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Re: How ADs work, another article from Medscape

Posted by amy_oz on September 25, 2002, at 19:35:24

In reply to How ADs work (article link), posted by Eddie Sylvano on September 25, 2002, at 16:17:06

Hi,
Thanks for that article. I have another one here from Medscapes weekly newsletter which goes out to Doctors (mainly in USA but anyone can access this). I am so thrilled that the knowledge in this article is finally getting out to primary health care providers, especially the knowledge that SSRI's aren't necessarily brilliant firstline treatment. Although it might be seen as bit of a marketing push for duloxetine.

Cheers,
Amy


A New Paradigm for Treating Depression in the Primary Care Setting
Introduction

Depression is a major medical illness with high morbidity, mortality, and economic impact. With time has come a better understanding of the neurophysiology and natural history of this disorder. However, despite newer and better-tolerated antidepressants, rates of depression and suicide in the general population are increasing, while the average age of onset for the initial episode of depression is decreasing. Re-evaluating the present treatment strategies and developing a new paradigm are therefore appropriate. Medical school education needs to better prepare students to recognize and treat this illness in the real world, and continuing medical education programs for physicians must review topics on depression to promote proper treatment and diagnosis. Early and aggressive intervention is a necessary component of the new paradigm in treating depression.

We now know that depression is a chronic and relapsing neurodegenerative disease with a worsening prognosis over time. Expanding a psychotherapeutic intervention in addition to pharmacotherapy may be another valuable means to improve disease outcomes. A tripartite model of depression has been introduced to explain the symptoms of depression and to therapeutically target these symptoms for optimal pharmacotherapy. This tripartite model hypothesizes that symptoms of depression can be related to diminished serotonin modulation, diminished norepinephrine/dopamine activation, or diminished serotonin and norepinephrine activity at neural synapses. Evidence suggests that, for many patients with depression, enhancing both serotonin modulation and catecholamine (norepinephrine/dopamine) activation is preferred with respect to increasing the probability of achieving complete symptom resolution (remission).[1-3] Improved outcomes may also be related to an enhanced reduction in the somatic anxiety and painful symptoms associated with depression through a synergistic activity between serotonin and norepinephrine.

Epidemiology and Demographics of Depression

Many review articles have been written discussing the high prevalence rates of major depression in primary care settings.[4] Approximately 19 million adults within the United States will experience a depressive disorder this year. One in 6 persons in the United States will at some point suffer from major depression.[5] More than half of the depressed patients never seek medical attention and suffer devastating outcomes with regard to suicide and quality-of-life issues. Of those who do enter the medical system, the majority flow through the primary care system, thus establishing primary care as the primary mental healthcare network.[6] The consensus is that 30% of patients seen in primary care have significant depressive symptoms, while approximately 10% of outpatients suffer from major depression according to Diagnostic and Statistical Manual of Mental Disorder, fourth edition (DSM-IV) criteria.[7] Although it is estimated that more than half of the depressed patients remain undiagnosed and untreated, outcome data in this regard are confusing and confounded by miscoding, which is often intentional, by primary care physicians. The basis for this lies in the fact that mental illness, including depression, is not a reimbursable diagnosis for full payment of office fees by Medicare and some HMOs. Also, many primary care physicians make a conscious effort not to stigmatize their patients with a diagnosis that could otherwise rate them on disability or life insurance or affect their employment.

Many other factors mitigate against timely and proper diagnosis of depression in primary care, including: (1) limited physician contact time, (2) somatic nature of most patients' visits, (3) comorbid medical illness with overlapping symptoms of depression (~50% of depressed patients), and (4) stigmatization and patient resistance of a diagnosis of mental illness.

Chronic medical illness and depression share a bidirectional relationship in that either one may cause or intensify the other. Therefore, the economic burden of depression is perhaps even heavier than we appreciate, given the fact that the outcomes of many chronic medical illnesses are worsened by comorbid depression. Depression was the fourth leading cause of major disability in 1990, and it is projected that, by 2020, it will be the second major cause of disability adjusted life years.[8] Of note, major depressive disease is already the number two cause of disability in females, who experience depressive episodes twice as often as men in the years between menarche and menopause. It is estimated that the economic burden, as well as the disability experienced by those with depression, will be second only to coronary artery disease by the year 2020.[9] This fact alone makes it imperative that we develop new treatment paradigms for depression in the next 10 to 20 years, and this underscores the need to review our present treatment approach and to re-evaluate accepted practice guidelines.

The odds for experiencing depression differ greatly across gender lines. Before puberty, the gender ratio for depression is one to one. Later, during reproductive years, this ratio changes dramatically, and women are found to be twice as likely as men to become depressed.[10] In addition, women are 6 times more likely than men to develop depression after physical illness or injury, and other data suggest that women are twice as likely to develop depression after myocardial infarction.[10] It should be noted, however, in either a man or a woman who is experiencing depression, both the frequency and severity of depressive episodes are equivalent for each gender. To date, treatment approaches for both genders have been essentially identical, with one notable exception: there seems to be some synergetic therapeutic effect between selective serotonin reuptake inhibitors (SSRIs) and estrogen replacement therapy for peri- and postmenopausal women as well as an independent beneficial effect of SSRI therapy in premenstrual dysphoric disorder. This would lead us to begin to re-evaluate some of our treatment approaches on a gender basis (eg, with respect to hormonal intervention).

The emerging field of antiaging medicine, with multifaceted hormonal and nutritional supplementation, may yield valuable insight into restoring and/or enhancing functional losses associated with aging. Age itself has not been thought to be a cause of depression; however, this may need further examination. As we age, neurotransmitter levels of serotonin, norepinephrine, dopamine, and acetylcholine decrease, while monoamine oxidase levels in the brain remain the same. Many other factors mitigate toward increasing stress with age as well, particularly loss of vision and independence, as well as bereavement and loss of occupation. It is hard to imagine that rates of depression are thought not to be higher in older patients, especially when other psychiatric disorders, such as general anxiety disorder, are more prevalent. Rovner[11] performed a retrospective analysis of patients who had been admitted to skilled nursing facilities and found that those with undiagnosed depression upon admission had a 59% greater rate of mortality in the first year, independent of other risk factors. Perhaps we need to re-evaluate our old beliefs that aging is not associated with increased rates of depression in the same way that we reassessed the relationship between obesity and depression. Recent data suggest higher rates of depression in obese patients who, for many years, were thought to be at no greater risk.[12]

Treatment Strategies

Recent evidence suggests that poorly treated and recurrent, persistent depression results in neurodegenerative changes, primarily in the hippocampus and prefrontal cortex. This is associated with elevations of cortisol and may be secondary to reduction in brain-derived neurotrophic factor (BDNF). BDNF acts to protect the brain cells from neurotoxins.[13-15] Thus, under stress, with persistent depression and reduced BDNF, brain cells atrophy and die at an accelerated rate. This may explain the natural course of untreated depression in which we see less stress over time resulting in depressive episodes. Similarly, it would explain more frequent, more severe, and more treatment-resistant depression occurring over time with shorter intervals between depressive episodes. This compelling evidence of neurodegenerative process makes early, aggressive treatment of depression to full symptom resolution (remission) imperative.

Before the advent of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors, psychotherapy was the mainstay of treatment for depression. It is widely accepted that psychotherapy is as effective in treating milder cases of depression as pharmacotherapy.[16] Additionally, Keller[17] has shown that combined psychotherapy and pharmacotherapy together have been shown to produce a more robust response, at least in the initial phase of treatment. The emergence of safe and well-tolerated pharmacotherapy has been associated with a de-emphasis on the training for, and the use of, psychotherapy as primary and/or adjunctive treatment for depression. Managed care obstacles and limited financial resources have further prevented many patients from taking advantage of psychotherapy. Poor motivation and cognitive difficulty associated with depression may also interfere with getting to a therapist and/or gaining value while participating in psychotherapy. For these reasons, the best outcomes have been associated with early and aggressive pharmacotherapy coupled with psychotherapy. At times, initiation of antidepressant therapy will be the motivating factor that brings a patient to psychotherapy and that enables him/her to make the cognitive and behavioral changes that are necessary.

Before the advent of SSRI antidepressants, monoamine oxidase inhibitors and tricyclic compounds such as amitriptyline were the mainstay of pharmacotherapy for depression. Primarily raising the levels of 3 principle neurotransmitters in the neuronal synapse (serotonin, norepinephrine, and dopamine), these compounds were effective when dosed in the proper ranges. However, they were (and still are) difficult to tolerate, frequently underdosed, and often fatal in overdose. Unfortunately, TCAs target so many receptor sites other than the 3 principal monoamines that their safety, tolerability, and effectiveness are limited by their adverse event and side effect profiles.

With the availability of fluoxetine in 1988, soon to be followed in the United States by 4 more SSRIs as well as 4 newer antidepressants with slightly different neurotransmitter profiles (or mechanisms of action), a new paradigm was established for the primary care treatment of depressed patients. Finally, 9 newer, well-tolerated antidepressants that were both patient and doctor friendly, with simple daily dosing regimens, became available (Table 1).

Table 1. Newer Antidepressants
Citalopram Bupropion
Fluoxetine Mirtazapine
Fluvoxamine Nefazodone
Paroxetine Trazodone
Sertraline Venlafaxine

In re-evaluating this paradigm shift, many patients who otherwise would not have been treated for their depression in the primary care setting were given pharmacotherapy. Recent safety data have resulted in the elimination of one of these newer agents, nefazodone, from first-line use due to the risk of hepatic failure. Outcome data evaluating response and remission rates for depression, however, suggest that SSRIs, with their monoamine (serotonin) activity, may not elicit complete symptom resolution (remission) in some depressed patients.[1]

It is estimated that approximately 10% to 15% of patients who begin antidepressant therapy with the newer antidepressants stop therapy within the first week. This may be related to adverse events as well as poor patient follow up. Of those who continue on treatment, the National Institute of Mental Health estimates that approximately 20% do not respond (less than a 50% improvement in depressive symptoms). Of those who do respond to treatment (at least a 50% improvement), the majority do not reach total symptom resolution (remission), which is the goal of treatment. Suboptimal responses and nonresponses are associated with continued risk of suicide, poor role functioning, and high rates of relapse and recurrence. Thus, although we treat many more people with drugs that are easily prescribed and well tolerated, many patients never get completely better and may have residual depressive symptoms, including anxiety, apathy, melancholy, and pain.

Depression: The Heterogeneous Disease

There are many emotional and physical symptoms associated with depression. Typical emotional symptoms are sadness and tearfulness, fear, loss of interest, anxiety/irritability, hopelessness, concentration difficulties, guilt, and suicidal ideation. Some of the physical symptoms associated with depression include tiredness/fatigue, sleep disturbances, headaches, psychomotor changes, gastrointestinal disturbances, appetite changes, and body aches and pains.[18]

Most patients with mental disorders will present themselves with fatigue, insomnia, pain, gastrointestinal symptoms, or other somatic symptoms rather than declaring, "I'm depressed" or "It must be my nerves."[19] A common problem arises where the patients are treated numerous times for their physical symptoms alone and their depression is subsequently overlooked and undiagnosed. It has been found that 69% to 80% of primary care patients with depression present with an exclusive complaint related to a physical symptom.[20] Women are, however, more likely than men to report a higher number of depressive physical symptoms (ie, 7 or 8).[10] In one study, pain was found to be the chief complaint among 30% to 60% of patients with physical symptoms.[21] Up to 43% of patients complaining of nonspecific musculoskeletal pain and 39% of patients with lower back pain are likely depressed.[22] Thus, beyond sleep disturbances and fatigue, physical symptoms, particularly pain complaints, are highly predictive of depression.

Jackson and colleagues[23] performed a study showing that having 5 or more physical symptoms is an independent predictor of major depression in outpatients, with an odds ratio of 4.0 in favor of depression. In support of this finding, Kroenke and colleagues[24] observed that the likelihood of depression increased with the number of physical complaints. DSM-IV recognizes "excessive worry over physical health, and complaints of pain (eg, headaches or joint, abdominal, or other pain)" as symptoms of depression. It is important that the clinician recognize that certain physical symptoms such as low energy, fatigue, and pain are commonly associated with depression. Frequency of office visits relating to somatic complaints may also be another key indicator of depression. One study evaluating the prevalence of high use in an HMO found that within the top 10% of healthcare users (who used 50% of the HMO proceeds), one half had a mood disorder, and two thirds of those had recurrent major depression. This group of chronically depressed, undiagnosed patients made 6 or more visits per year to their primary care physician for somatic complaints, and were usually treated with anxiolytics, hypnotics, and narcotics.[25] This did nothing for treating their primary illness (ie, depression) and put them at an increased risk for addiction. It is imperative, therefore, that physicians maintain a high index of suspicion for masked depression and inquire about the mood of the patients, especially in high users with multiple somatic complaints.

In comparison with patients who visit a psychiatrist's office and who are already aware and accepting of their mood disorder, patients in primary care are often resistant to accepting that their physical complaints may be driven or intensified by feelings and emotions. Many times, these patients will seek treatment for their physical symptoms and attribute them to another source rather than to depression. Thus, in primary care, naive patients who are depressed with a multitude of physical complaints are far less likely to accept a psychiatric diagnosis and even more unlikely to accept psychiatric consultation. One of the greatest challenges for a primary care physician is to refocus the somatically presenting depressed patient in such a way that he/she can appreciate the connection of physical symptoms with depression.

When patients experience nonspecific physical symptoms, the clinician should assess them carefully for the 9 target symptoms of major depression. Often, the use of a mnemonic, such as SADAFACES, may be of assistance in a well-focused and brief interview (Figure 1).


Figure 1. Target symptoms for depression.
Major depression would be diagnosed if the patient complained of at least 5 of the possible 9 target symptoms, including either bad mood or anhedonia, or both for at least 2 weeks. It is especially important to inquire as to whether the patients are experiencing difficulty sleeping, increased levels of stress or anxiety, and/or problems with experiencing pleasure, motivation, or satisfactory cognition, and whether they are experiencing any physical pain.

The Tripartite Model of Depression

The newest models of depression are described by Clark and Watson[26] as a tripartite system that divides depression into 3 clusters of symptoms: serotonin related, catecholamine related, and general distress related (Figure 2).


Figure 2. Tripartite model of depression.
Serotonergic (5HT)-related symptoms from poor modulation of anxiety and impulsivity would include tachycardia, diaphoresis, tachypnea, gastrointestinal upset, chest discomfort, etc. They would be most commonly seen in anxious depressed patients and anxiety disordered patients. Catecholaminergic (norepinephrine) symptoms from reduced activation would include poor concentration, low energy, low motivation, and apathy. General distress, including fatigue, tension, restlessness, worry, and hopelessness, could be related to either of these treatment arms. Most depressed patients fall into one of these categories: poor modulation of anxiety with relative serotonin deficiency, diminished activation relative to norepinephrine/dopamine deficiency, or a combination of both. Treating only one arm of this tripartite model will often not yield any results for a patient who is experiencing depressive symptoms related to the other arm. The symptoms of general distress can be treated from either end of the spectrum.

Many patients with depression suffer from a constellation of symptoms that relate to both decreased modulation from serotonin as well as diminished activation from norepinephrine/dopamine. One would presume that since many patients with depression have both serotonin and catecholamine deficiency states, medication(s) that enhance more than one monoamine neurotransmitter may produce the best results. There is evidence-based research to support this hypothesis. A trial was conducted that analyzed the remission rates between the SSRI citalopram[2] and the tricyclic serotonin and norepinephrine reuptake inhibitor (SNRI) clomipramine. Results indicated that clomipramine had a significantly higher remission rate over citalopram of 60% vs 30%, respectively. Subsequently, trials were conducted combining an SSRI (fluoxetine) with a norepinephrine reuptake inhibitor (desipramine) to further examine the dual action approach. The results of this combination trial of both an SSRI and a norepinephrine reuptake inhibitor substantiated the claim that improved remission rates were associated with dual action treatment.

Additional studies with venlafaxine have shown similar results. Thase and colleagues[1] have compiled data in a pooled analysis comparing SSRIs (paroxetine, fluoxetine, fluvoxamine; n = 748) vs the SNRI venlafaxine (n = 851) in randomized, double-blind, and placebo-controlled clinical trials. Results showed the SSRIs having a remission rate of 35% (n = 748) vs the placebo in one study, which had a rate of 25% (n = 446). The remission rate for the combined SNRI venlafaxine was 45% (n=851).

These data suggest that dual uptake inhibition may improve remission rates for many depressed patients. Treating only one arm of this tripartite model (eg, enhancing serotonin tone) will often not produce sufficient benefit for a patient who is experiencing diminished catecholamine (norepinephrine/dopamine) activity. In an atypically depressed patient who sleeps and eats too much, bupropion, which is a norepinephrine/dopamine reuptake inhibitor, would be the appropriate treatment. The same holds true for using catecholamine agonists (ie, bupropion) in a patient who has primarily an anxiety disorder and who needs enhanced serotonin tone (ie, SSRI, SNRI, selective estrogen receptor modulator). Patients exhibiting anxiety disorders, such as panic disorder, need increased modulation of anxiety and impulsivity with primarily serotonergic effect and would be excellent candidates for SSRI treatment. Additionally, symptoms of pain appear to be best treated with both serotonin and norepinephrine enhancement rather than with either neurotransmitter alone. Descending inhibitory pain pathways in the spinal cord, mediated by both serotonin and norepinephrine, may account for this response. This synergistic effect on pain may predict better outcomes in terms of full symptom resolution when dual reuptake inhibition (5HT, norepinephrine) is achieved. More comparative analysis between single acting and dual acting agents needs to be done to evaluate this hypothesis.

In order to achieve dual neurotransmitter effect, one may choose 2 complementary antidepressants with different monoamine activity or a single agent with dual activity. The one current downside to these findings is that there are very few drugs that have the ability to increase levels of both neurotransmitters. TCAs are fraught with side effects and toxicity, and are not considered first-line drugs for treating depressed patients. Venlafaxine inhibits the reuptake of both neurotransmitters; however, the inhibition for norepinephrine will only occur at higher doses.[27] Duloxetine may prove to be a more balanced and potent drug choice for the inhibition of both norepinephrine and serotonin.[28]

Currently, duloxetine is under review by the US Food and Drug Administration. Like venlafaxine, it is a dual reuptake inhibitor. The main advantage of duloxetine is its potency and ability to block the reuptake serotonin and norepinephrine at both starting and therapeutic doses.[27] A phase 2 depression study was completed that demonstrated that the duloxetine treatment arm shared similar response rates to the SSRI fluoxetine (64% to 53%, respectively); however, their remission rates differed significantly (56% to 30%, respectively), favoring duloxetine. Pooled clinical data for duloxetine 60 mg showed a remission rate of 31% for active drug vs 15% for placebo, for a relative benefit of 112%. This may, in fact, be related to the treatment of the full spectrum of depressive symptoms as well as enhanced relief of painful physical symptoms associated with depression.

Studies suggest that antidepressants that enhance norepinephrine and serotonin have the capability to act as analgesics. Nonspecific pain may be the result of reduced inhibition of descending nociceptive pathways. Increasing the levels of neurotransmitters (ie, serotonin and/or norepinephrine) can inhibit nociceptive pain via descending inhibitory pathways in the spinal cord. This results in both improved mood as well as attenuated pain perception. Lynch[29] performed 59 randomized, placebo-controlled trials examining the analgesic effect of antidepressants. He found that the TCAs -- which indirectly increase both serotonin and norepinephrine -- possessed significant analgesic properties, while the SSRIs -- which only increase serotonin directly -- did not. In addition, a review of pharmacologic treatments for neuropathic pain showed similar results, finding TCAs to be the most effective.[30]

Often, TCAs are used as first-line therapy for a variety of neuropathic pain syndromes. In fact, amitriptyline, nortriptyline, and desipramine have all been established as analgesics independent of their antidepressant effects.[31]

A main consideration for avoiding the use of TCAs is their adverse effect profiles. They have been associated with weight gain, constipation, urinary hesitation, blurred vision, sedation, tachycardia, orthostatic hypotension, and falls. Overdose of TCAs has also been correlated with an increased risk of arrhythmia and death. Many of these adverse events come as the result of the anticholinergic activity of TCAs.

The better, and many times safer, alternative for the treatment of both depression and pain is the use of dual reuptake inhibitors. The experimental drug milnacipran, a derivative of cyclopropane, inhibits both serotonin and norepinephrine at presynaptic sites. Clinical trials for this drug are limited, but the findings are promising. Meta-analysis by Puech and colleagues[32] showed that more milnacipran patients experienced symptom remission (38.7%) than did SSRI patients (27.6%). Milnacipran is currently being tested in the United States for the treatment of fibromyalgia, and it is approved for the treatment of depression in Japan.

Venlafaxine has been shown to possess analgesic effects at higher doses and has proven successful for the treatment of diabetic neuropathy. Venlafaxine is also found to be more effective than SSRIs with respect to remission[1] and overall patient work productivity.[33] Although venlafaxine has been shown to correlate with higher remission rates when compared with other antidepressants, its unbalanced effects on serotonin and norepinephrine require dose titration and higher doses to attain dual action (> 150 mg).

Duloxetine has been shown to be effective in the treatment of depression and associated painful physical conditions.[28] A multicenter, double-blind, parallel-group clinical trial was performed by Detke and colleagues[28] comparing duloxetine with placebo for relief from depression and pain in depressed patients (placebo, n = 122; duloxetine 60 mg once daily, n = 123). It was found that 62% of the duloxetine patients responded to treatment (compared with 29% of placebo patients). Remission rates were 44% for the duloxetine group, compared with only 16% for the placebo group. The same study also showed duloxetine to significantly reduce overall pain after 2 weeks of treatment. The study was conducted on patients who reflected the average depressed patient who had a mild level of pain (28 or 29 points on a 100 point Visual Analogue Scale). Back pain, in particular, was shown to significantly decrease after 1 week. It is possible that this increased benefit in improving painful physical complaints associated with depression independently contributes to duloxetine's high remission rates. Studies examining duloxetine vs SSRIs addressing their affects on the physical aspects of depression (eg, pain) need to be conducted in order to further test this theory.

Conclusion

As our knowledge of depressive disease continues to expand and the present practice paradigm gives way to newer treatment strategies, we must re-evaluate our approach to depression throughout the entire healthcare system. The gravity and impact of depression, which is felt psychologically, economically, and experienced globally by patients with comorbid medical illness, needs to be appreciated by medical educators and mirrored in the teaching curriculum in an ongoing fashion. More sophisticated analysis of the relationship between depression and gender differences, its impact on medical outcomes, and the most effective treatment strategies (both psychological as well as pharmacologic) are paramount in developing and implementing more effective treatment algorhythms. Evidence suggests that the majority of patients with depression do not avail themselves of treatment within our healthcare system.[6] Additionally, when treated, less than one third of patients reach full symptom resolution (remission), which is the goal of treatment. Unresolved symptoms of depression may be either psychological or physical. Attention needs to be given to the role of medications that affect more than one neurotransmitter, as evidence suggests an improved remission rate and improved analgesic effect with dual reuptake inhibition.[34] Ideally, other factors such as tolerability and cost (access) need to be included in any prospective analysis, as patients must remain on antidepressants for sufficient time to avoid relapse or recurrence of depression and achieve an optimal outcome.

References

Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001;178:234-241.
Danish University Antidepressant Group. Citalopram: clinical effect profile in comparison with clomipramine. A controlled multicenter study. Danish University Antidepressant Group. Psycopharmacology (Berl). 1986;90:131-138.
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;48:303-307.
Montano CB. Primary care issues related to the treatment of depression in elderly patients. J Clin Psychiatry. 1999;60(suppl 20):45-51.
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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;342:1462-1470.
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Bymaster FP, Dreshfield Ahmed LJ, Threlkeld PG, et al. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, hyman serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology. 2001;25:871-880.
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--------------------------------------------------------------------------------


Authors and Disclosures


Authors
C. Brendan Montano MD
Assistant Clinical Instructor, Department of Family Practice, University of Connecticut & Albany Medical College, Albany New York; Staff Physician, Middlesex Memorial Hospital, Department of Medicine, Middletown, Connecticut

Disclosure: C. Brendan Montano, MD, has disclosed that he has served as an advisor or consultant for Lilly, Takeda Abbott, Elan, Forest, Pfizer, GlaxoSmithKline, Pharmacia, Organon, Roche, Merck, and Wyeth. He has also disclosed that he will be discussing the following investigational products: milnacipran and duloxetine.

Michael B. Montano BS
University of Connecticut Graduate Program, Farmington, Connecticut

Disclosure: Michael B. Montano, BS, has no significant financial interests to disclose. He has disclosed that he will be discussing the following investigational products: milnacipran and duloxetine.



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