. 2022 Oct 24;3:1022767. doi: 10.3389/fpain.2022.1022767

Table 1B.

Selected characteristics of clinical trials and observational studies pertaining to CDAP.

	Han et al. (50)	Jiang et al. (41)	Kudoh et al. (52)
Year (N)	2022 (275)	2016 (120)	2002 (95)
Mean Age (Female%)	32 (100%)	42 (44%)	47
Study duration	28 days	5 days	3 days
Study design	Double-blind RCT of ketamine vs in patient-controlled intravenous analgesia control	Double-blind RCT of ketamine vs placebo	RCT of ketamine vs placebo with 3 groups: MDD patients + ketamine (group A), MDD patients + placebo (group B), and control group + ketamine (group C)
Dose (route)	0.5 mg/kg (intravenously, esketamine)	0.75 mg/kg (intravenously)	1.0 mg/kg (intravenously)
Diagnosis	Pregnant women undergoing caesarean section	Orthopedic surgery patients	MDD patients undergoing orthopedic surgery
Outcome measures	EPDS (postpartum depression) VAS (pain)	PHQ₉ (depression) VAS (pain) Serum BDNF	HDRS₂₁ (depression) VAS (pain)
Findings	1. Rate of depression significantly lower in esketamine group at 3 and 14 days after cesarean section (p < 0.05). 2. EPDS significantly lower in esketamine group at 3 and 14 days postpartum (p's < 0.001); EPDS not lower at day 28. 3. VAS significantly lower in the esketamine group at 4, 8, 12, and 24 h after cesarean section (p's < 0.05).	1. VAS scores were lower in the ketamine group at 1 and 5 days post-surgery (p < 0.01 and p < 0.01, respectively). 2. PHQ₉ scores were lower in the ketamine group at 1 and 5 days post-surgery (p = 0.04 and p = 0.03, respectively). 3. Serum BDNF levels were higher in the ketamine group on both days (p = 0.02 and p = 0.03 at day 1 and 5, respectively).	1. HDRS₂₁ score in group A was lower than in group B at day 1 post-surgery (p < 0.05). 2. No differences between the group A and B in HDRS₂₁ scores at 3 days post-surgery. 3. VAS scores in group A at 8 and 16 h post-surgery were lower than Group B (p < 0.05). 4. No differences in VAS scores between group A and B at day 1 post-surgery.
Adverse effects	• Headache • Nausea • Dizziness • Drowsiness • Vomiting	• Nausea • Insomnia	• Short post-operative confusion
Limitations	• Small sample only including Chinese adults from a single center • Dose of 0.5 mg/kg lower than the subanesthetic dose for treatment of depression • Cannot determine long-term effects	• Short study duration • No diagnosis of mental disorder	• Short study duration • Lack of baseline pain assessment • No reports of the exact p-values • No reports of SD for pain scores • Missing reports of mean values for depression scores

	Ma et al. (43)	Wang et al. (48)	Wang et al. (55)
Year (N)	2019 (654)	2019 (90)	2022 (240)
Mean Age (Female%)	Mean age not reported (100%)	40 (69%)	30 (100%)
Study duration	2 months	7 days	3 months
Study design	Double-blind RCT of ketamine vs placebo	Double-blind RCT of ketamine vs placebo	Retrospective cohort study with control, low-, and high-dose groups
Dose (route)	0.5 mg/kg (intravenously during operation plus 160 mg post-operation via patient-controlled intravenous analgesia)	0.4 mg/kg (intravenously)	0.2–0.5 mg/kg (intravenously, esketamine)
Diagnosis	Pregnant women undergoing caesarean section	Post-operative bariatric surgery patients	Pregnant women undergoing caesarean section
Outcome measures	EPDS (postpartum depression) NRS (pain)	VAS and MPQ (pain) BDI and MADRS (depression)	NRS (pain) EPDS (postpartum depression) GAD₇ (postpartum anxiety)
Findings	1. EPDS score at postpartum day 4 was lower in the ketamine group (p = 0.01). 2. At day 4, prevalence of postpartum blues was lower in the ketamine group (p = 0.02). 3. There were no differences between the groups on EPDS score at postpartum day 42 (p = 0.07). 4. At day 42, prevalence of PPD was lower in the ketamine group (p = 0.02). 5. NRS scores at day 1 and 2 post-surgery were not different between the groups (p = 0.20 and p = 0.67, respectively).	1. VAS score decreased over time (time effect p < 0.001) but no significant difference between groups were seen (group-by-time interaction p = 0.966). 2. MPQ demonstrated a significant decrease in ketamine group on post-operation day 2. 3. Change in BDI decreased over time (time effect p < 0.001) but no significant differences between groups (p = 0.389). 4. MADRS values decreased over time but no significant differences between groups (p = 0.674).	1. NRS (at rest) at 2, 4, 8, 24, and 48 h postpartum lower in the esketamine group (p = 0.021, p = 0.002, p < 0.001). 2. NRS (while coughing) was similar between ketamine and control groups within 2 h (p = 0.108); lower in the esketamine group at other time points (p = 0.031, p = 0.005, p = 0.017, p = 0.007). 3. EPDS not significantly different at antenatal day 1 (p = 0.544); EPDS lower in the esketamine group within 3 months postpartum (p < 0.001). 4. Morphine consumption within 24 h postpartum lower in the esketamine group (p < 0.001). 5. GAD₇ score lower in the esketamine group within 1 week (p < 0.001). esketamine group (p = 0.001). 6. NRS (at rest) at 24 and 48 h postpartum lower in high-dose group than low-dose group (p < 0.001 and p = 0.011, respectively); NRS (while coughing) at 24 h postpartum lower in the high-dose group than low-dose group; no significant difference between 2 subgroups in postpartum EPDS.
Adverse effects	• Vomiting • Dizziness • Hallucinations • Nystagmus	• Nausea • Dizziness • Dysphoria • Visual hallucination	• Nausea • Vomiting • Dizziness • Pruritus
Limitations	• Study with healthy participants • Short-term pain assessment (up to 2 days post-surgery) • No reports of SD for pain scores	• Baseline MADRS and BDI were low indicating a lack of severe depression symptoms	• Time difference between the control and esketamine group • Doses in the subgroup dose analysis mainly dependent on body weight perhaps leading to selection bias • Retrospective study • No data on spousal relationship, family income, and domestic violence
	Xu et al. (47)	Yao et al. (49)
Year (N)	2017 (330)		2020 (330)
Mean Age (Female%)	32 (100%)		30 (100%)
Study duration	6 weeks		4 weeks
Study design	Double-blind RCT of ketamine vs placebo		Double-blind RCT of ketamine vs placebo
Dose (route)	0.25 mg/kg (intravenously)		0.25 mg/kg (intravenously)
Diagnosis	Pregnant women undergoing caesarean section		Pregnant women undergoing caesarean section
Outcome measures	EPDS (postpartum depression) NRS (pain)		EPDS (postpartum depression) NRS (pain)
Findings	1. No differences on EPDS scores or the prevalence of PPD between the groups at any of the time points (p = 0.97 and p = 0.90). 2. At 3 days postpartum, there were no differences between the groups on NRS scores. 3. At 6 weeks postpartum, NRS scores were lower in the ketamine group (p = 0.01).		1. Significant difference in degree of postpartum depression symptoms between ketamine and placebo group at 1 week postpartum (p = 0.029). 2. No difference was found between subjects in two groups at 2 weeks and 1 month postpartum (p = 0.209 and p = 0.319). 3. NRS score of wound pain and uterine contraction pain was lower in the ketamine group at 2 days postpartum (p < 0.001).
Adverse effects	• Hallucinations • Dizziness • Headache • Vomiting • Drowsiness • Diplopia		• Hallucinations • Dizziness • Headache
Limitations	• Low treatment dose • No reports of SD scores • No baseline assessment • Study with healthy participants		• Low treatment dose • No baseline assessment • Study with healthy participants

BDNF, Brain-derived Neurotrophic Factor; BDI, Beck Depression Inventory; EPDS, Edinburgh Postnatal Depression Scale; GAD₇, Generalized Anxiety Disorder (7 item-long); HDRS₂₁, Hamilton Depression Rating Scale (21 item-long); MADRS, Montgomery-Åsberg Depression Rating Scale; MDD, Major Depressive Disorder; MPQ, McGill Pain Questionnaire; NRS, Numerical Rating Scale; PHQ₉, Patient Health Questionnaire (9 item-long); PPD, Postpartum Depression; RCT, Randomized Controlled Trial; SD, Standard Deviation; VAS, Visual Analog Scale.