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Perspective

Pharmacotherapy for generalized anxiety disorder in adult and pediatric patients: an evidence-based treatment review

ORCID Icon, , , &
Pages 1057-1070 | Received 08 Apr 2018, Accepted 19 Jun 2018, Published online: 29 Jul 2018

References

  • Ramsawh HJ, Chavira DA, Stein MB. Burden of anxiety disorders in pediatric medical settings: prevalence, phenomenology, and a research agenda. Arch. Pediatr. Adolesc. Med. 2010;164(10):965–972.
  • Baxter AJ, Vos T, Scott KM, et al. The global burden of anxiety disorders in 2010. Psychol. Med. 2014;44:2363–2374.
  • Beesdo-Baum K, Knappe S. Developmental epidemiology of anxiety disorders. Child Adolesc. Psychiatr. Clin. N. Am. 2012;21:457–478.
  • Beesdo K, Pine DS, Lieb R, et al. Incidence and risk patterns of anxiety and depressive disorders and categorization of generalized anxiety disorder. Arch. Gen. Psychiatry. 2010;67:47–57.
  • Nutt DJ, Wittchen HU, Ballenger JC, et al. Generalized anxiety disorder: nature and course. J. Clin. Psychiatry. 2001;62(Suppl 11):15–21.
  • Wittchen HU. Generalized anxiety disorder: prevalence, burden, and cost to society. Depress. Anxiety. 2002;16:162–171.
  • Hoffman DL, Dukes EM, Wittchen H-U. Human and economic burden of generalized anxiety disorder. Depress. Anxiety. 2008;25:72–90.
  • Wittchen HU, Kessler RC, Pfister H, et al. Why do people with anxiety disorders become depressed? A prospective-longitudinal community study. Acta Psychiatr. Scand. Suppl. 2000;14–23.
  • Pine D, Cohen P, Gurley D, et al. The risk for early-adulthood anxiety and depressive disorders in adolescents with anxiety and depressive disorders. Arch. Gen. Psychiatry. 1998;55:56–64.
  • Husky MM, Olfson M, He J, et al. Twelve-month suicidal symptoms and use of services among adolescents: results from the national comorbidity survey. Psychiatr. Serv. [Internet]. 2012;63:989–996.
  • Nepon J, Belik SL, Bolton J, et al. The relationship between anxiety disorders and suicide attempts: findings from the national epidemiologic survey on alcohol and related conditions. Depress. Anxiety. 2010;27:791–798.
  • Walkup JT, Albano AM, Piacentini J, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N. Engl. J. Med. 2008;359:2753–2766.
  • Strawn JR, Sakolsky DJ, Rynn MA. Psychopharmacologic treatment of children and adolescents with anxiety disorders. Child Adolesc.Psychiatr.Clin. N Am. 2012;21:527–539.
  • Beidel DC, Turner SM, Sallee FR, et al. SET-C versus fluoxetine in the treatment of childhood social phobia. J. Am. Acad. Child Adolesc. Psychiatry. 2007;46:1622–1632.
  • Wetherell JL, Petkus AJ, White KS, et al. Antidepressant medication augmented with cognitive-behavioral therapy for generalized anxiety disorder in older adults. Am. J. Psychiatry. 2013;170:782–789.
  • Hidalgo RB, Tupler LA, Davidson JRT. An effect-size analysis of pharmacologic treatments for generalized anxiety disorder. J. Psychopharmacol. 2007;21:864–872.
  • Katzman MA, Bleau P, Blier P, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14:S1.
  • Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: A revision of the 2005 guidelines from the British association for psychopharmacology. J. Psychopharmacol. 2014;28:403–439.
  • Altamura AC, Moro AR, Percudani M. Clinical pharmacokinetics of fluoxetine. Clin. Pharmacokinet. 1994;26:201–214.
  • Leonard BE. Pharmacological differences of serotonin reuptake inhibitors and possible clinical relevance. Drugs. 1992;43:3–10.
  • Birmaher B, Axelson DA, Monk K, et al. Fluoxetine for the treatment of childhood anxiety disorders. J. Am. Acad. Child Adolesc. Psychiatry. 2003;42:415–423.
  • Warrington SJ. Clinical implications of the pharmacology of sertraline. Int. Clin. Psychopharmacol. 1991;6(Suppl 2):11–21.
  • Rudberg I, Hermann M, Refsum H, et al. Serum concentrations of sertraline and N-desmethyl sertraline in relation to CYP2C19 genotype in psychiatric patients. Eur. J. Clin. Pharmacol. 2008;64:1181–1188.
  • Wang JH, Liu ZQ, Wang W, et al. Pharmacokinetics of sertraline in relation to genetic polymorphism of CYP2C19. Clin. Pharmacol. Ther. 2001;70:42–47.
  • Findling RL, McNamara NK, Stansbrey RJ, et al. The relevance of pharmacokinetic studies in designing efficacy trials in juvenile major depression. J. Child Adolesc. Psychopharmacol. 2006;16:131–145.
  • Rynn MA, Siqueland L, Rickels K. Placebo-controlled trial of sertraline in the treatment of children with generalized anxiety disorder. Am. J. Psychiatry. 2001;158:2008–2014.
  • Rynn MA, Walkup JT, Compton SN, et al. Child/adolescent anxiety multimodal study: evaluating safety. J. Am. Acad. Child Adolesc. Psychiatry. 2015;54:180–190.
  • Pollack MH, Zaninelli R, Goddard A, et al. Paroxetine in the treatment of generalized anxiety disorder: results of a placebo-controlled, flexible-dosage trial. J. Clin. Psychiatry. 2001;62:350–357.
  • Rickels K, Zaninelli R, McCafferty J, et al. Paroxetine treatment of generalized anxiety disorder: a double-blind, placebo-controlled study. Am. J. Psychiatry. 2003;160:749–756.
  • Bielski RJ, Bose A, Chang -C-C. A double-blind comparison of escitalopram and paroxetine in the long-term treatment of generalized anxiety disorder. Ann. Clin. Psychiatry. 2005;17:65–69.
  • Roseboom PH, Kalin NH. Citalopram and S-citalopram. 4th ed. ed. Am. Psychiatric Publishing. Textbook of Psychopharmacol; 2013.
  • Beach SR, Kostis WJ, Celano CM, et al. Meta-analysis of selective serotonin reuptake inhibitor-associated QTc prolongation. J. Clin. Psychiatry. 2014;75(5):e441-9.
  • Baumann P. Clinical pharmacokinetics of citalopram and other selective serotonergic reuptake inhibitors (SSRI). Int. Clin. Psychopharmacol. 1992;6(Suppl 5):13–20.
  • Goodman WK, Bose A, Wang Q. Treatment of generalized anxiety disorder with escitalopram: pooled results from double-blind, placebo-controlled trials. J. Affect. Disord. 2005;87:161–167.
  • Allgulander C, Florea I, Akt H. Prevention of relapse in generalized anxiety disorder by escitalopram treatment. Int. J. Neuropsychopharmacol. 2006;9:495–505.
  • Sheehan DV. Attaining remission in generalized anxiety disorder: venlafaxine extended release comparative data. J. Clin. Psychiatry. 2001;62:26–31.
  • Rickels K, Pollack MH, Sheehan DV, et al. Efficacy of extended-release venlafaxine in nondepressed outpatients with generalized anxiety disorder. Am. J. Psychiatry. 2000;157:968–974.
  • Gelenberg AJ, Lydiard RB, Rudolph RL, et al. Efficacy of venlafaxine extended-release capsules in nondepressed outpatients with generalized anxiety disorder. JAMA [Internet]. 2000;283:3082.
  • Rickels K, Etemad B, Khalid-Khan S, et al. Time to relapse after 6 and 12 months’ treatment of generalized anxiety disorder with venlafaxine extended release. Arch. Gen. Psychiatry. 2010;67:1274–1281.
  • Rynn MA, Riddle MA, Yeung PP, et al. Efficacy and safety of extended-release venlafaxine in the treatment of generalized anxiety disorder in children and adolescents: two placebo-controlled trials. Am. J. Psychiatry. 2007;164:290–300.
  • Zhang Y, Huang G, Yang S, et al. Duloxetine in treating generalized anxiety disorder in adults: a meta-analysis of published randomized, double-blind, placebo-controlled trials. Asia. Pac. Psychiatry. 2016;8:215–225.
  • Davidson JR, Wittchen HU, Llorca PM, et al. Duloxetine treatment for relapse prevention in adults with generalized anxiety disorder: a double-blind placebo-controlled trial. Eur Neuropsychopharmacol. 2008;18:673–681.
  • Alaka KJ, Noble W, Montejo A, et al. Efficacy and safety of duloxetine in the treatment of older adult patients with generalized anxiety disorder: a randomized, double-blind, placebo-controlled trial. Int. J. Geriatr. Psychiatry. 2014;29:978–986.
  • Strawn JR, Prakash A, Zhang Q, et al. A randomized, placebo-controlled study of duloxetine for the treatment of children and adolescents with generalized anxiety disorder. J Am Acad Child Adolesc Psychiatry. 2015;54:283–293.
  • RUPP. The Pediatric Anxiety Rating Scale (PARS): development and psychometric properties. J. Am. Acad. Child Adolesc. Psychiatry. 2002;41:1061–1069.
  • Gommoll C, Durgam S, Mathews M, et al. A double-blind, randomized, placebo-controlled, fixed-dose phase III study of vilazodone in patients with generalized anxiety disorder. Depress. Anxiety. 2015;32:451–459.
  • Durgam S, Gommoll C, Forero G, et al. Efficacy and safety of vilazodone in patients with generalized anxiety disorder: a randomized, double-blind, placebo-controlled, flexible-dose trial. J. Clin. Psychiatry. 2016;77:1687–1694.
  • Sato H, Ito C, Tashiro M, et al. Histamine H1 receptor occupancy by the new-generation antidepressants fluvoxamine and mirtazapine: A positron emission tomography study in healthy volunteers. Psychopharmacology (Berl). 2013;230:227–234.
  • Goodnick PJ, Puig A, DeVane CL, et al. Mirtazapine in major depression with comorbid generalized anxiety disorder. J. Clin. Psychiatry. 1999;60:446–448.
  • Gambi F, De Berardis D, Campanella D, et al. Mirtazapine treatment of generalized anxiety disorder: a fixed dose, open label study. J. Psychopharmacol. 2005;19:483–487.
  • Orsolini L, Tomasetti C, Valchera A, et al. New advances in the treatment of generalized anxiety disorder: the multimodal antidepressant vortioxetine. Expert Rev. Neurother. 2016;16(5):483–495.
  • Bidzan L, Mahableshwarkar AR, Jacobsen P, et al. Vortioxetine (Lu AA21004) in generalized anxiety disorder: results of an 8-week, multinational, randomized, double-blind, placebo-controlled clinical trial. Eur. Neuropsychopharmacol. 2012;22:847–857.
  • Rothschild AJ, Mahableshwarkar AR, Jacobsen P, et al. Vortioxetine (Lu AA21004) 5mg in generalized anxiety disorder: results of an 8-week randomized, double-blind, placebo-controlled clinical trial in the United States. Eur. Neuropsychopharmacol. 2012;22:858–866.
  • Christensen MC, Loft H, Florea I, et al. Efficacy of vortioxetine in working patients with generalized anxiety disorder. CNS Spectr. 2017;1–9.
  • Mahableshwarkar AR, Jacobsen PL, Chen Y, et al. A randomised, double-blind, placebo-controlled, duloxetine-referenced study of the efficacy and tolerability of vortioxetine in the acute treatment of adults with generalised anxiety disorder. Int. J. Clin. Pract. 2014;68:49–59.
  • Pae C-U, Wang S-M, Han C, et al. Vortioxetine, a multimodal antidepressant for generalized anxiety disorder: a systematic review and meta-analysis. J. Psychiatr. Res. 2015;64:88–98.
  • Findling RL, Robb AS, DelBello M, et al. Pharmacokinetics and safety of vortioxetine in pediatric patients. J. Child Adolesc. Psychopharmacol. 2017;27(6):526–534.
  • Stein MB, Sareen J. Clinical practice. generalized anxiety disorder. N. Engl. J. Med. 2015;373:2059–2068.
  • Reinhold JA, Rickels K. Pharmacological treatment for generalized anxiety disorder in adults: an update. Expert Opin. Pharmacother. 2015;16:1669–1681.
  • Gomez AF, Barthel AL, Hofmann SG. Comparing the efficacy of benzodiazepines and serotonergic anti-depressants for adults with generalized anxiety disorder: a meta-analytic review. Expert Opin. Pharmacother. 2018;883–894.
  • Goddarda W, Brouette T, Almai A, et al. Early coadministration of clonazepam with sertraline for panic disorder. Arch. Gen. Psychiatry. 2001;58(7):681–686.
  • Seedat S, Stein MB. Double-blind, placebo-controlled assessment of combined clonazepam with paroxetine compared with paroxetine monotherapy for generalized social anxiety disorder. J. Clin. Psychiatry. 2004;65:244–248.
  • Simeon JG, Ferguson HB, Knott V, et al. Clinical, cognitive, and neurophysiological effects of alprazolam in children and adolescents with overanxious and avoidant disorders. J. Am. Acad. Child Adolesc. Psychiatry. 1992;31:29–33.
  • Graae F, Milner J, Rizzotto L, et al. Clonazepam in childhood anxiety disorders. J. Am. Acad. Child Adolesc. Psychiatry. 1994;33:372–376.
  • Pollack M, Kinrys G, Krystal A, et al. Eszopiclone coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder. Arch. Gen. Psychiatry. 2008;65:551–562.
  • Nelson JC. Tricyclic and tetracyclic drugs. essentials clin. psychopharmacol. 3rd ed; 2013. p. 5–28.
  • Feighner JP. Mechanism of action of antidepressant medications. J. Clin. Psychiatry. 1999;60(Suppl 4):4–11.
  • Bailey B, Buckley NA, Amre DK. A meta-analysis of prognostic indicators to predict seizures, arrhythmias or death after tricyclic antidepressant overdose. J. Toxicol. - Clin. Toxicol. 2004;42(6):877–888.
  • Rickels K, Downing R, Schweizer E, et al. Antidepressants for the treatment of generalized anxiety disorder. A placebo-controlled comparison of imipramine, trazodone, and diazepam. Arch. Gen. Psychiatry. 1993;50:884–895.
  • Hoehn-Saric R, McLeod DR, Zimmerli WD. Differential effects of alprazolam and imipramine in generalized anxiety disorder: somatic versus psychic symptoms. J. Clin. Psychiatry. 1988;49:293–301.
  • Rynn M, Garc??a-Espa??a F, Greenblatt DJ, et al. Imipramine and buspirone in patients with panic disorder who are discontinuing long-term benzodiazepine therapy. J Clin Psychopharmacol. 2003;23:505–508.
  • Youdim MBH, Edmondson D, Tipton KF. The therapeutic potential of monoamine oxidase inhibitors. Nat. Rev. Neurosci. 2006;7:295–309.
  • Thase ME. The role of monoamine oxidase inhibitors in depression treatment guidelines. J. Clin. Psychiatry. 2012;73(Suppl 1):10–16.
  • Chessick CA, Allen MH, Thase M, et al. Azapirones for generalized anxiety disorder. Cochrane Database Syst. Rev. 2006;CD006115.
  • Strawn JR, Mills JA, Cornwall GJ, et al. Buspirone in children and adolescents with anxiety: a review and Bayesian analysis of abandoned randomized controlled trials. J. Child Adolesc. Psychopharmacol. 2018;28(1):2–9.
  • Guaiana G, Barbui C, Cipriani A. Hydroxyzine for generalised anxiety disorder. Cochrane Database Syst. Rev. 2010.
  • Fink K, Dooley DJ, Meder WP, et al. Inhibition of neuronal Ca2+ influx by gabapentin and pregabalin in the human neocortex. Neuropharmacology. 2002;42:229–236.
  • Strawn JR, Geracioti TD. The treatment of generalized anxiety disorder with pregabalin, an atypical anxiolytic. Neuropsychiatr. Dis. Treat. 2007;3:237–243.
  • Pande AC, Crockatt JG, Feltner DE, et al. Pregabalin in generalized anxiety disorder: A placebo-controlled trial. Am. J. Psychiatry. 2003;160:533–540.
  • Hamilton M. The assessment of anxiety states by rating. Br. J. Med. Psychol. 1959;32:50–55.
  • Hindmarch I, Trick L, Ridout F. A double-blind, placebo- and positive-internal-controlled (alprazolam) investigation of the cognitive and psychomotor profile of pregabalin in healthy volunteers. Psychopharmacology (Berl). 2005;183:133–143.
  • Feltner DE, Crockatt JG, Dubovsky SJ, et al. A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder. J Clin Psychopharmacol. 2003;23:240–249.
  • Rickels K, Pollack MH, Feltner DE, et al. Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam. Arch. Gen. Psychiatry. 2005;62:1022–1030.
  • Montgomery S, Chatamra K, Pauer L, et al. Efficacy and safety of pregabalin in elderly people with generalised anxiety disorder. Br. J. Psychiatry. 2008;389–394.
  • Olivares JM, Álvarez E, Carrasco JL, et al. Pregabalin for the treatment of patients with generalized anxiety disorder with inadequate treatment response to antidepressants and severe depressive symptoms. Int. Clin. Psychopharmacol. 2015;30:265–271.
  • Montgomery SA, Tobias K, Zornberg GL, et al. Efficacy and safety of pregabalin in the treatment of generalized anxiety disorder: a 6-week, multicenter, randomized, double-blind, placebo-controlled comparison of pregabalin and venlafaxine. J. Clin. Psychiatry. 2006;67:771–782.
  • Bonnet U, Scherbaum N. How addictive are gabapentin and pregabalin? A systematic review. Eur. Neuropsychopharmacol. 2017;27(12):1185–1215.
  • Boschen MJ. A meta-analysis of the efficacy of pregabalin in the treatment of generalized anxiety disorder. Can. J. Psychiatry. 2011;56(9):558–566.
  • Schwartz TL, Nihalani N. Tiagabine in anxiety disorders. Expert Opin. Pharmacother. 2006;7:1977–1987.
  • Rosenthal M. Tiagabine for the treatment of generalized anxiety disorder: a randomized, open-label, clinical trial with paroxetine as a positive control. J. Clin. Psychiatry. 2003;64:1245–1249.
  • Schaller JL, Thomas J, Rawlings D. Low-dose tiagabine effectiveness in anxiety disorders. MedGenMed. 2004;6:8.
  • Schwartz TL. The use of tiagabine augmentation for treatment-resistant anxiety disorders: a case series. Psychopharmacol. Bull. 2002;36:53–57.
  • Pollack MH, Tiller J, Xie F, et al. Tiagabine in adult patients with generalized anxiety disorder: results from 3 randomized, double-blind, placebo-controlled, parallel-group studies. J Clin Psychopharmacol. 2008;28:308–316.
  • Bymaster FP, Calligaro DO, Falcone JF, et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology. 1996;14:87–96.
  • Kassahun K, Mattiuz E, Nyhart E, et al. Disposition and biotransformation of the antipsychotic agent olanzapine in humans. Drug Metab. Dispos. 1997;25:81–93.
  • Ring BJ, Catlow J, Lindsay TJ, et al. Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine. J. Pharmacol. Exp. Ther. 1996;276:658–666.
  • Pollack MH, Simon NM, Zalta AK, et al. Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study. Biol. Psychiatry. 2006;59:211–215.
  • Guy W, Clinical Global CGI. Impressions. ECDEU Assess. Man. 1976;217–222.
  • Snydermae SH, Rynn MA, Rickels K. Open-label pilot study of ziprasidone for refractory generalized anxiety disorder [2]. J. Clin. Psychopharmacol. 2005;497–499.
  • Goff DC. Risperidone and paliperidone. American Psychiatric Publishing Textbook of Psychopharmacol. 4th ed. Washington, DC; 2009. p. 627–640.
  • Simon NM, Hoge EA, Fischmann D, et al. An open-label trial of risperidone augmentation for refractory anxiety disorders. J. Clin. Psychiatry. 2006;67:381–385.
  • Brawman-Mintzer O, Knapp RG, Nietert PJ. Adjunctive risperidone in generalized anxiety disorder: a double-blind, placebo-controlled study. J Clin Psychiatry. 2005;66:1321–1325.
  • Lieberman JA. Aripiprazole. Am Psychiatr Publishing Textbook. 2004;487–494.
  • Menza MA, Dobkin RD, Marin H. An open-label trial of aripiprazole augmentation for treatment-resistant generalized anxiety disorder. J. Clin. Psychopharmacol. 2007;27(2):207–210.
  • Hoge EA, Worthington III JJ, Kaufman RE, et al. Aripiprazole as augmentation treatment of refractory generalized anxiety disorder and panic disorder. CNS Spectr. 2008;13(6):522–527.
  • Kapur S, Zipursky R, Jones C, et al. A positron emission tomography study of quetiapine in schizophrenia: A preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch. Gen. Psychiatry. 2000;57(6):553–559.
  • Kreys T-JM, Phan SV. A literature review of quetiapine for generalized anxiety disorder. Pharmacotherapy. 2015;35:175–188.
  • Mezhebovsky I, Mägi K, She F, et al. Double-blind, randomized study of extended release quetiapine fumarate (quetiapine XR) monotherapy in older patients with generalized anxiety disorder. Int. J. Geriatr. Psychiatry. 2013;28:615–625.
  • Merideth C, Cutler AJ, She F, et al. Efficacy and tolerability of extended release quetiapine fumarate monotherapy in the acute treatment of generalized anxiety disorder: a randomized, placebo controlled and active-controlled study. Int. Clin. Psychopharmacol. 2012;27:40–54.
  • Liebowitz M, Lam RW, Lepola U, et al. Efficacy and tolerability of extended release quetiapine fumarate monotherapy as maintenance treatment of major depressive disorder: a randomized, placebo-controlled trial. Depress. Anxiety. 2010;27:964–976.
  • Dubovsky SL, Warren C. Agomelatine, a melatonin agonist with antidepressant properties. Expert Opin. Investig. Drugs. 2009;18:1533–1540.
  • Stein DJ, Ahokas AA, De Bodinat C. Efficacy of agomelatine in generalized anxiety disorder: a randomized, double-blind, placebo-controlled study. J. Clin. Psychopharmacol. 2008;28:561–566.
  • Stein DJ, Ahokas A, Márquez MS, et al. Agomelatine in generalized anxiety disorder: an active comparator and placebo-controlled study. J. Clin. Psychiatry. 2014;75:362–368.
  • Stein DJ, Ahokas A, Jarema M, et al. Efficacy and safety of agomelatine (10 or 25 mg/day) in non-depressed out-patients with generalized anxiety disorder: A 12-week, double-blind, placebo-controlled study. Eur. Neuropsychopharmacol. 2017;27:526–537.
  • Stein DJ, Ahokas A, Albarran C, et al. Agomelatine prevents relapse in generalized anxiety disorder: a 6-month randomized, double-blind, placebo-controlled discontinuation study. J. Clin. Psychiatry. 2012;73:1002–1008.
  • Strawn JR, Compton SN, Robertson B, et al. Extended release guanfacine in pediatric anxiety disorders: a pilot, randomized, placebo-controlled trial. J. Child Adolesc. Psychopharmacol. 2017;27(1):29–37.
  • Soeter M, Kindt M. An abrupt transformation of phobic behavior after a post-retrieval amnesic agent. Biol. Psychiatry. 2015;78:880–886.
  • Woelk H, Schläfke S. A multi-center, double-blind, randomised study of the Lavender oil preparation silexan in comparison to lorazepam for generalized anxiety disorder. Phytomedicine. 2010;17:94–99.
  • Kasper S, Gastpar M, Müller WE, et al. Lavender oil preparation silexan is effective in generalized anxiety disorder – a randomized, double-blind comparison to placebo and paroxetine. Int. J. Neuropsychopharmacol. 2014;17:859–869.
  • Möller HJ, Volz HP, Dienel A, et al. Efficacy of silexan in subthreshold anxiety: meta-analysis of randomised, placebo-controlled trials. Eur. Arch. Psychiatry Clin. Neurosci. 2018. In press.
  • Henley DV, Lipson N, Korach KS, et al. Prepubertal gynecomastia linked to lavender and tea tree oils. N. Engl. J. Med. 2007;356:479–485.
  • Pittler MH, Ernst E. Kava extract versus placebo for treating anxiety. Cochrane Database Syst. Rev. 2003;(1):CD003383.
  • Connor KM, Davidson JRT. A placebo-controlled study of Kava kava in generalized anxiety disorder. Int. Clin. Psychopharmacol. 2002;17:185–188.
  • Ernst E. A re-evaluation of kava (Piper methysticum). Br. J. Clin. Pharmacol. 2007;415–417.
  • Davidson J, Zhang W, Connor K, et al. Review: a psychopharmacological treatment algorithm for generalised anxiety disorder (GAD). J. Psychopharmacol. 2010;24:3–26.
  • Bruce SE, Yonkers KA, Otto MW, 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;162:1179–1187.
  • Strawn JR, Mills JA, Sauley BA, et al. The impact of antidepressant dose and class on treatment response in pediatric anxiety disorders: a meta-analysis. J. Am. Acad. Child Adolesc. Psychiatry. 2018;57:235–244.
  • Wang Z, Whiteside SPH, Sim L, et al. Comparative effectiveness and safety of cognitive behavioral therapy and pharmacotherapy for childhood anxiety disorders: a systematic review and meta-analysis. JAMA Pediatr. 2017;171:1049.
  • Strawn JR, Welge JA, Wehry AM, et al. Efficacy and tolerability of antidepressants in pediatric anxiety disorders: a systematic review and meta-analysis. Depress. Anxiety. 2015;32:149–157.
  • Brent DA, Emslie GJ, Clarke GN, et al. Predictors of spontaneous and systematically assessed suicidal adverse events in the treatment of SSRI-resistant depression in adolescents (TORDIA) study. Am. J. Psychiatry. 2009;166:418–426.
  • Cipriani A, Zhou X, Del GC, et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. Lancet. 2016;388(10047):881–890.
  • Murrin LC, Sanders JD, Bylund DB. Comparison of the maturation of the adrenergic and serotonergic neurotransmitter systems in the brain: implications for differential drug effects on juveniles and adults. Biochem. Pharmacol. 2007;73:1225–1236.
  • Ressler KJ, Nemeroff CB. Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress. Anxiety. 2000;12(Suppl 1):2–19.

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