According to Reuters, FDA officials will seek a strong "black box" warning for antiepileptic drugs, warning about the risk of suicidal thoughts and behaviour, based on an analysis carried out previously by the agency (see NeLM link). Advice is being sought from an advisory panel due to meet later on in the week.

A large case-control study provides further support for an increased risk of upper gastrointestinal bleeding with SSRI antidepressants; it also suggests a lesser increase in risk with venlafaxine, indicates an interaction with other drugs that increase the risk (e.g. NSAIDs), and that acid-suppressant therapy may possibly reduce the risk. There is increasing evidence that SSRIs may increase the risk of upper gastrointestinal bleeding, probably via an effect on platelet serotonin levels. This study was carried out to support earlier work, to investigate possible risk factors and whether acid-suppressing drugs might reduce the risk, and to determine whether venlafaxine, which is pharmacologically related to a SSRI, might also have an effect. The authors used data from the UK Health Improvement Network, which records details of patients in primary care. They identified a source cohort of patients aged 40 to 84 with at least two years data in the system in the years 2000 to 2005 inclusive, excluding those with major causative factors such as cancer, liver disease, coagulopathy, etc. This source cohort was followed from the start date until they became a case, reached age 85, developed one of the exclusion criteria, died, or the study ended. Cases were those who had an upper gastrointestinal complication and not one of the excluded conditions; controls were randomly selected to match by age, sex, and index event year. For cases and controls, antidepressive drug exposure was determined at the index date (symptom onset or diagnosis for cases) and classed as SSRI, SNRI (venlafaxine, duloxetine), tricyclics with an effect on serotonin uptake, and tricyclics with no effect on serotonin uptake. Other factors considered were other medications that potentially increase the risk of upper gastrointestinal bleeding (NSAID, antiplatelet agents, systemic corticosteroids, and warfarin), and use of acid-suppressing drugs. The main outcomes for the study were risk of bleeding with SSRI, and the effect of acid-suppressing drugs. There were 1321 cases for evaluation, matched with 10,000 controls. There were more current users of SSRIs in the cases compared to controls (5.3% vs. 3.0%, adjusted odds ratio 1.6; 95% CI, 1.2 to 2.1) and also more current venlafaxine users in the cases compared to controls (1.1% vs. 0.3%, OR 2.9; 95% CI, 1.5 to 5.6). There was an interaction with NSAID use: risk with concurrent use of either SSRI or SNRI with a NSAID was greater than the sum of the individual affects (OR, 4.8; 95% CI, 2.8 to 8.3). There was also indication of an added risk with systemic corticosteroids (OR, 4.0; 95% CI, 1.3 to 12.3) however concurrent use of antiplatelet drugs and oral anticoagulants did not appear to be associated with increased risk. Acid suppressing drugs were more likely to be used in cases than controls, leading to confounding by indication, however analysis suggested that use of these drugs reduced the risk with SSRI and SNRI combined (OR for use with acid suppressant 1.4; 95% CI, 0.8 to 2.3; compared to OR for non-use, 2.0; 95% CI, 1.5 to 2.8). Concurrent use of an acid suppressing drug reduced the risk of combination with NSAID (OR, 9.1; 95% CI, 4.8 to 17.3 in nonusers vs. OR, 1.1; 95% CI, 0.3 to 3.4 in current users). Numbers needed to harm (NNH) calculations indicate that the absolute risk is low: for all SSRI/SNRI combined, 2000 patients would need to be treated for one additional case of upper gastrointestinal bleeding. Even in combination with NSAID, the NNH is 250. Concurrent use of acid-suppressing drugs would reduce the risk to give an estimated NNH of 5000. The authors conclude that their results confirm that antidepressive drugs blocking serotonin reuptake increase the risk of upper gastrointestinal bleeding. They note that the results add to anecdotal evidence that SNRIs (venlafaxine) also have this effect. A positive interaction was seen with NSAID and systemic corticosteroids, however concurrent use of acid

The July issue of the Drug Safety Update from the MHRA provides a reminder of the reports of suicidal thoughts and behaviour, not only in those with pre-existing psychiatric conditions or other psychosocial risk factors, but also in users of varenicline who have no known pre-existing psychiatric conditions, and in those who continue to smoke. The following advice for healthcare professionals is reiterated: • Patients should be told to stop treatment and contact their doctor immediately if they develop suicidal thoughts or behaviour. • Varenicline should be stopped immediately if agitation, depressed mood, or changes in behaviour are observed that are of concern to the patient, family, or caregivers. • The safety and efficacy of varenicline in people with serious psychiatric illness have not been established; those with such a history should be monitored closely while taking varenicline.

This review examines the scale of substance use disorders among young people and how healthcare practitioners can intervene. It addresses the following questions: • What constitutes substance misuse? • Is substance use increasing? • What do we know about rates of misuse and dependence? • Does substance misuse impair the developing brain? • How dangerous is substance misuse? • Management

Findings from the SMaRT oncology 1 study published in the Lancet shows the benefit of a nurse-delivered intervention for depression in a mixed group of outpatients with cancer. The study conducted in a regional cancer centre in Scotland involved 200 outpatients (mean age 56.6, 71% female) with a prognosis of greater than 6 months and major depressive disorder. They were randomised to usual care (n= 99) or to usual care plus the intervention (n= 101). In the usual care group, the patient's GP and oncologist were informed of their diagnosis of major depressive disorder and advice was provided on choice of antidepressant drug if requested. Patients in the intervention group were offered in addition to usual care, a maximum of 10 one-to-one sessions over 3 months, delivered by a cancer nurse at the centre with no previous psychiatric experience. The intervention know as Depression Care for People with Cancer, comprised education about depression and its treatment, problem-solving treatment to teach the patients coping strategies designed to overcome feelings of helplessness; and communication about management of major depressive disorder with each patient's oncologist and GP. The patients’ GPs prescribed all antidepressant medication. A psychiatrist reviewed patients' progress with the nurses every week. For 3 months after the treatment sessions progress was monitored by monthly telephone calls. The primary outcome was the difference in mean score on the self-reported Symptom Checklist-20 (SCL-20) depression scale (range 0 to 4) at 3 months after randomisation. The intention to treat analysis of 196 patients for whom data at 3 months were available found that depression scores on the SCL-20 fell between baseline and 3 months in both groups, but more so in the intervention group. The median baseline depression score was 2.35 in the intervention and 2.25 in the usual care group; after 3 months, this fell to 1.20 and 1.55 respectively. The mean reduction at 3 months in the intervention group compared with usual care, adjusted for baseline SCL-20 score and other variables, was 0.34 (95% CI 0.13–0.55; p=0.002), a treatment effect that was sustained at 6 and 12 months. The intervention which also improved anxiety and fatigue but not pain or physical functioning, was estimated to cost an additional £5278 per quality-adjusted life-year gained. The researchers conclude from this study that their intervention “offers a model for the management of major depressive disorder in patients with cancer and other medical disorders who are attending specialist medical services that is feasible, acceptable, and potentially cost effective.” An accompanying comment notes that these findings are an important addition to publications on the treatment of depression in medical populations, adding that “such multicomponent interventions are potentially feasible in cancer treatment centres and can be perceived by patients as less stigmatising than referral to a mental-health specialist.”

The European Committee of Medicinal Products for Human Use (CHMP) has recommended strengthening the existing warnings for varenicline (Champix®) with regards to suicide-related events (SRE) following a review of spontaneous reporting data. Mention of the fact that not all patients experiencing depression and suicidal thoughts had a previous history of psychiatric illness or had stopped smoking will be added to the SPC, as well as instructions on stopping treatment and contacting doctors when patients develop agitation, depressed mood, changes in behaviour or suicidal thoughts.

The Department of Health has published guidance designed to assist mental health trusts and other specialist mental health service providers in developing their plans for responding to an influenza pandemic. The guidance consists of general contingency advice for planners and details a national approach, setting out the key planning assumptions and principles, roles and responsibilities that should inform the development of local plans. The guidance on preparing mental health services is supplementary to Pandemic flu: A national framework for responding to an influenza pandemic, and can be read in conjunction with it and other national guidance on pandemic influenza planning (see pandemic planning link above).

Antidepressants show only limited activity in children and adolescents, with some indication of increasing benefit with older age, and possibly greater effect with fluoxetine, according to the results of a meta-analysis. The authors note that the use of antidepressants in children and adolescents is receiving considerable attention, particularly due to the apparent increase in suicidal thoughts associated with SSRI treatment. The primary aim of this meta-analysis was to evaluate the efficacy of all antidepressants in this age group; other aims were to compare effect in younger children and adolescents, to compare SSRI with other agents, and identify factors affecting efficacy. They carried out a comprehensive literature search for randomised placebo-controlled trials of antidepressive drugs in people aged under 20 with depressive illness, where responder rates were reported as participant counts (not as average change in symptom scores). Data from reports was extracted to give responder rates for the primary outcome of each included study. Doses were compared by using standardised imipramine equivalent dose, derived from manufacturer's recommended doses, textbook summaries, and clinical practice. Initial searches located 304 potentially eligible studies for screening, of which 29 were eligible for inclusion. One study included three arms (tricyclic, SSRI, and placebo), to yield 30 comparisons for analysis with a total of 3,069 participants. Mean age was 13.5 years (range 6 to 20) and only four studies (all involving tricyclics) reported results for children and adolescents separately. There were 14 comparisons with placebo for tricyclics, 12 for SSRI, and 4 for others (moclobemide, mirtazapine, and nefazodone). Most were relatively short duration, with a mean of 8.7 weeks (median 8, range 1 to 12); symptom scores indicated that participants generally had moderate to severe depression. The analysis found a modest pooled response rate (RR 1.22; 95% CI, 1.15 to 1.31). Overall response rate difference was 10.9% (60.1% drug vs. 49.2% placebo; NNT=9). When analysed by drug, the response rates differed: as NNT, tricyclics NNT=14 > SSRI NNT=9 > others NNT=8; however ranges overlapped considerably and overall did not show significant superiority for any group. There was some indication that adolescents were more likely to respond than younger children (NNT =8 vs. NNT =21). Pooled efficacy for fluoxetine was somewhat higher than for other drugs. The authors conclude that antidepressants have only modest efficacy in children. There is some indication that fluoxetine may be more effective, and adolescents seem to respond better than younger children. There is an urgent need for more research on treatments for depression in this age group.

According to a report by BioSpace.com, the US Food and Drug has approved an extended indication for extended release methylphenidate tablets (Concerta) for the treatment of attention deficit hyperactivity disorders in adults aged 18 to 65 years. The dose range is from 18 to 72 mg daily. [Currently in the UK, Concerta XL is licensed for children and adolescents with ADHD.]

The European Medicines Agency’s (EMEA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending license extension of duloxetine (Cymbalta®) to include the treatment of generalised anxiety disorder (GAD).

NICE is developing public health intervention guidance to encourage the optimal provision of needle exchange schemes amongst injecting drug misusers. The Institute is now inviting registered stakeholders to comment on the evidence that has been assembled to inform the development of this guidance, including a review of effectiveness and cost effectiveness, a review of qualitative evidence and an economic analysis. Please see the link above for details.

DIA news reports on a US court case covered by the Wall Street Journal (20 June) in which plaintiffs allege a link between suicides and gabapentin. A British neurologist testified at the hearing, which was being jointly held by judges for U.S. District Court in Boston and a New York state court, that he had advised Parke-Davis, (now part of Pfizer Inc) to include a warning on the drug's label for potential side effects of depression and aggression, but his advice was not followed. He claimed that there was a “plausible biological pathway” that could lead from the drug "to suicidal behaviour, hostility, and aggression." Under cross-examination, attorneys for Pfizer challenged his claims, describing them as “a patchwork of studies that didn't prove a biological connection."

According to a report on the BBC Health website, the research company Medix has found that over half of 355 GPs questioned are regularly prescribing risperidone or olanzapine to elderly patients with dementia, despite concerns that the use of these medicines in this patient group may be associated with an increased risk of stroke and of death. Only 15 doctors out of the 355 questioned said they would never use anti psychotic medication for dementia patients. The rest cited several symptoms for which they would prescribe such drugs, including aggression, inappropriate behaviour, disinhibition, wandering or being noisy. A total of 72% of the doctors had prescribed risperidone for dementia patients in the past four years, and 53% had similarly prescribed olanzapine. In 2004, the CSM considered the evidence available and concluded that the use of atypical antipsychotics [mainly evidence for risperidone and olanzapine] increases the risk of stroke, particularly in elderly patients with dementia. The Committee recommended that risperidone or olanzapine should not be used for the treatment of behavioural symptoms of dementia (see link above to view related NeLM news item). More recently, the use of antipsychotics to treat dementia-related psychosis has been linked to an increased risk of mortality (see link above to view FDA alert). Ivan Lewis, Minister for Care Services, said that the prescribing of these medicines was ‘indefensible’ for many dementia patients, and that they will be considering how to toughen enforcement in this area. In defence, a BMA representative postulated that such prescribing was occurring in situations where the patient is “physically very disturbed and is at risk of doing violence to themselves or others". Dr Tim Kendall of NICE commented: "A doctor prescribing for 90% of their patients an anti-psychotic when there is enough guidance to say don't - it's unacceptable….I think the doctors should be disciplined”.

The US Food and Drug Administration has issued an alert notifying healthcare professionals that both conventional and atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis. This follows an earlier alert issued in April 2005 in which the FDA notified healthcare professionals that patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death. However, since issuing the notification, the FDA has reviewed additional information that indicates the risk is also associated with conventional antipsychotics. The FDA suggests that healthcare professionals should consider the following (taken directly from source): • Elderly patients with dementia-related psychosis treated with conventional or atypical antipsychotic drugs are at an increased risk of death. • Antipsychotic drugs are not approved for the treatment of dementia-related psychosis. Furthermore, there is no approved drug for the treatment of dementia-related psychosis. Healthcare professionals should consider other management options. • Physicians who prescribe antipsychotics to elderly patients with dementia-related psychosis should discuss this risk of increased mortality with their patients, patients’ families, and caregivers. The prescribing information for all antipsychotic drugs will now include the same information about this risk in a “boxed warning” and the warnings section.

The Medicines Healthcare and Regulatory Agency (MHRA) and MetWest Pharmaceuticals have issued a Drug Alert recalling a batch of diazepam 5mg tablets. The batch is being recalled because some cartons have been found to contain diazepam 2mg tablets. The following batch number is affected: 1240701. The expiry date of this batch is 30/11/2010, and it was first distributed on 19/02/2008. Recipients are requested to quarantine any remaining stock and return it to their supplier for credit. Additionally, for medical information and stock return enquiries please contact Metwest Customer Service on 020 7835 5990.

Second-generation antipsychotic drugs are associated with a small increase in risk of diabetes compared to first-generation drugs, according to a meta-analysis, although retrospective analysis of data from a clinical trial suggests that an increased risk with aripiprazole may be less likely. People with schizophrenia have an increased incidence of type 2 diabetes, and there is evidence that some of the increase in risk may be due to antipsychotic drugs, especially second-generation agents. A systematic review and meta-analysis published in the British Journal of Psychiatry attempts to clarify the risk using clinical trial data. The authors carried out a comprehensive search for studies of any type where a first-generation antipsychotic was compared with a second generation drug in patients with schizophrenia, where diabetes was an outcome (primary or secondary). Relevant data were pooled and used to determine risk of diabetes. The initial search identified 1,974 papers, of which 73 were selected as potentially relevant. From these, 14 were eligible for the systematic review and 11 provided sufficient data to be included in the meta-analysis. Most were cross-sectional (n=4), retrospective cohort (n=4) or case-control (n=2). Only 3 were prospective in design. The second-generation antipsychotic drugs included were clozapine, olanzapine, risperidone and quetiapine; four studies looked at clozapine alone. Most studies clearly excluded pre-existing diabetes and used appropriate diagnostic criteria, however some did not differentiate clearly and some used prescription of anti-diabetic medication as the criterion. Many studies were relatively short - excluding cross-sectional studies, median duration of follow-up was 12 months (range 2 to 62 months). Meta-analysis found that prescription of a second-generation antipsychotic was associated with a modest increase in the risk of being diagnosed with diabetes, with a relative risk of 1.32 (95% CI 1.15 to 1.51). Testing for heterogeneity suggested a high degree of variability across studies. Sensitivity analyses were carried out to explore this further: these suggested differing relative risks for separate second-generation drugs. These were risperidone 1.16 (95% CI 0.99 to 1.35; n=6 studies), quetiapine 1.28 (95% CI 1.14 to 1.45; n=3), olanzapine 1.28 (95% CI 1.12 to 1.45; n=8) and clozapine 1.39 (95% CI 1.24 to 1.55; n=7). The authors conclude that the available data tentatively suggest an increase in risk of diabetes associated with second-generation antipsychotic drugs compared to first-generation drugs. They note a number of limitations to the analysis - many of the studies were not of high quality, and criteria for diagnosis of both schizophrenia and diabetes were uncertain. Although the short duration of many could be seen as a limitation, there is evidence that any pro-diabetic effect of these drugs appears fairly soon after initiation. They note that in epidemiological terms, a relative risk of less than 2 is considered low, and the weaknesses of the underlying data mean that this study should not be used to guide medication switching or for implementing protocols. Further evidence comes for aripiprazole, which was not included in the meta-analysis because there were insufficient relevant data. A retrospective analysis of data from a major clinical trial of aripiprazole (STAR) was used to determine whether biochemical changes measured in trial participants could indicate whether any were at increased risk of diabetes. In the STAR trial, aripiprazole was compared to 'standard care': the clinician's choice of quetiapine, olanzapine, or risperidone. Metabolic data were collected as part of pre-specified safety outcomes. The analysis of this data, compared to data from known models of diabetes and CHD risk, suggested that aripiprazole was not associated with metabolic changes that predicted a high risk of diabetes or cardiovascular disease. This analysis should be taken

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A small controlled trial found no difference between St John's Wort (SJW) and placebo in the symptomatic treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children and adolescents. While symptoms of ADHD can often be improved by treatment with stimulant medications, this is controversial and parents of affected children may seek alternative non-drug therapies. SJW is one of the herbal products that is used in this situation: it is pharmacologically feasible that it may be useful, and this study aimed to determine whether it had demonstrable effects. Participants were aged 6 to 17 and had confirmed ADHD. They were randomised to treatment with SJW (300mg, standardized to 0.3% hypericin) or placebo three times daily. A one week placebo run-in period was used to exclude those who were non-adherent to medication, or showed an exaggerated placebo response. Study duration was 8 weeks, and primary outcome measures were performance on the ADHD Rating Scale–IV (range, 0-54) and Clinical Global Impression Improvement Scale (range, 0-7), and adverse events. Sample size calculations indicated that the study was sufficiently powered to detect a clinically meaningful response on the ADHD rating scale. Initial screening of 146 potential participants yielded 104 who were eligible, of whom 59 agreed to participate: 54 were randomised to treatment, 27 in each group. Analysis at eight weeks found no significant differences between the study groups in any of the main outcomes. Further analysis on a range of other behavioural problems also found no significant difference between the groups. Based on their results, the authors conclude that there was no significant benefit from the SJW product used in children and adolescents with ADHD. They note that recent research indicates that another constituent of SJW may be responsible for its activity - the content of this in the product used was low when measured at the end of the study, probably because of its instability. While there seems little benefit in further research on current SJW products, it may be worth examining products containing stable levels of the presumed active component if these become available.

The National Institute for Health and Clinical Excellence (NICE) is developing a clinical practice guideline on the treatment and management of borderline personality disorder for use in the NHS in England, Wales and Northern Ireland. The Institute is now consulting on a draft version of the guideline, and registered stakeholders are invited to comment on the provisional recommendations up until 4th August 2008. Please see the link below for details.

This is one of a series of occasional articles about how to manage a pre-existing medical condition during pregnancy. The current article includes a case scenario and discusses the management of pregnant injecting drug users. The following topics are discussed in the article: • How common is injecting drug use in pregnancy? • What is the impact of pregnancy on the course of opioid dependence? • How does opioid dependency affect pregnancy progression and outcome? • How should opioid dependence be managed in pregnancy? • Is methadone safe in pregnancy? • Pregnancy planning • Clinical management at different stages of pregnancy • Do any alternatives to methadone exist?