Current Pharmaceutical Design - Volume 21, Issue 23, 2015

Pharmacological treatment forms part of much routine psychiatric practice. Many psychotropic drugs and psychotherapies are available for treating patients with mental disorders, but considerable numbers of individuals remain troubled by incapacitating symptoms even after a succession of evidence-based treatments. In this situation, many doctors consider prescribing a psychotropic medication outside the narrow terms of its market authorisation or ‘product licence’, in an attempt to optimise clinical outcomes and increase the chance of recovery. Despite expressed concerns about potential hazards and increased physician liability, many authorities agree that using a drug outside the narrow terms of its product licence can be an important part of clinical practice. This paper illustrates the nature and extent of the use of licensed drugs for unlicensed applications in psychiatric and other medical settings, indicates potential drawbacks and hazards, and makes recommendations for a suggested process when prescribing ‘off-label’, as an appropriate part of the overall management of individual patients.

Introduction: New antipsychotics continuously arrive on the market, which thereby influences the approved and off-label prescribing (OLP) schemes. We aimed to identify the recent trends in the OLP of antipsychotics. We conducted a literature review based on three different populations: adult, pediatric, and elderly patients. Methods: A literature search was performed in the PubMed and ScienceDirect databases using the following keyword algorithm: “offlabel” AND (“antipsychotic*” OR “neuroleptic*”). The period investigated ranged from January 2000 to January 2015. Only Englishwritten pharmacoepidemiological studies were included. Results: Seventy-seven relevant results were identified. Among adults, OLP consisted of 40 to 75% of all antipsychotic prescriptions. The main indications were mood disorders, anxiety disorders, insomnia and agitation. Quetiapine was the most frequently prescribed offlabel antipsychotic, especially for anxiety and insomnia. Among children, OLP was estimated between 36 and 93.2% of all antipsychotic prescriptions. Risperidone and aripiprazole were primarily used and were most often prescribed for attention deficit hyperactivity disorder, anxiety, or mood disorders. Among elderly individuals, OLP consisted of 22 to 86% of all antipsychotic prescriptions. Antipsychotic OLP was particularly frequent for agitation; however, a recent decrease in this OLP was identified. Discussion: Antipsychotics have largely been prescribed off-label in recent years. The types of antipsychotic OLP practices differ according to the age category of patients. OLP is often used in cases of therapeutic dead-ends or for specific disorders with few or no currently approved medications. However, other OLP practices only reflect temporary prescription trends for mild symptoms, which may induce safety concerns.

Background: Cannabis use disorder (CUD) is setting an increasing demand on health services. Although there are objective physical symptoms of cannabis dependence, there is no validated pharmacotherapy for CUD treatment, which is mainly based on behavioral interventions. The goal of such pharmacotherapies in CUD may be abstinence or consumption reduction. Besides, a growing literature tests the efficacy of different drugs that have already been validated for other diseases, thus opening up possibilities for their off-label use. Here we led a systematic literature review to examine the level of evidence of their efficacy, indications and safety for off-label use to treat CUD. Methods: Systematic review via the PubMed, Web of Science, and ScienceDirect databases. Results: Although 43 relevant articles were found, only 13 were double-blind, randomized placebo-controlled trials, and only 4 of these 13 trials had positive results. These trials concerned dronabinol, nabiximols, N-acetylcysteine and gabapentin. Conclusion: Given the small number of positive trials for each drug, there is no indication for routine off-label prescription in CUD. However, off-label prescribing may be an option in cases where behavioral therapies have failed. Benefit-risk balance is acceptable for N-acetylcysteine but remains to be confirmed for gabapentin, dronabinol and nabiximols.

There is a high rate of benzodiazepine use in the population. Benzodiazepines are used for multiple indications (anxiety, seizures, alcohol withdrawal, muscular relaxation and anesthesia). Benzodiazepines are also addictive substances and a non-negligible fraction of regular users will develop dependence. There is currently no approved pharmacotherapy for benzodiazepine use disorder treatment and optimal strategies for treatment are unclear. In this review, we aimed to summarize the findings on off-label pharmacologic therapy that have been used for BZD dependence. One classical approach is to provide a slow taper associated with counseling. Anti-epileptic drugs appear also to alleviate symptoms of withdrawal. The long-term strategies of maintenance therapy (with benzodiazepine) or of blocking therapy (with a GABA antagonist such as flumazenil) could provide some clinical benefit but have not yet been tested appropriately. Pregabalin appears promising and deserves further investigation. There is a clear need for more clinical trials in this area to improve care.

Borderline personality disorder (BPD) is a common mental disorder characterized by a pervasive pattern of emotional Borderline personality disorder (BPD) is a common mental disorder characterized by a pervasive pattern of emotional lability, impulsivity, interpersonal difficulties, identity disturbances, and disturbed cognition. Traditional pharmacotherapies are effective in treating some of these core symptoms but have only modest effects on the domain of interpersonal dysfunction of BPD. Thus there is a need to develop new, neurobiologically informed pharmacological treatments for BPD. This review focuses on the potential use of intranasal oxytocin (OXT), which has key roles in the regulation of complex social cognition and behaviors, to target symptoms of interpersonal dysfunction in BPD. Surprisingly, despite promising data on the prosocial effects of OXT, only 5 trials in BPD have been published to date. These trials show mixed results with on one hand, a decrease of emotional responses to stress and on the other hand, some "paradoxical" reactions with worsened interpersonal anxiety and decreased cooperative behavior. These mixed results are interpreted according to different theoretical models and also in light of some methodological limitations. Further studies are needed to understand the effect of OXT in patients with BPD and ongoing clinical trials will provide some answers to remaining questions on the use of OXT in BPD. Recommendations for future studies are also proposed in this review.

Patients with severe mental illnesses, such as schizophrenia and bipolar disorder, are at increased risk of developing metabolic disorders including obesity, diabetes, and dyslipidemia. All of these comorbidities increase the risk of cardiovascular disease and mortality. Different approaches, including diet and lifestyle modifications, behavioral therapy and switching antipsychotic agents, have been proposed to manage these metabolic abnormalities. However, these interventions may be insufficient, impractical or fail to counteract the metabolic dysregulation. Consequently, a variety of pharmacological agents such as antidiabetic drugs, have been studied in an attempt to reverse the weight gain and metabolic abnormalities evident in these patients. Despite a significant effect, many of these treatments are used off-label. This qualitative review focuses on pharmacological agents that could offer significant benefits in the management of cardio-metabolic disorders associated with serious mental illness.

This review paper discusses the central role of gamma-aminobutyric acid (GABA) in diverse physiological systems and functions and the therapeutic potential of the benzodiazepine antagonist flumazenil (Ro 15- 1788) for a wide range of disorders of the central nervous system (CNS). Our group and others have studied the potential of flumazenil as a treatment for benzodiazepine dependence. A small but growing body of research has indicated that flumazenil may also have clinical application in CNS disorders such as Parkinson’s disease, idiopathic hypersomnia and amyotrophic lateral sclerosis. Despite this body of research the therapeutic potential of flumazenil remains poorly understood and largely unrealized. The purpose of this paper is not to provide an exhaustive review of all possible therapeutic applications for flumazenil but rather to stimulate research interest, and discussion of the exciting therapeutic potential of this drug for a range of chronic debilitating conditions.

Although trazodone is approved and marketed in most countries worldwide for the sole treatment of Major Depressive Disorder, the use for this medication is very common for many other conditions, such as primary or secondary insomnia, Generalised Anxiety Disorder, Panic Disorder, Post-Traumatic Stress Disorder and Obsessive- Compulsive Disorder. Other, not officially approved, uses of trazodone include: the treatment of bulimia, benzodiazepine and/or alcohol dependence or abuse, fibromyalgia, degenerative diseases of the central nervous system such as dementia and other organic disorders, schizophrenia, chronic pain, and diabetic neuropathy. In addition, due to its 5HT2A receptor antagonistic action, trazodone may be used to prevent the occurrence of initial and long-term side effects of SSRI, such as anxiety, insomnia and sexual dysfunction. Despite the favorable clinical experience and the encouraging results from the studies that have tested the efficacy of trazodone for some of its off-label indications, it is paramount that large, randomized and controlled clinical trials be conducted in the near future to evaluate which of the many off-label indications are supported by a strong scientific evidence.

Bipolar disorders (BD) present with abnormalities of circadian rhythmicity and sleep homeostasis, even during phases of remission. These abnormalities are linked to the underlying neurobiology of genetic susceptibility to BD. Melatonin is a pineal gland secreted neurohormone that induces circadian-related and sleep-related responses. Exogenous melatonin has demonstrated efficacy in treating primary insomnia, delayed sleep phase disorder, improving sleep parameters and overall sleep quality, and some psychiatric disorders like autistic spectrum disorders. In order to evaluate the efficacy of melatonin among patients with BD, this comprehensive review emphasizes the abnormal melatonin function in BD, the rationale of melatonin action in BD, the available data about the exogenous administration of melatonin, and melatonin agonists (ramelteon and tasimelteon), and recommendations of use in patients with BD. There is a scientific rationale to propose melatonin-agonists as an adjunctive treatment of mood stabilizers in treating sleep disorders in BD and thus to possibly prevent relapses when administered during remission phases. We emphasized the need to treat insomnia, sleep delayed latencies and sleep abnormalities in BD that are prodromal markers of an emerging mood episode and possible targets to prevent future relapses. An additional interesting adjunctive therapeutic effect might be on preventing metabolic syndrome, particularly in patients treated with antipsychotics. Finally, melatonin is well tolerated and has little dependence potential in contrast to most available sleep medications. Further studies are expected to be able to produce stronger evidence-based therapeutic guidelines to confirm and delineate the routine use of melatonin-agonists in the treatment of BD.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopment disorder occurring during childhood. However, ADHD persists into adulthood in 45.7% of cases. The global prevalence of adult ADHD is estimated to 5.3%, with no difference between Europe and North America. ADHD is often comorbid with substance use disorder (SUD), with Odds Ratio ranges from 1.5 to 7.9, depending on the substance and the dependence level. Conversely, the prevalence of ADHD among patients with SUD is 10.8%, versus 3.8% for patients without SUD. Methylphenidate (MPH) alleviates ADHD symptoms and, as such, is currently considered as a first choice medication. MPH blocks the dopamine and norepinephrine transporters leading to an increase in extracellular dopamine. It should be noted that its subjective effects are highly dependent on the pharmacokinetic and especially on the rate of input, which highlights the importance of choosing a sustainedrelease formulation. Meanwhile, prescribing MPH to patients with comorbid SUD has always been challenging for clinicians. The aim of this review is to address the benefits and pitfalls of using MPH in adults with ADHD comorbid SUD, depending on each of the following types of SUD: amphetamine, cocaine, nicotine, alcohol, cannabis and opiates. Overall, due to the prevalence of ADHD in SUD and to the benefits of MPH observed in this population, and considering the mild or low side effects observed, the response to MPH treatment should be evaluated individually in adults with comorbid ADHD and SUD. The choice of the formulation should favor sustained- release MPH over immediate release MPH. Cardiovascular parameters also have to be monitored during long-term use.

Almost 10% of the world’s population is affected by alcohol use disorder (AUD). The combination between psychosocial intervention and pharmacological treatment seems to be the most effective approach for patients affected by AUD. Among effective drugs useful in the treatment of AUD, GABAB-ergic medications have been tested with encouraging results (i.e. sodium oxybate, baclofen, gabapentin, pregabalin and tiagabine). The present review will summarize available data on these medications.

Schizophrenia is a severe and frequent neuropsychiatric disorder. Despite antipsychotic medications, up to 30% of patients with schizophrenia still report disabling treatment-resistant symptoms. Transcranial direct current stimulation (tDCS) has been proposed as a novel method to alleviate such symptoms. Here, we review studies investigating the effects of tDCS on symptoms, cognition, brain activity and cortical plasticity in patients with schizophrenia. We provide an up-to-date and comprehensive overview of the use of tDCS in patients with schizophrenia. More specifically, we first present the effects of tDCS on treatment-resistant symptoms of schizophrenia. We report that tDCS applied over the frontotemporal regions reduced auditory hallucinations, with a mean 34% reduction of symptoms. Moreover, tDCS applied over both prefrontal cortices reduced negative symptoms and catatonia. We discuss the need for further sham-controlled studies to confirm these effects. Second, we present the impact of tDCS on cognitive functions in patients with schizophrenia. Positive effects of tDCS have been reported on learning, working memory, attention and source-monitoring. Third, we review the effects of tDCS on brain activity in patients with schizophrenia. Although only few studies investigated the effects of tDCS using neuroimaging technics, these studies are helpful at identifying the mechanisms of action of tDCS in schizophrenia. Fourth, we present tDCS studies on cortical plasticity showing reduced cortical plasticity in patients with schizophrenia that tDCS may beneficially modulate. Lastly, we discuss the safety aspects of tDCS in patients with schizophrenia and potential directions to improve efficacy for this clinical populations.

fMRI-based neurofeedback (fMRI-NF) is a non-invasive technique that allows participants to achieve control of their own brain activity using the real-time feedback of the activity (measured indirectly based on the BOLD signal) of a particular brain region or network. The feasibility of fMRI-NF in healthy subjects has been documented for a variety of brain areas and neural systems, and this technique has also been proposed for the treatment of psychiatric disorders in recent years. Through a systematic review of the scientific literature this paper probes the rationale and expected applications of fMRI-NF in psychiatry, discusses issues that must be addressed in the use of this technique to treat mental disorders. Six relevant references and five ongoing studies were identified according to our inclusion criteria. These studies show that in most psychiatric disorders (major depressive disorder, schizophrenia, personality disorders, addiction), patients are able to learn voluntary control of the neuronal activity of the targeted brain region(s). Interestingly, in some cases, this learning is associated with clinical improvement, showing that fMRI-NF can potentially be developed into a therapeutic tool. However, only low-level evidence is available to support the use of this relatively new technique in clinical practice. Notably, no randomized, controlled trial is currently available in this field of research. Finally, methodological issues and clinical perspectives (especially the potential use of pattern recognition in fMRI-NF protocols) are discussed.

A variety of physiological and pharmacological factors are known to influence stress responses. Cold restraint stress (CRS) induced gastric ulcerogenesis in both the sexes but such ulceration was found to be markedly higher in male than in female rats. In males, CRS induced significant increases in both ulcer number and ulcer severity; while the females though showed a trend towards increase in both the parameters, the extent of changes was far less than in males. Pre-administration of the NO mimetic, L-Arginine (500 and 1000 mg/kg), prior to CRS, dose dependently decreased ulcer number and severity in male rats. In female rats, L-Arginine also induced a gastric cytoprotective effect during CRS but to a much lesser extent. On the other hand, inhibition of NO synthesis by LNAME (25 and 50 mg/kg) further aggravated such stress ulcerogensis in both males and females, with aggravations being more extensive in males. CRS induced ulcerogenesis was associated with reductions in levels of brain and plasma NOx and GSH levels while MDA levels were elevated in both male and female rats- the magnitude of these changes being higher in males than in females. In female rats, pretreatment with formestane (aromatase inhibitor) but not tamoxifen (estrogen receptor blocker) aggravated stress ulcer formation as compared to vehicle treated CRS exposed rats. Formestane pretreatment also induced greater suppressions in brain NOx and GSH and elevations in brain MDA, as compared to vehicle treated CRS rats. These results indicate that estrogen and its interactions with oxidative stress markers and NO plays a key role in the gender based differences in stress induced gastric ulcerogenesis. It may be speculated that, in males, CRS induces greater reductions in brain NO and enhancement in oxidative injury resulting in greater severity of gastric ulceration. On the other hand, greater resistance of females to ulcerogenic effects of CRS may be due to the protection conferred by estrogen and this effect seems to be related to interactions with brain NO.

Esophageal adenocarcinoma (EAC) originates from the neoplastic changes in the esophageal epithelium. Barrett’s esophagus (BE) precedes EAC. In BE metaplasia, the normal stratified squamous epithelium is replaced by the intestinal columnar epithelium. Esophageal metaplasia might further progress to dysplasia, neoplasia, and EAC. The neoplastic progression from BE to EAC is accompanied with marked histological and molecular changes including deregulation of key signaling pathways and expression of various genes including microRNA (miRNA). To date, stable and progressive changes in expression levels of different miRNA subsets are shown for each stage of EAC carcinogenesis. This suggests that miRNAs might become promising markers for BE/EAC diagnosis and prognosis of survival of EAC patients and lymph node tumor metastases. Development of new molecular markers based on the assessment of miRNAs circulating in patients’ biofluids would improve the effectiveness and cost-effectiveness of esophageal cancer surveillance regimens and open new possibilities for high throughput screening programs to identify BE patients who are at high-risk for the development of highgrade dysplasia or progression to EAC.

The anti-carcinogenic effect of the new quinazolinone compound, named MMD, was tested on MCF-7 human breast cancer cell line. The synthesis of quinazolinone-based compounds attracted strong attention over the past few decades as an alternative mean to produce analogues of natural products. Quinazolinone compounds sharing the main principal core structures are currently introduced in the clinical trials and pharmaceutical markets as anti-cancer agents. Thus, it is of high clinical interest to identify a new drug that could be used to control the growth and expansion of cancer cells. Quinazolinone is a metabolite derivative resulting from the conjugation of 2-aminobenzoyhydrazide and 5-methoxy-2- hydroxybenzaldehyde based on condensation reactions. In the present study, we analysed the influence of MMD on breast cancer adenoma cell morphology, cell cycle arrest, DNA fragmentation, cytochrome c release and caspases activity. MCF-7 is a type of cell line representing the breast cancer adenoma cells that can be expanded and differentiated in culture. Using different in vitro strategies and specific antibodies, we demonstrate a novel role for MMD in the inhibition of cell proliferation and initiation of the programmed cell death. MMD was found to increase cytochrome c release from the mitochondria to the cytosol and this effect was enhanced over time with effective IC50 value of 5.85 ± 0.71 μg/mL detected in a 72-hours treatment. Additionally, MMD induced cell cycle arrest at G0/G1 phase and caused DNA fragmentation with obvious activation of caspase-9 and caspases-3/7. Our results demonstrate a novel role of MMD as an anti-proliferative agent and imply the involvement of mitochondrial intrinsic pathway in the observed apoptosis.