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Alzheimer's disease NSAIDs and cognitive function Observational studies have identified an association between use of NSAIDs and a reduced risk of Alzheimer's disease (AD) but there is also evidence that NSAIDs could adversely affect cognitive function. The Alzheimer's Disease Anti‐inflammatory Prevention Trial (ADAPT) of primary prevention of cognitive decline has further fuelled the debate ( Arch Neurol 2008;65:896‐905). A total of 2528 men and women aged at least 70 years, with a family history of AD but no cognitive impairment at baseline, were randomised to placebo, the selective COX‐2 inhibitor celecoxib 400mg daily, or the non‐selective NSAID naproxen 440mg daily. Cognitive function was measured annually. The trial was suspended when evidence emerged of an increased cardiovascular risk with celecoxib in another trial. By then, the median time to the last cognitive assessment was 736–737 days. Compared with placebo, both drugs were associated with increasing risk of cognitive decline. Naproxen was also associated with significantly greater global decline compared with placebo, raising the possibility of a deleterious effect. Antipsychotics benefit doubtful New data from Clinical Anti‐psychotics Trials of Intervention Effectiveness (CATIE) suggest that atypical antipsychotics can improve some symptoms of Alzheimer's disease but with questionable overall benefit ( Am J Psychiatry 2008; 165:844‐54). CATIE included 421 patients (mean age 78 years) with Alzheimer's disease associated with psychosis or agitated or aggressive behaviour. They were randomised to placebo or treatment with risperidone, olanzapine or quetiapine for 36 weeks. Around 80 per cent of patients discontinued their assigned drug, with a median duration of treatment of seven weeks. The apparent effectiveness of the drugs varied depending on which scale was used to assess symptoms and the effect sizes were usually small; there were no overall differences in cognitive function. Among patients continuing treatment at 12 weeks, the antipsychotics did not improve functional abilities, care needs or quality of life compared with placebo. Lithium for early disease Lithium treatment is not to be taken lightly but there are few options for patients with mild to moderate Alzheimer's disease. Psychiatrists in London have reported a feasibility and tolerability study of nonblinded treatment for up to one year in 22 patients (mean Mini‐Mental State Examination (MMSE) 16–19) ( Int J Geriatr Psychiatry 2008; 23:704‐11). The primary endpoint was safety. The mean length of treatment was 25 weeks. Eight patients completed treatment. Two patients died of unrelated causes. Of the 12 who stopped treatment, two did so due to adverse effects; one was withdrawn after admission; four requested discontinuation; carers were unable to guarantee adherence for two patients; and investigators withdrew lithium from three patients. There were no differences in adverse reaction scores between patients who completed and those who stopped treatment. Efficacy was a secondary end‐point. Lithium levels did not correlate with cognitive function and there was no difference between treated and control patients in the change in cognitive function. Depression Adjunctive donepezil A pilot study from the USA suggests that the cholinesterase inhibitor donepezil may be a useful adjunct to antidepressant therapy in older people with depression and cognitive impairment ( Int J Geriatr Psychiatry 2008;23:670‐6). Twenty‐three patients (mean MMSE score 26) were initially treated with sertraline for eight weeks; of these, 21 entered a randomised double‐blind comparison between additional donepezil (5mg increasing to 10mg daily) and placebo for 12 weeks. Six patients then continued open‐label donepezil in a 32‐week extension phase and six continued without donepezil. The initial response rate with sertraline was 61 per cent; this was associated with improvement in verbal memory tests compared with non‐responders. Patients then randomised to donepezil continued to improve compared with placebo over 12 weeks. Continued treatment with open‐label donepezil was associated with still superior test performance but there was a diminishing difference compared with no treatment over one year. Donepezil was well tolerated. Maintenance therapy difficult Another study has documented how difficult it can be to deliver maintenance therapy for depression – even to inpatients ( Br J Psychiatry 2008;193:163‐4). This Finnish study reports a five‐year follow‐up of 269 inpatients with confirmed major depression. Maintenance therapy was indicated for 86 inpatients, of whom 57 per cent received at least one course. However, maintenance therapy was too short – the median duration of indication was 23 months but the median duration of treatment was 2.8 months. Although patients needing maintenance therapy had consulted a psychiatrist twice as often as others in the group, contact was lost with two‐thirds. After multivariate analysis, only good adherence to acute treatment with an antidepressant predicted success delivering maintenance therapy. STAR*D on index episode duration New data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial show that the duration of the initial episode of depression does not affect the likelihood of remission after treatment with an antidepressant ( J Clin Psychiatry 2008; published online July 29 pii:ej07m03626). Categorising duration of the episode of depression on admission to the trial as ≤six months, 7‐23 months, 24–41 months and ≥42 months, there was an association between longer duration of depression and reduced likelihood of remission. However, after adjustment for clinical and demographic factors associated with longer episodes (age, comorbidity, lower income, ethnicity) the link was lost. The authors conclude that antidepressant therapy is useful regardless of the duration of the current episode though earlier intervention could help to reduce some of the many factors contributing to chronicity. Onset of treatment effects Studies of the time to onset of effects of antidepressants have produced inconsistent findings, prompting investigators from The Netherlands to explore the issue in older patients ( Int J Geriatr Psychiatry 2008;23:769‐71). This post hoc analysis of a trial of venlafaxine and nortriptyline in 81 depressed patients aged at least 60 years found no significant differences between the two drugs and so pooled the results. There was a significant decrease in scores for the somatic and psychological subscales of the Hamilton Depression Rating Scale (HAM‐D) scale over 12 weeks; this was greatest after the first week's treatment and was matched by changes in Montgomery‐Åsberg Depression Rating Scale (MADRS). Core mood symptoms improved as quickly as sleep disturbances. Stopping antidepressants in patients with dementia Antipsychotics are, controversially, prescribed as part of the management of behaviour disorders associated with dementia – but, say Norwegian researchers, so too are antidepressants and little is known about the effects of discontinuing treatment ( Int J Geriatr Psychiatry 2008;23:877‐9). They report the withdrawal of antipsychotics or antidepressants after at least three months' treatment in 23 older patients (mean age 84 years) with dementia. Ten patients completed 24 weeks with‐drawal; of the remainder, four restarted medication. The findings were based on low numbers but suggested that, consistent with other studies, stopping antipsy‐chotics did not affect behavioural symptoms or depression. By contrast, stopping antidepressants was associated with a reduction in both dementia‐associated behavioural symptoms and depression symptoms. Donepezil not for bipolar disorder Donepezil does not improve cognitive function or activities of daily living in older people with bipolar disorder, a US study has shown ( Int J Geriatr Psychiatry 2008; 23:693‐8). A series of 12 older patients (mean age 74 years) with stable bipolar I or II disorder and evidence of cognitive dysfunction received donepezil 5mg daily increased to 10mg daily for a total of 12 weeks. Attention and activities of daily living were assessed at baseline, at 12 weeks and three months after treatment was discontinued. Nine participants continued donepezil for three months; of these, two experienced re‐emergent depression after discontinuing donepezil. Of the three who stopped early, one did so because of nausea and a further two did so after manic activation. There were no significant changes in cognitive function or activities of daily living during donepezil treatment but seven patients requested continued treatment because they believed they had benefited from it. Schizophrenia New cholinergic drugs Investigations of acetylcholine as a modulator of dopamine function in the treatment of schizophrenia have been limited by the lack of agents with sufficient selectivity but two recent studies suggest this could be a useful approach. In this pilot study of the muscarinic M 1 and M 4 agonist xanomeline, 20 patients (with a worsening response to antipsychotic therapy for schizophrenia but who were medication‐free for three to eight days) were randomised to placebo or xanomeline 25mg (titrated to 75mg daily) three times daily over four weeks ( Am J Psychiatry 2008; 165:1033‐9). Two patients in the xanomeline group and three patients in the placebo group stopped treatment due to lack of efficacy. Compared with placebo, xanomeline improved scores for overall symptom severity and positive and negative symptoms, with improvements in learning and memory (but not attention or information processing). Xano‐meline was associated with nau‐sea, vomiting and gastrointestinal distress. Noting that many patients with schizophrenia smoke heavily, US investigators report a Phase II trial of the nicotinic agonist 3‐(2,4‐dimethoxybenzylidene) anabeisine (DMXB‐A) ( Am J Psychiatry 2008; 165:1040‐7) in 31 patients with schizophrenia. This agent has already been shown to improve cognitive function in short‐term use. In this study, however, its effects on tests of cognitive function were indistinguishable from placebo. Nonetheless, DMXB‐A was associated with improvements in scores of negative symptoms. Given that participants had continued to take their antipsychotic therapy during the study, this suggests a potential role for DMXB‐A in treating resistant symptoms. Adverse effects included tremor and nausea. Oestrogen for schizophrenia? Transdermal oestrogen is a useful adjunct in the treatment of schizo‐phrenia in women, say Australian investigators ( Arch Gen Psychiatry 2008;65:955‐60). They randomised 102 women to placebo or transdermal oestradiol 100µg daily while continuing their antipsychotic medication. Over one month, oestrogen therapy was associated with signifiant improvements in PANSS positive symptom score and scores of general psycho‐pathological symptoms and positive symptoms, but not negative symptoms compared with antipsy‐chotic medication alone. Two patients discontinued the patch due to menstrual bleeding. Aripiprazole helps weight loss Patients who gain weight during treatment with an atypical anti‐psychotic may benefit from switching to – or adding – aripiprazole, according to a study from The Netherlands ( Acta Psychiatr Scand 2008;118:246‐50). This uncontrolled study followed a group of 53 patients with schizophrenia for one year. Their mean BMI was 31kg per m2; 81 per cent were treated with olanzapine, clozapine or risperidone. Aripiprazole was added to current treatment, with the intention of tailing this off. After one year, 55 per cent had taken aripiprazole for a year and of these, just over half took it as monotherapy. Mean weight loss with aripiprazole was 3.0kg with monotherapy and 4.4kg with combination therapy. The combination of clozapine plus aripiprazole was associated with a reduction of 28 per cent in the dose of clozapine (mean final dose 328mg daily). Multiple sclerosis Modelling natalizumab A health economic model of the risks and benefits of natalizumab suggests it is a cost‐effective treatment for relapsing‐remitting multiple sclerosis despite concerns about the risk of progressive multifocal leucoencephalopathy (PML) ( Neurology 2008;71:357‐64). Based on data from key clinical trials, the model compared natalizumab (68 per cent relative reduction in risk of relapse, 19 per cent relative reduction in progression and 27 per cent annual risk of adverse effects) with interferon beta‐1a (32, 13 and 40 per cent respectively). The risk of PML was assumed to be 1 per 1000 patients treated for 17.9 months. Over 20 years, an untreated (‘natural history’) cohort accumulated a total of 8.70 Quality‐adjusted Life Years (QALYs). Natalizumab was associated with an additional 0.80 QALYs and interferon beta‐1a with an additional 0.42 QALYs. A theoretical ‘perfect’ treatment accumulated an additional 1.89 QALYs. Most of the health gain from treatment derived from reducing relapses and the impact of PML was small: the authors estimated that the incidence would have to increase more than seven‐fold to reduce the health gain from natalizumab to below that of interferon beta‐1a. Cognition Fish oil as a cognition enhancer Supplementation with fish oil does not affect cognitive performance in older people with no evidence of impaired cognition ( Neurology 2008;71:430‐8). A total of 302 individuals (mean age 70 years) were randomised to placebo or low (400mg) or high (1.8g) doses of eicosapentaenoic acid/docosahexaenoic acid. After six months, performance across a range of cognitive function tests was not significantly changed in any group. Two subgroups did improve while taking fish oil: men and carriers of the APOE‐ϵ4 allele (both showing improvements in attention). Pain Duloxetine in fibromyalgia… A meta‐analysis of six three‐month randomised trials of duloxetine with a total of 1696 patients has found that it is as effective for fibromyalgia as it is for painful diabetic neu‐ropathy ( BMC Neurology 2008;8:29 doi:10.1186/1471‐2377‐8‐29). The number needed to treat for 50 per cent pain relief (NNT) for 60mg duloxetine versus placebo was 5.8 and for 120mg duloxetine versus placebo it was 5.7, with no differences between neuropathy and fibromyalgia. For all dosages of duloxetine (including 20mg daily), the number needed to harm for withdrawal due to adverse events (NNH) was 15. This was due to nau‐sea (NNH 6.3), somnolence (NNH 11), constipation (NNH 11) and reduced appetite (NNH 18). The authors attempted an indirect comparison of duloxetine with other antidepressants as treatment for painful diabetic neuropathy. They found that, even though other antidepressants are widely recommended in management guidelines, studies of their effects tended to be smaller and of poorer quality. Other meta‐analyses used global improvement as their endpoint, for which NNTs ranged from 1.1 to 3.2. …and peripheral neuropathic pain New data presented at the 12th World Congress on Pain in Glasgow, in August as a poster showed dulox‐etine maintained pain reduction in the treatment of diabetic peripheral neuropathic pain (DPNP) for more than six months. The open‐label study is the first to assess duloxe‐tine's efficacy in DPNP beyond three months, says Boehringer Ingelheim, which jointly develops and commer‐cialises duloxetine with Eli Lilly. The study enrolled 216 patients with DPNP who began eight weeks of treatment with 60mg of duloxe‐Diarytine once daily. Over this initial eight‐week period, 53 per cent (n=115) of enrolled patients experienced clinically significant improvement in pain reduction (defined as at least 30 per cent pain reduction) as measured by the Brief Pain Inventory (BPI) 24‐hour average pain rating. This group of responders was maintained on duloxetine 60mg (n=103) once daily for up to 26 weeks. Results at study end showed that the reduction in pain was maintained in 74.8 per cent (n=77) of the sustained responders with 60mg duloxetine over the full study period. ‘DPNP is a chronic, potentially disabling, condition requiring treatment over a long period of time,’ Vladimir Skljarevski, lead author of the study and a neurologist and medical fellow at Lilly Research Laboratories, said. ‘This study showed duloxetine reduced pain over a six‐month period, making this the longest data analysis of duloxetine for the treatment of DPNP.’ During the course of the eight‐week acute therapy and 26‐week maintenance therapy periods, the most common treatment‐emergent adverse events (those occurring in more than 5 per cent of patients) for those taking 60mg duloxetine were nausea, somnolence, hyper‐hydrosis, dry mouth, anorexia, asthenia, fatigue and headache. An estimated 246 million adults worldwide suffer from diabetes. By 2025, that number is expected to rise to 380 million, according to the International Diabetes Federation. An estimated 17.2 million to 49.2 million patients with diabetes have been diagnosed with DPNP, says Boehringer Ingelheim. Copyright © 2008 Wiley Interface Ltd