Liraglutide and the management of overweight and obesity in people with severe mental illness: qualitative sub-study.

BACKGROUND: People with severe mental illness are two to three times more likely to be overweight or have obesity than the general population and this is associated with significant morbidity and premature mortality. Liraglutide 3 mg is a once daily injectable GLP-1 receptor agonist that is licensed for the treatment of obesity in the general population and has the potential to be used in people with severe mental illness. AIMS: To record the expectations and experiences of people with schizophrenia, schizoaffective disorders or first episode psychosis taking daily liraglutide 3 mg injections in a clinical trial for the treatment of obesity. To seek the views of healthcare professionals about the feasibility of delivering the intervention in routine care. METHODS: Qualitative interviews were undertaken with a purposive sub-sample of people with schizophrenia, schizoaffective disorders or first episode psychosis with overweight or obesity who were treated with a daily injection of liraglutide 3 mg in a double-blinded, randomised controlled pilot study evaluating the use of liraglutide for the treatment of obesity. Interviews were also conducted with healthcare professionals. RESULTS: Seventeen patient participants were interviewed. Sixteen took part in the baseline interview, eight completed both baseline and follow-up interviews, and one took part in follow-up interview only. Mean interview duration was thirteen minutes (range 5-37 min). Despite reservations by some participants about the injections before the study, most of those who completed the trial reported no challenges in the timing of or administering the injections. Key themes included despondency regarding prior medication associated weight gain, quality of life impact of weight loss, practical aspects of participation including materials received and clinic attendance. Healthcare professionals reported challenges with recruitment, however, overall it was a positive experience for them and for participants. CONCLUSION: Liraglutide appears to be an acceptable therapy for obesity in this population with limited side effects. The quality of life benefits realised by several intervention participants reinforce the biomedical benefits of achieved weight loss.

The use of liraglutide 3.0 mg daily in the management of overweight and obesity in people with schizophrenia, schizoaffective disorder and first episode psychosis: Results of a pilot randomized, double-blind, placebo-controlled trial.

AIM: To investigate the feasibility and acceptability of using liraglutide 3.0 mg daily in the management of overweight and obesity in people with schizophrenia, schizoaffective disorder and first episode psychosis. MATERIALS AND METHODS: A double-blind, randomized, placebo-controlled pilot trial took place in mental health centres and primary care within Southern Health NHS Foundation Trust. The participants were adults with schizophrenia, schizoaffective or first-episode psychosis prescribed antipsychotic medication who were overweight or obese. The intervention was once-daily subcutaneous liraglutide or placebo, titrated to 3.0 mg daily, for 6 months. The primary outcomes were recruitment, consent, retention and adherence. The secondary exploratory outcomes were weight, HbA1c and Brief Psychiatric Rating Scale. RESULTS: Seven hundred and ninety-nine individuals were screened for eligibility. The most common reasons for exclusion were ineligibility (44%) and inability to make contact (28%). The acceptance rate, as a proportion of all eligible participants, was 12.2%. The most commonly stated reason why eligible candidates declined to participate related to the study-specific medication and protocol (n = 50). Forty-seven participants were randomized, with 79% completing the trial. Participants in the liraglutide arm lost a mean 5.7 ± 7.9 kg compared with no significant weight change in the placebo group (treatment difference -6.0 kg, p = .015). Body mass index, waist circumference and HbA1c were reduced in the intervention group. CONCLUSIONS: This study supports the need for a larger randomized controlled trial to evaluate the use of liraglutide (maximum dose 3.0 mg daily) in the management of obesity in people with severe mental illness.

Antidepressant medication as a risk factor for type 2 diabetes and impaired glucose regulation: systematic review.

OBJECTIVE: Antidepressant use has risen sharply over recent years. Recent concerns that antidepressants may adversely affect glucose metabolism require investigation. Our aim was to assess the risk of type 2 diabetes associated with antidepressants through a systematic review. RESEARCH DESIGN AND METHODS: Data sources were MEDLINE, Embase, PsycINFO, The Cochrane Library, Web of Science, meeting abstracts of the European Association for the Study of Diabetes, American Diabetes Association, and Diabetes UK, Current Controlled Trials, ClinicalTrials.gov, U.K. Clinical Research Network, scrutiny of bibliographies of retrieved articles, and contact with relevant experts. Relevant studies of antidepressant effects were included. Key outcomes were diabetes incidence and change in blood glucose (fasting and random). RESULTS: Three systemic reviews and 22 studies met the inclusion criteria. Research designs included 1 case series and 21 observational studies comprising 4 cross-sectional, 5 case-control, and 12 cohort studies. There was evidence that antidepressant use is associated with type 2 diabetes. Causality is not established, but rather, the picture is confused, with some antidepressants linked to worsening glucose control, particularly with higher doses and longer duration, others linked with improved control, and yet more with mixed results. The more recent, larger studies, however, suggest a modest effect. Study quality was variable. CONCLUSIONS: Although evidence exists that antidepressant use may be an independent risk factor for type 2 diabetes, long-term prospective studies of the effects of individual antidepressants rather than class effects are required. Heightened alertness to potential risks is necessary until these are complete.

The relationship between depression, anxiety and cardiovascular disease: findings from the Hertfordshire Cohort Study.

BACKGROUND: Previous studies suggest a link between depression, anxiety and cardiovascular disease (CVD). The aim of the study was to determine the relationship between depressive and anxiety symptoms and CVD in a population based cohort. METHODS: In total 1578 men and 1,417 women from the Hertfordshire Cohort Study were assessed for CVD at baseline and after 5.9 ± 1.4 years. Depressive and anxiety symptoms were measured using the HADS scale. RESULTS: Baseline HAD-D score, but not HAD-A, was significantly associated with baseline plasma triglycerides, glucose and insulin resistance (men only) and HDL cholesterol (women only). After adjustment for CVD risk factors, higher baseline HAD-D scores were associated with increased odds ratios for CVD (men: 1.162 [95% CI 1.096-1.231]; women: 1.107 [1.038-1.181]). Higher HAD-A scores associated with increased CVD in men only. High HAD-D scores predicted incident CVD (adjusted OR 1.130 [1.034-1.235]), all-cause mortality (adjusted HR 1.081, [1.012-1.154]) and cardiovascular mortality (adjusted HR 1.109 [1.002-1.229]) in men but not in women. LIMITATIONS: The use of a self-report measure of depressive and anxiety symptoms, 'healthy' responder bias and the low number of cardiovascular events are all limitations. CONCLUSIONS: Depressive and anxiety symptoms are commoner in people with CVD. These symptoms are independent predictors of CVD in men. Although HAD-D score was significantly associated with several cardiovascular risk factors, this did not fully explain the association between HAD-D and CVD.

Antipsychotics and hyperprolactinaemia: mechanisms, consequences and management.

Hyperprolactinaemia is a common side effect in people receiving antipsychotics. The propensity to cause hyperprolactinaemia differs markedly between antipsychotics as a result of differential dopamine D(2) receptor-binding affinity and ability to cross the blood-brain barrier. Sexual dysfunction is common and under-recognized in people with severe mental illness and is in part caused by hyperprolactinaemia. There are a number of long-term consequences of hyperprolactinaemia, including osteoporosis. Regular monitoring before and during treatment will help identify those developing antipsychotic-induced hyperprolactinaemia. The treatment includes dose reduction and change in antipsychotic. Where this is not possible because of the risk of relapse of the mental illness, sex steroid replacement may be helpful in improving symptoms secondary to hypogonadism and reducing the risk of osteoporosis. Tertiary prevention of complications should also be considered.

Relationship between loneliness and proangiogenic cytokines in newly diagnosed tumors of colon and rectum.

OBJECTIVE: To investigate the association of serum levels of proangiogenic cytokines with different indices of social support and loneliness by measuring the levels of expression of two important proangiogenic cytokines, vascular endothelial growth factor (VEGF), and interleukin-6 in tumors of colon and rectum. Lack of social support has been prospectively associated with cancer progression. METHODS: Fifty-one newly diagnosed patients with colorectal tumors (mean age, 68.3 years) completed two measures of loneliness 1 to 2 days before their surgical treatment. The first was an explicit self-report questionnaire, which tapped into negative feelings as a result of low social support. The second was a standardized computer-based task, which measured loneliness implicitly. Immunohistochemical analyses were performed on tumor tissues post surgery to determine the expression of cytokines. RESULTS: Logistic regression showed that higher levels of implicit loneliness independently predicted stronger expression of VEGF, controlling for Dukes stage and explicit loneliness, both of which were nonsignificant predictors. No significant relationships were found between the loneliness measures and interleukin-6. CONCLUSIONS: The results of this study suggest VEGF to be an angiogenic mechanism through which loneliness may lead to worse cancer-related outcomes. Implications are discussed in terms of devising targeted psychosocial and immunotherapeutic interventions for cancer patients with low social support.

Obesity, serious mental illness and antipsychotic drugs.

The prevalence of overweight and obesity is higher in people with mental illness than in the general population. Body weight is tightly regulated by a complex system involving the cortex and limbic system, the hypothalamus and the gastrointestinal tract. While there are justifiable concerns about the weight gain associated with antipsychotic medication, it is too simplistic to ascribe all obesity in people with serious mental illness (SMI) to their drug treatment. The development of obesity in SMI results from the complex interaction of the genotype and environment of the person with mental illness, the mental illness itself and antipsychotic medication. There are dysfunctional reward mechanisms in SMI that may contribute to poor food choices and overeating. While it is clear that antipsychotics have profound effects to stimulate appetite, no one receptor interaction provides an adequate explanation for this effect, and many mechanisms are likely to be involved. The complexity of the system regulating body weight allows us to start to understand why some individuals appear much more prone to weight gain and obesity than others.

A review of the association between antipsychotic use and hyperprolactinaemia.

Recent evidence linking hyperprolactinaemia to longer-term clinical sequelae, including osteoporosis, hip fractures and possibly breast cancer, is increasing clinical awareness of the relevance of hyperprolactinaemia. A review of the literature finds clinical trials reporting some degree of comparative prolactin data among antipsychotics. Many of the randomised clinical trials (RCTs) do not report categorical rates of hyperprolactinaemia in contrast with the naturalistic studies, making it complex for clinicians to evaluate the extent and severity of hyperprolactinaemia. Hyperprolactinaemia is one of the commonest adverse events reported in clinical trials and can be found in association with all antipsychotics. The highest rates of hyperprolactinaemia are reported in association with risperidone and amisulpride, often as high as 80-90% of all female subjects and consistently greater than with the typical antipsychotics. Significant rates of hyperprolactinaemia of lesser severity and more transience have also been reported in association with other atypical antipsychotics.

Antipsychotics and hyperprolactinaemia: clinical recommendations.

A group of international experts in psychiatry, medicine, toxicology and pharmacy assembled to undertake a critical examination of the currently available clinical guidance on hyperprolactinaemia. This paper summarises the group's collective views and provides a summary of the recommendations agreed by the consensus group to assist clinicians in the recognition, clinical assessment, investigation and management of elevated plasma prolactin levels in patients being treated for severe mental illness. It also deals with the special problems of particular populations, gives advice about information that should be provided to patients, and suggests a strategy for routine monitoring of prolactin. The recommendations are based upon the evidence contained in the supplement 'Hyperprolactinaemia in schizophrenia and bipolar disorder: Clinical Implications' (2008). The guidance contained in this article is not intended to replace national guidance (such as that of the National Institute of Clinical Excellence), however, it does provide additional detail that is unlikely to be covered in existing guidelines, and focuses on areas of uncertainty and disagreement. We hope it will add to the debate about this topic.

A randomized, controlled trial of duloxetine alone vs. duloxetine plus a telephone intervention in the treatment of depression.

OBJECTIVE: We hypothesized that combining antidepressant medication with a standardized telephone adherence support intervention would lead to superior outcomes in the treatment of depression compared with antidepressant medication alone. METHOD: Patients with depression were randomized to receive the antidepressant duloxetine alone (DLX), or duloxetine plus a standardized telephone intervention (DLX+TI), for 12 weeks of open-label treatment. The primary outcome measure was remission (HAMD 17 total score 90% at every visit) in both groups. CONCLUSIONS: A telephone intervention in combination with antidepressant medication (duloxetine) did not improve depression outcomes compared with antidepressant alone in this clinical trial, perhaps due to high drug adherence in both treatment groups. Addition of a telephone intervention was, however, associated with increased reporting of AEs.

Association between antipsychotic drugs and diabetes.

The link between atypical antipsychotic drugs and the development of diabetes has been hotly debated in the literature. In this review, we attempt to classify the various types of data published and presented in a hierarchical basis. Case reports and retrospective pharmacoepidemiological studies suggest that both conventional and atypical antipsychotic medications are associated with an increased risk of glucose abnormalities or diabetes. Prospective data examining the relationship between atypical antipsychotic drugs and diabetes began to emerge in 2003 and are much less conclusive. Estimates of the attributable risk associated with atypical antipsychotic drugs are low. The few studies that have included a placebo group suggest that we cannot necessarily blame antipsychotic medication when diabetes develops in an individual with schizophrenia.

The relationship of disordered eating habits and attitudes to clinical outcomes in young adult females with type 1 diabetes.

OBJECTIVE: To describe the clinical outcomes of adolescent and young adult female subjects with type 1 diabetes in relation to the disturbance of eating habits and attitudes over 8-12 years. RESEARCH DESIGN AND METHODS: Patients were recruited from the registers of pediatric and young adult diabetes clinics (including nonattenders) and interviewed in the community. A total of 87 patients were assessed at baseline (aged 11-25 years), and 63 (72%) were reinterviewed after 8-12 years (aged 20-38 years). Eating habits and attitudes were assessed by a semistructured research diagnostic interview (Eating Disorder Examination). RESULTS: Clinical eating disorders ascertained from the interview and/or case note review at baseline or follow-up were found in 13 subjects (14.9% [95% CI 8.2-24.2]), and an additional 7 subjects had evidence of binging or purging, bringing the total affected to 26%. Insulin misuse for weight control was reported by 31 (35.6% [25.7-46.6]) subjects. Overall outcome was poor; serious microvascular complications were common and mortality was high. There were significant relationships between disordered eating habits, insulin misuse, and microvascular complications. CONCLUSIONS: Although the cross-sectional prevalence of clinical eating disorders in young women with diabetes is modest, the cumulative incidence of eating problems continues to increase after young adulthood, and this is strongly associated with poor physical health outcomes. The combination of an eating disorder and diabetes puts patients at high risk of mortality and morbidity. Better methods of detection and management are needed.

Modifiable risk factors for non-adherence to immunosuppressants in renal transplant recipients: a cross-sectional study.

BACKGROUND: Non-adherence to immunosuppressants is a major cause of renal transplant failure. Interventions to improve adherence need to target modifiable risk factors. METHODS: Adherence was measured using the 'gold standard' measure of electronic monitoring in 58 adult renal transplant recipients from a UK transplant unit. Subjects were identified from a stratified random sample of 153 recipients recruited to a larger cross-sectional study comparing different measures of adherence. Inclusion criteria included age over 18 years and a functioning renal transplant, transplanted 6-63 months previously. Exclusion criteria included residence outside the region served by the unit and inability to give informed consent. Health beliefs, depression and functional status were measured using standardized questionnaires (Beliefs about Medicines Questionnaire, Illness Perception Questionnaire, Revised Clinical Interview Schedule and SF-36) and semi-structured interview. Transplant and demographic details were collected from the notes. RESULTS: Seven [12%, 95% confidence interval (CI) 4-20%] subjects missed at least 20% of days medication and 15 (26%, 15-37%) missed at least 10% of days. Lower belief in the need for medication and having a transplant from a live donor were the major factors associated with non-adherence. Depression was common, although not strongly associated with non-adherence. CONCLUSIONS: Beliefs about medication are a promising target for interventions designed to improve adherence. The lower adherence in recipients of transplants from live donors needs confirming but may be clinically important in light of the drive to increase live donation.

Frequency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review.

Nonadherence to immunosuppressants is recognized to occur after renal transplantation, but the size of its impact on transplant survival is not known. A systematic literature search identified 325 studies (in 324 articles) published from 1980 to 2001 reporting the frequency and impact of nonadherence in adult renal transplant recipients. Thirty-six studies meeting the inclusion criteria for further review were grouped into cross-sectional and cohort studies and case series. Meta-analysis was used to estimate the size of the impact of nonadherence on graft failure. Only two studies measured adherence using electronic monitoring, which is currently thought to be the most accurate measure. Cross-sectional studies (n=15) tended to rely on self-report questionnaires, but these were poorly described; a median (interquartile range) of 22% (18%-26%) of recipients were nonadherent. Cohort studies (n=10) indicated that nonadherence contributes substantially to graft loss; a median (interquartile range) of 36% (14%-65%) of graft losses were associated with prior nonadherence. Meta-analysis of these studies showed that the odds of graft failure increased sevenfold (95% confidence interval, 4%-12%) in nonadherent subjects compared with adherent subjects. Standardized methods of assessing adherence in clinical populations need to be developed, and future studies should attempt to identify the level of adherence that increases the risk of graft failure. However, this review shows nonadherence to be common and to have a large impact on transplant survival. Therefore, significant improvements in graft survival could be expected from effective interventions to improve adherence.

Measuring compliance with drug regimens after renal transplantation: comparison of self-report and clinician rating with electronic monitoring.

Nonadherence to immunosuppressants in renal transplant recipients is a major factor affecting graft survival, but it is difficult to detect accurately in clinical practice. Adherence was measured in 153 adult renal transplant recipients using self-report questionnaires and interview, clinician rating, and cyclosporine levels. The sensitivity and specificity of these measures were determined by comparison with electronic monitoring in a randomly selected subsample of 58 subjects. Measures of adherence in current clinical use do not perform well when tested against electronic monitoring. Self-report at a confidential interview was the best measure of adherence for the detection of both missed doses and erratic timing of medication. However, the use of a confidential interview is not directly applicable to a clinical setting. Further research on how best to facilitate disclosure in clinical settings may be the best way to develop adherence measures for use in routine practice.

Poor prognosis of young adults with type 1 diabetes: a longitudinal study.

OBJECTIVE: To determine the role of early behavioral and psychological factors on later outcomes in young adults with childhood- or adolescent-onset type 1 diabetes. RESEARCH DESIGN AND METHODS: We conducted a longitudinal cohort study of patients recruited from the register of the young adult outpatient diabetes clinic, Oxford, U.K. A total of 113 individuals (51 male subjects) aged 17-25 years completed assessments, and 87 (77%) were reinterviewed as older adults (aged 28-37 years). Longitudinal assessments were made of glycemic control (HbA(1c)) and complications. Psychological state at baseline was assessed using the Present State Examination and self-report Symptom Checklist, with corresponding interview schedules administered at follow-up. RESULTS: There was no significant improvement between baseline and follow-up in mean HbA(1c) levels (8.5 vs. 8.6% in men, 9.3 vs. 8.7% in women). The proportion of individuals with serious complications (preproliferative or laser-treated retinopathy, proteinuria or more severe renal disease, peripheral neuropathy, and autonomic neuropathy) increased from 3-37% during the 11-year period. Women were more likely than men to have multiple complications (23 vs. 6%, difference 17%, 95% CI 4-29%, P = 0.02). Psychiatric disorders increased from 16 to 28% (20% in men, 36% in women at follow-up, difference NS), and 8% had psychiatric disorders at both assessments. Baseline psychiatric symptom scores predicted follow-up scores (beta = 0.32, SE [beta] 0.12, P = 0.008, 95% CI 0.09-0.56) and recurrent admissions with diabetic ketoacidosis (odds ratio 9.1, 95% CI 2.9-28.6, P < 0.0001). CONCLUSIONS: The clinical and psychiatric outcome in this cohort was poor. Psychiatric symptoms in later adolescence and young adulthood appeared to predict later psychiatric problems.