CLINICAL INQUIRIES

From the Family Physicians Inquiries Network

How should we treat major depression combined with anxiety?

Valley Family Medicine Residency, Renton, Wash

University of Washington Health Sciences Libraries, Seattle

  Evidence summary

Antidepressants have similar positive effects

A systematic review of 28 randomized trials comparing various antidepressant medications found no significant differences in reduction of symptoms of depression and anxiety for patients who had both.² Patients in these trials met DSM (Diagnostic and Statistical Manual of Mental Health) criteria for major depression, with symptom severity as measured by a standardized scale, the Hamilton Rating Scale for Depression (HAM-D). They also had moderate to severe levels of anxiety symptoms as measured by standardized scales (Hamilton Rating Scale for Anxiety [HAM-A], Covi Anxiety Rating Scale, or the anxiety/somatization factors on the HAM-D).

Trials ranged from 6 to 24 weeks long, with outcomes including reductions in depression and anxiety symptom scores as measured by standardized scales. Study quality was variable; only 8 trials used a placebo control, and many were sponsored by pharmaceutical manufacturers.

Although some individual studies found differences in outcomes between medications, no significant differences in efficacy were seen in combined data from each comparison group. Medication was more efficacious than placebo in most studies that used a placebo control. Side-effect profiles were not described.

Patients with major depression and high anxiety levels relapsed more often than those with low anxiety levels with discontinuation of fluoxetine compared with placebo in a double-blind placebo-controlled parallel trial with 596 patients.³

Three trials evaluated antidepressant medication for patients who met diagnostic criteria for both major depression and generalized anxiety disorder. A manufacturer-sponsored RCT (N=90) found no differences in HAM-A or HAM-D score reduction among fluoxetine, venlafaxine, and placebo (except at 12 weeks, when venlafaxine significantly differed from placebo).⁴ Two open-label cohort trials (N=153) found that fluoxetine and fluvoxamine (Luvox, an older SSRI) reduced both depression and anxiety by about half.^5,6

Adding benzodiazepines is not a long-term solution

A Cochrane systematic review (10 RCTs, N=731) compared antidepressants alone vs combinations with benzodiazepines for patients with major depression and a 35% to 85% estimated prevalence of anxiety symptoms. Three studies used standardized scales to measure anxiety symptom severity.

Antidepressants in combination with benzodiazepines were more likely than antidepressants alone to reduce depression scores by 50% or more (for 50% depression improvement at 1 week, number needed to treat [NNT]=12; at 4 weeks, NNT=8). The combination group also had fewer dropouts (relative risk [RR]=0.63, 95% confidence interval [CI], 0.49–0. 81). The authors concluded that potential benefits of adding a benzodiazepine to an antidepressant must be balanced against possible harms, such as the development of dependence.⁷

Psychotherapy appears likely to help

A review of 13 controlled clinical trials⁸ evaluated standardized depression and anxiety score reductions for patients with generalized anxiety disorder receiving cognitive behavioral therapy compared with various control treatments (waiting list, pill placebo, or alternative therapy—such as supportive listening psychotherapy). Approximately half of the patients were also taking medication (not specified).

After an average of 10 sessions, cognitive behavioral therapy reduced anxiety and depression symptom scores more than control treatments (difference in effect size were 0.71 and 0.66, respectively). At 6- to 12-month follow-up, cognitive behavioral therapy gains were maintained (difference in effect size=0.30 for anxiety scores and 0.21 for depression scores). (An effect size of 0.2 is usually considered small, 0.5 moderate, and 0.8 is large.)

Another trial assigned primary care patients (N=464) with depression or mixed depression and anxiety to 1 of 2 psychological therapy groups (cognitive behavioral therapy or non-directive counseling for 12 sessions) vs usual general practitioner care. At 4 months, both psychological therapy groups had lower Beck Depression Index scores (by 4–5 points) than the usual general practitioner care group, but by 12 months there were no significant differences among all groups.⁹

Recommendations from others

The National Collaborating Centre for Mental Health guidelines state: “when depressive symptoms are accompanied by anxious symptoms, the first priority should usually be to treat the depression. Psychological treatment for depression often reduces anxiety, and many antidepressants also have sedative/anxiolytic effects.”¹⁰

The Brigham and Women’s Hospital guideline recommends adjunctive therapy with anxiolytics—such as lorazepam (Ativan) and clonazepam (Klonopin)—for some patients with depression and mild to moderate anxiety, to help control symptoms such as sleeplessness and restlessness.¹¹

References

1.   US Food and Drug Administration web site. Antidepressant use in children, adolescents and adults. Available at: www.fda.gov/cder/drug/antidepressants/default.htm. Accessed on March 7, 2007.
2. Panzer MJ. Are SSRIs really more effective for anxious depression? Ann Clin Psychiatry 2005;17:23–29.
3. Joliat MJ, Schmidt ME, Fava M, Zhang S, Michelson D, Trapp NJ, Miner CM. Long-term treatment outcomes of depression with associated anxiety: efficacy of continuation treatment with fluoxetine. J Clin Psychiatry 2004;65:373–378.
4. Silverstone PH, Salina E. Efficacy of venlafaxine extended release in patients with major depressive disorder and comorbid generalized anxiety disorder. J Clin Psychiatry 2001;62:523–529.
5. Sonawalla SB, Farabaugh A, Johnson MW, et al. Fluoxetine treatment of depressed patients with comorbid anxiety disorder. J Psychopharmacol 2002;16:215–219.
6. Sonawalla SB, Spillman MK, Kolsky AR, et al. Efficacy of fluvoxamine in the treatment of major depression with comorbid anxiety disorders. J Clin Psychiatry 1999;60:580–583.
7. Furukawa TA, Streiner DL, Young LT, Kinoshita Y. Antidepressants plus benzodiazepines for major depression. Cochrane Database Syst Rev 2001;(2):CD001026.
8. Borkovec TD, Ruscio AM. Psychotherapy for generalized anxiety disorder. J Clin Psychiatry 2001;62(suppl 11):37–42.
9. King M, Sibbald B, Ward E, et al. Randomised controlled trial of non-directive counseling, cognitive-behaviour therapy and usual general practitioner care in the management of depression as well as mixed anxiety and depression in primary care. Health Technol Assess 2000;4(19):1–83.
10. National Collaborating Centre for Mental Health. Depression: Management of Depression in Primary and Secondary Care. London, England: National Institute for Clinical Excellence (NICE); 2004. Available at: www.nice.org.uk/page.aspx?o=cg023. Accessed on March 21, 2007.
11. Brigham and Women’s Hospital. Depression: A Guide to Diagnosis and Treatment. Boston, Mass: Brigham and Women’s Hospital; 2001. Available at: www.brighamandwomens.org/medical/handbookarticles/depression/depression_frame.asp. Accessed on March 21, 2007.

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