Clinical Supplement

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Moderator: Donna E. Stewart, MD, FRCPC; Presenters: Marta Meana, PhD; Kathleen T. Brady, MD, PhD; Vivien K. Burt, MD, PhD; Section editor: David L. Ginsberg, MD

July 2004


Funding for this supplement was provided by Eli Lilly and Company.


Worldwide studies have demonstrated that women suffer from depression at approximately twice the rate of men globally and attempt suicide at 1.5 times the rate of men.

•  Unexplained physical and painful symptoms are becoming increasingly recognized as part of the depressive condition, particularly in women. Understanding the relationship between emotional and physical symptoms is important for treatment. 

Antidepressants with a combined norepinephrine and serotonin effect are generally well-tolerated and show efficacy in ameliorating both emotional and painful physical symptoms in depression.



It is estimated that depression will become the second most disabling condition worldwide by the year 2020. Overcoming some of the challenges of global epidemiology, studies worldwide have shown that women are affected by depression at twice the rate of men, with earlier age of onset and higher rates of hospitalization. Depression in young women can cause failure during critical life transitions, such as occupational advancement and child rearing, which has a cascading effect on the severity and chronic course of depression. This is compounded by the fact that speed of initial treatment contact is inversely related to age. Depression in both men and women is a treatable condition that may be ameliorated if detected and addressed at early onset. Physicians must be aware that while emotional symptoms are usually the focus of the diagnosis and treatment of depression, many depressed patients present only with physical symptoms. New evidence suggests a common neurochemical pathway for the physical symptoms in depression, which implicates both serotonin and norepinephrine dysregulation. Dual reuptake inhibitors may have advantages over selective serotonin reuptake inhibitors and tricyclic antidepressants in achieving a more robust response and complete remission of depression. 

Donna E. Stewart, MD—Moderator  

Prevalence of Somatic Symptoms in Depression

Physical and emotional symptoms are of equal importance in recognition and management of depression (Slide 1). In fact,   the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition1 criteria for its diagnosis includes physical features such as excessive worry over physical health or complaints of pain.


Patients who have psychosocial complaints are more likely to get accurately diagnosed with depression than those who present with somatic complaints. However, a large percentage of psychiatric patients complain of stomach pain, chest pain, fatigue, lack of energy, headaches, dizziness, weakness in various parts of the body, muscle aches and pains, and rheumatism. In an international study of >1,000 patients with depression, Simon and colleagues2 found that 69% reported only physical symptoms as the reason for their physician visit. Kirmayer and colleagues3 found that 76% of study patients diagnosed with depression or anxiety had made somatic presentations, which tended to obscure the diagnosis of depression (Slide 2).


In a large cross-national study4 of26,000 patients screened in 15 primary care centers across 14 countries, ~10% of a subset of ~5,000 who underwent clinical interview were found to have depression; 45% to 90% presented only with somatic symptoms, 50% had multiple unexplained symptoms, and 11% denied depression even when specifically asked about emotional symptoms. Somatic presentation was more common in patients who did not have an ongoing relationship with the physician. This indicates that walk-in patients, those who frequently change doctors, and those who seek care in after-hours clinics, have a very high prevalence of depression. In addition, fewer than half of all cases of depression were recognized, of which only a small percentage were appropriately treated. Beyond mood symptoms, the most commonly reported symptoms of depression across all countries were insomnia, weakness, loss of energy, and suicidal thoughts.

Physical Symptoms in Primary Care

Results of several studies indicate the need for physicians, especially primary care physicians (PCPs), to ask patients about both physical and psychological symptoms. Physical symptoms account for ~50% of all PCP visits. Such symptoms cause Americans to restrict their activities ~10 days per year and visit the physician 2–3 times per year. Most of the symptoms are never explained by any known disease or injury and are often subjected to extensive nonproductive investigations.5


Gureje and colleagues6 assessed >5,000 patients from 15 sites across 14 countries via interview and questionnaires. Approximately 22% of patients presenting to a PCP had persistent pain that lasted for >6 months, causing them to seek care or obtain disability payments. Those patients were much more likely to have an anxiety or depressive disorder.


Despite the connection between depression and physical pain, in many PCP clinics elaborate investigations are undertaken to track down sources of somatic complaints without making the appropriate psychosocial inquiries. When the physician attends to the physical symptoms alone the underlying diagnosis is usually missed. Furthermore, millions of dollars are spent determining causes of such elusive somatic symptoms which may in fact be “calling cards” for depression.

High Utilizers of Medical Care

Approximately 50% of high utilizers of medical care are psychologically distressed. Katon and colleagues7 administered psychiatric interviews to high utilizers of medical care and found a high prevalence of psychiatric disorder; 40% had major depression, 22% suffered from generalized anxiety disorder (GAD), 20% met strict criteria for somatization disorder; and a substantial number had panic disorder and/or alcohol abuse. Depression and GAD patients were the highest cost patients in medical systems across all countries. 


Patients who have many unexplained physical symptoms are likely to have a mood disorder.8 This likelihood increases with the number of physical complaints. Patients with one physical symptom have a ~2% chance of having depression, those with six to eight symptoms have a 44% chance of depression, and those with nine or more unexplained symptoms have a >60% likelihood of depression (Slide 3). Approximately one third of patients with depression will experience depressive physical symptoms for >5 years before they get adequately diagnosed.7 

Theoretical Concepts of Pain and Depression

The causal relationship between pain and depression remains unknown. Complaints of pain among patients with depression vary from 35% to >65%. Prevalence of depression among chronic pain patients varies from ~30% to almost 100%. Many patients with chronic pain become much less dysfunctional once the depression is treated.


In Canada’s National Population Health Survey,9 only ~3% of 700,000 people who reported no pain or discomfort suffered from depression. This percentage increased to 6% when people who complained of mild pain were included, and increased further to 12% among people who complained of moderate pain. Among those who complained of severe pain or discomfort, almost 14% had depression. This provides clear epidemiologic data for a high prevalence of depression among people who complain of pain and discomfort.


In the mid 1900s, one theoretical concept regarding the link between physical symptoms and depression was that psychological factors were invoked to imply hysteria, malingering, or variations on the concept of secondary gain. Today, this perspective is referred to as “blaming the victim.” In the 1990s there was an interest in symptom amplification, where it became clear that having depression or severe anxiety states markedly increased the perception and expression of pain.10


In the 21st century, it was determined that both 5-hydroxytryptamine and norepinephrine dysregulation can be implicated in the pathogenesis of depression and the perception of pain. Dysregulation of serotonin and norepinephrine in the brain is strongly associated with depression; however, the same imbalance also occurs in the spinal cord, which may amplify the pain signal. This may explain why physical symptoms are often the chief complaint in depressed patients.11

Barriers to Treatment of Depression

Tricyclic antidepressants and selective serotonin reuptake inhibitors are current common treatments for depression, but problems exist with each and a better option is needed (Slide 4). Because serotonin and norepinephrine pathways inhibit pain signals, dual serotonin norepinephrine reuptake inhibitors appear to be good treatments for patients with depression and physical symptoms.


One major concern in depression treatment is that not everybody gets a full response; ~30% to 45% of patients who receive treatment show partial response or no response. Approximately one third of treated patients achieve full remission. One of the reasons patients may not remit is due to inadequate diagnosis and treatment of physical symptoms and complaints. 


Denninger (unpublished data, 2003) looked at outpatients with high depression ratings on the 17-Item Hamilton Rating Scale for Depression, and found that reduction in somatic complaints highly correlates with degree of score improvement. Once a depressed patient’s somatic symptoms are under control, he or she is much more likely to obtain full remission. However, patients who continue to experience physical symptoms despite improvement in psychological symptoms, are much more likely to relapse.



1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, CD: American Psychiatric Association; 1994.


2. Simon GE, VonKorff M, Piccinelli M, Fullerton C, Ormel J. An international study of the relation between somatic symptoms and depression. N Engl J Med. 1999;341(18):1329-1335.


3. Kirmayer LJ, Robbins JM, Dworking M, Yaffe MJ. Somatization and the recognition of depression and anxiety in primary care. Am J Psychiatry. 1993;150(5):734-741.


4. Weissman MM, Bland RC, Canino GJ, et al. Cross-national epidemiology of major depression and bipolar disorder. JAMA. 1996;276(4):293-299.


5. Kroenke K, Mangelsdorff AD. Common symptoms in ambulatory care: incidence, evaluation, therapy, and outcome. Am J Med. 1989;86(3):262-266.


6. Gureje O, Simon GE, von Korff M. A cross-national study of the course of persistent pain in primary care. Pain. 2001;92(1-2):195-200.


7. Katon W, von Korff M, Lin E, et al. Distressed high utilizers of medical care. DSM-III diagnoses and treatment needs. Gen Hosp Psychiatry. 1990;12(6):355-362.


8. Kroenke K, Spitzer RL, Williams JB, et al. Physical symptoms in primary care. Predictors of psychiatric disorders and functional impairment. Arch Fam Med. 1994;3(9):774-779.


9. Lesse S. The masked depression syndrome—results of a seventeen-year clinical study. Am J Psychiatry. 1983;37(4):456-475.


10. Meana M. The meeting of pain and depression: comorbidity in women. Can J Psychiatry. 1998;43(9):893-899.


11. Blier P, Abbott FV. Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and pain. J Psychiatry Neurosci. 2001;26(1):37-43. 


Dr. Stewart is professor and chair of Women’s Health at the University of Toronto, and the incoming president of the International Association for Women’s Mental Health. 


Disclosure: Dr. Stewart is a consultant to Eli Lilly; is on the speaker’s bureaus of Eli Lilly and Wyeth; has received honorarium/expenses from Eli Lilly, Forest, and Wyeth, and has received grant/research support from Eli Lilly.


Marta Meana, PhD

Global Burden of Depression in Women

Major depression exists worldwide, with a higher prevalence in women than men. In 1998, the World Health Organization (WHO) instituted the International Consortium in Psychiatric Epidemiology (ICPE) to coordinate comparative analyses of data.1 Surveys conducted from 1990–1999 in 10 countries (Canada, the United States, Brazil, Chile, Mexico, the Czech Republic, Germany, the Netherlands, Turkey, Japan) showed a lifetime prevalence of depression in both men and women of 12.6% in Brazil, 8.3% in Canada, 9% in Chile, 7.8% in the Czech Republic, 11.5% in Germany, 3% in Japan, 8.1% in Mexico, 15.7% in the Netherlands, 6.3% in Turkey, and 16.9% in the US. Gender ratios for depression in 9 out of 10 countries ranged from 1.9 to 2.4 (Slide 5). Gender was the only sociodemographic variable that predicted depression with complete cross-national consistency.


There is evidence indicating that the gender difference in depression is not a result of self-report bias. First, the difference is found with informant reports and not just with self-reports.2 Second, methodological studies that have targeted the potential biases have found no evidence for it.3 Third, depressed women are much more likely than men to report less stigmatizing, physical symptoms of depression.4          

Human Toll and Economic Burden


Depression is the leading cause of disability among females >5 years of age worldwide.5 Depression impacts families by resulting in dysfunctional parenting and generating stressful life events through occupational failures, divorces, and social and interpersonal dysfunction.6 Depression-generated stressors, in turn, worsen the disorder by making its recurrence more likely and more severe. In many women, depression begins in the adolescent and early adult years, during critical life transitions involving education, career, marriage, accruing debt, and childbearing. A major misstep in any of these life transitions can have an adverse impact contributing to the frequency and severity of depressive episodes. 


The societal toll of depression is enormous, at an annual cost of $70 billion in the US alone.7 This figure is based on depression treatment cost, lost earnings due to suicide, and losses in workplace productivity. Not included in this figure are caregiver costs, treatment of comorbid conditions, divorce, and other costs that emanate directly from the dysfunction of the depressed individual. Depressed individuals also have two to three times the medical expenses of nondepressed individuals, excluding mental healthcare expenses; these costs are even higher in the depressed patient who has physical symptoms. More than 50% of the economic burden of depression is borne by employers in the form of lost workplace productivity.


In 2000, the rank order of major causes of disability worldwide (determined according to disability-adjusted life years) was lower respiratory infections, perinatal conditions, human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS), unipolar major depression, and diarrheal diseases. It is estimated that by the year 2020, depression will become the second major cause of disability preceded only by ischemic heart disease and followed by road traffic accidents, cerebrovascular disease, and chronic obstructive pulmonary disease.5 

Age of Onset/Course of Illness

Depression is a chronic episodic disorder, globally characterized by persistent recurrent episodes lasting <1 year. In the WHO ICPE survey, 75% of individuals endorsing at least one depressive episode in their lifetime also reported recurrences.1 The growing consensus is that the chronicity of the disorder is similar in both genders.


Anxiety is shown to be highly comorbid with depression worldwide. In the WHO ICPE survey, 33% of individuals who reported at least one lifetime episode of depression also reported having suffered at least one anxiety disorder.1 Anxiety and panic appear to precede major depressive episodes and may be considered risk factors for depression.


Major depression has an earlier age of onset than most other chronic conditions. In the WHO ICPE sample, the risk for depression was low in the early years, rose through adolescence and the mid-twenties, and decreased in the later years. The gender difference for anxiety and depression begins to appear at 11–14 years of age.8 In the National Comorbidity Study (NCS), 33% of women 15–24 years of age reported at least one episode of depression compared to 20% of men in that age group. The gender difference in the prevalence of depression was particularly striking among those 15–16 years of age.9

Gender Differences in Suicide

Suicide is the most disturbing correlate and consequence of depression. Global suicide rates for women ranged from 4–10 per 100,000 women between 1965 and 1998.10 A variation in rates between countries was evident, and has been attributed to economic and other sociocultural characteristics.


A Canadian study11 demonstrated that men kill themselves at approximately four to five times the rate of women, although women are hospitalized for attempted suicide at a rate of ~1.5 times that of men. Government databases revealed a female suicide rate of 5.8/100,000 and a male rate of 22.6/100,000 (Slide 6).11 Hospitalization rates for suicide attempts were higher among females, at 103.9/100,000 compared to the male rate of 69.2/100,000 (Slide 7).11 One explanation for the gender difference in completed suicide lies in the greater lethality of male attempts: men favor suffocation and firearms, while women opt for medications.

Barriers to Recognition and Treatment

According to the WHO ICPE surveys in Canada, the US, Germany, and the Netherlands, the speed of initial contact with a healthcare provider seems to be inversely related to age, ie, younger sufferers take longer to seek treatment.1 Only 50% of the depressed 15–24-year-olds in the NCS had told a professional, and a minority of those actually received treatment. This is particularly concerning because early onset indicates a more persistent and severe course and because the prevalence of depression is becoming higher in successively younger cohorts. In the US, the lifetime prevalence has experienced a five-fold increase over a period of 40 years.3 The increase appears primarily in secondary depression, which is less likely to be familial and more likely the result of depressogenic life experiences.


Research has revealed other major deficits in the recognition, long-term prevention, and management of depression. Depressed people often do not realize that they need treatment, they are in denial because of the discrimination associated with mental illness, or the disorder itself may instill a sense of hopelessness about the potential for the efficacy of any treatment. Those who do seek medical care are much more likely to consult a PCP than a psychiatrist. The PCP, however, is more likely to diagnose and treat the patient’s physical symptoms, such as insomnia, pain, or fatigue, than the underlying depression. Germany’s Depression 2000 study12 found that only 38% of the ~1,300 individuals in the study who had fulfilled research criteria for major depression had been correctly diagnosed by their PCP. The recognition rates were especially poor in individuals <40 years of age. 

Recommendations for Prevention

The paradigm shift to viewing depression as a preventable chronic disorder requires public health efforts against discrimination of individuals with depression. Aggressive outreach to target vulnerable groups, such as young women and early-onset cases, may be conducted through school screenings. In addition, clinicians must make complete remission the goal. Partial response, incomplete remission, and undetected or persistent comorbid conditions must be targeted.


Despite treatment, remission rates are not sufficiently high, warranting continued development of interventions. Moreover, research on pharmaceutical and psychotherapeutic interventions should be translated into clinical practice expeditiously. The development of dual serotonin norepinephrine agents will likely be useful in managing both psychiatric and physical symptoms of depression. Psychotherapeutic interventions, such as cognitive-behavioral therapy or interpersonal therapy, need to find a broader patient base with an increased recognition by insurers of their efficacy. Education for PCPs and mental health professionals, who are routinely undertreating depression, must include the recognition of diffuse pain with high functional interference as a likely marker of depression.


Finally, battling depressogenic conditions remains a lofty but worthwhile goal. More research is warranted to examine the environmental conditions that predispose to depression, particularly secondary depression, worldwide.       



1. Andrade L, Caraveo-Anduaga JJ, Berglund P, et al. The epidemiology of major depressive episodes: results from the International Consortium of Psychiatric Epidemiology (ICPE) Surveys. Int J Methods Psychiatr Res. 2003;12(1):3-21.


2. Kendler KS, David CG, Kessler RC. The familial aggregation of common psychiatric and substance use disorders in the National Comorbidity Survey: a family history study. Br J Psychiatry. 1997;170:541-548.


3. Kessler RC. Epidemiology of women and depression. J Affect Disord. 2003;74(1):5-13.


4. Kessler RC, McGonagle KA, Nelson CB, et al. Sex and depression in the National Comorbidity Survey. II: cohort effects. J Affect Disord. 1994;30(1):15-26.


5. World Health Organization. The World Health Report 2001: Mental Health: New Understanding, New Hope. Geneva, Switzerland: World Health Organization; 2001. 


6. Kessler RC, Walters EE, Forthofer MS. The social consequences of psychiatric disorders, III: probability of marital stability. Am J Psychiatry. 1998;155(8):1092-1096.


7. Greenberg PE, Leong SA, Birnbaum HG, Robinson RL. The economic burden of depression with painful symptoms. J Clin Psychiatry. 2003;64(suppl 7):17-23.


8. Angold A, Costello EJ, Worthman CW. Puberty and depression: the role of age, pubertal status, and pubertal timing. Psychol Med. 1998;28:51-61.


9. Kessler RC, Walters EE. Epidemiology of DSM-III-R major depression and minor depression among adolescents and young adults in the National Comorbidity Study. Depress Anxiety. 1998;7(1):3-14.


10. Levi F, La Vecchia C, Saracano B. Global suicide rates. Eur J Public Health. 2003;13(2):97-98.


11. Langlois S, Morrison P. Suicide deaths and suicide attempts. Health Rep. 2002;13(2):9-22.


12. Wittchen HU, Holsboer F, Jacobi F. Met and unmet needs in the management of depressive disorder in the community and primary care: the size and breadth of the problem. J Clin Psychiatry. 2001;62(Suppl 26):23-28.


Dr. Meana is associate professor and associate director of clinical training in the Department of Psychology at the University of Nevada in Las Vegas.


Disclosure: Dr. Meana has received honorarium and expenses from Eli Lilly.


Kathleen T. Brady, MD, PhD

Distinct Roles of Serotonin and Norepinephrine


Serotonin and norepinephrine have broad roles in terms of bodily processes. Both of these neurotransmitters are intimately involved in many cognitive and mood processes, as well as physiologic and physical symptoms. Serotonin and norepinephrine have some overlapping domains in terms of their impact on mood and cognition, but they also have some very distinct profiles. Serotonin is typically thought to be involved in impulsivity, aggression, appetite, and sex drive. In contrast, norepinephrine is thought to be involved in the modulation of vigilance, activity levels, motivation (Slide 8).1 Many symptoms are controlled and modulated by both of these systems, including symptoms associated with depression, such as anxiety, irritability, pain syndromes, cognitive function, mood, and other emotional states. 


One line of evidence indicating distinct profiles of norepinephrine and serotonin in terms of mood states come from studies that look at neurotransmitter depletion. These studies indicate that there is some independent symptom constellations controlled by the serotonergic noradrenergic systems. In patients who respond to selective serotonin reuptake inhibitors, depletion of serotonin causes a recurrence of depression, but the depletion of norepinephrine does not. Conversely, if a patient is very responsive to noradrenergic-acting drugs the depletion of norepinephrine will cause symptoms to return, while depletion of serotonin will not.2


In norepinephrine depletion studies, norepinephrine is rapidly depleted by blocking the rate-limiting enzyme tyrosine hydroxylase from producing norepinephrine. Serotonin depletion studies concentrate on preventing the rate-limiting element tryptophan from synthesis of serotonin, which can be done using a tryptophan-free diet. Studies employing these methods lend evidence to the distinction between noradrenergic and serotonergic function in terms of depleting depression. Depletion of norepinephrine and serotonin each causes different symptom reactions: norepinephrine depletion has a larger impact on reducing concentration, interest, and energy levels, while depletion of serotonin has a larger impact on anxiety symptoms (Slide 9).3 Both neurotransmitters appear to be relatively equal in terms of their mood impact—a testament to their distinguishable yet overlapping spectrums of activity.

Pain and Psychiatric Comorbidity


Serotonin and norepinephrine are important systems involved in pain perception. The pain signal is processed in the central nervous system and modulated through serotonergic and noradrenergic neural circuits. The pathways lead to the frontal cortex, hypothalamus, and the temporal lobe (Slide 10).


Pain coexists with many psychiatric conditions, including depression. Kroenke and colleagues4 reported that 59% of patients presented to PCPs with joint or limb pain; back pain, headache, chest pain, and abdominal pain had respectively lower but still very high percentages. Among these patients, 25% to 35% also had an anxiety disorder and 30% to 50% had a mood disorder (Slide 11).


These associations are important for women in particular because of gender differences in medical comorbidity, pain presentations, and depression. Depressed women have a greater frequency of presentation with chronic pain syndromes, such as migraines, chronic fatigue, fibromyalgia, and irritable bowel syndrome.


SNRIs: An Option for Depression and Pain


Serotonin and norepinephrine mediate a broad spectrum of both depressive and pain symptoms each in a distinct way, lending to overlapping yet distinguishable profiles. In understanding this relationship, it is a logical conclusion that dual-action agents may provide the broadest spectrum of therapeutic effect for emotional and physical symptoms of depression. 


Animal studies demonstrate that dual serotonin norepinephrine reuptake inhibitor (SNRI) antidepressants, such as venlafaxine and duloxetine, increase both serotonin and norepinephrine levels in the brain.5 Venlafaxine has been on the market for several years now and duloxetine should become available shortly.


Tricyclic antidepressants (TCAs) have demonstrated efficacy in treating chronic pain, particularly neuropathic pain. Amitriptyline, in particular, has been used by neurologists for many years to treat neuropathic pain.6 Despite their efficacy, the TCAs are limited by their side-effect profiles as well as toxicity and safety issues. Although SSRIs are effective treatments for depression, they do no have much impact on pain.7 This creates a potential role for SNRI agents which have the ability to modulate both pain and mood. They also have better side-effect profiles than the TCAs. 


Animal models involving formalin injected into the paws of rodents have shown good dose-dependent effects for SNRIs in decreasing pain response. The TCAs gabapentin and amitriptyline show similar positive results although they have limited utility because of their side-effect profile.8


A crossover study of dual-action antidepressants showed amitriptyline to be quite effective over the course of 2 weeks in decreasing diabetic neuropathic pain compared to placebo.6 Data for the SNRI venlafaxine is also quite compelling and similar.9 At lower doses, only the serotonergic system is likely targeted, but at higher doses venlafaxine produces a significant decrease in diabetic neuropathic pain. 


Finally, data looking at duloxetine show the same type of  dose-dependent decrease.10 Mean change in the 24-hour average pain scale over the first 2 weeks of treatment shows a fairly rapid effect, particularly at the high dose of 120 mg/day (Slide 12).

Treatment Implications


Both serotonin and norepinephrine are very important in the pathophysiology of depression. They are also both very involved in the modulation of the descending pain pathways, which are the determinants of pain perception. Antidepressants that have an effect on both serotonin and norepinephrine might be particularly efficacious and really more efficacious than single-acting agents in that they can provide relief of both the emotional and the physical symptoms and actually raise remission rates. Thus, these dual-acting agents may be particularly efficacious in the depressive subtypes and with the kinds of medical comorbidities commonly seen in women.



1. Blier P, Abbott FV. Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and pain. J Psychiatry Neurosci. 2001;26(1):37-43.


2. Delgado PL, Charney DS, Price LH, et al. Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry. 1990;47(5):411-418.


3. Delgado PL, Moreno FA. Noradrenaline dysfunction in depression. Presented at:?22nd Annual Congress of the Collegium Internationale Neuro-Psychopharmacologicum; July 9-13, 2000; Brussels, Belgium.


4. Kroenke K, Spitzer RL, Williams JB, et al. Physical symptoms in primary care. Predictors of psychiatric disorders and functional impairment. Arch Fam Med. 1994;3(9):774-779.


5. Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, et al. Comparitive affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology. 2001;25(6):871-880.


6. Lynch ME. Antidepressants as analgesics: a review of randomized controlled trials. J Psychiatry Neurosci. 2001;26(1):30-36.


7. Sindrup SH, Jensen TS. Antidepressants in the treatment of neuropathic pain. In:?Hansson PT, et al, eds. Neuropathic Pain: Pathophysiology and Treatment. Seattle, WA: IASP Press; 2001.

8. Eli Lilly and Company, data on file.

9. Kunz NR, Goli V, Entsuah AR, Rudolph RL. Diabetic neuropathic pain management with venlafaxine extended release. Eur Neuropsychopharmacol. 2000;10(suppl 3):S389.


10. Goldstein DJ, Lu Y, Iyengar S, et al. Duloxetine in the treatment of pain associated with diabetic neuropathy. Presented at: 156th Annual Meeting of the American Psychiatric Association; May 17-22, 2003; San Francisco, California.


Dr. Brady is a professor of psychiatry in the Department of Psychiatry and Behavioral Sciences at the Medical University of South Carolina in Charleston, South Carolina. 


Disclosure: Dr. Brady is a consultant to, on the speaker’s bureaus of, receives grant/research support from, and receives honorarium/expenses from Abbott, Bristol-Myers Squibb, Cephalon, Eli Lilly, and Pfizer.


Vivien K. Burt, MD, PhD

Remission Rates for Depression

With depression, obtaining even partial relief of symptoms requires a waiting period of at least 2 weeks. Full remission (Hamilton Rating Scale for Depression [HAM-D] score  7), if obtained, often takes 4–8 weeks, and up to 30% of patients with first-onset depression fail to achieve complete remission after 2 years.1 The implications of this are that patients with chronic depression suffer, causing impairment psychosocially, at home, and at work. They respond poorly to monotherapy and are among the highest utilizers of healthcare services. Patients who achieve partial remission have a 50% to 80% chance of relapse.2 

Gender Differences in Depression

It is important to consider gender differences in depression in order to screen high-risk populations. Depressed women are more likely to pinpoint a specific stressor that preceded their depression, while men are more likely to have new-onset depression with no apparent exogenous stressor. Depressed women are more likely to have a family history of psychiatric disorder, to have a comorbid anxiety disorder, or to have subsyndromal anxiety. Women are much more likely than men to have a seasonal component to their depression, to have atypical depression, including hypersomnia and hyperphagia, and are more likely to gain weight. Depression and physical discomfort in association with pain is more common in women. 


Women are more likely to be vulnerable to depression at times when they are hormonally challenged, such as during premenstrual days, postpartum, and perimenopausally. For some women, mood is negatively affected by exposure to oral contraceptives. Some women also experience depressive symptoms in association with discontinuation of hormone therapy.


Patients who are depressed present with a variety of symptoms in emotional, anxious, and physical domains. This is particularly true for women, who often present with multiple painful somatic symptoms or physical symptoms (eg, headaches and gastrointestinal disturbances), with an overlay of anxiety. Targeting physical symptoms and anxiety in addition to strictly depressive symptoms may make it possible to achieve remission rather than simply response.

Clinical Trials of Dual-Action Agents

Targeting serotonin and norepinephrine may result in a broader treatment of depressive symptoms and promote increased remission rates. A meta-analysis of 25 studies looking at efficacy of treatment with tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) revealed that the TCAs, particularly the dual-acting ones, are more efficacious than the SSRIs in the treatment of depression (Slide 13).


Nelson and colleagues3 compared the SSRI fluoxetine and the TCA desipramine combination treatment, to desipramine alone, as measured by HAM-D score reductions. As early as the first week of treatment, the combination of the more noradrenergic desipramine with fluoxetine was shown to be more efficacious than the SSRI alone. In addition, Thase and colleagues4 looked at eight different studies and the evidence suggested that clomipramine, a TCA with effects on both serotonin and norepinephrine, has a more rapid and effective result than the SSRI paroxetine. This study was replicated with another SSRI, citalopram, and the results were essentially the same. Remission rates for the selective norepinephrine reuptake inhibitor (SNRI) venlafaxine were significantly greater than the SSRIs. However, there was no advantage to venlafaxine over the SSRIs at 75 mg/day and only a modest advantage at 150 mg/day. The significant difference occurred at the much higher dose of at least 225 mg/day, which suggests that with an increase in dose above 150 mg/day the dual action of venlafaxine begins to contribute to the efficacy. 


Another pooled study by Thase and colleagues5 compared the efficacy and onset of action of SNRI antidepressants versus SSRI antidepressants. Once again, in each case the dual-acting agent was more efficacious than placebo and the SSRI, with statistical significance appearing at week 2 and becoming more significant over 8 weeks.  


In a study by Wheatley and colleagues,6 the dual-acting agent mirtazapine was more effective in treating depression than fluoxetine over a 6-week trial. In a study of elderly patients,7 mirtazapine was shown to reduce HAM-D17 scores significantly more than the SSRI paroxetine. There was no statistically significant difference between the dual-acting agents mirtazapine and venlafaxine in terms of remission.8


Duloxetine, a potent and balanced SNRI which is not yet approved by the Food and Drug Administration, has shown a significant improvement in HAM-D17 scores compared to placebo beginning at week 2 and continuing over a 9-week study.9 At a dose of 60 mg/day, duloxetine also showed improvement on the anxiety subscale of the HAM-D17 compared to placebo (Slide 14). In a study by Detke and colleagues,10 duloxetine was statistically superior to placebo in improving painful symptoms associated with depression as measured by a visual analogue scale.


When comparing placebo-controlled duloxetine studies to those of SSRI studies, 43% of duloxetine-treated patients achieved remission compared to 38% of SSRI-treated patients and 28% of placebo-treated patients. Among the more severely depressed patients, remission percentages were 38% for duloxetine versus 29% for SSRIs versus 18% for placebo, suggesting increased remission rates with dual-action agents (Slide 15).5

Balanced Strategies for Remission

There are a variety of ways to obtain dual action for depressed patients, such as using those TCAs that have dual action, venlafaxine at higher doses, mirtazapine, and perhaps duloxetine. TCAs are effective antidepressants, but they present problems such as cardiotoxicity, particularly in the setting of overdose, and need to be administered with great care to elderly patients or those with preexisting cardiac difficulties. Dose titration is needed to achieve a clinical effect and there are significant adverse events, such as anticholinergic effects and orthostatic hypotension, even at therapeutic doses.


With venlafaxine, the higher doses needed to achieve a dual-action effect may cause cardiovascular side effects, particularly hypertension. Mirtazapine is comparable to venlafaxine in terms of efficacy, but is associated with increased appetite and somnolence. The most prominent side effect for duloxetine seems to be nausea.


In addition to pharmacology, psychotherapy can increase efficacy of depression treatment. In a landmark study by Keller and colleagues,11 outpatients with chronic recurrent depression were given the antidepressant nefazodone in addition to a 12-week cognitive-behavioral analysis program. The combination was significantly more efficacious than either treatment alone.


In another study, Frank and colleagues12 evaluated the results of treating women with interpersonal therapy (IPT) followed by a combination of IPT and fluoxetine for the nonremitters. They compared this regimen to using IPT in combination with imipramine alone. They found that sequential therapy of IPT alone, followed by IPT and fluoxetine for the nonremitters, was more effective than IPT monotherapy or IPT/imipramine combination in terms of achieving remission. This suggests that combination psychotherapy and medication may enhance improvement compared to either treatment alone. Psychotherapy, both as monotherapy, and in conjunction with medication treatment for non-remitters, may be an attractive and efficacious option for women in the childbearing years. However, more randomized placebo-controlled, blinded, long-term studies are needed.


In conclusion, the unmet need of remission should be the goal for treatment of depression. It is important to recognize that women with depression tend to exhibit somatic and anxious symptoms more than men with depression. With treatment, clinicians should recognize that serotonin and norepinephrine are shared biochemical mediators in modulating depression, including the physical and anxious symptoms of depression. The new-generation dual-reuptake inhibitors appear to have advantages over selective agents in the treatment of depression. Balanced and potent dual-reuptake inhibition may offer further advantages with regard to increased efficacy with fewer side effects. Finally, the role of psychotherapy should not be neglected to further enhance response and achieve remission.



1. Keller MB, Klerman GL, Lavori PW, et al. Long-term outcome of episodes of major depression. Clinical and public health significance. JAMA. 1984;252(6):788-792.


2. Cornwall PL, Scott J. Partial remission in depressive disorders. Acta Psychiatr Scand. 1997;95(4):265-271.


3. Nelson JC, Mazure CM, Bowers MB Jr, Jatlow PI. A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Arch Gen Psychiatry. 1991;48(4):303-307.


4. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001;178:234-241.


5. Thase ME, Lu Y, Joilat M, Detke MJ. Remission in placebo-controlled trials of duloxetine with an SSRI comparator. Presented at: 156th Annual Meeting of the American Psychiatric Association; May 17-22, 2003; San Francisco, Calif.


6. Wheatley DP, van Moffaert M, Timmerman L, Kremer CM. Mirtazapine: efficacy and tolerability in comparison with fluoxetine in patients with moderate to severe major depressive disorder. J Clin Psychiatry. 1998;59(6):306-312.


7. Schatzberg AF, Kremer C, Rodrigues HE, Murphy GM Jr. Double-blind, randomized comparison of mirtazapine and paroxetine in elderly depressed patients. Am J Geriatr Psychiatry. 2002;10(5):541-550.


8. Guelfi JD, Ansseau M, Timmerman L, Korsgaard S, Mirtazapine-Venlafaxine Study Group. Mirtazapine versus venlafaxine in hospitalized severely depressed patients with melancholic features, J Clin Psychopharmacol. 2001;21(4):425-431.


9. Dunner DL, Goldstein DJ, Mallinckrodt C, et al. Duloxetine in treatment of anxiety symptoms associated with depression. Depress Anxiety. 2003;18(2):53-61.


10. Detke M, Lu Y, Goldstein DJ, et al. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry. 2002;63(4):308-315.


11. Keller MB, McCullough JP, Klein DN, et al. A comparison of nefazodone, the cognitive-behavioral analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med. 2000;342(20):1462-1470.


12. Frank E, Grochocinski VJ, Spanier C, et al. Interpersonal psychotherapy and antidepressant medication: evaluation of a sequential treatment strategy in women with recurrent major depression. J Clin Psychiatry. 2000;61(1):51-57.



Dr. Burt is professor of clinical psychiatry in the Department of Psychiatry and Biobehavioral Sciences at the David Geffen School of Medicine at UCLA in Los Angeles, California.  


Disclosure: Dr. Burt is a consultant to Eli Lilly, GlaxoSmithKline, and Wyeth; is on the speaker’s bureaus of AstraZeneca, Eli Lilly, GlaxoSmithKline, snf Pfizer; receives grant/research support from Eli Lilly; and receives honorarium/expenses from AstraZeneca, Eli Lilly, and GlaxoSmithKline.

Question & Answer Forum  

Q: What can be predicted about global burden of depression considering the lack of data from many countries? 


Dr. Meana: Seven of the countries I discussed are primarily Western in terms of their cultural influence. The parts of the world that we do not have data from are those which have less of a tradition of mental health research. However, the WHO should have data from these countries shortly. They have already found that Japan has a prevalence of depression much lower than the other countries, at 3%, yet it had the highest gender ratio, at 2.5. More of such unexpected patterns may emerge when we have more data across cultures.


Dr. Burt: Globally, depression is fifth in terms of burden of disease according to the WHO data. Ahead of depression are problems, such as lower respiratory tract infections, human immunodeficiency virus, diarrheal diseases, and perinatal diseases, which makes sense in a global study looking at the poorest of countries. Among US women, depression is second only to heart disease in terms of burden of disease. The WHO predicts that this will be the case globally by the year 2020. All of the diseases that we have ammunition for, such as diarrheal, cholera, perinatal diseases, are going to be eliminated.


Dr. Stewart: In terms of gender differences, the United Nations has predicted that although depression will be second for the general population by the year 2020, it is going to be first in women. The UN and the WHO have looked at the conceptualization of depression cross-culturally and have found that what North Americans view as depression may be quite different from what other countries understand as depression. It may manifest differently, have different terminology associated with it, and express itself differently. A better understanding of how different cultures express this phenomenon is needed. 


Q: What explains the placebo response of clinical trials, and what are the treatment implications of it?  


Dr. Burt: The placebo response is real and can be explained in a variety of ways, including simply the interaction with a professional. But one of the things that is not accounted for is that someone might meet criteria for depression today, and 2 weeks later things may change. Perhaps it has to do with environmental changes, eg, being arrested for drug abuse, which could trigger depressive feelings, or being awarded star student of the school, which may make one feel better. Yet, while the placebo response is real and a lot of answers lie with medications, clinicians should use all of the ammunition available, including psychotherapy.


Dr. Meana: What accounts for much of the placebo response is the installation of hope. Hopelessness is a key aspect of depression. The mere fact that the patient has made a decision to seek help, be it with placebo or medication, may be beneficial. 


Q: Patients in randomized trials are carefully followed up and are consistently asked about side effects. Does such attention improve treatment results?


Dr. Burt: On one hand, patients in clinical trials are highly encouraged by investigators to continue treatment until completion. On the other hand, patients who are not in a clinical trial have more available options, such as other medications, psychotherapy, and alternative treatments. In the Women’s Life Center, where we routinely ask our patients if they have ever received alternative treatment, we find that many patients spend a lot of money on acupuncture, massage, and yoga, but are hesitant to spend money on psychiatric services. These alternative treatments must be helping them feel better in some way. Thus, there are many modalities physicians should consider in order to help their patients.


Dr. Meana: Efficacy of different techniques are compared in psychotherapy trials as well. The literature points to the positive effect of nonspecific factors, such as attention, which involves someone caring about the patient enough to spend time talking to them about their life experiences and treatment options. 


Q: Considering the various healthcare systems available, why are the vast majority of patients not diagnosed and treated properly?


Dr. Stewart: Although some countries, such as Canada, have government-provided health services that are free to all citizens, that does not necessarily mean they are accessible. For example, it may take many months to get a psychiatric opinion, psychotherapy, or medication. There are long waiting lists for many of these treatments and patients may not be able to afford the costs of medication. The problem is not limited to access. Stigma may be involved as a barrier to treatment as well. People often do not come for treatment, because they are worried about the discriminatory effects this may have on their jobs, or perceptions of their colleagues, friends, and families.


Dr. Burt: People do not like to admit to themselves or others that they have a psychological problem, which is why they are loath to say they are depressed and need help. It is terrifying to admit something that is going to have a negative impact on one’s life even if they get better. This applies to physicians as well, who are generally not identifying, screening, or helping their suicidal colleagues. The American Medical Women’s Association has a keynote address on suicide and female physicians because 5 years ago the vice president of the organization killed herself. One should recognize that although women are more likely to attempt suicide while men are more likely to complete suicide, this does not apply to physicians. Female physicians are equally likely as male physicians to complete suicide. 

Q: Is there an advantage to treating depression with an SNRI over an SSRI plus a low-dose TCA?


Dr. Burt: I use SSRIs combined with a TCA in my practice all the time. However, theoretically one would prefer a single agent that does all of that without significant drug interactions, and can be used in the elderly as well as the young. We prefer monotherapy with agents that work really well with minimal side effects. But up until now, we have had to resort to such combination treatment to achieve optimal results.