Digest

Paying for patient adherence It is unusual for small studies to have much of an impact but an East London team made the national news after paying non‐adherent patients to have their depot injections ( Psychiatric Bull 2007;31:4‐7). They trialled the effectiveness of paying five non‐adherent assertive outreach patients £5 to £15 as an incentive to accept their depot injections. The patients had been admitted for at least 50 days in the previous two years as a result of non‐adherence. One declined the offer; of those who agreed to the scheme, three were not subsequently admitted and the fourth had already been readmitted but his adherence improved. All those within the payment scheme were still living independently and experienced fewer problems with neighbours and the police. There has been no attempt to discontinue payments and other patients have not demanded similar treatment. Seventy outreach teams responded to a questionnaire about the issues raised by the scheme. None had used payment as an incentive for adherence. Three‐ quarters had objections to the scheme, stating it was unethical (42 per cent), coercive (8 per cent) or would negatively affect the therapeutic relationship (9 per cent). Coenzyme Q10 and GPI‐1485 for PD Among the compounds identified by the US National Institute for Neurological Disorders as candidates for the treatment of Parkinson's disease (PD) are the cofactor coenzyme Q10 and the immunophilin ligand GPI‐1485. With no pharmaceutical company supporting these compounds, neurologists have to decide whether there is sufficient evidence to justify further research. They have now reported a ‘futility study’ designed to test the potential value of Phase III trials ( Neurology 2007;68:20‐8). The study was essentially a small (n=213) randomised double‐ blind placebo‐controlled trial of both agents. Statistical analysis showed that, compared with historical controls from the DATATOP study, both coenzyme Q10 and GPI‐1485 had sufficient effectiveness to warrant further study. However, their benefits were modest and, when compared with controls taken from contemporary clinical practice, they were actually not effective. Despite this partial endorsement, a large trial of coenzyme Q10 has already been planned. Selegiline withdrawal and BP in patients with PD Selegiline can cause orthostatic hypotension in patients with PD –but how does withdrawing treatment affect blood pressure in patients with advanced disease? Neurologists in Finland measured orthostatic changes in 14 patients before and after withdrawal of selegiline ( Acta Neurol Scand 2007;115:104‐8). During treatment with selegiline, orthostatic hypotension occurred in four patients (one symptomatic) during the ‘on’ phase and in six (two symptomatic) in the ‘off’ phase. There was a modest improvement after discontinuation: the corresponding figures were three (none symptomatic) in the ‘on’ phase and five (three symptomatic) in the ‘off’ phase. Smoking cessation in patients with psychoses Nicotine replacement therapy plus intensive motivational support does help some patients with psychoses to reduce smoking –but not to stop, according to an Australian study ( Am J Psychiatry 2006;163:1934‐42). They randomised 298 patients with schizophrenia who were regular smokers to a programme of eight sessions of motivational interviewing, cognitive behavioural therapy and nicotine replacement therapy, or routine care from the GP and mental health team. There were no overall significant differences between the groups in continuous abstinence rates or point‐prevalence abstinence at 3, 6 and 12 months. However, significantly more session participants reduced consumption by at least 50 per cent (31 vs 18 per cent) at 12 months and there was a trend for higher abstinence and rates of smoking reduction among those who attended more sessions (about half attended all sessions). Atypical antipsychotics not as cost effective A first‐generation antipsychotic is so cheap that treatment of schizophrenia with an atypical agent is not cost effective by comparison, say US investigators ( Am J Psychiatry 2006;163:2080‐9). Their economic analysis of 1493 patients in the CATIE study found no significant differences in efficacy or quality‐of‐life ratings between perphenazine and the atypicals olanzapine, quetiapine, risperidone and ziprasidone. Total health care costs for perphenazine were 20‐30 per cent lower than for the atypicals, due to its lower purchase cost. The difference persisted even when subsequent therapy switches to other antipsychotics were excluded. The most telling statistic from the CATIE study remains the fact that dropout rates were very high: only 17‐36 per cent of patients completed 18 months' treatment with an atypical and only 25 per cent did so with perphenazine. Metformin for weight gain with atypicals in young people Weight gain associated with the use of atypical antipsychotics in children and adolescents is a potentially alarming problem, given the possible duration of treatment they face. The mechanism underlying this problem is still uncertain but insulin resistance and impaired insulin secretion have been identified as likely factors. US psychiatrists therefore tested metformin, an oral hypoglycaemic agent that acts by reducing hepatic glucose production and increasing peripheral insulin sensitivity ( Am J Psychiatry 2006;163:2072‐9). Thirty‐eight children aged 10‐17 years who experienced an average weight gain of 10kg during treatment with olanzapine, risperidone or quetiapine (plus multiple psychotropic medication) were randomised to placebo or metformin 850mg twice daily, both in combination with dietary counselling. After 16 weeks, weight remained stable in those taking metformin but the others gained a further 4kg. Body mass index decreased by 0.4 and increased by 1.1 in metformin and placebo groups respectively. Insulin resistance was slightly reduced with metformin but increased in the placebo group. Metformin was not associated with adverse effects or a worsening of psychiatric symptoms. The authors suggest that adjunctive metformin should be considered at the start of treatment with an atypical antipsychotic. Low‐dose amitriptyline for clozapine‐associated sialorrhoea A case study from India suggests that low‐dose amitriptyline may reduce sialorrhoea associated with clozapine ( Br J Clin Pharmacol 2006;63:128‐9). The 35‐year‐old man developed nocturnal enuresis and sialorrhoea after the dose of clozapine was titrated to 400mg daily over four weeks. Amitriptyline 25mg at night was prescribed to control enuresis but it also reduced nocturnal and abolished daytime sialorrhoea. The authors note that amitriptyline has previously been shown to reduce clozapine‐induced sialorrhoea, but only at a dose of 87‐100mg daily. New roles for zonisamide? Two studies have reported possible new roles for the antiepileptic zonisamide. In the USA, a 16‐week placebo‐controlled trial of zonisamide for binge eating in 60 obese patients ( J Clin Psychiatry 2006;67:1897‐906) showed that, compared with placebo, it reduced body weight (9kg vs 1kg), obsessive‐compulsive behaviour and dis‐ inhibited eating. By intention‐ to‐treat (ITT) analysis, zonisamide did not significantly reduce binge episodes by the end of the study. Excluding patients who had discontinued treatment (zonisamide, 60 per cent; placebo, 40 per cent), bingeing stopped in 92 per cent of patients taking zonisamide compared with 44 per cent assigned to placebo. • Neurologists in Japan have reported a 12‐week dose‐ranging study of zonisamide 25, 50 or 100mg daily as an adjunct in 347 patients with PD with an insufficient response to levodopa (approximately 350mg daily) ( Neurology 2007;68:45‐50). Compared with placebo, the two lower doses of zonisamide significantly reduced the UPDRS score, with response rates (at least 30 per cent reduction) of 35 and 39 per cent with 25mg and 50mg respectively vs 22 per cent with placebo. The two higher doses significantly decreased total daily ‘off’ time and the 50mg dose was associated with a reduction in disabling dyskinesias. Adverse events were increased only with zonisamide 100mg daily. Guanfacine fails in post‐ traumatic stress disorder The alpha‐2 agonist guanfacine does not improve the symptoms of post‐traumatic stress disorder (PTSD) ( Am J Psychiatry 2006; 163:2186‐8). US psychiatrists say that, despite enthusiasm for treating PTSD with alpha agonists, there is no trial evidence to support their use. Given the apparent importance of adrenergic systems in PTSD symptoms, they speculated that guanfacine might be helpful. Their eight‐week placebo‐controlled trial showed the opposite. At a mean dose of 2.4mg daily, guanfacine had no significant effect on symptoms, sleep quality, quality of life or mood disturbances in patients with PTSD. Dry mouth, somnolence and lightheadedness were common adverse effects. Treating amfetamine dependence Amfetamine is the illegal drug most frequently injected in Finland, prompting specialists in Helsinki to explore pharmacological options for management. Although psychological and educational strategies do help, they say, there is little to show they reduce drug use and there is no specific drug treatment for amfetamine dependence. They intended to compare aripiprazole 15mg daily and modified‐ release methylphenidate up to 54mg daily in a 20‐week placebo‐ controlled trial in 210 patients but an interim analysis of results from 53 patients led to the early termination of the trial ( Am J Psychiatry 2007;164:160‐2). The primary endpoint was the proportion of patients with a urine sample positive for amfetamine during the treatment period. After adjustment for age, aripiprazole treatment was associated with a higher frequency of positive samples than placebo (odds ratio, OR, 3.77; CI 95% 1.55‐9.18) whereas methylphenidate halved the frequency (OR 0.46; CI 95%0.26‐0.81). In those taking methylphenidate, amfetamine use began to decrease after 10 weeks but became statistically significant only after 18 weeks. The authors add that it is useful to supply methylphenidate on a daily basis and as a modified‐ release formulation to minimise its abuse potential. Co‐therapy for acute bipolar mania Combining a mood stabiliser and an antipsychotic as acute treatment for bipolar mania is more effective than monotherapy with a mood stabiliser –but not for all patients, according to a new meta‐analysis from the UK ( Acta Psychiatrica Scand 2007;115:12‐20). The analysis included eight randomised trials involving a total of 1124 patients treated with haloperidol, olanzapine, risperidone or quetiapine in combination with lithium, valproate semisodium or carbamazepine. Overall, combined therapy was more effective (defined by the Young Mania Rating Scale, YMRS, score) than mood stabiliser monotherapy in patients who had not responded to a mood stabiliser alone. Response rates (50 per cent reduction in YMRS score) were 53 per cent higher for combined therapy overall and 66 per cent higher for quetiapine. Only combined therapy with risperidone was associated with significantly fewer withdrawals for any reason than monotherapy. Only olanzapine was associated with significantly fewer withdrawals due to lack of efficacy but withdrawals due to adverse events were six times greater than with monotherapy. All atypicals were associated with weight gain, with olanzapine having the greatest effect. The authors say the available trials are methodologically flawed but their findings are broadly consistent. Phenylbutyrate for spinal muscular atrophy A pilot study by Italian neurologists showed that phenylbutyrate increased muscle function in patients with spinal muscular atrophy. Disappointingly, this promise has not been fulfilled in a larger Phase II study ( Neurology 2007;68:51‐5). They randomised 107 children aged 2‐12 years to placebo or phenylbutyrate 500mg per kg daily in an intermittent regimen (alternate weeks on and off medication). After 13 weeks, functional score improved in both groups but there was no significant difference between them; there were also no differences in upper limb myometric assessments or forced vital capacity. Although compliance was generally good, phenylbutyrate was associated with bad taste, nausea and vomiting in several children. Oestrogens, stroke and migraine Paradoxically, premenopausal oestrogens appear to protect women against stroke whereas HRT is believed to increase the risk of ischaemic stroke, say Spanish epidemiologists. In a case‐control study ( Neurology 2007;68:33‐8), they compared exposure to endogenous and prescribed oestrogens in 430 cases of non‐embolic ischaemic stroke and 905 controls matched for age and area of residence. Use of HRT or oral contraception was not associated with a significantly increased stroke risk, though numbers of cases were low. After adjusting for cardiovascular risk, lifetime exposure to endogenous oestrogens of less than 34 years, and age at menarche of less than 13 years, were each associated with a 50 per cent increased risk. By contrast, no significant increased risk was associated with older age at menopause (>53 years). The authors suggest that longer exposure to endogenous oestrogen is protective provided it does not start too early in life. • Prophylaxis of menstrual migraine with cyclical estrogen does reduce attack frequency, say UK investigators –but subsequently increases attacks ( Neurology 2006;67:2159‐63). Using a fertility monitor to determine the time of ovulation, 35 women applied estradiol 1.5mg daily as a gel (to their arms or thighs) from day ten of the cycle (nine days after the LH surge) until the second day of menstruation. During treatment, the number of days affected by migraine decreased by 22 per cent overall compared with placebo; attacks were milder and less often associated with nausea. However, in the five days of the cycle following gel application, the risk of an attack was 40 per cent greater than with placebo; in some women, these oestrogen‐withdrawal attacks were more likely to be moderate or severe. 1 in 100 Campaign 2007 calender launched A 2007 calendar showcasing a range of work from artists at the Sheffield Care Trust has been launched in the UK. The calendar has been produced by Janssen‐Cilag as part of their ongoing ‘1 in 100’ Campaign, which raises awareness of schizophrenia and provides information and support to those people living with the condition. To obtain a calendar, healthcare professionals should speak to their local Janssen‐ Cilag sales representative. Copyright © 2007 Wiley Interface Ltd