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Atomoxetine dose influences rate of adverse effects An analysis of five randomised trials involving a total of 447 children confirms that slow dose titration reduces the incidence of adverse effects of atomoxetine ( J Am Acad Child Adolesc Psychiatry 2007; 46:566‐72). Two initiation regimens were evaluated: once‐daily dosing to achieve the target dose of 1.2mg per kg per day over three days or twice‐daily dosing to reach the target dose over two weeks. During the first two weeks, fast titration was associated with a higher rate of adverse effects, including decreased appetite (14 versus 8 per cent) and somnolence (14 versus 4 per cent); by contrast, slow titration was associated with a higher frequency of headache (7 versus 17 per cent). Buprenorphine versus methadone for heroin dependence Buprenorphine/naloxone may be safer than methadone as maintenance therapy for heroin dependence – but is it as effective? Swedish specialists compared the two treatments in a maintenance programme for 96 people self‐referred with heroin dependence (mean use 10 years) ( Am J Psychiatry 2007;164:797‐803). The dose of buprenorphine was stepped up to a maximum of 32mg daily; if higher doses were needed, patients were switched to methadone, with further dose escalation if required. After a 24‐day induction phase and six months' maintenance treatment, there was no difference between retention rates (78 per cent), though 20 of 48 patients randomised to buprenorphine switched to methadone. Eighty per cent of urine samples were free of illicit drugs, with no difference between treatments, and there were no differences in addiction severity scores at the end of the study period. Adverse reaction rates were similar. Differences in brain metabolism in antidepressant and CBT responders In people with depression, the response to venlafaxine or cognitive behavioural therapy (CBT) is associated with similar changes in brain glucose metabolism – but there are differences too, say Canadian researchers ( Am J Psychiatry 2007;164:778‐88). Using PET scans, they showed that in 24 patients with major depressive disorder the response to either therapy was associated with a reduction in glucose metabolism in the orbitofrontal and left medial prefrontal cortex, together with an increase in glucose metabolism in the right occipital‐temporal cortex. However, CBT was uniquely associated with increases in glucose metabolism in Brodmann's area 32, a decrease in the thalamus, a decrease in Brodmann's area 29 (increased with venlafaxine) and an increase in Brodmann's areas 20 and 21 (decreased with venlafaxine). The authors suggest further investigation of pretreatment differences in brain glucose metabolism may help to predict which is the more effective treatment. Aromatherapy for agitation Lavender inhalation reduces agitation in patients with dementia, say Hong Kong investigators ( Int J Geriatr Psychiatry 2007;22:405‐10). Their three plus three week crossover trial in 70 patients found that lavender inhalation significantly reduced scores of agitation compared with baseline whereas there was no change with placebo (sunflower oil inhalation). There were also improvements in aggressive behaviour, irritability and dysphoria, and patients with vascular dementia did rather better than those with Alzheimer's disease. No adverse effects were reported. Depression increases non‐adherence risk People who report being depressed are more likely to avoid taking prescribed medication on grounds of cost, according to a US study ( Arch Gen Psychiatry 2007;64:602‐8). Interviews with 13 835 elderly people and people with disabilities using the US Medicare programme revealed that 13 and 44 per cent respectively reported being depressed in the previous year. Of those with disabilities, 38 per cent of those reporting depression and 22 per cent of those not doing so said they had not taken their medicine as prescribed because of cost (missed or reduced doses, or did not have a prescription dispensed). Among the elderly, the corresponding figures were 19 and 12 per cent. Adjusting for risk factors, depression increased the risk of cost‐related non‐adherence by 70 per cent in people with disabilities and 40 per cent among the elderly. Venlafaxine metabolite on the horizon? As the patent life of venlafaxine nears its end, researchers are establishing the efficacy of its active metabolite desvenlafaxine ( J Clin Psychiatry 2007;68:677‐88). An eight‐week dose‐ranging study in 461 adults with depression found that desvenlafaxine 100‐400mg daily was associated with response rates of 45‐51 per cent compared with 35 per cent with placebo. Remission rates were 28‐32 per cent and 19 per cent respectively. Adverse events were similar in nature to those of the parent compound. Gabapentin for dysautonomia Dysautonomia (‘autonomic storms’) associated with traumatic brain injury causes significant morbidity and is difficult to manage. Neurologists from Australia and Denmark now believe that gabapentin may offer a new treatment option ( J Neurol Neurosurg Psychiatry 2007;78:539‐41). They report six patients with dysautonomia following severe brain injury in whom gabapentin (300‐600mg two to three times daily) reduced paroxysms, spasticity and posturing. Conventional treatment (analgesia, intrathecal baclofen, clonidine, morphine, sufentanil, bromocriptine, metoprolol) was partially successful. In one patient, treatment with sodium valproate was ineffective. The authors say that these results cannot be explained solely by gabapentin's effect on neuropathic pain. Generic versus branded antiepileptic drugs The thorny issue of generic substitution of antiepileptic drugs has been raised again, this time by neurologists from the UK and The Netherlands ( Lancet Neurology 2007;6:465‐8). They argue that, although there are large potential savings from switching to a generic drug, it is still unclear whether they outweigh the risks to patients. European rules mean that the equivalence of generic and branded drugs lies within the range 80‐125 per cent. In the treatment of epilepsy, where small changes in dose may be needed to balance seizure control and adverse effects, this range may allow clinically significant differences. Generic substitution should be tested in clinical trials before being accepted into clinical practice, they conclude. Psychiatrists' writing failing GPs Discharge letters and written advice about patients with dementia from old‐age psychiatrists to GPs falls below acceptable standards, a Yorkshire study has shown ( Psychiatric Bull 2007;31:176‐8). A 2002 audit found that psychiatrists in the East Riding communicated poorly to their colleagues in primary care about their use of antipsychotics in patients with dementia. A repeat audit in 2005, after the Royal College of Psychiatrists published management guidance on the use of antipsychotics in patients with dementia, found the situation had deteriorated. Over two‐thirds of discharge letters did not state the indication for treatment, 91 per cent failed to mention the recommended three‐monthly review and 91 per cent did not provide advice on the duration of treatment or the need for review. Coincidentally, the audit also revealed that benzodiazepines had been prescribed without appropriate advice to GPs about reviewing treatment. Improving gait in Parkinson's disease Freezing, small steps and instability in patients with advanced Parkinson's disease are difficult to treat. There is evidence that both dopaminergic and adrenergic function may be implicated, prompting French neurologists to test the efficacy of methylphenidate ( J Neurol Neursurg Psychiatry 2007;78:470‐5). Assessment of 17 patients on video after three months' treatment with methylphenidate 1mg per kg three times daily showed, in the absence of levodopa, a reduction in postural instability and freezing, improved walking and reduced sleepiness and symptom scores. The levodopa‐induced improvement was also greater after methylphenidate treatment. No cardiovascular adverse effects were found; adverse effects included dry mouth, anorexia and weight loss. NSAIDs do not prevent Alzheimer's disease NSAIDs are not effective as primary prevention of Alzheimer's disease (AD) – in the short‐term, at least ( Neurology 2007;68:published early online). The AD Anti‐inflammatory Prevention Trial (ADAPT) compared naproxen (a non‐COX selective NSAID), celecoxib (a COX‐2 selective NSAID) and placebo in 2528 patients aged over 70 years. The trial was stopped because of concerns about possible adverse cardiovascular effects but there was also a non‐significant trend for an increased incidence of AD among patients taking either NSAID compared with placebo for up to four years. Conversely, the authors point out that ADAPT does not provide sufficient evidence that people at risk of AD should avoid NSAIDs. Transdermal rivastigmine for Alzheimer's disease A rivastigmine patch is as effective as the conventional capsules in patients with mild‐to‐moderate AD, investigators say, and what is more, caregivers prefer them ( Int J Geriatr Psychiatry 2007;22:456‐67 and 485‐91). Their six‐month trial in 1195 patients showed that a 10cm 2 rivastigmine patch (delivering 9.5mg every 24 hours) was as effective as 12mg daily given as capsules, and a 20cm 2 patch was significantly more effective, in improving the ADAS‐Cog score. The patch was better tolerated, with a much lower incidence of nausea (7 versus 23 per cent) and vomiting (6 versus 17 per cent) than oral administration, though skin irritation or pruritus was found in 7‐8 per cent of patients using the patch. Similar proportions of patients completed the study (78‐80 per cent with rivastigmine, 88 per cent with placebo). Analysis of caregiver preferences showed that 72 per cent preferred the patch over capsules because of ease of use and they expressed greater overall satisfaction with treatment and less interference with daily life. Subtle effects of modafinil in schizophrenia? The lack of satisfactory treatment for negative symptoms of schizophrenia prompted psychiatrists in California to try modafinil, a treatment for excessive sleepiness ( J Clin Psychiatry 2007;68:705‐10). In an eight‐week trial in 20 patients with schizophrenia with prominent negative symptoms despite antipsychotic therapy, they found that negative and total symptom scores decreased modestly with both placebo and modafinil 100‐200mg daily. However, modafinil was associated with a higher rate of global improvement (Clinical Global Impressions Inventory, CGI‐I) and a higher mean final CGI‐I score. Modafinil was associated with greater reductions in day and night‐time sleep and weight loss than placebo, but the differences were not statistically significant. Steroids do not relieve medication overuse headache One hundred adults with headache meeting International Headache Society criteria for medication over‐use headache were admitted to hospital to stop their analgesic use ( Neurology 2007;69:published early online). They were then randomised to receive placebo or prednisone 60mg, 40mg and 20mg for two days at each dose. During the six‐day dosing period and the 28‐day study period, there was no difference between the groups in headache severity. There were also no differences in concurrent use of antiemetics or days without headache, and no differences in response between sub‐groups with migraine, tension type headache or mixed type headache. Risperidone improves ADHD aggression, say parents US researchers report differences in parental and teacher assessments of the efficacy of risperidone on aggression in children with ADHD ( J Am Acad Child Adolesc Psychiatry 2007;46:558‐65). Twenty‐five children with significant aggressive behaviour despite treatment with a psychostimulant were randomised to placebo or augmentation with risperidone 0.5‐2mg daily. After four weeks, parental assessments suggested a greater than 30 per cent reduction in scores for aggressive behaviour in all children taking risperidone and in 77 per cent of those assigned to placebo, a significant difference. By contrast, teachers detected no differences and reported a response rate of only 27 per cent with risperidone. There were no significant differences in clinical global assessments. Now pregabalin for restless legs syndrome A chance observation that patients taking pregabalin for neuropathic pain also experienced improvement in restless legs syndrome (RLS) led specialists in Germany to test the drug in more patients ( Acta Neurol Scand 2007;115:347‐50). They report uncontrolled observations in a total of 19 patients with RLS secondary to neuropathy or idiopathic RLS. Sixteen patients reported satisfactory or good symptom relief and continued treatment with pregabalin (mean dose 305mg daily); five patients required additional medication. Two patients discontinued pregabalin because of fatigue or loss of efficacy and one after developing a rash. STAR*D: social factors influence CBT acceptance Two new analyses from the US Sequenced Treatment Alternatives to relieve Depression (STAR*D) study show that sociodemographic characteristics are important factors associated with accepting cognitive behavioural therapy (CBT) when initial drug treatment fails ( Am J Psychiatry 2007;164:753‐60). CBT was one option for patients who did not respond to a 12‐week course of citalopram, either as a switch from or an addition to their drug treatment. Overall, 26 per cent of patients accepted CBT as part of a switch or augmentation strategy. Patients willing to accept CBT were more likely to be better educated, have a family history of depression or bipolar disorder, or a longer duration of initial treatment. They were less likely to accept a switch to CBT, rather than augmenting continuing use of citalopram, if they had experienced fewer adverse effects, if citalopram was more effective or they had recurrent depression. A second analysis shows that efficacy outcomes after augmenting citalopram therapy, regardless of patients' chosen care pathway, are not significantly different ( Am J Psychiatry 2007;164:739‐52). Remission rates were 23‐31 per cent with CBT plus citalopram and 33 per cent with two antidepressants; response rates were 35 and 28 per cent respectively. The response to CBT augmentation was slower than with drug treatment whereas adverse effects were more frequent and more severe with drug treatment. Adverse effects accounted for withdrawal from treatment in 19 per cent of patients who opted for drug augmentation and 9 per cent in those who chose CBT augmentation. Extrastriatal D2 occupancy causes dysphoria Occupancy of striatal dopamine D2 receptors is believed to be one mechanism by which antipsychotics exert their therapeutic effects, and also their adverse effects on motor function. US investigators have now shown that D2 occupancy else‐where in the brain contributes to subjective adverse effects ( Am J Psychiatry 2007;164:630‐7). Using PET scans, they measured striatal and non‐striatal D2 occupancy in twelve patients with recent onset schizophrenia after administration of olanzapine or risperidone. After two weeks' continuous treatment, D2 occupancy was 50‐91 per cent in the striatum and 4‐95 per cent in non‐striatal regions. Scores of subjective well‐being correlated with both striatal and temporal occupancy, but not with frontal or thalamic occupancy. In particular, there were statistically significant correlations between striatal blockade and mental functioning, and temporal blockade and emotional regulation. Olanzapine and risperidone had similar effects. The authors suggest that the extent of non‐striatal D2 occupancy may determine subjective experience of treatment, and may even account for early discontinuation of treatment. Copyright © 2007 Wiley Interface Ltd