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New Frontiers in the Treatment of Depression

Posted by jrbecker on October 8, 2003, at 11:42:38

http://www.medscape.com/viewprogram/2689_pnt

New Frontiers in the Treatment of Depression

Introduction

The recent National Comorbidity Survey concludes that major depression is widely distributed in the population and associated with significant symptom severity and impairment in work and daily activities.[1] Depression is the fourth leading cause of disability in the United States; it is imperative that physicians prioritize the recognition and aggressive treatment of this costly and debilitating illness. It is projected that depression will become the second leading cause of disability by 2020 (Figure 1).


Figure 1. Depression: impact on society.
Rates of depression in the United States remain at approximately 16.2 lifetime prevalence and 6.6 1-year prevalence.[1] Suicide is the 11th leading cause of death in the United States, resulting in more deaths annually than HIV disease.[2] Recognition rates for depression in primary care have improved over the last 2 decades, since the introduction of the SSRIs, but it is still estimated that only about 50% of those presenting with depression to primary care providers are appropriately diagnosed.[3]

This, however, is probably an underestimate since the reporting of depression is often omitted or the office visit coded as a primary medical problem. Stigmatization for depression and failure to be properly reimbursed for patient visits when using diagnostic codes associated with mental illness result in many doctors intentionally not coding for depression.[4] Nevertheless, many factors do obstruct primary care physicians from adequately diagnosing and treating depression. Some of these include: a time pressured environment, comorbid medical illness, symptom overlap with other disorders, and a tendency to focus on comorbid anxiety without treating the entire depressive spectrum.[5] Additionally, it is estimated that of the 57% of patients with depression who are receiving treatment for such in the primary care setting, only 1 in 5 (20%) is adequately treated.[1] This estimate is also subject to some controversy as the definition of adequate treatment varies among healthcare providers. In the recent National Comorbidity Survey, adequate treatment was defined as staying on medication or seeing one's psychotherapist over a 30-day period.[1] Most physicians in primary care psychiatry feel strongly that adequate treatment should be defined as reaching full remission of the depressive symptoms and continuing treatment following remission of the first episode of depression for an adequate length of time, which has been estimated to be 9 months.[6] For those individuals with 3 or more episodes of depression, maintenance therapy may indeed be life-long.

More than a decade with continuous remission of the symptoms has been the standard goal in the treatment of depression. Symptoms of depression, however, until recently, were thought to consist primarily of the emotional components of a depressed psyche. As the treatment paradigm of depression expands, adequate relief from physical symptoms associated with depression may share equal importance in achieving remission.[6] It is now generally well understood that enhancing more than one monoamine neurotransmitter is associated with more rapid and more robust treatment responses for both emotional and physical symptoms associated with mood disorders, resulting in higher remission rates.[7] Once the full spectrum of depressive symptoms, both physical and emotional, is adequately treated, patients are then enabled to function at full capacity both in their personal lives as well as professionally.

Initial Presentation

Most depressed patients enter the medical system through the primary care setting.[5] Many are unaware of their diagnosis and may at first resist the notion that their somatic complaints are in fact associated with depression. An international study by Simon and colleagues[8] of the 1146 patients with major depression from the World Health Organization (WHO) collaborative study of psychological problems in general healthcare found that the overall prevalence of depressed patients presenting to the physician with only somatic symptoms was 69%. Frequently, pain is the exclusive complaint of a depressed patient presenting in the primary care system. Gerber and colleagues[9] studied the physical complaints of 1042 patients who presented in 4 primary care offices. Each patient completed a 49-item self-report screening inventory identifying how often a variety of symptoms have been present in the preceding week. The researchers found that 43% of patients presenting with nonspecific musculoskeletal complaints and 39% presenting with back pain had a positive predictive value for depression. Sleep disturbance and fatigue were noted in more than half of the respondents, and approximately one half of the depressed patients presented with multiple unexplained symptoms (Figure 2).


Figure 2. Painful physical symptoms as potential markers for depression.
Another study, by Ohayon and Schatzberg,[10] assessing the prevalence of chronic painful symptoms and major depressive disorder reported that 43% of patients with major depressive disorder had at least one chronic painful condition, which was 4 times more common than those patients without major depressive disorder. Headaches, backaches, and limb pain were the most frequently reported physical complaints in the depressed population. The presence of chronic painful conditions often leads to a missed diagnosis of depression; physicians should routinely evaluate these patients for depression.

Kirmayer and colleagues[11] evaluated the clinical presentations of 685 patients presenting at 2 family medicine clinics and correlated the presentation with the recognition of major depression or anxiety disorder. In patients who presented with psychosocial complaints, 77% were accurately recognized as having a mood disorder. Conversely, in patients who presented primarily with somatic symptoms but screened positively for depression, only 22% were identified as such by the primary-care physicians. It is noteworthy that even patients who presented with frank clinical depressive symptoms were not universally recognized (Figure 3).


Figure 3. Depression is often missed when the presentation is physical.
Kroenke and colleagues[12] examined the prevalence of physical symptoms reported by primary care patients and their relationship to mood disorders, primarily depression as determined by the Primary Care Evaluation of Mental Disorders procedure. A total of 1000 patients from 4 primary care clinics were recruited to complete a questionnaire that identified the prevalence of 15 common physical symptoms and found that patients with mood disorders presented with anywhere from 0 to more than 9 physical symptoms. As the number of physical symptoms increased, the predictive value of depression also increased: of the 225 patients presenting with 2 to 3 physical symptoms, only 12% had depression, whereas 44% of the 230 patients with 6 to 8 physical symptoms had depression (Figure 4). This observation may help to explain the high levels of overutilization of health resources seen in patients with mood disorders.


Figure 4. Relationship between physical symptoms and depression.
Pearson and colleagues[13] investigated the prevalence of unrecognized or unsuccessfully treated depression among high utilizers of medical care within 3 HMOs located in different geographic regions of the United States. A total of 12,773 members were identified as high utilizers and 10,461 patients met eligibility criteria for depression using the Structured Clinical Interview for DSM-IV. In 7203 patients, 20% screened positive for current major depression or depression in partial remission. Of this 20%, a significant number (42%) had previously been recognized as having mental health problems. Despite this, a large percentage of high utilizers still suffered from active depression that either went unrecognized or had not been successfully treated. The prevalence of well-defined medical conditions was equal in both patients with and without evidence of depression.

A similar survey of the Group Health Cooperative of Puget Sound by Katon and colleagues[14] found that of the top 10% of utilizers who used 50% of the financial resources of the HMO, one half had a mood disorder and two thirds of this group suffered from recurrent major depressive illness. This latter group made more than 6 visits per year to primary care physicians, usually for somatic complaints, and were treated for somatic symptoms rather than for the depression. Especially noteworthy was the excessive use of hypnotics, anxiolytics, and narcotics. In addition, unnecessary consultations and hospitalizations were also frequently noted.

The Relationship Between Physical Symptoms and Depression

The interrelationship between physical symptoms, including pain, and depression may be explained by a common neurochemical link.[15-17] Abnormalities in the regulation of serotonin and norepinephrine in the brain are strongly associated with depression. In addition, approximately 25% of neurons exit the brain and descend into the spinal cord where serotonin and norepinephrine are key modulators for pain sensitivity via the descending inhibitory pathway and, as such, are part of the body's endogenous analgesic system. Neurochemical dysregulation in this system as well as in the brain may explain why depressed patients often experience physical symptoms, such as pain, as their chief complaint. Serotonin and norepinephrine also modify the effects of substance P, glutamate, GABA, and other pain mediators. Additionally, the central nervous system, via neurotransmitters including serotonin and norepinephrine, controls numerous bodily functions such as gastrointestinal motility, vasoconstriction, urethral sphincter contraction, bladder wall relaxation, and pilomotor contraction (Figure 5).


Figure 5. Serotonin and norepinephrine are key in many brain and body processes.
This shared neurochemical link between depression and physical symptoms has a common denominator via dysregulation of serotonin and norepinephrine.[18,19] The diagnostic challenge for physicians is to explain to their patients, who may not volunteer emotional symptoms or mistakenly attribute the source of their distress and physical complaints, that depression is the common final pathway. Successful treatment depends on changing the patient's agenda from physical complaints to depression and anxiety. The pathophysiology of pain and depression helps us to accomplish this. Aggressive and early intervention in the treatment of depression that otherwise may go unnoticed will hopefully result in fewer unnecessary and costly evaluations and hospitalizations while patients continue to suffer. If, after early and adequate treatment, the patient's symptoms persist, then the physician must continue, at their discretion, to evaluate comorbid medical conditions. It is not uncommon for depression to coexist with comorbid medical illness and to worsen both quality of life and the overall prognosis from the comorbid condition.[20-22]

Remission as a Goal

The goal of the treatment of depression is remission. Remission is defined as full functional and psychological recovery and restoration to the nondepressed state. However, it is estimated that approximately only 1 out of 3 treated patients reach full remission and that another 30% to 45% respond partially, which is defined as a 50% improvement in depressive symptoms. The remainder, approximately one third, do not respond.[23] Given the relationship between depression and somatic symptoms, it becomes important that we expand upon the definition of inadequately treated depression to include residual physical symptoms of depression. Hence, patients with lingering physical symptoms who do not achieve remission may often present again with those symptoms. This is particularly important in the primary care setting where the advent of the newer antidepressants, and in particular SSRIs, has led to primary care physicians treating many more patients with depression than in times past.

Paykel and colleagues[24] evaluated patients with major depression every 3 months to remission and thereafter. Residual symptoms reaching 8 or more on the 17-item Hamilton Depression Scale were present in 32% of patients (19/60) who remitted by 15 months. In patients with more severe initial illness, residual physical symptoms were more common, but these residual symptoms were not related to any other factors, including longer prior illness, dysthymia, or lower dose of drug treatment during the period of depression. These residual physical symptoms were very strong predictors of subsequent early relapse, which occurred in 76% of patients within 10 months but only in 25% of patients without residual symptoms. The importance of such information should not be underestimated, and this finding occurred in spite of the Hamilton Depression Scale being heavily weighted for psychological symptoms (66%) vs physical symptoms (34%).

Consequences of Inadequately Treated Depression

Inadequate treatment of depression has been associated with increased mortality and morbidity. In addition, depressive symptoms such as loss of interest or pleasure, insomnia, psychic anxiety, panic attacks, diminished concentration, and alcohol abuse have all been identified as short-term predictors of suicide within 1 year.[25] There is also a connection between stress and depression. The influence of stress on neurotransmitters has been associated with a shift in the hypothalamic-pituitary-adrenal axis, increasing circulating levels of catecholamine and cortisol.[26-28] These increased levels of glucocorticoids have been associated with hippocampal atrophy, which is associated with depression.

Neurodegenerative changes such as hippocampal atrophy are thought to be related to a reduction in the expression of genes that are important in the production of brain-derived neurotrophic factor (BDNF), which is critical to the survival and function of neurons. Thus, inadequately treated depression and associated stress may result in neurodegenerative changes, possibly irreversible, in the central nervous system. This may help to explain the natural history of depression as a chronic and recurrent illness with shorter time intervals between episodes and a worsening prognosis over time. It has also been shown that adequate antidepressant treatment increases cAMP, resulting in increased BDNF, which is hypothesized to induce neuronal regeneration.[29] This provides a compelling argument for treating depression early in its course and aggressively to complete symptom resolution of both the physical and emotional symptoms. In summary, in addition to neurodegenerative changes in the brain, the potential consequences for failing to achieve remission in depression include greater risk of relapse, sustained elevation of suicide and substance abuse risks, worsening prognosis of Axis III disorders, increased utilization of medical services, and continued psychosocial and working impairment (Figure 6).


Figure 6. Summary: potential consequences of failing to achieve complete symptom resolution.


Treatment Considerations

The spectrum of depressive symptoms is differentially affected by enhancing one or more monoamine neurotransmitters.[7,30] Demodulated depression is associated with high anxiety states often seen in patients with anxiety disorders. Obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, social anxiety disorder, and posttraumatic stress disorder are usually responsive to serotonin enhancement. On the other hand, deactivated depression characterized by fatigue and low energy, low motivation, reduced interest in pleasure, and poor concentration seems to be best improved with catecholamines such as norepinephrine and dopamine. Thus, the type of depressive symptoms can predict the probable response to drugs that enhance or downregulate monoamine neurotransmitters, as well as vulnerability to the drug's side effects during treatment. Therefore, it is important for the clinician to consider targeting the symptoms of depression in a way that can achieve the best results. Many patients will best be served by covering the broad range of depressive symptoms with a broader antidepressant therapy that enhances more then one neurotransmitter -- these drugs are often referred to as dual agents. There is strong evidence suggesting that dual acting antidepressants that incorporate both serotonin and norepinephrine reuptake inhibition might have a broader spectrum of action and have higher rates of remission in depressed patients than do those that affect only one neurotransmitter such as the selective serotonin reuptake inhibitors.[31-33]

Single Vs Dual Action Antidepressants

The Danish studies[31,32] showed clear superiority with respect to remission rates for clomipramine, a tricyclic agent that enhances both serotonin and norepinephrine, when compared with patients treated with the SSRIs paroxetine or citalopram. Craig Nelson's[33] work evaluating the combination of fluoxetine and imipramine vs fluoxetine alone showed similar superiority for serotonin plus norepinephrine activity compared with serotonin activity alone. Pooled analysis of venlafaxine in 2 large surveys comparing SSRIs and venlafaxine showed significantly greater remission rates for the dual reuptake agent venlafaxine.[34] High rates of remission, 3 times that of placebo (44% vs 16%), are also seen with duloxetine, a balanced serotonin norepinephrine reuptake inhibitor that is awaiting final approval by the US Food and Drug Administration.[35]

Beyond Depression

Especially noteworthy with these dual agents is their ability to significantly improve painful symptoms in depressed patients independent of the antidepressant effects, and this may significantly enhance their ability to treat the full spectrum of depressive symptoms, both physical and psychological. Bair and colleagues[36] have recently published a study illustrating the differential depressive symptoms affected by SSRIs and found that compared with many of the core depressive symptoms, physical symptoms have the lowest level of improvement. By comparison, both in preclinical rat models and clinical studies, dual agents such as amitriptyline, venlafaxine, and duloxetine have shown efficacy in treating pain. Tricyclics such as amitriptyline have been used for years for such discomforts as painful peripheral neuropathy and fibromyalgia. However, the toxicity and side effect profiles of this class of medications make it less desirable for treating depressed patients with painful physical complaints.[37] Recent case studies suggest some efficacy from the use of venlafaxine to treat diabetic peripheral neuropathy.[38,39] This may be explained by the differential norepinephrine response seen with venlafaxine, which increases with higher dosages. Nevertheless, this becomes a very important strategy in the treatment of painful physical complaints. Duloxetine has published data from registration trials at 60 mg showing significant improvement in patients' visual analogue scales for pain of approximately 30% in overall pain as early as week two.[40] This would include headache, backache, and shoulder pain, and the analgesic effect was found to be independent of the antidepressant effect.

Conclusion

In summary, in treating depression in the 21st century, practitioners must strive for complete symptom resolution or remission. This would include not only resolving psychological pain but also physical pain as much as possible. Serotonin and norepinephrine are shared biochemical mediators in modulating both depression and pain, but the degree of physical symptom improvement may be enhanced by either using combination antidepressant therapy affecting more than one monoamine neurotransmitter or by using medication with dual reuptake inhibition. Molecular targeting and combining neurotransmitter effects will address a broader variety of emotional and physical symptoms of depression, and may give the patient a better opportunity to recover fully from depression.

References

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Lithner F. Venlafaxine in treatment of severe painful peripheral diabetic neuropathy. Diabetes Care. 2000;23:1710-1711. Abstract
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--------------------------------------------------------------------------------


Authors and Disclosures


Authors
C. Brendan Montano, MD
University of Connecticut School of Medicine, Farmington, Connecticut

Disclosure: Dr. Montano is a consultant to and on the Speakers' Bureaus of Abbott, Elan, Eli Lilly, GlaxoSmithKline, Roche, and Wyeth. He discusses the unapproved or investigational uses of duloxetine.

Clinical Editors
Robert Kennedy
Psychiatry Site Editor/Program Director, Medscape

Disclosure: Robert Kennedy has no significant financial interests or relationships to disclose.


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