Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Unipolar depression in adults: Treatment with anxiolytics

Andrew Goddard, MD
Section Editor
Peter P Roy-Byrne, MD
Deputy Editor
David Solomon, MD


Unipolar major depression that includes high levels of anxiety symptoms (often called anxious depression) is common [1,2]. In a study of 2876 patients with major depression, high levels of anxiety were present in more than 50 percent [3].

Treatment of anxious depression frequently includes anxiolytic drugs [4]. In addition, insomnia that is part of the depressive syndrome often responds to anxiolytic (hypnotic) therapy [5].

This topic reviews the use of anxiolytics to treat unipolar major depression, including their indications, contraindications, administration, and efficacy. Choosing a medication regimen for the initial treatment of depression and for treatment resistant depression is discussed separately. (See "Unipolar major depression in adults: Choosing initial treatment" and "Unipolar depression in adults: Treatment of resistant depression".)


Unipolar major depression that includes high levels of anxiety symptoms is often called “anxious depression” [6]. The clinical features and diagnosis of anxious depression are discussed separately. (See "Unipolar depression in adults: Clinical features", section on 'Anxious' and "Unipolar depression in adults: Assessment and diagnosis", section on 'Depressive episode subtypes (specifiers)'.)  


Indications for augmenting antidepressants with anxiolytics to treat unipolar major depression include:

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Jun 15, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Köhler S, Unger T, Hoffmann S, et al. Acute and long-term treatment outcome in depressed inpatients with vs. without anxious features: results of a one-year follow-up study. J Affect Disord 2013; 150:1055.
  2. Wu Z, Chen J, Yuan C, et al. Difference in remission in a Chinese population with anxious versus nonanxious treatment-resistant depression: a report of OPERATION study. J Affect Disord 2013; 150:834.
  3. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry 2008; 165:342.
  4. Furukawa TA, Streiner DL, Young LT. Antidepressant plus benzodiazepine for major depression. Cochrane Database Syst Rev 2001; :CD001026.
  5. Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry 2006; 59:1052.
  6. Ionescu DF, Niciu MJ, Henter ID, Zarate CA. Defining anxious depression: a review of the literature. CNS Spectr 2013; 18:252.
  7. Katz C, Yaseen ZS, Mojtabai R, et al. Panic as an independent risk factor for suicide attempt in depressive illness: findings from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC). J Clin Psychiatry 2011; 72:1628.
  8. Richey SM, Krystal AD. Pharmacological advances in the treatment of insomnia. Curr Pharm Des 2011; 17:1471.
  9. Allen MH, Currier GW, Hughes DH, et al. The Expert Consensus Guideline Series. Treatment of behavioral emergencies. Postgrad Med 2001; :1.
  10. Sinclair LI, Christmas DM, Hood SD, et al. Antidepressant-induced jitteriness/anxiety syndrome: systematic review. Br J Psychiatry 2009; 194:483.
  11. Papakostas GI, Clain A, Ameral VE, et al. Fluoxetine-clonazepam cotherapy for anxious depression: an exploratory, post-hoc analysis of a randomized, double blind study. Int Clin Psychopharmacol 2010; 25:17.
  12. Jeffreys M, Capehart B, Friedman MJ. Pharmacotherapy for posttraumatic stress disorder: review with clinical applications. J Rehabil Res Dev 2012; 49:703.
  13. Pascual JC, Martín-Blanco A, Soler J, et al. A naturalistic study of changes in pharmacological prescription for borderline personality disorder in clinical practice: from APA to NICE guidelines. Int Clin Psychopharmacol 2010; 25:349.
  14. Manthey L, Lohbeck M, Giltay EJ, et al. Correlates of benzodiazepine dependence in the Netherlands Study of Depression and Anxiety. Addiction 2012; 107:2173.
  15. Tannenbaum C, Paquette A, Hilmer S, et al. A systematic review of amnestic and non-amnestic mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid drugs. Drugs Aging 2012; 29:639.
  16. Haroutiunian S, Lecht S, Zur AA, et al. The challenge of pain management in patients with myasthenia gravis. J Pain Palliat Care Pharmacother 2009; 23:242.
  17. George CF, Bayliff CD. Management of insomnia in patients with chronic obstructive pulmonary disease. Drugs 2003; 63:379.
  18. Freudenreich O, Nejad SH, Francis A, Fricchione GL. Psychosis, mania, and catatonia. In: Textbook of Psychosomatic Medicine: Psychiatric Care of the Medically Ill, Second Edition, Levenson JL (Ed), American Psychiatric Publishing, Washington, DC 2011. p.219.
  19. Rothschild AJ. Clinical Manual for Diagnosis and Treatment of Psychotic Depression, American Psychiatric Publishing, Inc., Washington, DC 2009.
  20. Work Group on Psychiatric Evaluation, American Psychiatric Association Steering Committee on Practice Guidlines. Psychiatric evaluation of adults. Second edition. American Psychiatric Association. Am J Psychiatry 2006; 163:3.
  21. American Psychiatric Association Practice Guideline for the Psychiatric Evaluation of Adults, Second Edition, 2006. http://www.psych.org/MainMenu/PsychiatricPractice/PracticeGuidelines_1.aspx (Accessed on July 18, 2011).
  22. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), American Psychiatric Association, Arlington 2013.
  23. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001; 16:606.
  24. Kroenke K, Spitzer RL, Williams JB. The Patient Health Questionnaire-2: validity of a two-item depression screener. Med Care 2003; 41:1284.
  25. Spitzer RL, Kroenke K, Williams JB, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med 2006; 166:1092.
  26. Steer RA, Ranieri WF, Beck AT, Clark DA. Further evidence for the validity of the Beck Anxiety Inventory with psychiatric outpatients. J Anxiety Disord 1993; 7:195.
  27. Muntingh AD, van der Feltz-Cornelis CM, van Marwijk HW, et al. Is the Beck Anxiety Inventory a good tool to assess the severity of anxiety? A primary care study in the Netherlands Study of Depression and Anxiety (NESDA). BMC Fam Pract 2011; 12:66.
  28. HAMILTON M. The assessment of anxiety states by rating. Br J Med Psychol 1959; 32:50.
  29. Shear MK, Brown C, Clark DB. Anxiety disorders measures. In: Handbook of Psychiatric Measures, Second Edition, Rush Jr AJ, First MB, Blacker D (Eds), American Psychiatric Publishing, Inc., Washington, DC 2008. p.529.
  30. Fava GA, Ruini C, Rafanelli C. Sequential treatment of mood and anxiety disorders. J Clin Psychiatry 2005; 66:1392.
  31. Trivedi MH, Thase ME, Fava M, et al. Adjunctive aripiprazole in major depressive disorder: analysis of efficacy and safety in patients with anxious and atypical features. J Clin Psychiatry 2008; 69:1928.
  32. Thase ME, Demyttenaere K, Earley WR, et al. Extended release quetiapine fumarate in major depressive disorder: analysis in patients with anxious depression. Depress Anxiety 2012; 29:574.
  33. Smith WT, Londborg PD, Glaudin V, Painter JR. Short-term augmentation of fluoxetine with clonazepam in the treatment of depression: a double-blind study. Am J Psychiatry 1998; 155:1339.
  34. Smith WT, Londborg PD, Glaudin V, et al. Is extended clonazepam cotherapy of fluoxetine effective for outpatients with major depression? J Affect Disord 2002; 70:251.
  35. Furukawa TA, Streiner DL, Young LT. Is antidepressant-benzodiazepine combination therapy clinically more useful? A meta-analytic study. J Affect Disord 2001; 65:173.
  36. Chang CM, Wu EC, Chen CY, et al. Psychotropic drugs and risk of motor vehicle accidents: a population-based case-control study. Br J Clin Pharmacol 2013; 75:1125.
  37. Dassanayake T, Michie P, Carter G, Jones A. Effects of benzodiazepines, antidepressants and opioids on driving: a systematic review and meta-analysis of epidemiological and experimental evidence. Drug Saf 2011; 34:125.
  38. Westra HA, Stewart SH, Conrad BE. Naturalistic manner of benzodiazepine use and cognitive behavioral therapy outcome in panic disorder with agoraphobia. J Anxiety Disord 2002; 16:233.
  39. Feet PO, Larsen S, Lillevold PE, Robak OH. Withdrawal reactions to diazepam in combined imipramine/diazepam treatment of primary nonagitated depressed outpatients. Acta Psychiatr Scand 1988; 78:341.
  40. van Marwijk H, Allick G, Wegman F, et al. Alprazolam for depression. Cochrane Database Syst Rev 2012; :CD007139.
  41. Fava M, Asnis GM, Shrivastava RK, et al. Improved insomnia symptoms and sleep-related next-day functioning in patients with comorbid major depressive disorder and insomnia following concomitant zolpidem extended-release 12.5 mg and escitalopram treatment: a randomized controlled trial. J Clin Psychiatry 2011; 72:914.
  42. FDA Drug Safety Communication: Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist). http://www.fda.gov/Drugs/DrugSafety/ucm334033.htm (Accessed on June 26, 2014).
  43. Fava M, Schaefer K, Huang H, et al. A post hoc analysis of the effect of nightly administration of eszopiclone and a selective serotonin reuptake inhibitor in patients with insomnia and anxious depression. J Clin Psychiatry 2011; 72:473.
  44. FDA Drug Safety Communication: FDA warns of next-day impairment with sleep aid Lunesta (eszopiclone) and lowers recommended dose. http://www.fda.gov/Drugs/DrugSafety/ucm397260.htm (Accessed on June 26, 2014).
  45. Dannlowski U, Baune BT, Böckermann I, et al. Adjunctive antidepressant treatment with quetiapine in agitated depression: positive effects on symptom reduction, psychopathology and remission rates. Hum Psychopharmacol 2008; 23:587.
  46. McIntyre RS, Weiller E, Zhang P, Weiss C. Brexpiprazole as adjunctive treatment of major depressive disorder with anxious distress: Results from a post-hoc analysis of two randomised controlled trials. J Affect Disord 2016; 201:116.
  47. Portella MJ, de Diego-Adeliño J, Ballesteros J, et al. Can we really accelerate and enhance the selective serotonin reuptake inhibitor antidepressant effect? A randomized clinical trial and a meta-analysis of pindolol in nonresistant depression. J Clin Psychiatry 2011; 72:962.
  48. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006; 354:1243.
  49. Sanacora G, Kendell SF, Levin Y, et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry 2007; 61:822.