How should we treat major depression combined with anxiety?

Journal of Family Practice, April, 2007 by Bonnie Trotter, Gary Kelsberg, Leilani St. Anna

Evidence-based answer

One approach is to use antidepressants alone, which reduce symptoms for patients with major depression plus symptoms of anxiety or major depression plus generalized anxiety disorder. Selective serotonin reuptake inhibitors (SSRIs), tricyclics (TCAs), bupropion, mirtazapine, nefazodone, and venlafaxine are equally effective for combined symptom relief (strength of recommendation [SOR]: A, based on systematic review of randomized controlled trials [RCTs]).

Another approach is to add a benzodiazepine to the antidepressant. This reduces anxiety symptoms (more in the short term) and decreases patient dropout, but it also has possible harms, including development of dependence and accident proneness (SOR: A, based on systematic review of RCTs).

Psychotherapy, particularly cognitive behavioral therapy, produces and maintains reductions in symptoms of anxiety and depression that are comparable with the reductions seen with medication (SOR: A, based on systematic review of RCTs).

Clinical commentary

Talk to the patient about risks and benefits of drug therapy, and the need to closely monitor him in the first few weeks

Such discussions are essential, in light of the Food and Drug Administration's mandate that all classes of antidepressant carry a black box warning label about increased suicidality (suicidal thinking and behavior) among patients taking these medications. (1)

Benzodiazepine medications are effective in mitigating symptoms of anxiety but have additional risks such as altered cognition, tolerance, and abuse potential. In addition, benzodiazepine can be lethal in overdose with alcohol. Therefore, using a benzodiazepine alone for a patient who has both anxiety and depression is unwise. Even when used in combination with an antidepressant, benzodiazepine therapy should be brief.

Vincent Lo, MD

San Joaquin Family Medicine Residency, French

Camp, Calif

* 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 Trials (8) 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).