CBT treatment delivery formats for panic disorder: a systematic review and network meta-analysis of randomised controlled trials.

Several in-person and remote delivery formats of cognitive-behavioural therapy (CBT) for panic disorder are available, but up-to-date and comprehensive evidence on their comparative efficacy and acceptability is lacking. Our aim was to evaluate the comparative efficacy and acceptability of all CBT delivery formats to treat panic disorder. To answer our question we performed a systematic review and network meta-analysis of randomised controlled trials. We searched MEDLINE, Embase, PsycINFO, and CENTRAL, from inception to 1st January 2022. Pairwise and network meta-analyses were conducted using a random-effects model. Confidence in the evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). The protocol was published in a peer-reviewed journal and in PROSPERO. We found a total of 74 trials with 6699 participants. Evidence suggests that face-to-face group [standardised mean differences (s.m.d.) -0.47, 95% confidence interval (CI) -0.87 to -0.07; CINeMA = moderate], face-to-face individual (s.m.d. -0.43, 95% CI -0.70 to -0.15; CINeMA = Moderate), and guided self-help (SMD -0.42, 95% CI -0.77 to -0.07; CINeMA = low), are superior to treatment as usual in terms of efficacy, whilst unguided self-help is not (SMD -0.21, 95% CI -0.58 to -0.16; CINeMA = low). In terms of acceptability (i.e. all-cause discontinuation from the trial) CBT delivery formats did not differ significantly from each other. Our findings are clear in that there are no efficacy differences between CBT delivered as guided self-help, or in the face-to-face individual or group format in the treatment of panic disorder. No CBT delivery format provided high confidence in the evidence at the CINeMA evaluation.

Pharmacological treatments in panic disorder in adults: a network meta-analysis.

BACKGROUND: A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines. OBJECTIVES: To compare, via network meta-analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability. To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability. To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses. MAIN RESULTS: Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants. There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta-analysis. Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined. Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest. Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials. Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest. Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo. For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs. For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise. For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs. The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low. AUTHORS' CONCLUSIONS: In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes.

Comparative efficacy and acceptability of psychotherapies for panic disorder with or without agoraphobia: systematic review and network meta-analysis of randomised controlled trials.

BACKGROUND: Psychotherapies are the treatment of choice for panic disorder, but which should be considered as first-line treatment is yet to be substantiated by evidence. AIMS: To examine the most effective and accepted psychotherapy for the acute phase of panic disorder with or without agoraphobia via a network meta-analysis. METHOD: We conducted a systematic review and network meta-analysis of randomised controlled trials (RCTs) to examine the most effective and accepted psychotherapy for the acute phase of panic disorder. We searched MEDLINE, Embase, PsycInfo and CENTRAL, from inception to 1 Jan 2021 for RCTs. Cochrane and PRISMA guidelines were used. Pairwise and network meta-analyses were conducted using a random-effects model. Confidence in the evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). The protocol was published in a peer-reviewed journal and in PROSPERO (CRD42020206258). RESULTS: We included 136 RCTs in the systematic review. Taking into consideration efficacy (7352 participants), acceptability (6862 participants) and the CINeMA confidence in evidence appraisal, the best interventions in comparison with treatment as usual (TAU) were cognitive-behavioural therapy (CBT) (for efficacy: standardised mean differences s.m.d. = -0.67, 95% CI -0.95 to -0.39; CINeMA: moderate; for acceptability: relative risk RR = 1.21, 95% CI -0.94 to 1.56; CINeMA: moderate) and short-term psychodynamic therapy (for efficacy: s.m.d. = -0.61, 95% CI -1.15 to -0.07; CINeMA: low; for acceptability: RR = 0.92, 95% CI 0.54-1.54; CINeMA: moderate). After removing RCTs at high risk of bias only CBT remained more efficacious than TAU. CONCLUSIONS: CBT and short-term psychodynamic therapy are reasonable first-line choices. Studies with high risk of bias tend to inflate the overall efficacy of treatments. Results from this systematic review and network meta-analysis should inform clinicians and guidelines.

Dismantling cognitive-behaviour therapy for panic disorder: a systematic review and component network meta-analysis.

Cognitive-behaviour therapy (CBT) for panic disorder may consist of different combinations of several therapeutic components such as relaxation, breathing retraining, cognitive restructuring, interoceptive exposure and/or in vivo exposure. It is therefore important both theoretically and clinically to examine whether specific components of CBT or their combinations are superior to others in the treatment of panic disorder. Component network meta-analysis (NMA) is an extension of standard NMA that can be used to disentangle the treatment effects of different components included in composite interventions. We searched MEDLINE, EMBASE, PsycINFO and Cochrane Central, with supplementary searches of reference lists and clinical trial registries, for all randomized controlled trials comparing different CBT-based psychological therapies for panic disorder with each other or with control interventions. We applied component NMA to disentangle the treatment effects of different components included in these interventions. After reviewing 2526 references, we included 72 studies with 4064 participants. Interoceptive exposure and face-to-face setting were associated with better treatment efficacy and acceptability. Muscle relaxation and virtual-reality exposure were associated with significantly lower efficacy. Components such as breathing retraining and in vivo exposure appeared to improve treatment acceptability while having small effects on efficacy. The comparison of the most v. the least efficacious combination, both of which may be provided as 'evidence-based CBT,' yielded an odds ratio for the remission of 7.69 (95% credible interval: 1.75 to 33.33). Effective CBT packages for panic disorder would include face-to-face and interoceptive exposure components, while excluding muscle relaxation and virtual-reality exposure.

Psychological therapies for panic disorder with or without agoraphobia in adults: a network meta-analysis.

BACKGROUND: Panic disorder is characterised by the presence of recurrent unexpected panic attacks, discrete periods of fear or anxiety that have a rapid onset and include symptoms such as racing heart, chest pain, sweating and shaking. Panic disorder is common in the general population, with a lifetime prevalence of 1% to 4%. A previous Cochrane meta-analysis suggested that psychological therapy (either alone or combined with pharmacotherapy) can be chosen as a first-line treatment for panic disorder with or without agoraphobia. However, it is not yet clear whether certain psychological therapies can be considered superior to others. In order to answer this question, in this review we performed a network meta-analysis (NMA), in which we compared eight different forms of psychological therapy and three forms of a control condition. OBJECTIVES: To assess the comparative efficacy and acceptability of different psychological therapies and different control conditions for panic disorder, with or without agoraphobia, in adults. SEARCH METHODS: We conducted the main searches in the CCDANCTR electronic databases (studies and references registers), all years to 16 March 2015. We conducted complementary searches in PubMed and trials registries. Supplementary searches included reference lists of included studies, citation indexes, personal communication to the authors of all included studies and grey literature searches in OpenSIGLE. We applied no restrictions on date, language or publication status. SELECTION CRITERIA: We included all relevant randomised controlled trials (RCTs) focusing on adults with a formal diagnosis of panic disorder with or without agoraphobia. We considered the following psychological therapies: psychoeducation (PE), supportive psychotherapy (SP), physiological therapies (PT), behaviour therapy (BT), cognitive therapy (CT), cognitive behaviour therapy (CBT), third-wave CBT (3W) and psychodynamic therapies (PD). We included both individual and group formats. Therapies had to be administered face-to-face. The comparator interventions considered for this review were: no treatment (NT), wait list (WL) and attention/psychological placebo (APP). For this review we considered four short-term (ST) outcomes (ST-remission, ST-response, ST-dropouts, ST-improvement on a continuous scale) and one long-term (LT) outcome (LT-remission/response). DATA COLLECTION AND ANALYSIS: As a first step, we conducted a systematic search of all relevant papers according to the inclusion criteria. For each outcome, we then constructed a treatment network in order to clarify the extent to which each type of therapy and each comparison had been investigated in the available literature. Then, for each available comparison, we conducted a random-effects meta-analysis. Subsequently, we performed a network meta-analysis in order to synthesise the available direct evidence with indirect evidence, and to obtain an overall effect size estimate for each possible pair of therapies in the network. Finally, we calculated a probabilistic ranking of the different psychological therapies and control conditions for each outcome. MAIN RESULTS: We identified 1432 references; after screening, we included 60 studies in the final qualitative analyses. Among these, 54 (including 3021 patients) were also included in the quantitative analyses. With respect to the analyses for the first of our primary outcomes, (short-term remission), the most studied of the included psychological therapies was CBT (32 studies), followed by BT (12 studies), PT (10 studies), CT (three studies), SP (three studies) and PD (two studies).The quality of the evidence for the entire network was found to be low for all outcomes. The quality of the evidence for CBT vs NT, CBT vs SP and CBT vs PD was low to very low, depending on the outcome. The majority of the included studies were at unclear risk of bias with regard to the randomisation process. We found almost half of the included studies to be at high risk of attrition bias and detection bias. We also found selective outcome reporting bias to be present and we strongly suspected publication bias. Finally, we found almost half of the included studies to be at high risk of researcher allegiance bias.Overall the networks appeared to be well connected, but were generally underpowered to detect any important disagreement between direct and indirect evidence. The results showed the superiority of psychological therapies over the WL condition, although this finding was amplified by evident small study effects (SSE). The NMAs for ST-remission, ST-response and ST-improvement on a continuous scale showed well-replicated evidence in favour of CBT, as well as some sparse but relevant evidence in favour of PD and SP, over other therapies. In terms of ST-dropouts, PD and 3W showed better tolerability over other psychological therapies in the short term. In the long term, CBT and PD showed the highest level of remission/response, suggesting that the effects of these two treatments may be more stable with respect to other psychological therapies. However, all the mentioned differences among active treatments must be interpreted while taking into account that in most cases the effect sizes were small and/or results were imprecise. AUTHORS' CONCLUSIONS: There is no high-quality, unequivocal evidence to support one psychological therapy over the others for the treatment of panic disorder with or without agoraphobia in adults. However, the results show that CBT - the most extensively studied among the included psychological therapies - was often superior to other therapies, although the effect size was small and the level of precision was often insufficient or clinically irrelevant. In the only two studies available that explored PD, this treatment showed promising results, although further research is needed in order to better explore the relative efficacy of PD with respect to CBT. Furthermore, PD appeared to be the best tolerated (in terms of ST-dropouts) among psychological treatments. Unexpectedly, we found some evidence in support of the possible viability of non-specific supportive psychotherapy for the treatment of panic disorder; however, the results concerning SP should be interpreted cautiously because of the sparsity of evidence regarding this treatment and, as in the case of PD, further research is needed to explore this issue. Behaviour therapy did not appear to be a valid alternative to CBT as a first-line treatment for patients with panic disorder with or without agoraphobia.

Psychological therapies versus pharmacological interventions for panic disorder with or without agoraphobia in adults.

BACKGROUND: Panic disorder is common and deleterious to mental well-being. Psychological therapies and pharmacological interventions are both used as treatments for panic disorder with and without agoraphobia. However, there are no up-to-date reviews on the comparative efficacy and acceptability of the two treatment modalities, and such a review is necessary for improved treatment planning for this disorder. OBJECTIVES: To assess the efficacy and acceptability of psychological therapies versus pharmacological interventions for panic disorder, with or without agoraphobia, in adults. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Group Specialised Register on 11 September 2015. This register contains reports of relevant randomised controlled trials from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950 to present), Embase (1974 to present), and PsycINFO (1967 to present). We cross-checked reference lists of relevant papers and systematic reviews. We did not apply any restrictions on date, language, or publication status. SELECTION CRITERIA: We included all randomised controlled trials comparing psychological therapies with pharmacological interventions for panic disorder with or without agoraphobia as diagnosed by operationalised criteria in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and resolved any disagreements in consultation with a third review author. For dichotomous data, we calculated risk ratios (RR) with 95% confidence intervals (CI). We analysed continuous data using standardised mean differences (with 95% CI). We used the random-effects model throughout. MAIN RESULTS: We included 16 studies with a total of 966 participants in the present review. Eight of the studies were conducted in Europe, four in the USA, two in the Middle East, and one in Southeast Asia.None of the studies reported long-term remission/response (long term being six months or longer from treatment commencement).There was no evidence of a difference between psychological therapies and selective serotonin reuptake inhibitors (SSRIs) in terms of short-term remission (RR 0.85, 95% CI 0.62 to 1.17; 6 studies; 334 participants) or short-term response (RR 0.97, 95% CI 0.51 to 1.86; 5 studies; 277 participants) (very low-quality evidence), and no evidence of a difference between psychological therapies and SSRIs in treatment acceptability as measured using dropouts for any reason (RR 1.33, 95% CI 0.80 to 2.22; 6 studies; 334 participants; low-quality evidence).There was no evidence of a difference between psychological therapies and tricyclic antidepressants in terms of short-term remission (RR 0.82, 95% CI 0.62 to 1.09; 3 studies; 229 participants), short-term response (RR 0.75, 95% CI 0.51 to 1.10; 4 studies; 270 participants), or dropouts for any reason (RR 0.83, 95% CI 0.53 to 1.30; 5 studies; 430 participants) (low-quality evidence).There was no evidence of a difference between psychological therapies and other antidepressants in terms of short-term remission (RR 0.90, 95% CI 0.48 to 1.67; 3 studies; 135 participants; very low-quality evidence) and evidence that psychological therapies did not significantly increase or decrease the short-term response over other antidepressants (RR 0.96, 95% CI 0.67 to 1.37; 3 studies; 128 participants) or dropouts for any reason (RR 1.55, 95% CI 0.91 to 2.65; 3 studies; 180 participants) (low-quality evidence).There was no evidence of a difference between psychological therapies and benzodiazepines in terms of short-term remission (RR 1.08, 95% CI 0.70 to 1.65; 3 studies; 95 participants), short-term response (RR 1.58, 95% CI 0.70 to 3.58; 2 studies; 69 participants), or dropouts for any reason (RR 1.12, 95% CI 0.54 to 2.36; 3 studies; 116 participants) (very low-quality evidence).There was no evidence of a difference between psychological therapies and either antidepressant alone or antidepressants plus benzodiazepines in terms of short-term remission (RR 0.86, 95% CI 0.71 to 1.05; 11 studies; 663 participants) and short-term response (RR 0.95, 95% CI 0.76 to 1.18; 12 studies; 800 participants) (low-quality evidence), and there was no evidence of a difference between psychological therapies and either antidepressants alone or antidepressants plus benzodiazepines in terms of treatment acceptability as measured by dropouts for any reason (RR 1.08, 95% CI 0.77 to 1.51; 13 studies; 909 participants; very low-quality evidence). The risk of selection bias and reporting bias was largely unclear. Preplanned subgroup and sensitivity analyses limited to trials with longer-term, quality-controlled, or individual psychological therapies suggested that antidepressants might be more effective than psychological therapies for some outcomes.There were no data to contribute to a comparison between psychological therapies and serotonin-norepinephrine reuptake inhibitors (SNRIs) and subsequent adverse effects. AUTHORS' CONCLUSIONS: The evidence in this review was often imprecise. The superiority of either therapy over the other is uncertain due to the low and very low quality of the evidence with regard to short-term efficacy and treatment acceptability, and no data were available regarding adverse effects.The sensitivity analysis and investigation of the sources of heterogeneity indicated three possible influential factors: quality control of psychological therapies, the length of intervention, and the individual modality of psychological therapies.Future studies should examine the long-term effects after intervention or treatment continuation and should provide information on risk of bias, especially with regard to selection and reporting biases.

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.

A review of methods for addressing components of interventions in meta-analysis.

Many healthcare interventions are complex, consisting of multiple, possibly interacting, components. Several methodological articles addressing complex interventions in the meta-analytical context have been published. We hereby provide an overview of methods used to evaluate the effects of complex interventions with meta-analytical models. We summarized the methodology, highlighted new developments, and described the benefits, drawbacks, and potential challenges of each identified method. We expect meta-analytical methods focusing on components of several multicomponent interventions to become increasingly popular due to recently developed, easy-to-use, software tools that can be used to conduct the relevant analyses. The different meta-analytical methods are illustrated through two examples comparing psychotherapies for panic disorder.

Which psychotherapy is effective in panic disorder? And which delivery formats are supported by the evidence? Study protocol for two systematic reviews and network meta-analyses.

INTRODUCTION: Panic disorder is among the most prevalent anxiety diseases. Although psychotherapy is recommended as first-line treatment for panic disorder, little is known about the relative efficacy of different types of psychotherapies. Moreover, there is little evidence concerning the effectiveness of different formats of major psychotherapeutic types, such as cognitive-behavioural therapy (CBT). In this protocol, we present an overarching project consisting of two systematic reviews and network meta-analyses (NMA) to shed light on which psychotherapy (NMA-1), and specifically, which CBT delivery format (NMA-2) should be considered most effective for adults suffering from panic disorder with or without agoraphobia. METHODS AND ANALYSES: Starting from a common pool of data, we will conduct two systematic reviews and NMA of randomised controlled trials examining panic disorder. A comprehensive search will be performed in electronic databases MEDLINE, Embase, PsycINFO and the Cochrane Register of Controlled Trials-CENTRAL from database inception to 1 January 2021 to identify relevant studies. A systematic approach to searching, screening, reviewing and data extraction will be applied. Titles, abstract and-whenever necessary-full texts will be examined independently by at least two reviewers. The quality of the included studies will be assessed using the revised Cochrane risk of bias tool V.2. The primary efficacy outcome will be anxiety symptoms at study endpoint. The primary acceptability outcome will be all-cause discontinuation, as measured by the proportion of patients who had discontinued treatment for any reason at endpoint. Data will be pooled using a random-effects model. Pairwise and NMA will be conducted. ETHICS AND DISSEMINATION: No ethical approval is necessary for these two studies, as there will be no collection of primary data. The results will be disseminated through peer-reviewed publications and presentations at national and international conferences and meetings.

Dismantling, personalising and optimising internet cognitive-behavioural therapy for depression: a study protocol for individual participant data component network meta-analysis.

INTRODUCTION: Psychotherapy is a complex intervention, consisting of various components and being implemented flexibly in consideration of individual patient's characteristics. It is then of utmost importance to know which of the various components or combinations thereof are more efficacious, what their specific effect sizes are and which types of patients may benefit more from different components or their combinations. METHODS AND ANALYSIS: Internet-delivered cognitive-behavioural therapy (iCBT) offers a unique opportunity to systematically review and quantitatively disentangle the efficacy of various components because, unlike face-to-face cognitive-behavioural therapy, it allows identification of constituent components that are actually delivered to patients. We will systematically identify all randomised controlled trials that compared any form of iCBT against another form or a control intervention in the acute phase treatment of adult depression. We will apply component network meta-analysis (cNMA) to dismantle efficacy of individual components. We will use individual participant data in the cNMA to identify participant-level prognostic factors and effect modifiers for different components. ETHICS AND DISSEMINATION: The investigators of the primary trials will have obtained ethical approval for the data used in the present study and for sharing the data, if this was necessary, according to local requirements and was not covered from the initial ethic assessment. Results from this study will be published in peer-reviewed journals and presented at relevant conferences. PROSPERO REGISTRATION NUMBER: CRD42018104683.