Table 2.

Main outcomes and conclusions of the included studies

Study	Outcomes	Conclusions
Brin et al., 2020 [15]	BT-A 30 U application reduced MADRS total scoreat week 6 from baseline (p = 0.053) and reached significance least-squares mean differences: −3.6 to −4.2; p < 0.05 (two-sided) at 3 and 9 weeks. A single application of BT-A 30 U showed a efficacy signal across multiple depression symptom scales for 12 or more weeks. BT-A 30 U/placebo MADRS differences of ≥ 4.0 points (up to week 15) and ≥ 2.0 points (weeks 18–24).	BT-A is not associated with systemic effects of conventional antidepressants and may be a treatment option for depression.
Finzi and Rosenthal, 2014 [16]	Response rates at week 6 after BT-A were 52%in the group that received BT-A and 15% in the placebo group (chi-square = 11.2, p < 0.001, Fisher p < 0.001). BT-A group showed lower MADRS score of 10 or less (chi-square = 5.1, p < 0.02, Fisher p < 0.03). Six weeks after a BT-A single treatment, MADRS scores in BT-A group were reduced on average by 47%, and 21% to the placebo group.	A BT-A single application in the upper third muscles induces a significant and sustained antidepressant effect in patients with major depression.
Lewis, 2018 [18]	There was animprovement in mood (lower HADS scores) when BT-A was applied only to frown lines (p < 0.01). There was not significant difference in HADS scores when BT-A was applied in frown lines and crow’s feet from baseline (p > 0.05). There was a reduction in the emotion recognition ability and the overall orgasm satisfaction score after BT-A treatment.	The application of BT-A in the frown lines improved the MDD scores. In addition, BT-A treatment was associated with reduced emotion recognition and sexual function.
Magid et al., 2014 [11]	There was a significant reduction in MDD symptoms in the groups that received BT-A. HDRS-21 response rates were 55% in the group that received BTA- at week 0.24% in the group that received BTA at week 12, and 0% in the placebo group (p < 0.0001). HDRS-21 remission rates were 18%, 18%, and 0%, respectively (p = 0.057). HDRS-21 scores dropped −46% and −35% in the BTA-week 0 and BTA-week 12 versus −2% in the placebo group (p < 0.0001). The BDI response rate was 45% (5/11) in the BTA-week 0, 33% in the BTA-week 12 group, and 5% in the placebo group (p = 0.0067). BDI remission rates were 27%, 33%, and 5%, respectively (p = 0.09). BDI scores dropped −42% and −35% in the BTA-week 0 and -week 12, respectively, versus −15% in the placebo group (p < 0.0001).	BT-A injection in the glabellar region was associated with significant improvement in depressive symptoms in the MDD.
Zamanian et al., 2017 [17]	BDI was stastistically different after 6 weeks of the BT-A application (p = 0.004), but at baseline and after two weeks, there was no significant difference (p > 0.05).	BT-A was effective and safe for treating patients with major depression.
Wollmer et al., 2012 [6]	There was a reduction in the HAM-D17 scores at the visit after 6 weeks versus baseline in the BT-A group (47,1%) when compared to the placebo group (9,2%) (p = 0.002) Treatment-dependent clinical improvement was also reflected in the BDI, and in the CGIS.	The application of BT-A can be an effective and safe intervention in the treatment of depression.
Wollmer et al., 2014 [8]	Participants with higher agitation scores at baseline showed a greater improvement in the HAM-D17 score (D HAM-D17) compared to those with lower agitation scores (p = 0.01), while no other single item of the HAM-D or the BDI was associated with treatment response.	Patients with agitated depression may particularly benefit from BT-A treatment.

BT-A, botulinum toxin-A; U, units; MADRS, Montgomery-Åsberg Depression Rating Scale; HADS, Hospital Anxiety and Depression Scale; MDD, major depressive disorder; HDRS-21, 21-item Hamilton Depression Rating Scale; BDI, Beck Depression Inventory; CGI, Clinical Global Impressions Scale; HAM-D, Hamilton Depression Rating Scale.