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Background: There is little evidence of patient acceptability for drug-resistant tuberculosis (DRTB) care in the context of new treatment regimens and HIV co-infection. We aim to describe experiences of DRTB-HIV care among patients in KwaZulu-Natal province, South Africa., Methods: In this qualitative study using Bury's framework for chronic illness, we conducted 13 focus groups at a tertiary hospital with 55 patients co-infected with DRTB and HIV (28 women, 27 men) who were receiving new bedaquiline-based treatment for DRTB, concurrent with antiretroviral therapy. Eligible patients were consenting adults (aged >18 years) with confirmed DRTB and HIV who were enrolled into the PRAXIS study within 2 weeks of initiating bedaquiline-based treatment for DRTB. Participants were recruited from the PRAXIS cohort to participate in a focus group based on their time in DRTB treatment: early (2-6 weeks after treatment initiation), middle (2-6 months after discharge or treatment initiation if never hospitalised), and late (>6 months after treatment initiation). Focus groups were carried out in isiZulu language, audio recorded, and translated to English within 4 weeks. Participants were asked about their experiences of DRTB and HIV care and treatment, and qualitative data were coded and thematically analysed., Findings: From March, 2017, to June, 2018, distinctive patient challenges were identified at four critical stages of DRTB care: diagnosis, marked by centralised hospitalisation, renunciation from routine life, systemic stigmatisation and, for patients with longstanding HIV, renewed destabilisation; treatment initiation, marked by side-effects, isolation, and social disconnectedness; discharge, marked by brief respite and resurgent therapeutic and social disruption; and continuity, marked by deepening socioeconomic challenges despite clinical recovery. The periods of diagnosis and discharge into the community were particularly difficult. Treatment information and agency in decision making was a persistent gap. Sources of stigmatisation shifted with movement between the hospital and community. Resilience was built by connecting to peers, self-isolating, financial and material security, and a focus on recovery., Interpretation: People with DRTB and HIV undergo disruptive, life-altering experiences. The lack of information, agency, and social protections in DRTB care and treatment causes wider-reaching challenges for patients compared with HIV. Decentralised, community, peer-support, and differentiated care models for DRTB might be ameliorative and help to maximise the promise of new regimens., Funding: US National Institutes of Health., Translation: For the isiZulu translation of the abstract see Supplementary Materials section., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Standard multidrug-resistant tuberculosis (MDR-TB) treatment is lengthy, toxic, and insufficiently effective. New drugs and a shorter treatment regimen (SCR) are now recommended. However, patient and health-care worker (HCW) perspectives regarding the SCR are unknown. We aimed to determine the views and experiences of patients with MDR-TB and HCW regarding the SCR in Karakalpakstan, Uzbekistan., Methods: In a qualitative study, we conducted 48 in-depth interviews with 24 people with MDR-TB and 20 HCW, purposively recruited to include those with a range of treatment-taking experiences and employment positions. Data were analysed thematically using Nvivo 12, to identify emergent patterns, concepts, and categories. Principles of grounded theory were drawn upon to generate findings inductively from participants' accounts., Results: All patients viewed the SCR favourably. The SCR was seen as enabling an expedited return to work, studies, and "normality". This reduced the burden of treatment and difficulties with treatment fatigue. The SCR appeared to improve mental health, ease difficulties with TB-related stigma, and foster improved adherence. While patients wanted shorter treatment, it was also important that treatment be tolerable and effective. However, HCW doubted the appropriateness and effectiveness of the SCR, which influenced their confidence in prescribing the regimen., Conclusion: The SCR was said to benefit treatment completion and patients' lives. HCW concerns about SCR appropriateness and effectiveness may influence who receives the regimen. These are important considerations for SCR implementation and MDR-TB treatment developments, and dissonance between patient and HCW perspectives must be addressed for successful implementation of shorter regimens in the future., Competing Interests: The authors have declared that no competing interests exist.

Background: Two-drug regimens (2DR) to treat HIV infection have the potential to reduce long-term toxicity and increase therapeutic options for people living with HIV (PLHIV). Prior phase III trials, SWORD-1 and SWORD-2, as well as GEMINI-1 and GEMINI-2, have demonstrated that a dolutegravir-based 2DR is as effective as three- or four-drug regimens among virologically suppressed patients. Limited information exists, however, on patient and provider experiences with 2DR to inform roll-out and integration into routine clinical care., Methods: We conducted 39 in-depth interviews with PLHIV currently on 2DR in the context of routine care and 8 of their clinical care providers in the United States (U.S.) and Spain. Participants included 33 male and 6 female PLHIV and 8 providers. Interview topics explored perceptions of and experiences with 2DR compared to prior anti-retroviral regimens (ARVs), side effects, patient satisfaction, and clinical performance. Interviews were audio-recorded, transcribed and analyzed using thematic content analysis., Results: Participants viewed 2DR as a significant and positive advance, in terms of its ability to effectively treat HIV with reduced toxicity and essentially no reported side effects. Patients noted the central role providers played in the decision to switch to a 2DR regimen and, among U.S. participants, the importance of insurance coverage making this preferred option feasible. Patients and providers agreed that a 2DR regimen would be appropriate for any PLHIV regardless of whether they were treatment naïve or had significant experience with ARVs., Conclusions: Participants' experiences with a 2DR regimen were positive with no participants, reporting side effects and all reporting continued viral suppression. Providers valued the reduced toxicity offered by 2DR and served as the primary gateway to a transition to 2DR for patients in both settings. This study provides a foundation for further research on the transition to 2DR regimens in other populations and contexts including low- and middle-income settings., Competing Interests: Authors WD, AM, TK, and DK received support for this study via a ViiV Healthcare contract; authors UFB, SM, SM, HK, AC were investigators on trials supported in part by ViiV Healthcare; author YP is an employee of ViiV Healthcare and author MM was an employee of ViiV Healthcare at the time of this research. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.

Background: In pharmacological conditioning associations are formed between the effects of medication and contextual factors related to the medication. Pharmacological conditioning with placebo medication can result in comparable treatment effects and reduced side effects compared to regular treatment in various clinical populations, and may be applied to achieve enhanced drug effects. In the current study protocol, pharmacological conditioning is applied to achieve enhanced treatment effects in patients with recent-onset rheumatoid arthritis (RA). The results from this study broaden the knowledge on the potential of pharmacological conditioning and provide a potential innovative treatment option to optimize long-term pharmacological treatment effectiveness for patients with inflammatory conditions, such as recent-onset RA., Methods: A multicenter, randomized controlled clinical trial is conducted in patients with recent-onset RA. Participants start on standardized pharmacological treatment for 16 weeks, which consists of methotrexate (MTX) 15 mg/week and a tapered schedule of prednisone 60 mg or 30 mg. After 4 months, participants in clinical remission (based on the rheumatologist's opinion and a targeted score below 1.6 on a 44-joint disease activity score (DAS44)) are randomized to 1 of 2 groups: (1) the control group (C), which continues with a standardized treatment schedule of MTX 15 mg/week or (2) the pharmacological conditioning group (PC), which receives an MTX treatment schedule in alternating high and low dosages. In the case of persistent clinical remission after 8 months, treatment is tapered and discontinued linearly in the C group and variably in the PC group. Both groups receive the same cumulative amount of MTX during each period. Logistic regression analysis is used to compare the proportion of participants with drug-free clinical remission after 12 months between the C group and the PC group. Secondary outcome measures include clinical functioning, laboratory assessments, and self-reported measures after each 4-month period up to 18 months after study start., Discussion: The results from this study broaden the knowledge on the potential of pharmacological conditioning and provide a potential innovative treatment option to optimize long-term pharmacological treatment effectiveness in patients with inflammatory conditions, such as recent-onset RA., Trial Registration: Netherlands Trial Register, NL5652. Registered on 3 March 2016.

The success of combination antiretroviral therapy (cART) has transformed HIV infection into a chronic condition, resulting in an increase in the number of older, cART-treated adults living with HIV. This has increased the incidence of age-related, non-AIDS comorbidities in this population. One of the most common comorbidities is depression, which is also associated with cognitive impairment and a number of neuropathologies. In older people living with HIV, treating these overlapping disorders is complex, often creating pill burden or adverse drug-drug interactions that can exacerbate these neurologic disorders. Depression, NeuroHIV and many of the neuropsychiatric therapeutics used to treat them impact the dopaminergic system, suggesting that dopaminergic dysfunction may be a common factor in the development of these disorders. Further, changes in dopamine can influence the development of inflammation and the regulation of immune function, which are also implicated in the progression of NeuroHIV and depression. Little is known about the optimal clinical management of drug-drug interactions between cART drugs and antidepressants, particularly in regard to dopamine in older people living with HIV. This review will discuss those interactions, first examining the etiology of NeuroHIV and depression in older adults, then discussing the interrelated effects of dopamine and inflammation on these disorders, and finally reviewing the activity and interactions of cART drugs and antidepressants on each of these factors. Developing better strategies to manage these comorbidities is critical to the health of the aging, HIV-infected population, as the older population may be particularly vulnerable to drug-drug interactions affecting dopamine., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: Physician-patient communication when discussing the need for additional oral medication for type 2 diabetes (add-on) may affect the self-care of people with this condition. We aimed to investigate physicians' recalled experiences of the add-on consultation., Methods: We conducted a cross-sectional survey of physicians treating people with type 2 diabetes in 26 countries, as part of a large cross-national study of physician-patient communication during early treatment of type 2 diabetes (IntroDia®). The survey battery included novel questions about physician experiences at add-on and the Jefferson Scale of Physician Empathy., Results: Of 9247 eligible physicians, 6753 responded (73.0% response rate). Most (82%) agreed that physician-patient discussions at add-on strongly influence patients' disease acceptance and treatment adherence. Half the physicians reported ≥1 challenge in most or all add-on conversations, with a significant inverse relationship between frequency of challenges and Jefferson Scale of Physician Empathy score (standardised β coefficient: -0.313; p < 0.001). Physicians estimated that only around half their patients with type 2 diabetes follow their self-care advice. Exploratory factor analysis of physician beliefs about why their patients did not follow recommendations yielded two distinct dimensions: psychosocial barriers (e.g. depressed mood) and personal failings of the patient (e.g. not enough willpower) (r = 0.37, p < 0.001)., Conclusions: Physicians' empathy and beliefs about their patients may play a significant role in their success with the add-on conversation and, consequently, promotion of patient engagement and self-care. Although the study was limited by its retrospective, cross-sectional nature, the findings from IntroDia® may inform efforts to improve diabetes care., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Prior research shows that cannabis use during treatment for Alcohol Use Disorders (AUD) is related to fewer abstinent days from alcohol, although only among those who use cannabis 1-2x/month. Here we extend prior research by assessing the relationship between the frequency of cannabis use during AUD treatment and post-treatment alcohol-related consequences., Methods: Data come from the Combined Pharmacotherapies and Behavioral Interventions (COMBINE) Study, a large US randomized control trial of treatments for AUD. The current analyses include 206 cannabis users and 999 cannabis abstainers and compare longitudinal drinking data between those who used cannabis versus those who abstained during COMBINE treatment. The primary exposure was quartiles of cannabis use (Q1: less than 1x/month during treatment, Q2: 1-2x/month, Q3: 4-8x/month, Q4: 12x/month or more), with cannabis abstainers as the reference group. Outcomes were alcohol-related problems at the end of treatment and one-year post-treatment as measured by the Drinker Inventory Consequences., Results: Compared to cannabis abstinence, the most frequent use during treatment was related to 1.44 times as many physical consequences one-year post-treatment. Cannabis use was not related to physical consequences immediately after treatment, or to intrapersonal, interpersonal, social responsibility or impulse control problems at either post-treatment time point., Conclusions: In a sample of individuals in treatment for AUD, using cannabis 12x/month or more during treatment is associated with increased rates of physical consequences attributed to alcohol use. Individuals in treatment for AUD who also use cannabis might benefit from reducing or stopping cannabis use to avoid alcohol-related physical problems., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Mesothelioma is an aggressive thoracic tumour with a poor prognosis. The only treatment that extends survival is chemotherapy. However, in the UK, up to 50% of patients who are suitable for chemotherapy choose not to receive it, opting for active symptom control instead. The aim of this prospective, single-centre observational study was to describe the characteristics of patients who chose active symptom control over chemotherapy and explore their reasons for doing so., Methods: Two hundred consecutive patients with mesothelioma from one UK centre were included. Eligibility for chemotherapy and choice of first-line treatment were recorded prospectively. Patient characteristics and outcomes were compared using descriptive statistics, regression analysis and survival analysis. Reasons for choosing active symptom control over chemotherapy were extracted, retrospectively., Results: People who chose active symptom control were older, more likely to be female and had worse performance statuses than patients who received front-line chemotherapy. Concern over side effects, the modest survival benefit and previous adverse experiences with chemotherapy were reported as reasons for the decision. Median survival was 13.9 months in the chemotherapy group compared with 6.7 months in the active symptom control group., Conclusions: This is the first study to describe the characteristics of patients with mesothelioma who chose active symptom control over chemotherapy, in the front-line setting. Important differences were seen between this group and patients who received chemotherapy, although confounding is likely to have affected some outcomes. Future research could use qualitative methods to explore patients' reasons for choosing active symptom control, and to further elucidate the decision-making process.

Multiple systematic reviews were conducted investigating factors associated with medication adherence worldwide. However, investigations from the Middle East and North Africa (MENA) region were largely underrepresented in those reviews. Therefore, the objective of this systematic review is to identify the factors influencing medication adherence among patients with diabetes in the MENA region. A systematic literature search was conducted through Cochrane Library, EBSCO, EMBASE, Google Scholar, ISI Web of Science, PubMed, ScienceDirect, SCOPUS, and ProQuest. Studies were included if they determined factors associated with medication adherence among patients with diabetes within the MENA region. Quality was assessed using Crow Critical Appraisal Tool. Thirty primary studies from 10 MENA countries were included. The factors associated with medication adherence were categorized into demographics-related; disease- and medication-related; perception, attitude and psychological feelings-related; and societal-related factors. Positively associated factors included knowledge about the disease and medications, regular follow-up visits, and patients' positive beliefs about effectiveness and motivations about medications, while negatively associated factors included forgetfulness, side effects, and polypharmacy. Factors associated with medication adherence among patients with diabetes in the MENA region are highly diverse. The identified factors can serve as potential targets for culturally-relevant interventions to improve medication adherence and overall health outcomes., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Adherence is a major factor in the effectiveness of preexposure prophylaxis (PrEP) for HIV prevention. Modeling patterns of adherence helps to identify influential covariates of different types of adherence as well as to enable clinical trial simulation so that appropriate interventions can be developed. We developed a Markov mixed-effects model to understand the covariates influencing adherence patterns to daily oral PrEP. Electronic adherence records (date and time of medication bottle cap opening) from the Partners PrEP ancillary adherence study with a total of 1147 subjects were used. This study included once-daily dosing regimens of placebo, oral tenofovir disoproxil fumarate (TDF), and TDF in combination with emtricitabine (FTC), administered to HIV-uninfected members of serodiscordant couples. One-coin and first- to third-order Markov models were fit to the data using NONMEM ® 7.2. Model selection criteria included objective function value (OFV), Akaike information criterion (AIC), visual predictive checks, and posterior predictive checks. Covariates were included based on forward addition (α = 0.05) and backward elimination (α = 0.001). Markov models better described the data than 1-coin models. A third-order Markov model gave the lowest OFV and AIC, but the simpler first-order model was used for covariate model building because no additional benefit on prediction of target measures was observed for higher-order models. Female sex and older age had a positive impact on adherence, whereas Sundays, sexual abstinence, and sex with a partner other than the study partner had a negative impact on adherence. Our findings suggest adherence interventions should consider the role of these factors., (© 2016, The American College of Clinical Pharmacology.)

Patients with type 2 diabetes (T2DM) and inadequate glycaemic control on combination metformin (MET) and sulphonylurea (SU) were enrolled in a 24-week, double-blind, randomized, placebo-controlled study with a 28-week extension. The five-dimension EuroQol questionnaire (EQ-5D), SHIELD Weight Questionnaire-9 (WQ-9), Impact of Weight on Quality of Life-Lite (IWQOL-Lite) questionnaire and the Diabetes Treatment Satisfaction Questionnaire (DTSQ) were used to evaluate health status and health-related quality of life (HRQoL) at baseline and week 52. Patients with dapagliflozin 10 mg + MET + SU (n = 108) were compared with patients treated with placebo + MET + SU (n = 108), using a repeated-measures mixed model. EQ-5D visual analogue scale scores, IWQOL-Lite and DTSQ scores improved in the dapagliflozin and placebo groups from baseline to week 52; however, there was no significant difference between groups (p > 0.20). EQ-5D index scores remained the same from baseline to week 52 for dapagliflozin and placebo (p = 0.54). A numerically greater proportion of the dapagliflozin group reported improvement in all nine SHIELD WQ-9 items compared with placebo, and the difference was statistically significant for physical health (p = 0.017). Over 52 weeks of therapy, patients maintained their health status and HRQoL when dapagliflozin was added to the treatment., (© 2015 John Wiley & Sons Ltd.)

Multiple drug intolerance to antihypertensive medications (MDI-HTN) is an overlooked cause of nonadherence. In this study, 55 patients with MDI-HTN were managed with a novel treatment algorithm utilizing sequentially initiated monotherapies or combinations of maximally tolerated doses of fractional tablet doses, liquid formulations, transdermal preparations, and off-label tablet medications. A total of 10% of referred patients had MDI-HTN, resulting in insufficient pharmacotherapy and baseline office blood pressure (OBP) of 178±24/94±15 mm Hg. At baseline, patients were intolerant to 7.6±3.6 antihypertensives; they were receiving 1.4±1.1 medications. After 6 months on the novel MDI-HTN treatment algorithm, both OBP and home blood pressure (HBP) were significantly reduced, with patients receiving 2.0±1.2 medications. At 12 months, OBP was reduced from baseline by 17±5/9±3 mm Hg (P<.01, P<.05) and HBP was reduced by 11±5/12±3 mm Hg (P<.01 for both) while patients were receiving 1.9±1.1 medications. Application of a stratified medicine approach allowed patients to tolerate increased numbers of medications and achieved significant long-term lowering of blood pressure., (© 2015 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals, Inc.)

Background: Older people often have multimorbidity requiring a complex regime of medications, which may change following hospital discharge, thus presenting new challenges. The experiences of older people, who manage their own medications, in particular following hospital discharge, have rarely been studied., Aim: This study investigates the experiences of older people with multimorbidity taking multiple medications after hospital discharge and how they cope with medication-taking., Method: A qualitative-descriptive approach with ten interviews was chosen. The data were coded openly into two groups according to Saldaña (2013)., Results: It is important for older people, in spite of their multimorbidity, to maintain their independence and maintain responsibility for taking their medications. Routines are developed from taking medications over many years and the new medications are easily integrated. Unclear information by the medical staff and the inability of the older people to obtain the medications after discharge may lead to mistakes or interruptions in the drug therapy at home. The key person for this group is the general practitioner, even concerning the drug therapy initiated in hospital., Conclusion: It is advisable to adapt discharge education to the needs of older people, especially with regard to their drug therapy, to its integration into their daily routine, and to any possible shortcomings in their medication management.

Objectives: This study aimed to assess the effect of multivitamin use during the pill-free interval on the continuation rate and side effects of combined oral contraceptives (COCs) within the first few cycles of use., Methods: In this trial, 332 women presenting to public health centres in an Iranian city each received a COC pack containing 21 pills and were randomised to one of three groups: two of the groups also received 42 multivitamin pills or 42 placebo pills to be taken once a day for 7 days before starting COCs and again during the 7-day pill-free interval for five cycles, while the third group received no multivitamin or placebo pills with their COCs. The groups were compared using Cox regression and χ(2) tests., Results: There were no losses to follow-up. Continuation rates at the sixth cycle were 88% for the multivitamin group, 75% for the placebo group and 67% for the no intervention group. Compared with the multivitamin group, the six-cycle discontinuation rate was significantly higher in the placebo group (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.15-4.45; p = 0.019) and no intervention group (HR 3.15, 95% CI 1.66-5.99; p < 0.001). Nausea, mood changes, weight gain and breast tenderness were significantly less common in the multivitamin group than in the other groups in all cycles, and spotting/irregular bleeding and dizziness were significantly less common in most of the second, third and sixth cycle follow-up., Conclusions: Multivitamin supplements could significantly reduce the side effects of COCs in the initial cycles and improve continuation rates. However, the study limitations do not allow for any definite conclusion for their use in clinical practice, especially in communities rich in nutrients.

Background: Little is known about how people living with human immunodeficiency virus (HIV) experience malaria and the concomitant use of anti-malarial treatments with anti-retrovirals (ARVs). An understanding of how patients make sense of these experiences is important to consider in planning and supporting the clinical management and treatment for co-infected individuals., Methods: A qualitative study was conducted in Tanzania alongside a clinical trial of concomitant treatment for HIV and malaria co-infection. Focus group discussions were held with people receiving treatment for HIV and/or malaria, and in-depth interviews with health workers responsible for HIV care and members of the clinical trial team. Data were analysed inductively to identify themes and develop theoretical narratives., Results: Results suggest that people living with HIV perceived malaria to be more harmful to them due to their compromised immune status but saw the disease as unavoidable. For those enrolled in the clinical controlled study, taking anti-malarials together with ARVs was largely seen as unproblematic, with health workers' advice and endorsement of concomitant drug taking influential in reported adherence. However, perceptions of drug strength appeared to compel some people not enrolled in the clinical study to take the drugs at separate times to avoid anticipated harm to the body., Conclusions: Management of HIV and malaria concurrently often requires individuals to cross the domains of different disease programmes. In the context of a trial concerned with both diseases, patients experienced the support of clinicians in guiding and reassuring them about when and how to take drugs concomitantly. This points towards the need to continue to strive for integrated care for patients with HIV.

Patients with schizophrenia who are nonadherent to medication are at risk for repeated relapse and rehospitalization from this chronic and lifelong mental illness. Effective, oral medications can be difficult for patients to maintain on a daily basis, and long-acting injectable (LAI) antipsychotics can help to alleviate this challenge. However, some physicians' attitudinal barriers that need to be overcome include the belief that patients do not have adherence problems, concerns about LAI antipsychotic efficacy over traditional oral agents, the perception that the time and cost to administer this formulation outweighs its benefit, and the perception that injectable medications undermine patients' autonomy. A better understanding of LAIs and their potential benefits may help physicians to implement a long-term treatment plan that provides the best outcome for patients., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

Background: Hepatitis C virus (HCV) infections are a severe burden on public health worldwide, causing mortality rates triple that of the general population. Since 2011, for both therapy-naive and therapy-experienced genotype 1 patients, the first generation of direct acting antivirals (DAAs), i.e., the protease-inhibitors (PI) telaprevir and boceprevir have been added to existing dual therapies. The therapeutic effect of the resulting triple therapy is striking; however, treatment regimens are complex and commonly cause side effects. Little is known of how patients implement therapy in their daily lives, or of how they deal with these effects.This study aims to describe HCV patients' experiences with protease-inhibitor-based triple therapy and their support needs., Methods: A qualitative design was used. Patients from three outpatient clinics, with ongoing, completed or discontinued PI treatment experience were recruited using a maximum variation sampling approach. Open-ended interviews were conducted and analyzed using thematic analysis according to Braun & Clarke (Qual Res Psychol 3:77-101, 2006)., Results: Thirteen patients participated in the interviews. All described themselves as highly motivated to undergo treatment, since they saw the new therapy as a "real chance" for a cure. However, all later described the therapy period as a struggle. The constitutive theme-"Fighting an uphill battle"- describes the common existential experience of and negative consequences of coping with side effects. The processes that fostered this common experience followed three sub-themes: "encountering surprises", "dealing with disruption" and "reaching the limits of systems"., Conclusion: HCV patients undergoing outpatient protease-inhibitor-based triple therapy need systematic support in symptom management. This will require specially trained professionals to advise and support them and their families, and to provide rapid responses to their needs throughout this complex course of therapy. As the generation of DAAs for all genotypes, are expected to have less severe side effects, and many HCV patients require treatment, this knowledge can improve treatment support tremendously, especially for patients who are quite difficult to treat. Furthermore, these findings are helpful to illustrate development in HCV treatment.

All currently available antipsychotic drugs are the dopamine D2 receptor antagonists and are capable of producing extrapyramidal side-effects (EPS). Anticholinergic drugs are primarily used to treat EPS or prevent EPS induced by antipsychotics in the treatment of psychosis and schizophrenia. However, they can cause a variety of distressing peripheral side-effects (e.g. dry mouth, urinary disturbances, and constipation) and central adverse effects (e.g. cognitive impairment, worsening of tardive dyskinesia, and delirium). Disturbances in cognitive abilities are cardinal features of schizophrenia from its earliest phases and account for much of the functional disability associated with the illness. It is likely that long-term concomitant administration of anticholinergics exacerbates the underlying cognitive impairment in patients with schizophrenia and subsequently affects patients' quality of life. Thus, current treatment guidelines for schizophrenia generally do not recommend the prophylactic and long-term use of anticholinergics. However, the high use of long-term anticholinergic drugs with antipsychotics has been identified as an important issue in the treatment of schizophrenia in several countries. To assess the benefits and limits of anticholinergic use in psychosis and schizophrenia, this article will provide a brief review of the pharmacology and clinical profiles of anticholinergic drugs and will focus on their effects on cognitive function in schizophrenia, particularly during the course of the early phase of the illness. In addition, we will address the effects of discontinuation of anticholinergics on cognitive function in patients with schizophrenia and provide a strategy for adjunctive anticholinergic use in patients treated with long-acting injectable antipsychotics., (© 2013 The Authors. Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology.)

Chronic heart failure (CHF) is a serious health problem today. Despite all advances in modern medicine, the high morbidity and mortality rates of CHF force physicians to search for new more effective methods for its control. At the same time, the fact that the designing of new effective medicaments is complex and expensive and that patients show low compliance with drug therapy increases the value of non-drug treatments for heart failure, such as patient education, higher treatment compliance, which make it possible to significantly enhance the efficiency of current combined drug therapy, to improve quality of life, and, possibly, to reduce future heart failure death rates.

Aims: To explore attitudes towards medicines, polypharmacy and adherence in patients with chronic kidney disease (CKD)., Background: Polypharmacy is common in CKD and associated with medication non-adherence., Methods: As part of a mixed methodology project, a purposive sample of ten participants were recruited and interviewed to explore attitudes to medicines and reasons for adherent and non-adherent behaviour., Results: Several reasons for non-adherence were reported. Interviewees described a variety of attitudes towards medicines. Complex medicine regimes were a frequently cited contributing factor in poor adherence. Concerns about or experience of side effects had a negative impact on adherence. Prioritisation of medicines was evident and the importance of communication with health professionals was a consistent theme., Conclusions: Non-adherence with prescribed medicines in CKD is a complex phenomenon, which has implications for clinical outcomes and cost. Adherent behaviour may change over time. Further research in this field is needed. No single intervention is likely to enhance adherence for all and clinicians should consider a variety of options to improve adherence with prescribed medicines., (© 2013 European Dialysis and Transplant Nurses Association/European Renal Care Association.)

Background: Different patient groups are known to use herbal remedies and conventional drugs concomitantly (co-use). This poses a potential risk of herb-drug interaction through altering the drug's pharmacokinetics or pharmacodynamics. Little is known about co-use among patients in general practice. The primary aim of this study was to compare patients in general practice that co-use herbal remedies and conventional drugs with those who do not. The secondary aim was to register the herb-drug combinations with potential clinical relevant interactions among the co-users., Method: A questionnaire based cross-sectional study conducted in the autumn 2011 in a general practice office with four general practitioners (GPs) and one intern in Western Norway. Adults >18 years who came for an office visit were invited. The questionnaire asked about demographics, herbal use, conventional drug use and communication about herbal use. Multivariable logistic regression was used to compare co-users to the other patients., Results: Of the 381 patients who completed the questionnaire, the prevalence of herbal use was 44%, with bilberry (41%), green tea (31%), garlic (27%), Aloe vera (26%) and echinacea (18%) as the most frequently used. Among those using conventional drugs regularly, 108 (45%) co-used herbs. Close to 40% of patients on anticoagulants co-used herbs, with garlic and bilberry as the most frequent herbs. Compared to all other patients, co-users had significantly (p < 0.05) increased odds to be female (adjOR 2.0), age above 70 years (adjOR 3.3), use herbs to treat an illness (adjOR 4.2), use two or more herbs (polyherbacy, adjOR 12.1) and having experienced adverse effects of herbal use (adjOR 37.5). Co-use was also associated with use of analgesics or dermatological drugs (adjOR 5.1 and 7.9 respectively). Three out of four patients did not discuss herbal use with any health care professional., Conclusion: A sizable proportion of the GP patients co-used herbs with conventional drugs, also combinations with reported interaction potential or additive effects like anticoagulants and garlic. The low disclosure of herbal use to their GP, polyherbacy and the risk of interactions in vulnerable groups like elderly and chronically ill patients, warrant increased awareness among GPs.

Introduction: Hypertension is a condition which in many cases is treated with more than one drug. Additionally, patients with hypertension often suffer from other concomitant diseases, such as diabetes mellitus or dyslipidemia, which adds to the number of pills that patients need to take (pill burden). The aim of this study was to investigate the impact of this pill burden on patients with hypertension in clinical practice in Germany., Methods: This prospective, open-label, observational study enrolled adult patients for whom their physician considered treatment with a single-pill combination of amlodipine, valsartan, and hydrochlorothiazide as indicated. At the start of the observation period, physicians and patients filled in a respective questionnaire., Results: The questionnaires of 7,101 patients and 905 physicians were analyzed. The survey among the patients showed that the majority of patients felt burdened by the high number of pills to be taken. This was also seen as a potential reason for medication errors. Approximately half of the patients would be willing to make an out-of-pocket payment for reducing the number of pills to half. The results of the physician questionnaire indicate that the physicians were well aware of the set of problems that is generally associated with the high pill burden and that there is a clear willingness to use combination products in order to reduce the pill burden., Conclusion: A high number of pills is considered a burden by the patients. This burden increases with the number of pills taken per day.

Background: The Bipolar Comprehensive Outcomes Study (BCOS) is a 2-year, prospective, non-interventional, observational study designed to explore the clinical and functional outcomes associated with 'real-world' treatment of participants with bipolar I or schizoaffective disorder. All participants received treatment as usual. There was no study medication., Methods: Participants prescribed either conventional mood stabilizers (CMS; n = 155) alone, or olanzapine with, or without, CMS (olanzapine ± CMS; n = 84) were assessed every 3 months using several measures, including the Young Mania Rating Scale, 21-item Hamilton Depression Rating Scale, Clinical Global Impressions Scale - Bipolar Version, and the EuroQol Instrument. This paper reports 24-month longitudinal clinical, pharmacological, functional, and socioeconomic data., Results: On average, participants were 42 (range 18 to 79) years of age, 58%; were female, and 73%; had a diagnosis of bipolar I. Polypharmacy was the usual approach to pharmacological treatment; participants took a median of 5 different psychotropic medications over the course of the study, and spent a median proportion of time of 100%; of the study on mood stabilizers, 90%; on antipsychotics, 9%; on antidepressants, and 5%; on benzodiazepines/hypnotics. By 24 months, the majority of participants had achieved both symptomatic and syndromal remission of both mania and depression. Symptomatic relapse rates were similar for both the CMS alone (65%;) and the olanzapine ± CMS (61%;) cohorts., Conclusions: Participants with bipolar I or schizoaffective disorder in this study were receiving complex medication treatments that were often discordant with recommendations made in contemporary major treatment guidelines. The majority of study participants demonstrated some clinical and functional improvements, but not all achieved remission of symptoms or syndrome.

Objective: Only two-thirds of depressive patients respond to antidepressant treatment. In recent years, addition of an atypical antipsychotic drug to ongoing treatment with an antidepressant has been considered effective and well-tolerated. In the present study, we compared the efficacy between paroxetine and sertraline augmented with aripiprazole in patients with refractory major depression., Subjects and Methods: Twenty-four patients who met the DSM-IV criteria for major depressive disorder who did not at least two different classes of antidepressants were enrolled in the study. Nine were male and thirteen were female, and their ages ranged from 28 to 66 (mean±SD=39±12) years. Patients were prescribed paroxetine (n=11) or sertraline (n=13) for 4weeks. Then, those whose scores on the 17-item Hamilton Rating Scale for Depression (HAMD17) decreased below 50% received adjunctive therapy of aripiprazole for 4weeks., Results: Although the use of either combination treatment decreased the HAMD17 scores compared to the respective monotherapy, there was no significant difference in HAMD17 scores between the paroxetine plus aripiprazole group and sertraline plus aripiprazole group., Conclusion: Aripiprazole augmentation therapy with paroxetine or sertraline was equally effective and tolerated in patients with refractory major depressive order., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To investigate the relationship between specific levels of placebo response rates and the drug response rate and the relative risk of response to drug versus placebo in clinical trials of antidepressant monotherapy and adjunctive polypharmacy for MDD., Data Sources: MEDLINE/PubMed databases were searched for studies published in the English language between January 1980 and March 2011 by using the search terms depression, placebo, augmentation, adjunct, adjunctive, and each of the antidepressant agents identified. The search was supplemented by manual bibliographic review and examination of relevant review articles., Study Selection: The analysis included randomized, double-blind, placebo-controlled trials of antidepressants used as monotherapy for MDD, 4 weeks or longer, and of augmentation/combination treatments for antidepressant partial responders/nonresponders with MDD, 1 week or longer. 169 antidepressant monotherapy studies and 35 adjunctive polypharmacy studies were found eligible for inclusion in our analysis., Data Extraction: Data extracted included number of patients enrolled, patient characteristics, drug dosages and scheme (fixed vs flexible dosing), duration of the trial, and response rates., Results: In antidepressant monotherapy studies, a higher placebo response rate correlated with a lower risk ratio of responding to antidepressant versus placebo (P < .001) and correlated with higher antidepressant response rates (P < .001); the number needed to treat (NNT) for response was approximately 4, 6, and 9 in trials with placebo response rates < 30%, ≥ 30% and < 40%, and ≥ 40%, respectively. In adjunctive trials, a higher placebo response rate correlated with a lower risk ratio of responding to the adjunctive drug versus placebo (P < .001) and correlated with a trend toward statistical significance with higher response rates to the adjunctive drug (P = .050); the NNT was approximately 6, 7, 11, and 17 in trials with placebo response rates < 20%, ≥ 20% and < 30%, ≥ 30% and < 40%, and ≥ 40%, respectively., Conclusions: These results suggest that the relative efficacy of the active drug compared to placebo in clinical trials for MDD is highly heterogeneous across studies with different placebo response rates, with a worse performance in showing a superiority of the drug versus placebo for studies with placebo response rates ≥ 30% and ≥ 40%, respectively, for monotherapy and adjunctive trials. It is important to maintain placebo response rates below this critical threshold, since this is one of the most challenging obstacles for new treatment development in MDD., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Objective: Antidepressants targeting monoaminergic neurotransmitter systems, despite their immediate effects at the synaptic level, usually require several weeks of administration to achieve clinical efficacy. The authors propose a strategy of adding creatine monohydrate (creatine) to a selective serotonin reuptake inhibitor (SSRI) in the treatment of patients with major depressive disorder. Such augmentation may lead to a more rapid onset of antidepressant effects and a greater treatment response, potentially by restoring brain bioenergetics at the cellular level., Method: Fifty-two women with major depressive disorder were enrolled in an 8-week double-blind placebo-controlled clinical trial and randomly assigned to receive escitalopram in addition to either creatine (5 g/day, N=25) or placebo (N=27). Efficacy was primarily assessed by changes in the Hamilton Depression Rating Scale (HAM-D) score., Results: In comparison to the placebo augmentation group, patients receiving creatine augmentation showed significantly greater improvements in HAM-D score, as early as week 2 of treatment. This differential improvement favoring creatine was maintained at weeks 4 and 8. There were no differences between treatment groups in the proportion of patients who discontinued treatment prematurely (creatine: N=8, 32.0%; placebo: N=5, 18.5%) or in the overall frequency of all reported adverse events (creatine: 36 events; placebo: 45 events)., Conclusions: The current study suggests that creatine augmentation of SSRI treatment may be a promising therapeutic approach that exhibits more rapid and efficacious responses in women with major depressive disorder.

We examined whether augmentation with olanzapine would be superior to increased risperidone dose among acute schizophrenia patients showing early non-response to risperidone. We performed a rater-blinded, randomized controlled trial at psychiatric emergency sites. Eligible patients were newly admitted patients with acute schizophrenia. Early response was defined as Clinical Global Impressions-Improvement Scale score ≤3 following 2 weeks of treatment. Early non-responders were allocated to receive either augmentation with olanzapine (RIS+OLZ group) or increased risperidone dose (RIS+RIS group). The 78 patients who completed 2 weeks of treatment were divided into 52 early responders to risperidone and 26 early non-responders to risperidone (RIS+OLZ group, n=13; RIS+RIS group, n=13). No difference in the achievement of ≥50% improvement in Positive and Negative Syndrome Scale total score was observed between RIS+OLZ and RIS+RIS groups. Although time to treatment discontinuation for any cause was significantly shorter in the RIS+RIS group (6.8 weeks [95% confidence interval, 5.2-8.4]) than in early responders to risperidone (8.6 weeks [7.9-9.3]; P=0.018), there was no significant difference between the RIS+OLZ group (7.9 weeks [6.3-9.5]) and early responders to risperidone. Secondary outcomes justify the inclusion of augmentation arms in additional, larger studies comparing strategies for early non-responders., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: This study examined the effects of modafinil on apathetic symptomatology, performance of activities of daily living (ADLs), and caregiver burden in individuals with Alzheimer's disease (AD)., Method: 23 participants with a diagnosis of mild-to-moderate probable AD according to National Institute of Neurologic and Communicative Disorder and Stroke-Alzheimer's Disease and Related Disorders criteria were randomized into the experimental (modafinil 200 mg daily) or control (placebo) groups. All participants were also receiving stable doses of a cholinesterase inhibitor medication. Participants completed assessments at baseline and after 8 weeks of treatment. Outcome measures included family report measures of apathy, ADL performance, and caregiver burden, as well as direct assessment of ADL performance. The study was conducted at a private psychiatric hospital in Rhode Island from September 2005 until September 2007., Results: Both the experimental and control groups showed reductions in apathy on the Frontal Systems Behavior Scale between baseline and final assessments (F1,20 = 18.017, P < .001, η2 = 0.474), and there was no significant additional reduction in apathy with modafinil (F1,20 = 0.008, P = .932, η2 = 0.000). Groups did not show significant changes in caregiver report of ADL performance over time (F1,19 = 0.268, P = .611). The correlation between change in apathy and change in caregiver burden was not significant (r = 0.355, P = .053), but there was a trend toward improved levels of apathy being related to decreased levels of caregiver burden., Conclusions: The addition of modafinil to the standard of care treatment (cholinesterase inhibitor medication) did not result in significant additional reductions in apathy or improvements in ADL functioning. The reduction in reported apathy observed in both groups between baseline and final assessments was likely due to placebo effect. However, reductions in perceived apathetic symptomatology were correlated with reductions in reported caregiver distress and burden. Larger studies with more statistical power are needed to confirm the absence of significant effects., Trial Registration: ClinicalTrials.gov identifier: NCT01172145., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Depression is a medical condition with a complex biological pattern of aetiology, involving genetic and epigenetic factors, along with different environmental stressors. Recent evidence suggests that oxidative stress processes might play a relevant role in the pathogenic mechanism(s) underlying many major psychiatric disorders, including depression. Reactive oxygen and nitrogen species have been shown to modulate levels and activity of noradrenaline (norepinephrine), serotonin, dopamine and glutamate, the principal neurotransmitters involved in the neurobiology of depression. Major depression has been associated with lowered concentrations of several endogenous antioxidant compounds, such as vitamin E, zinc and coenzyme Q10, or enzymes, such as glutathione peroxidase, and with an impairment of the total antioxidant status. These observations introduce new potential targets for the development of therapeutic interventions based on antioxidant compounds. The present review focuses on the possible role of oxidative stress processes in the pathogenesis of depression. The therapeutic potential of antioxidant compounds as a co-adjuvant treatment to conventional antidepressants is discussed. For instance, N-acetyl-cysteine has been shown to have a significant benefit on depressive symptoms in a randomized placebo-controlled trial. Additionally, curcumin, the yellow pigment of curry, has been shown to strongly interfere with neuronal redox homeostasis in the CNS and to possess antidepressant activity in various animal models of depression, also thanks to its ability to inhibit monoamine oxidases. There is an urgent need to develop better tolerated and more effective treatments for depressive disorders and several antioxidant treatments appear promising and deserve further study.

Objective: To characterize the impact of S-adenosyl methionine (SAMe) on homocysteine and potential risk of adverse cardiovascular effects by examining plasma levels of SAMe, S-adenosyl homocysteine (SAH), total homocysteine (tHCY), methionine (MET), and 5-methyltetrahydrofolate (5-MTHF) in 35 of 73 patients from a 6-week randomized double-blind, placebo-controlled trial of SAMe augmentation in serotonin reuptake inhibitor partial responders with DSM-IV major depressive disorder (MDD), published in 2010., Method: Subjects were randomized from June 4, 2004, until August 8, 2008, to adjunctive placebo or SAMe 800-1600 mg/d for 6 weeks. Primary outcome measures included changes in one-carbon cycle intermediates within each treatment arm (by paired t test) and between treatment arms (by independent samples t test). Univariate analysis of variance and Fisher Protected Least Significant Difference were carried out to compare posttreatment levels of each one-carbon cycle intermediate. Secondary outcome measures included associations between clinical improvement and change in plasma intermediate levels, examined by linear regression (for change in Hamilton Depression Rating Scale scores) and logistic regression (for response or remission)., Results: We found significant differences in pretreatment plasma levels of tHCY (P = .03) between the SAMe and placebo arms. Following 6 weeks of treatment, plasma SAMe (P = .002) and SAH (P < .0001) levels increased significantly in the SAMe arm; no intermediates in the placebo group changed significantly. Posttreatment plasma SAMe (P = .0035), SAH (P < .0001), and tHCY (P = .0016) levels differed significantly between the SAMe and placebo groups. No significant associations were found between plasma intermediate levels and clinical improvement, response, or remission., Conclusions: Despite concerns about the impact that SAMe therapy may have on homocysteine levels and risk of adverse cardiovascular effects, the lack of significant increase in tHCY levels after treatment suggests that no toxic effects from SAMe should be expected. Our findings, however, have some significant limitations and should be interpreted with caution., Trial Registration: ClinicalTrials.gov identifier: NCT00093847., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Background: Observations that antagonists of the N-methyl-d-aspartate (NMDA) receptor of glutamatergic neurons can mimic symptoms of schizophrenia have raised the hope that NMDA agonists can improve symptoms. On the basis of encouraging results of trials in which NMDA agonists were added to antipsychotics, we conducted an adequately powered randomized controlled trial adding d-serine, an NMDA modulator, to antipsychotics., Method: This study was a 195-patient, multicenter, double-blind, randomized, placebo-controlled, 16-week trial of d-serine 2 g/d as an add-on treatment to antipsychotics. Subjects had DSM-IV schizophrenia or schizoaffective disorder and were inpatients or outpatients stabilized on antipsychotics, with persistent negative symptoms. The primary outcome measures were changes in negative symptoms and cognition as measured by the Scale for the Assessment of Negative Symptoms (SANS) and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery, respectively. The study was performed between 2003 and 2007., Results: Mean total Positive and Negative Syndrome Scale scores at baseline were 75.5. Subjects receiving d-serine and placebo improved in scores on the SANS and MATRICS, but no significant differences were observed between groups: improvement on SANS was 11.4% for d-serine vs 14.8% for placebo, F1,147=1.18, P=.32; and improvement on MATRICS was 6.8% for d-serine vs 6.1% for placebo, F1,125=0.96, P=.39, respectively. d-Serine was well tolerated., Discussion: This study did not find a significant difference between drug and placebo. However, the results are limited by a relatively large placebo response and somewhat lower-achieved doses than in prior studies. Future studies will administer higher doses and will attempt to affect the NMDA receptor using other mechanisms, such as agonists of the presynaptic metabotropic glutamate 2/3 receptor or glycine reuptake inhibitors., Trial Registration: ClinicalTrials.gov identifier: NCT00138775., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

High rates of attrition have been reported in randomized controlled trials of patients with severe psychiatric illness, including psychotic depression (MDpsy). The purpose of this study is to examine factors associated with overall attrition and with subtypes of attrition in the Study of the Pharmacotherapy of Psychotic Depression (STOP-PD). Secondary analysis of data collected in a multi-site, randomized, placebo-controlled trial. Clinical services of academic hospitals. Participants comprised 259 persons with MDpsy, aged 18-93 years. The intervention consisted of the random allocation to 12 weeks of treatment of either olanzapine plus sertraline or olanzapine plus placebo. Demographic and clinical variables associated with overall non-completion and sub-types of non-completion of randomized treatment. One hundred and seventeen (45.2%) subjects did not complete 12 weeks of randomized treatment. In a logistic regression analysis, inpatient entry status, olanzapine monotherapy, and higher cumulative medical burden were statistically significant independent predictors of overall non-completion. In a multinomial logistic regression model that examined predictors of subtypes of non-completion, subjects who entered the study as an inpatient were less likely to complete because of inadequate efficacy as determined by the investigator, and older subjects were less likely to complete because of poorer tolerability. Subjects who were assigned to olanzapine monotherapy, younger subjects, and subjects who entered the study as inpatients were less likely to complete because of reasons other than efficacy or tolerability. Understanding factors that contribute to premature discontinuation in studies of MDpsy, and to the specific reasons for attrition, has the potential to improve the management of this disorder, as well as improve the design of future clinical trials of MDpsy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Bile duct ligation (BDL) induces primary biliary cirrhosis characterized by cholestasis, impaired liver function and cognition including impairment of memory formation and anxiety-like behaviors. Endogenous opioid and acetylcholine levels are elevated in animal model of cholestasis. In addition, there is no data about the effects of interaction opioidergic and cholinergic systems of dorsal hippocampus (CA1) on amnesia-induced by cholestasis. Male mice weighing 25-35 g were used in this study. Cholestasis was induced by the ligation of the common bile duct. One-trial step-down and hole-board paradigms were used for the assessment of memory retrieval and anxiety-like behaviors respectively. All drugs injected intra-CA1. The data showed that cholestasis (24 days after BDL) decreased memory retrieval. Sole intra-CA1 injection of higher dose of mecamylamine (0.125, 0.25, 0.5 and 1 μg/mice) and scopolamine (0.125, 0.25, 0.5 1 and 2 μg/mice) but not all doses of naloxone (0.0125, 0.025 and 0.05 μg/mice) decreased memory retrieval in the sham operated BDL. The ineffective doses of naloxone (0.025 and 0.05 μg/mice), mecamylamine (0.5 μg/mice) and scopolamine (0.5 μg/mice) restored cholestasis-induced amnesia 24 days after BDL. Further, all cross co-administration ineffective doses of naloxone (0.0125 μg/mice), mecamylamine (0.125 μg/mice) and scopolamine (0.125 μg/mice) reversed cholestasis-induced amnesia. All doses of the drugs have no effect on exploratory behaviors. The data strongly revealed that synergistic effect between opioidergic and cholinergic systems of CA1 on the modulation of cholestasis-induced amnesia., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: This 22-week, open-label study, conducted between November 2006 and September 2008 in a community setting, was designed to determine if weight gain during olanzapine treatment can be prevented or mitigated with adjunctive treatment algorithms that include amantadine, metformin, and zonisamide., Method: Outpatients with schizophrenia or schizoaffective disorder (DSM-IV-TR criteria) were randomly assigned to olanzapine alone (n = 50), olanzapine plus algorithm A (olanzapine + A [amantadine 200 mg/d with possible switches to metformin 1,000-1,500 mg/d and then to zonisamide 100-400 mg/d; n = 76]), or olanzapine plus algorithm B (olanzapine + B [metformin 1,000-1,500 mg/d with possible switches to amantadine 200 mg/d and then to zonisamide 100-400 mg/d; n = 73]). Brief weight management education was provided at baseline. The primary outcome measure was comparison of mean weight gain between olanzapine and pooled olanzapine + A and olanzapine + B results., Results: Least squares mean ± SE weight gain was 2.76 ± 0.75 kg for olanzapine, 2.40 ± 0.65 kg for olanzapine + A, and 0.65 ± 0.63 kg for olanzapine + B. Mean weight gain during olanzapine treatment did not differ significantly from pooled results for olanzapine + A and olanzapine + B (P = .065). Participants treated with olanzapine + B experienced significantly less mean weight gain than olanzapine-treated participants (P = .036)., Conclusions: Pooled treatment algorithm results were not significantly different from olanzapine monotherapy in mitigating weight gain. However, participants who received treatment with metformin with possible progression to amantadine and then zonisamide had significantly less mean weight gain than participants treated with olanzapine alone. Progression of some participants through the algorithm indicated that a single therapy solution may not be adequate for every patient. Patients treated with olanzapine should receive regular weight monitoring., Trial Registration: clinicaltrials.gov Identifier: NCT00401973., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Background: The progressive nature of type 2 diabetes necessitates exogenous insulin use for most patients; basal insulin plus oral anti-diabetes drugs (OADs) is a well-validated way to facilitate insulin initiation. The primary aim of this study was to explore insulin initiation strategies and outcomes for patients using insulin detemir or glargine plus oral anti-diabetes drugs., Methods: LIGHT was a 3-month, longitudinal observational study conducted across 761 French centres in insulin-naïve type 2 diabetes patients managed under routine clinical care conditions, in either primary or secondary care. Endpoints included changes in HbA(1c) , fasting plasma glucose (FPG), rate of hypoglycaemia, weight, and adverse events., Results: Most physicians initiated a basal analogue to improve glycaemic control (97%), with many delaying beginning treatment for several months (9 ± 9.0 months for general practitioners, 10.2 ± 16.2 months for specialists). Most patients continued oral anti-diabetes drug therapy (95%) and lifestyle measures (92%), with 2-3 blood glucose readings per day and follow-up telephone calls for dose optimization. Mean change in HbA(1c) from baseline was - 1.3%, and - 3.1 mmol/L for fasting plasma glucose (both p < 0.0001). Hypoglycaemia increased from 1.4 to 5.6 events/patient/year (p < 0.0001), and weight decreased on average by 0.5 kg with detemir, with no change in glargine. Most patients (93%) reported being satisfied or very satisfied with their insulin., Conclusions: Insulin initiation with detemir or glargine can be successfully managed in both primary and secondary care; the benefits of basal analogues (once-daily dosing, low rates of hypoglycaemia compared with neutral protamine Hagedorn) may have contributed to patient acceptance of the regimen., (Copyright © 2011 John Wiley & Sons, Ltd.)

Objective: Patients with bipolar disorder suffer from significant cognitive impairment that contributes directly to functional disability, yet few studies have targeted these symptoms for treatment, and the optimal study design remains unclear. We evaluated the effects of the dopamine D₂/D₃ receptor agonist pramipexole on cognition in bipolar disorder., Method: Fifty stable outpatients with DSM-IV-diagnosed bipolar I or bipolar II disorder enrolled in an 8-week, double-blind, randomized, placebo-controlled cognitive enhancement trial between July 2006 and April 2010. Patients completed neurocognitive testing at baseline and at week 8, and the primary outcome measures were change scores calculated for each of the 11 tasks. Symptoms and side effects were monitored weekly., Results: Forty-five patients completed the study (placebo, n = 24; pramipexole, n = 21), and groups were well matched on demographic and clinical features. Primary cognitive analyses indicated no compelling cognitive benefit of pramipexole versus placebo; however, secondary analyses highlight several important methodological issues for future trials and identify a subgroup of patients who might benefit more readily from cognitive enhancement strategies. This outcome suggests that the study design played a very important role in the results-implying a failed rather than altogether negative trial. Specifically, we found that even very subtle, subsyndromal mood symptoms at baseline had a significant influence on the degree of improvement due to active drug, with strictly euthymic patients faring best (multivariate analysis of variance, P = .03 in euthymic subgroup). In addition, the extent of baseline cognitive impairment also contributed to the likelihood of treatment response. Finally, concomitant medications may weaken, or in some cases enhance, response to cognitive treatment and should be accounted for in study design., Conclusions: Although our results point toward a lack of clear effect of pramipexole on cognition in bipolar patients, our data revealed a potentially beneficial effect of pramipexole in a subgroup, providing some enthusiasm for pursuing this line of research in the future. Moreover, this study emphasizes the importance of rigorous subject selection for cognitive trials in bipolar illness. Future studies will be necessary to determine the possible clinical and functional implications of these results., Trial Registration: clinicaltrials.gov Identifier: NCT00597896., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Background: Curcumin is the active principle of Curcuma longa, one of the widely used components in the traditional system of medicine in India. Despite its efficacy in experimental studies aiming at neuronal disorders like depression, curcu-min's poor water solubility challenges the production of therapeutic formulations. This study investigates the antidepressant-like activity of novel water-soluble curcumin formulations, dispensed in three different concentrations. Further, the study comparatively evaluates St. John's wort (SJW), another herbal preparation., Methods: These compounds were evaluated in the forced swimming test in mice, and the corresponding changes in the neurotransmitter levels were measured., Results: Three water-soluble curcumin formulations, C-5, C-20 and C-50 (50-200 mg/kg p.o.) decreased the immobility period, and increased serotonin and dopamine levels in the brain tissues. A subeffective dose (50 mg/kg) of these formulations enhanced the antidepressant-like effect of classical antidepressants with varied mechanisms of action. In addition, an SJW dose of 25 mg/kg showed a significant antidepressant-like effect in all the behavioral studies and also significantly increased brain neurotransmitter levels, especially that of serotonin. The effects produced by C-5 were comparable with those of SJW and fluoxetine, respectively., Conclusion: In all these observations, the water-soluble formulations showed a significant antidepressant-like effect, including enhancement of neurotransmitter levels as compared to the similar dose of a conventional curcumin preparation. Thus, these formulations may be used as a novel treatment option in the management of mental depression., (Copyright © 2012 S. Karger AG, Basel.)

To examine changes in partially responsive anxiety symptoms utilizing adjunctive treatment with atomoxetine in the treatment of adult ADHD patients with comorbid partially responsive anxiety symptoms. Consenting adult patients (n=29) with confirmed diagnosis of generalized anxiety and comorbid attention deficit hyperactivity disorder (ADHD) participated in this open-label study. All patients had significant comorbid anxiety symptoms (HAM-A>7) and failed to respond to 8-week trials of selective serotonin reuptake inhibitors (SSRIs) or noradrenaline reuptake inhibitors (SNRIs). All patients were treated with atomoxetine as adjunctive to SSRIs or to SNRIs and were followed for at least 12 weeks. The primary outcome measure was the Clinical Global Impression severity subscale. Other scales included the Hamilton Anxiety Scale (HAM-A), the adult ADHD Self-Report Scale (ASRS-v1.1) symptom checklist, and Sheehan's Disability Scale. Baseline measures prior to the treatment with atomoxetine were compared to those at 4, 8, and at 12 weeks of treatment. Monitoring for pulse, blood pressure, and weight changes was carried out at baseline and at end point. Twenty-seven patients (93%) completed this open-label study. There was significant resolution of symptoms of all outcome measures, including the symptoms of anxiety, as shown by changes from baseline in HAM-A, ASRS-v1.1, and CGI at 12 weeks (P<.001). Also, there was significant reduction in the disability score at 12 weeks. Patients completed the study, tolerated the adjunctive treatment, and there were no significant cardiovascular or weight changes. Two patients withdrew from the study during the first 4 weeks of treatment due to side effects. Atomoxetine can be used as an adjunctive treatment in adult patients with ADHD and comorbid partially responsive anxiety symptoms.

Attitudes and beliefs about antiretroviral therapy (ART) may affect sexual risk behaviors among the general population in sub-Saharan Africa. We performed a cross-sectional population-based study in Kisumu, Kenya to test this hypothesis in October 2006. A total of 1655 participants were interviewed regarding attitudes and beliefs about ART and their sexual risk behaviors. The majority of participants, (71%) men and (70%) women, had heard of ART. Of these, 20% of men and 29% of women believed ART cures HIV. Among women, an attitude that "HIV is more controllable now that ART is available" was associated with sex with a non-spousal partner, increased lifetime number of sexual partners as well as a younger age at sexual debut. No significant associations with this factor were found among men. The belief that "ART cures HIV" was associated with younger age of sexual debut among women. The same belief was associated with an increased likelihood of exchanging sex for money/gifts and decreased likelihood of condom use at last sex among men. These findings were most significant for people aged 15-29 years. In high HIV seroprevalence populations with expanding access to ART, prevention programs must ensure their content counteracts misconceptions of ART in order to reduce high risk sexual behaviors, especially among youth.

This paper reviews the literature on various mental health problems and their impact on adherence to antiretroviral therapy (ART). Depression, anxiety disorders, and disorders related to substance abuse were identified as key role-players influencing adherence. The severity of symptoms related to these disorders was found to be inversely related to ART adherence, with the possible exception of post-traumatic stress disorder (PTSD). PTSD was found to have both positive and negative implications for adherence, with severity of symptoms ranging from health-protective concern to disabling distress. Possible solutions aimed at addressing the adverse effects of mental health problems on adherence are discussed. Routine screening in ART settings is suggested in settings where follow-up of positive screen scores are possible, along with the necessary interventions to resolve the disorder of concern. Suggested interventions include utilising psychotherapeutic treatment, both in isolation and in conjunction with medication, to address mental health problems. Furthermore, finding effective ways of marshalling social support is recommended for ensuring optimal adherence, and possibly mitigating the adverse effects of mental health problems. Further research is needed to find feasible ways of identifying, assessing and treating patients with mental health problems in resource-constrained settings where HIV prevalence is highest.

The sequential parallel comparison design (SPCD) has been proposed to increase the likelihood of success of clinical trials in therapeutic areas where high-placebo response is a concern. The trial is run in two stages, and subjects are randomized into three groups: (i) placebo in both stages; (ii) placebo in the first stage and drug in the second stage; and (iii) drug in both stages. We consider the case of binary response data (response/no response). In the SPCD, all first-stage and second-stage data from placebo subjects who failed to respond in the first stage of the trial are utilized in the efficacy analysis. We develop 1 and 2 degree of freedom score tests for treatment effect in the SPCD. We give formulae for asymptotic power and for sample size computations and evaluate their accuracy via simulation studies. We compute the optimal allocation ratio between drug and placebo in stage 1 for the SPCD to determine from a theoretical viewpoint whether a single-stage design, a two-stage design with placebo only in the first stage, or a two-stage design is the best design for a given set of response rates. As response rates are not known before the trial, a two-stage approach with allocation to active drug in both stages is a robust design choice., (Copyright © 2011 John Wiley & Sons, Ltd.)

Arts-based programs have improved HIV-related knowledge, attitudes, and behavior in general and at-risk populations. With HIV transformed into a chronic condition, this study compares patients at consecutive stages of receiving antiretroviral treatment, coinciding with exposure to a radio-and-theater-based educational program (unexposed [N = 120], just exposed [N = 77], Exposed a month ago [N = 60]). Exposure was associated with significantly higher HIV-related knowledge (15-20%, all p < .01), lower levels of stigma (2-7% lower, all p < .10), and over four times the adjusted odds of asking doctors questions about HIV (p = .07). Higher dose of exposure was associated with lower felt stigma (28% reduction per message recalled), greater odds of consistent condom use (adjusted odds ratio [AOR]: 1.12, p = .01), doctor-patient communication (AOR: 1.20, p = .003), peer advice-giving (AOR: 1.18, p = .03) and HIV-related advocacy (AOR: 2.35, p = .07). Similar partnerships between arts-based nongovernmental organizations and government hospitals may improve patient outcomes in HIV treatment settings.

Background and Objectives: Buprenorphine and methadone are widely used for the treatment of opioid dependence, but their diversion and/or misuse are frequent. In principle, buprenorphine/naloxone combination therapy should be associated with a lower frequency of drug abuse/misuse than methadone. This study assessed the efficacy of the substitution of buprenorphine treatment with the buprenorphine/naloxone combination in opioid-dependent patients., Material and Methods: 3812 drug-addicted outpatients selected from 10 Italian Public Services for Addiction (Ser.T.) centres in Naples (Italy) were enrolled: 3105 (81.5%) were treated with methadone and 707 (18.5%) with buprenorphine. The buprenorphine treatment was switched to buprenorphine/naloxone (4:1), and the patients were followed for about 1 year. The number of subjects still on treatment after 1 year, their status according to social, educational and toxicologic (assessed by a urine toxicology test) parameters were assessed., Results: 1 year after the therapy switch, the number of patients still on treatment was similarly reduced with methadone (2883; -7.5%) and buprenorphine/naloxone (632; -10.6%; p=0.369). However, in patients treated with buprenorphine/naloxone, a significant improvement was reported in social life status (63% versus 39% of the buprenorphine/naloxone and methadone treated subjects, respectively, were married/cohabiting p<0.001), in the educational level (43% of buprenorphine/naloxone treated versus 32% of the methadone treated subjects obtained at least a high school certificate, p<0.001) and in the toxicological conditions (53% of buprenorphine/naloxone treated subject versus 30% of methadone treated individuals had opioid- and cocaine- negative urine tests, p<0.001)., Discussion: These preliminary data suggest that buprenorphine/naloxone treatment of opioid dependence reduces the percentage of treated subjects similarly to methadone, and is associated with an improvement in social life, educational and toxicological conditions, compared with methadone treatment. However, we cannot exclude a selection bias, i.e. patients who were more likely to stabilize their opiate dependence switched to buprenorphine/naloxone.

In short-term efficacy studies, coprescription of a benzodiazepine improves first-month adherence and response to antidepressant treatment. We used Veterans Health Administration data to examine the impact of coprescribed benzodiazepines on initial antidepressant adherence in routine clinical practice and the risks of long-term benzodiazepine use, abuse, and dependence. Our study population was 43,915 Veterans Health Administration patients diagnosed with depression and started on an antidepressant between October 2006 and September 2007. Using logistic regression, adjusting for demographic and clinical covariates, we predicted the likelihood that patients received antidepressant treatment for an adequate duration (90 days), with our primary independent variable of interest being receipt of a benzodiazepine on the same day as the start of the antidepressant. We also assessed the frequency and characteristics of patients whose benzodiazepine use persisted for 1 year or who were diagnosed with anxiolytic abuse or dependence after receiving combined treatment. The adjusted probability of receiving antidepressant treatment of adequate duration was 42.4% for patients who received a benzodiazepine with their initial antidepressant compared with 39.3% for patients initially treated with an antidepressant alone (P < 0.001). Among patients who received combined treatment, 14.1% subsequently used benzodiazepines for at least 1 year, and 0.7% were diagnosed with anxiolytic abuse or dependence. Anxiolytic abuse or dependence, but not long-term benzodiazepine use, was associated with other substance use disorders. These findings should be considered by clinicians when assessing the individual risks and benefits of combining a benzodiazepine with antidepressant treatment.