Areas covered: The authors have performed an updated systematic review of pharmacological studies (phase III onwards) to examine whether advances have been made in the last five years. Only four studies were included. D-cycloserine no longer seemed promising as a cognitive-behavioral therapy (CBT) enhancer. Some preliminary findings concerning the optimization of recommended medications deserved consideration, including: the possibility that SSRIs are more effective than CBT alone in treating panic attacks, combined therapy is preferable when agoraphobia is present, and clonazepam is more potent than paroxetine in decreasing panic relapse.

Expert opinion: Given the lack of novel treatments, expanding a personalized approach to the existing medications seems to be the most feasible strategy to improve pharmacotherapy outcomes regarding PD. Recent technological progress, including wearable devices collecting real-time data, ‘big data’ platforms, and application of machine learning techniques might help make outcome prediction more reliable. Further research on previously promising novel treatments is also recommended.     

Pharmacokinetics,pharmacodynamics and pharmacogenetics associated with nonsteroidal anti-inflammatory drugs and opioids in pediatric cancer patients

Introduction: Advancing appropriate and adequate analgesic pharmacotherapy in pediatric patients with cancer is an area of clinical need. Few studies have been performed to evaluate the selection of an analgesic and appropriate dosing corresponding to analgesic effect among pediatric cancer patients. This review describes information related to pharmacokinetic, pharmacodynamic, and pharmacogenomic (when applicable) considerations for analgesics that are commonly used to manage pain experienced by pediatric patients with cancer.

Areas covered: Analgesics commonly used to treat pediatric patients with malignancy patterned after the World Health Organization’s ‘analgesic ladder’ for cancer pain management.

Expert opinion: Addressing pain management safely and effectively in pediatric patients with cancer will require advances in both drug development, to increase the armament of analgesics available for children, and our pharmacologic understanding of those analgesics in current use. However, performing the necessary types of studies to develop new analgesics, or gain knowledge of existing therapy, within a population that is relatively small, diverse, and who experience pain originating from a variety of sources, is a tremendous challenge.     

Safety of selective serotonin reuptake inhibitor treatment in recovering stroke patients

Introduction: Selective serotonin reuptake inhibitors (SSRIs) are widely used for psychiatric complications after stroke. Studies have indicated additional effects, and SSRIs could potentially be used as enhancers of stroke recovery. However, beneficial effects should be weighed against potential adverse effects. In particular, the possible association with cerebrovascular events has raised concern.

Areas covered: We review the literature on cerebrovascular events associated with SSRI treatment after stroke. The possible beneficial effects of SSRI treatment for stroke recovery and survival, and potential safety concerns, are discussed.

Expert opinion: Evidence suggests that SSRIs may enhance stroke recovery. Most studies on cerebrovascular risk are from non-stroke populations and little is known about recurrent events and mortality post-stroke. In non-stroke populations treatment has been associated with increased risk of intracerebral and intracranial hemorrhage; however the absolute risk is low. The association between SSRIs and ischemic stroke is less clear. Randomized stroke trials indicate that treatment is safe and well tolerated, and the most common side effects are often benign and transient. The trials are small however and not powered to detect potential differences in cerebrovascular events. We await several ongoing large randomized trials before SSRIs can be recommended as a routine pharmacotherapy in stroke recovery.     

Current and future treatment options for community-associated MRSA infection

Introduction: Community-associated MRSA (CA-MRSA) represents a global epidemic which beautifully encapsulates the fascinating ability of bacterial organisms to adapt quickly on an evolutionary basis to the extreme selective pressure of antibiotic exposure. In stark contrast to Healthcare-associated MRSA (HA-MRSA), it has become apparent that CA-MRSA is less straight forward of a challenge in terms of controlling its transmission, and has forced clinicians to adjust empiric management of clinical syndromes such as skin and soft tissue infection (SSTI) as well as pneumonia.

Areas covered: This review details the history and epidemiology of CA-MRSA, while covering both current and future treatment options that are and may be available to clinicians. The authors reviewed both historic and more recent literature on this ever-evolving topic.

Expert opinion: While development of new anti-MRSA agents should be encouraged, the importance of antimicrobial stewardship in the battle to stay ahead of the curve with regards to the ongoing control of the MRSA epidemic should be emphasised.     

Clinical trial transparency update: an assessment of the disclosure of results of company-sponsored trials associated with new medicines approved in Europe in 2012

Background:

The objective of this study was to assess the timely disclosure of results of company-sponsored clinical trials related to all new medicines approved by the European Medicines Agency (EMA) during 2012. This is an extension of the previously reported study of trials related to all new medicines approved in Europe in 2009, 2010 and 2011, which found that over three-quarters of all these trials were disclosed within 12 months and almost 90% were disclosed by the end of the study.

Methods:

The methodology used was exactly as previously reported. Various publicly available information sources were searched for both clinical trial registration and disclosure of results. All completed company-sponsored trials related to each new medicine approved for marketing by the EMA in 2012, carried out in patients and recorded on a clinical trials registry and/or included in an EMA European Public Assessment Report (EPAR), were included. Information sources were searched between 1 May and 31 July 2014.

Outcome measures and results:

The main outcome measure was the proportion of trials for which results had been disclosed on a registry or in the scientific literature either within 12 months of the later of either first regulatory approval or trial completion, or by 31 July 2014 (end of survey). Of the completed trials associated with 23 new medicines licensed to 17 different companies in 2012, results of 90% (307/340) had been disclosed within 12 months, and results of 92% (312/340) had been disclosed by 31 July 2014.

Conclusions:

The disclosure rate within 12 months of 90% suggests the industry is now achieving disclosure in a timely manner more consistently than before. The overall disclosure rate at study end of 92% indicates that the improvement in transparency amongst company-sponsored trials has been maintained in the trials associated with new medicines approved in 2012.     

Interplay between the key proteins of serotonin system in SSRI antidepressants efficacy

Introduction: Selective serotonin reuptake inhibitors (SSRIs) are the most effective and most used antidepressant drugs. Acting by inhibiting serotonin (5-HT) transporter, SSRIs display a typical 3–4-week delay in their therapeutic effects, with nearly 40% of depressed patients remaining treatment-resistant. Recent evidence suggests complex interplay between 5-HT receptors and key proteins of 5-HT metabolism in molecular mechanisms of such delay and resistance to SSRIs.

Area covered: This paper concentrates on the interplay between 5-HT receptors in the delay of therapeutic effect of SSRIs, and the interaction between tryptophan hydroxylase 2 and 5-HT transporter in the SSRI resistance. Specifically, it discusses: (1) the data on the association between antidepressant drug efficacy and genetically defined characteristics of key proteins in the 5-HT signaling (TPH2, MAOA, SERT and 5-HT_1A receptor), (2) the effect of dimerization of 5-HT₇ and 5-HT_1A receptors on the internalization and functioning of 5-HT_1A presynaptic receptors, (3) the role of Tph2 deficiency in the resistance to SSRIs treatment. We shift the emphasis from individual proteins to their interactions in explaining antidepressant action of SSRI.

Expert opinion: These interactions should be considered when developing more effective antidepressant drugs as well as for predicting and improving the efficacy of antidepressant therapies.     

Pharmacological treatment for generalized anxiety disorder in adults: an update

Introduction: Modest response and remission rates for the selective serotonin reuptake inhibitors and the serotonin-norepinephrine reuptake inhibitors, coupled with mounting evidence that the tolerability of the antidepressants (ADs) may have been overstated in the literature, has contributed to changes in prescribing patterns for generalized anxiety disorder (GAD). New interest in the absence of evidence that supports these standard therapies as superior to benzodiazepines stimulated a review of the literature.

Areas covered: A literature search was conducted in the MedLine database with search terms ‘generalized anxiety disorder’ and ‘treatment’ for purposes of including relevant literature related to pharmacologic treatment of GAD. Aside from a review of pivotal literature, the authors also included newer studies that evaluated novel drug treatments. Last, the database was searched for benzodiazepine comparisons to standard therapy secondary to concerns that such literature is sparse. The review of newer modalities and the decision to include related literature was also based on the strength of the evidence and the status of their approval for the treatment of GAD.

Expert opinion: Although ADs remain the most frequently prescribed medications for GAD, alternative and off-label therapies such as pregabalin, the atypical antipsychotics and vortioxetine are garnering interest. Based on the evidence available to us, it is our recommendation that along with the ADs, benzodiazepines be considered a possible first-line therapy in eligible patients based on the discretion and clinical judgment of the treating physician.     

Efficacy of antidepressants: bias in randomized clinical trials and related issues

Introduction: Countless antidepressant randomized trials were conducted and showed statistically significant benefits of selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) over placebo. Meanwhile, critics are increasing regarding the efficacy of antidepressants in the treatment of MDD because at least a proportion of clinical trials could be hampered by various biases. In contrast, number of failed trials is increasing in the recent years which have made developing psychiatric medications progressively more time-consuming and expensive.

Areas covered: Biases and related issues in clinical trials for antidepressants can be identified as an important common contributing factor to the two paradoxical phenomenon. This review identifies possible biases that can occur before, during, and after clinical trials of antidepressant.

Expert commentary: Recent studies not only may over-estimate efficacy of antidepressants, but also may exaggerate placebo response because of various biases. Sponsorship and publication biases have been one of the targets of the criticism and ethical debate. Thus, initiating new trend of research by re-organizing academic-industry partnership will be the most important task in the next five years.     

Dosing strategies to optimize currently available anti-MRSA treatment options (Part 2: PO options)

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is a problematic pathogen in both outpatient and inpatient settings. Research to optimize the dosing of these agents is needed to slow the development of antimicrobial resistance and to decrease the likelihood of clinical failure.

Areas covered: This review summarizes the available data for orally administered antimicrobials routinely used as monotherapy for MRSA infections. We make recommendations and highlight the current gaps in the literature. A PubMed (1966 – Present) search was performed to identify relevant literature for this review.

Expert commentary: There is a vast divide in the amount of pharmacokinetic/pharmacodynamic data to guide dosing decisions for older MRSA agents compared with the oxazolidenones.

Five-year view: Additional retrospective data will become available for the older MRSA agents in severe MRSA infections.     

The safety of pharmacologic treatment for pediatric obesity

Introduction: Pediatric obesity is a serious public health concern. Five medications have been approved by the Food and Drug Administration (FDA) for chronic weight management in adults with obesity, when used as an adjunct to lifestyle modification. Orlistat is the only FDA-approved medication for pediatric patients aged 12 years and above.

Areas covered: This paper summarizes safety and efficacy data from clinical trials of weight loss medications conducted among pediatric samples. Relevant studies were identified through searches in PubMed.

Expert opinion: Orlistat, as an adjunct to lifestyle modification, results in modest weight losses and may be beneficial for some pediatric patients with obesity. However, gastrointestinal side effects are common and may limit use. In adults taking orlistat, rare but severe adverse events, including liver and renal events, have been reported. Recent pediatric pharmacokinetic studies of liraglutide have demonstrated similar safety and tolerability profiles as found in adults, with gastrointestinal disorders being the most common adverse events. Clinical trials are needed of liraglutide, as well as other medications for obesity, that systematically evaluate their risks and benefits in pediatric patients.     

Advances in therapy for the prevention of HIV transmission from mother to child

Introduction: Actually, ~17.8 million women and 1.8 million children (<15 years) are currently infected with the Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS). Particularly, the majority of pediatric infections (>90%) resulted from ‘HIV mother-to-child transmission’ (MTCT), both in pregnancy, labour, delivery and later by breastfeeding. Due to its high pediatric incidence, MTCT represents a public health concern.

Areas covered: In this review, we focus on available treatments and antiretroviral drugs recommended by the World Health Organization, and the main clinical investigations in antiretroviral pharmacotherapy to prevent the MTCT.

Expert opinion: The MTCT has been improved dramatically in the last few years mainly due to prophylactic perinatal antiretroviral therapy for pregnant women living with HIV. However, there is still a milestone to reach since HIV MTCT remains as a public health challenge associated with MTCT though breastfeeding (post-natal transmission). In this context, different strategies could be employed as an attempt to reduce pediatric HIV infections. One of them involves the improvement of patient adherence to the HIV therapy. One possible solution is the development of novel long-acting formulations for prophylaxis of mothers and children, and a second possible solution is increase the inclusion of mothers and infants in care programs to more effectively prevent the vertical transmission.     

Lidocaine 5% medicated plaster for localized neuropathic pain in thoracic surgical patients

Context: Neuropathic pain is a common and distressing symptom in thoracic surgical patients. When it consistently presents with measurable sensory changes in a circumscribed area, neuropathic pain can be diagnosed as localized neuropathic pain (LNP).

Objective: The purpose of this study was to report the efficacy of lidocaine 5% medicated plaster (Lido5%P) in the treatment of LNP in thoracic surgical patients.

Methods: We retrospectively reviewed the records of sixteen cancer and noncancer thoracic patients treated with Lido5%P for LNP. Patients had been assessed before and during treatment with standardized forms and questionnaires for pain intensity, sleep quality, drug dosages and adverse events.

Results: Treatment with Lido5%P yielded a significant and lasting improvement in pain symptomatology. In oncological patients as an add-on therapy, Lido5%P improved pain intensity and sleep quality, and delayed opioid dose escalation. In non-oncological patients as monotherapy or in association with antineuropathic drugs, Lido5%P attenuated LNP. No local or systemic adverse events were recorded.

Conclusions: Lido5%P was effective in relieving thoracic LNP, and was well tolerated.     

Cognitive defusion versus experiential avoidance in the reduction of smoking behaviour: an experimental and preliminary investigation

Background: Brief procedures that reduce smoking behaviour may be useful in reaching the many people that do not seek help for smoking addiction.

Objectives: The current study aimed to determine if one component of Acceptance and Commitment Therapy (ACT), cognitive defusion, could be useful in reducing smoking behaviour in a sample of students.

Methods: The study employed a between-subjects three-arm design. For one week, participants were asked to reduce their cigarette consumption. To aid them in their reduction, participants were randomly allocated to one of three conditions: the first received a defusion procedure, the second received an experiential avoidance procedure and a control condition received no procedure. For a second week, the instruction to reduce cigarette consumption was lifted. During both weeks participants were required to monitor their smoking behaviour via a tally diary system.

Results: The defusion condition smoked significantly less than the control condition during week one and significantly less than the control and experiential avoidance conditions during week two.

Conclusion: Results are discussed in terms of the potential utility of defusion in this domain, and the limitations of this preliminary research that would need to be addressed in future investigations.     

Pharmacotherapy for premature ejaculation

Introduction: Four premature ejaculation (PE) subtypes are distinguished on the basis of the duration of the intravaginal ejaculation latency time (IELT), its course in life, and frequency of complaints. Since the 1930s oral drug treatment and local anesthetics have been used to treat PE. Apart from dapoxetine, all currently available drugs to treat PE (SSRIs, clomipramine, and local anesthetics) are off-label. Not only men with lifelong and acquired PE, but also men with normal IELT values may want to postpone their ejaculation time.

Areas covered: The guideline of the International Society for Sexual Medicine for the treatment of PE has provided evidence-based recommendations for the pharmacotherapy of lifelong and acquired PE. Selective serotonin reuptake inhibitors (SSRIs) delay ejaculation by interfering with the serotonin (5-HT) neurotransmission system in the central nervous system. Attention is given not only to the well-known but also to the recently published, very rare side effects of SSRIs.

Expert opinion: Men with normal IELT values who want to postpone ejaculation do not need “drugs for the treatment of PE” but “ejaculation delaying drugs.” Pharmacological research of these ejaculation-delaying drugs ought to be investigated in men with normal IELT values, such as in men with subjective PE, variable PE, and in male volunteers.     

New pharmacotherapy options for pulmonary arterial hypertension

Introduction: Epoprostenol was the first targeted therapy available for the treatment of pulmonary arterial hypertension (PAH). Since then great advances in our knowledge of the disease have been made and the spectrum of therapeutic options for PAH has expanded. After an overview of current available treatments, this article describes the new pharmacotherapy options and their place in the management of PAH.

Areas covered: This paper is based on a literature search and the review of studies published on PAH pharmacotherapy using the MEDLINE database.

Expert opinion: The last decade has been particularly important in PAH management with the emergence of six new molecules, the development of novel routes of administration and improvement of pharmacokinetics. Moreover, pediatric formulations have been developed. However, further research is required to inform clinicians regarding optimal choices of combination therapies (progressive add-on therapy or upfront combination therapy, selection of associated molecules regarding the patient’s profile...), to continue to improve the quality of life of patients with new drugs and to reach the ultimate goal of curing the disease.     

Long-term treatment in pediatric asthma: an update on chemical pharmacotherapy

Introduction: Asthma is the most common chronic disease in childhood, affecting approximately 10% of all children, and is the leading cause of hospitalization in developed countries.

In this paper we aimed to review the evidence on chemical pharmacotherapy for long-term treatment of pediatric asthma, according to the latest updates.

Area covered: Long-term treatment, essential for controlling symptoms and reducing future risks including exacerbations and decline in lung function, includes control agents such as inhaled corticosteroids, long-acting beta2-adrenergic agonists, and leukotriene modifiers. More recent strategies based on the use of a biological drug such as omalizumab, which is a monoclonal antibody directed against immunoglobulin E (IgE), can be considered in selected patients with severe asthma.

Expert opinion: In the near future, the challenge of childhood asthma treatment will be to improve the chemical drugs that already exist as well as to carefully characterize the several different asthma subtypes, with special regard to children with severe disease. A better definition of patient features, made possible by the current advanced knowledge of the pathobiology of severe asthma, can ultimately allow the identification of specific phenotypes and endotypes of severe asthma, aimed to personalize pharmacological treatment.