| by Pamela J. Black |
Memory fails, things disappear, a spouse dies, a medical crisis strikes. Financial security crumbles. All that was once known with easy confidence becomes a hazy memory. Sadly, not everyone is able to overcome the losses-of home, of dignity, of anything predictable-the loneliness, and the fear that are sometimes associated with aging. Many feel trapped and without hope.
The majority of those struggling to escape the devastating clutches of depression are the frail elderly-specifically, those institutionalized in long-term care facilities. Over the past several decades, hundreds of researchers have sought to understand the debilitating problem of depression, producing volumes of articles to describe their findings. All the while, countless sufferers continued to cry out for help.
The High Cost of Diagnostic Failures
In a longitudinal study conducted nearly ten years ago, Rovner et al.1 suggested that of patients with dementia, only half were correctly diagnosed. Furthermore, they found that 21% of those studied had delusions; however, these were rarely diagnosed or treated.
They concluded that many nursing home residents are often "underdiagnosed or misdiagnosed," and that such diagnostic failures on the part of those caring for these dependent patients actually contribute to their mortality.2, 3, 4
Rovner et al. further concluded that the same unfortunate breakdown can be extrapolated to the identification and treatment of patients with various types of depression. The researchers emphasized that depression is not a normal part of aging, and must not be accepted as such.5
Face to Face With a Problem
Consultant pharmacists routinely observe the diagnosis of depression printed in the chart, right along with a long list of other psychiatric and medical problems. Perhaps there is no diagnosis when indeed there ought to be one, or, more importantly, no treatment when treatment is indicated.
Pharmacists make note of the drug regimen, laboratory assessment, and monitoring tools, if they are being used. Perhaps psychiatric consults have been ordered, but more often than not, it is the facility doctor who is prescribing and changing a resident's psychoactive medications, frequently following the counsel of a nurse who sees the resident on a day-to-day basis.
Many times, the choice of psychoactive medication prescribed is not necessarily a well-informed decision. In fact, many medications are inappropriately prescribed for use in the elderly population, doses are often too high, and necessary laboratory monitoring is not ordered.
In addition, the nursing home physician does not always have the advantage of a good medical or drug therapy history and may be without a clear understanding of all of the available treatment options.
We Can Make a Difference
An understanding of the magnitude of the problems associated with depression in the institutionalized geriatric patient can suggest an approach for the consultant pharmacist striving to help improve the last years of life for these residents. We can make a difference, but only if we are integrated into all aspects of the process, including the identification and diagnosis of the problem. Making recommendations for treatment with all options in mind is the best way for the consultant pharmacist to contribute to an optimal outcome.
The prevalence of mental disorders in the nursing home setting is as high as 50%-55%.6 Of these disorders, depression ranks the highest, at 25%-30%.2, 7, 8, 9 By chart review alone, a clinician can expect to find 15%-32% of long-term care residents with a diagnosis of depression.1, 10, 11
Eleven percent of those diagnosed with depression have major affective disorder.7 Medical comorbidity is the hallmark of the depressed elderly and, more often than not, adds to the challenge of effective treatment.8, 12 With an accurate diagnosis and effective treatment, however, full recovery for the depressed elderly patient can-and should-be expected.3
Avenues of Approach
There are currently several specific areas of research being directed toward this profoundly disabled population. Besides striving toward improved subtyping in the diagnostic assessment, researchers are following a number of other avenues. They are, for example:
A number of clinicians actively working in this arena enthusiastically support the role and respect the value of the consultant pharmacist, particularly the informed and actively involved pharmacist who has access to the clinical record and deliberately seeks out opportunities to meet in person with caregiver and resident.
The Chicken or the Egg?
One of the first questions to ask in dealing with a possible diagnosis of depression is: Which is the real cause, and which is the effect? Is depression the primary problem, or secondary to something else?
Unfortunately, these can be very difficult questions to answer. Decreased functional abilities can lead to depression, as they sometimes do for patients with Parkinson's disease; on the other hand, depression can lead to a decline in functional abilities, such as performance in activities of daily living.
In fact, 40%-90% of Parkinson's patients have depressive symptoms,2 and 10%-50% of the medically ill elderly will be depressed.13 It can become a vicious circle, where each component reinforces the other in a downward spiral.
This is precisely the dilemma that a conscientious clinician faces. According to Dr. Lon Schneider, a highly regarded expert in this field, more work needs to be done to better sub-type depression in the geriatric population, especially in long-term care. Only then can the efficacy of treatment be significantly improved.14
Diagnostic Assessment
As was mentioned earlier, depression is often overlooked in the institutionalized geriatric patient. Although chronic medical problems, both physical and cognitive, mandate the attention of the medical professional, a "depressed" state is often considered normal in light of other confounding medical problems.11 Therefore, it goes untreated.
The alert clinican will keep in mind the fact that some diseases can actually be predictors of depression. For example, patients with thyroid disorders often develop depression. When the disease is managed, the depression improves.
Likewise, some psychiatric illnesses, such as anxiety disorders or panic attacks, may be precursors to depression,15 and some depression, such as that which often accompanies bereavement or loss, is predictable, yet frequently left unaddressed.
Most perplexing for the clinician, though, is the demented patient with an underlying depression. Ten to fifteen percent of depressed patients are misdiagnosed with dementia due to a phenomenon of presentation unique to the depressed elderly.2 In geriatric depression, the presentation is often "masked." The patient may focus on physical complaints, such as back pain or constipation, rather than on affective problems.2
Given these facts, the consultant pharmacist should be prompted to look for signs and symptoms of depression in all demented residents. Obviously, the clinician cannot change a patient's age or cognitive status, but depression, once recognized, can be treated, offering the patient an improved quality of life and giving the consultant pharmacist the opportunity to improve patient care.
Navigating the Maze
Assessing functional status for the patient diagnosed with senile dementia of the Alzheimer's type is multifactoral and includes age, cognition, and probable depression. In fact, persistent depression moderately increases the risk of developing dementia, primarily Alzheimer's disease.16 At least 25% of all patients with dementia have a diagnosis of depression.7, 9
One of the primary indicators by which one can measure functional status (thereby reflecting quality of life) is the patient's ability to perform activities of daily living such as dressing, bathing, personal hygiene, toileting, eating, and mobility. By carefully searching within the chart, interviewing the nursing staff, and observing the resident, even a relatively inexperienced, but informed, consultant pharmacist should be able to pinpoint the hallmarks of depression. If a patient is diagnosed with dementia, the consultant should have a high level of suspicion that there may be a concurrent depression.
This is especially true in the early stages of dementia, since it is well established that patients with relatively higher cognitive function are more likely to suffer with depression. Depression is a treatable illness, not a chronic, progressive disease,7 and the consultant pharmacist is certainly positioned to have a significant impact on the outcome for each afflicted resident.
Subtyping Depression
Since many long-term care residents have an underlying dementia, accuracy of assessment is vital to ensuring a positive outcome.4 All psychiatric disorders are technically classified by using the criteria set forth in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). This resource provides the clinician with the necessary tools to more accurately subtype the particular depression demonstrated by a patient, and ultimately aids in the overall understanding of the etiology for a given presentation.
A diagnosis of depression may be further classified into a number of sub types under the heading of mood disorders. These include:
In the DSM-IV, each classification is clearly described and accompanied by algorithms to assist the clinician in determining a precise diagnosis and treatment plan. Diagnostic criteria for seasonal depression are also outlined.
Dysthymia, or depressive neurosis, is one specific subtype of depression frequently seen in the elderly.5, 16, 17 It is defined as a depressed mood for most of the day, more days than not, for at least two years, and must include at least two of the following:
Devanand et al.16 have suggested that although this particular sub type of depression is commonly experienced by institutionalized geriatric residents, it is rarely diagnosed correctly. When it is identified and treated, personality traits and social adjustment are markedly improved in recovered elderly, although the risk of recurrence still exists.18
Coexisting Medical Malfunctions
Further complicating the diagnosis of depression are concomitant medical conditions that affect mental health. For instance, chronic illnesses such as arthritis, hypertension, or cardiovascular disease often lead to depression, and underlying depression can complicate the management of these medical illnesses.2, 5, 11 The illness itself may not physiologically cause the depression, but simply increases the risk.
Not surprisingly, anatomical insults to specific areas of the brain will often alter an individual patient's presentation. For instance, the patient suffering a cerebral vascular accident (CVA), closed head injury, or cancer with metastases to the brain must be carefully screened for depression. Frontal damage seen in CVA patients predictably causes depression; in fact, 50% of all stroke patients will develop depression.2 In fact, structural changes in the brain appear to be more relevant in patients presenting with depression for the first time in late life, as opposed to those with genetic or psychosocial influences.19
It is also important to remember that both structural insults and changes in neural transmission and neuroendocrine regulatory mechanisms can cause depression.13
Much has been written about the role of specific neurotransmitters such as serotonin and norepinephrine in depression. The pathophysiology and pharmacotherapy of depression were recently addressed in The Consultant Pharmacist by Mandos.20
Evaluating Concurrent Drug Therapy
As a part of the clinical team, the consultant pharmacist should be sensitive to the common treatment goals of depression, including:
Consultant pharmacists must also be well informed concerning the many facets of drug information-pharmacology, pharmacokinetics, and pharmacodynamics-and be able to identify medications that can precipitate depression. For example, antihypertensives, analgesics (NSAIDs and narcotics), CNS depressants, and steroids list depression as an undesirable side effect.2, 21
Further, some antidepressants themselves can cause agitation, anxiety, or insomnia, complicating a patient's presentation, especially if that patient has a concurrent diagnosis of dementia.
A clinician might not necessarily correlate the onset of such undesirable behaviors with one of the patient's medications, but might instead assume it is related to the resident's dementia, often adding another drug. However, for an antidepressant to be judged effective for a depressed patient, the medication should also take care of any related anxiety, such as panic attacks, that may be associated with the depression.
Inappropriate or irrational pharmacotherapy in the long-term care setting must not be ignored. The consultant pharmacist must not only review for potential causative agents, but also pay special attention to medications that may have been added to the patient's regimen to treat related psychiatric symptoms. Make note of the addition of antidepressants (one or more), anxiolytics, sedatives, tacrine, donepezil, or Hydergine, any of which could be a telltale marker that the current regimen is not working as it should.14
Once the possibility of adverse medication effects has been ruled out, the chart must be reviewed for other useful information. Unfortunately, in the long-term care setting it is not always easy to find a complete history in the clinical record, nor is it a simple task to put all of the pieces together to discern an accurate diagnosis and to develop the best treatment approach.
Traditional Drug Therapy
Pharmacotherapy has long been established as the mainstay for the patient diagnosed with depression. Much has already been written about the various classes of antidepressants, and the pros and cons associated with each of those medications. All are equally effective, and regimens are customarily tailored to the individual patient presenting with depression.3, 10, 22-24 The oldest agents in the antidepression armamentarium are the monoamine oxidase (MAO) inhibitors, which are usually avoided in the geriatric population due to their propensity for food-drug and serious drug-drug interactions. Tricyclic antidepressants (TCAs) have many side effects relative to the newer agents, including toxicity in overdose, and can accumulate in the elderly. Selective serotonin reuptake inhibitors (SSRIs) are safer, and are swiftly moving into the place of first preference for most clinicians.25 Finally, there are a number of miscellaneous agents, such as bupropion, nefazodone, trazodone, and others. The anxiolytic buspirone also has antidepressant properties when used in higher doses.
Unconventional Drug Therapy
Medications other than antidepressants are being tried in some areas with positive results. Clozapine and olanzapine are effective in treating depressed patients refractory to the more traditional agents, says Schneider. However, without adequate monitoring and documentation by the prescribing physician, use of these medications could be seriously questioned, even to the extent of inviting annual state survey citations.
Adjunctive Drug Therapy
Adjunctive therapy is frequently used in the treatment of depressed patients. As clinicians, we often see anticonvulsants (carbamazepine, valproic acid), stimulants (methyl-phenidate), lithium, thyroid, and others used alone or with other antidepressants.26, 27 Schneider et al.14 have concluded that such augmentation "is not empirically effective." In contrast, in an article discussing the NIH Consensus Development Conference on the diagnosis and treatment of depression in late life, Ira Katz, MD asserts that "there is increased anecdotal and observational evidence that stimulants may be of value for the treatment of depression in elderly patients with significant medical illness."28 Clearly, the issue is controversial. It can be concluded that treatment must be individualized to each patient.
Dosing
Regardless of the drug chosen, adequate dosing and maintenance therapy are indicated for patients with late-onset depression, concomitant cognitive impairment, or recurrent depression, says Schneider.10, 27, 30 In general, a seasoned consultant should always be on the lookout for markers pointing to a probable depression in an undiagnosed patient, researching for a potential cause for those already diagnosed, and always carefully monitoring all aspects of a patient's drug regimen. With clearly diagnosed depression, continued use of antidepressants in the long-term care geriatric population should be the norm, not the exception.31
Antidepressant Withdrawal
Discontinuing antidepressant therapy may not be in the best interest of a patient and must be done cautiously, accompanied by close monitoring. Discontinuance of antidepressant medications can actually precipitate withdrawal symptoms, leading to psychosis. An unsuspecting caretaker may think dementia is worsening, when in reality the patient is experiencing an adverse drug reaction due to withdrawal. With Health Care Financing Administration regulations so focused on the area of psychoactive medication use and documentation of its need, practitioners occasionally-and unnecessarily-feel the pressure to decrease doses or discontinue antidepressant medications. Each situation must be closely examined on its own merits, and large dose reductions should be strongly resisted, especially if slow titration and close monitoring cannot be assured.
Non-Drug Treatment Modalities: ECT
A comprehensive treatment approach for patients with depression should include consideration of electroconvulsive therapy, even in the geriatric patient, according to Schneider.14 Drug therapy resistance is 10%-30% in the elderly;46 considering the long-term exposure to routine medication use vs. a brief treatment with ECT, the benefit may outweigh the perceived risks.11 Dr. Schneider suggests that the response rate to ECT is generally higher in old age.14
Careful prescreening is essential, as the efficacy of ECT is associated with a patient's presentation, although sub typing of depression may not necessarily be correlated to the efficacy of ECT treatment. For example, patients who lack psychosis, delusions, retardation, and/or agitation do not customarily respond remarkably to ECT. For patients with major depression, ECT is always a viable option.32
When ECT is used, the dose of current, length of the procedure, and anatomical location stimulated are all linked to the efficacy of treatment.33-38 In very general terms, high electrical dosage is related to a more rapid response, whereas unilateral treatment is associated with less severe cognitive side effects following the procedure.11, 37 Proponents of ECT argue that the adverse effects of retrograde amnesia and decrease in prospective ability to learn new information may be of relatively little consequence for the depressed geriatric patient who is refractory to drug therapy.34, 39, 40
Cognitive status prior to treatment may be a predictor of the disorientation expected in the acute post-ictal period. The procedure may be contraindicated for patients with known seizure disorders, although no evidence exists that ECT lowers seizure threshold.41 Furthermore, ECT can be safely administered to patients with severe cardiovascular disease.42 Finally, there is no credible evidence that ECT causes structural damage to the brain.40
The use of ECT as a viable treatment option in long-term care geriatric patients is almost unheard of, yet potentially affords refractory patients the promise of an improved quality of life. Without a doubt, many factors enter into its practicality and affect the likelihood of ECT becoming more common in the realm of long-term care.
Other Treatment Options
Psychotherapy is generally accepted as an important element in the treatment of depression, and its benefits may be synergistic to pharmacotherapy.4 The combination of the two is accepted as being more effective than either treatment alone.
Phototherapy, sleep deprivation, and psychosurgery are also documented therapeutic alternatives, depending upon the sub-type of depression and history of drug and non-drug treatment efficacy.43
The Role of the Consultant
As consultant pharmacists, we must be informed, and understanding the DSM-IV criteria is a good starting point. Then, we must assess for:
Making note of key indicators, such as recent changes in a patient's daily function, recognizing the hallmark signs and symptoms of depression, or noticing medication changes in the drug regimen, should cause a perceptive consultant to explore further. Unlike the insidious progression of dementia, depression generally has an abrupt onset. Symptoms such as poor sleep quality, weight loss, decreased energy, and loss of interest in pleasurable activities often characterize the depressed patient and ought to trigger the caretaker to consider a diagnosis of depression.
Apathy is more prominent in late-onset depression than with younger patients.44 Late life depression is also characterized by longer episodes, poorer outcome, and chronicity. Elderly patients have a higher risk of delusional depression, often confounding the diagnosis.13
Because of the specific nature of the constellation of symptoms and the way in which they differ in the elderly depressed patient presenting for the first time in late life, the focus will primarily be on somatic symptomology. Although this is the type of information that may not be readily available in the chart, solicitation from the immediate caretaker is often enlightening.
Being informed about drug-drug interactions, drugs with narrow therapeutic ranges, and side effects associated with medications-especially those commonly used in the geriatric population-is another useful tool for the consultant pharmacist. Knowledge of the metabolic pathways of drugs in the regimen is essential, since one can have an effect on the level of the other and lead to either desirable or undesirable effects.45 Likewise, monitoring for extraordinarily high levels of drugs such as digoxin may reveal another potential cause of a depressed presentation.29
The addition of medications to an existing regimen, including psychoactive drugs, should prompt a consultant to think of potential side effects caused by existing medications in the drug regimen, perhaps even those being used to treat depression. For example, the onset of agitation, anxiety, or insomnia may be associated with the use of an SSRI to treat depression.
Some antidepressants may cause undesirable effects: Fluoxetine, for example, causes a decrease in appetite in the elderly population. Our scope of drug regimen review extends beyond the resident's psychiatric needs; we must look at the whole person.
Continuous Monitoring
Depression is cyclical. It is, therefore, essential to be educated about the stages of response, remission, recovery, and relapse that can occur regardless of the careful attention given to the suffering patient. Kupfer has suggested that more than 50% of patients successfully treated for depression will have a second episode.30 With each episode, the risk of another becomes greater.
Understanding the unique aspects of a patient's presentation should influence the consultant's direction in the treatment plan. Important considerations in choosing the best therapeutic options include compliance, side effects, quality of life, and relief of depressive symptoms. Knowledge of all treatment options will surely capture the confidence of the physician and have a positive effect on the resident.
References
1. Rovner BW, German PS, Brandt LJ, Clark R, Burton L, Folstein MF. Depression and mortality in nursing homes. JAMA 1991;265(8):993-996.
2. Small GW. Recognition and treatment of depression in the elderly. J Clin Psychiatry 1991;52:(6, suppl):11-22.
3. Nemeroff CB. Evolutionary trends in the pharmacotherapeutic management of depression. J Clin Psychiatry 1994;55:(12, suppl):3-15.
4. Katz IR, Curlik S, Lesher EL. Use of antidepressants in the frail elderly. Clinics in Geriatric Medicine 1988;4(1):203-222.
5. Kanowski S. Depression in the elderly: clinical considerations and therapeutic approaches. J Clin Psychiatry 1994;55(4):166-173.
6. Kafonek S, Ettinger WH, Roca R, Kittner S, Taylor N, German PS. Instruments for screening depression and dementia in a long-term care facility. J Am Geriatr Soc 1989;37:29-34.
7. Reifler BV, Larson E, Teri L, Poulson M. Dementia of the Alzheimer's type and depression. J Amer Geriatr Soc 1986;34:855-859.
8. Reynolds CF, Lebowitz BD, Schneider LS. The NIH consensus development conference on the diagnosis and treatment of depression in late life: an overview. Psychopharmacol Bull 1993;29:83-85.
9. Fitz AG, Teri L. Depression, cognition, and functional ability in patients with Alzheimer's disease. J Am Geriatr Soc 1994;42:186-191.
10. Heston LL, Garrand J, Makris L, et al. Inadequate treatment of depressed nursing home elderly. J Amer Geriatr Soc 1992;40:1117-1122.
11. NIH Consensus Development Panel on Depression in Late Life. Diagnosis and treatment of depression in late life. JAMA 1992;268(8):1018-1024.
12. Parmelee PA, Katz IR, Lawton MP. Incidence of depression in long-term care settings. J Gerontology 1992;47(6):M189-M196.
13. Schneider LS. Psychobiologic features of geriatric affective disorder. Clinics in Geriatric Medicine 1992;8(2):253-265.
14. Schneider LS. Efficacy of treatment for geropsychiatric patients with severe mental illness. Psychopharmacol Bull 1993;29:501-524.
15. Fawcett J. Targeting treatment in patients with mixed symptoms of anxiety and depression. J Clin Psychiatry 1990;51(11, suppl):40-43.
16. Devanand DP, Nobler MS, Singer T, et al. Is dysthymia a different disorder in the elderly? Am J Psychiatry 1994;151(11):1592-1595.
17. Nobler MS, Devanand DP, Kim MK, et al. Fluoxetine treatment of dysthymia in the elderly. J Clin Psychiatry 1996;57(6):254-256.
18. Schneider LS, Zemansky MF, Bender M, Sloane RB. Personality in recovered depressed elderly. International Psychogeriatrics 1992;4(2):177-185.
19. Krishnan KR, McDonald WM. Arteriosclerotic depression. Medical Hypotheses 1995;44(2):111-115.
20. Mandos LA. Current issues in the diagnosis and management of depression in the elderly in the long-term care setting. Consult Pharm 1996;11:1241-1260.
21. Reynolds CF. Treatment of depression in late life. Am J Med 1994;97(6A, suppl):6A-39S.
22. Peabody CA, Whiteford HA, Hollister LE. Antidepressants and the elderly. J Am Geriat Soc 1986;34:869-874.
23. Salzman C. Pharmacologic treatment of depression in the elderly. J Clin Psychiatry 1993;54(2, suppl):23-28.
24. Andrews JM, Nemeroff CB. Contemporary management of depression. Am J Med 1994;97(6A, suppl):6A-24S.
25. Haider A, Miller DR, Staton D. Use of serotonergic drugs for treating depression in older patients. Geriatrics 1993;48:48-51.
26. Tariot PN, Schneider LS, Katz IR. Anticonvulsant and other non-neuroleptic treatment of agitation in dementia. J Geriatr Psychiatry & Neurology 1995;8(1, suppl):S28-S39.
27. Schneider LS Olin JT. Overview of clinical trials of hydergine in dementia. Archives of Neurology 1994;51(8):787-798.
28. Katz IR. Drug treatment of depression in the frail elderly: discussion of the NIH consensus development conference on the diagnosis and treatment of depression in late life. Psychopharmacol Bull 1993;29:101-108.
29. Pattern SB Love EJ. Drug-induced depression. Drug Safety 1994;10(3):203-219.
30. Kupfer DJ. Long-term treatment of depression. J Clin Psychiatry 1991;52(5, suppl):28-34.
31. Old Age Depression Interest Group. How long should the elderly take antidepressants? British J Psychiatry 1993;162:175-182.
32. Sobin C, Prudic J, Devanand DP, Nobler MS, Sackeim HA. Who responds to electroconvulsive therapy? British J Psychiatry 1996;169(3):322-328.
33. Sackeim HA, Luber B, Katzman GP, et al. The effects of electroconvulsive therapy on quantitative electroencephalograms. Archives of General Psychiatry 1996;53(9):814-824.
34. Sobin C, Sackeim HA, Prudic J, Devanand DP, Moody BJ, McElhiney MC. Predictors of retrograde amnesia following ECT. Amer J Psychiatry 1995;152(7):995-1001.
35. Sackeim HA, Long J, Luber B, et al. Physical properties and quantification of the ECT stimulus: I. Basic principles. Convulsive Therapy 1994;10(2):93-123.
36. Nobler MS, Sackeim HA, Solomou M, Luber B, Devanand DP, Prudic J. EEG manifestations during ECT: Effects of electrode placement and stimulus intensity. Biological Psychiatry 1993;34(5):321-330.
37. Sackeim HA, Prudic J, Devanand DP, et al. Effects of stimulus intensity and electrode placement on the efficacy and cognitive effects of electroconvulsive therapy. New Eng J Med 1993;328(12):839-846.
38. Kramer BA, Pollock VE, Schneider LS. Monitoring seizure duration during ECT. J Clin Psychiatry 1990;51(1):38.
39. Coleman EA, Sackeim HA, Prudic J, Devanand DP, McElhiney MC, Moody BJ. Subjective memory complaints prior to and following electroconvulsive therapy. Biological Psychiatry 1996;39(5):346-356.
40. Devanand DP, Dwork AJ, Hutchinson ER, Bolwig TG, Sackeim HA. Does ECT alter brain structure? Am J Psychiatry 1994;151(7):957-970.
41. Krueger RB, Fama JM, Devanand DP, Prudic J, Sackeim HA. Does ECT permanently alter seizure threshold? Biological Psychiatry 1993;33(4);272-276.
42. Zielinski RJ, Roose SP, Devanand DP, Woodring S, Sackeim HA. Cardiovascular complications of ECT in depressed patients with cardiac disease. Am J Psychiatry 1993;150(6):904-909.
43. Caldecott-Hazard S, Schneider LS. Clinical and biochemical aspects of depressive disorders: III. Treatment and controversies. Synapse 1992;10:141-168.
44. Krishnan KR, Hays JC, Tupler LA, George LK, Blazer DG. Clinical and phenomenological comparisons of late-onset and early-onset depression. Am J Psychiatry 1995;152(5):785-788.
45. DeVane CL. Pharmacogenetics and drug metabolism of newer antidepressant agents. J Clin Psychiatry 1994;55(12, suppl):38-45.
46. Nierenberg AA, Amsterdam JD. Treatment-resistant depression: Definition and treatment approaches. J Clin Psychiatry 1990;51(6, ):39-47.
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