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  string(144) "Esketamine for treatment-resistant depression in adults: Cochrane systematic review and meta-analysis on efficacy and tolerability of esketamine"
  ["project_narrative_summary"]=>
  string(637) "An international team and I are conducting a Cochrane systematic review and meta-analysis on esketamine for treatment resistant depression at the WHO collaborating and Cochrane centre of Verona led by Prof. Barbui. Here you can find the published protocol: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD015071/full (also attached).

Esketamine is a new medication available for treatment resistant depression and cumulative evidence is needed to define its profile in terms of efficacy and tolerability. Thus, we are collecting all available RCTs to perform a meta-analysis of efficacy, tolerability and side effects."
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      string(9) "GASTALDON"
      ["p_pers_degree"]=>
      string(7) "MD, PhD"
      ["p_pers_pr_affil"]=>
      string(123) "Department of Neuroscience, Biomedicine and Movement Sciences,  Section of Psychiatry, University of Verona, Verona, Italy."
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    ["label"]=>
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  ["property_scientific_abstract"]=>
  string(3120) "BACKGROUND: esketamine is a new medication for TRD, a comprehensive analysis of the literature on efficacy and tolerability is needed.

OBJ:The main aim of this Cochrane review is to assess the efficacy and tolerability of esketamine for treatment-resistant depression. Secondary aims are to assess the risk of specific adverse events during esketamine treatment, and its acceptability.

DESIGN: cochrane systematic review and meta-analysis of RCTs

PARTICIPANTS: Participants will be adults, aged 18 years or older. We will include studies that include both participants under 18 years and 18 years or older only if fewer than 20% of participants are younger than 18 years. We will define TRD as a primary diagnosis of a depressive episode with inadequate response to at least two trials of antidepressants (AD) of adequate dose and duration. We will include studies that applied any standardised diagnostic criteria for unipolar depression, including the Diagnostic and Statistical Manual of Mental Disorders or the International Classification of Diseases criteria.

PRIMARY AND SECONDARY OUTCOMES:

1. Efficacy (continuous outcome): change in depressive symptoms from baseline to study end point, measured with any rating scale for depression

2. Tolerability: number of participants who dropped out due to side eHects during the trial, as a proportion of the total number of randomised participants

3. Efficacy (dichotomous outcome): number of participants who responded  to treatment, where treatment response is defined as (1) a reduction of at least 50% compared to baseline on any depression scale.

4. a. Total number of participants experiencing at least one side effect, b. Total number of participants experiencing at least one serious adverse event,

5. Total number of participants experiencing the following specific side effects: dissociative symptoms or dissociative disorder,  sedation,  nausea,  vomiting, abuse or misuse ,completed suicide or attempted suicide, suicidal ideation or thoughts, agitation or anxiety, increased blood pressure or hypertension,  dizziness,  feeling abnormal or feeling drunk,  headache, vertigo, dysgeusia.

STATISTICAL ANALYSIS: We will analyse continuous outcomes by calculating the mean difference (MD) and 95% confidence intervals (CI) between groups,

if studies use the same outcome measure for comparison. When available. we will use the mean change from baseline to end point. If the mean change is not available, we will use the mean end point score. If different scales are used to assess the same outcome, we will calculate the standardised mean difference (SMD) and 95% CI. For dichotomous data, we will calculate the relative risk (RR) with corresponding 95% CI for dichotomous or event-like outcomes for each comparison. We will calculate response rates out of the total number of randomised participants.

If meta-analysis is not possible (e.g. due to insufficient data or substantial heterogeneity), we will provide a narrative assessment of the evidence. If heterogeneity is low ("
  ["project_brief_bg"]=>
  string(2614) "The term treatment resistant depression refers to a depressive episode that failed to respond or remit to one or more treatments (pharmacological, non-pharmacological, or both(Cosgrove2021). Among clinical studies, the most commonly used definition of treatment-resistant or treatment refractory depression is the absence of clinical improvement to at least two antidepressants, prescribed at adequate dose and duration (Brown 2019; Cosgrove 2021; Malhi 2016). Currently, switching to another antidepressant, adjunctive treatment (i.e. added treatment to assist the primary treatment),  psychotherapy, or neuro stimulation, are treatments that have been suggested for people with TRD (Kennedy 2016; NICE 2016). Considering the large body of evidence of involvement of

the glutamate  system in the pathophysiology of depression, pre-clinical studies  were conducted to assess the potential antidepressant efficacy of glutamate inhibition with NMDA receptor antagonists, such as ketamine and esketamine, with  positive results (Altamura 1995; Zarate 2006). However, clinical studies have not confirmed the eHicacy of ketamine for depression. in March 2019, the US Food and Drug Administration approved a nasal spray formulation of esketamine for people with TRD, and more recently, for people with MDD and acute suicidal ideation (FDA 2019; FDA Committee 2019). At the

end of 2019, esketamine was also granted marketing authorisation by the European Medicine Agency (EMA) for the same clinical indication (EMA 2019).  According to the FDA and EMA label, esketamine is indicated in TRD in association with antidepressant treatment. In Europe, this is the only licensed treatment for TRD, while in the USA, there is another treatment for TRD, which is a combination of fluoxetine and olanzapine.

Why it is important to do this review

There is a particular concern about esketamine safety and acceptability.  A safety signal, based on reports of esketamine-associated suicidal ideation, was detected and requires clarification and careful reanalyses of existing data (Gastaldon 2021). In addition to safety and acceptability, concerns have been raised about the clinical relevance of the esketamine-placebo difference (Cristea 2019; Gastaldon 2020; Turner 2019). Therefore, a thorough risk-benefit assessment of the esketamine profile in people with TRD is urgently needed to assist people with TRD, healthcare professionals, policy makers, and other interested stakeholders in making informed choices. Therefore, a comprehensive and indipendent analysis of all available evidence is needed."
  ["project_specific_aims"]=>
  string(253) "The main aim of this Cochrane review is to assess the efficacy and tolerability of esketamine for treatment-resistant depression.

Secondary aims are to assess the risk of specific adverse events during esketamine treatment, and its acceptability."
  ["project_study_design"]=>
  array(2) {
    ["value"]=>
    string(7) "meta_an"
    ["label"]=>
    string(52) "Meta-analysis (analysis of multiple trials together)"
  }
  ["project_study_design_exp"]=>
  string(0) ""
  ["project_purposes"]=>
  array(0) {
  }
  ["project_purposes_exp"]=>
  string(0) ""
  ["project_software_used"]=>
  array(2) {
    ["value"]=>
    string(86) "not_analyzing_participant_level_data__plan_to_use_another_secure_data_sharing_platform"
    ["label"]=>
    string(92) "I am not analyzing participant-level data / plan to use another secure data sharing platform"
  }
  ["project_software_used_exp"]=>
  string(237) "I will  notuse individual participant level data. I am performing a pairwise pooled meta-analysis and I need the pooled means of the studies, as some data is missing in the publications. I will do so on Revman web, the cochrane software."
  ["project_research_methods"]=>
  string(1170) "We searched databases and trial registers using relevant keywords.

Participants will be adults, aged 18 years or older. We will include studies that include both participants under 18 years and 18 years or older only if fewer than 20% of participants are younger than 18 years. Definition of treatment-resistant depression (TRD) We will define TRD as a primary diagnosis of a depressive episode with inadequate response to at least two trials of antidepressants (AD) of adequate dose and duration. We will exclude studies enrolling participants based on other explicit criteria defining  different levels of treatment resistance. We will include studies that applied any standardised diagnostic criteria for unipolar depression, including the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the International Classification of Diseases criteria (ICD-10 (WHO 1992)). Comorbidity: We will exclude studies with participants with comorbid schizophrenia or bipolar disorder. We will only include studies in which fewer than 20% of participants may be suffering from bipolar depression, and thus, at least 80% of participants will have unipolar disorder."
  ["project_main_outcome_measure"]=>
  string(1219) "Main outcomes

1. Efficacy (continuous outcome): change in depressive symptoms from baseline to study end point, measured with any rating scale for depression

2. Tolerability: number of participants who dropped out due to side eHects during the trial, as a proportion of the total number of randomised participants

Secondary outcomes

3. Efficacy (dichotomous outcome): number of participants who responded  to treatment, where treatment response is defined as (1) a reduction of at least 50% compared to baseline on any depression scale.

4. a. Total number of participants experiencing at least one side effect, b. Total number of participants experiencing at least one serious adverse event,

5. Total number of participants experiencing the following specific side effects: dissociative symptoms or dissociative disorder,  sedation,  nausea,  vomiting, abuse or misuse ,completed suicide or attempted suicide, suicidal ideation or thoughts, agitation or anxiety, increased blood pressure or hypertension,  dizziness,  feeling abnormal or feeling drunk,  headache, vertigo, dysgeusia.

6. Acceptability  (dichotomous outcome):a. Overall dropouts, b.due to lack of efficacy"
  ["project_main_predictor_indep"]=>
  string(317) "Efficacy (continuous outcome): change in depressive symptoms from baseline to study end point, measured with any

rating scale  for depression.

Tolerability: number of participants who dropped out due to side effects during the trial, as a proportion of the total number

of randomised participants"
  ["project_other_variables_interest"]=>
  string(890) "level of resistance: ie. number of previous treatments, doses, quality of studies (according to the ROB2 of cochrane)

We will assess the risk of bias according to the following domains:

(1) bias arising from the randomisation process;

(2) bias due to deviations from intended interventions;

(3) bias due to missing outcome data;

(4) bias in measurement of the outcome;

(5) bias in selection of the reported result.

Timing of outcome assessment

We will assess primary and secondary outcomes at the study end point. We will also consider the following time points for the primary outcomes:

1. At 24 hours, ranging between 12 and 36 hours after randomisation

2. At four weeks, ranging between three and six weeks afer randomizations

3. At three months, ranging between seven weeks and six months after randomizations"
  ["project_stat_analysis_plan"]=>
  string(1185) "Main planned comparisons

1. Esketamine versus placebo

2. Esketamine versus other active pharmacological treatments

3. Esketamine versus physical therapies

Analyses

we plan a pooled analysis of means of studies. We do not plan to use individual patient level  data.

We will analyse continuous outcomes by calculating the mean diHerence (MD) and 95% confidence intervals (CI) between groups,

if studies use the same outcome measure for comparison. When available. we will use the mean change from baseline to end point. If the mean change is not available, we will use the mean end point score. If different scales are used to assess the same outcome, we will calculate the standardised mean difference (SMD) and 95% CI. For dichotomous data, we will calculate the relative risk (RR) with corresponding 95% CI for dichotomous or event-like outcomes for each comparison. We will calculate response rates out of the total number of randomised participants.

If meta-analysis is not possible (e.g. due to insufficient data or substantial heterogeneity), we will provide a narrative assessment of the evidence. If heterogeneity is low ("
  ["project_timeline"]=>
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September-november: write up of results

November-december 2023: submission to Cochrane"
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