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Sleep disorders Safety of ramelteon There is great interest in the role of melatonin agonists as treatments for insomnia. Ramelteon is already available in the USA, where it is used to reduce sleep latency associated with primary insomnia. Licensing in Europe has been delayed after the European Medicines Agency questioned its efficacy. Two studies now report on the safety of ramelteon over one year. The first study enrolled 1213 adults taking ramelteon 16mg (18‐64 year age group) or 8mg (over‐65 years) and were considered compliant if they took it at least three nights per week ( J Clin Psychiatry 2009; pii:ej07m03834). In the younger group taking 16mg, 51 per cent discontinued treatment within six months and 62 per cent within 48 weeks; in the older group taking 8mg, the figures were 49 per cent and 58 per cent respectively. Reasons for discontinuation included adverse effects (12 per cent) and lack of efficacy (18 per cent in younger adults, 25 per cent in the over‐65s). There were few consistent effects on laboratory parameters with the exception of reductions in thyroxine in younger adults and testosterone in older men. The average duration of menses was increased by over one day after one month but at 12 months this difference decreased to 0.7 days. The commonest adverse events reported by participants were upper respiratory tract symptoms, headache, somnolence and diarrhoea but, as this was a non‐blinded uncontrolled study, the true risk of adverse effects is uncertain. Participants' sleep diaries recorded moderate improvement in symptoms and no marked latency effects on stopping treatment. The second study more closely monitored endocrine function in a group of 122 young adults taking ramelteon 16mg nightly or placebo for six months ( Human Psychopharmacology Clin Exp 2009;24:10311). Fewer participants taking ramelteon completed the study compared with placebo (25 vs 41). Compared with placebo, ramelteon was associated with significantly increased prolactin levels in women over the first four months; increases in prolactin at any time point were recorded in 38 per cent of women taking ramelteon and 11 per cent taking placebo. The mean increase in prolactin levels was considered small (4.9μg per litre) and there was no change in the duration of menses; prolactin levels were not raised in response to ramelteon in men. Ramelteon was not associated with consistent changes in thyroid hormones, oestradiol, FSH or LH, or cortisol or ACTH. Sleepiness with dopamine agonists Dopamine agonists for the treatment of Parkinson's disease (PD) can cause daytime sleepiness. To distinguish these effects from the sleep disorders that may be associated with PD itself, French investigators compared the effects of pramipexole, bromocriptine and levodopa in 12 healthy male volunteers ( Br J Clin Pharmacol 2009;67: 333‐40). They found that neither levo‐dopa nor bromocriptine significantly affected sleep latency time but, consistent with its pharmacokinetics, pramipexole was associated with reduced sleep latency after 3.5 and 5.5 hours compared with placebo. Pramipexole also significantly increased sleep duration. No subject was aware of increased sleepiness after taking pramipexole. This, the authors suggest, reflects a dissociation between sleep attacks and the normal warning signs.Antipsychotics Treating severe agitation in adolescents There is some evidence that intramuscular ziprasidone may be effective as a treatment for severe acute agitation requiring physical restraint in adolescents admitted as a psychiatric emergency but little is known about how it compares with older antipsychotics. US investigators have reported a retrospective analysis of 28 episodes of treatment with IM ziprasidone 10mg or 20mg and 24 episodes treated with haloperidol plus lorazepam ( Child Adolesc Psychiatry Mental Health 2009;3:9 doi:10.1186/1753‐2000‐3‐9). Overall, there were no differences between the treatments in the duration of required physical restraint (ziprasidone 55 minutes, haloperidol/lorazepam 65 minutes) or in the use of additional drugs. The drugs appeared to be equally well tolerated. The authors suggest that monotherapy with ziprasidone may be preferable in this setting because it may be associated with a lower risk of extrapyramidal effects, though they acknowledge their study could not confirm this. Predictors of weight gain Researchers from Germany have suggested that parental body mass index (BMI) is a risk factor for weight gain with atypical antipsychotics ( J Psychiatric Res 2009; 43:620‐6). Their retrospective study of records for 65 patients treated with clozapine, olanzapine or risperidone found that the proportion who were overweight or obese increased from 15 per cent before treatment to 69 per cent after a mean of seven years. They confirmed that pretreatment BMI, female gender and non‐smoking status all predicted weight gain but they also found a strong statistical association with parental overweight or obesity, as assessed in a face‐to‐face interview. They suggest that parental BMI should therefore be included in the factors determining treatment decisions.Neuropathic pain Duloxetine vs AEDs Duloxetine is comparable with the antiepileptic drugs (AEDs) gabapentin and pregabalin for the treatment of pain due to peripheral diabetic neuropathy, according to a meta‐analysis of 11 placebo‐controlled trials ( BMC Neurology 2009;9:6 doi:10.1186/1471‐2377‐96). All three drugs were superior to placebo for all efficacy endpoints and numbers needed to treat (NNTs) for a 50 per cent reduction in pain score were five for duloxetine and pregabalin (not reported for gabapentin). All were associated with dizziness and somnolence and duloxetine also with headache and nausea. Numbers needed to harm (NNHs) for discontinuation due to adverse effects compared with placebo were 11 for duloxetine, 19 for pregabalin and 63 for gabapentin. Patient ratings of efficacy slightly favoured pregabalin over duloxetine, but pregabalin was associated with a higher incidence of dizziness. Botulinum toxin type A effective A small double‐blind trial has shown that botulinum toxin type A (BTX A ) reduces neuropathic pain in patients with diabetic neuropathy ( Neurology 2009;72:e‐pub ahead of print). A total of 20 patients with neuropathic pain affecting both feet and of at least three years' duration were randomised to receive a single injection of BTX A or saline (placebo) in both feet, with a crossover to the other intervention after 12 weeks. There were 18 patients completing the trial (two did not do so for reasons unrelated to treatment). The mean visual analogue pain score (VAS) was 6.4 at baseline. After 12 weeks, this decreased by 2.53 after BTX A (with improvement evident after one week and most of the total reduction achieved after four weeks) and 0.53 with placebo. VAS was reduced by at least 3 points in 44 per cent of patients with BTX A and none after placebo. BTX A did not significantly improve sleep quality or quality of life compared with placebo at the study endpoint.Epilepsy Weight loss with zonisamide Weight loss is a recognised adverse effect of zonisamide. German specialists recently quantified the problem with a retrospective review of records for 103 patients with epilepsy treated with adjunctive zonisamide over a period of up to 26 months ( Acta Neurol Scand 2009;119:233‐8). During this period, zonisamide was discontinued in 45 per cent of patients after a mean of 7.5 months, leaving a mean duration of treatment of 13 months in the remainder. At baseline, median weight was 78.6kg; mean weight reduction after zonisamide treatment was 3.7 per cent and the proportion of patients classed as overweight decreased from 55 to 44 per cent. Overall, 35 per cent of patients lost at least 5 per cent of baseline body weight and 13 per cent gained weight. Weight loss was greatest in those who were overweight before treatment and was reversible; there was no correlation with dose of zonisamide, duration of treatment or concurrent medication.Multiple sclerosis Response to glatiramer Research published earlier this year showed that half of patients with multiple sclerosis (MS) responded to treatment with interferon beta‐1b monthly when assessed by monthly MRI scans ( Neurology 2009;66:39‐43). A second study has now compared interferon beta‐1b with glatiramer acetate using the same technique ( Neurology 2009; epub ahead of print). A total of 75 patients with relapsing‐remitting MS or syndrome suggestive of MS were randomised to treatment with glatiramer acetate or interferon beta‐1b. During the first year, the median numbers of combined active lesions per patient per scan were similar (glatiramer acetate, 0.58; interferon beta‐1b, 0.63). Only 21 per cent of patients receiving either treatment remained free of new lesions over two years and there was no difference in exacerbation rates. However, monthly MRI revealed a much higher level of subclinical disease activity (1462 new lesions) than relapse rates suggested (48 relapses). The authors say their protocol optimised the imaging sensitivity of MRI and caution against comparisons with studies using different methodology. Copyright © 2009 Wiley Interface Ltd