Digest

Abstract Paliperidone licensed for schizophrenia Paliperidone prolonged release tablets (brand named Invega) have been launched by Janssen‐Cilag for the treatment of schizophrenia. The atypical antipsychotic can be given once a day: it is formulated using OROS technology. Janssen says the drug is not extensively metabolised by the liver and is excreted largely unchanged through the kidneys. As a result, it is not anticipated to have clinically significant hepaticrelated drug‐drug or drug‐disease interactions, according to the company. Janssen‐Cilag says the drug's clinical development programme involved over 1200 patients in 23 countries as part of three pivotal studies (Marder S, et al . Poster presented at APA May 2006; Toronto, Canada, 20–25; Davidson M, et al . Schizophrenia Res 2007:93;117–30; Kane J, et al . Schizophrenia Res 2006:90;147–61). It is the first treatment for schizophrenia to receive authorisation for inclusion of social functioning (PSP scale) in its product labelling and has demonstrated a significant improvement in personal and social performances in people with schizophrenia. Personal and social functioning is recognised as a key treatment goal by physicians and a measure of efficacy and tolerability, says Janssen. In trials paliperidone has generally been well tolerated and adverse events were similar to placebo at the recommended dose (6mg). Changes in lipid levels, including total cholesterol, LDL‐cholesterol, HDL‐cholesterol and triglycerides, were low and comparable with placebo across the dose range. In clinical trials, the most frequently observed side‐effects for all studied doses included headache, tachycardia, akathisia, sinus tachycardia, extrapyramidal disorder, somnolence, dizziness, sedation, tremor, hypertonia, dystonia, orthostatic hypotension and dry mouth. Discontinuation rates due to adverse events for all dose groups were 6 per cent for placebo, and for paliperidone: 2 per cent for 3mg, 7 per cent for 6mg, 4 per cent for 9mg, 5 per cent for 12mg. Specific treatment‐emergent adverse events (TEAEs) associated with paliperidone, which occurred at a rate of greater than or equal to 5 per cent and twice that of placebo in any of the dosing arms, were tachycardia, hyperkinesia and extrapyramidal disorders. In some patients, although an elevation in mean serum prolactin was apparent, the incidence of potentially prolactin‐related adverse events were low. Antidepressants for Parkinson's disease psychosis Some patients with Parkinson's disease who develop psychosis may respond to treatment with an antidepressant, US neurologists have found ( Int J Geriatr Psychiatry 2007;22:601–4). They report a series of 10 patients with Parkinson's disease who presented with psychosis of varying severity; in five, symptoms were partially or completely refractory to treatment with an antipsychotic and a further three had only mild visual hallucinations. After treatment with citalopram or venlafaxine, symptom scores (British Psychiatric Rating Scale) improved significantly; remission was achieved in five patients and two no longer needed nursing home care. Psychosis had been preceded by anxiety or depression in seven patients; depression scores also improved in those whose psychosis responded to treatment. Antidepressants do not improve post‐MI outcomes About one‐fifth of patients who have a myocardial infarction (MI) subsequently suffer depression, a development that doubles their risk of further cardiac events. What little is known about treating post‐MI depression suggests it does not improve cardiac outcomes. Now, investigators in The Netherlands have sought to provide more definitive evidence ( Br J Psychiatry 2007;190:460–6). Of 2177 patients admitted with MI who underwent screening, 17 per cent met the diagnostic criteria for depression; of these, 331 were randomised to usual care or additional treatment with mirtazepine. All patients with an inadequate response after eight weeks were offered non‐blinded treatment with citalopram then, if needed, tailored treatment. After 18 months there was no difference between the groups in the prevalence of depression (about 30 per cent), disability or quality of life. The rate of cardiac events was also similar in both groups (13–14 per cent) and in the subgroups who did or did not ultimately receive treatment with an antidepressant, and according to severity or recurrence of depression. The authors conclude that an active treatment strategy for depression did not improve outcomes compared with usual care post‐MI. However, they acknowledge that they did not manage to reduce depression and therefore cannot refute the possibility that doing so may improve cardiac outcomes. Statins users have more post‐stroke collaterals Statins have been shown to increase the development of collateral vessels in patients with MI, prompting a US team to determine whether the same is true in patients with acute stroke ( Neurology 2007;68:2129–31). Their retrospective analysis compared collateralisation of the cervicocephalic arterial tree in patients admitted with acute stroke over a four‐year period. Multivariate analysis demonstrated that a history of hypertension and high systolic pressure on admission were associated with less collateralisation, and statin use and high HDL‐cholesterol levels were associated with greater collateralisation. Use of antithrombotic and antihypertensive medication did not affect the finding and statin use was not associated with reduced stroke severity on admission. Nonadherence with antidepressants and antipsychotics Non‐adherence with prescribed antidepressants is common – but does it make any difference whether a psychiatrist or GP initiates the treatment? To find out, US researchers analysed early and six‐month adherence rates in 11 878 healthcare programme participants prescribed an antidepressant for the first time ( J Clin Psychiatry 2007;68:867–73). They found that 18 per cent did not get their first prescription dispensed; of the remainder, 43 per cent were subsequently non‐adherent (more than 52 days without treatment during the next six months). The odds of non‐adherence were reduced by 30 per cent for patients treated by a psychiatrist rather than a primary care physician. By contrast, treatment by another specialist was associated with increased odds of 40 per cent. Immediate non‐adherence was less likely with fluoxetine and sertraline than other antidepressants but fluoxetine and citalopram were associated with greater odds of non‐adherence after six months. Switching antidepressants also increased the likelihood of non‐adherence. Non‐adherence at six months was more likely among younger patients but there was no difference between patients treated by a psychiatrist or primary care physician. Treatment by multiple providers reduced the odds of non‐adherence at six months. In a second observational study, analysis of records for 6662 patients in Canada who were prescribed an atypical antipsychotic agent and were living in the community revealed that 33 per cent were not taking their treatment after one year ( J Clin Psychiatry 2007;68:818–25). Of those still having their medication dispensed at one year, 79 per cent were adherent, ie they had medication available for at least 80 per cent of the time. Persistence and adherence were associated with treatment with clozapine rather than olanzapine, higher intensity treatment and prior use of a typical antipsychotic. In the UK, analysis of the 2000 British Survey of National Psychiatric Morbidity of 634 participants taking oral psychotropic medication showed that 34 per cent did not completely follow prescribed instructions (Acta Psychiatr Scand 2007;116:47–53). The commonest reasons were forgetting, losing drugs or running out (37 per cent), belief it was unnecessary (25 per cent), dislike of taking medication (19 per cent) and adverse effects (14 per cent). Nine per cent said they had taken more than the prescribed dose, usually to obtain better symptom control. Liothyronine plus sertraline for depression remission? Can enhancing thyroid function increase the likelihood of remission with antidepressant therapy? US psychiatrists believe the prevalence of subclinical thyroid dys‐function is increased in most patients with depression, even though they are euthyroid. They randomised 124 patients to treatment with sertraline alone or in combination with liothyronine 40–50µg daily ( Arch Gen Psychiatry 2007;64:679–88). About a quarter had been taking an antidepressant for the current episode of depression. After eight weeks, 38 per cent of patients had discontinued treatment. Compared with sertraline monotherapy, combined treatment achieved higher rates of response (70 vs 50 per cent) and remission (58 vs 38 per cent) measured using the Hamilton Rating Scale for Depression. In patients taking liothyronine, clinical outcome improved with increasing reduction in thyrotropin levels and the remission rate was higher in those with initially lower tri‐iodothyronine levels; in the placebo group there was no such difference. No adverse effects were attributed to liothyronine. Augmentation of antidepressant therapy The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study showed that about two‐thirds of patients with depression do not obtain an adequate treatment response with the first antidepressant prescribed. Interest is therefore growing in augmentation of antidepressant therapy. In the US, the atypical antipsychotic aripiprazole has been shown to improve depression scores in patients who did not respond to an initial eight‐week course of a single SSRI or venlafaxine ( J Clin Psychiatry 2007;68:843–53). Of 781 who entered the initial treatment phase, 20 per cent discontinued treatment and 58 per cent of the remainder failed to achieve the criteria for response. A total of 362 patients were randomised to treatment with aripiprazole 2–15mg daily or placebo while continuing antidepressant therapy. After six weeks, a further 10 per cent of patients had withdrawn. The mean change in Montgomery‐Asberg Depression Rating Scale score was significantly greater with aripiprazole (−8.8 vs −5.8; baseline score 26), with a difference emerging within two weeks. Aripiprazole was associated with more adverse events, especially akathisia and restlessness. A meta‐analysis of ten randomised trials of antidepressant augmentation with atypical antipsychotics involving a total of 1500 patients concluded that rates of response and remission are increased ( J Clin Psychiatry 2007;68:826–31). The analysis included trials lasting 4–12 weeks involving olanzapine, risperidone and quetiapine but not aripiprazole or ziprasidone. It found that the risk ratio was 1.35 for response (pooled rates 57 vs 35 per cent) and 1.75 for remission (47 vs 22 per cent) with augmentation versus placebo. There was no difference in discontinuation rates overall or due to lack of efficacy but the discontinuation rate for adverse events was three times greater with augmentation. A third study evaluated augmentation with bupropion, nortriptyline or lithium in older patients ( Am J Psychiatry 2007;164:892–9). Of 195 who received paroxetine and psychotherapy for 16 weeks, 54 per cent had an inadequate response. Of these, 66 per cent received augmentation (the others withdrew consent or had contraindications). Patients who needed augmentation were less likely to recover (defined by HAMD score) than those who did not (55 vs 87 per cent) and experienced more adverse effects. Baseline medical burden and significant anxiety were associated with slower recovery times. Overheating during heat waves with psychotropic drugs Heat waves are no longer exceptional in northern Europe, posing a new risk for people taking medicines that may impair temperature regulation. Psychotropic drugs can affect heat dissipation due to their serotonergic or anticholinergic activity, or secondarily by causing dehydration (for example, with lithium). A case‐control study from France has now investigated the relationship between hospital admission during a heat wave and use of psychotropic drugs ( Eur Psychiatry 2007; published early online, DOI 10.1016/j.eurpsy.2007.03.007). During August 2003, daytime temperatures in Bordeaux remained above 35°C for ten days. A total of 1405 patients were admitted to accident and emergency; of these, 56 (4 per cent) presented with conditions related to heat (mean age 83 years, 63 per cent women). Mortality was 43 per cent, mostly within 24 hours. Compared with controls matched for area of residence, cases were four to five times more likely to be taking an antipsychotic and two to three times more likely to be taking an anxiolytic. Other significant associations included taking any antide‐pressant (odds ratio, OR, 3.6), tricyclic antidepressant (OR 4.5), antiepileptics (OR 3.8) and cholinesterase inhibitors (OR 4.7). The weakness of this study is that controls could not be matched for morbidity and patients' activity was not assessed. Nonetheless, the findings confirm data reported in the US and offer a timely warning of the risks to older patients. Data from CATIE on neurocognition Recent data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study suggest that atypical antipsychotics may reduce neurocognitive impairment in patients with schizophrenia – but less so than perphenazine ( Arch Gen Psychiatry 2007;64:633–47). Neurocognitive testing was completed by 817 patients before and after up to 18 months of treatment. After two and six months, there were small improvements in test scores in patients taking atypical (olanzapine, quetiapine, ziprasidone, risperidone) and typical (perphenazine) agents. At 18 months, greatest improvement was associated with perphenazine. The authors note that other studies have shown greater neurocognitive improvement with atypicals than older antipsychotics, concluding that methodological differences and the ‘real‐life’ nature of CATIE probably explain the different findings. Migraine days reduced for 12 months by topiramate Data from the phase III PROMPT study (PROlonged Migraine Prevention with Topiramate) showed that topiramate reduced the mean number of migraine days from 8.9 days a month to 5.8 days (p<0.0001) during the first six months. The results were presented at the 13th International Headache Conference in Stockholm in June. The PROMPT study was a 12‐month multicentre study. Of the 818 adults experiencing four or more migraine days every four weeks without treatment enrolled, 559 completed the initial six‐month open‐label phase, taking 25mg topi‐ramate daily, increased weekly by 25mg increments to a target dose of 100mg daily (range: 50–200mg daily) by week 22. Of those, 512 were randomised to continue on topiramate or receive placebo for the double‐blind phase, which ran for 26 weeks. Patients taking placebo experienced a significant increase in the number of migraine days in the last four weeks of the double‐blind phase versus the last four weeks of the open‐label phase (+1.2 migraine days per four weeks). In comparison those who continued on topiramate saw an increase of 0.1 day (p = 0.0011) in the number of migraine days in the last four weeks of the double‐blind phase as compared with the last four weeks of the open‐label phase. During the double‐blind phase, 68 per cent of patients taking topiramate and 58 per cent of those taking placebo reported adverse events, the most common of which was paraesthesia. Long‐acting risperidone finds favoura From the UK, a three‐year retrospective review of experience with long‐acting risperidone injection found that over half of patients continued treatment for at least one year ( Acta Psychiatr Scand 2007;116:36–46). Of 90 patients treated, 44 discon‐tinued treatment – due largely to lack of effectiveness (41 per cent), refusal (27 per cent) and adverse effects (18 per cent). The median duration of treatment was 9.5 months and of the 67 patients who started treatment a least one year before the evaluation point, 58 per cent were still continuing treatment. Compared with previous treatment, long‐acting risperidone was associated with significantly fewer admissions (33 vs 65) and total inpatient days (2188 vs 4550). The mean reduction in inpatient stay was 29 days per patient per year and the estimated overall cost saving was £1172 per patient per year. During the study period, the average duration of hospital stay for patients with schizophrenia increased from 46 to 69 days. About one‐third of patients' notes documented no adverse effects and a further third had no record. In the remainder, extrapyramidal effects (9 per cent), raised prolactin (7 per cent), sedation (7 per cent) and sexual dys‐function (6 per cent) were most frequently reported. AstraZeneca says its new website – www.choicementalhealth.com – for mental health service users, carers and health care professionals is intended to help empower patient choice and improve standards. Copyright © 2007 Wiley Interface Ltd