, Volume 197, Issue 4, pp 675–681 | Cite as

Quetiapine augmentation of paroxetine CR for the treatment of refractory generalized anxiety disorder: preliminary findings

  • Naomi M. SimonEmail author
  • Kathryn M. Connor
  • Richard T. LeBeau
  • Elizabeth A. Hoge
  • John J. WorthingtonIII
  • Wei Zhang
  • Jonathan R. T. Davidson
  • Mark H. Pollack
Original Investigation



More data are needed to guide “next step” strategies for patients with generalized anxiety disorder (GAD) remaining symptomatic despite initial pharmacotherapy.


This study prospectively examined the relative efficacy of quetiapine versus placebo augmentation for individuals with GAD remaining symptomatic with initial paroxetine CR pharmacotherapy.

Materials and methods

Adult outpatients with GAD were recruited from 2004 to 2007 at two academic centers. Phase 1 consisted of 10 weeks of open-label paroxetine CR flexibly dosed to a maximum of 62.5 mg/day. Those remaining symptomatic (Hamilton Anxiety Scale [HAM-A] ≥ 7) at week 10 were randomized to quetiapine or placebo augmentation flexibly dosed from 25 to 400 mg/day.


For participants receiving paroxetine CR (n = 50), there was a significant reduction in HAM-A scores (baseline mean ± SD = 22.4 ± 4.2 to endpoint mean ± SD = 11.2 ± 6.9; paired t = 12.1, df = 49, t < 0.0001) with 40% (n = 20) achieving remission. Counter to our hypothesis, we did not find significant benefit for quetiapine augmentation of continued paroxetine CR (HAM-A reduction mean ± SD = 2.6 ± 5.8 points quetiapine, 0.3 ± 5.5 points placebo; t = 0.98, df = 20, p = n.s.) in the randomized sample (n = 22) with relatively minimal additional improvement overall in phase 2.


Although conclusions are considered preliminary based on the relatively small sample size, our data do not support the addition of quetiapine to continued paroxetine CR for individuals with GAD who remain symptomatic after 10 weeks of prospective antidepressant pharmacotherapy and suggest that further research examining strategies for GAD refractory to antidepressants is needed.


GAD Refractory Paroxetine Quetiapine Augmentation Anxiety Pharmacotherapy Treatment 



This study was supported by an investigator-initiated Collaborative Research Trial grant from GlaxoSmithKline with additional support provided by the Investigator-Sponsored Study Program of AstraZeneca.

Conflict of interest statement

Neither AstraZeneca nor Glaxo Smith Kline were involved in the original concepts and systematic review of existing trial evidence, the design, the choice of investigators, the control of allocation schedule, the conduct of the trial, the collection and monitoring of data, the analysis and interpretation, or the writing of the report. Both companies were given an opportunity to review the manuscript and make comments before submission, but edits were at the discretion of the authors. The study investigators have full control of all primary data and agree to allow the journal to review all data if requested.

Dr. Simon has received research support from AstraZeneca, Cephalon, Forest Laboratories, GlaxoSmithKline, Janssen, Eli Lilly, Pfizer, UCB Pharma, Sepracor, NARSAD, and NIMH; has served as a speaker for Forest Laboratories, Janssen, Lilly, UCB Pharma, Sepracor, and Pfizer; has served as an advisor for Solvay; and is a consultant for Paramount Biosciences.

Dr. Connor has received research support from GlaxoSmithKline and AstraZeneca and is an employee for Merck & Co., Inc.

Mr. LeBeau has no financial disclosures to report.

Dr. Hoge has received research support from the National Institutes of Health, the Dupont Warren Foundation, Eli Lilly, Inc., AstraZeneca, Cephalon, Forest Laboratories, GlaxoSmithKline, Lilly, Pfizer, UCB Pharma, Sepracor, and (through fellowships funded by unrestricted educational grants) Merck, and Pfizer, Inc.

Dr. Worthington has received research support from Abbott Laboratories, Alkermes, Aspect Medical Systems, AstraZeneca, Bristol-Myers Squibb Company, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals, Inc., GlaxoSmithKline, J & J Pharmaceuticals, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Novartis, Organon Inc., PamLab, LLC, Pfizer Inc., Pharmative, Roche, Sanofi-Aventis, Sepracor, Solvay Pharmaceuticals, Inc., UCB Pharma, and Wyeth-Ayerst Laboratories; and has served as a speaker for Bristol-Myers Squibb Company, Eli Lilly & Company, Forest Pharmaceuticals Inc., GlaxosmithKline, Pfizer Inc., Sanofi-Aventis and Wyeth-Ayerst Laboratores.

Dr. Zhang has received research support from AstraZeneca, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Pfizer, and UCB.

Dr. Davidson has received research support from Pfizer, Eli Lilly, GlaxoSmithKline, Forest, Bristol-Myers Squibb, Cephalon, AstraZeneca, UCB, Janssen, International Psychopharmacology Algorithm Project, and CME Institute; serves as an advisor for Actelion, Pfizer, GlaxoSmithKline, Forest, Eli Lilly, Roche, MediciNova, Jazz, AstraZeneca, Wyeth, Sanofi-Aventis, Janssen, Brain Cells, and Tracscept; receives royalties from MultiHealth Systems Inc., Guilford Publications, American Psychiatric Association, Current Medical Science, and Taylor and Francis; is a speaker for Solvay, Pfizer, GlaxoSmithKline, Forest, Henry Jackson Foundation, University of Hawaii, University of Utah, UNC, University of Chicago, NC Psychiatric Association, Psychiatric Society of Virginia, Texas Society of Psychiatric Physicians, Massachusetts Psychiatric Society, and Duke University Medical Center; and holds equity in Procter and Gamble.

Dr. Pollack is an advisor/consultant for AstraZeneca, Brain Cells Inc., Bristol-Myers Squibb, Cephalon, Forest Laboratories, GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Eli Lilly, Medavante, Neurocrine, Neurogen, Novartis, Otsuka Pharmaceuticals, Pfizer, Predix, Roche Laboratories, Sanofi, Sepracor, Solvay, Tikvah Therapeutics, Transcept Inc., UCB Pharma, and Wyeth; has received research grants from Bristol-Myers Squibb, Cephalon, Forest Laboratories, GlaxoSmithKline, Janssen, Eli Lilly, Pfizer, Sepracor, UCB Pharma, and Wyeth; is a member of the speaker programs of Bristol-Myers Squibb, Forest Laboratories, GlaxoSmithKline, Janssen, Lilly, Pfizer, Solvay, and Wyeth; and holds equity in Medavante and Mensante Corporation.


  1. Allgulander C, Bandelow B, Hollander E, Montgomery SA, Nutt DJ, Okasha A, Pollack MH, Stein DJ, Swinson RP (2003) WCA recommendations for the long-term treatment of generalized anxiety disorder. CNS Spectr 8:53–61PubMedGoogle Scholar
  2. Canadian Psychiatric Association (2006) Management of anxiety disorders. Can J Psychiatry 51:1S–93SGoogle Scholar
  3. Baldwin DS, Anderson IM, Nutt DJ, Bandelow B, Bond A, Davidson JR, den Boer JA, Fineberg NA, Knapp M, Scott J, Wittchen HU (2005) Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 19:567–596PubMedCrossRefGoogle Scholar
  4. Bandelow B, Zohar J, Hollander E, Kasper S, Moller HJ (2002) World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders. World J Biol Psychiatry 3:171–199PubMedGoogle Scholar
  5. Barnes TR (1989) A rating scale for drug-induced akathisia. Br J Psychiatry 154:672–676PubMedGoogle Scholar
  6. Bjerrum H, Allerup P, Thunedborg K, Jakobsen K, Bech P (1992) Treatment of generalized anxiety disorder: comparison of a new beta-blocking drug (CGP 361 A), low-dose neuroleptic (flupenthixol), and placebo. Pharmacopsychiatry 25:229–232PubMedGoogle Scholar
  7. Brawman-Mintzer O, Knapp RG, Nietert PJ (2005) Adjunctive risperidone in generalized anxiety disorder: a double-blind, placebo-controlled study. J Clin Psychiatry 66:1321–1325PubMedGoogle Scholar
  8. Brawman-Mintzer O, Nietert PJ, Rynn M, Rickels K (2006) Quetiapine monotherapy in patients with GAD. Proceedings of the 159th Annual Meeting of the American Psychiatric Association, Toronto, Ontario, CAGoogle Scholar
  9. Denys D, van Megen H, Westenberg H (2002) Quetiapine addition to serotonin reuptake inhibitor treatment in patients with treatment-refractory obsessive-compulsive disorder: an open-label study. J Clin Psychiatry 63:700–703PubMedGoogle Scholar
  10. Endicott J, Nee J, Harrison W, Blumenthal R (1993) Quality of Life Enjoyment and Satisfaction Questionnaire: a new measure. Psychopharmacol Bull 29:321–326PubMedGoogle Scholar
  11. Gao K, Muzina D, Gajwani P, Calabrese JR (2006) Efficacy of typical and atypical antipsychotics for primary and comorbid anxiety symptoms or disorders: a review. J Clin Psychiatry 67:1327–1340PubMedGoogle Scholar
  12. Golden RN, Nemeroff CB, McSorley P, Pitts CD, Dube EM (2002) Efficacy and tolerability of controlled-release and immediate-release paroxetine in the treatment of depression. J Clin Psychiatry 63:577–584PubMedGoogle Scholar
  13. Hamilton M (1959) The assessment of anxiety states by rating. Br J Med Psychol 32:50–55PubMedGoogle Scholar
  14. Hamner MB, Brodrick PS, Labbate LA (2001) Gabapentin in PTSD: a retrospective, clinical series of adjunctive therapy. Ann Clin Psychiatry 13:141–146PubMedCrossRefGoogle Scholar
  15. Hamner MB, Deitsch SE, Brodrick PS, Ulmer HG, Lorberbaum JP (2003) Quetiapine treatment in patients with posttraumatic stress disorder: an open trial of adjunctive therapy. J Clin Psychopharmacol 23:15–20PubMedCrossRefGoogle Scholar
  16. Henning ER, Turk CL, Mennin DS, Fresco DM, Heimberg RG (2007) Impairment and quality of life in individuals with generalized anxiety disorder. Depress Anxiety 24:342–349PubMedCrossRefGoogle Scholar
  17. Katzman M, Vermani M, Jacobs L, Marcus M, Kong B, Lessard S, Galarraga W, Gendron A (2006) A flexible dose, open-label trial evaluating the efficacy and safety of quetiapine (seroquel) as adjunctive pharmacotherapy for the treatment of generalized anxiety disorder (GAD). Proceedings of the 26th Annual Meeting of the Anxiety Disorders Association of America, Miami, FLGoogle Scholar
  18. Keene MS, Eaddy MT, Nelson WW, Sarnes MW (2005) Adherence to paroxetine CR compared with paroxetine IR in a Medicare-eligible population with anxiety disorders. Am J Manag Care 11:S362–369PubMedGoogle Scholar
  19. Kessler RC, Brandenburg N, Lane M, Roy-Byrne P, Stang PD, Stein DJ, Wittchen HU (2005) Rethinking the duration requirement for generalized anxiety disorder: evidence from the National Comorbidity Survey Replication. Psychol Med 35:1073–1082PubMedCrossRefGoogle Scholar
  20. Lehmann E (1989) The dose–effect relationship of 0.5, 1.0 and 1.5 mg fluspirilene on anxious patients. Neuropsychobiology 21:197–204PubMedCrossRefGoogle Scholar
  21. Lepola U, Bergtholdt B, St Lambert J, Davy KL, Ruggiero L (2004) Controlled-release paroxetine in the treatment of patients with social anxiety disorder. J Clin Psychiatry 65:222–229PubMedCrossRefGoogle Scholar
  22. Maier W, Heuser I, Philipp M, Frommberger U, Demuth W (1988) Improving depression severity assessment—II. Content, concurrent and external validity of three observer depression scales. J Psychiatr Res 22:13–19PubMedCrossRefGoogle Scholar
  23. Mendels J, Krajewski TF, Huffer V, Taylor RJ, Secunda S, Schless A, Sebastian JA, Semchyshyn G, Durr MJ, Melmed AS et al (1986) Effective short-term treatment of generalized anxiety disorder with trifluoperazine. J Clin Psychiatry 47:170–174PubMedGoogle Scholar
  24. Menza MA, Dobkin RD, Marin H (2007) An open-label trial of aripiprazole augmentation for treatment-resistant generalized anxiety disorder. J Clin Psychopharmacol 27:207–210PubMedCrossRefGoogle Scholar
  25. Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382–390PubMedCrossRefGoogle Scholar
  26. Nasrallah HA (2007) Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry 13:27–35PubMedCrossRefGoogle Scholar
  27. Pollack MH, Simon NM, Zalta AK, Worthington JJ, Hoge EA, Mick E, Kinrys G, Oppenheimer J (2006) Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study. Biol Psychiatry 59:211–215PubMedCrossRefGoogle Scholar
  28. Pollack MH, Zaninelli R, Goddard A, McCafferty JP, Bellew KM, Burnham DB, Iyengar MK (2001) Paroxetine in the treatment of generalized anxiety disorder: results of a placebo-controlled, flexible-dosage trial. J Clin Psychiatry 62:350–357PubMedCrossRefGoogle Scholar
  29. Rickels K, Rynn M, Iyengar M, Duff D (2006) Remission of generalized anxiety disorder: a review of the paroxetine clinical trials database. J Clin Psychiatry 67:41–47PubMedGoogle Scholar
  30. Rickels K, Zaninelli R, McCafferty J, Bellew K, Iyengar M, Sheehan D (2003) Paroxetine treatment of generalized anxiety disorder: a double-blind, placebo-controlled study. Am J Psychiatry 160:749–756PubMedCrossRefGoogle Scholar
  31. Rocca P, Fonzo V, Scotta M, Zanalda E, Ravizza L (1997) Paroxetine efficacy in the treatment of generalized anxiety disorder. Acta Psychiatr Scand 95:444–450PubMedCrossRefGoogle Scholar
  32. Ruscio AM, Chiu WT, Roy-Byrne P, Stang PE, Stein DJ, Wittchen HU, Kessler RC (2007) Broadening the definition of generalized anxiety disorder: effects on prevalence and associations with other disorders in the National Comorbidity Survey Replication. J Anxiety Disord 21:662–676PubMedCrossRefGoogle Scholar
  33. Schweizer E (1995) Generalized anxiety disorder. Longitudinal course and pharmacologic treatment. Psychiatr Clin North Am 18:843–857PubMedGoogle Scholar
  34. Sheehan DV, Burnham DB, Iyengar MK, Perera P (2005) Efficacy and tolerability of controlled-release paroxetine in the treatment of panic disorder. J Clin Psychiatry 66:34–40PubMedGoogle Scholar
  35. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20):22–33; quiz 34–57PubMedGoogle Scholar
  36. Simon NM, Hoge EA, Fischmann D, Worthington JJ, Christian KM, Kinrys G, Pollack MH (2006) An open-label trial of risperidone augmentation for refractory anxiety disorders. J Clin Psychiatry 67:381–385PubMedCrossRefGoogle Scholar
  37. Simpson GM, Angus JW (1970) A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 212:11–19PubMedCrossRefGoogle Scholar
  38. Stocchi F, Nordera G, Jokinen RH, Lepola UM, Hewett K, Bryson H, Iyengar MK (2003) Efficacy and tolerability of paroxetine for the long-term treatment of generalized anxiety disorder. J Clin Psychiatry 64:250–258PubMedCrossRefGoogle Scholar
  39. Timdahl K, Carlsson A, Stening G (2007) An analysis of safety and tolerability data from controlled, comparative studies of quetiapine in patients with schizophrenia, focusing on extrapyramidal symptoms. Hum Psychopharmacol 22:315–325PubMedCrossRefGoogle Scholar
  40. Vaishnavi S, Alamy S, Zhang W, Connor KM, Davidson JR (2007) Quetiapine as monotherapy for social anxiety disorder: a placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry 31:1464–1469PubMedCrossRefGoogle Scholar
  41. Wurthmann C, Klieser E, Lehmann E (1997) Side effects of low dose neuroleptics and their impact on clinical outcome in generalized anxiety disorder. Prog Neuropsychopharmacol Biol Psychiatry 21:601–609PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Naomi M. Simon
    • 1
    • 4
    Email author
  • Kathryn M. Connor
    • 2
    • 3
  • Richard T. LeBeau
    • 1
  • Elizabeth A. Hoge
    • 1
  • John J. WorthingtonIII
    • 1
  • Wei Zhang
    • 2
  • Jonathan R. T. Davidson
    • 2
  • Mark H. Pollack
    • 1
  1. 1.Massachusetts General Hospital and Harvard Medical SchoolBostonUSA
  2. 2.Duke UniversityDurhamUSA
  3. 3.Merck Research Laboratories, Merck & Co, Inc.Whitehouse StationUSA
  4. 4.Massachusetts General HospitalBostonUSA

Personalised recommendations