Skip to main content

Advertisement

SpringerLink
Log in

Clinical efficacy of escitalopram combined with botulinum toxin A in patients with generalized anxiety disorder and comorbid headache

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Background

Generalized anxiety disorder (GAD) is a common mental disorder that happens comorbidly with other diseases. Headache is a common anxiety comorbidity. Previous reports have shown that the selection of therapeutic drugs for GAD patients and comorbid headache is challenging. Therefore, our study aimed to investigate the clinical efficacy of escitalopram combined with botulinum toxin A (BoNT/A) in patients with GAD and comorbid headache and seek an alternative treatment strategy for the comorbidity of GAD and headache.

Methods

A prospective, randomized controlled, double-blind study was performed. The eligible GAD patients with comorbid headache were randomly assigned to the BoNT/A group and the placebo group. All the patients were given oral escitalopram therapy (10–20 mg/day) for the whole duration of the study. The BoNT/A group was given local injections of BoNT/A (50 U per person), whereas the placebo group was given local saline (0.9% NaCl) injections at the beginning and 3 months after the experiments. All participants were followed up for 6 months and relevant information was collected at months 0, 1, 2, 3, and 6. Primary outcomes included the following: (1) the Generalized Anxiety Disorder 7 (GAD-7); (2) the Self-rating Anxiety Scale (SAS); (3) the Hamilton Anxiety Rating Scales (HAMA); (4) days with headache per month; (5) visual analogue scale (VAS).

Results

A total of 101 patients (the sex ratio of female to male: 3.39:1) were finally included. Compared with the placebo group, the BoNT/A group showed a significant decrease in GAD-7 scores, SAS scores, HAMA scores, days with headache per month, and VAS scores at months 1, 2, 3, and 6 of follow-up (all p < 0.05). The average time to complete remission of anxiety symptoms (HAMA< 7 points) in the BoNT/A group was less than the placebo group (2 months vs. 3 months). At the same time, the results of the survival analysis showed a clear beneficial effect of BoNT/A relative to placebo on the time to remission of anxiety (log-rank test, p < 0.001). Mean daily doses of escitalopram at the sixth month in the BoNT/A group was smaller than the placebo group (12.5 mg vs. 16.04 mg, p < 0.001). The number of patients who relapsed (HAMA total score ≥ 14 points) at 6 months of follow-up in the BoNT/A group was less than the placebo group (2.2% vs. 14.9%, p < 0.05). The rates of response (HAMA subtraction rate ≥ 50%) were 93.8% for the BoNT/A group and 75.5% for the placebo group (p < 0.05), and the rates of remission (HAMA < 7 points) were 87.5% for the BoNT/A group and 64.2% for the placebo group (p < 0.01) at the sixth month.

Conclusion

The combination of escitalopram with BoNT/A is a significantly effective intervention in improving clinical efficacy and reducing the recurrence in patients with GAD and comorbid headache, and we believe that this approach will be an additional treatment strategy for future treatment of comorbid headache in GAD. Therefore, we recommend that escitalopram combined with BoNT/A should be given as early as possible in GAD patients and comorbid headache.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Ababneh OH, Cetinkaya A, Kulwin DR (2014) Long-term efficacy and safety of botulinum toxin A injections to treat blepharospasm and hemifacial spasm. Clin Exp Ophthalmol 42:254–261

    Article  Google Scholar 

  • Bakheit AM, Liptrot A, Newton R, Pickett AM (2012) The effect of total cumulative dose, number of treatment cycles, interval between injections, and length of treatment on the frequency of occurrence of antibodies to botulinum toxin type A in the treatment of muscle spasticity. Int J Rehabil Res 35:36–39

    Article  PubMed  Google Scholar 

  • Banzi R, Cusi C, Randazzo C, Sterzi R, Tedesco D, Moja L (2015) Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of migraine in adults. Cochrane Database Syst Rev  4:Cd002919

    PubMed  Google Scholar 

  • Bendtsen L, Evers S, Linde M, Mitsikostas DD, Sandrini G, Schoenen J (2010) EFNS guideline on the treatment of tension-type headache - report of an EFNS task force. Eur J Neurol 17:1318–1325

    Article  CAS  PubMed  Google Scholar 

  • Bittencourt da Silva L, Karshenas A, Bach FW, Rasmussen S, Arendt-Nielsen L, Gazerani P (2014) Blockade of glutamate release by botulinum neurotoxin type A in humans: a dermal microdialysis study. Pain Res Manag 19:126–132

    Article  Google Scholar 

  • Bodkin JA, Allgulander C, Llorca PM, Spann ME, Walker DJ, Russell JM, Ball SG (2011) Predictors of relapse in a study of duloxetine treatment for patients with generalized anxiety disorder. Hum Psychopharmacol 26:258–266

    CAS  PubMed  Google Scholar 

  • Burch R (2019) Antidepressants for preventive treatment of migraine. Curr Treat Options Neurol 21:18

    Article  PubMed  Google Scholar 

  • Chen WJ, Niu JQ, Chen YT, Deng WJ, Xu YY, Liu J, Luo WF, Liu T (2021) Unilateral facial injection of botulinum neurotoxin A attenuates bilateral trigeminal neuropathic pain and anxiety-like behaviors through inhibition of TLR2-mediated neuroinflammation in mice. J Headache Pain 22:38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chinese Medical Association, Chinese Medical Journals Publishing House, Chinese Society of General Practice, Anxiety Disorder Collaboration Group of Chinese Society of Psychiatry, Editorial Board of Chinese Journal of General Practitioners of Chinese Medical Association, Disease EGoGfPCoNS (2021) Guideline for primary care of generalized anxiety disorder(2021). Chin J Gen Pract 20:1232–1241

    Google Scholar 

  • Chiu SY, Burns MR, Malaty IA (2021) An update on botulinum toxin in neurology. Neurol Clin 39:209–229

    Article  PubMed  Google Scholar 

  • Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C (2009) Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet (London, England) 373:746–758

    Article  CAS  PubMed  Google Scholar 

  • Cook CL, Shedd GC (2018) Diagnosis and treatment of migraine in the patient with depression. J Am Assoc Nurse Pract 30:630–637

    Article  PubMed  Google Scholar 

  • da Silva LB, Kulas D, Karshenas A, Cairns BE, Bach FW, Arendt-Nielsen L, Gazerani P (2014) Time course analysis of the effects of botulinum neurotoxin type A on pain and vasomotor responses evoked by glutamate injection into human temporalis muscles. Toxins 6:592–607

    Article  PubMed  Google Scholar 

  • Do TP, Hvedstrup J, Schytz HW (2018) Botulinum toxin: a review of the mode of action in migraine. Acta Neurol Scand 137:442–451

    Article  CAS  PubMed  Google Scholar 

  • Durham RC, Allan T, Hackett CA (1997) On predicting improvement and relapse in generalized anxiety disorder following psychotherapy. Br J Clin Psychol 36:101–119

    Article  CAS  PubMed  Google Scholar 

  • Finzi E, Rosenthal NE (2019) Botulinum toxin therapy of social anxiety disorder: a case series. J Clin Psychopharmacol 39:410–412

    Article  PubMed  Google Scholar 

  • Gazerani P, Au S, Dong X, Kumar U, Arendt-Nielsen L, Cairns BE (2010) Botulinum neurotoxin type A (BoNTA) decreases the mechanical sensitivity of nociceptors and inhibits neurogenic vasodilation in a craniofacial muscle targeted for migraine prophylaxis. Pain 151:606–616

    Article  PubMed  Google Scholar 

  • Group of Head and facial Pain, Association PBotCM (2011) Guidelines for the diagnosis and treatment of migraine in China. Chin J Pain Med 17:65–86

    Google Scholar 

  • Hamdy SM, Samir H, El-Sayed M, Adel N, Hasan R (2009) Botulinum toxin: could it be an effective treatment for chronic tension-type headache? J Headache Pain 10:27–34

    Article  CAS  PubMed  Google Scholar 

  • Hennenlotter A, Dresel C, Castrop F, Ceballos-Baumann AO, Wohlschläger AM, Haslinger B (2009) The link between facial feedback and neural activity within central circuitries of emotion--new insights from botulinum toxin-induced denervation of frown muscles. Cereb Cortex 19:537–542

    Article  PubMed  Google Scholar 

  • Herd CP, Tomlinson CL, Rick C, Scotton WJ, Edwards J, Ives NJ, Clarke CE, Sinclair AJ (2019) Cochrane systematic review and meta-analysis of botulinum toxin for the prevention of migraine. BMJ open 9:e027953

    Article  PubMed  PubMed Central  Google Scholar 

  • Hidalgo RB, Sheehan DV (2012) Generalized anxiety disorder. Handbook of clinical neurology 106:343–362

    Article  PubMed  Google Scholar 

  • Kasper S, Spadone C, Verpillat P, Angst J (2006) Onset of action of escitalopram compared with other antidepressants: results of a pooled analysis. Int Clin Psychopharmacol 21:105–110

    Article  PubMed  Google Scholar 

  • Keller MB (2002) The long-term clinical course of generalized anxiety disorder. The J Clin Psychiatry 63(Suppl 8):11–16

    PubMed  Google Scholar 

  • Lake AE 3rd, Rains JC, Penzien DB, Lipchik GL (2005) Headache and psychiatric comorbidity: historical context, clinical implications, and research relevance. Headache 45:493–506

    Article  PubMed  Google Scholar 

  • Lewis MB, Bowler PJ (2009) Botulinum toxin cosmetic therapy correlates with a more positive mood. J Cosmet Dermatol 8:24–26

    Article  PubMed  Google Scholar 

  • Luvisetto S, Gazerani P, Cianchetti C, Pavone F (2015) Botulinum toxin type A as a therapeutic agent against headache and related disorders. Toxins 7:3818–3844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lyu A, Fan Y, Tang L, Guo X, Liu J, Huang Y, Zhou X, Hu H, Liu C, Luo W (2019) Clinical study on the efficacy and safety of botulinum toxin A in the treatment in Parkinson’s disease with depression. Chin J Neurol 52:745–751

    Google Scholar 

  • Magid M, Reichenberg JS, Poth PE, Robertson HT, LaViolette AK, Kruger TH, Wollmer MA (2014) Treatment of major depressive disorder using botulinum toxin A: a 24-week randomized, double-blind, placebo-controlled study. J Clin Psychiatry 75:837–844

    Article  CAS  PubMed  Google Scholar 

  • May A (2018) Hints on diagnosing and treating headache. Deutsches Arzteblatt international 115:299–308

    PubMed Central  Google Scholar 

  • Meng J, Ovsepian SV, Wang J, Pickering M, Sasse A, Aoki KR, Lawrence GW, Dolly JO (2009) Activation of TRPV1 mediates calcitonin gene-related peptide release, which excites trigeminal sensory neurons and is attenuated by a retargeted botulinum toxin with anti-nociceptive potential. J Neurosci : the official journal of the Society for Neuroscience 29:4981–4992

    Article  CAS  PubMed  Google Scholar 

  • Murinova N, Krashin D (2015) Chronic daily headache. Phys Med Rehabil Clin N Am 26:375–389

    Article  PubMed  Google Scholar 

  • Nutt D, Argyropoulos S, Hood S, Potokar J (2006) Generalized anxiety disorder: a comorbid disease. Eur Neuropsychopharmacol 16(Suppl 2):S109–S118

    Article  CAS  PubMed  Google Scholar 

  • Olesen J (2005) The international classification of headache disorders. Rev Neurol 161:689–691

    Article  CAS  PubMed  Google Scholar 

  • Pain and Sensory Disorders Group NBoCMDA (2020) Chinese expert consensus on the diagnosis and treatment of migraine and depressive disorder comorbidity. Chin J Pain Med 26:881–890

    Google Scholar 

  • Pollack M, Kinrys G, Krystal A, McCall WV, Roth T, Schaefer K, Rubens R, Roach J, Huang H, Krishnan R (2008) Eszopiclone coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder. Arch Gen Psychiatry 65:551–562

    Article  CAS  PubMed  Google Scholar 

  • Roy-Byrne P (2015) Treatment-refractory anxiety; definition, risk factors, and treatment challenges. Dialogues Clin Neurosci 17:191–206

    Article  PubMed  PubMed Central  Google Scholar 

  • Serafini G, Parisi VM, Aguglia A (2020) A specific inflammatory profile underlying suicide risk? Systematic review of the main literature findings. Int J Environ Res Public Health 17(7):2393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stein DJ, Ahokas A, Albarran C, Olivier V, Allgulander C (2012) Agomelatine prevents relapse in generalized anxiety disorder: a 6-month randomized, double-blind, placebo-controlled discontinuation study. J Clin Psychiatry 73:1002–1008

    Article  CAS  PubMed  Google Scholar 

  • Stein MB, Sareen J (2015) CLINICAL PRACTICE. Generalized anxiety disorder. N Eng J Med 373:2059–2068

    Article  CAS  PubMed  Google Scholar 

  • Tarlaci S (2009) Escitalopram and venlafaxine for the prophylaxis of migraine headache without mood disorders. Clin Neuropharmacol 32:254–258

    Article  CAS  PubMed  Google Scholar 

  • Telang S, Walton C, Olten B, Bloch MH (2018) Meta-analysis: second generation antidepressants and headache. J Affect Disord 236:60–68

    Article  CAS  PubMed  Google Scholar 

  • Tiihonen J, Lönnqvist J, Wahlbeck K, Klaukka T, Tanskanen A, Haukka J (2006) Antidepressants and the risk of suicide, attempted suicide, and overall mortality in a nationwide cohort. Arch Gen Psychiatry 63:1358–1367

    Article  CAS  PubMed  Google Scholar 

  • Weatherall MW (2015) Drug therapy in headache. Clin Med 15:273–279

    Article  PubMed  Google Scholar 

  • Wittchen HU, Essau CA, Krieg JC (1991) Anxiety disorders: similarities and differences of comorbidity in treated and untreated groups. Br J Psychiatry 159:23–33

    Article  Google Scholar 

  • Wittchen HU, Kessler RC, Beesdo K, Krause P, Höfler M, Hoyer J (2002) Generalized anxiety and depression in primary care: prevalence, recognition, and management. J Clin Psychiatry 63(Suppl 8):24–34

    PubMed  Google Scholar 

  • Wollmer MA, Makunts T, Krüger THC, Abagyan R (2021) Postmarketing safety surveillance data reveals protective effects of botulinum toxin injections against incident anxiety. Sci Rep 11:24173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yesudhas A, Radhakrishnan RK, Sukesh A, Ravichandran S, Manickam N, Kandasamy M (2021) BOTOX® counteracts the innate anxiety-related behaviours in correlation with increased activities of key antioxidant enzymes in the hippocampus of ageing experimental mice. Biochem Biophys Res Commun 569:54–60

    Article  CAS  PubMed  Google Scholar 

  • Yonkers KA, Warshaw MG, Massion AO, Keller MB (1996) Phenomenology and course of generalised anxiety disorder. Bri J Psychiatry 168:308–313

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Zhang H, Wei Y, Lian Y, Chen Y, Zheng Y (2017) Treatment of chronic daily headache with comorbid anxiety and depression using botulinum toxin A: a prospective pilot study. Int J Neurosci 127:285–290

    Article  CAS  PubMed  Google Scholar 

  • Zwart JA, Dyb G, Hagen K, Ødegård KJ, Dahl AA, Bovim G, Stovner LJ (2003) Depression and anxiety disorders associated with headache frequency. The Nord-Trøndelag Health Study. Eur J Neurol 10:147–152

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank all those who collaborated in the analysis, interpretation of data, and writing the article. This work was supported by the Natural Science Foundation of Shandong Province under grant number ZR2014HM064.

Funding

Natural Science Foundation of Shandong Province under grant number ZR2014HM064.

Author information

Authors and Affiliations

  1. Department of Neurology, The Affiliated Hospital of Qingdao University, Number 16 Jiangsu Road, Qingdao, 266003, Shandong Province, China

    Yao Wang, Xiaoyu Yang, Xiaojun Ji, Min Liu & Chang Zhou

Authors
  1. Yao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoyu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaojun Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Min Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chang Zhou.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Yang, X., Ji, X. et al. Clinical efficacy of escitalopram combined with botulinum toxin A in patients with generalized anxiety disorder and comorbid headache. Psychopharmacology 240, 2061–2070 (2023). https://doi.org/10.1007/s00213-023-06423-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-023-06423-6

Keywords

Search

Navigation