Acupuncture: A Promising Approach for Comorbid Depression and Insomnia in Perimenopause

Figures & data

Table 1 Common TCM Syndrome Patterns of PMI and PMD

Syndrome Patterns	Major Symptoms	Tongue	Pulse	Ratio
				PMI	PMD
Depression of liver and deficiency of kidney	Insomnia or dreamful sleep, depressed mood, fatigue, chest distress and preference for sighing, hot flushes and sweating, frequent urination or dribbling urination	Red tongue with little coating	Stringy and thready, or stringy and rapid	60.78%	30.42%
Liver depression and spleen deficiency	Depression or irritability, poor sleep, poor appetite, abdominal distension, loose stool	White coated tongue	Stringy and slow	24.02%	–
Stagnation of Qi due to depression of liver	Depression or irritability, preference for sighing, hypochondrium distress and/or pain, distending pain of breasts	Thin whitish coating of the tongue	Stringy	–	18.80%
Imbalance between heart-Yang and kidney-Yin	Irritability and insomnia, palpitation, dizziness and tinnitus, loss of memory, dry mouth, soreness and weakness of waist and knees	Red tongue with little coating	Thready and rapid	–	13.46%
Spleen–kidney Yang deficiency	Insomnia due to nocturia, soreness and weakness of waist and knees, chilly sensation and the cold limbs, diarrhea before dawn or loose stools, edema in the extremities	Pale and slight corpulent tongue with whitish and slippery fur	Deep and retarded without strength	4.31%	–
Deficiency of both kidney Yin and kidney Yang	Poor sleep, sometimes hot flushes and sweating and sometimes chilly sensation and the cold limbs, soreness and weakness of waist and knees, dizziness and tinnitus	Pale tongue with thin coating	Stringy and thready	4.31%	–
Heart-Gallbladder Qi deficiency	Palpitation, timidity, feeling fearful, difficulty in falling asleep, tendency to sleep lightly, nightmares, depressed mood, short of breath, spontaneous perspiration	Pale tongue with whitish coating	Stringy and thready	3.70%	6.72%
Heart–spleen deficiency	Insomnia, dreamful sleep, worry beyond measure, palpitation, poor appetite, loose stool, fatigue, sallow complexion, loss of memory	Pale tongue with whitish coating	Thin and weak	2.87%	6.11%
Hyperactivity of fire due to Yin deficiency	Vexation, irritable and depressed mood, dry mouth, tidal reddening of the cheeks, dysphoria in chest palms-soles	Red tongue with little coating	Stringy and rapid	–	4.65%

Table 1 is not a direct quote from any paper, but is compiled by us from data in two published papers (Ref 47 & 48 of this manuscript); Similarly, Table 3 is compiled by us from data in two published papers (Ref 19 & 50 of this manuscript); The rest of the tables and figures are original and do not require reference. 47 and 48.

Table 2 Summary of Clinical Trials Investigating the Effects and Safety of Acupuncture on PMI and PMD

Author/Year	Study Groups/No. of Participants	Disease (Diagnostic System)	TCM Syndrome Pattern	Acupuncture Interventions	Acupoints	Controls	Outcome Measures	Results (Compared with the Control Group) at Post-Treatment	Follow-Up	Adverse Events
Fu et al 2017^Citation51	- MA/n=37 - placebo-MA/n=37	PMI (ICSD-3)	NR	20 min/day for 10 sessions	BL18, BL23, GB25, LR14	Streitberger placebo-needle control	PSQI, ISI, PSG (SOL, TST, WASO, SE, Arl, N1%, N2%, N3%, REM%)	(i) Lower PSQI and ISI in MA group (ii) Shorter SOL and WASO, longer TST, higher SE, lower Arl, lower N1%, and higher REM% in MA group; no differences in N2% and N3% between two groups	No follow-up	- MA/n=0 - placebo-MA/n=4 (worsening of insomnia)
Wang 2015^Citation52	- EA/n=30 - placebo-EA/n=30	PMI (ICSD-3)	NR	30 min/day, 3 days/week for 8 weeks	BL15, BL18, BL23, CV3, CV4, CV6, CV12, EX-HN3, GV3, GV4, GV14, GV20, HT7, KI3, LR3, PC6, SP6, ST36	Streitberger placebo-needle control	PSQI, MRS, Men-QoL	No differences in PSQI, MRS and MEN-QoL between two groups	(1) No difference in PSQI and Men-QoL between two groups at 4-week follow-up (2) Lower MRS in EA group at 4-week follow-up	No adverse events
Lin et al 2017^Citation53	- MA/n=33 - waitlist-control/n=32	PMI (CCMD-3, CDTE-TCM)	NR	30 min/day, 3 days/week for 4 weeks	CV4, CV6, CV12, EX-HN3, GV20, GV24, HT7, PC6, SP6, ST36	Waitlist	PSQI, KI	Lower PSQI and KI in MA group	No follow-up	NR
Li et al 2020a^Citation54	- EA/n=42 - placebo-EA/n=42	PMI (ICSD-3)	Kidney Yin/Yang deficiency	− 30 min/day for 18 days (3 days/week for 4 weeks + 2 day/week for 2 weeks + 1 day/week for 2 weeks) - continuous wave, 2.5 Hz, 4–5 mA	BL23, CV4, CV6, EX, EX-HN3, GV4, GV20, GV24, HT7, KI3, KI7, SP6	Streitberger placebo-needle control	PSQI, MEN-QoL, Actigraphy (TST, WASO, SE, ATs, AA), ISI, SAS, SDS	(i) Lower PSQI, ISI, MEN-QoL, SAS in EA group; no differences in SDS between two groups (ii) Longer TST, higher SE, and less AA in EA group; no differences in ATs and WASO between two groups	Lower PSQI and Men-QoL in EA group at 4- and 12- week follow-ups	- EA/n=2 [mild bleeding (1); mild pain (1)] - placebo-EA/n=1 (mild pain)
Wang et al 2015^Citation55	- MA/n=33 - sham-MA/n=33	PMD (CCMD-3)	NR	30 min/day, 3 days/week for 8 weeks	KI6, LU7, PC6, SP4	Sham-MA [shallow puncture (2.5–5 mm), no De-qi, no retention of the needle]	SDS, Men-QoL	Lower SDS and Men-QoL in MA group	(i) Lower SDS in MA group at 4-week follow-up (ii) no difference in Men-QoL between two groups	NR
Li 2015a^Citation56	- EA/n=30 - sham-EA/n=30 - Escitalopram/n=30	PMD (ICD-10)	NR	− 30 min/day, 3 days/week for 12 weeks - dense-sparse wave, 10/50 Hz, 0.5–1 mA	CV4, EX-CA1, EX-HN3, GV20, LI4, LR3, SP6, ST25	(i) Sham-MA [shallow puncture (3 mm), no De-qi, no current output] (ii) Escitalopram 10 mg/day for 12 weeks	HAMD, Men-QoL, FSH, E2, LH	(i) Lower HAMD and Men-QoL in EA group, compared with sham-EA; no differences in HAMD and Men-QoL between EA and escitalopram groups (ii) No differences in FSH, LH and E2 levels between two groups (vs sham-EA or vs escitalopram)	(i) Lower HAMD in EA group in 4-week and 12-week follow-ups (vs sham-EA); no difference in HAMD between EA and escitalopram groups in 4-week and 12-week follow-ups (ii) Lower Men-QoL in EA in 4-week follow-up (vs sham-EA or vs escitalopram); Men-QoL from low to high (EA < escitalopram < sham-EA) at 8-week and 12-week follow-ups	- EA/n=2 (hematoma) - sham-EA/n=0 - Escitalopram/n=25 [fatigue (17); headache (2); sleep disturbance (7); dizziness (7); palpitation (4); sweating (10); dry mouth (14); constipation (8)]
Ma 2017^Citation97	- EA/n=37 - Progynova + Medroxyprogesterone acetate/n=36	PMI (CCMD-2-R)	NR	− 30 min/day, 3 days/week for 12 weeks - sparse-dense wave, 2/15 Hz	CV4, EX-CA1, EX-HN3, HT7, SP6, ST25	A total of 3 treatment cycles. Each treatment cycle includes Progynova 1mg daily for 21 consecutive days (with Medroxyprogesterone acetate 10mg daily added from day 14 to day 21) and then stop medication for 7 days	PSQI, KI, Men-QoL, FSH, E2	(i) Lower PSQI in EA group; no differences in KI and Men-QoL between two groups (ii) No differences in FSH level between two groups; higher E2 level in EA group	(i) Lower PSQI in EA group at 12-week follow-up (ii) No differences in KI MENQOL, and FSH and E2 levels between two groups	- EA/n=3 [hematoma (2); mild dizziness (1)] - Progynova + Medroxyprogesterone acetate/n=4 [breast tenderness (2); mild headache (1); colporrhagia (1)]
Chen et al 2013^Citation57	- EA/n=38 - Alprazolam/n=32	PMI (DSM-IV)	NR	− 30 min/day for 20 days (7 days off every 10 days) - continuous wave, 0.7 Hz	EX, GV20, HT7, KI3, KI7, KI10, LR3, PC6, SP6, SP9, SP10	Alprazolam 0.4 mg/day for 20 days	AIS	Lower AIS in EA group	No follow-up	- EA/n=0 - Estazolam/n=8 (development of drug dependence after treatment)
Luo 2020^Citation58	- MA/n=30 - Estazolam/n=30	PMI (CCMD-3, CDTE-TCM)	Incoordination between heart and kidney	30 min/day, 5 days/week for 12 weeks	BL15, BL23, BL62, EX, EX-HN1, GV20, KI3, KI6, PC6, SP6	Estazolam 1 mg/day, 3 days/week for 12 weeks	PSQI	No differences in PSQI between two groups	No follow-up	- MA/n=0 - Estazolam/n=5 [dizziness (2); nausea and vomiting (2); skin rashes (1)]
Du et al 2017^Citation59	- EA/n=41 - Estazolam/n=41	PMI (CCMD-3)	NR	− 30 min/day, 6 days/week for 4 weeks - continuous wave, >50 Hz	PC6, SP6, Sishenzhen (1.5 Cun apart from GV20), Dingshenzhen (0.5 Cun up to EX-HN3, and 0.5 Cun up to GB14)	Estazolam 1 mg/day, 7 days/week for 4 weeks	PSQI, KI, WHOQOL-BREF, FSH, E2	(i) Lower PSQI and KI, and higher WHOQOL-BREF in EA group (ii) Higher E2 levels, and lower FSH levels in EA group	No follow-up	- EA/n=6 (mild tension before EA) - Estazolam/n=26 [dizziness (26); daytime sleepiness (26)]
Kang 2015^Citation60	- MA/n=31 - Estazolam/n=33	PMI (CCMD-3)	Heart and Gallbladder Qi deficiency	40 min/day, 6 days/week for 4 weeks	EX, EX-HN1, GB13, GB15, GV16, GV20, GV24, scalp acupoint (1 Cun up to GB15)	Estazolam 1 mg/day, 7 days/week for 4 weeks	PSQI, KI	Lower PSQI and KI in MA group	No follow-up	- MA/n=0 - Estazolam/n=1 (mild nausea)
Lai 2016^Citation61	- MA/n=34 - Eszopiclone/n=33	PMI (CCMD-3)	Incoordination between heart and kidney	30 min/day, 6 days/week for 3 weeks (acupuncture on specific time)	BL62, KI6, LU7, SI3	Eszopiclone 3 mg/day, 7 days/week for 3 weeks	PSQI, KI	(i) Lower KI in MA group; no differences in PSQI between two groups	No follow-up	- MA/n=2 (hematoma) - Eszopiclone/n=3 [dizziness (1); dry mouth (2)]
Li 2014^Citation62	- MA/n=120 - Estazolam/n=120	PMI (CCMD-3)	NR	30 min/day for 30 days	SP6, SP8, Shenguan (Tianhuangfuxue)	Estazolam 2 mg/day for 30 days	PSQI	Lower PSQI in MA group	No follow-up	NR
Li et al 2018a^Citation63	- MA/n=60 - Alprazolam/n=62	PMI (CDTE-TCM)	NR	30–40 min/day, 5 days/week for 9 weeks	BL13, BL15, BL17, BL18, BL20, BL23, HT7	Alprazolam 0.4–0.8 mg/day, 7 days/week for 9 weeks	PSQI, FSH, E2, LH	(i) Lower PSQI in MA group (ii) Higher E2 levels, and lower FSH and LH levels in MA group	Follow-up 30 days; NR for valid data	NR
Lu et al 2014^Citation49	- MA/n=52 - Estazolam/n=52	PMI (CCMD-3, ICD-10)	NR	30 min/day for 30 days	CV12, EX-HN1, GB20, GV20, HT7, LR3, LR14, SP6, SP15	Estazolam 1 mg/day for 30 days	PSQI	Lower PSQI in MA group	No follow-up	NR
Ma 2014^Citation64	- EA/n=45 - Estazolam/n=45	PMI (CCMD-2)	Any TCM syndrome pattern according to CDTE-TCM	− 30 min/day, 3 days/week for 4 weeks - continuous wave, >50 Hz	PC6, SP6, Sishenzhen (1.5 Cun apart from GV20), Dingshenzhen (0.5 Cun up to EX-HN3, and 0.5 Cun up to GB14)	Estazolam 1 mg/day, 7 days/week for 4 weeks	PSQI, HAMD	Lower PSQI and HAMD in EA group	No follow-up	No adverse events
Qin 2018^Citation65	- MA/n=34 - Estazolam/n=33	PMI (CCMD-3, ICD-10)	Deficiency of kidney and hyperactivity of liver	30 min/day, 5 days/week for 4 weeks	BL17, BL18, BL23, EX, EX-HN1, GV20, KI3, LR3	Estazolam 1–2 mg/day, 7 days/week for 4 weeks	PSQI, HAMA MSMSMS (REM%)	(i) Lower PSQI in MA group (ii) Higher REM% in MA group	No follow-up	- MA/n=3 (hematoma) - Estazolam/n=7 [dizziness (2); daytime sleepiness (2); fatigue (3)]
Yang et al 2017^Citation66	- MA/n=81 - Estazolam/n=81	PMI (CCMD-2)	Liver and kidney Yin deficiency	30 min/day, 15 days/month (one treatment every other day) for 3 months	CV12, HT7, KI3, PC6, ST36, ST40, four scalp acupoints (middle 1/3 of frontal apical band, posterior 1/3 of frontal apical band, anterior 1/3 of skull base band, middle 1/3 of skull base band)	Estazolam 1 mg/day, 10 days/month for 3 months	PSQI, FSH, E2, LH	(i) Lower PSQI in MA group (ii) Higher FSH levels, and lower E2 and LH levels in MA group	No follow-up	NR
Zhang et al 2017^Citation67	- MA/n=31 - Estazolam/n=30	PMI (DTICA, CDTE-TCM)	Six syndrome patterns with liver as the core	30 min/day, 5 days/week for 4 weeks	BL17, BL18, EX, EX-HN1, GV20, LR3	Estazolam 1 mg/day, 7 days/week for 4 weeks	PSQI, KI, HAMA, HAMD	Lower PSQI, KI, HAMA and HAMD in MA group	No follow-up	- MA/n=1 (hematoma) - Estazolam/n=4 [dizziness (2); fatigue and daytime sleepiness (2); memory loss (2)]
Yan et al 2021^Citation68	- MA/n=42 - Estazolam/n=43	PMI (CCMD-3)	NR	30 min/day, 7 days/week for 12 weeks	CV4, CV6, GV20, GV24, HT7, SP6	Estazolam 1 mg/day, 7 days/week for 12 weeks	PSQI, Men-QoL	Lower PSQI and Men-QoL in MA group	No follow-up	- MA/n=4 [dizziness (3); hematoma (1)] - Estazolam/n=3 [dizziness (1); fatigue and daytime sleepiness (2)]
Li et al 2018b^Citation69	- EA/n=116 - Escitalopram/n=105	PMD (DSM-V, ICD-10)	NR	− 30 min/day, 3 days/week for 12 weeks - dilatational wave, 50 Hz, 0.5–1 mA	CV4, EX-CA1, EX-HN3, GV20, LI4, LR3, SP6, ST25	Escitalopram 10mg/day for 12 weeks	HAMD, Men-QoL, FSH, E2, LH	(i) No differences in HAMD and Men-QoL between two groups (ii) No differences in FSH, E2 and LH levels between two groups	(i) Lower HAMD in EA group at 4-and 12-week follow-ups (ii) Lower Men-QoL in EA group in 4-, 8-and 12-week follow-ups	- EA/n=14 (hematoma) - Escitalopram/n=18 (dizziness, palpitation, stomachache)
Chi et al 2011^Citation70	- MA/n=30 - Fluoxetine/n=30	PMD (CCMD-3)	NR	30 min/day for 4 weeks	EX-HN1, EX-HN3, GV20, KI3, LR3, LR14, SP6, ST36	Fluoxetine 20 mg/day for 4 weeks	HAMD	Lower HAMD in MA group	No follow-up	- MA/n=0 - Fluoxetine/n=3 [dizziness (1); nausea (2)]
Deng 2008^Citation71	- MA/n=29 - Deanxit/n=29	PMD (ICD-10)	NR	20–30 min/day, after 3 consecutive days of treatment, once treatment every 3 days for total 4 weeks	CV3, CV4, CV6, CV10, CV12, KI17, Qipang (0.5 Cun beside CV6), Xiafengshidian (1 Cun below and beside ST26)	Deanxit 20mg/day for 4 weeks	HAMD, KI, 5-HT	(i) No differences in HAMD and KI between two groups (ii) No differences in 5-HT levels between two groups	(i) Lower HAMD in MA at 2-week follow-up (ii) No difference in HAMD between two groups at 4-week follow-up (iii) No difference in KI between two groups at 2-and 4-week follow-ups	- MA/n=3 [changes of character of stool (2); palpitation (1)] - Deanxit/n=32 [changes of character of stool (6); dry mouth and halitosis (9); dysphoria (6); dreaminess (6); breast distending pain (5)]
Dong 2015^Citation85	- MA/n=30 - Nilestriol + Fluoxetine/n=30	PMD (CCMD-3, CDTE-TCM)	NR	30 min/day for 30 days	BL13, BL15, BL17, BL18, BL20, BL21, BL23	Nilestriol 2mg/15days for 30 days + Fluoxetine 20mg/day for 30 days	HAMD	Lower HAMD in MA group	No follow-up	NR
Li 2015b^Citation72	- MA/n=32 - Fluoxetine/n=32	PMD (CCMD-3)	Liver stagnation and kidney deficiency	30 min/day, 6 days/week for 12 weeks	BL15, BL18, BL23, EX-HN1, EX-HN3, GV20, GV24, PC6	Fluoxetine 20mg/day for 12 weeks	HAMD, KI	Lower HAMD and KI in MA group	Follow-up for 12 weeks; no data of HAMD and KI global scores for follow-up	- MA/n=0 - Fluoxetine/n=8 [nausea and vomiting (2); dry mouth (1); indigestion (1); diarrhea (1); dizziness (1); headache (1)]
Ma et al 2009^Citation73	- MA/n=30 - Fluoxetine/n=30	PMD (CCMD-3, CDTE-TCM)	NR	30 min/day, 5 days/week for 8 weeks	EX-HN1, EX-HN3, GV20, HT7, PC6, PC7, SP6, ST36	Fluoxetine 20mg/day for 8 weeks	HAMD	No differences in HAMD between two groups	No follow-up	- MA/n=0 - Fluoxetine/n=6 [nausea (2); dizziness (2)]
Niu et al 2017^Citation74	- MA/n=41 - Fluoxetine/n=41	PMD (CCMD-3)	Stagnation of liver Qi	30 min/day, 5 days/week for 6 weeks	BL13, BL15, BL17, BL18, BL20, BL23	Fluoxetine 20mg/day for 6 weeks	HAMD	Lower PSQI in MA	No follow-up	- MA/n=7 [dizziness (2); palpitation (1); dry mouth (1); nausea (3)] - Fluoxetine/n=6 [dizziness (1); palpitation (2); dry mouth (2); nausea (1)]
Qian et al 2007^Citation75	- MA/n=33 - Fluoxetine/n=30	PMD (CCMD-3)	NR	25 min/day, 5 days/week for 6 weeks	BL13, BL15, BL17, BL18, BL20, BL23	Fluoxetine 20mg/day for 6 weeks	HAMD	No differences in HAMD between two groups	No follow-up	- MA/n=2 [dizziness (1); palpitation (1)] - Fluoxetine/n=9 [insomnia (1); akathisia (1); dry mouth (1); nausea (1); palpitation (1); skin symptom (1); excitation and agitation (2)]
Qiang 2008^Citation76	- MA/n=30 - Fluoxetine/n=30	PMD (CCMD-3)	NR	25 min/day, 5 days/week for 6 weeks	BL15, BL18, BL23, EX-HN1, GB20	Fluoxetine 20mg/day for 6 weeks	HAMD	No differences in HAMD between two groups	No follow-up	NR
Shi et al 2018^Citation77	- EA/n=30 - Escitalopram/n=30	PMD (DSM-V)	NR	− 30 min/day, 3 days/week for 12 weeks - dense-sparse wave, 10/50Hz, 0.5–1.0mA	CV4, EX-CA1, EX-HN3, GV20, LI4, LR3, SP6, ST25	Escitalopram 10mg/day for 12 weeks	HAMD	Lower HAMD in EA group	Lower HAMD in EA at 4- and 12- week follow-ups	NR
Sun et al 2015^Citation78	- EA/n=21 - Escitalopram/n=21	PMD (DSM-V)	NR	− 30 min/day, 3 days/week for 12 weeks - dense-sparse wave, 10/50Hz, 0.5–1.0mA	CV4, EX-CA1, EX-HN3, GV20, LI4, LR3, SP6, ST25	Escitalopram 10mg/day for 12 weeks	HAMD	Lower HAMD in EA group	No follow-up	NR
Wang et al 2010^Citation79	- MA/n=21 - Deanxit/n=21	PMD (CCMD-3)	NR	30 min/day, after 3 consecutive days of treatment, once treatment every 3 days for total 4 weeks	CV3, CV4, CV6, CV10, CV12, KI17	Deanxit 10 mg/day for 4 weeks	HAMD	No differences in HAMD between two groups	Lower HAMD in MA at 2- and 4- week follow-ups	- MA/n=3 [changes of character of stool (2); palpitation (1)] - Deanxit/n=15 [dry mouth and halitosis (9); dysphoria, dreaminess, or breast distending pain (6)]
Zhang 2010^Citation86	- EA/n=44 - Nilestriol+ Fluoxetine/n=46	PMD (CCMD-3)	NR	− 30 min/day, 5 days/week for 12 weeks - dilatational wave, 8–9 mA, 6V	BL13, BL15, BL17, BL20, BL23, GV20, KI3, LR3, PC6, SP6	Nilestriol 2mg/14 days for 30 days + Fluoxetine 20mg/day for 12 weeks	HAMD, KI, FSH, E2, LH	(i) No differences in HAMD and KI between two groups (ii) No differences in FSH, LH and E2 levels between two groups	No follow-up	- EA/n=5 (sweating, dizziness, vomiting) - Nilestriol+ Fluoxetine/n=23 [dry mouth and halitosis (5); nausea (6); dysphoria (2); constipation (6); dreaminess (2); breast distending pain (2)]
Zhang 2013^Citation87	- MA/n=94 - Premarin + Provera + Fluoxetine/n=94	PMD (CCMD-3)	NR	30 min/day, 7 days/week for 12 weeks	EX-HN1, GB13, GV20, GV24, HT7	Premarin 0.625mg/day and Provera 6mg/day + Fluoxetine 20mg/day for 12 weeks	HAMD, FSH, E2, LH	(i) Lower HAMD in MA group (ii) No differences in FSH, LH and E2 levels between two groups	No follow-up	- MA/n=2 (feeling pain when inserting needle) - Premarin + Provera + Fluoxetine/n=12 [dizziness (5); nausea and vomiting (4); hypersomnia (3)]
Zheng et al 2010^Citation88	- MA/n=60 - Premarin + Provera + Fluoxetine/n=60	PMD (CCMD-3)	NR	30 min/day, 7 days/week for 12 weeks [needle retaining time for 8 hour in three acupoints (BL8, GV19, GV21) per session]	BL8, BL18, BL23, GV19, GV21, KI3, LR3, SP6	Premarin 0.625mg/day for 20 days + and Provera 6mg/day + Fluoxetine 20mg/day for 12 weeks	HAMD, KI, FSH, E2, LH	(i) No differences in HAMD and KI between two groups (ii) No differences in FSH and LH levels between two groups; Lower E2 level in MA group	Lower HAMD and KI in MA at 24-week follow-up	- MA/n=2 (feeling pain when inserting needle) - Premarin + Provera + Fluoxetine/n=18 [loss of appetite (5); dizziness (4); diarrhea (3); breast distending pain (3); leukorrhagia (2); spasmus (1)]
Ding et al 2007^Citation80	- MA/n=39 - Fluoxetine/n=39	PMD (CCMD-2-R)	NR	30 min/day, 6 days/week for 4 weeks	BL15, BL18, BL20, BL23, GV20, HT7, LR3, SP6	Fluoxetine 20mg/day for 4 weeks	HAMD, KI	No differences in HAMD between two groups; Lower KI in MA group	No follow-up	NR
Li et al 2020b^Citation81	- EA/n=30 - Fluoxetine/n=30	PMD (CDTE-TCM)	NR	− 25 min/day, 3 days/week for 6 weeks - dilatational wave, 15 Hz, 1 mA	EX-HN1, EX-HN3, GV20, HT7, LI4, PC6, SP6, ST36	Fluoxetine 20mg/day for 6 weeks	HAMD, HAMA	No differences in HAMD between two groups; Lower HAMA in EA group	No follow-up	NR
Zhang 2015^Citation82	- MA/n=29 - Deanxit/n=29	PMD (CCMD-3)	NR	30 min/day, after 3 consecutive days of treatment, once treatment every 3 days for total 4 weeks	CV3, CV4, CV6, CV10, CV12, KI17	Deanxit 20 mg/day for 4 weeks	HAMD	No differences in HAMD between two groups	Lower HAMD in MA at 2- and 4- week follow-ups	NR
Xing 2011^Citation83	- MA/n=120 - Fluoxetine/n=120	PMD (CCMD-3)	Stagnation of liver Qi, heart and spleen deficiency; liver depression and phlegm-heat	20 min/day, 7 days/week for 6 weeks	GV26, PC5	Fluoxetine 20mg/day for 6 weeks	HAMD	No differences in HAMD between two groups	No follow-up	NR
Zhou et al 2007^Citation84	- MA/n=30 - Fluoxetine/n=28	PMD (CCMD-3)	Liver and kidney Yin deficiency, spleen and kidney Yang deficiency, stagnated Qi transforming into fire, stagnation of phlegm and Qi	30 min/day, 6 days/week for 6 weeks	BL15, BL18, BL23, EX-HN1, GB13, GV24, SP6, ST36	Fluoxetine 20mg/day for 6 weeks	HAMD, 5-HIAA, NE, DA	(i) Lower HAMD in MA group (ii) No differences in 5-HIAA and NE levels between two groups; Lower DA level in MA group	No follow-up	NR
Gao et al 2014^Citation89	- MA + Estazolam/n=32 - Estazolam/n=32	PMI (CCMD-3)	NR	20 min/day, 6 days/week for 4 weeks	EX-B2	Estazolam 2 mg/day for 4 weeks	PSQI	Lower PSQI in MA + Estazolam group	No follow-up	NR
Xu 2020^Citation90	- MA + Alprazolam/n=50 - Alprazolam/n=50	PMI (CDTE-TCM)	NR	30 min/day, 7 days/week for 9 weeks	EX-HN1, GV24, HT7, KI3, LR3, PC6, SP6, ST36	Alprazolam 0.4–0.8 mg/day, 7 days/week for 9 weeks	PSQI	Lower PSQI in MA + Alprazolam group	No follow-up	NR
Ma 2016^Citation91	- MA + Estazolam/n=35 - Estazolam/n=35	PMI (CCMD-3)	NR	7 days/week for 4 weeks	EX, HT7, KI3, KI7, KI10, LR3, SP6, SP10, ST36	Estazolam 2 mg/day, 7 days/week for 4 weeks	PSQI, FSH, E2	(i) Lower PSQI in MA + Estazolam group (ii) Higher E2 levels, and lower FSH levels in MA + Estazolam group	No follow-up	NR
Zhu et al 2016^Citation92	- MA + Estazolam/n=37 - Estazolam/n=37	PMI (CCMD-3)	Heart and Spleen deficiency	20 min/day, 5 days/week for 4 weeks	CV12, EX, EX-HN1, GV20, GV24, HT7, KI3, LR3, SP9, ST25	Estazolam 1 mg/day, 5 days/week for 4 weeks	PSQI	No differences in PSQI between two groups	No follow-up	NR
Ma et al 2011^Citation95	- EA + Paroxetine/n=55 - Paroxetine/n=50	PMD (CCMD-3)	NR	− 45 min/day, 7 days/week for 6 weeks - dilatational wave, 8–9 mA	EX-HN3, GV20, LI4, PC6, ST36	Paroxetine 10mg/day for 6 weeks	HAMD	No differences in HAMD between two groups	No follow-up	- EA + Paroxetine/n=2 [dizziness (1); nausea (1)] - Paroxetine/n=3 [dizziness (1); elevated blood pressure (2)]
Liu et al 2019^Citation93	- MA + Sertraline/n=40 - Sertraline/n=40	PMD (CCMD-3, ICD-10)	NR	30 min/day, 3 days/week for 12 weeks	BL23, CV4, HT7, KI3, LI4, LR3, SP6	Sertraline 50mg/day for 6 weeks	HAMD, FSH, E2, 5-HT, GABA	(i) Lower HAMD in MA + Sertraline group (ii) Lower FSH level in MA + Sertraline group; higher E2, 5-HT and GABA levels in MA + Sertraline group	No follow-up	NR
Ning 2015^Citation94	- MA + Nilestriol + Fluoxetine/n=45 - Nilestriol + Fluoxetine/n=45	PMD (Psychiatry textbook)	NR	30 min/day, 7 days/week for 12 weeks	BL13, BL15, BL18, BL20, BL23, GV20, HT7, KI3, LI4, LR3	Nilestriol 2mg/15days + Fluoxetine 20mg/day for 12 weeks	HAMD, TESS	Lower HAMD and TESS in MA + Nilestriol + Fluoxetine group	No follow-up	NR

Abbreviations: NR, no report; MA, manual acupuncture; EA, electroacupuncture; PMI, perimenopausal insomnia; PMD, perimenopausal depression; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition); ICSD-3, International classification of sleep disorders (Third Edition); CCMD-2-R, revised Chinese Classification of Mental Disorders (Second Edition); CCMD-3, Chinese Classification of Mental Disorders (Third Edition); ICD-10, International Classification of Diseases (10th edition); DTICA, Guidelines for Diagnosis and Treatment of Insomnia in Chinese Adults (2012 Edition); CDTE-TCM, Criteria of Diagnosis and Therapeutic Effect of Diseases and Syndromes in TCM; PSQI, Pittsburgh Sleep Quality Index; ISI, Insomnia Severity Index; AIS, Athens Insomnia Scale; KI, Kupperman Index; MRS, Menopause Rating Scale; Men-QoL, Menopause-Specific Quality of Life; HAMA, Hamilton Anxiety Scale; HAMD, Hamilton Depression Scale; SAS, Self-Rating Anxiety Scale; SDS, Self-Rating Depression Scale; WHOQOL-BREF, World Health Organization’s quality of life scale-brief form questionnaire; TESS, Treatment Emergent Symptom Scale; PSG, polysomnography; MSMSMS, micromovement sensitive mattress sleep monitoring system; SOL, sleep onset latency; WASO, wake after sleep onset; TST, total sleep time; SE, sleep efficiency; ATs, awakening times; AA, average awakening; ArI, arousal index; REM, rapid eye movement; N1(2, 3, 4), 1st(2nd, 3rd, 4th) period of non-rapid eye movement sleep (NREM); FSH, follicle-stimulating hormone; LH, luteinizing hormone; E2, estradiol; 5-HT, 5-hydroxy tryptamine; NE, norepinephrine; DA, dopamine; GABA, gamma-aminobutyric acid; six syndrome patterns with liver as the core [liver stagnation (stasis); excessive liver fire due to emotional suppression; Disturbance of liver Yang; deficiency of kidney and hyperactivity of liver; liver depression invading the stomach; liver depression invading the heart]; five TCM syndrome patterns according to CDTE-TCM [excessive liver fire due to emotional suppression; disturbance of Heart due to phlegm heat; Yin deficiency leading to excessive fire; Heart and Spleen deficiency; Heart and Gallbladder Qi deficiency]; BL8, Luoque; BL13, Feishu; BL15, Xinshu; BL17, Geshu; BL18, Ganshu; BL20, Pishu; BL21, Weishu; BL23, Shenshu; BL62, Shenmai; CV3, Zhongji; CV3, Zhongji; CV4, Guanyuan; CV6, Qihai; CV10, Xiawan; CV12, Zhongwan; EX, Anmian; EX-B2, Jiaji; EX-CA1, Zigong; EX-HN1, Sishencong; EX-HN3, Yintang; GB13, Benshen; GB14, Yangbai; GB15, Toulinqi; GB20, Fengchi; GB25, Jingmen; GV3, Yaoyangguan; GV4, Mingmen; GV14, Dazhui; GV16, Fengfu; GV19, Houding; GV20, Baihui; GV21, Qianding; GV24, Shenting; GV26, Shuigou; HT7, Shenmen; KI3, Taixi; KI6, Zhaohai; KI7, Fuliu; KI10, Yingu; KI13, Qixue; KI17, Shangqu; LI4, Hegu; LR3, Taichong; LR14, Qimen; LU7, Lieque; PC5, Jianshi; PC6, Neiguan; PC7, Daling; SI3, Houxi; SP4, Gongsun; SP6, Sanyinjiao; SP8, Diji; SP9, Yinlingquan; SP10, Xuehai; SP15, Daheng; ST25, Tianshu; ST26, Wailing; ST36, Zusanli; ST40, Fenglong.

Table 3 Results of Meta-Analyses for Existing RCTs

Comparison	Study (n); Participants (n)	Outcomes	Mean/Std. Mean Difference IV, Random, 95% CI	p
Acupuncture vs waitlist-control or placebo-/sham- acupuncture	RCTs (n = 4); PMI women (n = 283)	PSQI	MD = −4.03, 95% CI (−6.85, −1.21)	<0.01
	RCTs (n < 3, no meta-analysis); PMD women (n = 126)	-	-	-
Acupuncture vs hypnotic	RCTs (n = 12); PMI women (n = 1204)	PSQI	MD = −2.24, 95% CI (−3.13, −1.36)	<0.01
	RCTs (n = 4); PMI women (n = 274)	KI	MD = −5.95, 95% CI (−10.68, −1.21)	0.01
Acupuncture vs antidepressant/antidepressant + HRT	RCTs (n = 21); PMD women (n = 1842)	HAMD at post-treatment	SMD = −0.54, 95% CI (−0.91, −0.16)	<0.01
	RCTs (n = 3); PMD women (n = 169)	HAMD at 2-week follow-up	SMD= −0.64, 95% CI (−0.95, −0.33)	0.01
	RCTs (n = 6); PMD women (n = 504)	HAMD at 4-week follow-up	SMD = −1.36, 95% CI (−2.72, 0.00)	0.05
	RCTs (n = 3); PMD women (n = 341)	HAMD at 12-week follow-up	SMD = −2.73, 95% CI (−6.14, 0.67)	0.12
	RCTs (n = 5); PMD women (n = 410)	KI	MD= −2.80, 95% CI (−5.60, −0.01)	0.05
Acupuncture + hypnotics vs hypnotics	RCTs (n = 4); PMI women (n = 308)	PSQI	MD = −2.80, 95% CI (−4.23, −1.37)	<0.01
Acupuncture + antidepressant/antidepressant + HRT vs antidepressant or antidepressant + HRT	RCTs (n = 3); PMD women (n = 275)	HAMD at post-treatment	SMD = −0.82, 95% CI (−1.07, −0.58)	<0.01

Note: Data from references 19 and 50.

Abbreviations: PSQI, Pittsburgh Sleep Quality Index; KI, Kupperman Index; HAMD, Hamilton Depression Scale; HRT, hormone replacement therapy.

Table 4 Common Defects of Study Design and Reporting Quality Among Current RCTs

Items	Limitations	Potential Negative Consequences
Study design	Lack of appropriate sample size estimation	Diminishment of credibility of the results; reduction in likelihood of finding an effect of the treatment
	Lack of sham-/placebo- acupuncture as parallel control in trials comparing acupuncture with Western medications	Potential bias and uncertainty on the placebo effects of acupuncture
	Without appropriate statistics (ie intention-to-treat analysis, etc) for data of those withdrawal/dropout patients	Increased risk of an overestimation/underestimation of the efficacy of acupuncture or Western medications
	Lack of follow-ups	Unable to evaluate medium- and long- term effects/safety of acupuncture
	Objective indices (ie, polysomnography, actigraphy, etc) is seldom used in PMI studies	(i) Unable to understand the effects of acupuncture on sleep architecture (ii) A biased judgement or even a question on acupuncture’s real efficacy due to a mismatch between the subjective and objective sleep-wake duration
	No discussion of the effects of acupuncture responding to specific/each TCM syndrome pattern (all TCM syndrome patterns are mixed for efficacy assessment)	Difficult to judge the real therapeutic effect of acupuncture
Reporting quality	Lack of reports on if or how allocation concealment and blinding of patients/outcome assessments are performed	Inadequate blinding is associated with an exaggeration of the estimated efficacy
	Lack of description and in-depth analysis of the specific causes of withdrawal/dropout	Unable to understand patient’s compliance and acceptance of acupuncture, placebo or Western medications
	Protocols and/or registration Information are not always available	Greatly weakens the reliability of the evidence
	Incomplete descriptions of needling details and/or treatment regimen, as well as acupuncturists’ background	(i) Poor reproducibility of the trial results (ii) Hinder the clinical promotion of effective acupuncture prescription

Table 5 Summary of Animal Studies Determining the Mechanisms Underlying Acupuncture on PMI and PMD

Author/Year	Animals	Disease Models	Methods of Modeling	Study Groups/No. of Participants	Interventions	Acupuncture Protocol	Acupoints	Outcome Measures	Results
Cao et al 2019^Citation152	SD rats, 280–320g, 12 months	PMI	(i) OVX (ii) Electrical stimulation	- EA/n= 12 - Model/n= 12 - Sham-surgery/n= 12	- EA/OVX + electrical stimulation + EA - Model/OVX + electrical stimulation - Sham-surgery/sham-OVX + electrical stimulation	− 20 min/day for 14 days - Dense wave, 50Hz	SP6	(i) MER (REM, SWS) (ii) 5-HT, 5-HIAA, 5-HT1A in hippocampus	(i) EA increased REM and SWS (ii) EA increased 5-HT and 5-HT1A levels; no significant change in 5-HIAA level
Cao et al 2020^Citation136	Wistar rats, 230–270g, 5–7 months	PMI	(i) OVX (ii) Electrical stimulation	- EA/n= 10 - Model/n= 10 - Sham-surgery/n= 10	- EA/OVX + electrical stimulation + EA - Model/OVX + electrical stimulation - Sham-surgery/sham-OVX + electrical stimulation	− 15 min/day for 21 days - Dense wave, 50Hz	EX-HN1, HT7	(i) MER (TST, REM, SWS, LS) (ii) L-PGDS, PGD2, PGE2 in CSF (iii) GABA in VLPO	(i) EA increased REM, SWS; no significant change in TST and LS (ii) EA increased L-PGDS and PGD2 levels; no significant change in PGE2 level (iii) EA increased GABA level
Jin et al 2010^Citation189	SD rats, 230–270g, 3 months	PMI	(i) OVX (ii) Electrical stimulation	- EA/n= 30 - Model/n= 30 - Sham-surgery/n= 30	- EA/OVX + electrical stimulation + EA - Model/OVX + electrical stimulation - Sham-surgery/sham-OVX + electrical stimulation	− 30 min/day for 7 days - Continuous wave, 15Hz, 2mA	BL23, SP6	(i) SOL and TST (ii) Heat-resistant time (iii) Energy (iv) Times of locomotor activity	(i) EA increased TST and reduced SOL (ii) EA increased heat-resistant time (iii) EA increased energy (iv) No significant change in times of locomotor activity (v) The earlier the intervention of EA in the perimenopausal period, the better the effect
Jin et al 2011^Citation190	SD rats, 150–180g	PMI	(i) OVX (ii) Electrical stimulation	- EA/n= 30 - Model/n= 30 - Sham-surgery/n= 30	- EA/OVX + electrical stimulation + EA - Model/OVX + electrical stimulation - Sham-surgery/sham-OVX + electrical stimulation	− 30 min/day for 7 days - Continuous wave, 15Hz, 2mA	BL23, SP6	(i) SOL and TST (ii) Heat-resistant time (iii) Energy	(i) EA increased TST and reduced SOL (ii) EA increased heat-resistant time (iii) EA increased energy (iv) The earlier the intervention of EA in the perimenopausal period, the better the effect
Xie 2013^Citation116	SD rats, 216–245.8g, 6–8 weeks	PMI	OVX	- EA/n= 25 - Model/n= 25 - Sham-surgery/n= 25 - Sham-EA/n= 25	- EA/OVX + EA - Model/OVX - Sham-surgery/sham-OVX -Sham-EA/OVX + sham-EA	− 15 min/day for 7 days - Continuous wave, 2Hz	BL23, EX	(i) EEG/EMG recording systems for rats and mice (WASO, REM, NREM) (ii) Serum FSH, E2 (iii) Estrogen receptor in VLPO and TMN (iv) Weight	(i) EA increased NREM, and reduced WASO and REM (ii) EA increased E2 and decreased FSH levels (iii) No significant change in estrogen receptor (iv) EA reduced weight
Yu 2012^Citation117	SD rats, 230–270g, 6–8 weeks	PMI	OVX	- EA/n= 12 - Model/n= 12 - Sham-surgery/n= 12 - Sham-EA/n= 12	- EA/OVX + EA - Model/OVX - Sham-surgery/sham-OVX - Sham-EA/OVX + sham-EA	− 15 min every other day for 7 days - Continuous wave, 2Hz	EX	(i) EEG/EMG recording systems for rats and mice (WASO, REM, NREM) (ii) Serum FSH, E2, LH	(i) EA increased NREM and reduced WASO; no significant change in REM; EA alleviated sleep fragmentation during the daytime (ii) EA increased E2 and reduced FSH levels; no significant change in LH level
Yang 2017^Citation121	SD rats, 230–270g, 6–8 weeks	PMI	OVX	- EA/n= 40 - Model/n= 40 - Sham-surgery/n= 40 - Sham-EA/n= 40	- EA/OVX + EA - Model/OVX - Sham-surgery/sham-OVX - Sham-EA/OVX + sham-EA	− 15 min/day for 7 days - Continuous wave, 15Hz	BL23, EX	(i) EEG/EMG recording systems for rats and mice (WASO, REM, NREM) (ii) serum E2 and 5-HT (iii) Adrenocortical E2 (iv) Hypothalamic 5-HT, NE, ER-α mRNA, ER-β mRNA	(i) EA increased NREM, and reduced WASO and REM; EA alleviated sleep fragmentation during the daytime (ii) EA increased E2 and 5-HT levels (iii) EA increased E2 level (iv) EA increased 5-HT, and decreased NE and ERβmRNA; no significant change in ERαmRNA
Jing et al 2020^Citation174	SD rats, 190–210g, 56–62days	PMD	(i) OVX (ii) CUMS	- EA/n= 10 - Control/n= 10 - Model/n= 10 - Sham-surgery/n= 10 - Clomipramine/n= 10	- EA/OVX + CUMS + EA - Control/no treatment - Model/OVX + CUMS - Sham-surgery/sham-OVX + CUMS - Clomipramine/OVX + CUMS + Clomipramine	− 20 min/day for 28 days-isperse-dense wave, 4/20Hz, 18V	BL23, GV20, SP6	(i) Behavioral tests (OFT, SPT) (ii) Serum E2, LH, GnRH (iii) GSK-3β mRNA, β-catenin mRNA in hippocampus (iv) β-Catenin protein, p-β-catenin protein in hippocampus	(i) EA improved rats’ depression-like behavior in behavioral tests (ii) EA increased E2, and decreased LH and GnRH levels (iii) EA decreased GSK-3β mRNA and increased β-catenin mRNA expression (iii) EA increased β-catenin protein and decreased p-β-catenin protein expression
Guo et al 2019^Citation145	KM mice, 18–22g	PMD	(i) OVX (ii) CUMS	- EA/n= 10 - Control/n= 10 - Model/n= 10 - Clomipramine/n= 10	- EA/OVX + CUMS + EA - Control/no treatment - Model/OVX + CUMS - Clomipramine/OVX + CUMS + Clomipramine	− 20 min/day for 28 days- disperse-dense wave, 2/10Hz, 18V	BL23, GV20, SP6	(i) Behavioral tests (FST, IAT, ADE, TSE) (ii) Serum E2, FSH, LH (iii) 5-HT, NE, DA in hippocampus	(i) EA improved mice’ depression-like behavior in behavioral tests (ii) EA increased E2 and decreased LH and FSH levels (ii) EA increased 5-HT, NE and DA levels
Seo et al 2018^Citation170	SD rats, 250–300g	PMD	OVX	- EA/n= NR - Model/n= NR - Sham-surgery/n= NR -Sham-EA/n= NR	- EA/OVX + EA - Model/OVX - Sham-surgery/sham-OVX - Sham-EA/OVX + sham-EA	60 seconds/day for 4 days	SP6	(i) Behavioral tests (FST, OFT, EPM) (ii) E2 and estrogen receptor expression in plasma and hippocampus (iii) BDNF and p-TrkB receptor in hippocampus (iv) NPY in hippocampus	(i) EA improved rats’ depression-like behavior in behavioral tests (ii) no significant change in E2 level or estrogen receptor expression (iii) EA increased BDNF and p-TrkB receptor levels (iv) EA increased NPY levels
Deng et al 2017^Citation185	SD rats, 190–210g, 56–62days	PMD	(i) OVX (ii) CUMS	- EA/n= 12 - Control/n= 12 - Model/n= 12 - Clomipramine/n= 12	- EA/OVX + CUMS + EA - Control/no treatment - Model/OVX + CUMS - Clomipramine/OVX + CUMS + Clomipramine	− 20 min/day for 28 days- disperse-dense wave, 4/20Hz, 18V	BL23, GV20, SP6	(i) Behavioral tests (FST, OFT) (ii) MAP-2, Notch1, Jagged1, Hes1 in hippocampus (iii) MAP-2 mRNA, Notch1 mRNA, Jagged1 mRNA, Hes1 mRNA in hippocampus	(i) EA improved rats’ depression-like behavior in behavioral tests (ii) EA increased MAP-2 protein and Notch1 protein levels, and decreased Jagged1 protein and Hes1 protein levels (ii) EA increased MAP-2 mRNA and Notch1 mRNA expression, and decreased Jagged1 mRNA and Hes1 mRNA expression
Deng 2017^Citation177	SD rats, 190–210g, 56–62days	PMD	(i) OVX (ii) CUMS	- EA/n= 10 - Control/n= 10 - Model/n= 10 - Sham-surgery/n= 10 - Clomipramine/n= 10	- EA/OVX + CUMS + EA - Control/no treatment - Model/OVX + CUMS - Sham-surgery/sham-OVX + CUMS - Clomipramine/OVX + CUMS + Clomipramine	− 20 min/day for 28 days- disperse-dense wave, 4/20Hz, 18V	BL23, GV20, SP6	(i) Behavioral tests (FST, OFT, SPT) (ii) GSK-3β, β-catenin in hippocampus (iii) β-catenin protein, p-β-catenin protein in hippocampus (iv) GSK-3β mRNA, β-catenin mRNA in hippocampus	(i) EA improved rats’ depression-like behavior in behavioral tests (ii) EA decreased GSK-3β and increased β-catenin contents (iii) EA increased β-catenin protein expression; no significant change in p-β-catenin protein expression (iv) EA decreased GSK-3β mRNA and increased β-catenin mRNA expression
Huangfu 2018^Citation129	SD rats, 190–210g, 56–62days	PMD	(i) OVX (ii) CUMS	- EA/n= 10 - Control/n= 10 - Model/n= 10 - Clomipramine/n= 10	- EA/OVX + CUMS + EA - Control/no treatment - Model/OVX + CUMS - Clomipramine/OVX + CUMS + Clomipramine	− 20 min/day for 28 days- disperse-dense wave, 4/20Hz, 18V	BL23, GV20, SP6	(i) Behavioral tests (FST, OFT, SPT, TSE) (ii) Glucocorticoid receptor, mineralocorticoid receptor in hippocampus	(ii) EA improved rats’ depression-like behavior in behavioral tests (ii) EA increased glucocorticoid receptor and mineralocorticoid receptor levels
Jiang 2017^Citation124	SD rats, 190–210g, 56–62days	PMD	(i) OVX (ii) CUMS	- EA/n= 12 - Control/n= 12 - Model/n= 12 - Sham-surgery/n= 12 - Clomipramine/n= 12	- EA/OVX + CUMS + EA - Control/no treatment - Model/OVX + CUMS - Sham-surgery/sham-OVX + CUMS - Clomipramine/OVX + CUMS + Clomipramine	− 20 min/day for 28 days- disperse-dense wave, 4/20Hz, 18V	BL23, GV20, SP6	(i) Behavioral tests (FST, SPT, TSE) (ii) Serum E2, FSH, LH, GnRH, CRH, ACTH, CORT, β-EP	(i) EA improved rats’ depression-like behavior in behavioral tests (ii) EA increased E2 andβ-EP, and decreased FSH, LH, GnRH, CORT, ACTH and CRH levels
Jiang et al 2017^Citation127	SD rats, 190–210g, 8–9 weeks	PMD	(i) OVX (ii) CUMS	- EA/n= 12 - Control/n= 12 - Model/n= 12 - Sham-surgery/n= 12 - Clomipramine/n= 12	- EA/OVX + CUMS + EA - Control/no treatment - Model/OVX + CUMS - Sham-surgery/sham-OVX + CUMS - Clomipramine/OVX + CUMS + Clomipramine	− 20 min/day for 28 days- disperse-dense wave, 4/20Hz, 18V	BL23, GV20, SP6	(i) Behavioral test (SPT) (ii) Serum E2, LH, GnRH, β-EP	(i) EA improved rats’ depression-like behavior in behavioral test (ii) EA increased E2 andβ-EP, and decreased LH and GnRH levels
Jing et al 2018^Citation178	SD rats, 180–220g, 17 weeks	PMD	(i) OVX (ii) CUMS	- EA/n= 12 - Control/n= 12 - Model/n= 12 - Clomipramine/n= 12	- EA/OVX + CUMS + EA - Control/no treatment - Model/OVX + CUMS - Clomipramine/OVX + CUMS + Clomipramine	− 20 min/day for 28 days- disperse-dense wave, 2/10Hz, 18V	BL23, GV20, SP6	(i) Behavioral test (TSE) (ii) E2, NE in hippocampus (iii) DKK1, LRP-5, LRP-6 in hippocampus	(i) EA improved rats’ depression-like behavior in behavioral test (ii) EA increased E2 and NE levels (iii) EA decreased DKK1, and decreased LRP-5 and LRP-6 expression
Zhou et al 2015^Citation146	SD rats, 220–260g	PMD	(i) OVX (ii) CUMS	- MA/n= 9 - Model-1/n= 9 - Model-2/n= 8 - Sham-surgery/n= 6 - Nilestriol + Fluoxetine/n= 9	- MA/OVX + CUMS + MA - Model-1/OVX + CUMS - Model-2/OVX - Sham-surgery/sham-OVX - Nilestriol + Fluoxetine/OVX + CUMS + Nilestriol + Fluoxetine	20 min/day for 21 days	BL23, GV20, SP6	(i) Behavioral test (OFT) (ii) 5-HT, NE, DA in hypothalamus	(i) MA improved rats’ depression-like behavior in behavioral test (ii) MA increased 5-HT level; no significant changes in NE and DA levels
Shi et al 2012^Citation147	SD rats, 300–350g, 4 months	PMD	(i) OVX (ii) CUMS	- MA/n= 10 - Model/n= 5 - Sham-surgery/n= 5 - Estradiol benzoate/n= 10	- MA/OVX + CUMS + MA - Model/OVX + CUMS - Sham-surgery/sham-OVX + CUMS - Estradiol benzoate/OVX + CUMS + Estradiol benzoate	30 min/session, once session every 2 days for total 30 sessions	CV4, CV6, LI4, LR3, PC6, SP6, ST36	(i) Serum E2 (ii) 5-HT in hypothalamus	(i) EA increased E2 level (ii) EA increased 5-HT level
Sun 2009^Citation118	(i) SD rats, 250–300g, 11–15 months (n= 45) (ii) Young SD rats, 150–200g, 4 months (n= 10)	PMD	CUMS	- EA/n= 15 - Model/n= 15 - Clomipramine/n= 15 - Young/n= 10	- EA/CUMS + EA - Model/CUMS - Clomipramine/CUMS + Clomipramine - Young/CUMS	− 20 min/day for 7 days- disperse-dense wave, 4/20Hz, 2V	BL18, BL23, GV20, SP6	(i) Behavioral tests (OFT) (ii) Serum E2, NE	(i) EA improved rats’ depression-like behavior in behavioral test (ii) EA increased E2 and NE levels
Wang et al 2016^Citation171	SD rats, 220–260g, 17weeks	PMD	(i) OVX (ii) CUMS	- EA/n= 10 - Control/n= 10 - Model/n= 10 - Clomipramine/n= 10	- EA/OVX + CUMS + EA - Control/no treatment - Model/OVX + CUMS - Clomipramine/OVX + CUMS + Clomipramine	− 20 min/day for 28 days- disperse-dense wave, 2/10Hz	BL23, GV20, SP6	(i) Behavioral test (OFT) (ii) CREB, BDNF in hippocampus	(i) EA improved rats’ depression-like behavior in behavioral test (ii) EA increased BDNF and CREB levels
Wu 2012^Citation148	(i) SD rats, 260–471g, 11–13 months (n= 73) (ii) Young SD rats, 140–191g, 4 months (n= 20)	PMD	CUMS	- EA/n= 18 - Model/n= 19 - Clomipramine/n= 18 - Herbal medicine/n= 18 - Young/n= 20	- EA/CUMS + EA - Model/CUMS - Clomipramine/CUMS + Clomipramine - Herbal medicine/ CUMS + XiaoYao-Pill - Young/CUMS	− 20 min/day for 10 days- disperse-dense wave, 2/15Hz, 2V	BL18, BL23, GV20, SP6, ST36	(i) Behavioral test (OFT) (ii) Serum E2 (iii) 5-HT2A mRNA, p-ERK 1/2 in hippocampus	(i) EA improved rats’ depression-like behavior in behavioral test (ii) EA increased E2 level (ii) EA decreased 5-HT2A mRNA expression; EA increased p-ERK 1/2 expression
Zhang 2009^Citation128	(i) SD rats, 250–300g, 11–15 months (n= 45) (ii) Young SD rats, 150–200g, 4 months (n= 10)	PMD	CUMS	- EA/n= 15 - Model/n= 15 - Clomipramine/n= 15 - Young/n= 10	- EA/CUMS + EA - Model/CUMS - Clomipramine/CUMS + Clomipramine - Young/CUMS	− 20 min/day for 7 days- continuous wave, 20Hz, 2V	BL18, BL23, GV20, SP6	(i) Behavioral test (OFT) (ii) Serum E2 (iii) β-EP in hippocampus	(i) EA improved rats’ depression-like behavior in behavioral test (ii) EA increased E2 level (ii) EA increased β-EP level
Zhao et al 2011^Citation149	(i) SD rats, 260–471g, 11–13 months (n= 66) (ii) Young SD rats, 140–191g, 4 months (n= 20)	PMD	CUMS	- EA/n= 15 - Model/n= 18 - Clomipramine/n= 17 - Herbal medicine/n= 16 - Young/n= 20	- EA/CUMS + EA - Model/CUMS - Clomipramine/CUMS + Clomipramine - Herbal medicine/ CUMS + XiaoYao-Pill - Young/CUMS	− 20 min/day for 28 days	BL18, BL23, GV20, SP6, ST36	(i) Behavioral test (OFT) (ii) Serum 5-HT, HDL	(i) EA improved rats’ depression-like behavior in behavioral test (ii) EA increased 5-HT and HDL levels
Song et al 2021^Citation119	KM mice, 18–22g, 5–6 weeks	PMD	(i) OVX (ii) Ice-water swimming stimulation (I-WSS)	- EA/n= 10 - Control/n= 10 - Model/n= 10	- MA/OVX + I-WSS + MA - Control/I-WSS - Model/OVX + I-WSS	− 30 min/day, 6 days/week for 4 weeks	CV4, KI3, KI15, SP6, SP10, ST36	Serum E2	EA increased E2 level

Abbreviations: NR, no report; PMI, perimenopausal insomnia; PMD, perimenopausal depression; MA, manual acupuncture; EA, electroacupuncture; OVX, ovariectomy; CUMS, chronic unpredictable mild stress; MER, multichannel electrophysiological recordings; SOL, sleep onset latency; TST, total sleep time; WASO, wake after sleep onset; REM, rapid eye movement; NREM, non-rapid eye movement; LS, light sleep; SWS, slow wave sleep; FSH, follicle-stimulating hormone; LH, luteinizing hormone; E2, estradiol; CSF, cerebrospinal fluid; VLPO, ventrolateral preoptic; TMN, tuberomammillary nucleus; PGD2, prostaglandin D2; PGE2, prostaglandin E2; L-PGDS, lipocalin-type prostaglandin D synthase; GABA, gamma-amino butyric acid; 5-HT, 5-hydroxytryptamine; 5-HIAA, 5-hydroxyindole acetic acid; NE, norepinephrine; DA, dopamine; ER-α, Estrogen receptor-α; ER-β, Estrogen receptor-β; GnRH, gonadotropin-releasing hormone; GSK-3β, glycogen synthase kinase-3β; p-β-catenin, phosphorylated β-catenin; BDNF, brain-derived neurotrophic factor; NPY, neuropeptide Y; MAP-2, microtubule- associated protein-2; CRH, corticotropin releasing hormone; ACTH, adrenocorticotropic hormone; CORT, cortisol; β-EP, beta-endorphin; DKK1, Dickkopf1; LRP-5, low density lipoprotein receptor related protein 5; LRP-6, low density lipoprotein receptor related protein 6; CREB, cyclic-AMP response binding protein; p-ERK 1/2, phosphorylated-extracellular regulated kinase 1/2; HDL, high-density lipoprotein; CUMS, chronic unpredictable mild stress; SPT, sucrose preference test; OFT, open field test; FST, forced swimming test; IAT, independent activity test; ADE, avoiding dark experiment; TSE, tail suspension experiment; EPM, elevated plus maze; BL18, Ganshu; BL23, Shenshu; CV4, Guanyuan; CV6, Qihai; EX, Anmian; EX-HN1, Sishencong; GV20, Baihui; HT7, Shenmen; KI3, Taixi; KI15, Zhongzhu; LI4, Hegu; LR3, Taichong; PC6, Neiguan; SP6, Sanyinjiao; SP10, Xuehai; ST36, Zusanli.

Figure 1 Potential mechanisms by which acupuncture may improve perimenopausal depression and insomnia. Manual- and/or electro-acupuncture may alter hypothalamic-pituitary-adrenal and -ovarian hyperactivity; modulate reproductive hormones and their receptors, or regulate neurotransmitters, signaling pathways, and oxidative stress. Green indicates an upregulation/increase by acupuncture (↑); red indicates a downregulation/decrease (↓). Acupuncture may also improve perimenopausal depression and insomnia by improving vasomotor symptoms, while this indirect effect is not shown. Images are adapted from Servier Medical Art under Creative Commons CC-BY license.

Abbreviations: HPA, hypothalamic-pituitary-adrenal; HPO, hypothalamic-pituitary-ovary; GR, glucocorticoid receptor; MR, mineralocorticoid receptor; GnRH, gonadotropin-releasing hormone; E2, estradiol; FSH, follicle-stimulating hormone; LH, luteinizing hormone; CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; CORT, cortisol; ERβ, estrogen receptor beta; 5-HT, 5-hydroxytryptamine; GABA, gamma-amino butyric acid; CREB, cAMP-response element-binding protein; BDNF, brain-derived neurotrophic factor; p-TrkB, phosphorylated-TrkB; PGD-2, prostaglandin D2; L-PGDS, lipocalin-type prostaglandin D synthase; LPO, lipid peroxidation; GSK-3β, glycogen synthase kinase-3 beta.

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