Treatment of Depression: Antidepressant Monotherapy and Combination Therapy

| November 8, 2007 | 0 Comments

by Elisa F. Cascade; Amir H. Kalali, MD; and Pierre Blier, MD, PhD

Ms. Cascade is Vice President, Strategic Research and Safety, Quintiles Inc., Falls Church, Virginia; Dr. Kalali is Vice President, Global Therapeutic Group Leader CNS, Quintiles Inc., San Diego, California, and Professor of Psychiatry, University of California, San Diego; and Dr. Blier is a Professor of Psychiatry and Cellular and Molecular Medicine, University of Ottawa, Canada Research Chair, Psychopharmacology, Endowed Chair and Director, Mood Disorders Research Unit, Institute of Mental Health Research, Ottawa, Canada.


Dr. Blier has received research grants, has been on advisory boards, was given honoraria for speaking engagements, and has produced educational material for Biovail, Lundbeck, Organon, and Wyeth.


We investigated the use of antidepressants in the treatment of depression. According to our data, antidepressants are most commonly used alone (85%); however, the prevalence of antidepressant monotherapy decreases as the physician’s impression of patient severity increases (92% mild, 84% moderate, 73% severe). Psychiatrists are more likely to use antidepressant combinations than primary care physicians (32% vs. 8%). With respect to combination therapy, the most likely agent to be used in combination with an antidepressant in the treatment of depression was another antidepressant (6.4%); followed by anxiety agents (5.2%), antipsychotics (2.4%), and mood stabilizers and sleep aids (1.2% each). An expert commentary on the data is provided.

Key words

depression, monotherapy, combination therapy, augmentation, antidepressants


To better understand how antidepressants are used in the treatment of depression, we conducted an analysis to determine how frequently physicians prescribe antidepressant monotherapy and whether practice patterns vary by specialty and physician impression of patient severity. We also sought to identify what types of agents were used when combination therapy was prescribed.


We obtained data on product treatment regimen from Verispan’s Prescription Drug & Diagnosis Audit (PDDA) database from September, 2006, to August, 2007, for depression as defined by ICD-9 diagnosis code 311. PDDA captures data on disease state and associated therapy from 3,100 office-based physicians representing 29 specialties across the United States. We looked at treatment regimen by specialty and by patient severity. Severity was assigned based on the physician’s impression of the patient; no standard scale was used to standardize the severity assessment.


As seen in Figure 1, 85 percent of depressed patients taking antidepressants were treated with monotherapy. The proportion treated with antidepressant monotherapy does vary with the physician’s assessment of the severity of the depression: 92 percent for mild patients, 84 percent for moderate patients, and 73 percent for severe patients. The prevalence of antidepressant monotherapy also varies by physician specialty. Psychiatrists tend to use more combination treatment than primary care physicians (62% monotherapy vs. 92% monotherapy, respectively).

In Table 1, we present a summary of the most common antidepressant regimens used to treat depression. Outside of antidepressant monotherapy, the most approach is for physicians to prescribe combination therapy with another antidepressant (6.4%). While some antidepressant regimens included an SSRI/SNRI + Wellbutrin (buproprion) other prescribed therapies included an SSRI/SNRI + tricyclic. The second most popular addition to antidepressants (5.2%) in the treatment of depression was an anxiety agent, such as a benzodiazepine or buspirone. Only 2.4 percent of regimens included an atypical antipsychotic. The only other two therapies with greater than one percent combination use with antidepressants were mood stabilizers (i.e., anti-epileptics, lithium) and sleep agents, each with 1.2 percent prevalence.

Expert Commentary

The figures of 92 percent of primary care physicians and 68 percent of psychiatrists using monotherapy to treat depression are troublesome as they appear low. The clinical reality is that only about a third of depressed patients achieve remission after an antidepressant medication trial given at an adequate dose for a sufficient time. The STAR*D results recently confirmed this figure in “real life” conditions in Level 1 treatment (a selective serotonin reuptake inhibitor given for up to 12 weeks).[1] Sequential switches may eventually lead to remission, but each step requires at least 6 to 8 weeks. A complicating factor is that about 50 percent of the patients stop their medication in the first three months of treatment and 70 percent in the first 9 months. Most patients are therefore treated for an insufficient time. With such poor success and adherence rates, it is not surprising that the global burden of major depression keeps increasing, currently being only second to cardiovascular diseases in industrialized countries.

Several studies have shown that the augmentation strategy is an effective approach. Although Level 2 in STAR*D showed a 10-percent higher remission rate with the augmentation over the switch approach, the added medication (bupropion or buspirone) was allocated by randomization.[2,3] In regular clinical practice, the additional medication is generally tailored to the profile of patients. For instance, a patient with poor concentration, low energy, and hypersomnia would, hopefully, be more likely to receive the stimulating antidepressant bupropion than the sedative agent mirtazapine. The latter would preferentially be given to patients with marked insomnia. Although such individualized choices may not be more efficacious, they certainly do promote adherence, which will necessarily improve effectiveness in the end.

In other fields of medicine, prescribing a single agent for an illness, like asthma or septicemia, would be considered inadequate. Moreover, in these two examples, two drugs are used concomitantly from treatment initiation. The latter approach to treat depression is currently under investigation at Columbia University in New York city and at the University of Ottawa; it is sponsored by the National Institute of Mental Health. This prevailing stigma against psychiatric disorders can be exemplified by the following: The use of more than one drug to treat depression is often tagged as a “drug cocktail” by the media, whereas the use of three drugs to treat HIV receives the noble denomination of a tri-therapy. Depression also kills, not only by suicide but also by worsening most other comorbid medical illnesses.[4] When treating depression judiciously with more than one medication to achieve and sustain remission, physicians should consider that they are using rational site-directed pharmacotherapy, not dirty polypharmacy.

1. Trivedi MH, Rush AJ, Wisniewski SR et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice. Am J Psychiatry 2006;163:28–40.
2. Rush AJ, Trivedi MH, Wisniewski SR et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Eng J Med 2006;354:1231–42.
3. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRs for depression. N Eng J Med 2006;354:1243–52.
4. Evans DL, Charney DS. Mood disorders and medical illness: A major public health problem. Biol Psychiat 2003;54:177–80.

Category: Mood Disorders, Past Articles, Psychiatry, Trend Watch

Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.