Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder

Rebecca L Dean; Claudia Hurducas; Keith Hawton; Styliani Spyridi; Philip J Cowen; Sarah Hollingsworth; Tahnee Marquardt; Annabelle Barnes; Rebecca Smith; Rupert McShane; Erick H Turner; Andrea Cipriani

doi:10.1002/14651858.CD011612.pub3

. 2021 Sep 12;2021(9):CD011612. doi: 10.1002/14651858.CD011612.pub3

Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder

Rebecca L Dean ¹, Claudia Hurducas ¹, Keith Hawton ², Styliani Spyridi ³, Philip J Cowen ⁴, Sarah Hollingsworth ¹, Tahnee Marquardt ¹, Annabelle Barnes ¹, Rebecca Smith ¹, Rupert McShane ^1,⁴, Erick H Turner ^5,⁶, Andrea Cipriani ^1,^4,^✉

Editor: Cochrane Common Mental Disorders Group

PMCID: PMC8434915 PMID: 34510411

Abstract

Background

Many studies have recently been conducted to assess the antidepressant efficacy of glutamate modification in mood disorders. This is an update of a review first published in 2015 focusing on the use of glutamate receptor modulators in unipolar depression.

Objectives

To assess the effects ‐ and review the acceptability and tolerability ‐ of ketamine and other glutamate receptor modulators in alleviating the acute symptoms of depression in people with unipolar major depressive disorder.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase and PsycINFO all years to July 2020. We did not apply any restrictions to date, language or publication status.

Selection criteria

Double‐ or single‐blinded randomised controlled trials (RCTs) comparing ketamine, memantine, esketamine or other glutamate receptor modulators with placebo (pill or saline infusion), other active psychotropic drugs, or electroconvulsive therapy (ECT) in adults with unipolar major depression.

Data collection and analysis

Three review authors independently identified studies, assessed trial quality and extracted data. The primary outcomes were response rate (50% reduction on a standardised rating scale) and adverse events. We decided a priori to measure the efficacy outcomes at different time points and run sensitivity/subgroup analyses. Risk of bias was assessed using the Cochrane tool, and certainty of the evidence was assessed using GRADE.

Main results

Thirty‐one new studies were identified for inclusion in this updated review. Overall, we included 64 studies (5299 participants) on ketamine (31 trials), esketamine (9), memantine (5), lanicemine (4), D‐cycloserine (2), Org26576 (2), riluzole (2), atomoxetine (1), basimglurant (1), citicoline (1), CP‐101,606 (1), decoglurant (1), MK‐0657 (1), N‐acetylcysteine (1), rapastinel (1), and sarcosine (1).

Forty‐eight studies were placebo‐controlled, and 48 were two‐arm studies. The majority of trials defined an inclusion criterion for the severity of depressive symptoms at baseline: 29 at least moderate depression; 17 severe depression; and five mild‐to‐moderate depression. Nineteen studies recruited only patients with treatment‐resistant depression, defined as inadequate response to at least two antidepressants.

The majority of studies investigating ketamine administered as a single dose, whilst all of the included esketamine studies used a multiple dose regimen (most frequently twice a week for four weeks). Most studies looking at ketamine used intravenous administration, whilst the majority of esketamine trials used intranasal routes.

The evidence suggests that ketamine may result in an increase in response and remission compared with placebo at 24 hours odds ratio (OR) 3.94, 95% confidence interval (CI) 1.54 to 10.10; n = 185, studies = 7, very low‐certainty evidence). Ketamine may reduce depression rating scale scores over placebo at 24 hours, but the evidence is very uncertain (standardised mean difference (SMD) ‐0.87, 95% CI ‐1.26 to ‐0.48; n = 231, studies = 8, very low‐certainty evidence). There was no difference in the number of participants assigned to ketamine or placebo who dropped out for any reason (OR 1.25, 95% CI 0.19 to 8.28; n = 201, studies = 6, very low‐certainty evidence).

When compared with midazolam, the evidence showed that ketamine increases remission rates at 24 hours (OR 2.21, 95% CI 0.67 to 7.32; n = 122,studies = 2, low‐certainty evidence). The evidence is very uncertain about the response efficacy of ketamine at 24 hours in comparison with midazolam, and its ability to reduce depression rating scale scores at the same time point (OR 2.48, 95% CI 1.00 to 6.18; n = 296, studies = 4,very low‐certainty evidence). There was no difference in the number of participants who dropped out of studies for any reason between ketamine and midazolam (OR 0.33, 95% CI 0.05 to 2.09; n = 72, studies = 1, low‐certainty evidence).

Esketamine treatment likely results in a large increase in participants achieving remission at 24 hours compared with placebo (OR 2.74, 95% CI 1.71 to 4.40; n = 894, studies = 5, moderate‐certainty evidence). Esketamine probably results in decreases in depression rating scale scores at 24 hours compared with placebo (SMD ‐0.31, 95% CI ‐0.45 to ‐0.17; n = 824, studies = 4, moderate‐certainty evidence). Our findings show that esketamine increased response rates, although this evidence is uncertain (OR 2.11, 95% CI 1.20 to 3.68; n = 1071, studies = 5, low‐certainty evidence). There was no evidence that participants assigned to esketamine treatment dropped out of trials more frequently than those assigned to placebo for any reason (OR 1.58, 95% CI 0.92 to 2.73; n = 773, studies = 4,moderate‐certainty evidence).

We found very little evidence for the remaining glutamate receptor modulators.

We rated the risk of bias as low or unclear for most domains, though lack of detail regarding masking of treatment in the studies reduced our certainty in the effect for all outcomes.

Authors' conclusions

Our findings show that ketamine and esketamine may be more efficacious than placebo at 24 hours. How these findings translate into clinical practice, however, is not entirely clear. The evidence for use of the remaining glutamate receptor modulators is limited as very few trials were included in the meta‐analyses for each comparison and the majority of comparisons included only one study.

Long term non‐inferiority RCTs comparing repeated ketamine and esketamine, and rigorous real‐world monitoring are needed to establish comprehensive data on safety and efficacy.

Plain language summary

Ketamine and other glutamate receptor modulators for depression in adults

Why is this review important?

Depression is one of the most common mental disorders, estimated to affect 350 million people worldwide. Antidepressant medication tends to be given as a first treatment for people with major depression. These drugs are however only effective in about one in four people at one year. Effective alternative medications to treat depression are needed, especially for rapid treatment. A new group of medications is called ‘glutamate receptor modulators’, which act on the glutamergic system. This group includes the medicine ketamine. In this review we examined the evidence for glutamate receptor modulators, including ketamine, as a treatment for depression.

Who will be interested in this review?

‐ People with depression, their friends and families.

‐ General practitioners, psychiatrists, psychologists and pharmacists.

‐ Professionals working in adult mental health services.

What questions does this review aim to answer?

1. Is treatment with ketamine and other glutamate receptor modulators more effective than treatment with placebo (dummy pill) or other drugs?

2. Is treatment with ketamine and other glutamate receptor modulators more acceptable than placebo or other drugs?

Which studies were included in the review?

We searched medical databases to find all relevant studies (specifically randomised controlled trials) completed up to 30 July 2020. To be included in the review, studies had to compare ketamine or other glutamate receptor modulators with placebo, other medicines or electroconvulsive therapy (ECT) for depression in adults (aged 18 and over). The studies also had to be single‐blind (the participant does not know which treatment they are receiving) or double‐blind (neither the participant or researcher know which treatment the participant is receiving), to attempt to reduce bias. We included 64 studies in the review, involving a total of 5299 people. The studies investigated16 different glutamate receptor modulator medications. The majority of participants had treatment‐resistant depression (depression which had not responded to two or more medications) at the start of the studies. Most studies were two‐armed, where the glutamate receptor modulator was compared with one other intervention.

What does the evidence from the review tell us?

Among the 16 drugs included in this review, only ketamine and esketamine were more effective than placebo at reducing symptoms of depression. The effects of ketamine lasted no more than one week after treatment and clearly disappeared after two weeks. Ketamine did, however, cause more side effects than placebo. The effects of esketamine were seen at 24 hours and could last up to four weeks with repeated doses. Esketamine caused a lot more side effects than placebo. The certainty of evidence varied considerably.

There was no evidence of a difference between the other glutamate receptor modulators included in this review and placebo or other medications.

What should happen next?

Ketamine and esketamine appear to reduce the symptoms of depression. However, the trials were all short term so we do not know about the long‐term effects. It is important to note that in some trials attempts to prevent participants and investigators from knowing what medicine was being given were not successful and this may have inflated the positive effects of the active drugs.

Future studies should examine what happens when people are repeatedly given the drug, with the aim to mimic the real‐world practice and assess longer‐term effects. More non‐inferiority trials should be conducted, where glutamate receptor modulators are compared with other active medications rather than placebo to find out whether they are better than alternative treatments.

In most of the ketamine trials in this review, participants were given the drug by injection into a vein. This restricts the wide‐scale application of ketamine in clinical settings, so trials of ketamine by other routes are needed. Esketamine trials usually used nasal sprays, which are easier to use and could potentially be taken at home if further monitoring and trials found that it was safe to do so. Further studies assessing administration are needed in order to draw more reliable and firm conclusions.

Summary of findings

Background

Description of the condition

Major depressive disorder is among the most commonly encountered psychiatric disorder, with reported lifetime and one‐year prevalence rates of 10.8% and 7.2%, respectively (Lim 2018) . Although an episode of depression may happen only once over a person's span, more commonly it is a recurrent condition. During an episode, symptoms are present most of the day, nearly every day, and may include feelings of sadness, emptiness, or unhappiness; loss of interest and pleasure in normal activities; sleep disturbances; tiredness and lack of energy; changes in appetite; frequent thoughts of death; suicidal thoughts; cognitive impairment; and unexplained physical problems. Major depressive disorder is diagnosed clinically by the presence of one or more major depressive episodes, in the absence of manic or hypomanic symptoms, and is also referred to as ’unipolar depression’ (APA 2013; WHO 2008a). Currently estimated to affect 350 million people worldwide, the disorder has been increasingly recognised as a major global health concern (De Leo 2014; WHO 2012), leading to substantial disability (WHO 2008b), impaired quality of life (Rapaport 2005), and considerable economic burden (Donohue 2007). Moreover, depressive illness is associated with an increased risk of suicide (Hawton 2009). Despite the clinical importance of depression, its underlying pathophysiology is still incompletely understood, with various factors suggested to be involved, as well as to serve as potential targets for treatment (Hasler 2010a). One of the most well‐researched theories of previous decades has been the monoamine hypothesis of depression, implying a dysregulation of the 5‐hydroxytryptamine (5‐HT, serotonin), noradrenaline, and dopamine systems (Coppen 1967; Hirschfeld 2000). However, even though robust evidence supports the idea that monoamine neurotransmitters, and serotonin in particular, have a role in the pathophysiology of depression, it appears that simple monoamine depletion is insufficient to account for the development of the disorder (Ruhe 2007).

Description of the intervention

The mainstay of the pharmacological treatment of depression for the last 40 or more years has been monoamine potentiating antidepressants. Tricyclic antidepressants (TCAs) were introduced in the 1950s, the first being imipramine (NICE 2009). The mode of action thought to be responsible for the mood‐elevating properties of this class of drugs is their ability to block the synaptic reuptake of noradrenaline and 5‐HT, exerting re‐uptake of these neurotransmitters at different levels. Although the introduction of the TCAs was welcome, their ability to blockade cholinergic, histaminergic, and other receptor systems resulted in side effects that reduced the acceptability of the drugs. Most TCAs were also potentially lethal in overdose. In response to this, new classes of antidepressants have been developed, including the selective serotonin reuptake inhibitors and related drugs; and also a range of other pharmacologically unrelated antidepressants, like mirtazapine or trazodone. The side effect profile of these agents varies considerably, although their mood‐elevating effects are again thought to be mediated through increasing intrasynaptic levels of monoamines, some primarily affecting noradrenaline, some 5‐HT, and others affecting both noradrenaline and 5‐HT to varying degrees and in different ways (NICE 2009). Generally, they have an improved safety profile relative to TCAs.  In addition to monoamines, various other neurotransmitters have been implicated in the pathogenesis of depression, including the amino acid neurotransmitters, ƴ‐aminobutyric acid (GABA) and glutamate. While decreased plasma levels of GABA have been demonstrated in depressed patients (Petty 1984), results from studies using magnetic resonance spectroscopy (MRS) to measure GABA levels in the brain have been less consistent. Overall, however, it seems likely that brain GABA levels in depression measured by MRS are decreased in depressed patients (Godfrey 2018). Generally, drugs that increase GABA activity, for example, benzodiazepines (Birkenhager 1995) are not thought to be effective antidepressants. Nevertheless, there is recent interest in the rapid antidepressant effect of a GABA‐modulating neurosteroid, brexanolone, which has been licensed for the treatment of post‐partum depression (Zheng 2019).  The discovery of the rapid antidepressant effects of the N‐methyl‐D‐aspartate (NMDA) receptor antagonist, ketamine, has been a great stimulus for investigations into the role of glutamatergic mechanisms in the pathophysiology of depression and its treatment. Magnetic resonance spectroscopy studies of glutamate again are somewhat inconsistent. Overall there may be a decrease in glutamate levels in frontal brain regions in depressed patients (Moriguchi 2019). However, some patient groups appear to have elevated glutamate metabolism in subcortical regions (Godlewska 2018). Post‐mortem findings of glutamate levels in people dying with depression are also inconsistent (Moriguchi 2019). Post‐mortem and in vivo positron emission tomography (PET) imaging evidence more reliably indicate a reduction in cortical and subcortical binding of the mGluR5 receptor, a metabotropic glutamate receptor (Moriguchi 2019). In addition, post‐mortem studies also reveal loss of glial cells in the medial frontal cortex of patients with depression. Glial cells play a key role in the metabolism and synthesis of neuronal glutamate and their loss would have a significant impact on glutamate cycling (Cotter 2001).  The first randomised cross‐over trial demonstrating antidepressant efficacy of a sub‐anaesthetic dose of ketamine (0.5mg/kg) took place in seven depressed patients with evidence of a fast (onset within 24 hours) antidepressant effect (Berman 2000). Since then, researchers have attempted to supplement these findings, mainly by increasing the size of the study population, as well as studying longer‐term effects like durability of benefit following repeated infusions (Diamond 2014; Murrough 2013; Valentine 2011; Zarate 2006a). Esketamine, the s‐enantiomer of ketamine, has recently been licensed for the treatment of resistant depression, following the completion of both acute and maintenance treatment trials. In these studies, nasal esketamine was usually administered once or twice weekly. Similar to intravenous ketamine, nasal esketamine requires administration in a supervised clinical setting.

How the intervention might work

The main pharmacological mechanism of action of ketamine is non‐competitive blockade of the ion channel associated with NMDA receptor complex. However, other drugs with an apparently similar pharmacological profile, for example, memantine, are not apparently effective antidepressants (Zarate 2006b). Therefore, other factors must be involved in ketamine’s antidepressant effect. The currently favoured hypothesis is that blockade of NMDA receptors on inhibitory GABA neurones leads to a glutamate ‘surge’ which then activates 2‐amino‐3‐ (5‐methyl‐3‐oxo‐1,2‐oxazol‐4‐yl)propanoic acid (AMPA) receptors. Simulation of AMPA receptors leads to increased neuroplasticity, with elevated levels of brain‐derived neurotrophic factor (BDNF) and phosphorylation of tropomyosin receptor kinase B (TrkB) (Wilkinson 2019).  Another suggested downstream effector of ketamine is the mammalian target of rapamycin (mTOR) pathway (Li 2010). Activation of the mTOR pathway by ketamine in a rat model has resulted in both an antidepressant effect and formation of spine synapses in the prefrontal cortex, whereas blockade of this pathway abolished this response (Li 2010). An unexplained, contradictory finding which has not yet been replicated is that in depressed patients, blockade of mTOR with rapamycin actually enhanced the antidepressant response to ketamine (Abdallah 2018). Ketamine also has some effects on opiate receptors and one study has shown that pre‐treatment with the opiate receptor blocker, naltrexone, prevented the antidepressant effect of ketamine, suggesting a possible role for opiate mechanisms in its antidepressant action (Williams 2018), although contradictory evidence has also been found in a pilot study (Yoon 2019). Thus, the precise way in which ketamine relieves depressive symptoms is not clear. Ketamine also has several disadvantages in its clinical use as an antidepressant, such as the risk of transient dissociative states following acute administration. There are also concerns about potential adverse effects during longer‐term maintenance treatment; for example, tolerance, dependence, adverse cognitive effects and bladder toxicity.  The surprising antidepressant efficacy of ketamine together with its disadvantages had led to the search for other glutamate modifying drugs as antidepressants. This includes well‐known compounds such as riluzole and d‐cycloserine, as well as agents newly discovered by Industry such as rapastinel and lanicemine. In this respect it is worth noting that the NMDA receptor has several binding sites that can be targeted pharmacologically. In addition, drugs working at the AMPA receptor or metabotropic glutamate autoreceptors may have clinical utility in depression (Wilkinson 2019).

Why it is important to do this review

This review is an update of the previous Cochrane Review (Caddy 2015) and is one of a pair; the other Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults is currently being updated (Dean 2021; McCloud 2015). Reliable information about ketamine and other glutamate receptor modulators in unipolar depression (including modes of administration, comparative efficacy, duration of effect, and safety) is not only clinically useful but also urgently needed because such evidence can improve patients’ outcomes in the treatment of depression and provide a basis for future clinical research and treatment guidelines.

Objectives

To assess the effects of ketamine and other glutamate receptor modulators in comparison to placebo (pill or saline infusion), other pharmacologically active agents, or electroconvulsive therapy (ECT) in alleviating the acute symptoms of depression in people with unipolar major depressive disorder.
To review the acceptability of ketamine and other glutamate receptor modulators in comparison to placebo (pill or saline infusion), other pharmacologically active agents, or ECT in people with unipolar major depressive disorder.

Methods

Criteria for considering studies for this review

Types of studies

We included only double‐blind or single‐blind randomised controlled trials (RCTs) (both published and unpublished) comparing ketamine, memantine, or other glutamate receptor modulators with other active psychotropic drugs or placebo (pill or saline infusion) in people with unipolar major depression.

For trials with a cross‐over design, we considered only results from the first period prior to cross‐over (see Unit of analysis issues for further details).

We planned to include cluster randomised trials (CRTs) where the effect of clustering was or could be accounted for in the statistical analysis (see Unit of analysis issues). However, no CRTs were identified.

We excluded quasi‐randomised trials, such as those allocating by using alternate days of the week, as well as trials that did not explicitly describe the method of allocation as randomised.

Types of participants

Participant characteristics and diagnosis

We considered for inclusion people of both sexes aged 18 years or older with a primary diagnosis of unipolar major depressive disorder according to any of the following standard operational criteria: Feighner criteria (Feighner 1972), Research Diagnostic Criteria (Spitzer 1978), DSM‐III (APA 1980), DSM‐III‐R (APA 1987), DSM‐IV (APA 1994), DSM‐IV‐TR (APA 2000), DSM‐5 (APA 2013), or ICD‐10 (WHO 1992). We included studies using operational diagnostic criteria essentially similar to the above.

We excluded studies using ICD‐9 ((International Classification of Diseases, 9th erevision), as it has only disease names and no diagnostic criteria. We also excluded studies that define depression as scoring above a certain cut‐off on a screening questionnaire.

We included studies recruiting participants with treatment‐resistant depression, and examined this in a sensitivity analysis.

Comorbidities

We included studies in which less than 20% of participants were diagnosed with bipolar depression, and thus at least 80% of participants had unipolar depression, and examined the validity of this decision in a sensitivity analysis. We did not consider concurrent secondary diagnosis of another psychiatric disorder an exclusion criterion. However, we excluded studies in which all participants had concurrent primary diagnosis of another Axis I or II disorder. We also excluded participants with a serious concomitant medical illness or with postpartum depression.

Setting

We applied no restriction on setting.

Subset data

We also included in the analysis studies with a subset of participants that met the review inclusion criteria, provided that we could extract data for this subset from the study report.

Types of interventions

Experimental interventions

Ketamine: any dose and pattern of administration
Riluzole: any dose and pattern of administration
Amantadine: any dose and pattern of administration
Dextromethorphan (alone or in combination with quinidine)
Quinolinic acid: any dose and pattern of administration
Memantine: any dose and pattern of administration
Atomoxetine: any dose and pattern of administration
Tramadol: any dose and pattern of administration
Lanicemine: any dose and pattern of administration
MK‐0657: any dose and pattern of administration
Any other glutamate receptor modulators (for example, D‐cycloserine, GLYX‐13)

Comparator interventions

Placebo (pill or saline infusion)
Any pharmacologically active agent (either conventional, like midazolam, or non‐conventional, like scopolamine or Hypericum) or agent included to mimic the psychotropic side effects of the glutamate agent
Electroconvulsive therapy (ECT)

All interventions could be either as monotherapy or combined with other treatments. We applied no restrictions on dose, frequency, intensity, route, and duration. We included trials that allowed rescue medications (as required, short‐term, infrequent use of medications aimed at emergent symptom relief only, for example short‐term use of hypnotics) as long as these medications were equally distributed among the randomised arms.

We did not include lamotrigine among the list of comparisons because the randomised evidence about this drug has been synthesised elsewhere (Goh 2019; Solmi 2016).

Types of outcome measures

We included studies that met the above inclusion criteria regardless of whether they reported on the following outcomes.

Primary outcomes

Efficacy outcome (dichotomous): number of participants who respond to treatment, where treatment response is defined as (1) a reduction of at least 50% compared to baseline on the Hamilton Rating Scale for Depression (HRSD) (Hamilton 1960), Montgomery‐Åsberg Depression Rating Scale (MADRS) (Montgomery 1979), or any other depression scale, depending on the study authors' definition, or (2) 'much or very much improved' (score 1 or 2) on the Clinical Global Impression‐Improvement scale (CGI‐S) (Guy 1976). Where both scales were provided we preferred the former criteria for judging response. We used the response rate instead of a continuous symptom score for the primary efficacy analysis in order to make the interpretation of results easier for clinicians (Guyatt 1998). To avoid possible outcome reporting bias, we did not use the original authors' definitions of response or remission, if different from above (Furukawa 2007a).
Adverse events outcome (dichotomous): We evaluated adverse events using the following outcome measures.
1. Total number of participants experiencing at least one side effect.
2. Total number of participants experiencing the following specific side effects:
  1. agitation/anxiety;
  2. constipation;
  3. delusions;
  4. diarrhoea;
  5. dissociative symptoms;
  6. dizziness;
  7. dry mouth;
  8. hallucinations;
  9. headache;
  10. hypo/hypertension;
  11. insomnia;
  12. mania/hypomania;
  13. nausea;
  14. seizure;
  15. sleepiness/drowsiness;
  16. urination problems;
  17. vomiting;
  18. tremor.

In order to avoid missing any relatively rare or unexpected, yet important side effects (for instance, sexual side effects), in the data extraction phase we collected information on all side effects data reported in the studies and discussed ways to summarise them post hoc. We extracted descriptive data regarding adverse‐effect profiles from all available studies. Due to a lack of consistent reporting of adverse effects (which came primarily from the study authors' descriptions), we combined terms describing similar side effects. For example, we combined 'dry mouth', 'reduced salivation', and 'thirst' into 'dry mouth'. We then grouped all adverse effect categories by organ system, such as neuropsychiatric, gastrointestinal, respiratory, sensory, genitourinary, dermatological, and cardiovascular.

Secondary outcomes

Efficacy outcome (dichotomous): number of participants who achieve remission. Remission is defined as (1) a score of less than 7 on the HRSD‐17 (Furukawa 2007b), or less than 8 for all the other longer versions of the HRSD, or less than 11 on the MADRS (Bandelow 2006), or less than 6 on the Quick Inventory of Depressive Symptomatology (16‐Item) (Self Report) (http://www.ids-qids.org/); or (2) participants who were 'not ill or borderline mentally ill' (score 1 or 2) on the Clinical Global Impression‐Severity scale out of the total number of randomised participants. Where both are provided, we used the former criterion for judging remission.
Efficacy outcome (continuous): mean endpoint scores or mean change scores in depression severity from baseline to the time point in question. We allowed a looser form of intention‐to‐treat (ITT) analysis, whereby all the participants with at least one post‐baseline measurement were represented by their last observations carried forward (LOCF), but in any pooled analysis we planned to examine the impact of the LOCF in a sensitivity analysis).
Suicidality, including suicidal ideation, suicide attempts (nonfatal self‐harm), and deaths by suicide. We examined suicidality and suicide ideation according to the outcome measures reported in the original studies (either as spontaneously reported or as a score on a standardised rating scale).
Cognition. We examined this according to the outcome measures reported in the original studies.
Loss of hope and other health‐related quality of life measures. We included data on any validated quality of life instruments.
Costs to healthcare services. We collected data according to what was reported in the original studies.
Acceptability (dichotomous), evaluated using the following outcome measures:
1. overall number of participants who dropped out during the trial as a proportion of the total number of randomised participants;
2. number of participants who dropped out due to lack of efficacy during the trial as a proportion of the total number of randomised participants
3. number of participants who dropped out due to side effects during the trial as a proportion of the total number of randomised participants.

Timing of outcome assessment

As study authors report response rates at various time points of trials, we decided a priori to subdivide the treatment indices as follows.

Ultra‐rapid response: at 24 hours, ranging between 12 and 36 hours (primary efficacy outcome).
Rapid response: at 72 hours, ranging between 37 and less than 96 hours.
Early response: at one week, ranging between four and 10 days.
Acute response: at two weeks, ranging between 11 days and less than three weeks.
Medium response: at four weeks, ranging between three and six weeks.
Long‐term response: at three months, ranging between seven weeks and six months.

Hierarchy of outcome measures

When several possible outcome measures are reported for the same outcome, we used the primary outcome according to the original study.

Search methods for identification of studies

Electronic searches

1. Bibliographic databases

For the second version of this review (first published in September 2015 (Caddy 2015)), the Information Specialist with the Cochrane Common Mental Disorders Group (CCMD) conducted update searches (30 July 2020) directly on the core bibliographic databases, from 2015 onwards (Appendix 1):

Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 7) in the Cochrane Library (searched 30 July 2020);
MEDLINE Ovid (2015 to July 28 2020);
Embase Ovid (2015 to 2020 Week 30);
PsycINFO Ovid (2015 to July Week 3).

Earlier searches of these databases was conducted via the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (all years to 9 January 2015) (Appendix 2).

2. International trial registries

International trial registries were searched via CENTRAL on the Cochrane Library and directly via the World Health Organization's trials portal (ICTRP) and ClinicalTrials.gov to identify unpublished or ongoing studies (30 July 2020).

3. Adverse events search

The information Specialist with CCMD also conducted a companion search for adverse events data (30 July 2020) on Ovid MEDLINE, Embase and PsycINFO (Appendix 3), although we have not incorporated these data into this version of the review.

We applied no restrictions on language or publication status to the searches.

Searching other resources

Grey literature

We conducted complementary searches on the websites of the following drug regulatory authorities for additional unpublished data: the US Food and Drug Administration (FDA), the Medicines and Healthcare products Regulatory Agency in the UK, the European Medicines Agency in the EU, the Pharmaceuticals and Medical Devices Agency in Japan, and the Therapeutic Goods Administration in Australia.

Reference lists

We checked the reference lists of all included studies and relevant systematic reviews and major textbooks of affective disorder written in English to identify additional studies missed from the original electronic searches (for example, unpublished or in‐press citations).

Correspondence

We contacted trialists and subject experts for information on unpublished or ongoing studies, or to request additional trial data.

Data collection and analysis

Selection of studies

Two review authors (RD, SH, SS, RS, AB) independently screened titles and abstracts for inclusion of all the potential studies we identified as a result of the search and coded them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We retrieved the full‐text study reports/publication, and two review authors (RD, SH, SS, RS, AB) independently screened the full text and identified studies for inclusion, and identified and recorded reasons for exclusion of the ineligible studies. Any disagreements were resolved through discussion or, if required, by consulting a third person (CH, AC). We identified and removed duplicate records and collated multiple reports that related to the same study so that each study, rather than each report, was the unit of interest in the review. We recorded the selection process in sufficient detail to complete a PRISMA (Moher 2009) flow diagram (Figure 1) and Characteristics of excluded studies tables.

Data extraction and management

We used a data collection form to extract study characteristics and outcome data that had been piloted on at least one study in the review. Two review authors (RD, SH, SS, RS, AB) extracted study characteristics and outcome data from included studies. We extracted the following study characteristics.

Participant characteristics (age, sex, depression diagnosis, comorbidity, depression severity, antidepressant treatment history for the index episode, study setting).
Intervention details (intended dosage range, mean daily dosage actually prescribed, cointervention if any, ketamine as investigational drug or as comparator drug, sponsorship).
Outcome measures of interest from the included studies.

Depression severity was defined using the same criteria set out by Cipriani 2012, with severe depression defined by a baseline score of 25 or more on the HRSD and 31 or more on the MADRS (Dozois 2004; Muller 2003).

We noted in the Characteristics of included studies tables if outcome data were not reported in a usable way. We resolved disagreements by consensus or by involving a third person (AC, CH). Two review authors (RD, SH, SS, RS, AB) transferred data into the Review Manager 5 (Revman 2020) file. We double‐checked that data were entered correctly by comparing the data presented in the systematic review with the study reports. A third review author (RD) checked study characteristics for accuracy against the trial report. The comparisons were done by individual drug (see Types of interventions).

Main comparisons

Ketamine versus placebo
Ketamine versus other glutamate receptor modulators
Ketamine versus other pharmacologically active agents (either conventional, like midazolam, or nonconventional, like scopolamine or Hypericum)
Other glutamate receptor modulators versus placebo
Other glutamate receptor modulators versus other pharmacologically active agents (either conventional, like midazolam, or nonconventional, like scopolamine or Hypericum)
Ketamine versus ECT
Other glutamate receptor modulators versus ECT

Other glutamate receptor modulators will be considered individually as separate comparisons. All interventions could be either as monotherapy or combined with other treatments. We applied no restrictions on dose, frequency, intensity, route, and duration.

Assessment of risk of bias in included studies

Five review authors (RD, SH, SS, RS, AB) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020). Any disagreements were resolved by discussion or by involving another review author (AC, CH). We assessed the risk of bias according to the following domains.

Random sequence generation
Allocation concealment
Blinding of participants and personnel
Blinding of outcome assessment
Incomplete outcome data
Selective outcome reporting
Other bias

We judged each potential source of bias as high, low, or unclear and provide a supporting quotation from the study report together with a justification for our judgement in the risk of bias tables. We summarised the risk of bias judgements across different studies for each of the domains listed. We considered blinding separately for different key outcomes where necessary (for example, for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a participant‐reported mood scale). Where information on risk of bias relates to unpublished data or correspondence with a trialist, we noted this in the risk of bias table.

When considering treatment effects, we took into account the risk of bias for the studies that contribute to that outcome.

Measures of treatment effect

Dichotomous data

We calculated the odds ratio (OR) with corresponding 95% confidence interval (95% CI) for dichotomous or event‐like outcomes. We calculated response rates out of the total number of randomised participants. We applied ITT analysis whereby all dropouts not included in the analysis were considered as nonresponders. For statistically significant results, we calculated the number needed to treat to benefit (NNTB) and the number needed to treat to harm (NNTH).

Continuous data

We calculated the mean difference (MD) or standardised mean difference (SMD) along with corresponding 95% CI for continuous outcomes. We used the MD where the same scale was used to measure an outcome. We employed the SMD where different scales were used to measure the same underlying construct.

For both continuous and dichotomous data, we undertook meta‐analyses only where this was meaningful, that is if the treatments, participants, and the underlying clinical question were similar enough for pooling to make sense. We described narratively skewed data reported as medians and interquartile ranges.

Where multiple trial arms were reported in a single trial, we included only the relevant arms.

Unit of analysis issues

Cluster‐randomised trials

No cluster‐randomised trials were found in the search, however we would have included cluster‐randomised trials if either of the two methods below were possible.

\if the cluster‐randomised trial was correctly analysed in the original report, we would have entered the effect estimate and standard error using the generic inverse variance method in RevMan 5 (Revman 2020).
If the original report failed to adjust for cluster effects, we planned to include such a trial in the meta‐analysis if we were able to extract the following information:
1. number of clusters randomised to each intervention or the average size of each cluster;
2. outcome data ignoring the cluster design for the total number of participants;
3. estimate of the intracluster correlation coefficient (ICC).

The ICC could be borrowed from similarly‐designed studies when such were available. We then conducted the approximately correct analysis following the procedures described in section 16.3.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020).

Cross‐over trials

A major concern of cross‐over trials is the potential of carry‐over effects, which occur when an effect (for example, pharmacological, physiological, or psychological) of the treatment in the first phase is carried over to the second phase. As a consequence, on entry to the second phase, the participants can differ systematically from their initial state, despite a washout phase. For the same reason, cross‐over trials are not appropriate if the condition of interest is unstable (Elbourne 2002). As both effects are very likely in major depression, we only used data from the first phase of cross‐over studies. However, we are aware that cross‐over trials for which only first period data are available should be considered to be at risk of bias (Higgins 2020).

Studies with multiple treatment groups

Where a study involved more than two treatment arms, we included all relevant treatment arms in comparisons. If data were binary, we simply added and combined them into one group or divided the comparison arm into two (or more) as appropriate. If data were continuous, we combined data following the formula in section 6.5.2.10 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020).

Dealing with missing data

Dichotomous data

We calculated treatment responders and treatment remitters on a strict ITT basis; we included dropouts in the analysis. Where participants were excluded from the trial before the endpoint, we assumed that they experienced a negative outcome (for example, failure to respond to treatment). We examined the validity of this decision in sensitivity analyses by applying worst‐ and best‐case scenarios (that is we assumed missing data to be responders or nonresponders in the corresponding sensitivity analyses). When dichotomous outcomes were not reported but baseline mean, endpoint mean, and corresponding standard deviations (SDs) of the HRSD (or other depression scale) were reported, we converted continuous outcome data expressed as mean and SD into the number of responding and remitted participants, based on a validated imputation method (Furukawa 2005). If a more sophisticated and arguably more valid imputation method was reported in the original study (for example mixed‐effects model), we used these numbers to impute the number of responders. We examined the validity of this imputation in sensitivity analyses.

Continuous data

When there were missing continuous data and the method of LOCF was used to perform an ITT analysis, we used the LOCF data.

Missing data

We contacted the original study authors for missing data.

Missing statistics

When only the standard error or t‐test or P values were reported, we calculated SDs as suggested by Altman 1996. Where SDs were not reported, we contacted trial authors and asked them to supply the data. In the absence of a response from the trial authors, we borrowed SDs from other studies in the review, if possible, or calculated the SDs according to a validated imputation method (Furukawa 2006). We examined the validity of this imputation in sensitivity analyses.

Assessment of heterogeneity

We first investigated heterogeneity between studies by visual inspection of the forest plots. If the 95% confidence intervals (CIs) of the ORs for each study in the pooled analysis did not include means of other studies, we investigated potential sources of heterogeneity. We also calculated the I² statistic (Higgins 2020). We used the Cochrane Handbook for Systematic Reviews of Interventions' rough guide to its interpretation as follows: 0% to 40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; and 75% to 100%, considerable heterogeneity. We also kept in mind that the importance of the observed value of I² depends on (i) the magnitude and direction of effects and (ii) the strength of evidence for heterogeneity (for example P value from the Chi² test, or a CI for I²). If the I² value was below 50%, but the direction and magnitude of treatment effects were suggestive of important heterogeneity, we investigated the potential sources of heterogeneity. Finally, we planned to perform subgroup analyses to investigate heterogeneity. We reported I² values in all analyses including two or more studies.

Assessment of reporting biases

We planned to enter data from included studies into a funnel plot (trial effect against trial variance) to investigate small‐study effects (Sterne 2000), but none of our analyses contained sufficient studies to allow this. In future updates of this review, we plan to use the test for funnel plot asymmetry only when at least 10 studies are included in the meta‐analysis, as per protocol. In the event of using a funnel plot, we will interpret results cautiously, with visual inspection of the funnel plots (Higgins 2011a). If we identify evidence of small‐study effects, we will investigate possible reasons for funnel plot asymmetry, including publication bias (Egger 1997).

Data synthesis

For the primary analysis, we calculated the pooled OR with corresponding 95% CI for dichotomous outcomes. We calculated the pooled MD or SMD as appropriate with corresponding 95% CIs for continuous outcomes. We presented any skewed data and non quantitative data descriptively. An outcome that has a minimum score of zero could be considered skewed when the mean is smaller than twice the SD. However, the skewness of change scores is difficult to depict as the possibility of negative values exists. We therefore used change scores for meta‐analysis of mean difference MDs. We considered a P value of less than 0.05 and a 95% CI that does not cross the line of no effect statistically significant. In forest plots with two or more studies we used a random‐effects model for both dichotomous and continuous variables. We adopted the random‐effects model under these circumstances because it has the highest generalisability for empirical examination of summary effect measures in meta‐analyses (Furukawa 2002). However, as recommended by the Cochrane Handbook for Systematic Reviews of Interventions (10.4.4.1), to assess the influence of small‐study effects on the results of a meta‐analysis with between‐study heterogeneity, we routinely examined the robustness by comparing the fixed‐effect model and the random‐effects model. We reported any material differences between the models.

Subgroup analysis and investigation of heterogeneity

As multiple analyses will lead to false‐positive and false‐negative conclusions, subgroup analyses should be performed and interpreted with caution (Brookes 2001; Brookes 2004). We planned the following subgroup analyses, where possible, for the following variables.

Depression severity (severe major depression, moderate or mild major depression): 'Severe major depression' was defined by a threshold baseline severity score for entry of 25 or more for the 17‐item HRSD (Dozois 2004), and 31 or more for MADRS (Muller 2003).
Treatment settings (psychiatric inpatients, psychiatric outpatients, primary care): As depressive disorder in primary care has a different profile than that of psychiatric inpatients or outpatients (Suh 1997), it is possible that results obtained from either of these settings may not be applicable to the other settings (Arroll 2009).
Older people (greater than 65 years of age), separately from other adult participants: Older people may be more vulnerable to adverse effects associated with antidepressants, and a decreased dosage is often recommended. We planned to pool groups whose mean age was more than 65 years.

Sensitivity analysis

We originally planned the following sensitivity analyses for primary outcomes.

Excluding trials with unclear allocation concealment or unclear double blinding.
Excluding studies that included participants with bipolar depression or psychotic features.
Excluding studies that recruited participants with treatment‐resistant depression (defined as inadequate response to at least two antidepressants).
Excluding studies with unfair dose comparisons (Cipriani 2009).
Excluding trials with a dropout rate greater than 20%.
Excluding trials for which the response rates had to be calculated based on an imputation method (Furukawa 2005), and for which the SD had to be borrowed from other trials (Furukawa 2006).

We decided post‐hoc to conduct the following additional sensitivity analyses for primary outcomes.

Excluding trials with add‐on ECT
Excluding multiple doses

Our routine comparisons of random‐effects and fixed‐effect models, as well as our secondary outcomes of remission rates and continuous severity measures, may be considered additional forms of sensitivity analyses.

Summary of findings and assessment of the certainty of the evidence

We constructed a summary of findings table for the main comparisons (ketamine versus placebo, ketamine versus midazolam, and esketamine versus placebo), with regard to the following five outcomes. Where possible, we presented data at all four prespecified time points for the primary outcomes. For secondary outcomes, we selected a primary time point of 24 hours as this was considered the most clinically relevant, and presented the data closest to this time point only.

Efficacy: number of participants who respond to treatment.
Acceptability: total dropouts.
Efficacy: number of participants who achieve remission.
Severity of depression at end of trial.
Acceptability: dropouts due to adverse effects.

In the summary of findings tables, we used GRADEproGDT software (GradePro GDT 2020) and the principles of the GRADE (Schünemann 2013) approach, which assesses the quality of a body of evidence based on the extent to which there can be confidence that the obtained effect estimate reflects the true underlying effect. The quality of a body of evidence is judged on the basis of the included studies’ risks of bias, the directness of the evidence, unexplained heterogeneity, imprecision, and the risk of publication bias. We used the average rate in all the arms of the included trials as the 'assumed risk' for each outcome because we did not expect salient differences in such risks among different agents. We therefore did not target any particularly high‐ or low‐risk populations; all the tables are for medium‐risk populations.

Results

Description of studies

Results of the search

CCMD’s Information Specialist ran update searches using two separate strategies, one for effectiveness (CENTRAL, Ovid MEDLINE, Embase, PsycINFO, Trial Registers 2015 to 30 July 2020) (n = 5075 refs), and one for adverse effects data (Ovid MEDLINE, Embase, PsycINFO, Trial Registers, 2015 to 30 July 2020) (n = 1834). This has been reported in the PRISMA (Moher 2009) diagram (Figure 1).

From a total of 6909 records retrieved from the searches, we removed 3096 duplicate records and excluded a further 3603 on the basis of the title and abstract. We retrieved the full‐text articles for 210 records, yielding 39 new studies.

Included studies

See: Characteristics of included studies; Figure 1.

The initial version of this Cochrane Review (Caddy 2015) identified 25 studies (corresponding to 23 primary references and 61 references overall; 1242 participants) which met the inclusion criteria for this review (Berk 2014; Berman 2000; Ghasemi 2013; Heresco‐Levy 2006; Heresco‐Levy 2013; Huang 2013; Ibrahim 2012a; Ibrahim 2012b; Jarventausta 2013; Lapidus 2014; Loo 2012; Michelson 2007; Murrough 2013; Nations 2012 (part I); Nations 2012 (part II); Omranifard 2014; Preskorn 2008; Sanacora 2014 (a); Sanacora 2014 (b); Smith 2013; Sos 2013; Yoosefi 2014; Zarate 2006a; Zarate 2006b; Zarate 2013). Of these 25 studies, eight RCTs assessed the efficacy of ketamine (Berman 2000; Ghasemi 2013; Lapidus 2014; Loo 2012; Murrough 2013; Sos 2013; Yoosefi 2014; Zarate 2006a); three assessed memantine (Omranifard 2014; Smith 2013; Zarate 2006b); three assessed AZD6765 (Sanacora 2014 (a); Sanacora 2014 (b); Zarate 2013); two assessed D‐cycloserine (Heresco‐Levy 2006; Heresco‐Levy 2013); two assessed Org26576 (Nations 2012 (part I); Nations 2012 (part II)); and one each assessed atomoxetine (Michelson 2007), CP‐101,606 (Preskorn 2008), MK‐0657 (Ibrahim 2012b), N‐acetylcysteine (Berk 2014), riluzole (Ibrahim 2012a), and sarcosine (Huang 2013). One study which was previously included in the ketamine comparison, was re‐evaluated as assessing esketamine (Jarventausta 2013).

Thirty‐nine new studies met the inclusion criteria for this updated review (Abbasinazari 2015; Amidfar 2016; Anderson 2017; Arabzadeh 2018; Canuso 2018; Carspecken 2018; Chen 2017; Chen 2018; Correia‐Melo 2020; Daly 2018; Downey 2016; Fava 2018; Fedgchin 2019; Fernie 2017; Fu 2020; Gálvez 2018; Grunebaum 2018; Hu 2016; Ionescu 2018; Ionescu 2020; Jagtiani 2014; Kuşçu 2015; Li 2016; Ochs‐Ross 2020; Preskorn 2015; Popova 2019; Quiroz 2016; Roohi‐Azizi 2017; Salardini 2016; Salehi 2015; Sanacora 2017; Shams Alizadeh 2015; Shiroma 2020; Singh 2016 a; Singh 2016 b; Su 2017; Sumner 2020; Tiger 2020; Umbricht 2020).

The new search identified an additional 22 RCTs for inclusion assessing the efficacy of ketamine (Anderson 2017; Arabzadeh 2018; Carspecken 2018; Chen 2017; Chen 2018; Correia‐Melo 2020; Downey 2016; Fava 2018; Fernie 2017; Gálvez 2018; Grunebaum 2018; Hu 2016; Ionescu 2018; Jagtiani 2014; Kuşçu 2015; Li 2016; Salehi 2015; Shams Alizadeh 2015; Shiroma 2020; Singh 2016 a; Su 2017; Sumner 2020; Tiger 2020); eight assessing esketamine (Canuso 2018; Correia‐Melo 2020; Daly 2018; Fedgchin 2019; Fu 2020; Ionescu 2020; Ochs‐Ross 2020; Popova 2019; Singh 2016 b); two assessing memantine (Abbasinazari 2015; Amidfar 2016); two assessing lanicemine (Downey 2016; Sanacora 2017), one assessing basimglurant (Quiroz 2016), one assessing citicoline (Roohi‐Azizi 2017); one assessing decoglurant (Umbricht 2020); one assessing rapastinel (Preskorn 2015); one assessing riluzole (Salardini 2016).

The majority of included studies were placebo‐controlled trials (48 out of 64, 75%), with the remaining 16 studies directly comparing a glutamate receptor modulator with an active comparison (citalopram, electroconvulsive therapy (ECT), esketamine, midazolam, methohexital, remifentanil hydrochloride, thiopental). The majority were two‐arm studies (48 out of 64, 75%), whilst nine of the remaining studies (Chen 2018; Fedgchin 2019; Li 2016; Nations 2012 (part II); Quiroz 2016; Sanacora 2014 (b); Sanacora 2017; Singh 2016 b; Su 2017) employed a three‐arm methodology, comparing differing doses of an active drug to placebo. Two studies utilised three‐arm methodologies to compare ketamine with both an active comparator and placebo (Downey 2016; Kuşçu 2015). Four used four‐ and five‐arm methodologies to test differing doses of ketamine versus placebo, respectively (Daly 2018; Fava 2018; Preskorn 2015; Umbricht 2020). Another used a four‐arm methodology to test differing treatment regimens (either two or three times weekly) for ketamine against placebo (Singh 2016 a).

Design

All of the studies were double‐blind randomised controlled trials (RCTs), with the exception of Ghasemi 2013, which was single‐blind study, and Kuşçu 2015 in which blinding was at least single‐blind but unclear on double‐blinding (for full details about study blinding, please refer to Characteristics of included studies). Eight of the 64 studies had a cross‐over design (Berman 2000; Heresco‐Levy 2006; Ibrahim 2012b; Lapidus 2014; Sos 2013; Sumner 2020; Zarate 2006a; Zarate 2013). The treatment period ranged from one single administration to 12 weeks.

Sample sizes

The total number of participants from the 64 studies was 5299, with a minimum sample size of five (Ibrahim 2012b; Gálvez 2018) and a maximum of 357 (Umbricht 2020).

Setting

The majority of trials treated patients on an outpatient basis (24 studies), inpatient basis (20 studies), or both (five studies), whilst in the remaining trials the setting was unclear (15 studies). Twenty‐three out of the 64 trials took place in the USA, 16 in Asia, eight in Europe, three in Australia, one in New Zealand one in South America, nine cross‐continental, and in three the study was unclear. Thirty‐one out of the 64 trials were single‐centre studies; 23 were multi‐centre and in the remaining 10 trials it was unclear whether the studies were single‐centred or multi‐centred.

Participants

All studies reported the demographic and/or clinical characteristics of patients, with the exception of Ibrahim 2012b, where no details were reported. The proportion of women ranged from 0% (Gálvez 2018) to 87.5% (Su 2017). Two studies (Omranifard 2014; Ochs‐Ross 2020) recruited older adults above age 60, whilst in the remaining studies mean age ranged from 25.7 to 58.7 years.

The majority of studies defined an inclusion criterion specifying the severity of depression: 29 of these studies specified at least moderate depression; 17 of these studies specified severe depression and five specified mild‐moderate depression. Nineteen studies (Carspecken 2018; Daly 2018; Fava 2018; Fedgchin 2019; Heresco‐Levy 2013; Ibrahim 2012a; Ibrahim 2012b; Jarventausta 2013; Kuşçu 2015; Murrough 2013; Popova 2019; Preskorn 2008; Salehi 2015; Sanacora 2014 (a); Sanacora 2014 (b); Shiroma 2020; Singh 2016 a; Singh 2016 b; Zarate 2006a) recruited only treatment‐resistant patients, which we defined as inadequate response to at least two antidepressants.

In 59 of the 64 studies patients had a diagnosis of unipolar major depression based on the DSM‐IV, DSM‐IV‐TR, or DSM‐V criteria. The remaining five studies (Berman 2000; Ghasemi 2013; Loo 2012; Anderson 2017; Gálvez 2018), recruited mixed samples of major depressive disorder and bipolar depression, with 11.11%, 5.56%, 19.57%, 15.7%, and 25% of the sample diagnosed with bipolar disorder, respectively. One study (Jarventausta 2013) recruited patients with recurrent severe or psychotic major depressive disorder, with 10 out of the 32 participants suffering from psychotic major depressive disorder.

Interventions

A total of 31 studies included ketamine as the experimental intervention; 16 compared ketamine with placebo (Anderson 2017; Arabzadeh 2018; Berman 2000; Chen 2017; Chen 2018; Hu 2016; Ionescu 2018; Lapidus 2014; Li 2016; Loo 2012; Shams Alizadeh 2015; Singh 2016 a; Sos 2013; Su 2017; Tiger 2020; Zarate 2006a); five compared ketamine with midazolam (Fava 2018; Gálvez 2018; Grunebaum 2018; Murrough 2013; Shiroma 2020); four compared ketamine with thiopental (Jagtiani 2014; Kuşçu 2015; Salehi 2015; Yoosefi 2014); one compared ketamine with esketamine (Correia‐Melo 2020); one compared ketamine with lanicemine (Downey 2016); one compared ketamine with methohexital (Carspecken 2018); one compared ketamine with propofol (Fernie 2017); one compared ketamine with remifentanil hydrochloride (Sumner 2020); and one compared ketamine with ECT (Ghasemi 2013).

Fifteen different glutamate receptor modulators were compared with placebo in 32 studies: esketamine (Canuso 2018; Daly 2018; Fedgchin 2019; Fu 2020; Ionescu 2020; Jarventausta 2013; Ochs‐Ross 2020; Popova 2019; Singh 2016 b); memantine (Abbasinazari 2015; Amidfar 2016; Omranifard 2014; Smith 2013; Zarate 2006b); lanicemine (Sanacora 2014 (a); Sanacora 2014 (b); Sanacora 2017; Zarate 2013); D‐cycloserine (Heresco‐Levy 2006; Heresco‐Levy 2013); Org 26576 (Nations 2012 (part I); Nations 2012 (part II)); riluzole (Ibrahim 2012a; Salardini 2016); atomoxetine (Michelson 2007); basimglurant (Quiroz 2016); citicoline (Roohi‐Azizi 2017); CP‐101,606 (Preskorn 2008); decoglurant (Umbricht 2020); MK‐0657 (Ibrahim 2012b); N‐acetylcysteine (Berk 2014); rapastinel (Preskorn 2015). Sarcosine was compared with an active comparator, citalopram, in one study (Huang 2013).

Ketamine was administered intravenously in all studies except three, of which two were administered intranasally (Gálvez 2018; Lapidus 2014), and one was administered orally (Arabzadeh 2018). Esketamine was administered intranasally in all studies except for three in which the drug was administered intravenously (Correia‐Melo 2020; Jarventausta 2013; Singh 2016 b). The majority of the remaining glutamate receptor modulators were administered orally, with the exception of CP‐101,606 (Preskorn 2008) and AZD6765 (Sanacora 2014 (a); Sanacora 2014 (b); Sanacora 2017; Zarate 2013), which were administered intravenously. All comparator interventions matched the administration method of the glutamate receptor modulator, with the exception of ECT versus ketamine (Ghasemi 2013).

In the majority of studies, patients received concomitant medication for their depression alongside the experimental intervention. However, in five studies this information was unclear (Abbasinazari 2015; Chen 2017; Michelson 2007; Sanacora 2014 (a); Yoosefi 2014).

Outcomes

Most studies reported on at least one dichotomous efficacy outcome of response and remission rate. There were eight exceptions (Carspecken 2018; Downey 2016; Fernie 2017; Jagtiani 2014; Salehi 2015; Shams Alizadeh 2015; Singh 2016 b; Sumner 2020).

The continuous efficacy outcome in all included studies was measured on MADRS or HRSD. We imputed missing response and remission rates for 10 studies (Berman 2000; Ghasemi 2013; Loo 2012; Michelson 2007; Murrough 2013; Nations 2012 (part I); Nations 2012 (part II); Sos 2013; Yoosefi 2014; Sanacora 2017) using a validated method reported by Furukawa 2005. We imputed the combined group depression rating scale scores for groups using the same glutamate receptor modulator at different doses (Chen 2018; Fedgchin 2019; Li 2016; Quiroz 2016; Sanacora 2017) using the validated method of Higgins 2011d. We imputed missing SDs for one study (Yoosefi 2014) using P values and a method validated by Altman 1996.

Five comparisons did not include any data about adverse events (namely ketamine versus esketamine, ketamine versus methohexital, ketamine versus propofol, ketamine versus remifentanil hydrochloride, and MK‐0657 versus placebo), while increase in systolic blood pressure and heart rate was the only adverse event with usable information in the comparison ketamine versus ECT. For acceptability outcomes, 23 studies reported data on total dropout rates, six on dropouts due to adverse events, and one on dropouts due to lack of efficacy.

Excluded studies

(See: Characteristics of excluded studies and Figure 1)

We excluded 174 studies. The main reasons for exclusions were study design (44), secondary publications (26), or wrong population (24).

Ongoing studies

(See Characteristics of ongoing studies and Figure 1)

After screening retrieved records and checking full‐texts, we identified 43 ongoing studies.

Studies awaiting classification

(See Characteristics of studies awaiting classification and Figure 1)

We identified 9 studies awaiting classification.

Risk of bias in included studies

See Characteristics of included studies for the risk of bias judgement for each study. A summary of the overall risk of bias is presented in Figure 2 and Figure 3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

We cannot rule out the potential bias introduced by inadequate blinding procedures. For instance, saline infusion does not necessarily provide adequate blinding for ketamine, as both patients and personnel can probably guess which treatment a patient has received based on differences during the infusion; for example, psychotomimetic side effects. The assessment of bias reported below is based on the adequacy of blinding attempts as described in each papers’ methods, not on the actual degree of blinding achieved. We rated studies as 'low risk' when all measures used to blind study participants and personnel from knowledge of which intervention a participant received was described. We rated studies as 'unclear risk' when there was a lack of information on blinding procedures. Of the 31 included studies assessing the efficacy of ketamine, five tested the blinding and provided information relating to whether the intended blinding was effective (Anderson 2017; Fava 2018; Shiroma 2020; Sumner 2020; Tiger 2020). Blinding was found to be ineffective in all of these studies, with the exception of one study in which participants received concomitant ECT (Anderson 2017).

Allocation

Random sequence generation

The majority of included studies (Abbasinazari 2015; Amidfar 2016; Anderson 2017; Arabzadeh 2018; Canuso 2018; Carspecken 2018; Chen 2017; Chen 2018; Correia‐Melo 2020; Daly 2018; Fava 2018; Fedgchin 2019; Fernie 2017; Fu 2020; Gálvez 2018; Grunebaum 2018; Heresco‐Levy 2013; Huang 2013; Ionescu 2018; Ionescu 2020; Jagtiani 2014; Lapidus 2014; Li 2016; Loo 2012; Michelson 2007; Murrough 2013; Nations 2012 (part I); Ochs‐Ross 2020; Omranifard 2014; Popova 2019; Preskorn 2015; Quiroz 2016; Roohi‐Azizi 2017; Salardini 2016; Salehi 2015; Sanacora 2017; Shams Alizadeh 2015; Shiroma 2020; Singh 2016 a; Singh 2016 b; Smith 2013; Sos 2013; Sumner 2020; Tiger 2020; Umbricht 2020; Yoosefi 2014; Zarate 2006a; Zarate 2013) reported detail on the method of random sequence generation and we classified them as 'low risk'. The remaining 16 studies (Berk 2014; Berman 2000; Downey 2016; Ghasemi 2013; Heresco‐Levy 2006; Hu 2016; Ibrahim 2012a; Ibrahim 2012b; Jarventausta 2013; Kuşçu 2015; Nations 2012 (part II); Preskorn 2008; Sanacora 2014 (a); Sanacora 2014 (b); Su 2017; Zarate 2006b) described the trials as randomised, but gave no details of the methods used to achieve random allocation, so we classified them as 'unclear risk'.

Allocation concealment

Thirty‐eight of the studies (Abbasinazari 2015; Amidfar 2016; Anderson 2017; Arabzadeh 2018; Canuso 2018; Carspecken 2018; Chen 2017; Chen 2018; Correia‐Melo 2020; Downey 2016; Fava 2018; Fedgchin 2019; Fernie 2017; Fu 2020; Huang 2013; Ibrahim 2012a; Ionescu 2018; Ionescu 2020; Jagtiani 2014; Lapidus 2014; Li 2016; Loo 2012; Murrough 2013; Nations 2012 (part I); Ochs‐Ross 2020; Omranifard 2014; Popova 2019; Preskorn 2008; Preskorn 2015; Quiroz 2016; Roohi‐Azizi 2017; Salardini 2016; Sanacora 2017; Shiroma 2020; Singh 2016 a; Smith 2013; Tiger 2020; Umbricht 2020) reported details on allocation concealment and we classified them as 'low risk'. We classified one study (Yoosefi 2014) as 'high risk' due to randomisation being conducted by one of the trial investigators. We classified the remaining 25 studies (Berk 2014; Berman 2000; Daly 2018; Gálvez 2018; Ghasemi 2013; Grunebaum 2018; Heresco‐Levy 2006; Heresco‐Levy 2013; Hu 2016; Ibrahim 2012b; Jarventausta 2013; Kuşçu 2015; Michelson 2007; Nations 2012 (part II); Salehi 2015; Sanacora 2014 (a); Sanacora 2014 (b); Shams Alizadeh 2015; Singh 2016 b; Sos 2013; Su 2017; Sumner 2020; Zarate 2006a; Zarate 2006b; Zarate 2013) as 'unclear risk' as they did not provide details of the methods used to achieve allocation concealment.

Blinding

Other potential sources of bias

We rated 14 studies as high risk due to being funded by pharmaceutical companies and authors having the potential to financially benefit from positive findings (Canuso 2018; Daly 2018; Downey 2016; Fava 2018; Fedgchin 2019; Fu 2020; Ionescu 2018; Ionescu 2020; Ochs‐Ross 2020; Popova 2019; Preskorn 2015; Quiroz 2016; Sanacora 2017; Umbricht 2020).

Effects of interventions

See: Table 1; Table 2; Table 3

Summary of findings 1. Ketamine compared to placebo for adults with unipolar major depressive disorder.

Ketamine compared to Placebo for adults with unipolar major depressive disorder
Patient or population: adults (aged 18 years+) with unipolar major depressive disorder  Setting: any setting (outpatient, inpatient, or both)  Intervention: ketamine  Comparison: placebo
Outcomes	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**			Certainty of the evidence (GRADE)	What happens
		Without ketamine	With ketamine	Difference
Efficacy: number of participants who respond to treatment ‐ at 24 hours (Response) assessed with: HDRS, HDRS‐17, MADRS № of participants: 185 (7 RCTs)	OR 3.94 (1.54 to 10.10)	Study population			⊕⊝⊝⊝ VERY LOW ^{1 2}
		8.8%	27.4% (12.9 to 49.2)	18.7% more (4.1 more to 40.4 more)
Efficacy: number of participants who achieve remission ‐ at 24 hours (Remission) assessed with: MADRS, HDRS № of participants: 75 (3 RCTs)	OR 5.60 (1.07 to 29.46)	Study population			⊕⊝⊝⊝ VERY LOW ^{3 4}
		2.4%	12.0% (2.5 to 41.8)	9.6% more (0.2 more to 39.4 more)
Depression rating scale score ‐ at 24 hours assessed with: HDRS, HDRS‐17, MADRS № of participants: 231 (8 RCTs)	‐	‐	‐	SMD 0.87 lower (1.26 lower to 0.48 lower)	⊕⊝⊝⊝ VERY LOW ^{1 2 5}
Acceptability: total dropouts № of participants: 201 (6 RCTs)	OR 1.25 (0.19 to 8.28)	Study population			⊕⊝⊝⊝ VERY LOW ^{1 2 6}
		34.0%	39.1% (8.9 to 81)	5.2% more (25.1 fewer to 47 more)
Acceptability: dropouts due to adverse effects ‐ not reported	‐	‐	‐		‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; HDRS: Hamilton Depression Rating Scale; MADRS: Montgomery‐Asberg Depression Rating Scale; OR: Odds ratio;RCT: randomised controlled trial;SMD: standardised mean difference.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Ketamine compared to Midazolam for adults with unipolar major depressive disorder
Patient or population: adults (aged 18 years+) with unipolar major depressive disorder  Setting: any setting (outpatient, inpatient, or both)  Intervention: ketamine  Comparison: midazolam
Outcomes	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**			Certainty of the evidence (GRADE)	What happens
		Without ketamine	With ketamine	Difference
Efficacy: number of participants who respond to treatment ‐ at 24 hours assessed with: HAM‐D‐6, HAM‐D‐17, MADRS № of participants: 296 (4 RCTs)	OR 2.48 (1.00 to 6.18)	Study population			⊕⊝⊝⊝ VERY LOW ^{1 2 3}
		25.9%	46.5% (25.9 to 68.4)	20.5% more (0 fewer to 42.5 more)
Efficacy: number of participants who achieve remission ‐ at 24 hours assessed with: MADRS № of participants: 122 (2 RCTs)	OR 2.21 (0.67 to 7.32)	Study population			⊕⊕⊝⊝ LOW ^{2 3}
		18.0%	32.7% (12.8 to 61.6)	14.7% more (5.2 fewer to 43.6 more)
Depression rating scale score ‐ at 24 hours assessed with: MADRS № of participants: 297 (4 RCTs)	‐	‐	‐	SMD 0.49 lower (0.87 lower to 0.1 lower)	⊕⊝⊝⊝ VERY LOW ^{1 2 3}
Acceptability: total dropouts № of participants: 72 (1 RCT)	OR 0.33 (0.05 to 2.09)	Study population			⊕⊕⊝⊝ LOW ⁴
		12.0%	4.3% (0.7 to 22.2)	7.7% fewer (11.3 fewer to 10.2 more)
Acceptability: dropouts due to adverse effects ‐ not reported	‐	‐	‐		‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval;HAM‐D: Hamilton Depression Rating Scale; MADRS: Montgomery‐Asberg Depression Rating Scale;OR: Odds ratio; RCT: randomised controlled trial; SMD: standardised mean difference.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Esketamine compared to Placebo for adults with unipolar major depressive disorder
Patient or population: adults (aged 18 years+) with unipolar major depressive disorder  Setting: any setting (outpatient, inpatient, or both)  Intervention: esketamine  Comparison: placebo
Outcomes	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**			Certainty of the evidence (GRADE)	What happens
		Without esketamine	With esketamine	Difference
Efficacy: number of participants who respond to treatment ‐ at 24 hours (Response) assessed with: MADRS № of participants: 1071 (5 RCTs)	OR 2.11 (1.20 to 3.68)	Study population			⊕⊕⊝⊝ LOW ^{1 2}
		15.0%	27.1% (17.5 to 39.4)	12.1% more (2.5 more to 24.4 more)
Efficacy: number of participants who achieve remission ‐ at 24 hours (Remission) assessed with: MADRS № of participants: 894 (5 RCTs)	OR 2.74 (1.71 to 4.40)	Study population			⊕⊕⊕⊝ MODERATE ¹
		7.2%	17.5% (11.7 to 25.4)	10.3% more (4.5 more to 18.2 more)
Depression rating scale score ‐ at 24 hours assessed with: MADRS № of participants: 824 (4 RCTs)	‐	‐	‐	SMD 0.31 lower (0.45 lower to 0.17 lower)	⊕⊕⊕⊝ MODERATE ¹
Acceptability: total dropouts № of participants: 773 (5 RCTs)	OR 1.58 (0.92 to 2.73)	Study population			⊕⊕⊕⊝ MODERATE ¹
		8.5%	12.9% (7.9 to 20.3)	4.3% more (0.6 fewer to 11.8 more)
Acceptability: dropouts due to adverse effects ‐ not reported	‐	‐	‐		‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).   CI: Confidence interval; MADRS: Montgomery‐Asberg Depression Rating Scale; OR: Odds ratio; RCT: randomised controlled trial; SMD: standardised mean difference.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Date	Event	Description
13 September 2021	Amended	Typo corrected in the search methods and Appendix 3.
9 September 2021	New citation required but conclusions have not changed	Review has been updated: Ketamine and esketamine may be more efficacious than placebo at 24 hours, however evidence is of low or very low quality.
9 September 2021	New search has been performed	Thirty‐nine new trials identified.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Response rate	12		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
1.1.1 at 24 hours	7	185	Odds Ratio (M‐H, Random, 95% CI)	3.94 [1.54, 10.10]
1.1.2 at 72 hours	4	83	Odds Ratio (M‐H, Random, 95% CI)	15.84 [3.68, 68.12]
1.1.3 at 1 week	5	196	Odds Ratio (M‐H, Random, 95% CI)	3.76 [0.98, 14.42]
1.1.4 at 2 weeks	4	206	Odds Ratio (M‐H, Random, 95% CI)	2.92 [0.48, 17.78]
1.1.5 at 4 weeks	4	202	Odds Ratio (M‐H, Random, 95% CI)	1.37 [0.50, 3.77]
1.1.6 at 3 months	3	117	Odds Ratio (M‐H, Random, 95% CI)	1.95 [0.24, 15.69]
1.2 AE Abdominal Pain	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
1.3 AE Agitation/anxiety	3	143	Odds Ratio (M‐H, Random, 95% CI)	3.44 [1.07, 11.04]
1.4 AE Blurred vision	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
1.5 AE Change in blood pressure	2	157	Odds Ratio (M‐H, Random, 95% CI)	3.23 [0.49, 21.31]
1.6 AE Confusion	2	76	Odds Ratio (M‐H, Random, 95% CI)	3.76 [1.13, 12.47]
1.7 AE Dissociative symptoms	3	145	Odds Ratio (M‐H, Random, 95% CI)	7.72 [1.31, 45.51]
1.8 AE Dizziness	3	196	Odds Ratio (M‐H, Random, 95% CI)	1.74 [0.52, 5.81]
1.9 AE Emotional blunting	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
1.10 AE Euphoria	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
1.11 AE Hallucinations	3	203	Odds Ratio (M‐H, Random, 95% CI)	2.19 [0.45, 10.78]
1.12 AE Headache	2	194	Odds Ratio (M‐H, Random, 95% CI)	1.23 [0.62, 2.45]
1.13 AE Infections and Infestations	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
1.14 AE Loss of Appetite	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
1.15 AE Mania/hypomania	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
1.16 AE Musculoskeletal and connective tissue disorders	2	137	Odds Ratio (M‐H, Random, 95% CI)	1.39 [0.07, 26.35]
1.17 AE Nausea/vomiting	5	353	Odds Ratio (M‐H, Random, 95% CI)	1.83 [0.81, 4.13]
1.18 AE Nervousness	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
1.19 AE Nervous system disorders	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
1.20 AE Palpitations	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.21 AE Psychiatric disorders	2	137	Odds Ratio (M‐H, Fixed, 95% CI)	0.93 [0.30, 2.93]
1.22 AE Restlessness	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.23 AE Skin and subcutaneous tissue disorders	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.24 AE Suicidal Ideas	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.25 AE Tremor	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.26 Remission rate	9		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
1.26.1 at 24 hours	3	75	Odds Ratio (M‐H, Random, 95% CI)	5.60 [1.07, 29.46]
1.26.2 at 72 hours	4	83	Odds Ratio (M‐H, Random, 95% CI)	6.60 [1.51, 28.92]
1.26.3 at 1 week	5	196	Odds Ratio (M‐H, Random, 95% CI)	4.64 [1.37, 15.68]
1.26.4 at 2 weeks	4	206	Odds Ratio (M‐H, Random, 95% CI)	1.67 [0.38, 7.27]
1.26.5 at 4 weeks	4	202	Odds Ratio (M‐H, Random, 95% CI)	1.46 [0.54, 3.95]
1.26.6 at 3 months	2	90	Odds Ratio (M‐H, Random, 95% CI)	1.09 [0.45, 2.67]
1.27 Depression rating scale score	12		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
1.27.1 at 24 hours	8	231	Std. Mean Difference (IV, Random, 95% CI)	‐0.87 [‐1.26, ‐0.48]
1.27.2 at 72 hours	6	148	Std. Mean Difference (IV, Random, 95% CI)	‐0.68 [‐1.28, ‐0.07]
1.27.3 at 1 week	6	143	Std. Mean Difference (IV, Random, 95% CI)	‐0.72 [‐1.10, ‐0.33]
1.27.4 at 2 weeks	5	236	Std. Mean Difference (IV, Random, 95% CI)	‐0.43 [‐0.90, 0.04]
1.27.5 at 4 weeks	2	107	Std. Mean Difference (IV, Random, 95% CI)	‐0.68 [‐1.07, ‐0.29]
1.28 Suicidal ideation composite	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.28.1 at 24 hours	1	48	Mean Difference (IV, Random, 95% CI)	0.02 [‐0.78, 0.82]
1.28.2 at 72 hours	2	68	Mean Difference (IV, Random, 95% CI)	0.34 [‐0.25, 0.93]
1.28.3 at 1 week	1	19	Mean Difference (IV, Random, 95% CI)	‐0.30 [‐1.56, 0.96]
1.28.4 at 2 weeks	1	19	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐1.46, 1.06]
1.29 Cognition scores	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.29.1 Immediate‐term Memory	1	127	Mean Difference (IV, Random, 95% CI)	0.80 [0.12, 1.48]
1.29.2 Short‐term Memory	1	127	Mean Difference (IV, Random, 95% CI)	6.90 [5.01, 8.79]
1.29.3 Long‐term Memory	1	127	Mean Difference (IV, Random, 95% CI)	4.50 [2.79, 6.21]
1.30 Quality of Life	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.30.1 EQ‐5D‐3L INDEX at 2 weeks	1	64	Mean Difference (IV, Random, 95% CI)	0.11 [‐0.05, 0.27]
1.31 Acceptability	6	201	Odds Ratio (M‐H, Random, 95% CI)	1.25 [0.19, 8.28]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Response rate	5		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.1.1 at 24 hours	4	296	Odds Ratio (M‐H, Random, 95% CI)	2.48 [1.00, 6.18]
2.1.2 at 72 hours	3	218	Odds Ratio (M‐H, Random, 95% CI)	2.20 [0.92, 5.28]
2.1.3 at 1 week	2	126	Odds Ratio (M‐H, Random, 95% CI)	3.11 [1.38, 7.04]
2.1.4 at 2 weeks	1	53	Odds Ratio (M‐H, Random, 95% CI)	4.89 [1.49, 16.10]
2.1.5 at 4 weeks	1	5	Odds Ratio (M‐H, Random, 95% CI)	0.50 [0.01, 19.56]
2.1.6 at 3 months	1	5	Odds Ratio (M‐H, Random, 95% CI)	3.00 [0.08, 115.34]
2.2 AE Abnormal dreams	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.2.1 at 4 weeks	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.3 AE Agitation/anxiety	4		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.3.1 Infusion day	1	144	Odds Ratio (M‐H, Random, 95% CI)	1.99 [0.69, 5.75]
2.3.2 at 1 week	3	278	Odds Ratio (M‐H, Random, 95% CI)	1.32 [0.69, 2.50]
2.3.3 48‐72 hours after last treatment	1	5	Odds Ratio (M‐H, Random, 95% CI)	0.50 [0.01, 19.56]
2.4 AE Back pain	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.4.1 at 4 weeks	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.5 AE Blurred vision	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.5.1 Infusion day	1	72	Odds Ratio (M‐H, Random, 95% CI)	8.52 [1.80, 40.39]
2.5.2 at 1 week	2	126	Odds Ratio (M‐H, Random, 95% CI)	1.03 [0.23, 4.70]
2.6 AE Chest pain	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.6.1 Infusion day	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.6.2 at 1 week	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.7 AE Chills	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.7.1 Infusion day	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.8 AE Constipation	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.8.1 Infusion day	1	72	Odds Ratio (M‐H, Random, 95% CI)	2.80 [0.13, 60.66]
2.8.2 at 1 week	3	206	Odds Ratio (M‐H, Random, 95% CI)	1.98 [0.42, 9.27]
2.9 AE Decreased energy	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.9.1 Infusion day	1	72	Odds Ratio (M‐H, Random, 95% CI)	1.28 [0.30, 5.47]
2.9.2 at 1 week	2	126	Odds Ratio (M‐H, Random, 95% CI)	1.17 [0.44, 3.13]
2.10 AE Decreased libido	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.10.1 48‐72 hours after last treatment	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.11 AE Depression	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.11.1 at 4 weeks	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.12 AE Diarrhea	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.12.1 Infusion day	1	72	Odds Ratio (M‐H, Random, 95% CI)	1.07 [0.09, 12.37]
2.12.2 at 1 week	2	152	Odds Ratio (M‐H, Random, 95% CI)	0.82 [0.18, 3.83]
2.12.3 at 4 weeks	1	99	Odds Ratio (M‐H, Random, 95% CI)	1.24 [0.06, 26.93]
2.13 AE Difficulty swallowing	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.13.1 Infusion day	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.14 AE Dizziness	4		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.14.1 Infusion day	2	224	Odds Ratio (M‐H, Random, 95% CI)	3.42 [1.44, 8.14]
2.14.2 at 1 week	4	283	Odds Ratio (M‐H, Random, 95% CI)	1.05 [0.43, 2.56]
2.15 AE Dry mouth	4		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.15.1 Infusion day	2	152	Odds Ratio (M‐H, Random, 95% CI)	2.10 [0.66, 6.70]
2.15.2 at 1 week	3	206	Odds Ratio (M‐H, Random, 95% CI)	0.79 [0.22, 2.91]
2.15.3 48‐72 hours after last treatment	1	5	Odds Ratio (M‐H, Random, 95% CI)	3.00 [0.08, 115.34]
2.16 AE Dry skin	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.16.1 Infusion day	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.16.2 at 1 week	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.17 AE Fatigue	4		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.17.1 Infusion day	2	152	Odds Ratio (M‐H, Random, 95% CI)	0.29 [0.00, 22.84]
2.17.2 at 1 week	4	211	Odds Ratio (M‐H, Random, 95% CI)	1.42 [0.62, 3.27]
2.18 AE General malaise	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.18.1 Infusion day	1	72	Odds Ratio (M‐H, Random, 95% CI)	0.18 [0.04, 0.75]
2.18.2 at 1 week	3	131	Odds Ratio (M‐H, Random, 95% CI)	1.90 [0.32, 11.44]
2.19 AE Insomnia	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.19.1 at 1 week	1	54	Odds Ratio (M‐H, Random, 95% CI)	2.57 [0.43, 15.41]
2.19.2 at 4 weeks	1	99	Odds Ratio (M‐H, Random, 95% CI)	1.24 [0.06, 26.93]
2.20 AE Headache	4		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.20.1 Infusion day	2	152	Odds Ratio (M‐H, Random, 95% CI)	0.94 [0.19, 4.56]
2.20.2 at 1 week	3	206	Odds Ratio (M‐H, Random, 95% CI)	0.85 [0.32, 2.29]
2.20.3 at 4 weeks	1	99	Odds Ratio (M‐H, Random, 95% CI)	5.18 [0.29, 93.01]
2.21 AE Increased blood pressure or heart rate	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.21.1 at 1 week	1	54	Odds Ratio (M‐H, Random, 95% CI)	9.37 [2.49, 35.25]
2.21.2 at 4 weeks	1	99	Odds Ratio (M‐H, Random, 95% CI)	1.24 [0.06, 26.93]
2.22 AE Increase in systolic blood pressure and heart rate	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.22.1 Infusion day	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.23 AE Increased perspiration	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.23.1 Infusion day	1	72	Odds Ratio (M‐H, Random, 95% CI)	2.86 [0.32, 25.91]
2.23.2 at 1 week	2	126	Odds Ratio (M‐H, Random, 95% CI)	1.48 [0.23, 9.58]
2.24 AE Indigestion	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.24.1 at 4 weeks	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.25 AE Insomnia	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.25.1 at 4 weeks	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.26 AE Irritability	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.26.1 at 1 week	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.27 AE Itching	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.27.1 Infusion day	1	72	Odds Ratio (M‐H, Random, 95% CI)	1.07 [0.09, 12.37]
2.27.2 at 1 week	2	126	Odds Ratio (M‐H, Random, 95% CI)	3.54 [0.58, 21.59]
2.27.3 48‐72 hours after last treatment	1	5	Odds Ratio (M‐H, Random, 95% CI)	8.33 [0.22, 320.38]
2.28 AE Loss of consciousness	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.28.1 Infusion day	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.29 AE Memory problems	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.29.1 at 1 week	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.30 AE Muscle/bone/joint pain	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.30.1 at 1 week	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.31 AE Nasal congestion	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.31.1 at 4 weeks	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.32 AE Nausea/vomiting	4		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.32.1 Infusion day	2	152	Odds Ratio (M‐H, Random, 95% CI)	3.62 [1.13, 11.58]
2.32.2 at 1 week	2	126	Odds Ratio (M‐H, Random, 95% CI)	2.57 [0.78, 8.52]
2.32.3 at 4 weeks	1	99	Odds Ratio (M‐H, Random, 95% CI)	7.12 [0.40, 125.66]
2.33 AE Numbness	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.33.1 Infusion day	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.34 AE Pain in extremities	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.34.1 at 4 weeks	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.35 AE Palpitations	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.35.1 Infusion day	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.35.2 at 1 week	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.36 AE Poor concentration	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.36.1 Infusion day	1	72	Odds Ratio (M‐H, Random, 95% CI)	3.94 [0.81, 19.27]
2.36.2 at 1 week	3	131	Odds Ratio (M‐H, Random, 95% CI)	1.51 [0.18, 12.31]
2.37 AE Poor co‐ordination	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.37.1 Infusion day	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.37.2 at 1 week	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.38 AE Poor quality sleep	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.38.1 at 4 weeks	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.39 AE Rash	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.39.1 Infusion day	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.39.2 at 1 week	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.40 AE Reduced duration of sleep	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.40.1 48‐72 hours after last treatment	1	5	Odds Ratio (M‐H, Random, 95% CI)	0.50 [0.01, 19.56]
2.40.2 at 1 week	1	80	Odds Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 8.22]
2.41 AE Restlessness	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.41.1 48‐72 hours after last treatment	1	5	Odds Ratio (M‐H, Random, 95% CI)	3.00 [0.08, 115.34]
2.41.2 at 1 week	1	54	Odds Ratio (M‐H, Random, 95% CI)	6.28 [0.29, 137.16]
2.42 AE Sensory disturbance	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.42.1 Infusion day	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.42.2 at 1 week	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.43 AE Sexual dysfunction	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.43.1 at 1 week	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.44 AE Sleepiness/drowsiness	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.44.1 Infusion day	1	80	Odds Ratio (M‐H, Random, 95% CI)	0.21 [0.07, 0.66]
2.44.2 at 1 week	1	54	Odds Ratio (M‐H, Random, 95% CI)	2.57 [0.43, 15.41]
2.45 AE Stomach or abdominal discomfort	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.45.1 at 1 week	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.46 AE Suicide attempt	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.46.1 at 4 weeks	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.47 AE Suicidal ideas	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.47.1 at 4 weeks	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.48 AE Tachycardia	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.48.1 at 4 weeks	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.49 AE Tinnitus	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.49.1 Infusion day	1	72	Odds Ratio (M‐H, Random, 95% CI)	1.07 [0.09, 12.37]
2.49.2 at 1 week	2	126	Odds Ratio (M‐H, Random, 95% CI)	0.99 [0.26, 3.73]
2.49.3 48‐72 hours after last treatment	1	5	Odds Ratio (M‐H, Random, 95% CI)	2.00 [0.05, 78.25]
2.50 AE Tooth Abscess	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.50.1 at 4 weeks	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.51 AE Tremor	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.51.1 Infusion day	1	72	Odds Ratio (M‐H, Random, 95% CI)	7.99 [0.43, 147.87]
2.51.2 at 1 week	2	126	Odds Ratio (M‐H, Random, 95% CI)	1.14 [0.23, 5.74]
2.52 AE Urination issues	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.52.1 Infusion day	1	216	Odds Ratio (M‐H, Random, 95% CI)	Not estimable
2.52.2 at 1 week	2	126	Odds Ratio (M‐H, Random, 95% CI)	2.19 [0.08, 63.59]
2.53 Remission rate	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
2.53.1 at 24 hours	2	122	Odds Ratio (M‐H, Random, 95% CI)	2.21 [0.67, 7.32]
2.53.2 at 72 hours	2	118	Odds Ratio (M‐H, Random, 95% CI)	1.73 [0.74, 4.04]
2.53.3 at 1 week	2	126	Odds Ratio (M‐H, Random, 95% CI)	1.86 [0.80, 4.32]
2.53.4 at 2 weeks	1	53	Odds Ratio (M‐H, Random, 95% CI)	2.29 [0.76, 6.92]
2.53.5 at 4 weeks	1	5	Odds Ratio (M‐H, Random, 95% CI)	0.50 [0.01, 19.56]
2.53.6 at 3 months	1	5	Odds Ratio (M‐H, Random, 95% CI)	Not estimable
2.54 Depression rating scale score	4		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
2.54.1 at 24 hours	4	297	Std. Mean Difference (IV, Random, 95% CI)	‐0.49 [‐0.87, ‐0.10]
2.54.2 at 72 hours	3	207	Std. Mean Difference (IV, Random, 95% CI)	‐0.39 [‐0.70, ‐0.08]
2.54.3 at 1 week	3	212	Std. Mean Difference (IV, Random, 95% CI)	‐0.38 [‐0.69, ‐0.08]
2.54.4 at 2 weeks	2	137	Std. Mean Difference (IV, Random, 95% CI)	‐0.37 [‐0.84, 0.10]
2.54.5 at 4 weeks	1	86	Std. Mean Difference (IV, Random, 95% CI)	‐0.57 [‐1.10, ‐0.04]
2.55 Suicidal ideation composite	1	57	Mean Difference (IV, Random, 95% CI)	‐1.32 [‐2.52, ‐0.12]
2.56 Acceptability	1	72	Odds Ratio (M‐H, Random, 95% CI)	0.33 [0.05, 2.09]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Response rate	1		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1.1 at 3 days	1	31	Odds Ratio (M‐H, Random, 95% CI)	2.64 [0.10, 69.88]
3.1.2 at 4 weeks	1	31	Odds Ratio (M‐H, Random, 95% CI)	0.81 [0.05, 14.28]
3.2 AE Blood Pressure Rise	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
3.3 AE Delirium	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
3.4 AE Emergence reactions	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
3.5 AE Headache	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
3.6 AE Heart Rate Rise	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
3.7 AE Increased secretions	1		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
3.8 AE Nausea/vomiting	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
3.9 Depression rating scale score	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.9.1 at 72 hours	1	29	Mean Difference (IV, Random, 95% CI)	‐3.87 [‐6.08, ‐1.66]
3.9.2 at 1 week	1	60	Mean Difference (IV, Random, 95% CI)	‐6.96 [‐9.82, ‐4.10]
3.9.3 at 2 weeks	2	89	Mean Difference (IV, Random, 95% CI)	‐4.84 [‐13.42, 3.73]
3.9.4 at 4 weeks	1	29	Mean Difference (IV, Random, 95% CI)	‐0.22 [‐2.64, 2.20]
3.10 Acceptability	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Depression rating scale score	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1.1 At 72 hours	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
5.1 Depression rating scale score	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
5.1.1 At 2 weeks	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
5.1.2 At 3 months	1	Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Depression rating scale score	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
6.1.1 at 24 hours	1	30	Mean Difference (IV, Random, 95% CI)	‐7.74 [‐14.03, ‐1.45]
6.1.2 at 1 week	1	30	Mean Difference (IV, Random, 95% CI)	‐7.54 [‐14.13, ‐0.95]
6.1.3 at 2 weeks	1	30	Mean Difference (IV, Random, 95% CI)	‐1.00 [‐6.98, 4.98]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Response Rate	1		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
7.1.1 at 24 hours	1	63	Odds Ratio (M‐H, Random, 95% CI)	1.07 [0.40, 2.89]
7.1.2 at 72 hours	1	63	Odds Ratio (M‐H, Random, 95% CI)	1.56 [0.58, 4.22]
7.1.3 at 1 week	1	63	Odds Ratio (M‐H, Random, 95% CI)	2.34 [0.85, 6.45]
7.2 Cognition	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
7.2.1 CADSS scores during infusion	1	63	Mean Difference (IV, Random, 95% CI)	3.30 [‐4.70, 11.30]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Response rate	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
8.1.1 at 24 hours	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
8.1.2 at 72 hours	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
8.1.3 at 1 week	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
8.1.4 at 2 weeks	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
8.2 AE Increase in systolic blood pressure and heart rate	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
8.3 Remission rate	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
8.3.1 at 24 hours	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
8.3.2 at 72 hours	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
8.3.3 at 1 week	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
8.3.4 at 2 weeks	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
8.4 Depression rating scale score	1	72	Mean Difference (IV, Random, 95% CI)	‐2.98 [‐7.07, 1.12]
8.4.1 at 24 hours	1	18	Mean Difference (IV, Random, 95% CI)	‐8.90 [‐11.72, ‐6.08]
8.4.2 at 72 hours	1	18	Mean Difference (IV, Random, 95% CI)	‐3.40 [‐5.99, ‐0.81]
8.4.3 at 1 week	1	18	Mean Difference (IV, Random, 95% CI)	‐1.00 [‐3.45, 1.45]
8.4.4 at 2 weeks	1	18	Mean Difference (IV, Random, 95% CI)	1.20 [‐1.20, 3.60]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Response rate	7		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
9.1.1 at 24 hours	5	1071	Odds Ratio (M‐H, Random, 95% CI)	2.11 [1.20, 3.68]
9.1.2 at 72 hours	2	451	Odds Ratio (M‐H, Random, 95% CI)	1.34 [0.92, 1.96]
9.1.3 at 1 week	6	1115	Odds Ratio (M‐H, Random, 95% CI)	1.60 [1.09, 2.34]
9.1.4 at 2 weeks	2	451	Odds Ratio (M‐H, Random, 95% CI)	1.57 [1.09, 2.28]
9.1.5 at 4 weeks	5	1117	Odds Ratio (M‐H, Random, 95% CI)	1.84 [1.44, 2.37]
9.2 AE Aggression	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
9.3 AE Agitation/anxiety	4	933	Odds Ratio (M‐H, Random, 95% CI)	1.06 [0.46, 2.42]
9.4 AE Arrhythmia	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
9.5 AE Change in blood pressure	4	933	Odds Ratio (M‐H, Random, 95% CI)	2.67 [1.52, 4.70]
9.6 AE Constipation	2	452	Odds Ratio (M‐H, Random, 95% CI)	4.07 [1.60, 10.39]
9.7 AE Depersonalisation/derealization	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
9.8 AE Depression	2	452	Odds Ratio (M‐H, Random, 95% CI)	0.62 [0.08, 5.05]
9.9 AE Diabetic ketoacidosis	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
9.10 AE Diarrhoea	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
9.11 AE Dissociative symptoms	4	933	Odds Ratio (M‐H, Random, 95% CI)	8.76 [5.19, 14.77]
9.12 AE Dizziness	4	933	Odds Ratio (M‐H, Random, 95% CI)	3.67 [2.54, 5.31]
9.13 AE Dizziness postural	2	569	Odds Ratio (M‐H, Random, 95% CI)	4.70 [1.06, 20.80]
9.14 AE Double vision	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
9.15 AE Euphoria	2	571	Odds Ratio (M‐H, Random, 95% CI)	5.27 [0.94, 29.64]
9.16 AE Fatigue	2	481	Odds Ratio (M‐H, Random, 95% CI)	1.90 [0.89, 4.04]
9.17 AE Feeling drunk	2	571	Odds Ratio (M‐H, Random, 95% CI)	7.58 [1.37, 41.77]
9.18 AE Headache	4	933	Odds Ratio (M‐H, Random, 95% CI)	1.18 [0.80, 1.74]
9.19 AE Hypertransaminasemia	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
9.20 AE Increased sweating	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
9.21 AE Infections and Infestations	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
9.22 AE Insomnia	4	933	Odds Ratio (M‐H, Random, 95% CI)	0.87 [0.53, 1.42]
9.23 AE Lethargy	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
9.24 AE Mental impairment	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
9.25 AE Nasal discomfort	2	571	Odds Ratio (M‐H, Random, 95% CI)	0.84 [0.42, 1.68]
9.26 AE Nausea/vomiting	4	933	Odds Ratio (M‐H, Random, 95% CI)	3.24 [1.84, 5.72]
9.27 AE Paresthesia/neuropathy exacerbation	3	708	Odds Ratio (M‐H, Random, 95% CI)	3.51 [1.62, 7.62]
9.28 AE Pericardial effusion	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
9.29 AE Pneumothorax	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
9.30 AE Sensory disturbance	3	796	Odds Ratio (M‐H, Random, 95% CI)	7.25 [3.55, 14.78]
9.31 AE Sedation	3	796	Odds Ratio (M‐H, Random, 95% CI)	5.31 [2.18, 12.94]
9.32 AE Sleepiness/drowsiness	3	796	Odds Ratio (M‐H, Random, 95% CI)	2.11 [1.39, 3.21]
9.33 AE Sore throat	2	571	Odds Ratio (M‐H, Random, 95% CI)	1.65 [0.70, 3.87]
9.34 AE Suicide attempt	2	452	Odds Ratio (M‐H, Random, 95% CI)	0.99 [0.24, 4.02]
9.35 AE Suicidal ideas	3	796	Odds Ratio (M‐H, Random, 95% CI)	0.69 [0.38, 1.26]
9.36 AE Taste perversion	4	933	Odds Ratio (M‐H, Random, 95% CI)	1.39 [0.95, 2.04]
9.37 AE Tremor	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
9.38 AE Urination issues	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
9.39 AE Vertigo	3	796	Odds Ratio (M‐H, Random, 95% CI)	12.25 [4.09, 36.67]
9.40 AE Vision blurred	3	796	Odds Ratio (M‐H, Random, 95% CI)	3.02 [1.37, 6.66]
9.41 Remission rate	7		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
9.41.1 at 24 hours	5	894	Odds Ratio (M‐H, Random, 95% CI)	2.74 [1.71, 4.40]
9.41.2 at 72 hours	3	517	Odds Ratio (M‐H, Random, 95% CI)	1.55 [0.91, 2.64]
9.41.3 at 1 week	6	948	Odds Ratio (M‐H, Random, 95% CI)	1.54 [0.88, 2.69]
9.41.4 at 2 weeks	4	832	Odds Ratio (M‐H, Random, 95% CI)	1.52 [1.07, 2.16]
9.41.5 at 4 weeks	5	957	Odds Ratio (M‐H, Random, 95% CI)	1.57 [1.18, 2.10]
9.42 Depression rating scale score	7		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
9.42.1 at 24 hours	4	824	Std. Mean Difference (IV, Random, 95% CI)	‐0.31 [‐0.45, ‐0.17]
9.42.2 at 72 hours	3	517	Std. Mean Difference (IV, Random, 95% CI)	‐0.30 [‐0.50, ‐0.11]
9.42.3 at 1 week	5	884	Std. Mean Difference (IV, Random, 95% CI)	‐0.23 [‐0.37, ‐0.10]
9.42.4 at 2 weeks	4	857	Std. Mean Difference (IV, Random, 95% CI)	‐0.21 [‐0.34, ‐0.07]
9.42.5 at 4 weeks	6	1182	Std. Mean Difference (IV, Random, 95% CI)	‐0.27 [‐0.39, ‐0.16]
9.42.6 at 3 months	1	38	Std. Mean Difference (IV, Random, 95% CI)	‐0.12 [‐0.75, 0.52]
9.43 Suicidal ideation composite	3		Mean Difference (IV, Random, 95% CI)	Subtotals only
9.43.1 at 24 hours	2	450	Mean Difference (IV, Random, 95% CI)	‐0.15 [‐0.44, 0.15]
9.43.2 at 72 hours	2	451	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.49, 0.08]
9.43.3 at 1 week	3	660	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.10, 0.13]
9.43.4 at 2 weeks	3	659	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.22, 0.02]
9.43.5 at 4 weeks	3	647	Mean Difference (IV, Random, 95% CI)	‐0.04 [‐0.12, 0.05]
9.44 Acceptability	5	773	Odds Ratio (M‐H, Random, 95% CI)	1.58 [0.92, 2.73]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Response rate	4		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
10.1.1 at 1 week	2	63	Odds Ratio (M‐H, Random, 95% CI)	1.07 [0.06, 18.82]
10.1.2 at 2 weeks	1	32	Odds Ratio (M‐H, Random, 95% CI)	0.31 [0.01, 8.28]
10.1.3 at 4 weeks	4	185	Odds Ratio (M‐H, Random, 95% CI)	1.22 [0.25, 5.89]
10.1.4 at 3 months	3	123	Odds Ratio (M‐H, Random, 95% CI)	0.48 [0.18, 1.24]
10.2 AE Abdominal Pain	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.3 AE Active suicidal ideation	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.4 AE Agitation/anxiety	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.5 AE Appetite increase	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.6 AE Back pain	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.7 AE Balance or gait problems	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.8 AE Carbohydrate craving	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.9 AE Chest pain	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.10 AE Chills	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.11 AE Clammy hands	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.12 AE Confusion/decreased mental clarity	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.13 AE Conjunctival swelling	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.14 AE Constipation	2	88	Odds Ratio (M‐H, Random, 95% CI)	0.82 [0.20, 3.29]
10.15 AE Decreased appetite	2	93	Odds Ratio (M‐H, Random, 95% CI)	1.57 [0.24, 10.10]
10.16 AE Delusions	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.17 AE Diaphoresis	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.18 AE Difficulty breathing	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.19 AE Dissociative symptoms	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.20 AE Dizziness	3	181	Odds Ratio (M‐H, Random, 95% CI)	0.83 [0.33, 2.13]
10.21 AE Dry mouth	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.22 AE Dyskinesia	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.23 AE Dyspepsia	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.24 AE Ear pain/jaw pain	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.25 AE Emotional lability	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.26 AE Eye photosensitivity	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.27 AE Facial twitching	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.28 AE Falls	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.29 AE Fatigue	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.30 AE Feeling flushed/hot	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.31 AE Generalised aches	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.32 AE Head pressure/ear pressure	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.33 AE Headache	3	150	Odds Ratio (M‐H, Random, 95% CI)	1.44 [0.56, 3.72]
10.34 AE Heart palpitations	1		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
10.35 AE Hypomania/mania	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.36 AE Increased menstrual pain	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.37 AE Insomnia	2	93	Odds Ratio (M‐H, Random, 95% CI)	0.69 [0.19, 2.58]
10.38 AE Internal sensation of speed or rapid thoughts	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.39 AE Irritability	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.40 AE Leg weakness	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.41 AE Nausea	3	150	Odds Ratio (M‐H, Random, 95% CI)	0.75 [0.17, 3.38]
10.42 AE Nightmares	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.43 AE Paresthesia/neuropathy exacerbation	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.44 AE Passive suicidal ideation	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.45 AE Perceived weight gain	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.46 AE Perceived weight loss	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.47 AE Pruritus	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.48 AE Rash	3	150	Odds Ratio (M‐H, Random, 95% CI)	1.45 [0.25, 8.55]
10.49 AE Sedation	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.50 AE Skin lesion	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.51 AE Sleepiness/drowsiness	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.52 AE Sleepwalking	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.53 AE Sore throat	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.54 AE Taste perversion	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.55 AE Tinnitus	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.56 AE Upper respiratory infection symptoms	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.57 AE Vomiting	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.58 AE Worsened acne	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.59 AE Worsened sleep apnoea	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
10.60 Remission rate	4		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
10.60.1 at 1 week	2	63	Odds Ratio (M‐H, Random, 95% CI)	6.11 [0.27, 138.45]
10.60.2 at 4 weeks	4	185	Odds Ratio (M‐H, Random, 95% CI)	1.39 [0.46, 4.26]
10.60.3 at 3 months	3	123	Odds Ratio (M‐H, Random, 95% CI)	0.76 [0.15, 3.77]
10.61 Depression scale rating score	3		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
10.61.1 at 1 week	2	59	Std. Mean Difference (IV, Random, 95% CI)	‐0.11 [‐1.10, 0.89]
10.61.2 at 2 weeks	1	28	Std. Mean Difference (IV, Random, 95% CI)	‐0.09 [‐0.83, 0.65]
10.61.3 at 4 weeks	3	112	Std. Mean Difference (IV, Random, 95% CI)	0.11 [‐0.26, 0.48]
10.61.4 at 3 months	3	110	Std. Mean Difference (IV, Random, 95% CI)	0.23 [‐0.14, 0.61]
10.62 Quality of life	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
10.62.1 at 4 weeks	1	57	Mean Difference (IV, Random, 95% CI)	‐0.70 [‐5.04, 3.64]
10.62.2 at 3 months	1	57	Mean Difference (IV, Random, 95% CI)	‐1.21 [‐5.78, 3.36]
10.63 Acceptability	3	123	Odds Ratio (M‐H, Random, 95% CI)	0.78 [0.23, 2.66]
10.64 Acceptability ‐ adverse events	2	63	Odds Ratio (M‐H, Random, 95% CI)	0.68 [0.10, 4.47]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 Response rate	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
11.1.1 at 24 hours	1	22	Odds Ratio (M‐H, Random, 95% CI)	7.74 [0.35, 170.10]
11.1.2 at 72 hours	1	22	Odds Ratio (M‐H, Random, 95% CI)	2.74 [0.10, 74.87]
11.1.3 at 1 week	1	22	Odds Ratio (M‐H, Random, 95% CI)	2.74 [0.10, 74.87]
11.1.4 at 4 weeks	1	298	Odds Ratio (M‐H, Random, 95% CI)	1.03 [0.63, 1.69]
11.2 AE Agitation/anxiety	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
11.3 AE Back pain	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
11.4 AE Blood Pressure Rise	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
11.5 AE Dissociative symptoms	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
11.6 AE Dizziness	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
11.7 AE Dry mouth	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
11.8 AE Feeling drunk	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
11.9 AE Insomnia	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
11.10 AE Muscle/bone/joint pain	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
11.11 AE Nausea	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
11.12 AE Rash	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
11.13 AE Sedation	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
11.14 AE Upper respiratory infection symptoms	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
11.15 AE Vomiting	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
11.16 AE Weight gain	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
11.17 Remission rate	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
11.17.1 at 24 hours	1	22	Odds Ratio (M‐H, Random, 95% CI)	5.00 [0.21, 117.21]
11.17.2 at 72 hours	1	22	Odds Ratio (M‐H, Random, 95% CI)	2.74 [0.10, 74.87]
11.17.3 at 1 week	1	22	Odds Ratio (M‐H, Random, 95% CI)	2.74 [0.10, 74.87]
11.17.4 at 4 weeks	1	298	Odds Ratio (M‐H, Random, 95% CI)	1.38 [0.75, 2.52]
11.18 Depression rating scale score	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
11.18.1 at 24 hours	1	22	Mean Difference (IV, Random, 95% CI)	‐8.65 [‐17.81, 0.51]
11.18.2 at 72 hours	1	21	Mean Difference (IV, Random, 95% CI)	‐6.27 [‐13.93, 1.39]
11.18.3 at 1 week	1	21	Mean Difference (IV, Random, 95% CI)	‐6.55 [‐14.07, 0.97]
11.18.4 at 4 weeks	1	298	Mean Difference (IV, Random, 95% CI)	‐0.11 [‐1.42, 1.20]
11.18.5 at 3 months	1	298	Mean Difference (IV, Random, 95% CI)	0.51 [‐1.05, 2.07]
11.19 Acceptability	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
12.1 Response rate	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
12.1.1 at 24 hours	2	54	Odds Ratio (M‐H, Random, 95% CI)	0.81 [0.09, 7.13]
12.1.2 at 72 hours	2	54	Odds Ratio (M‐H, Random, 95% CI)	0.80 [0.16, 3.90]
12.1.3 at 1 week	2	54	Odds Ratio (M‐H, Random, 95% CI)	1.40 [0.31, 6.28]
12.1.4 at 2 weeks	2	54	Odds Ratio (M‐H, Random, 95% CI)	2.24 [0.61, 8.22]
12.1.5 at 4 weeks	1	30	Odds Ratio (M‐H, Random, 95% CI)	0.82 [0.18, 3.74]
12.2 AE Abnormal dreams	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
12.3 AE Back pain	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
12.4 AE Disturbance in attention	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
12.5 AE Dizziness	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
12.6 AE Fatigue	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
12.7 AE Feeling drunk	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
12.8 AE Headache	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
12.9 AE Insomnia	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
12.10 AE Irritability	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
12.11 AE Muscle twitching	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
12.12 AE Nasal congestion	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
12.13 AE Nausea	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
12.14 AE Palpitations	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
12.15 AE Post‐lumbar puncture syndrome	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
12.16 AE Rash	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
12.17 AE Sedation	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
12.18 AE Sensory disturbance	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
12.19 AE Sleepiness/drowsiness	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
12.20 AE Total	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
12.21 Remission rate	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
12.21.1 at 72 hours	2	54	Odds Ratio (M‐H, Random, 95% CI)	0.47 [0.03, 8.60]
12.21.2 at 1 week	2	54	Odds Ratio (M‐H, Random, 95% CI)	1.52 [0.21, 11.06]
12.21.3 at 2 weeks	2	54	Odds Ratio (M‐H, Random, 95% CI)	2.29 [0.43, 12.15]
12.21.4 at 4 weeks	1	30	Odds Ratio (M‐H, Random, 95% CI)	0.64 [0.13, 3.14]
12.22 Depression rating scale score	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
12.22.1 at 24 hours	2	54	Mean Difference (IV, Random, 95% CI)	‐0.51 [‐4.14, 3.13]
12.22.2 at 72 hours	2	54	Mean Difference (IV, Random, 95% CI)	‐0.88 [‐4.67, 2.91]
12.22.3 at 1 week	2	54	Mean Difference (IV, Random, 95% CI)	‐1.43 [‐5.31, 2.44]
12.22.4 at 2 weeks	2	54	Mean Difference (IV, Random, 95% CI)	‐2.61 [‐7.32, 2.09]
12.22.5 at 4 weeks	1	30	Mean Difference (IV, Random, 95% CI)	‐1.25 [‐8.14, 5.64]
12.23 Acceptability ‐ adverse events	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
13.1 Response rate	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
13.1.1 at 24 hours	1	42	Odds Ratio (M‐H, Random, 95% CI)	1.23 [0.35, 4.36]
13.1.2 at 72 hours	1	42	Odds Ratio (M‐H, Random, 95% CI)	2.62 [0.64, 10.61]
13.1.3 at 1 week	1	42	Odds Ratio (M‐H, Random, 95% CI)	2.40 [0.51, 11.26]
13.1.4 at 2 weeks	2	102	Odds Ratio (M‐H, Random, 95% CI)	1.41 [0.27, 7.26]
13.1.5 at 4 weeks	2	102	Odds Ratio (M‐H, Random, 95% CI)	1.57 [0.09, 28.00]
13.2 AE Abdominal Pain	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.3 AE Appetite decrease	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.4 AE Appetite increase	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
13.5 AE Agitation/anxiety	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.6 AE Blurred vision	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.7 AE Chest pain	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.8 AE Concentration difficulty	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.9 AE Confusion	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.10 AE Constipation	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
13.11 AE Coughing	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
13.12 AE Cramps	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.13 AE Decreased appetite	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.14 AE Decreased motor activity	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.15 AE Decreased libido	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.16 AE Dental problems	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.17 AE Depression	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.18 AE Dermatologic/skin irritation/lesions	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.19 AE Diarrhoea	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
13.20 AE Dizziness	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
13.21 AE Dry mouth	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
13.22 AE Eye irritation	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.23 AE Flatulence	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.24 AE Flu/upper respiratory infection	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.25 AE Genital discomfort	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.26 AE Gum problems	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.27 AE Headache	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
13.28 AE Increased libido	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.29 AE Increased thirst	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.30 AE Insomnia	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.31 AE Irritability	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.32 AE Memory problems	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.33 AE Mouth ulcer	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.34 AE Muscle/bone/joint pain	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.35 AE Nasal congestion	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.36 AE Nausea	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
13.37 AE Oedema	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.38 AE Sexual dysfunction	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.39 AE Shortness of breath	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.40 AE Sleepiness/drowsiness	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
13.41 AE Sore throat	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.42 AE Sore tongue	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.43 AE Stomach or abdominal discomfort	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.44 AE Suicidal ideas	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.45 AE Sweating	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.46 AE Tachycardia	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.47 AE Tinnitus	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.48 AE Tiredness/fatigue	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.49 AE Urination problems	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.50 AE Weight gain	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.51 AE Weight loss	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
13.52 Remission rate	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
13.52.1 at 24 hours	1	42	Odds Ratio (M‐H, Random, 95% CI)	0.71 [0.14, 3.64]
13.52.2 at 72 hours	1	42	Odds Ratio (M‐H, Random, 95% CI)	1.33 [0.30, 5.84]
13.52.3 at 1 week	1	42	Odds Ratio (M‐H, Random, 95% CI)	1.00 [0.18, 5.63]
13.52.4 at 2 weeks	1	42	Odds Ratio (M‐H, Random, 95% CI)	1.00 [0.13, 7.85]
13.52.5 at 4 weeks	2	102	Odds Ratio (M‐H, Random, 95% CI)	1.19 [0.12, 12.13]
13.53 Depression rating scale score	2		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
13.53.1 at 24 hours	1	42	Std. Mean Difference (IV, Random, 95% CI)	‐0.26 [‐0.87, 0.35]
13.53.2 at 72 hours	1	41	Std. Mean Difference (IV, Random, 95% CI)	‐0.25 [‐0.86, 0.37]
13.53.3 at 1 week	1	38	Std. Mean Difference (IV, Random, 95% CI)	‐0.06 [‐0.70, 0.58]
13.53.4 at 2 weeks	2	97	Std. Mean Difference (IV, Random, 95% CI)	‐0.36 [‐1.20, 0.47]
13.53.5 at 4 weeks	2	87	Std. Mean Difference (IV, Random, 95% CI)	‐0.18 [‐1.19, 0.84]
13.54 Acceptability	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
14.1 Response rate	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.1.1 at 3 months	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.2 AE Agitation/anxiety	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.3 AE Constipation	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.4 AE Depressed mood	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.5 AE Diarrhea	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.6 AE Dizziness	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.7 AE Dry mouth	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.8 AE Fatigue	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.9 AE Flatulence	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.10 AE Headache	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.11 AE Increased sweating	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.12 AE Insomnia	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.13 AE Nasopharyngitis	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.14 AE Nausea	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.15 AE Tremor	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.16 Remission rate	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.16.1 at 3 months	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.17 Depression rating scale score	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
14.17.1 at 3 months	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
14.18 Acceptability	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.19 Acceptability ‐ adverse events	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
14.20 Acceptability ‐ lack of efficacy	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
15.1 Response rate	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
15.1.1 at 4 weeks	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
15.2 AE Dizziness	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
15.3 AE Dry mouth	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
15.4 AE Fatigue	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
15.5 AE Headache	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
15.6 AE Insomnia	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
15.7 AE Nasopharyngitis	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
15.8 AE Nausea	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
15.9 Remission rate	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
15.9.1 at 4 weeks	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
15.10 Depression rating scale score	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
15.10.1 at 4 weeks	1	Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
16.1 Response rate	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
16.1.1 at 4 weeks	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
16.2 AE Abdominal Pain	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
16.3 AE Appetite decrease	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
16.4 AE Appetite increase	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
16.5 AE Dizziness	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
16.6 AE Diarrhoea	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
16.7 AE Headache	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
16.8 AE Insomnia	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
16.9 AE Nausea	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
16.10 AE Sedation	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
16.11 Remission rate	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
16.11.1 at 4 weeks	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
17.1 AE Change in blood pressure	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
17.2 AE Dissociative reaction	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
17.3 Depression rating scale score	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
17.3.1 at 24 hours	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
17.3.2 at 1 week	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
17.3.3 at 2 weeks	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
17.4 Acceptability	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

PERMALINK

Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder

Rebecca L Dean

Claudia Hurducas

Keith Hawton

Styliani Spyridi

Philip J Cowen

Sarah Hollingsworth

Tahnee Marquardt

Annabelle Barnes

Rebecca Smith

Rupert McShane

Erick H Turner

Andrea Cipriani

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Participant characteristics and diagnosis

Comorbidities

Setting

Subset data

Types of interventions

Experimental interventions

Comparator interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Timing of outcome assessment

Hierarchy of outcome measures

Search methods for identification of studies

Electronic searches

1. Bibliographic databases

2. International trial registries

3. Adverse events search

Searching other resources

Grey literature

Reference lists

Correspondence

Data collection and analysis

Selection of studies

1.

Data extraction and management

Main comparisons

Assessment of risk of bias in included studies

Measures of treatment effect

Dichotomous data

Continuous data

Unit of analysis issues

Cluster‐randomised trials

Cross‐over trials

Studies with multiple treatment groups

Dealing with missing data

Dichotomous data

Continuous data

Missing data

Missing statistics

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Outcome or subgroup title	No. of studies	Statistical method	Effect size
18.1 Response rate	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.1.1 at 2 weeks	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.1.2 at 4 weeks	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.2 AE Agitation/anxiety	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.3 AE Concentration difficulties	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.4 AE Constipation	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.5 AE Failing memory	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.6 AE Headache	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.7 AE Increased dream activity	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.8 AE Increased duration of sleep	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.9 AE Increased sexual desire	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.10 AE Increased tendency to sweat	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.11 AE Nausea/vomiting	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.12 AE Palpitation/tachycardia	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.13 AE Sleepiness/drowsiness	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.14 AE Urination issues	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.15 Remission rate	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.15.1 at 4 weeks	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
18.16 Depression rating scale score	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
18.16.1 at 2 weeks	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
18.16.2 at 4 weeks	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
18.17 Acceptability	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
19.1 Response Rate	1	309	Odds Ratio (M‐H, Random, 95% CI)	2.04 [1.23, 3.38]
19.1.1 at 4 weeks	1	309	Odds Ratio (M‐H, Random, 95% CI)	2.04 [1.23, 3.38]
19.2 AE Diarrhea	1	357	Odds Ratio (M‐H, Random, 95% CI)	0.91 [0.42, 1.99]
19.3 AE Dizziness	1	357	Odds Ratio (M‐H, Random, 95% CI)	2.01 [1.03, 3.94]
19.4 AE Headache	1	357	Odds Ratio (M‐H, Random, 95% CI)	1.02 [0.61, 1.70]
19.5 AE Nausea	1	357	Odds Ratio (M‐H, Random, 95% CI)	1.38 [0.74, 2.59]
19.6 AE Sleepiness/drowsiness	1	357	Odds Ratio (M‐H, Random, 95% CI)	4.78 [0.61, 37.26]
19.7 AE Vomiting	1	357	Odds Ratio (M‐H, Random, 95% CI)	2.11 [0.79, 5.65]
19.8 Remission rate	1	309	Odds Ratio (M‐H, Random, 95% CI)	1.60 [0.95, 2.69]
19.8.1 at 4 weeks	1	309	Odds Ratio (M‐H, Random, 95% CI)	1.60 [0.95, 2.69]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
20.1 Depression rating scale score	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
20.1.1 at 24 hours	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
20.1.2 at 72 hours	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
20.1.3 at 1 week	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
20.1.4 at 2 weeks	1	Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
21.1 Response rate	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
21.1.1 at 2 weeks	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
21.1.2 at 4 weeks	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
21.1.3 at 3 months	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
21.2 AE Back pain	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
21.3 AE Gastrointestinal problems	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
21.4 AE Joint pain	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
21.5 AE Muscle spasms	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
21.6 Remission rate	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
21.6.1 at 2 weeks	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
21.6.2 at 4 weeks	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
21.6.3 at 3 months	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
21.7 Depression rating scale score	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
21.7.1 at 2 weeks	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
21.7.2 at 4 weeks	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
21.7.3 at 3 months	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
21.8 Quality of life	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
21.8.1 at 3 months	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
21.9 Acceptability	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
21.10 Acceptability ‐ adverse events	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
22.1 Response rate	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.1.1 at 2 weeks	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.1.2 at 4 weeks	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.2 AE Total	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.3 AE Agitation/anxiety	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.4 AE Asthenia/increased fatigability	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.5 AE Constipation	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.6 AE Concentration difficulties	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.7 AE Depression	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.8 AE Dizziness	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.9 AE Dystonia	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.10 AE Headache/migraine	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.11 AE Increased dream activity	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.12 AE Increased duration of sleep	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.13 AE Nausea/vomiting	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.14 AE Palpitations/tachycardia	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.15 AE Reduced duration of sleep	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.16 AE Sleepiness/drowsiness	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.17 AE Tremor	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.18 AE Weight gain	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.19 AE Weight loss	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.20 Remission rate	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.20.1 at 2 weeks	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.20.2 at 4 weeks	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
22.21 Depression rating scale score	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
22.21.1 at 2 weeks	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
22.21.2 at 4 weeks	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
22.22 Acceptability	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
23.1 Response rate	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
23.1.1 at 24 hours	1	27	Odds Ratio (M‐H, Random, 95% CI)	18.76 [0.92, 383.10]
23.1.2 at 72 hours	1	27	Odds Ratio (M‐H, Random, 95% CI)	33.46 [1.65, 677.83]
23.1.3 at 1 week	1	27	Odds Ratio (M‐H, Random, 95% CI)	33.46 [1.65, 677.83]
23.1.4 at 2 weeks	1	27	Odds Ratio (M‐H, Random, 95% CI)	20.80 [2.04, 211.79]
23.1.5 at 4 weeks	3	132	Odds Ratio (M‐H, Random, 95% CI)	2.00 [0.68, 5.85]
23.1.6 at 3 months	2	47	Odds Ratio (M‐H, Random, 95% CI)	3.95 [0.16, 97.23]
23.2 Remission rate	4		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
23.2.1 at 24 hours	1	27	Odds Ratio (M‐H, Random, 95% CI)	3.48 [0.13, 93.30]
23.2.2 at 72 hours	1	27	Odds Ratio (M‐H, Random, 95% CI)	6.30 [0.27, 144.70]
23.2.3 at 1 week	1	27	Odds Ratio (M‐H, Random, 95% CI)	6.30 [0.27, 144.70]
23.2.4 at 2 weeks	1	27	Odds Ratio (M‐H, Random, 95% CI)	3.90 [0.35, 43.36]
23.2.5 at 4 weeks	3	132	Odds Ratio (M‐H, Random, 95% CI)	2.19 [0.85, 5.66]
23.2.6 at 3 months	2	90	Odds Ratio (M‐H, Random, 95% CI)	1.09 [0.45, 2.67]
23.3 Depression rating scale score	4		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
23.3.1 at 24 hours	2	75	Std. Mean Difference (IV, Random, 95% CI)	‐0.47 [‐1.11, 0.18]
23.3.2 at 72 hours	3	94	Std. Mean Difference (IV, Random, 95% CI)	‐0.28 [‐1.18, 0.62]
23.3.3 at 1 week	2	45	Std. Mean Difference (IV, Random, 95% CI)	‐0.52 [‐1.69, 0.65]
23.3.4 at 2 weeks	3	126	Std. Mean Difference (IV, Random, 95% CI)	‐0.73 [‐1.31, ‐0.15]
23.3.5 at 4 weeks	2	107	Std. Mean Difference (IV, Random, 95% CI)	‐0.68 [‐1.07, ‐0.29]
23.4 Suicidal ideation composite	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
23.4.1 at 24 hours	1	48	Mean Difference (IV, Random, 95% CI)	0.02 [‐0.78, 0.82]
23.4.2 at 72 hours	2	68	Mean Difference (IV, Random, 95% CI)	0.34 [‐0.25, 0.93]
23.4.3 at 1 week	1	19	Mean Difference (IV, Random, 95% CI)	‐0.30 [‐1.56, 0.96]
23.4.4 at 2 weeks	1	19	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐1.46, 1.06]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
24.1 Response rate	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
24.1.1 at 24 hours	2	48	Odds Ratio (M‐H, Random, 95% CI)	15.11 [1.97, 115.92]
24.1.2 at 72 hours	2	48	Odds Ratio (M‐H, Random, 95% CI)	14.00 [2.07, 94.75]
24.1.3 at 1 week	3	99	Odds Ratio (M‐H, Random, 95% CI)	3.41 [0.95, 12.27]
24.1.4 at 2 weeks	1	51	Odds Ratio (M‐H, Random, 95% CI)	0.93 [0.31, 2.83]
24.2 Remission rate	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
24.2.1 at 24 hours	2	48	Odds Ratio (M‐H, Random, 95% CI)	6.60 [0.96, 45.09]
24.2.2 at 72 hours	2	48	Odds Ratio (M‐H, Random, 95% CI)	7.88 [1.17, 53.21]
24.2.3 at 1 week	3	99	Odds Ratio (M‐H, Random, 95% CI)	7.24 [1.70, 30.81]
24.2.4 at 2 weeks	1	51	Odds Ratio (M‐H, Random, 95% CI)	0.95 [0.28, 3.24]
24.3 Depression rating scale score	3		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
24.3.1 at 24 hours	2	46	Std. Mean Difference (IV, Random, 95% CI)	‐1.63 [‐2.86, ‐0.39]
24.3.2 at 72 hours	2	46	Std. Mean Difference (IV, Random, 95% CI)	‐1.21 [‐1.87, ‐0.55]
24.3.3 at 1 week	3	91	Std. Mean Difference (IV, Random, 95% CI)	‐0.75 [‐1.19, ‐0.31]
24.3.4 at 2 weeks	1	46	Std. Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.68, 0.48]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
25.1 Response rate	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
25.1.1 at 24 hours	3	620	Odds Ratio (M‐H, Random, 95% CI)	4.33 [1.08, 17.31]
25.1.2 at 1 week	3	632	Odds Ratio (M‐H, Random, 95% CI)	2.73 [1.41, 5.28]
25.1.3 at 4 weeks	2	543	Odds Ratio (M‐H, Random, 95% CI)	1.92 [1.34, 2.75]
25.2 Remission rate	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
25.2.1 at 24 hours	2	377	Odds Ratio (M‐H, Random, 95% CI)	6.51 [1.93, 21.92]
25.2.2 at 1 week	2	399	Odds Ratio (M‐H, Random, 95% CI)	7.76 [1.75, 34.48]
25.2.3 at 2 weeks	1	315	Odds Ratio (M‐H, Random, 95% CI)	2.30 [1.02, 5.17]
25.2.4 at 4 weeks	1	317	Odds Ratio (M‐H, Random, 95% CI)	1.39 [0.84, 2.30]
25.3 Depression rating scale score	2		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
25.3.1 at 24 hours	1	310	Std. Mean Difference (IV, Random, 95% CI)	‐0.25 [‐0.49, ‐0.01]
25.3.2 at 1 week	1	340	Std. Mean Difference (IV, Random, 95% CI)	‐0.28 [‐0.51, ‐0.06]
25.3.3 at 2 weeks	1	340	Std. Mean Difference (IV, Random, 95% CI)	‐0.32 [‐0.54, ‐0.09]
25.3.4 at 4 weeks	2	542	Std. Mean Difference (IV, Random, 95% CI)	‐0.28 [‐0.45, ‐0.10]
25.3.5 at 3 months	1	38	Std. Mean Difference (IV, Random, 95% CI)	‐0.12 [‐0.75, 0.52]
25.4 Suicidal ideation composite	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
25.4.1 at 1 week	1	209	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.08, 0.18]
25.4.2 at 2 weeks	1	208	Mean Difference (IV, Random, 95% CI)	‐0.07 [‐0.21, 0.07]
25.4.3 at 4 weeks	1	196	Mean Difference (IV, Random, 95% CI)	‐0.02 [‐0.11, 0.07]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
26.1 Response rate	1		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
26.1.1 at 24 hours	1	224	Odds Ratio (M‐H, Random, 95% CI)	1.40 [0.79, 2.49]
26.1.2 at 72 hours	1	224	Odds Ratio (M‐H, Random, 95% CI)	1.52 [0.88, 2.62]
26.1.3 at 1 week	1	224	Odds Ratio (M‐H, Random, 95% CI)	1.29 [0.76, 2.18]
26.1.4 at 2 weeks	1	224	Odds Ratio (M‐H, Random, 95% CI)	1.71 [1.01, 2.91]
26.1.5 at 4 weeks	1	224	Odds Ratio (M‐H, Random, 95% CI)	1.85 [1.09, 3.14]
26.2 Remission rate	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
26.2.1 at 24 hours	2	290	Odds Ratio (M‐H, Random, 95% CI)	2.25 [1.13, 4.49]
26.2.2 at 72 hours	2	290	Odds Ratio (M‐H, Random, 95% CI)	1.61 [0.59, 4.34]
26.2.3 at 1 week	2	290	Odds Ratio (M‐H, Random, 95% CI)	1.22 [0.70, 2.13]
26.2.4 at 2 weeks	2	290	Odds Ratio (M‐H, Random, 95% CI)	1.39 [0.83, 2.32]
26.2.5 at 4 weeks	2	290	Odds Ratio (M‐H, Random, 95% CI)	1.48 [0.91, 2.42]
26.3 Depression rating scale score	2		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
26.3.1 at 24 hours	2	290	Std. Mean Difference (IV, Random, 95% CI)	‐0.35 [‐0.58, ‐0.12]
26.3.2 at 72 hours	2	290	Std. Mean Difference (IV, Random, 95% CI)	‐0.41 [‐0.64, ‐0.17]
26.3.3 at 1 week	2	290	Std. Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.43, 0.04]
26.3.4 at 2 weeks	2	290	Std. Mean Difference (IV, Random, 95% CI)	‐0.14 [‐0.37, 0.09]
26.3.5 at 4 weeks	2	290	Std. Mean Difference (IV, Random, 95% CI)	‐0.25 [‐0.48, ‐0.02]
26.4 Suicidal ideation composite	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
26.4.1 at 24 hours	1	224	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.63, 0.23]
26.4.2 at 72 hours	1	224	Mean Difference (IV, Random, 95% CI)	‐0.30 [‐0.69, 0.09]
26.4.3 at 1 week	1	224	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.56, 0.16]
26.4.4 at 2 weeks	1	224	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.43, 0.23]
26.4.5 at 4 weeks	1	224	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.53, 0.13]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
27.1 Response rate	5		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
27.1.1 at 24 hours	5	1071	Odds Ratio (M‐H, Random, 95% CI)	2.11 [1.20, 3.68]
27.1.2 at 72 hours	2	451	Odds Ratio (M‐H, Random, 95% CI)	1.34 [0.92, 1.96]
27.1.3 at 1 week	5	1083	Odds Ratio (M‐H, Random, 95% CI)	1.64 [1.05, 2.54]
27.1.4 at 2 weeks	2	451	Odds Ratio (M‐H, Random, 95% CI)	1.57 [1.09, 2.28]
27.1.5 at 4 weeks	4	994	Odds Ratio (M‐H, Random, 95% CI)	1.81 [1.40, 2.34]
27.2 Remission rate	5		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
27.2.1 at 24 hours	5	894	Odds Ratio (M‐H, Random, 95% CI)	2.74 [1.71, 4.40]
27.2.2 at 72 hours	3	517	Odds Ratio (M‐H, Random, 95% CI)	1.55 [0.91, 2.64]
27.2.3 at 1 week	5	916	Odds Ratio (M‐H, Random, 95% CI)	1.62 [0.91, 2.89]
27.2.4 at 2 weeks	4	832	Odds Ratio (M‐H, Random, 95% CI)	1.52 [1.07, 2.16]
27.2.5 at 4 weeks	4	834	Odds Ratio (M‐H, Random, 95% CI)	1.51 [1.12, 2.04]
27.3 Depression rating scale score	5		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
27.3.1 at 24 hours	4	824	Std. Mean Difference (IV, Random, 95% CI)	‐0.31 [‐0.45, ‐0.17]
27.3.2 at 72 hours	3	517	Std. Mean Difference (IV, Random, 95% CI)	‐0.30 [‐0.50, ‐0.11]
27.3.3 at 1 week	4	857	Std. Mean Difference (IV, Random, 95% CI)	‐0.24 [‐0.37, ‐0.10]
27.3.4 at 2 weeks	4	857	Std. Mean Difference (IV, Random, 95% CI)	‐0.21 [‐0.34, ‐0.07]
27.3.5 at 4 weeks	5	1059	Std. Mean Difference (IV, Random, 95% CI)	‐0.27 [‐0.40, ‐0.15]
27.3.6 at 3 months	1	38	Std. Mean Difference (IV, Random, 95% CI)	‐0.12 [‐0.75, 0.52]
27.4 Suicidal ideation composite	3		Mean Difference (IV, Random, 95% CI)	Subtotals only
27.4.1 at 24 hours	2	450	Mean Difference (IV, Random, 95% CI)	‐0.15 [‐0.44, 0.15]
27.4.2 at 72 hours	2	451	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.49, 0.08]
27.4.3 at 1 week	3	660	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.10, 0.13]
27.4.4 at 2 weeks	3	659	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.22, 0.02]
27.4.5 at 4 weeks	3	647	Mean Difference (IV, Random, 95% CI)	‐0.04 [‐0.12, 0.05]