Psychotherapy and Nefazodone for Treatment of Chronic Depression


Synopsis: The combination of psychotherapy and an antidepressant was significantly more efficacious than either treatment alone.

Source: Keller MB, et al. N Engl J Med 2000;342:1462-1470.

Chronic depression accounts for an inordinate proportion of the enormous burden of illness associated with depression. At any one time, at least 3% of the U.S. population suffers from a chronic form of depression. The majority of these are women. Chronic forms of depression are associated with increased health care use and more frequent suicide attempts than acute depression. Professionally formulated treatment algorithms specify that the combination of psychotherapy and psychotropics is more efficacious than either psychotherapy or the use of antidepressants alone, but this is not what patients are generally offered. This recommendation is buttressed by a limited number of small clinical trials. The present study was undertaken to determine if the recommendation for combination therapy applied to those with chronic depression. A total of 681 adults participated, roughly 65% of whom were women. Most were married. The mean age of participants was approximately 43 years, with mean onset of illness at 26 years. At the time of randomization, subjects met a number of rigorous inclusion and exclusion criteria and were required to withdraw from other psychotropic medications. To receive the diagnosis of chronic depression, a given subject had to have a score on the Hamilton Rating Scale for Depression of at least 20. Only outpatients were included, and they had to have had a diagnosis of depression of at least two years’ duration. Subjects were randomized in a 1:1:1 ratio to receive nefazodone (Serzone), psychotherapy, or a combination of both. The intent of psychotherapy was to teach patients how their cognitive and behavioral patterns produce and perpetuate their interpersonal problems, so that they could learn to remedy maladaptive behavioral patterns. Responses were categorized as remission if the Hamilton Rating Score fell to at least 8, favorable if the score fell by 50% and was less than 15, and no response if the above response criteria were not fulfilled.

Although most participants had undergone treatment in the past, the results of the present interventions were encouraging. Of those who completed the trial, the rates of remission or favorable response were 55% for those who received only nefazodone, 52% for those who only received psychotherapy, and 85% for those who received both. Dropout rates were comparable in all arms, although those receiving nefazodone reported more symptoms such as headache, somnolence, and dry mouth.


This is a well-done study with interesting results. Since depression is so common in women, I thought it worthwhile to bring it to your attention. The patient with chronic depression is a challenge to all physicians. Because of the tendency to experience concomitant somatic and psychiatric symptoms, these patients, who are likely to be women, frequently seek the attention of obstetricians-gynecologists and family physicians. It can be difficult to determine which patients have symptoms that are at least partially attributable to physiological processes such as perimenopause and which have symptoms mostly reflecting chronic depression and, thus, need the care of a mental health specialist. For those not trained in psychiatry, there is a tendency to attribute symptoms to physiologic, somatic processes, but it is important to consider the diagnosis of chronic depression should therapies aimed at somatic complaints not ease the symptom complex. Nonetheless, recognizing chronic depression in a general practice is easier said than done. While many patients with chronic depression also have a co-existing personality (approximately 60%) or anxiety (approximately 33%) disorder, this pattern of presentation may serve more to confuse than clarify. In a better world, there would be more liberal access to trained specialists who can perform the appropriate diagnostic maneuvers and who have the clinical experience to confidently render a diagnosis. The main point of this report, however, is to alert us to the fact that these patients do much better if given combined psycho- and pharmaco therapy. It is commonplace to offer those with chronic depression an antidepressant and to then "let them go" without access to more than monitoring for side effects. As this study points out, this is better than nothing, but far from ideal. Patients with chronic depression need an opportunity to develop more adaptive coping patterns. It is this type of cognitive-behavioral intervention that most ob-gyns and family doctors are less adept at providing. One can only hope this study comes to the attention of those who make policy for health insurance providers as well as the physicians charged with helping these desperately unhappy people. As the study reveals, with proper therapy, there is hope for an improved quality of life. This is an important result that counters the usual clinical nihilism about the prospects for those so afflicted.

This study is also important because it highlights what I predict will be a sea change in the way we approach chronic illness. Gone are the days of monotherapy. Herald the dawn of polypharmacy. The difficult task confronting us now is to determine which combinations make the most sense. I suspect it will be a busy century.