Benzodiazepines versus placebo for panic disorder in adults.

BACKGROUND: Panic disorder is characterised by recurrent unexpected panic attacks consisting of a wave of intense fear that reaches a peak within a few minutes. Panic disorder is a common disorder, with an estimated lifetime prevalence of 1% to 5% in the general population and a 7% to 10% prevalence in primary care settings. Its aetiology is not fully understood and is probably heterogeneous.Panic disorder is treated with psychological and pharmacological interventions, often used in combination. Although benzodiazepines are frequently used in the treatment of panic disorder, guidelines recommend antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), as first-line treatment for panic disorder, particularly due to their lower incidence of dependence and withdrawal reaction when compared to benzodiazepines. Despite these recommendations, benzodiazepines are widely used in the treatment of panic disorder, probably because of their rapid onset of action. OBJECTIVES: To assess the efficacy and acceptability of benzodiazepines versus placebo in the treatment of panic disorder with or without agoraphobia in adults. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR Studies and References), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950-), Embase (1974-), and PsycINFO (1967-) up to 29 May 2018. We handsearched reference lists of relevant papers and previous systematic reviews. We contacted experts in the field for supplemental data. SELECTION CRITERIA: All double-blind (blinding of patients and personnel) controlled trials randomising adults with panic disorder with or without agoraphobia to benzodiazepine or placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently checked the eligibility of studies and extracted data using a standardised form. Data were then entered data into Review Manager 5 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details, settings, and outcome measures in terms of efficacy, acceptability, and tolerability. MAIN RESULTS: We included 24 studies in the review with a total of 4233 participants, of which 2124 were randomised to benzodiazepines and 1475 to placebo. The remaining 634 participants were randomised to other active treatments in three-arm trials. We assessed the overall methodological quality of the included studies as poor. We rated all studies as at unclear risk of bias in at least three domains. In addition, we judged 20 of the 24 included studies as having a high risk of bias in at least one domain.Two primary outcomes of efficacy and acceptability showed a possible advantage of benzodiazepines over placebo. The estimated risk ratio (RR) for a response to treatment was 1.65 (95% confidence interval (CI) 1.39 to 1.96) in favour of benzodiazepines, which corresponds to an estimated number needed to treat for an additional beneficial outcome (NNTB) of 4 (95% CI 3 to 7). The dropout rate was lower among participants treated with benzodiazepines (RR 0.50, 95% CI 0.39 to 0.64); the estimated NNTB was 6 (95% CI 5 to 9). We rated the quality of the evidence as low for both primary outcomes. The possible advantage of benzodiazepine was also seen for remission (RR 1.61, 95% CI 1.38 to 1.88) and the endpoint data for social functioning (standardised mean difference (SMD) -0.53, 95% CI -0.65 to -0.42), both with low-quality evidence. We assessed the evidence for the other secondary outcomes as of very low quality. With the exception of the analyses of the change score data for depression (SMD -0.22, 95% CI -0.48 to 0.04) and social functioning (SMD -0.32, 95% CI -0.88 to 0.24), all secondary outcome analyses showed an effect in favour of benzodiazepines compared to placebo. However, the number of dropouts due to adverse effects was higher with benzodiazepines than with placebo (RR 1.58, 95% CI 1.16 to 2.15; low-quality evidence). Furthermore, our analyses of adverse events showed that a higher proportion of participants experienced at least one adverse effect when treated with benzodiazepines (RR 1.18, 95% CI 1.02 to 1.37; low-quality evidence). AUTHORS' CONCLUSIONS: Low-quality evidence shows a possible superiority of benzodiazepine over placebo in the short-term treatment of panic disorders. The validity of the included studies is questionable due to possible unmasking of allocated treatments, high dropout rates, and probable publication bias. Moreover, the included studies were only short-term studies and did not examine the long-term efficacy nor the risks of dependency and withdrawal symptoms. Due to these limitations, our results regarding the efficacy of benzodiazepines versus placebo provide only limited guidance for clinical practice. Furthermore, the clinician's choice is not between benzodiazepines and placebo, but between benzodiazepines and other agents, notably SSRIs, both in terms of efficacy and adverse effects. The choice of treatment should therefore be guided by the patient's preference and should balance benefits and harms from treatment in a long-term perspective.

Antidepressants versus placebo for panic disorder in adults.

BACKGROUND: Panic disorder is characterised by repeated, unexpected panic attacks, which represent a discrete period of fear or anxiety that has a rapid onset, reaches a peak within 10 minutes, and in which at least four of 13 characteristic symptoms are experienced, including racing heart, chest pain, sweating, shaking, dizziness, flushing, stomach churning, faintness and breathlessness. It is common in the general population with a lifetime prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions. Amongst pharmacological agents, the National Institute for Health and Care Excellence (NICE) and the British Association for Psychopharmacology consider antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), as the first-line treatment for panic disorder, due to their more favourable adverse effect profile over monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). Several classes of antidepressants have been studied and compared, but it is still unclear which antidepressants have a more or less favourable profile in terms of effectiveness and acceptability in the treatment of this condition. OBJECTIVES: To assess the effects of antidepressants for panic disorder in adults, specifically:1. to determine the efficacy of antidepressants in alleviating symptoms of panic disorder, with or without agoraphobia, in comparison to placebo;2. to review the acceptability of antidepressants in panic disorder, with or without agoraphobia, in comparison with placebo; and3. to investigate the adverse effects of antidepressants in panic disorder, with or without agoraphobia, including the general prevalence of adverse effects, compared to placebo. SEARCH METHODS: We searched the Cochrane Common Mental Disorders' (CCMD) Specialised Register, and CENTRAL, MEDLINE, EMBASE and PsycINFO up to May 2017. We handsearched reference lists of relevant papers and previous systematic reviews. SELECTION CRITERIA: All double-blind, randomised, controlled trials (RCTs) allocating adults with panic disorder to antidepressants or placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently checked eligibility and extracted data using a standard form. We entered data into Review Manager 5 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details and settings. Primary outcomes included failure to respond, measured by a range of response scales, and treatment acceptability, measured by total number of dropouts for any reason. Secondary outcomes included failure to remit, panic symptom scales, frequency of panic attacks, agoraphobia, general anxiety, depression, social functioning, quality of life and patient satisfaction, measured by various scales as defined in individual studies. We used GRADE to assess the quality of the evidence for each outcome MAIN RESULTS: Forty-one unique RCTs including 9377 participants overall, of whom we included 8252 in the 49 placebo-controlled arms of interest (antidepressant as monotherapy and placebo alone) in this review. The majority of studies were of moderate to low quality due to inconsistency, imprecision and unclear risk of selection and performance bias.We found low-quality evidence that revealed a benefit for antidepressants as a group in comparison with placebo in terms of efficacy measured as failure to respond (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.66 to 0.79; participants = 6500; studies = 30). The magnitude of effect corresponds to a number needed to treat for an additional beneficial outcome (NNTB) of 7 (95% CI 6 to 9): that means seven people would need to be treated with antidepressants in order for one to benefit. We observed the same finding when classes of antidepressants were compared with placebo.Moderate-quality evidence suggested a benefit for antidepressants compared to placebo when looking at number of dropouts due to any cause (RR 0.88, 95% CI 0.81 to 0.97; participants = 7850; studies = 30). The magnitude of effect corresponds to a NNTB of 27 (95% CI 17 to 105); treating 27 people will result in one person fewer dropping out. Considering antidepressant classes, TCAs showed a benefit over placebo, while for SSRIs and serotonin-norepinephrine reuptake inhibitor (SNRIs) we observed no difference.When looking at dropouts due to adverse effects, which can be considered as a measure of tolerability, we found moderate-quality evidence showing that antidepressants as a whole are less well tolerated than placebo. In particular, TCAs and SSRIs produced more dropouts due to adverse effects in comparison with placebo, while the confidence interval for SNRI, noradrenergic reuptake inhibitors (NRI) and other antidepressants were wide and included the possibility of no difference. AUTHORS' CONCLUSIONS: The identified studies comprehensively address the objectives of the present review.Based on these results, antidepressants may be more effective than placebo in treating panic disorder. Efficacy can be quantified as a NNTB of 7, implying that seven people need to be treated with antidepressants in order for one to benefit. Antidepressants may also have benefit in comparison with placebo in terms of number of dropouts, but a less favourable profile in terms of dropout due to adverse effects. However, the tolerability profile varied between different classes of antidepressants.The choice of whether antidepressants should be prescribed in clinical practice cannot be made on the basis of this review.Limitations in results include funding of some studies by pharmaceutical companies, and only assessing short-term outcomes.Data from the present review will be included in a network meta-analysis of psychopharmacological treatment in panic disorder, which will hopefully provide further useful information on this issue.

The evidence-practice gap in specialist mental healthcare: systematic review and meta-analysis of guideline implementation studies.

BACKGROUND: Clinical practice guidelines are not easily implemented, leading to a gap between research synthesis and their use in routine care. AIMS: To summarise the evidence relating to the impact of guideline implementation on provider performance and patient outcomes in mental healthcare settings, and to explore the performance of different strategies for guideline implementation. METHOD: A systematic review of randomised controlled trials, controlled clinical trials and before-and-after studies comparing guideline implementation strategies v. usual care, and different guideline implementation strategies, in patients with severe mental illness. RESULTS: In total, 19 studies met our inclusion criteria. The studies did not show a consistent positive effect of guideline implementation on provider performance, but a more consistent small to modest positive effect on patient outcomes. CONCLUSIONS: Guideline implementation does not seem to have an impact on provider performance, nonetheless it may influence patient outcomes positively.

Implementation of treatment guidelines for specialist mental health care.

BACKGROUND: A huge gap exists between the production of evidence and its uptake in clinical practice settings. To fill this gap, treatment guidelines, based on explicit assessments of the evidence base, are commonly used in several fields of psychiatry, including schizophrenia and related psychotic disorders. However, it remains unclear whether treatment guidelines have any material impact on provider performance and patient outcomes, and how implementation should be conducted to maximise benefit. OBJECTIVES: The primary objective of this review was to examine the efficacy of guideline implementation strategies in improving process outcomes (performance of healthcare providers) and patient outcomes. We also explored which components of different guideline implementation strategies could influence them. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Register (March 2012 and August 2015), as well as references of included studies. SELECTION CRITERIA: Studies that examined schizophrenia-spectrum disorders to compare guideline implementation strategies with usual care or to assess the comparative efficacy of different guideline implementation strategies. DATA COLLECTION AND ANALYSIS: Review authors worked independently and in duplicate to critically appraise records from 990 studies; six individual studies met the inclusion criteria. Among the six included studies, significant heterogeneity was found in the focus of the guideline, target of the intervention, implementation strategy, and outcome measures, so meta-analysis was carried out for antipsychotic co-prescribing only. MAIN RESULTS: This review now includes six studies, with a total of 1727 participants. Of the six included studies, practitioner impact was assessed in four. Overall, risk of bias was rated as low or unclear, and all evidence in the 'Summary of findings' tables was graded as low or very low quality. Meta-analysis revealed that a combination of several guideline dissemination and implementation strategies targeting healthcare professionals did not reduce antipsychotic co-prescribing in schizophrenia outpatients (2 RCTs, N = 1082, RR 1.10 CI 0.99 to 1.23; corrected for cluster design: N = 310, RR 0.97, CI 0.75 to 1.25, very low-quality evidence). One trial, which studied a nurse-led intervention aimed at promoting cardiovascular disease screening, found a significant effect in the proportion of people receiving screening (Framingham score: N = 110, RR 0.69, 95% CI 0.55 to 0.87), although in the analysis corrected for cluster design, the effect was no longer statistically significant (N = 38, RR 0.71, 95% CI 0.48 to 1.03, very low-quality evidence).One trial reported the patient outcomes of global state, satisfaction with care, treatment adherence, and drug attitude; no effect between treatments was seen. Quality of life was not reported by any of the studies.One trial, which studied the use of re-written guideline text compared to original text, did not find a significant effect on staff receiving training (N = 68, RR 1.03, 95% CI 0.87 to 1.21, low-quality evidence), staff receiving supervision (N = 68, RR 0.86, 95% CI 0.64 to 1.17, low-quality evidence), or staff providing psychological interventions (N = 68, RR 0.86, 95% CI 0.62 to 1.18, low-quality evidence).Regarding participant outcomes, only one trial assessed the efficacy of a shared decision-making implementation strategy and found no impact on psychopathology, satisfaction with care, or drug attitude. Another single trial studied a multifaceted intervention to promote medication adherence and found no effect on adherence rates. AUTHORS' CONCLUSIONS: Considering the available evidence, it is not possible to arrive at definitive conclusions. The preliminary pattern of evidence suggests that uncertainty remains about clinically meaningful and sustainable effects of treatment guidelines on patient outcomes and how best to implement such guidelines for maximal benefit.

Antidepressants and benzodiazepines for panic disorder in adults.

BACKGROUND: A panic attack is a discrete period of fear or anxiety that has a rapid onset, reaches a peak within 10 minutes and in which at least four of 13 characteristic symptoms are experienced, including racing heart, chest pain, sweating, shaking, dizziness, flushing, stomach churning, faintness and breathlessness. Panic disorder is common in the general population with a lifetime prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions. Amongst pharmacological agents, antidepressants and benzodiazepines are the mainstay of treatment for panic disorder. Different classes of antidepressants have been compared; and the British Association for Psychopharmacology, and National Institute for Health and Care Excellence (NICE) consider antidepressants (mainly selective serotonin reuptake inhibitors (SSRIs)) as the first-line treatment for panic disorder, due to their more favourable adverse effect profile over monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). In addition to antidepressants, benzodiazepines are widely prescribed for the treatment of panic disorder. OBJECTIVES: To assess the evidence for the effects of antidepressants and benzodiazepines for panic disorder in adults. SEARCH METHODS: The Specialised Register of the Cochrane Common Mental Disorders Group (CCMDCTR) to 11 September 2015. This register includes relevant randomised controlled trials from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950-), Embase (1974-) and PsycINFO (1967-). Reference lists of relevant papers and previous systematic reviews were handsearched. We contacted experts in this field for supplemental data. SELECTION CRITERIA: All double-blind randomised controlled trials allocating adult patients with panic disorder to antidepressants or benzodiazepines versus any other active treatment with antidepressants or benzodiazepines. DATA COLLECTION AND ANALYSIS: Two review authors independently checked eligibility and extracted data using a standard form. Data were entered in RevMan 5.3 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details, settings and outcome measures in terms of efficacy, acceptability and tolerability. MAIN RESULTS: Thirty-five studies, including 6785 participants overall (of which 5365 in the arms of interest (antidepressant and benzodiazepines as monotherapy)) were included in this review; however, since studies addressed many different comparisons, only a few trials provided data for primary outcomes. We found low-quality evidence suggesting no difference between antidepressants and benzodiazepines in terms of response rate (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.67 to 1.47; participants = 215; studies = 2). Very low-quality evidence suggested a benefit for benzodiazepines compared to antidepressants in terms of dropouts due to any cause, even if confidence interval (CI) ranges from almost no difference to benefit with benzodiazepines (RR 1.64, 95% CI 1.03 to 2.63; participants = 1449; studies = 7). We found some evidence suggesting that serotonin reuptake inhibitors (SSRIs) are better tolerated than TCAs (when looking at the number of patients experiencing adverse effects). We failed to find clinically significant differences between individual benzodiazepines. The majority of studies did not report details on random sequence generation and allocation concealment; similarly, no details were provided about strategies to ensure blinding. The study protocol was not available for almost all studies so it is difficult to make a judgment on the possibility of outcome reporting bias. Information on adverse effects was very limited. AUTHORS' CONCLUSIONS: The identified studies are not sufficient to comprehensively address the objectives of the present review. The majority of studies enrolled a small number of participants and did not provide data for all the outcomes specified in the protocol. For these reasons most of the analyses were underpowered and this limits the overall completeness of evidence. In general, based on the results of the current review, the possible role of antidepressants and benzodiazepines should be assessed by the clinician on an individual basis. The choice of which antidepressant and/or benzodiazepine is prescribed can not be made on the basis of this review only, and should be based on evidence of antidepressants and benzodiazepines efficacy and tolerability, including data from placebo-controlled studies, as a whole. Data on long-term tolerability issues associated with antidepressants and benzodiazepines exposure should also be carefully considered.The present review highlights the need for further higher-quality studies comparing antidepressants with benzodiazepines, which should be conducted with high-methodological standards and including pragmatic outcome measures to provide clinicians with useful and practical data. Data from the present review will be included in a network meta-analysis of psychopharmacological treatment in panic disorder, which will hopefully provide further useful information on this issue.

Rigour of development of clinical practice guidelines for the pharmacological treatment of bipolar disorder: systematic review.

BACKGROUND: There is an increasing concern about the quality of clinical practice guidelines. Because no information is available on the rigour of development of clinical practice guidelines for bipolar disorder, we carried out a systematic review of those focusing on its pharmacological treatment. METHODS: We searched the National Guideline Clearinghouse, MEDLINE, EMBASE, PsychINFO and CINHAL for guidelines published from 2003 to 2014. The quality of each guideline was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE II). RESULTS: Fourteen guidelines were appraised. The overall quality of included guidelines varied considerably, both within and across AGREE II domains. Overall, six guidelines were rated as "recommended", two "recommended with modifications", and six were not recommended according to AGREE II ratings. The mean score for rigour of development was 46.8% of the maximum possible score, with no guidelines scoring the maximum score in this domain. Guidelines with lower editorial independence scores also had lower rigour of development scores, whereas those with higher-quality domain scores scored high in both domains. LIMITATIONS: As current appraisal focused on guidelines for the pharmacological treatment of bipolar disorder, it will be important to critically assess the rigour of development of other guidelines for bipolar and other psychiatric disorders. CONCLUSIONS: Health care providers, policy makers, physicians and patients alike need to be aware of the variability in guideline quality and identify the high-quality guidelines that meet their needs.

Effectiveness of lithium in subjects with treatment-resistant depression and suicide risk: results and lessons of an underpowered randomised clinical trial.

BACKGROUND: As lithium treatment might be effective in reducing the risk of deliberate self-harm (DSH) in adult patients with unipolar affective disorders, we designed a pragmatic randomised trial to assess its efficacy in more than 200 patients with treatment-resistant depression. However, we randomised 56 patients only. The aim of this report is therefore twofold: first, to disseminate the results of this underpowered study which may be incorporated into future meta-analytical reviews; second, to analyse some critical aspects of the study which might explain failure to reach the target sample size. METHODS: We carried out a randomised, parallel group, assessor-blinded superiority clinical trial. Adults with a diagnosis of major depression, an episode of DSH in the previous 12 months and inadequate response to at least two antidepressants given sequentially at an adequate dose for an adequate time for the current depressive episode were allocated to add lithium to usual care (intervention arm) versus usual care alone (control arm). Suicide completion and acts of DSH during the 12 months of follow-up constituted the composite primary outcome. RESULTS: Of 58 patients screened for inclusion, 29 were allocated to lithium plus usual care and 27 were assigned to usual care without lithium. Six patients in the lithium plus usual care group and seven in the usual care group committed acts of DSH during the follow-up phase. The survival probability did not differ between the two treatment arms (Chi2 = 0.17, p =0.676). With regard to changes in the severity of depressive symptomatology from baseline to endpoint, no significant differences were detected. CONCLUSIONS: The present study failed to achieve the minimum sample size needed to detect a clinically meaningful difference between the two treatment arms. Consequently, the finding that lithium, in addition to usual care, did not exert a positive effect in terms of reduction of DSH after 12 months of follow-up is likely due to the lack of sufficient statistical power to detect a difference, if a difference existed. The dissemination of the results of this underpowered study will inform future meta-analytical reviews on lithium and suicide-related outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00927550.

Azapirones versus placebo for panic disorder in adults.

BACKGROUND: Panic disorder is common in the general population. It is often associated with other psychiatric disorders, such as drug dependence, major depression, bipolar disorder, social phobia, specific phobia and generalised anxiety disorder. Azapirones are a class of drugs used as anxiolytics. They are associated with less drowsiness, psychomotor impairment, alcohol potentiation and potential for addiction or abuse than benzodiazepines. However, azapirones are not widely used in the treatment of panic disorder and evidence for their efficacy is unclear. It is important to find out if azapirones are effective and acceptable in the treatment of panic disorder. OBJECTIVES: To assess the effects of azapirones on panic disorder in adults, specifically:1. to determine the efficacy of azapirones in alleviating symptoms of panic disorder, with or without agoraphobia, in comparison with placebo;2. to review the acceptability of azapirones in panic disorder, with or without agoraphobia, in comparison with placebo; and3. to investigate adverse effects of azapirones in panic disorder with or without agoraphobia, including general prevalence of adverse effects, compared with placebo. SEARCH METHODS: We searched the Cochrane Depression Anxiety and Neurosis Group Trials Specialised Register (CCDANCTR, search date: 10th January 2014), which includes relevant randomised controlled trials from The Cochrane Library (all years), MEDLINE (1950-), EMBASE (1974-), and PsycINFO (1967-). SELECTION CRITERIA: Randomised controlled trials that compared azapirones with placebo for panic disorder in adults. DATA COLLECTION AND ANALYSIS: Three review authors independently identified studies, assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: Three studies involving 170 participants compared the azapirone buspirone with placebo. No study provided enough usable information on our primary efficacy outcome (response). For our primary acceptability outcome, moderate-quality evidence indicated that azapirones had lower acceptability than placebo: risk ratio (RR) for dropouts for any reason 2.13 (95% confidence interval (CI) 1.11 to 4.07; 3 studies, 170 participants. Evidence for secondary efficacy outcomes were of low quality. Results on efficacy between azapirone and placebo in terms of agoraphobia (standardised mean difference (SMD) -0.01, 95% CI -0.56 to 0.53; 1 study, 52 participants), general anxiety (mean difference (MD) -2.20, 95% CI -5.45 to 1.06; 2 studies, 115 participants) and depression (MD -1.80, 95% CI -5.60 to 2.00; 1 study, 52 participants) were uncertain. None of the studies provided information for the assessment of allocation concealment or sequence generation. Conflicts of interest were not explicitly expressed. The risk of attrition bias was rated high for all three studies. Information on adverse effects other than dropouts for any reason was insufficient to include in the analyses. AUTHORS' CONCLUSIONS: The efficacy of azapirones is uncertain due to the lack of meta-analysable data for the primary outcome and low-quality evidence for secondary efficacy outcomes. A small amount of moderate-quality evidence suggested that the acceptability of azapirones for panic disorder was lower than for placebo. However, only trials of one azapirone (namely buspirone) were included in this review; this, combined with the small sample size, limits our conclusions. If further research is to be conducted, studies with larger sample sizes, with different azapirones and with less risk of bias are necessary to draw firm conclusions regarding azapirones for panic disorder.

Implementation of treatment guidelines for specialist mental health care.

Although treatment guidelines are commonly employed in healthcare settings, it remains unclear whether their use has any positive impact on the performance of mental health services or whether they improve patient outcomes. This systematic review is based on a search carried out in March 2012 and includes 5 randomized studies that examined the effectiveness of guideline implementation strategies in improving healthcare services and outcomes for people with mental illness. The 5 studies were generally at unclear risk of bias, and all evidence in the "Summary of Findings" table was graded by review authors as of very low quality. Although single studies provided initial evidence that implementation of treatment guidelines may achieve small changes in mental health practice, with only 5 studies meeting inclusion criteria, and with limited usable information, it is not possible to arrive at definitive conclusions. A gap in knowledge still exists about how guideline implementation strategies might improve patient outcomes and health services. This leaves scant information for people with mental health problems, health professionals, and policy makers. More large-scale, well-designed and well-conducted studies are necessary to fill this gap in knowledge.

Implementation of treatment guidelines for specialist mental health care.

BACKGROUND: A huge gap exists between the production of evidence and its take-up in clinical practice settings. To fill this gap, treatment guidelines, based on explicit assessments of the evidence base, are commonly employed in several fields of medicine, including schizophrenia and related psychotic disorders. It remains unclear, however, whether treatment guidelines have any impact on provider performance and patient outcomes, and how implementation should be conducted to maximise benefit. OBJECTIVES: The primary objective of this review was to examine the efficacy of guideline implementation strategies in improving process outcomes (performance of healthcare providers) and patient outcomes. We additionally explored which components of different guideline implementation strategies can influence process and patient outcomes. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Register (March 2012), as well as references of included studies. SELECTION CRITERIA: Studies that examined schizophrenia-spectrum disorders to compare guideline implementation strategies with usual care or to assess the comparative efficacy of different guideline implementation strategies. DATA COLLECTION AND ANALYSIS: Review authors worked independently and in duplicate to critically appraise records from 882 studies; five individual studies met the inclusion criteria and were considered. As critical appraisal of the five included studies revealed substantial heterogeneity in terms of focus of the guideline, target of the intervention, implementation strategy and outcome measures, meta-analysis was carried out for antipsychotic co-prescribing only. MAIN RESULTS: Of the five included studies, practitioner impact was assessed in three. The five studies were generally at unclear risk of bias, and all evidence in the 'Summary of findings' table was graded by review authors as of very low quality. Meta-analysis of two studies revealed that a combination of several guideline dissemination and implementation strategies targeting healthcare professionals did not reduce antipsychotic co-prescribing in schizophrenia outpatients (two studies, n = 1,082, risk ratio (RR) 1.10, 95% confidence interval (CI) 0.99 to 1.23; corrected for cluster design: n = 310, RR 0.97, CI 0.75 to 1.25). One trial, which studied a nurse-led intervention aimed at promoting cardiovascular disease screening, found a significant effect in terms of the proportion of people receiving screening (blood pressure: n = 96, RR 0.07, 95% CI 0.02 to 0.28; cholesterol: n = 103, RR 0.46, 95% CI 0.30 to 0.70; glucose: n = 103, RR 0.53, 95% CI 0.34 to 0.82; BMI: n = 99, RR 0.22, 95% CI 0.08 to 0.60; smoking status: n = 96, RR 0.28, 95% CI 0.12 to 0.64; Framingham score: n = 110, RR 0.69, 95% CI 0.55 to 0.87), although in the analysis corrected for cluster design, the effect was statistically significant for blood pressure and cholesterol only (blood pressure, corrected for cluster design: n = 33, RR 0.10, 95% CI 0.01 to 0.74; cholesterol, corrected for cluster design: n = 35, RR 0.49, 95% CI 0.24 to 0.99; glucose, corrected for cluster design: n = 35, RR 0.58, 95% CI 0.28 to 1.21; BMI, corrected for cluster design: n = 34, RR 0.18, 95% CI 0.02 to 1.37; smoking status, corrected for cluster design: n = 32, RR 0.25, 95% CI 0.06 to 1.03; Framingham score, corrected for cluster design: n = 38, RR 0.71, 95% CI 0.48 to 1.03; very low quality). Regarding participant outcomes, one trial assessed the efficacy of a shared decision-making implementation strategy and found no impact in terms of psychopathology, satisfaction with care and drug attitude. Another single trial studied a multifaceted intervention to promote medication adherence and found no impact in terms of adherence rates. AUTHORS' CONCLUSIONS: With only five studies meeting inclusion criteria, and with limited low or very low quality usable information, it is not possible to arrive at definitive conclusions. The preliminary pattern of evidence suggests that, although small changes in psychiatric practice have been demonstrated, uncertainty remains in terms of clinically meaningful and sustainable effects of treatment guidelines on patient outcomes and how best to implement such guidelines for maximal benefit.

Effectiveness of lithium in subjects with treatment-resistant depression and suicide risk: a protocol for a randomised, independent, pragmatic, multicentre, parallel-group, superiority clinical trial.

BACKGROUND: Data on therapeutic interventions following deliberate self harm (DSH) in patients with treatment-resistant depression (TRD) are very scant and there is no unanimous consensus on the best pharmacological option for these patients. There is some evidence that lithium treatment might be effective in reducing the risk of completed suicide in adult patients with unipolar affective disorders, however no clear cut results have been found so far. The primary aim of the present study is to assess whether adding lithium to standard therapy is an effective treatment strategy to reduce the risk of suicidal behaviour in long term treatment of people with TRD and previous history of DSH. METHODS/DESIGN: We will carry out a randomised, parallel group, assessor-blinded superiority clinical trial. Adults with a diagnosis of major depression, an episode of DSH in the previous 12 months and inadequate response to at least two antidepressants given sequentially at an adequate dose for an adequate time for the current depressive episode will be allocated to add lithium to current therapy (intervention arm) or not (control arm). Following randomisation, treatment is to be taken daily for 1 year unless some clear reason to stop develops. Suicide completion and acts of DSH during the 12 months of follow-up will constitute the composite primary outcome. To preserve outcome assessor blindness, an independent adjudicating committee, blind to treatment allocation, will anonymously review all outcome events. DISCUSSION: The results of this study should indicate whether lithium treatment is associated with lower risk of completed suicide and DSH in adult patients with treatment resistant unipolar depression, who recently attempted suicide. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00927550.

Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia: a 12-month, randomized, naturalistic trial.

BACKGROUND: Long-term studies for patients with resistant schizophrenia are necessary to assess the effectiveness of combination strategies on persisting positive symptoms. AIMS AND METHODS: This multicenter, naturalistic, randomized, superiority study (ClinicalTrials.gov identifier: NCT00395915) aimed to compare clinical efficacy and tolerability of haloperidol versus aripiprazole as combination treatment with clozapine in patients with resistant schizophrenia. RESULTS: One hundred six patients were followed up for 12 months. After 12 months, the proportion of patients who discontinued treatment was not significantly different between aripiprazole and haloperidol (37% vs 28%, respectively; P = 0.431). The change in the Brief Psychiatric Rating Scale score was similar in the aripiprazole and haloperidol groups (-7.0 vs -7.9, respectively; P = 0.389), whereas the tolerability total score decreased significantly more in the aripiprazole group (-7.2 vs -2.3; P = 0.008). CONCLUSIONS: While the effectiveness of clozapine augmentation with a second antipsychotic agent is not clearly demonstrated yet, results from this study suggest that augmentation with aripiprazole offers no substantial benefit over haloperidol in efficacy. Aripiprazole was perceived more tolerable than haloperidol, but it is uncertain how this finding may translate into the real world of clinical practice.

Guideline implementation strategies for specialist mental healthcare.

PURPOSE OF REVIEW: Clinical practice guidelines in mental healthcare are viewed as an essential asset if appropriately developed and implemented. The purpose of this article was to review the existing literature on how guidelines should be implemented to optimize their impact on provider performance and patient outcomes in specialist mental healthcare settings. RECENT FINDINGS: Findings from recent studies suggest a trend toward an improvement in process and patient outcomes following guideline implementation. However, studies are heterogeneous in terms of design, implementation strategies and outcome measures, making it very difficult to draw firm conclusions about which implementation strategy is effective in different healthcare contexts. SUMMARY: Current knowledge about how guidelines should be implemented is still sparse and inconclusive in mental healthcare. Future studies should attempt to employ more rigorous designs, including random allocation of patients or clusters of patients, to shed further light on this compelling issue. Research on guideline implementation strategies should additionally take into account potential barriers to knowledge translation, which can heavily influence the implementability of treatment recommendations.

Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia in routine clinical care: a randomized, controlled trial.

This multisite study was conducted to compare the efficacy and tolerability of combination treatment with clozapine plus aripiprazole versus combination treatment with clozapine plus haloperidol in patients with schizophrenia who do not have an optimal response to clozapine. Patients continued to take clozapine and were randomly assigned to receive daily augmentation with aripiprazole or haloperidol. Physicians prescribed the allocated treatments according to usual clinical care. Withdrawal from allocated treatment within 3 months was the primary outcome. Secondary outcomes included severity of symptoms on the Brief Psychiatric Rating Scale and antipsychotic subjective tolerability on the Liverpool University Neuroleptic Side Effect Rating Scale. A total of 106 patients with schizophrenia were randomly assigned to treatment. After 3 months, we found no difference in the proportion of patients who discontinued treatment between the aripiprazole and haloperidol groups (13.2% vs 15.1%, P = 0.780). The 3-month change of the Brief Psychiatric Rating Scale total score was similar in the aripiprazole and haloperidol groups (-5.9 vs -4.4 points, P = 0.523), whereas the 3-month decrease of the Liverpool University Neuroleptic Side Effect Rating Scale total score was significantly higher in the aripiprazole group than in the haloperidol group (-7.4 vs -2.0 points, P = 0.006). These results suggest that augmentation of clozapine with aripiprazole offers no benefit with regard to treatment withdrawal and overall symptoms in schizophrenia compared with augmentation with haloperidol. However, an advantage in the perception of adverse effects with aripiprazole treatment may be meaningful for patients.

Superiority, equivalence or non-inferiority?

One of the most important critical decision to be taken when designing a randomized controlled trial (RCT) in clinical psychopharmacology is the choice of the comparator. This choice is crucial because it affects many issues related to both internal and external validity. The aim of a RCT may be to establish efficacy in absolute terms, against an inert treatment (usually a placebo), or to establish efficacy with respect to another treatment (also known as comparator), a trial may be designed to demonstrate that the new drug is superior to the control intervention or, by contrast, that the new drug is similar to the control intervention in terms of, say, symptoms' reduction. Three kinds of RCTs may be designed: Superiority trials, Equivalence studies, Non-inferiority studies.