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  ["property_scientific_abstract"]=>
  string(1657) "Background: (R,S)-ketamine (ketamine) and its enantiomer (S)-ketamine (esketamine) can produce rapid and substantial antidepressant effects. However, individual response to ketamine/esketamine is variable, and there are no well-accepted methods to differentiate persons who are more likely to benefit. -

Objective: To conduct a pre-registered systematic review and meta-analysis (PROSPERO protocol CRD42020206937) of clinical predictors of response to ketamine/esketamine in individuals in a major depressive episode (MDE) in major depressive disorder (MDD) and bipolar disorder (BD).

Study Design: This systematic review and meta-analysis will combine the data on esketamine from the YODA project with other clinical trials conducted with ketamine and/or esketamine identified by systematic searches. Meta-analytical calculations will be conducted if there are at least three comparable studies on the same clinical predictor.

Participants: Adult human subjects with a MDE in MDD or BD who participated in clinical trials (randomized controlled and/or open label) and received at least one dose of ketamine or esketamine.

Main Outcome Measure(s): In the quantitative summary, results across studies will be compared using response status as primary outcome (i.e., responder versus non-responder where response is defined as at least 50% improvement in standardized depression measures).

Statistical Analysis: The meta-analyses will utilize a random-effects models with inverse-variance weighting. Effect sizes will be reported as standardized mean differences (continuous variables) or odds-ratio (categorical variables)."
  ["project_brief_bg"]=>
  string(2254) "There is a substantial body of research showing that (R,S)-ketamine (ketamine) and its (S)-ketamine enantiomer (esketamine) are effective in treating a major depressive episode (MDE) in major depressive disorder (MDD) and bipolar disorder (BD), including difficult-to-treat cases. However, individual patients respond differently to ketamine/esketamine, and about 30 to 60% of the persons with treatment-resistant depression show limited response to ketamine/esketamine (1-9). There is also the risk of side effects such cardiovascular symptoms and short term psychotomimetic and dissociative symptoms, which in severe cases can lead to the interruption of treatment. Therefore, there is a need to identify persons that are more likely to respond to ketamine/esketamine, which will increase treatment success and maximize the use of available resources.

Despite continued efforts to identify biomarkers of response to ketamine/esketamine, the results have been inconsistent, and unable to reliability inform treatment selection (10-15). In addition, costs associated with obtaining neuroimaging or more comprehensive blood-based biomarkers may be prohibitive given their current limited clinical utility (16). In contrast, potential clinical predictors can be easily and freely obtained from naturalistic clinical care practice.

Previous studies have indicated potential clinical predictors of response to ketamine/esketamine such as a personal and/or family history of alcohol use disorder (17-19), higher body mass index (BMI) (18), and the presence of co-occurring anxiety disorder (20).  Clinical features suggestive of a more severe depressive course, such as history of psychiatric hospitalization (21, 22) or suicide attempts (18), have also been shown to correlate with worse outcomes. However, these studies have been conducted in generally with small samples, and is still unclear if findings replicate across different studies (23). Consequently, there are still no well-established clinical approaches to guide selection of ketamine/esketamine, highlighting the need to perform a systematic and rigorous summary of current evidence to comprehensively assess the utility of clinical predictors of response to ketamine/esketamine."
  ["project_specific_aims"]=>
  string(1290) "Aim 1: To investigate whether demographic characteristics are associated with response to ketamine/esketamine . Hypothesis: Responders, when compared to non-responders, will have a higher socioeconomic status (e.g., better education and occupational level).

Aim 2: To investigate whether psychiatric and medical characteristics are associated with response to ketamine/esketamine. Hypothesis: Responders, when compared to non-responders, will have lower rates of psychiatric/medical comorbidities, lower duration of current episode, lower number of previous psychiatric hospitalizations, and greater BMI.

Aim 3: To investigate whether treatment-related side effects are associated with response to ketamine/esketamine. Hypothesis: Responders, when compared to non-responders, will have higher scores in the derealization and depersonalization subscales of the Clinician-Administered Dissociative States Scale (CADSS).

Aim 4: To investigate whether concurrent medications are associated with response to ketamine/esketamine. Hypothesis: Responders, when compared to non-responders, will have lower rates of use of medications that reduce glutamatergic neurotransmission (e.g., lamotrigine) or medications that enhance GABAergic neurotransmission (e.g., benzodiazepines)."
  ["project_study_design"]=>
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  ["project_research_methods"]=>
  string(1212) "The data provided by the YODA project will be combined with other clinical trials, which will identified by electronic searches in five databases and manual searches - see attachment 1 for current list of clinical trials that were identified.

We will include manuscripts that 1) examined adult human subjects, 2) studied individuals with a MDE in MDD or BD, 3) were published in English, 4) reported on clinical trials (randomized controlled and/or open label) that administered at least one dose of ketamine or its S-enantiomer esketamine, 5) measured improvement of depressive symptoms with a standardized depression tool, and 6) assessed the association between clinical variables and improvement of depressive symptoms after ketamine/esketamine treatment.

This study will exclude articles that 1) investigated individuals with current psychotic symptoms, 2) examined persons with depressive symptoms due to other disorders besides MDD and BD, 3) allowed concurrent neuromodulatory treatments (concurrent medications and psychotherapy will be allowed), 4) studied individuals with serious comorbid medical or neurological diseases, and 5) assessed individuals in surgical/perioperative settings."
  ["project_main_outcome_measure"]=>
  string(775) "The main goal of this study is to investigate associations between clinical variables and improvement of depressive symptoms in individuals who were treated with ketamine or esketamine. In the qualitative summary (systematic review), we will report on the association between levels of blood-based biomarkers and any measure of improvement, including continuous improvement in depression scores (such as absolute and percentage changes in depression scores) and categorical improvement (such as response and remission). In the quantitative summary (meta-analysis), results across studies will be compared using response status as primary outcome (i.e., responder versus non-responder where response is defined as at least 50% improvement in standardized depression measures)."
  ["project_main_predictor_indep"]=>
  string(990) "We will assess four categories of clinical predictors:

- Demographic characteristics such as age (in years), sex (male versus female), education (in years of education), and occupational status (employed versus non-employed).

- Psychiatric and medical characteristics such as duration of depressive episode (in months), age at illness onset (in years), psychiatric and medical comorbidities (yes versus no), BMI (in kg/m2), previous suicide attempts (yes versus no), and previous hospitalizations (yes versus no).

- Treatment-related side effects such as dissociation (change in Clinician Administered Dissociative States Scale - CADSS), psychotomimetic symptoms (change in Brief Psychiatric Rating Scale ? BPRS), cardiovascular changes (changes in blood pressure and heart rate) and onset oof other physical side effects (e.g., vertigo, dissociation, somnolence and dizziness).

- Concurrent medications including lamotrigine and benzodiazepines (yes versus no)."
  ["project_other_variables_interest"]=>
  string(403) "Meta-regressions will be performed to identify potential effect modifiers, and will examine the impact of variables such as number of treatments (single versus multiple), primary diagnosis (MDD versus bipolar depression), and treatment-resistance status. As recommended by Cochrane, meta-regressions will be conducted only if the number of studies is ten or more in the meta-analytical calculation (24)."
  ["project_stat_analysis_plan"]=>
  string(955) "Meta-analytical calculations will be conducted if there are at least three comparable studies on the same clinical predictor. If there are studies with overlapping samples, only the study with the largest sample will be included in the quantitative summary. Clinical predictors compared between responders and non-responders using standardized mean differences for continuous variables, and odds-ratio for categorical variables. A significant degree of heterogeneity between studies is anticipated, therefore, random-effects models will be used (inverse-variance weighting).

Heterogeneity between studies was examined using I2 where values between 0 and 40% are considered trivial heterogeneity, values between 30 and 60% are considered moderate heterogeneity, values between 50 and 90% are considered substantial heterogeneity, and between 75 and 100% are seen as considerable heterogeneity (24). Publication bias will be assessed by funnel plots."
  ["project_timeline"]=>
  string(309) "- Systematic searches: finished in October, 2021

- Screening process: ongoing (estimated to be finished by February, 2022)

- Data extraction: March and April, 2022

- Data analysis: May and June, 2022

- Manuscript elaboration: July, 2022

- Manuscript submission: August, 2022"
  ["project_dissemination_plan"]=>
  string(147) "This systematic review and meta-analysis will be submitted for publication in a peer-reviewed journal, and for presentation in scientific meetings."
  ["project_bibliography"]=>
  string(5679) "
1. Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. American Journal of Psychiatry. 2013;170(10):1134-42.

2. Grunebaum MF, Ellis SP, Keilp JG, Moitra VK, Cooper TB, Marver JE, et al. Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam?controlled randomized clinical trial. Bipolar disorders. 2017;19(3):176-83.

3. Grunebaum MF, Galfalvy HC, Choo T-H, Keilp JG, Moitra VK, Parris MS, et al. Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. American Journal of Psychiatry. 2018;175(4):327-35.

4. Phillips JL, Norris S, Talbot J, Birmingham M, Hatchard T, Ortiz A, et al. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. American Journal of Psychiatry. 2019;176(5):401-9.

5. Correia-Melo FS, Leal GC, Vieira F, Jesus-Nunes AP, Mello RP, Magnavita G, et al. Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, non-inferiority study. Journal of Affective Disorders. 2020;264:527-34.

6. Su T-P, Chen M-H, Li C-T, Lin W-C, Hong C-J, Gueorguieva R, et al. Dose-related effects of adjunctive ketamine in Taiwanese patients with treatment-resistant depression. Neuropsychopharmacology. 2017;42(13):2482-92.

7. Zarate Jr CA, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biological psychiatry. 2012;71(11):939-46.

8. Molero P, Ramos-Quiroga J, Martin-Santos R, Calvo-Snchez E, Gutirrez-Rojas L, Meana J. Antidepressant efficacy and tolerability of ketamine and esketamine: a critical review. CNS drugs. 2018;32(5):411-20.

9. Marcantoni WS, Akoumba BS, Wassef M, Mayrand J, Lai H, Richard-Devantoy S, et al. A Systematic Review and Meta-Analysis of the Efficacy of Intravenous Ketamine Infusion for Treatment Resistant Depression: January 2009?January 2019. Journal of Affective Disorders. 2020.

10. Medeiros GC, Greenstein D, Kadriu B, Yuan P, Park LT, Gould TD, et al. Treatment of depression with ketamine does not change plasma levels of brain-derived neurotrophic factor or vascular endothelial growth factor. Journal of affective disorders. 2020;280(Pt A):136-9.

11. Park M, Newman LE, Gold PW, Luckenbaugh DA, Yuan P, Machado-Vieira R, et al. Change in cytokine levels is not associated with rapid antidepressant response to ketamine in treatment-resistant depression. Journal of psychiatric research. 2017;84:113-8.

12. Farmer CA, Gilbert JR, Moaddel R, George J, Adeojo L, Lovett J, et al. Ketamine metabolites, clinical response, and gamma power in a randomized, placebo-controlled, crossover trial for treatment-resistant major depression. Neuropsychopharmacology. 2020;45(8):1398-404.

13. Grunebaum MF, Galfalvy HC, Liu J, Huang Y-y, Marcott S, Burke AK, et al. Opioid receptor ?-1 and ketamine effects in a suicidal depression trial: a post hoc exploration. Journal of Clinical Psychopharmacology. 2020;40(4):420-2.

14. Lundin N, Niciu M, Luckenbaugh D, Ionescu D, Richards E, Voort JV, et al. Baseline vitamin B12 and folate levels do not predict improvement in depression after a single infusion of ketamine. Pharmacopsychiatry. 2014;47:141.

15. Kadriu B, Ballard ED, Henter ID, Murata S, Gerlus N, Zarate Jr CA. Neurobiological biomarkers of response to ketamine. Advances in Pharmacology (San Diego, Calif). 2020;89:195-235.

16. Abi-Dargham A, Horga G. The search for imaging biomarkers in psychiatric disorders. Nature medicine. 2016;22(11):1248-55.

17. Permoda-Osip A, Skibinska M, Bartkowska-Sniatkowska A, Kliwicki S, Chlopocka-Wozniak M, Rybakowski JK. Factors connected with efficacy of single ketamine infusion in bipolar depression. Psychiatr Pol. 2014;48(1):35-47.

18. Niciu MJ, Ionescu DALDF, Guevara S, Machado-Vieira R, Richards EM, Brutsche NE, et al. Clinical predictors of ketamine response in treatment-resistant major depression. The Journal of clinical psychiatry. 2014;75(5):417-23.

19. Phelps LE, Brutsche N, Moral JR, Luckenbaugh DA, Manji HK, Zarate Jr CA. Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist. Biological psychiatry. 2009;65(2):181-4.

20. Lucchese AC, Sarin LM, Magalhes EJM, Del Sant LC, B Puertas C, Tuena MA, et al. Repeated subcutaneous esketamine for treatment-resistant depression: impact of the degree of treatment resistance and anxiety comorbidity. Journal of Psychopharmacology. 2021;35(2):142-9.

21. Zheng W, Zhou Y-L, Liu W-J, Wang C-Y, Zhan Y-N, Li H-Q, et al. Rapid and longer-term antidepressant effects of repeated-dose intravenous ketamine for patients with unipolar and bipolar depression. Journal of psychiatric research. 2018;106:61-8.

22. Zheng W, Zhou Y-L, Liu W-J, Wang C-Y, Zhan Y-N, Lan X-F, et al. A preliminary study of adjunctive ketamine for treatment-resistant bipolar depression. Journal of Affective Disorders. 2020;275:38-43.

23. Fanelli D. Negative results are disappearing from most disciplines and countries. Scientometrics. 2012;90(3):891-904.

24. Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane. 2021.
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