Long-Term Pharmacological Treatments of Anxiety Disorders: An Updated Systematic Review
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Many aspects of long-term pharmacological treatments for anxiety disorders (AnxDs) are still debated. We undertook an updated systematic review of long-term pharmacological studies on panic disorder (PD), generalized anxiety disorder (GAD), and social anxiety disorder (SAD). Relevant studies dating from January 1, 2012 to August 31, 2015 were identified using the PubMed database and a review of bibliographies. Of 372 records identified in the search, five studies on PD and 15 on GAD were included in the review. No studies on SAD were found. Our review confirms the usefulness of long-term pharmacological treatments for PD and GAD and suggests that they can provide further improvement over that obtained during short-term therapy. Paroxetine, escitalopram, and clonazepam can be effective for long-term treatment of PD. However, further studies are needed to draw conclusions about the long-term benzodiazepine use in PD, particularly for the possible cognitive side-effects over time. Pregabalin and quetiapine can be effective for long-term treatment of GAD, while preliminary suggestions emerged for agomelatine and vortioxetine. We did not find any evidence for determining the optimal length and/or dosage of medications to minimize the relapse risk. Few investigations have attempted to identify potential predictors of long-term treatment response. Personalized treatments for AnxDs can be implemented using predictive tools to explore those factors affecting treatment response/tolerability heterogeneity, including neurobiological functions/clinical profiles, comorbidity, biomarkers, and genetic features, and to tailor medications according to each patient’s unique features.
KeywordsAnxiety Long term Pharmacological treatment Panic disorder Generalized anxiety disorder Social anxiety disorder
The authors thank Massimiliano Grassi, MSc, and Raffaele Balletta, MD, Department of Clinical Neurosciences, Villa San Benedetto Menni, Hermanas Hospitalarias, FoRiPsi, Albese con Cassano, Como, Italy, for their contribution to literature search. Mr. Grassi and Mr. Balletta have no conflicts of interest to declare.
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The authors declare that they have no competing interests.
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This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 2.American Psychiatric Association. Diagnostic and statistical manual of mental disorders (fifth ed.). Arlington: American Psychiatric Association; 2013.Google Scholar
- 3.Bruce SE, Yonkers KA, Otto MW, Eisen JL, Weisberg RB, Pagano M, et al. Influence of psychiatric comorbidity on recovery and recurrence in generalized anxiety disorder, social phobia, and panic disorder: a 12-year prospective study. Am J Psychiatry. 2005;162(6):1179–87. doi: 10.1176/appi.ajp.162.6.1179.PubMedCentralCrossRefPubMedGoogle Scholar
- 4.Berger A, Edelsberg J, Bollu V, Alvir JM, Dugar A, Joshi AV, et al. Healthcare utilization and costs in patients beginning pharmacotherapy for generalized anxiety disorder: a retrospective cohort study. BMC Psychiatry. 2011;11:193. doi: 10.1186/1471-244X-11-193.PubMedCentralCrossRefPubMedGoogle Scholar
- 8.American Psychiatric Association. Diagnostic and statistical manual of mental disorders DSM-III. Washington, DC: Amer Psychiatric Pub; 1980.Google Scholar
- 9.American Psychiatric Association. Diagnostic and statistical manual of mental disorders DSM-III-R. Washington, DC: Amer Psychiatric PuB; 1987.Google Scholar
- 10.American Psychiatric Association. Diagnostic and statistical manual of mental disorders DSM-IV. Washington, DC: Amer Psychiatric Pub; 1994.Google Scholar
- 12.Centers for Disease Control and Prevention. International Classification of Diseases, Ninth Revision (ICD-9). http://www.cdc.gov/nchs/icd/icd9.htm.
- 13.Centers for Disease Control and Prevention. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). http://www.cdc.gov/nchs/icd/icd9cm.htm.
- 14.Centers for Disease Control and Prevention. International Classification of Diseases, Tenth Revision (ICD-10). http://www.cdc.gov/nchs/icd/icd10.htm.
- 15.American Psychiatric Association. Practice Guidelines for the treatment of patients with Panic Disorder. Second ed. American Psychiatric Association; 2009. http://www.psychiatryonline.com/pracGuide/pracGuideTopic_9.aspx
- 17.Nardi AE, Freire RC, Mochcovitch MD, Amrein R, Levitan MN, King AL, et al. A randomized, naturalistic, parallel-group study for the long-term treatment of panic disorder with clonazepam or paroxetine. J Clin Psychopharmacol. 2012;32(1):120–6. doi: 10.1097/JCP.0b013e31823fe4bd.CrossRefPubMedGoogle Scholar
- 18.Van Apeldoorn FJ, Van Hout WJ, Timmerman ME, Mersch PP, den Boer JA. Rate of improvement during and across three treatments for panic disorder with or without agoraphobia: cognitive behavioral therapy, selective serotonin reuptake inhibitor or both combined. J Affect Disord. 2013;150(2):313–9. doi: 10.1016/j.jad.2013.04.012.CrossRefPubMedGoogle Scholar
- 19.Hendriks GJ, Keijsers GP, Kampman M, Oude Voshaar RC, Verbraak MJ, Broekman TG, et al. A randomized controlled study of paroxetine and cognitive-behavioural therapy for late-life panic disorder. Acta Psychiatr Scand. 2010;122(1):11–9. doi: 10.1111/j.1600-0447.2009.01517.x.CrossRefPubMedGoogle Scholar
- 21.Choi KW, Woo JM, Kim YR, Lee SH, Lee SY, Kim EJ, et al. Long-term escitalopram treatment in Korean patients with panic disorder: a prospective, naturalistic, open-label, multicenter trial. Clin Psychopharmacol Neurosci. 2012;10(1):44–8. doi: 10.9758/cpn.2012.10.1.44.PubMedCentralCrossRefPubMedGoogle Scholar
- 22.Miniati M, Calugi S, Rucci P, Shear MK, Benvenuti A, Santoro D, et al. Predictors of response among patients with panic disorder treated with medications in a naturalistic follow-up: the role of adult separation anxiety. J Affect Disord. 2012;136(3):675–9. doi: 10.1016/j.jad.2011.10.008.CrossRefPubMedGoogle Scholar
- 24.Wetherell JL, Petkus AJ, White KS, Nguyen H, Kornblith S, Andreescu C, et al. Antidepressant medication augmented with cognitive-behavioral therapy for generalized anxiety disorder in older adults. Am J Psychiatry. 2013;170(7):782–9. doi: 10.1176/appi.ajp.2013.12081104.PubMedCentralCrossRefPubMedGoogle Scholar
- 29.Katzman MA, Brawman-Mintzer O, Reyes EB, Olausson B, Liu S, Eriksson H. Extended release quetiapine fumarate (quetiapine XR) monotherapy as maintenance treatment for generalized anxiety disorder: a long-term, randomized, placebo-controlled trial. Int Clin Psychopharmacol. 2011;26(1):11–24. doi: 10.1097/YIC.0b013e32833e34d9.CrossRefPubMedGoogle Scholar
- 30.Sheehan DV, Svedsater H, Locklear JC, Eriksson H. Effects of extended-release quetiapine fumarate on long-term functioning and sleep quality in patients with Generalized Anxiety Disorder (GAD): data from a randomized-withdrawal, placebo-controlled maintenance study. J Affect Disord. 2013;151(3):906–13. doi: 10.1016/j.jad.2013.07.037.CrossRefPubMedGoogle Scholar
- 36.••Lohoff FW, Aquino TD, Narasimhan S, Multani PK, Etemad B, Rickels K. Serotonin receptor 2A (HTR2A) gene polymorphism predicts treatment response to venlafaxine XR in generalized anxiety disorder. Pharmacogenomics J. 2013;13(1):21–6. doi: 10.1038/tpj.2011.47. The first study showing a role of serotonergic system polymorphisms in long-term treatment response in generalized anxiety disorder.CrossRefPubMedGoogle Scholar
- 37.Lohoff FW, Narasimhan S, Rickels K. Interaction between polymorphisms in serotonin transporter (SLC6A4) and serotonin receptor 2A (HTR2A) genes predict treatment response to venlafaxine XR in generalized anxiety disorder. Pharmacogenomics J. 2013;13(5):464–9. doi: 10.1038/tpj.2012.33.CrossRefPubMedGoogle Scholar
- 40.Ruiz MA, Alvarez E, Carrasco JL, Olivares JM, Perez M, Rejas J. Modeling the longitudinal latent effect of pregabalin on self-reported changes in sleep disturbances in outpatients with generalized anxiety disorder managed in routine clinical practice. Drug Des Devel Ther. 2015;9:4329–40. doi: 10.2147/DDDT.S88238.PubMedCentralCrossRefPubMedGoogle Scholar
- 41.Alvarez E, Carrasco JL, Olivares JM, Lopez-Gomez V, Vilardaga I, Perez M. Broadening of generalized anxiety disorders definition does not affect the response to psychiatric care: findings from the observational ADAN study. Clin Pract Epidemiol Ment Health. 2012;8:158–68. doi: 10.2174/1745017901208010158.PubMedCentralCrossRefPubMedGoogle Scholar
- 47.National Collaborating Centre for Mental Health. Generalised anxiety disorder in adults: management in primary, secondary and community care. National clinical guideline number 113 ed. Leicester: The British Psychological Society and The Royal College of Psychiatrists; 2011.Google Scholar
- 48.•Bandelow B, Lichte T, Rudolf S, Wiltink J, Beutel ME. The diagnosis of and treatment recommendations for anxiety disorders. Dtsch Arztebl Int. 2014;111(27-28):473–80. doi: 10.3238/arztebl.2014.0473. Recent recommendations for pharmacological and non-pharmacological treatments in Anxiety Disorders.PubMedCentralPubMedGoogle Scholar
- 65.•Freiesleben SD, Furczyk K. A systematic review of agomelatine-induced liver injury. J Mol Psychiatry. 2015;3(1):4. doi: 10.1186/s40303-015-0011-7. An updated review, based on clinical trials, non-interventional studies and pharmacovigilance databases, on potential agomelatine-related risk of liver injury.PubMedCentralCrossRefPubMedGoogle Scholar
- 69.•Blanco C, Bragdon LB, Schneier FR, Liebowitz MR. The evidence-based pharmacotherapy of social anxiety disorder. Int J Neuropsychopharmacol. 2013;16(1):235–49. doi: 10.1017/S1461145712000119. A recent review on pharmacological treatments for Social Anxiety Disorder based on placebo-controlled studies and meta-analyses.CrossRefPubMedGoogle Scholar
- 70.•Canton J, Scott KM, Glue P. Optimal treatment of social phobia: systematic review and meta-analysis. Neuropsychiatr Dis Treat. 2012;8:203–15. doi: 10.2147/NDT.S23317. A systematic literature review and meta-analysis on the evidence-based pharmacological and non-pharmacological treatments for social phobia.PubMedCentralPubMedGoogle Scholar
- 71.••Perna G, Schruers K, Alciati A, Caldirola D. Novel investigational therapeutics for panic disorder. Expert Opin Investig Drugs. 2015;24(4):491–505. doi: 10.1517/13543784.2014.996286. A recent review on novel mechanism-based anti-panic drugs under current investigation in animal studies up to phase- II studies, with a focus on the translational validity of animal models.CrossRefPubMedGoogle Scholar
- 76.Park YM, Kim DW, Kim S, Im CH, Lee SH. The loudness dependence of the auditory evoked potential (LDAEP) as a predictor of the response to escitalopram in patients with generalized anxiety disorder. Psychopharmacology (Berl). 2011;213(2-3):625–32. doi: 10.1007/s00213-010-2061-y.CrossRefGoogle Scholar
- 77.Lenze EJ, Dixon D, Mantella RC, Dore PM, Andreescu C, Reynolds 3rd CF, et al. Treatment-related alteration of cortisol predicts change in neuropsychological function during acute treatment of late-life anxiety disorder. Int J Geriatr Psychiatry. 2012;27(5):454–62. doi: 10.1002/gps.2732.PubMedCentralCrossRefPubMedGoogle Scholar