Background and Aims
To assess the efficacy and tolerability of adjunctive pharmacotherapy for smoking cessation in adults with serious mental illness (SMI) by means of a systematic review and network ...meta‐analysis.
Method
We searched Embase, Medline, PsychINFO and the Cochrane Central Register of Controlled Trials from database inception to 1 December 2014 for randomized controlled trials (RCTs) published in English. We included all studies of smokers with SMI (including schizophrenia, schizoaffective disorder, bipolar disorder, delusional disorder and depressive psychoses) who were motivated to quit smoking. Pharmacotherapies included nicotine replacement therapy (NRT), bupropion and varenicline delivered as monotherapy or in combination compared with each other or placebo. The efficacy outcome was self‐reported sustained smoking cessation, verified biochemically at the longest reported time‐point. The tolerability outcome was number of patients discontinuing the trial due to any adverse event.
Results
Seventeen study reports were included, which represented 14 individual RCTs. No trials were found in patients with depressive psychoses, delusional disorder or that compared NRT monotherapy with placebo. A total of 356 and 423 participants were included in the efficacy and tolerability analyses, respectively. From the network meta‐analysis, both bupropion and varenicline were more effective than placebo odds ratio (OR) = 4.51, 95% credible interval (CrI) = 1.45–14.04 and OR = 5.17, 95% CrI = 1.78–15.06, respectively. Data were insensitive to an assessment of varenicline versus bupropion (OR = 1.15, 95% CrI = 0.24–5.45). There were no significant differences in tolerability. All outcomes were rated by GRADE criteria as very low quality.
Conclusions
The limited evidence available to date suggests that bupropion and varenicline are effective and tolerable for smoking cessation in adults with serious mental illnesses.
Summary Background Substantial concerns have been raised about the neuropsychiatric safety of the smoking cessation medications varenicline and bupropion. Their efficacy relative to nicotine patch ...largely relies on indirect comparisons, and there is limited information on safety and efficacy in smokers with psychiatric disorders. We compared the relative neuropsychiatric safety risk and efficacy of varenicline and bupropion with nicotine patch and placebo in smokers with and without psychiatric disorders. Methods We did a randomised, double-blind, triple-dummy, placebo-controlled and active-controlled (nicotine patch; 21 mg per day with taper) trial of varenicline (1 mg twice a day) and bupropion (150 mg twice a day) for 12 weeks with 12-week non-treatment follow-up done at 140 centres (clinical trial centres, academic centres, and outpatient clinics) in 16 countries between Nov 30, 2011, and Jan 13, 2015. Participants were motivated-to-quit smokers with and without psychiatric disorders who received brief cessation counselling at each visit. Randomisation was computer generated (1:1:1:1 ratio). Participants, investigators, and research personnel were masked to treatment assignments. The primary endpoint was the incidence of a composite measure of moderate and severe neuropsychiatric adverse events. The main efficacy endpoint was biochemically confirmed continuous abstinence for weeks 9–12. All participants randomly assigned were included in the efficacy analysis and those who received treatment were included in the safety analysis. The trial is registered at ClinicalTrials.gov (number NCT01456936 ) and is now closed. Findings 8144 participants were randomly assigned, 4116 to the psychiatric cohort (4074 included in the safety analysis) and 4028 to the non-psychiatric cohort (3984 included in the safety analysis). In the non-psychiatric cohort, 13 (1·3%) of 990 participants reported moderate and severe neuropsychiatric adverse events in the varenicline group, 22 (2·2%) of 989 in the bupropion group, 25 (2·5%) of 1006 in the nicotine patch group, and 24 (2·4%) of 999 in the placebo group. The varenicline–placebo and bupropion–placebo risk differences (RDs) for moderate and severe neuropsychiatric adverse events were −1·28 (95% CI −2·40 to −0·15) and −0·08 (−1·37 to 1·21), respectively; the RDs for comparisons with nicotine patch were −1·07 (−2·21 to 0·08) and 0·13 (−1·19 to 1·45), respectively. In the psychiatric cohort, moderate and severe neuropsychiatric adverse events were reported in 67 (6·5%) of 1026 participants in the varenicline group, 68 (6·7%) of 1017 in the bupropion group, 53 (5·2%) of 1016 in the nicotine patch group, and 50 (4·9%) of 1015 in the placebo group. The varenicline–placebo and bupropion–placebo RDs were 1·59 (95% CI −0·42 to 3·59) and 1·78 (−0·24 to 3·81), respectively; the RDs versus nicotine patch were 1·22 (−0·81 to 3·25) and 1·42 (−0·63 to 3·46), respectively. Varenicline-treated participants achieved higher abstinence rates than those on placebo (odds ratio OR 3·61, 95% CI 3·07 to 4·24), nicotine patch (1·68, 1·46 to 1·93), and bupropion (1·75, 1·52 to 2·01). Those on bupropion and nicotine patch achieved higher abstinence rates than those on placebo (OR 2·07 1·75 to 2·45 and 2·15 1·82 to 2·54, respectively). Across cohorts, the most frequent adverse events by treatment group were nausea (varenicline, 25% 511 of 2016 participants), insomnia (bupropion, 12% 245 of 2006 participants), abnormal dreams (nicotine patch, 12% 251 of 2022 participants), and headache (placebo, 10% 199 of 2014 participants). Efficacy treatment comparison did not differ by cohort. Interpretation The study did not show a significant increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo. Varenicline was more effective than placebo, nicotine patch, and bupropion in helping smokers achieve abstinence, whereas bupropion and nicotine patch were more effective than placebo. Funding Pfizer and GlaxoSmithKline.
Evins and Cather discuss the need to address barriers to provision of first-line pharmacotherapy for tobacco use disorder, highlighting the study by White et al on the issue. Expert clinical ...consensus guidelines call for clinicians to offer a prescription to all patients who smoke tobacco; to provide strong, clear, and personalized advice to patients to quit as soon as possible; and to proactively connect patients to behavioral support for tobacco smoking cessation. This guidance is rooted in the recognition that tobacco smoking is a chronic substance use disorder caused by addiction to nicotine. Pharmacotherapy for smoking cessation is recommended for all who smoke tobacco and will accept such therapy, regardless of their readiness to quit, and with rare exception.
There have been extensive policy shifts in the legality of recreational and therapeutic use of cannabis in the United States, as well as a steady increase in the number of people using the drug on a ...regular basis. Given these rapid societal changes, defining what is known scientifically about the consequences of cannabis use on mental health takes on added public health significance. The purpose of this circumspectives piece is to discuss evidence of cannabis' effects on two psychiatric conditions: post-traumatic stress disorder and psychotic disorders. Dr Haney and Dr Evins will discuss two viewpoints regarding the benefit and harm of cannabis use for these conditions, while outlining what remains unproven and requires further testing to move the field forward.
Current tobacco treatment guidelines have established the efficacy of available interventions, but they do not provide detailed guidance for common implementation questions frequently faced in the ...clinic. An evidence-based guideline was created that addresses several pharmacotherapy-initiation questions that routinely confront treatment teams.
Individuals with diverse expertise related to smoking cessation were empaneled to prioritize questions and outcomes important to clinicians. An evidence-synthesis team conducted systematic reviews, which informed recommendations to answer the questions. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to rate the certainty in the estimated effects and the strength of recommendations.
The guideline panel formulated five strong recommendations and two conditional recommendations regarding pharmacotherapy choices. Strong recommendations include using varenicline rather than a nicotine patch, using varenicline rather than bupropion, using varenicline rather than a nicotine patch in adults with a comorbid psychiatric condition, initiating varenicline in adults even if they are unready to quit, and using controller therapy for an extended treatment duration greater than 12 weeks. Conditional recommendations include combining a nicotine patch with varenicline rather than using varenicline alone and using varenicline rather than electronic cigarettes.
Seven recommendations are provided, which represent simple practice changes that are likely to increase the effectiveness of tobacco-dependence pharmacotherapy.
Activation of oncogenic KRAS is the most common driving event in lung adenocarcinoma development. Despite the existing rationale for targeting activated KRAS and its downstream effectors, the failure ...of clinical trials to date indicates that the mechanism of KRAS-driven malignancy remains poorly understood. Here we report that histone deacetylase 10 (HDAC10) might function as a putative tumor suppressor in mice carrying a spontaneously activated oncogenic
allele.
deletion accelerated KRAS-driven early-onset lung adenocarcinomas, increased macrophage infiltration in the tumor microenvironment, and shortened survival time in mice. Highly tumorigenic and stem-like lung adenocarcinoma cells were increased in
-deleted tumors compared with
wild-type tumors. HDAC10 regulated the stem-like properties of KRAS-expressing tumor cells by targeting SOX9. Expression of SOX9 was significantly increased in
-deleted tumor cells and depletion of SOX9 in
knockout (KO) lung adenocarcinoma cells inhibited growth of tumorspheres. The genes associated with TGFβ pathway were enriched in
KO tumor cells, and activation of TGFβ signaling contributed to SOX9 induction in
KO lung adenocarcinoma cells. Overall, our study evaluates the functions and mechanisms of action of HDAC10 in lung carcinogenesis that will inform the rationale for targeting its related regulatory signaling as an anticancer strategy. SIGNIFICANCE: These findings linking HDAC10 and lung tumorigenesis identify potential novel strategies for targeting HDAC10 as a treatment for lung cancer.
Addiction to tobacco-derived nicotine remains highly prevalent in the United States, with 18% using daily, and 53% of those with serious mental illness using daily. While smokers with serious mental ...illness have been excluded from most large nicotine-dependence treatment studies, a growing evidence base is available to guide clinicians in assisting their patients with psychiatric illness to quit smoking. The aim of this review is to present the evidence on safety and efficacy of smoking cessation interventions for those with serious mental illness. Smokers with schizophrenia spectrum disorders should receive varenicline or bupropion with or without nicotine replacement therapy in combination with behavioral treatment. Although more research is needed, preliminary evidence suggests that varenicline in combination with behavioral support is efficacious and well tolerated for smoking cessation for those with bipolar disorder and major depressive disorder. Controlled trials have found no evidence that in patients with serious mental illness, the use of pharmacotherapeutic cessation aids worsens psychiatric symptoms or increases the rate of psychiatric adverse events. Converging evidence indicates that a majority of smokers with serious mental illness want to quit smoking and that available pharmacotherapeutic cessation aids combined with behavioral support are both effective for, and well tolerated by, these smokers.
With a political debate about the potential risks and benefits of cannabis use as a backdrop, the wave of legalization and liberalization initiatives continues to spread. Four states (Colorado, ...Washington, Oregon, and Alaska) and the District of Columbia have passed laws that legalized cannabis for recreational use by adults, and 23 others plus the District of Columbia now regulate cannabis use for medical purposes. These policy changes could trigger a broad range of unintended consequences, with profound and lasting implications for the health and social systems in our country. Cannabis use is emerging as one among many interacting factors that can affect brain development and mental function. To inform the political discourse with scientific evidence, the literature was reviewed to identify what is known and not known about the effects of cannabis use on human behavior, including cognition, motivation, and psychosis.
Mitochondrial DNA (mtDNA) mutations are a major cause of genetic disease, but their prevalence in the general population is not known. We determined the frequency of ten mitochondrial point mutations ...in 3168 neonatal-cord-blood samples from sequential live births, analyzing matched maternal-blood samples to estimate the de novo mutation rate. mtDNA mutations were detected in 15 offspring (0.54%, 95% CI = 0.30–0.89%). Of these live births, 0.00107% (95% CI = 0.00087–0.0127) harbored a mutation not detected in the mother's blood, providing an estimate of the de novo mutation rate. The most common mutation was m.3243A→G. m.14484T→C was only found on sub-branches of mtDNA haplogroup J. In conclusion, at least one in 200 healthy humans harbors a pathogenic mtDNA mutation that potentially causes disease in the offspring of female carriers. The exclusive detection of m.14484T→C on haplogroup J implicates the background mtDNA haplotype in mutagenesis. These findings emphasize the importance of developing new approaches to prevent transmission.
For people with current and remitted substance use disorder (SUD), the COVID-19 pandemic increases risk for symptom exacerbation and relapse through added stressors and reduced service access. In ...response, mutual-help groups and recovery community organizations have increased access to online recovery support meetings. However, rigorous studies examining online recovery support meeting participation to inform best practices have not yet been conducted. In the absence of such studies, a review of relevant literature, considered in context of potential barriers and drawbacks, suggests the risk-to-benefit ratio is favorable. Particularly given limited in-person SUD service access resulting from COVID-19 precautions, online recovery support meetings may help mitigate a key public health problem during an ongoing, public health pandemic.
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