Does isotretinoin cause depression and suicide?

Isotretinoin is a retinoid that is approved for the treatment of cystic acne. There has been a growing interest in the possible relationship between isotretinoin use and increased risk of depression and suicide. The issue, however, remains controversial. This review examines the available evidence on this association, including published case reports, studies of challenge-rechallenge, reports to government agencies of isotretinoin-related adverse events involving suicide and depression, and possible biological mechanisms of action. Given the evidence to date, clinicians are advised to counsel their patients about the risk of depression and suicide as possible side effects of isotretinoin use, and to administer self-report questionnaires during treatment to screen for the development of depression. Further epidemiological and neurobiological studies are needed to assess the possible relationship between isotretinoin administration and depression and suicide.     

Does therapeutic use of acetaminophen cause acute liver failure?

STUDY OBJECTIVE: To compare the reported occurrence of liver failure in subjects in prospective trials with that in patients in retrospective reports after repeated use of therapeutic dosages of acetaminophen. DESIGN: Systematic review of the medical literature. DATA SOURCE: MEDLINE and EMBASE biomedical and pharmacologic databases. SUBJECTS: Adults who received repeated dosing of acetaminophen 4 g/day or lower for at least 24 hours. MEASUREMENTS AND MAIN RESULTS: Articles written in several languages were abstracted by trained personnel using a structured abstraction form. Data were categorized by methodology (prospective vs retrospective), acetaminophen dosage, and type of liver effect. A total of 791 articles were identified, which included 30,865 subjects in prospective studies and 9337 patients in retrospective reports. The prospective studies reported no cases of fulminant hepatic injury, liver transplantation, or death due to acetaminophen. Of the 30,865 subjects in these studies, 129 (0.4%) were identified who had a serum aminotransferase level that exceeded the upper limit of normal, including 61 subjects in randomized trials in which the proportion of serum aminotransferase level increase was the same as or less than that in the placebo group and 68 subjects in trials without a placebo group. In addition, 4263 (13.8%) received the maximum recommended therapeutic dosage (3.9-4 g/day). In the retrospective reports, 96 patients (1.0%) had a serum alanine aminotransferase level that exceeded the upper limit of normal, one (0.01%) underwent liver transplantation, and six (0.06%) died. Causality relationship of acetaminophen for each retrospective case was assessed with the Naranjo adverse drug reaction probability scale. The mean +/- SD Naranjo score for all 103 retrospective cases was 3.2 +/- 1.9, indicating a possible relationship between the increased aminotransferase levels and acetaminophen use. Some retrospective reports contained information suggesting that the patient had ingested an overdose despite a history of therapeutic use. CONCLUSION: Prospective studies indicated that repeated use of a true therapeutic acetaminophen dosage may slightly increase the level of serum aminotransferase activity, but hepatic failure or death was not reported. Retrospective reports indicated a higher rate of increased serum aminotransferase levels, and several reported associated liver injury and death. The differing results and presence of evidence indicating inaccurate acetaminophen dosage information in some case reports suggests that these cases may be inadvertent overdoses, rather than true therapeutic dosages.     

Modulation of receptor sensitivity: possible therapeutic target?

Ischaemic preconditioning and post-conditioning are cardioprotective interventions that salvage ischaemic myocardium and reduce infarct size. Yet this cardioprotective effect is not the sole response of the heart to ischaemic preconditioning and post-conditioning. It was known that protein kinase C activation in the signalling cascade of ischaemic preconditioning increased the affinity of the adenosine A_2b receptor so that much lower concentrations of adenosine caused A_2b receptor-dependent signalling. In this issue of the British Journal of Pharmacology, these cardioprotective interventions are shown to block desensitization of surface receptors on the sarcolemma of the cardiomyocyte and this receptor effect is divorced from any cardioprotection. Modulating receptor function through signalling pathways is a novel idea but, currently, whether these observations have any clinical relevance is not known. Additional investigations are warranted to determine whether this effect on receptors can be generalized to other surface receptors, and whether the effect can be harnessed to improve treatment of the patient with acute myocardial infarction.     

Comparison of buprenorphine and methadone in the treatment of opiate withdrawal: possible advantages of buprenorphine for the treatment of opiate-benzodiazepine codependent patients?

The study is a preliminary investigation to compare the effectiveness of buprenorphine and methadone as opiate detoxification treatments. The sample comprised 123 drug misusers who were dependent upon opiates only or who were codependent upon opiates and benzodiazepines. Drug misusers dependent upon methadone doses up to 70 mg were eligible for the study. Detoxification took place within a specialist inpatient drug-dependence unit. Withdrawal symptom severity was assessed on a daily basis by means of the Short Opiate Withdrawal Scale. Outcome was assessed for reductions in severity of withdrawal symptoms, treatment retention, and treatment completion. Buprenorphine detoxification was associated with less severe opiate withdrawal symptoms than methadone. Opiate/Benzodiazepine codependent patients reported less severe withdrawal symptoms during treatment with buprenorphine than with methadone and were also more likely to complete detoxification when treated with buprenorphine.     

Molecular mechanisms of α-crystallinopathy and its therapeutic strategy

α-B-Crystallin (CryAB, gene map locus: 11q22.3-q23.1) is a member of the small heat shock protein (HSP) family, a group of proteins that prevent protein aggregation upon exposure of a cell to heat and/or restore the biological activity of cell substrates. The missense mutation and the deletion mutation of CryAB can cause various forms of muscular disorder, including restrictive, hypertrophic, and dilated cardiomyopathies, heart failure, and skeletal muscle weakness. Collectively, these diseases constitute a rare autosomal-dominant inherited disorder called α-crystallinopathy (crystallinopathy), also known as desmin-related cardiomyopathy. The disease is a misfolded protein-related disease characterized by the formation of insoluble protein aggregates consisting of the CryAB protein in the patient's cardiomyocytes and skeletal myocytes. The details of crystallinopathy are unclear at the present time; what has been discovered concerning the disease mechanisms underlying crystallinopathy has been through experiments with genetically modified mice such as the CryAB knockout mouse and various mutant CryAB transgenic (TG) mice. Crystallinopathy can be recapitulated in TG mice by expressing the mutant CryAB Arg120Gly (R120G) protein, a causal mutation of crystallinopathy, specifically in the cardiomyocytes. CryAB R120G causes perinuclear formation of aggresomes containing preamyloid oligomer intermediates, which are wellknown as a primary toxic species in neurodegenerative disease. This suggests that crystallinopathy caused by the CryAB mutation could be considered one of the aggresomal and amyloid-related diseases. Moreover, recent findings have indicated that enhancement of HSP induction and inhibition of apoptotic cell death by mitochondrial protection may be a new therapeutic strategy for patients with crystallinopathy.     

Senolytic drugs in respiratory medicine: is it an appropriate therapeutic approach?

Introduction: Aging is the major risk factor for most of the chronic diseases. Cellular senescence is one of the main hallmarks of aging. A growing body of evidence implicates accelerated mechanisms of aging, including cellular senescence, in idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) pathogenesis. Senolytics are pharmaceutical agents that eliminate senescent cells, thus blocking tissue degeneration and late life complications and allowing tissue regeneration.

Areas covered: The potential use of senolytic drugs in respiratory medicine is examined and discussed.

Expert opinion: The promising signal generated by preclinical studies supports proof-of-principle clinical studies with senolytic agents in the treatment of IPF, but this signal is not very strong, and furthermore, senolytic drugs could be detrimental in IPF patients. On the other hand, the preclinical evidence that these agents are able to influence the natural history of COPD is still lacking. COPD is a very heterogeneous lung disease presenting different (mixed) phenotypes. Given the difference in underlying pathology of these phenotypes, it can be envisaged that lung aging is more or differently involved in some of these phenotypes than others. Consequently, it will be difficult to determine which COPD patient will benefit from a treatment with senolytics.     

Non-canonical Golgi-compartmentalized Gβγ signaling: mechanisms,functions, and therapeutic targets

G protein Gβγ subunits are key mediators of G protein-coupled receptor (GPCR) signaling under physiological and pathological conditions; their inhibitors have been tested for the treatment of human disease. Conventional wisdom is that the Gβγ complex is activated and subsequently exerts its functions at the plasma membrane (PM). Recent studies have revealed non-canonical activation of Gβγ at intracellular organelles, where the Golgi apparatus is a major locale, via translocation or local activation. Golgi-localized Gβγ activates specific signaling cascades and regulates fundamental cell processes such as membrane trafficking, proliferation, and migration. More recent studies have shown that inhibiting Golgi-compartmentalized Gβγ signaling attenuates cardiomyocyte hypertrophy and prostate tumorigenesis, indicating new therapeutic targets. We review novel activation mechanisms and non-canonical functions of Gβγ at the Golgi, and discuss potential therapeutic interventions by targeting Golgi-biased Gβγ-directed signaling.     

Does subtle disturbance of neuronal migration contribute to schizophrenia and other neurodevelopmental disorders? Potential genetic mechanisms with possible treatment implications

Pathways associated with genes that regulate neuronal migration by influencing the function of microtubules in the developing fetal brain may be interfered with as part of the “first-hit” of schizophrenia. In the fully-developed brain, these same pathways that impact microtubule function mediate at least some aspects of experience-dependent plasticity, which may also be impaired in schizophrenia. Whereas severe presentations of “lissencephaly” are associated with mutations and deletions of DISC1, LIS1 and the gene for the very low-density lipoprotein receptor, genetic variations of these loci are good candidate schizophrenia genes. Importantly, in the fully-developed brain, there is a possibility that at least some of the consequences of these disturbed genetic pathways that adversely affect microtubule function may be “bypassed” or mitigated.     

Adolescent smoking and depression: Which comes first?

Despite the well-known health risks of smoking, adolescents continue to smoke at alarming rates. Smoking is also known to be associated with depression, but the direction of this relation is unclear. This study used data from the National Longitudinal Study of Adolescent Health (Add Health) to evaluate the direction of the relation between cigarette smoking and depression among adolescents. A total of 14,634 adolescents (7132 males and 7502 females) completed in-home surveys in 1995 and 1996 and were split into four smoking status groups. Adolescents who were Starters, Quitters, and Maintainers were found to be 1.5, 1.4, and 2.0 times more likely, respectively, than Nevers to be depressed at Time 2. In addition, females showed a striking pattern of increases in depression around the onset of smoking and decreases around the time of quitting. While these findings do not prove that smoking leads to depression, they are consistent with such a prediction.     

French general practitioners' attitudes and prescription patterns toward buprenorphine maintenance treatment: does doctor shopping reflect buprenorphine misuse?

This study investigated attitudes toward buprenorphine maintenance treatment (BMT) among general practitioners (GPs) and their maintained patients' propensity to turn to several prescribers (doctor shopping), among a sample of 345 GPs prescribing BMT in South-Eastern France. Survey data were anonymously matched to administrative data that provided information about GPs' patients. A simultaneous equation model suggests that GPs' attitude influenced doctor shopping, not the reverse. Doctor shopping was lower among GPs who reported inducting BMT with 8 mg of buprenorphine per day or more, and was higher for GPs endorsing a stringent attitude toward patients. Thus doctor shopping should not be understood exclusively as a deviant behaviour. It is partially physician-driven, and further research is needed to assess whether it reflects patients' dissatisfaction toward inappropriate care supply and the difficulty to establish a good therapeutic relationship between an opiate-dependent patient and a general practitioner.     

Does nefazodone improve both depression and Parkinson disease? A pilot randomized trial

Some of the selective serotonin reuptake inhibitors (SSRI)-induced motor side effects are mediated by stimulating 5-HT2 receptors in the basal ganglia, probably because serotonin inhibits the subsequent neuronal dopamine release. We hypothesized that nefazodone, a serotonin 2 antagonist/reuptake inhibitor (SARI) that selectively blocks 5-HT2 receptors, could disrupt the aforementioned inhibitory pathway. Therefore, increased dopamine levels in the postsynaptic milieu and an improvement in the motor symptoms in depressed patients with Parkinson disease (PD) should be observed. This study was designed to determine whether nefazodone has a dual activity as an antidepressant and as an agent capable of reducing the extrapyramidal symptoms in depressed parkinsonian patients. Depressed patients with PD were randomly assigned to 2 therapeutic groups: nefazodone or fluoxetine. Patients were evaluated by a psychiatrist and were blindly assessed by a neurologist with an array of scales. Patients on nefazodone (n = 9) showed a significant improvement over time in the total Unified Parkinson Disease Rating Scale score (UPDRS) (part II + part III) (P = 0.004) and in the UPDRS subscore part III (P = 0.003). None of these scores changed over time in the fluoxetine group (n = 7). Both, nefazodone and fluoxetine were equally effective as antidepressants: Beck Depression Inventory scores significantly improved (P < 0.001), with no significant differences between treatment groups (P = 0.97). If our results can be confirmed in a larger clinical trial, nefazodone ought to be considered over fluoxetine given its secondary beneficial effects regarding the reduction of extrapyramidal symptoms in depressed PD patients.     

Genes associated with epithelial-mesenchymal transition: possible therapeutic targets in ductal pancreatic adenocarcinoma?

Epithelial to mesenchymal transition (EMT) is a biological process that allows well-differentiated, polarized epithelial cells to undergo a conversion to motile, unpolarized mesenchymal cells. EMT plays crucial roles during implantation, embryogenesis, and organ development (Type 1 EMT), is associated with tissue regeneration and organ fibrosis (Type 2 EMT), and involved in cancer invasion, metastasis, and drug resistance (Type 3 EMT). Since aggressiveness and drug resistance are hallmarks of ductal pancreatic cancer, significant effort has been undertaken in recent years to elucidate molecular EMT mechanisms in this dismal malignancy. This represents a formidable challenge for several reasons: EMT is a dynamic process, both with regard to spatial and temporal heterogeneity. Moreover, EMT is induced and regulated by a complex network of traditional signaling pathways and new players like microRNAs. Interestingly, similar molecular characteristics link EMT-type cells also to the concept of cancer stem cells. This review tries to integrate the current knowledge regarding EMT and pancreatic cancer; furthermore to outline not only the perspective on novel EMT-associated therapeutic targets, but also on overcoming drug resistance by interfering with EMT.     

Serotonin and depression: pathophysiological mechanism or marketing myth?

The notion that impaired serotonin (5-HT) function can lead to clinical depression has a long history but is still controversial. Some have argued that the 5-HT hypothesis has been misused by the pharmaceutical industry to promote a simplistic biological model of depression to market selective serotonin reuptake inhibitors (SSRIs) to medical practitioners and the public. By contrast, there is now substantial evidence that unmedicated depressed patients have abnormalities in brain 5-HT function; however, the relation of these abnormalities to the clinical syndrome is unclear. The best evidence that 5-HT contributes to the pathophysiology of depression comes from studies of tryptophan depletion, which show that lowering brain 5-HT levels can induce acute symptomatic relapse in recovered depressed patients. Clarification of the mechanism of this effect will enable an understanding of how impaired 5-HT activity contributes to the subjective experience of depression.     

5-HT and depression: is the glass half-full?

Mood disorders such as major depression are common illnesses with considerable morbidity and significant mortality. A long-standing theory is that a breakdown in brain serotonin (5-hydroxytryptamine; 5-HT) signalling is critically involved in the symptoms and drug treatment of clinical depression. However, the nature of this 5-HT defect has proved to be frustratingly elusive, and it remains unclear how the 5-HT signalling effects of antidepressant drugs might alter neuropsychological mechanisms to bring about relief of depressed mood. This article highlights recent discoveries that advance our understanding of how 5-HT-evoked changes at molecular, cellular and neuropsychological levels might interact to alleviate the symptoms of clinical depression.     

The perceived and actual consequences of intranasal administration of buprenorphine or burprenorphine–naloxone by prisoners

Aims: Previous research has highlighted that intranasal administration of buprenorphine is common amongst the UK prison population. However, there is a scarcity of research exploring the effects of intranasal administration of buprenorphine–naloxone. We sought to explore the experiences and perceptions of intranasal administration of buprenorphine–naloxone with different opioid drugs.

Methods: A cross-sectional survey in a male remand prison in the North of England.

Findings: A total of 85 prisoners completed the survey (mean age 35 years). Compared to buprenorphine, prisoners perceived that they were significantly less likely to experience euphoria after intranasal administration of buprenorphine–naloxone alone (χ²?=?4, p?<?0.05). No statistically significant differences were found for actual experiences of intranasal administration of drugs, but this was limited by reduced statistical power due to the small numbers of prisoners with experience.

Conclusions: This study is the first to assess the relative consequences of intranasal misuse of buprenorphine and buprenorphine–naloxone within a prison setting. Prisoners perceived a reduced euphoric effect following intranasal administration of buprenorphine–naloxone compared to buprenorphine alone. Since intranasal administration of illicit buprenorphine is common in prison settings, buprenorphine–naloxone should be used as the first line buprenorphine product for those engaged in the criminal justice system. However, since the research was conducted in just one prison, findings should be interpreted with caution as they might not be representative of the wider prison population.