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The article presents the future agenda for evidence-based psychopharmacology in mental health. It examines the healthcare interventions outcome and strategies developed to increase systematic review quality. It discusses the issues and give strategies to improve the clinical treatment implementation based on the best available evidence-based practice including need for reliable information on treatment effectiveness and innovation in psychopharmacology.

Question: Is haloperidol alone more effective than haloperidol plus promethazine for rapid tranquillisation of mentally ill patients? Patients: 316 adults presenting to the psychiatric emergency room with agitation or dangerous behaviour requiring intramuscular sedation, for whom an attending doctor was available to record the diagnosis and severity of the episode. Setting: One psychiatric emergency room, Rio de Janeiro, Brazil; January 2004 to July 2004. Intervention: Single intramuscular injection of haloperidol (5 or 10 mg) or haloperidol (5 or 10 mg) plus promethazine (up to 50 mg). In the haloperidol alone group, 29% received 5 mg and 71% received 10 mg. In the haloperidol plus promethazine group 50% received 5 mg haloperidol and 50% received 10 mg. Outcomes: Primary outcome: proportion of patients tranquil (calm and non-agitated with no threatening behaviour) or asleep at 20 min. Secondary outcomes included: tranquil or asleep at 40, 60 and 120 min; need for further medical attention within 24 h; adverse events. Patient follow-up: Data available for 98.4% for the primary outcome; 100% analysed in conservative intention to treat analysis. METHODS Design: Pragmatic randomised controlled trial. Allocation: Concealed. Blinding: Unblinded. Follow-up period: 20 min following antipsychotic injection (primary outcome); 40, 60, and 120 min, 24 h and 2 weeks following (secondary outcomes). MAIN RESULTS Haloperidol plus promethazine increased the proportion of patients tranquil or asleep at 20 min compared with haloperidol alone (proportion tranquil or asleep: 72% with combined treatment vs 55% with haloperidol alone; RR 1.30, 95% CI 1.10 to 1.55). The combined treatment increased the proportion of patients asleep at 20 min (19% with combined treatment vs 8% with haloperidol alone; RR 2.33, 95% CI 1.26 to 4.27). There was no difference between interventions in the proportion of patients tranquil or asleep after 20 min (40 min: RR 1.07, 95% CI 0.95 to 1.20; 60 min: RR 1.07, 95% CI 0.97 to 1.17; 120 min: RR 1.03, 95% CI 0.96 to 1.11). Haloperidol plus promethazine increased the proportion of patients who did not need to have a doctor recalled (77% with combined treatment vs 65% with haloperidol alone; RR 1.18, 95% CI 1.02 to 1.36). Haloperidol alone increased the risk of serious adverse events compared with haloperidol plus promethazine (1% with combined treatment vs 7% with haloperidol alone; RR 0.09, 95% CI 0.01 to 0.68). Most of the serious adverse events in the haloperidol alone group were acute dystonia (10 cases vs none with haloperidol plus promethazine). CONCLUSIONS There is no benefit of giving haloperidol alone compared to haloperidol plus promethazine for agitated or aggressive patients with mental illness presenting to the psychiatric emergency room. The combination is faster acting and has reduced risk of serious adverse events. ABSTRACTED FROM Huf G, Coutinho ESF, Adams CE, et al. Rapid tranquillisation in psychiatric emergency settings in Brazil: pragmatic randomised controlled trial of intramuscular haloperidol versus intramuscular haloperidol plus promethazine. BMJ 2007;335:869-72. [ABSTRACT FROM AUTHOR]

The author reflects on the Italian Law Number 180, a psychiatric reform in Italy. He mentions that the effects Law 180 included the placement of patients who were living in psychiatric hospitals into the community and lower availability of psychiatric beds in Italy. He also states that the law's indicator of failure is the chronicity and not the expected natural outcome.

Question: How effective and safe is aripiprazole when added to antidepressants in people with major depressive disorder and a history of incomplete response?Patients: 362 adults with major depressive disorder (DSMIV-TR) whose current episode had failed to show complete response to an 8-week trial of standard antidepressant plus adjunctive placebo. Incomplete response was defined as <50% reduction in 17-item Hamilton Rating Scale for Depression (HAM-D17) total score, HAM-D17 score >/= 14, and a Clinical Global Impressions-Improvement scale score >/= 3. Participants enrolled in the 8-week trial had to have HAM-D17 total score 18, and a history of inadequate response (<50% reduction in Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (ATRQ)) to 1-3 adequate antidepressant treatments (>6 weeks using adequate dose as specified in the ATRQ) for their current depressive episode. Setting: 24 sites in the USA; June 2004 to April 2006.Intervention: Adjunctive aripiprazole (2-20 mg daily depending on antidepressant being used, response, and tolerability; mean dose 11.8 mg daily) or placebo. Participants continued to receive the antidepressant at the same dose as during the preceding 8 weeks.Outcomes: Primary outcome: change in depression symptoms (Montgomery-Asberg Depression Rating Scale (MADRS) total score). Main secondary outcome: change in illness-related functional impairment (Sheehan Disability Scale).Patient follow-up: 88% completed treatment; 97.5% included in primary last observation carried forward analyses.METHODSDesign: Randomised controlled trial.Allocation: Unclear.Blinding: Double blind.Follow-up period: 14 weeks (treatment period only).MAIN RESULTSAdding aripiprazole to antidepressants significantly improved depression symptoms compared with adding placebo (mean change in MADRS score at 14 weeks: -8.8 with aripiprazole vs -5.8 with placebo; p<0.001). Although there was a trend towards greater improvement in overall functional impairment with aripiprazole, this difference was not significant (results displayed graphically). Aripiprazole increased akathisia and restlessness compared with placebo (akathisia: 23.1% with aripiprazole vs 4.5% with placebo; restlessness: 14.3% with aripiprazole vs 3.4% with placebo; p values not reported). Discontinuations due to adverse effects were similar in both groups (2.2% with aripiprazole vs 1.7% with placebo; p value not reported).CONCLUSIONSAdding aripiprazole to standard antidepressant treatment improves depression symptoms more than adding placebo in people with major depressive disorder that have shown incomplete response to antidepressants alone. [ABSTRACT FROM AUTHOR]

Question: How effective are atypical antipsychotics as adjunctive therapy for treatment resistant depression? Outcomes: Primary outcome: remission rates using the Hamilton Rating Scale for Depression (HAM-D) or Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes: discontinuation rates and response rates.METHODSDesign: Systematic review with meta-analysis.Data sources: Studies in any language were searched for in MEDLINE, PubMed, the Cochrane database and EMBASE from inception; as well as abstracts of multinational psychiatric meetings since 2000, and the clinical trial registries of anti-psychotic manufacturers or direct contact with manufacturers not having such registries. The search date was not reported.Study selection and analysis: Double-blind, randomised, placebo-controlled trials of an antipsychotic as an adjunct to an antidepressant for treatment resistant depression using and assessing either the HAM-D or MADRS as their primary outcome were included. Exclusions: trials in bipolar disorder, psychotic major depression, minor depression, alcohol or substance abuse, comorbidity, dysthymic disorder or seasonal affective disorder. Outcomes were meta-analysed using a random-effects model after testing for heterogeneity.MAIN RESULTSTen randomised controlled trials of 1500 outpatients were included (4 using olanzapine in combination with fluoxetine; 4 using quetiapine in combination with an SSRI or SNRI; and 2 with risperidone plus various antidepressants). Trial durations ranged from 4-12 weeks. Adjunctive antipsychotic treatment increased remission and response rates compared with adjunctive placebo (RR for remission: 1.75, 95% CI 1.36 to 2.24; p<0.001; RR for response: 1.35 95% CI 1.13 to 1.63; p = 0.001). Tests for heterogeneity were non-significant for both remission and response rates. Overall rates of discontinuation were not significantly different between antipsychotic and placebo groups (RR 1.18, 95% CI 0.93 to 1.49; p = 0.133). However, discontinuation due to adverse effects was higher with anti-psychotics than placebo (RR 3.38; 95% CI 1.98 to 5.76; p<0.001).CONCLUSIONSAntipsychotics (olanzapine, quetiapine and risperidone) are effective adjunctive treatment for depression that has failed to respond to an adequate trial of standard treatment. However, they do increase discontinuation due to adverse effects. No studies of adjunctive aripiprazole or ziprasidone were identified so results may not apply to these drugs. [ABSTRACT FROM AUTHOR]

The article reflects on the study which concentrates on the efficacy of an atypical antipsychotic for treatment resistant behaviour. It states that the study failed to provide the data with patient's baseline characteristics and the results from individual trials. It argues that the findings of the study is more effective in terms of response and remission. It suggests the need of a careful analysis in drawing the conclusion with the research.

Are first and second generation antipsychotics equally effective and safe for people with first-episode non-affective psychosis?METHODDesign: Randomised controlled trial.Allocation: Unclear.Blinding: Unclear.Follow-up period: Six weeks (treatment period only).Setting: One outpatient and one inpatient clinic at a university hospital, Cantabria, Spain; enrolment February 2001 to February 2005.Patients: 182 adults (15-60 years old; 93% antipsychotic naive) with non-affective psychotic disorder (DSM-IV) and psychotic symptoms of moderate severity or greater (Scale for the Assessment of Positive Symptoms). Exclusions: DSM-IV mental retardation, DSM-IV drug dependence, or >/= 6 weeks' total lifetime adequate antipsychotic treatment.Intervention: Haloperidol (3-9 mg/day; mean modal dose 5.4 mg/day) risperidone (3-6 mg/day; mean modal dose4 mg/day), or olanzapine (5-20 mg/day; mean modal dose 15.3 mg/day).Outcomes: Response (>/= 40% reduction in Brief Psychiatric Rating Scale score), adverse events including treatment-emergent parkinsonism (Simpson-Angus Scale >3) and akathisia (Barnes Akathisia Scale global score >/= 2).Patient follow-up: 95% included in last observation carried forward analyses.MAIN RESULTSAll treatments showed similar effectiveness in inducing response by the sixth week (% responders: 57.1% with haloperidol vs 52.5% with risperidone vs 63.6% with olanzapine; p = 0.476). Haloperidol increased parkinsonism compared with the second generation antipsychotics (46.6% with haloperidol vs 5.5% with olanzapine vs 24.6% with risperidone; p<0.001). Haloperidol also increased akathisia (55.4% with haloperidol vs 26.2% with risperidone vs 5.5% with olanzapine; p<0.001). Olanzapine increased weight gain compared to the other antipsychotics (% people with >/= 4 kg weight gain: 47% with olanzapine vs 23% with risperidone vs 9% with haloperidol; p<0.001). Olanzapine and haloperidol increased somnolence compared with risperidone (46% with olanzapine vs 46% with haloperidol vs 23% with risperidone; p = 0.012).CONCLUSIONSHaloperidol, risperidone and olanzapine are similarly effective for first-episode non-affective psychosis. Haloperidol increases parkinsonism and akathisia, while olanzapine increases weight gain. Both olanzapine and haloperidol increase somnolence. [ABSTRACT FROM AUTHOR]

How effective is co-therapy (an antipsychotic plus a mood stabiliser) compared with monotherapy (mood stabiliser alone) for people with bipolar mania?METHODDesign: Systematic review with meta-analysis.Data sources: MEDLINE, EMBASE, PsycINFO and Cochrane Central Register of Controlled Trials (searched March 2006).Study selection and analysis: Included studies were randomised controlled trials (RCTs) comparing co-therapy (an antipsychotic plus a mood stabiliser) versus monotherapy (mood-stabiliser alone) or another co-therapy for acute bipolar mania. Drugs had to be licensed in the UK or US for treatment of bipolar disorder (valproate semisodium, lithium, carbamazepine, lamotrigine, aripiprazole, olanzapine, risperidone, ziprasidone, quetiapine, haloperidol, chlorpromazine, Rupentixol, fluphenazine, perphenazine, prochlorperazine and zuclopenthixol). Studies of mixed diagnostic groups were included if randomisation was stratified by bipolar type and data for people with bipolar disorder could be obtained. Meta-analyses were performed using the Mantel--Haenszel method for binary outcomes, and the inverse variance method for continuous outcomes. Treatment effects were expressed either as relative risk or differences in mean values.Outcomes: Manic symptoms (using the Young Mania Rating Scale (YRMS); higher score indicates greater symptom severity), withdrawal from treatment, extrapyramidal symptoms and weight gain.MAIN RESULTSEight RCTs met inclusion criteria (n = 1124). Atypical antipsychotic co-therapy significantly reduced manic symptoms compared with mood stabiliser monotherapy (see http://ebmh.cmj.com/supplemental for table). There were no significant differences in overall treatment withdrawal rates (all causes) between atypical antipsychotic co-therapy and mood stabiliser monotherapy. Significantly more people receiving monotherapy withdrew from treatment because of a lack of efficacy compared with those receiving atypical antipsychotic co-therapy. Olanzapine co-therapy significantly increased withdrawal because of adverse events compared with mood stabiliser monotherapy. There were no significant differences in withdrawal because of adverse events with haloperidol, risperidone or quetiapine co-therapy compared with mood stabiliser monotherapy. Atypical antipsychotic co-therapy significantly increased weight gain compared with mood stabiliser monotherapy. Different studies used different measures of extrapyramidal side effects, and so meta-analyses were not performed.CONCLUSIONSCo-therapy with an antipsychotic and a mood stabiliser reduces manic symptoms compared with a mood stabiliser alone in people with acute bipolar mania. [ABSTRACT FROM AUTHOR]

What are the relative efficacies of antidepressants, antipsychotics, or combinations of such drugs, for psychoticMETHODSDesign: Systematic review and meta-analysis.Data sources: Cochrane Central Register of Controlled Trials (search date not reported), MEDLINE (1966-2004), EMBASE (1984-2004), and trials known to the authors.Study selection and analysis: Randomised controlled trials (RCTs) of antidepressant and/or antipsychotic treatment for people with psychotic depression (unipolar major depressive disorder with a current episode featuring psychotic symptoms). This included RCTs where not all participants had psychotic features, or where some participants had bipolar depression, but where results for the subgroup with unipolar psychotic depression were reported separately. RCTs with less than 20% of participants with bipolar depression were also included. Meta-analysis was carried out using RevMan 4.2 software.Outcomes: Clinical response (as defined by individual studies based an improvement on observer-rated symptom measures, for example >/=50% reduction in symptom severity an Hamilton Rating Scale for Depression); withdrawal rate.MAIN RESULTSTen RCTs met the inclusion criteria (n = 548). There was no significant difference between antidepressant (amitryptyline) mono-therapy and placebo in clinical response (1 RCT, 27 people; RR 8.4, 95% CI 0.5 to 142.3), or between antipsychotic monotherapy and placebo (2 three-arm RCTs, 249 people; RR 1.1, 95% CI 0.7 to 1.7). However, the combination of antidepressant (fluoxetine) plus antipsychotic (olanzapine) improved clinical response rates compared with placebo (1 three-armed RCT, 124 people, RR 1.9, 95% CI 1.2 to 2.8). There was no significant difference in response between antidepressant (amitriptyline) monotherapy and antipsychotic (perphenazine) monotherapy (1 three-arm RCT, 58 people; RR 2.1, 95% CI 0.6 to 6.8). A combination of an antidepressant plus an antipsychotic was more effective than antipsychotic alone (3 RCTs, 188 people; RR 1.9, 95% CI 1.2 to 2.8), but was not more effective than antidepressant alone (2 RCTs, 77 people; RR 1.4, 95% CI 0.9 to 2.4). There were no significant differences in withdrawal rates between any of the treatments. from antidepressant alone, although the comparison of antidepressant monotherapy versus placebo did not show a statistical difference in clinical response rates.NOTESSome comparisons may have been underpowered to detect clinically relevant differences between treatments, as there were few RCTs and they had small sample sizes. The trials differed in their definitions of 'clinical response', and were clinically heterogeneous. [ABSTRACT FROM AUTHOR]

Over 25% of people with schizophrenia, psychoses, or severe mental disorders fail to adhere to treatment programmes. People with schizophrenia, psychoses, or severe mental disorders were taken for the study ; participant recruitment in a psychiatric setting and treatment adherence, is considered as primary outcome measure. Studies set in general medical wards and emergency rooms, studies on compulsory treatment, and studies examining adherence to initial psychiatry appointments. The overall weighted mean rate of non-adherence was 25.78%. Patients most associated with non-adherence were young males with a historv of substance abuse, low social functioning, unemployment or with limited insight into their illness.

Determines the beneficial and adverse effects of low dose tricyclic antidepressants for adults with acute phase depression. Design of the study; Data sources; Study selection; Data extraction; Evidence that people receiving low dose tricyclics were more likely to respond to treatment at four weeks compared to placebo.

QUESTIONS: In patients with depression, are multiple daily doses (MDD) of antidepressants more effective than single daily doses (SDD)? Does the pharmacokinetic half life of a drug influence the antidepressant activity of single daily doses?Data sourcesStudies were identified by searching (PubMed}* with the terms antidepressants, single daily dosing versus, multiple daily closing, and antidepressant efficacy.Study selectionStudies were selected if they were randomised controlled trials (RCT's) that compared dosing schedules of the same antidepressant (with 1 group receiving SDD) and if the total daily dose in the SDD and MDD groups were the same.Data extractionData were extracted on study characteristics, drug regimen, sample size, compliance, mean baseline rating on depression scales, and percentage change at end point. Treatment effects were calculated and weighted in a meta-analysis. 3 different weights were used for each treatment effect to reflect 3 different assumptions about the correlation between baseline and follow up depression scores (p=0.9 [worst case scenario], p=0.5, and p=0).Main results22 studies met the selection criteria, and 17 provided sufficient data for meta-analysis. Sample sizes ranged from 6-241 patients (mean 78 patients). Antidepressants were trazodone (5 RCTs), amitriptyline (3 RCTs), venlafaxine (1 RCT), nomifensine (1 RCT), bupropion (1 RCT), nefazodone (l RCT), amoxapine (1 RCT), moclobemide (1 RCT), zimelidine (1 RCT), fluvoxamine (7 RCT), desipramine (1 RCT), doxepin (1 RCT), imipramine (1 RCT), clomipramine (2 RCTs), and mianserin (1 RCT). SDD and MDD did not differ in treatment effect. 10 studies of antidepressants with short half lives (< 12 h) did not show a difference in treatment effect between SDD and MDD (mean improvement from baseline 61% for SDD and 62% for MDD). In 3 studies of antidepressants with intermediate half lives (> 12 to < 24 h), SDD was better than MDD for all 3 treatment effects (p < 0.001 for worst case scenario [p=0.9]); the mean improvement was 58% for SDD and 51(% for MDD. In 4 studies of antidepressants with long half lives (> 24 h), the difference in favour of SDD was statistically significant only when the correlation between baseline and follow up scores was assumed to be 0.9 (worst case scenario, p=0.01). The mean improvement from baseline was 90% for SDD and 87% for MDD.ConclusionsIn patients with depression, multiple daily doses of antidepressants are not more effective than single daily doses. Grouping the studies by pharmacokinetic half life of the drug does not show an advantage for multiple daily doses over single daily doses.*Information provided by author. [ABSTRACT FROM AUTHOR]