Recognizing Difficult-to-Treat Late-Life Depression: Knowing When to Refer

The Geriatric Syndrome of Late-Life Depression

“The task,” began Gary J. Kennedy, MD, Professor of Psychiatry and Behavioral Sciences and Director, Division of Geriatric Psychiatry and Fellowship Training Program, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, “is to recognize the difficulties in treating depression, and the assumption is that the more you know about depression, the more sensitive you become about when to refer and when to start the patient on treatment from the onset.” While Dr. Kennedy agrees that it is important for primary care physicians and providers from other disciplines to lower the threshold at which they offer treatment for depression—the current trend in the treatment of depression—he warned that certain difficulties in treatment extend beyond this. “Late-life depression,” stressed Dr. Kennedy, “should be viewed as one of the geriatric syndromes,” which also include incontinence, falls, cognitive impairment, and polypharmacy. “Realizing that late-life depression is a syndrome—that it’s a family of disturbances and problems, not all of which are simply mood disturbances—is important in forging a treatment that is really going to be effective,” he asserted.

Depressive symptoms are known to be more common than major depressive disorder in late life. While there is sufficient evidence that primary care providers have improved in recognizing major depression, the less obvious forms of depression still present a challenge in diagnosis and treatment, and are also far more prevalent. Dr. Kennedy reinforced that, in terms of symptoms, one need not be overtly depressed to have a major depressive disorder. Apathy and irritability are sufficient symptoms, and, in fact, more common characteristics of depression in older adults. One of the difficulties associated with the treatment of depressive symptoms in older adults is their spontaneous recovery rate of about 50% observed within two years. This presents obvious challenges in evaluating the efficacy of the treatment that is administered to these adults. In addition, one must keep in mind that in determining whether the goal of treatment has been reached, “[one must] depend on the subjective impressions of the clinician, the patient, or the family,” warned Dr. Kennedy.

This creates what he referred to as soft therapeutic endpoints. “We’re not looking at laboratory values. Furthermore, the terminology we use to describe depressive symptoms is less than a decade old, and I think we are still learning how to apply it.” “Most older adults historically—and this may still be true—have been treated more often with a sedative/ hypnotic than with an antidepressant,” stated Dr. Kennedy. The problem is that, although definitive antidepressants are available as treatment, patients are still being administered sedatives. Of the antidepressant prescriptions that are dispensed, about half of them are either not filled or not refilled because of high cost. It is essential that the physician verifies that the patient can afford the drug prior to prescribing the medication.

Dr. Kennedy quoted a number nearing 50% for patients who either show a partial response to treatment or one of outright failure (this number includes patients who did not take any or all of their medication). Dr. Kennedy believes that the most effective approach to treatment of geriatric depression as a syndrome is the comprehensive approach, which encompasses definitive treatments for other conditions that the patient may have, as well as eliciting the support of the patient’s family. “The state of the art,” said the speaker, “is both psychotherapy and antidepressant medication. Together they yield much better results in efficacy.” He mentioned the need to improve pain management and palliative care in psychiatry, adding that the risk of an older person becoming dependent on a pain medication is probably negligible. He also encouraged clinicians to be on guard for the abuse and neglect of older patients, typically perpetrated by family members or caregivers. The Table provides a brief overview of medications currently used in the treatment of depression. Dr. Kennedy cautioned that in order for an antidepressant medication efficacy trial to be valid, patients must have been put on therapeutic levels of medication for a period of at least six weeks.

Suggested Reading

Kennedy GJ. Geriatric Mental Health Care: A   Treatment Guide for the Health Professions. New York, NY: Guilford Publications; 2000.

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When Psychosis Foils the Treatment of Depression 

Barnett S. Meyers, MD, Professor of Psychiatry, Weill Medical College, Cornell University, Ithaca, NY, Professor in the Program of Clinical Epidemiology and Health Services, Weill Graduate School of Medical Sciences, Cornell University, and Chief of the Specialized Practice for Older Adults, New York Presbyterian Hospital–Westchester Division, White Plains, NY, began his discussion by explaining, “What I mean by psychotic depression is its most common form, particularly in the elderly, which is referred to as delusional depression. In delusional depression, the major depression is associated with delusions or sustained irrational beliefs.” Psychotic depression is not a common condition; its prevalence among elderly persons living in the community is 0.1% compared with 2.6% for nonpsychotic depression. However, in a clinical setting of hospitalized elderly psychiatric patients with major depression, more than 40% have psychotic depression compared to 5-15% of hospitalized young adults with major depression.

The prevalence of psychotic depression in primary care patients is not known. Elderly patients with depression are less likely than young adults to complain of feeling depressed or anxious, but are more likely to have somatic preoccupations. In fact, up to 60% of elderly depressed patients have been shown to have somatic preoccupations, and these are delusional in 12%. “In diagnoses, distinguishing between delusional depression, somatoform depression, OCD [obsessive-compulsive disorder], and anxious/ruminative major depression may not be an easy task,” reminded Dr. Meyers. Delusional depression is very different from OCD and from major depression with comorbid generalized anxiety; patients with OCD and generalized anxiety know that their worries are not rational. The elderly, who make up 13% of the population, are responsible for 25% of all completed suicides. Depression associated with delusions is also associated with an increased risk for suicide: 27% of completed suicides have been associated with psychotic depression versus 12% in patients with nonpsychotic depression. Statistics show that 75% of elderly patients who have completed suicide had visited a primary care physician within one month prior to the suicide, 40% within one week, and 20% within one day.

“Why didn’t they see a psychiatrist instead, or why did they make the visits at all?” asked Dr. Meyers. Perhaps they felt worried about a physical symptom rather than feeling depressed. This is why a patient who appears to be excessively worried should be assessed for whether the concern is delusional. The course of psychotic depression is not encouraging, reported Dr. Meyers. Psychotic depression is marked by longer and more frequent episodes with more residual symptoms, higher relapse, and higher hospitalization rates than nonpsychotic depression. This type of depression is also chronic and has significant mortality rates. Dr. Meyers discussed treatment studies on psychotic depression, beginning with a 1975 study by Glassman and Roose¹ and ending with his own more recent study. Data show that psychotic depression has a poor response to traditional antidepressants, such as nortriptyline, a greater than 70% response rate to electroconvulsive therapy, and an intermediate response rate to antipsychotic/antidepressant combination treatment. Evidence for the efficacy of combination pharmacotherapy in geriatric psychotic depression is lacking. “We need to know more about the acute and continuation efficacy of the newer antidepressants— SSRIs [selective serotonin reuptake inhibitors] and mirtazapine,” said the speaker, offering this issue as a suggestion for future research. Tolerability of high-dose atypical antipsychotic medications in the elderly is unknown. “The most important public health problem,” concluded Dr. Meyers, “is that we want to get people better, and we have to keep them well. We also need to have ways of getting these highly vulnerable-to-relapse, elderly patients in ongoing treatment and monitoring by a physician to accomplish this.”

Reference
1. Glassman AH, Roose SP. Delusional depression: A distinct clinical entity? Arch Gen Psychiatry 1981;38:424-427.

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Treatment of Depression Confounded by Comorbid Illness 

Soo Borson, MD, Professor of Psychiatry and Behavioral Sciences, and Director of Geropsychiatry Services, University of Washington Medical Center, Seattle, focused her discussion on chronic disease—one of the three principle risk factors for depression in late life. Chronic disease is at least as potent as the other two major risk factors for late-life depression: loss of a spouse and caring for a disabled, demented family member. Several studies have clearly demonstrated the direct relationship between health and major depression. This explains why nursing home residents have the highest depression rates, followed by patients in primary care settings, and by the healthy elderly living in the community.

Depression, much like the chronic diseases that may provoke it, is a chronic condition. Past studies have shown that depression is a relapsing disease at all ages, with the likelihood of relapse increasing in the elderly. Studies in older medical patients have also revealed that depression is associated with specific disease conditions (predictors): chronic lung disease, alcoholism, and cataracts—the most common cause of visual impairment in older adults. Other studies focused on patients with specific medical diseases have shown high rates of depression in those with neurodegenerative diseases, stroke, arthritis, and other common chronic diseases of later life. In regard to treatment and drug efficacy, Dr. Borson stated that few studies have addressed management of depression in chronic medical diseases. Generally in older patients, tricyclic antidepressants, SSRIs, and dual-action agents (such as mirtazapine and venlafaxine) appear to be equally efficacious. However, one recent study elicited differences in cognitive response to sertraline and nortriptyline.¹

As depression in the older patient is often associated with some degree of cognitive impairment—even in those who do not have dementia—effective treatment can be expected to improve cognition. However, antidepressants are not all alike in this respect. It appears that the anticholinergic effects of nortriptyline may limit the cognitive benefits to be realized by effective treatment of depression in older adults. Another study compared mirtazapine to paroxetine and found that, while the response rates to both drugs are equal, mirtazapine’s onset of action occurs significantly earlier—by about one week.² 

“I’m not persuaded that this difference is necessarily clinically meaningful, but it is interesting from the standpoint of mechanism of action,” stated Dr. Borson. On choosing treatment for depression with comorbid disease, Dr. Borson commented that “choosing a drug may really relate more to what you want to protect the patient from than to its efficacy.” In Alzheimer’s disease, which is associated with weight loss and high sensitivity to central anticholinergic activity, the issues to be considered are anticholinergic and sedative effects of drugs and malnutrition. One of the newer SSRIs, citalopram, was shown to be a good choice for patients with Alzheimer’s disease and mood disorder in a study by Nyth and Gottfries.³ With stroke, it is important to protect the patient from hypotension, falls, and problems related to cardiac conduction or cognitive impairment; therefore, sedative, cardiovascular, and potential cognitive effects of medications must be taken into account in choosing an antidepressant medication. Nortriptyline, which is also shown to be relatively safe for the heart,⁴ has demonstrated outstanding efficacy in older patients, but its tendency to cause some anticholinergic side effects in many patients has limited its use.

Special risks to be considered in the patient with depression and ischemic heart disease are tachycardia, cardiac conduction defects, and hypotension. Nelson et al,⁵ in a comparison study of nortriptyline with paroxetine, found that the two drugs produce  very similar responses and remission rates. Researchers discovered that both medications lead to a reduction in abnormal platelet activation, although it appeared that the effect of paroxetine was observed earlier in treatment. Dr. Borson remarked, “This study is very exciting because it shows the systemic nature of depression, that it involves many mechanisms affecting organs outside the brain, and that, in fact, treating depression may ultimately benefit patients with cardiovascular disease, mediated, at least in part, through reducing the likelihood that further ischemic events will occur.” Dr. Borson’s study⁶ in chronic obstructive pulmonary disease confirmed that nortriptyline is a very good anxiolytic, as well as antidepressant, and significantly improves everyday physical and psychosocial function. These effects were mediated by the psychotropic actions of the drug, as no effect on pulmonary function, motor speed, or blood gases was observed. The drug did not, however, improve cognitive function in these patients.

Dr. Borson also reported one episode of cardiotoxicity possibly due to the 10-hydroxy metabolite of nortriptyline. In conclusion, studies evaluating the treatment of depression in older adults with serious concurrent diseases remain limited due to difficulties that arise in the design, selection, recruitment, and completion stages. Controversy still surrounds the question of whether different antidepressant medications have differential efficacy for specific patient populations, and whether they have differential safety for the heart and brain of medically vulnerable older adults. An element of uncertainty is present in deciding upon next steps to be taken when a seriously medically ill patient responds poorly to an antidepressant. Augmentation strategies, particularly with stimulant medications, switching to a different antidepressant, cautiously combining two different antidepressants, and the use of electroconvulsive therapy are all acceptable approaches in selected patients. Consultation with a geriatric psychiatrist skilled in the management of mental disorders in the medically ill may help to resolve therapeutic uncertainty and support an optimal outcome for the patient in the shortest possible time.

References

1. Bondareff W, Alpert M, Friedhoff AJ, et al. Comparison of sertraline and nortriptyline in the treatment of major depressive disorder in late life. Am J Psychiatry 2000;157:729-736.

2. Shatzberg AF, Kremer C, Rodrigues HE, et al. Mirtazapine versus paroxetine in elderly depressed patients. Paper presented at: European College of Neuropsychopharmacology; 2000.

3. Nyth AL, Gottfries CG. The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders: A Nordic multicentre study. Br J Psychiatry 1990;157:894-901.

4. Miller MD, Curtiss EI, Marino L, et al. Long-term ECG changes in depressed elderly patients treated with nortiptyline: A double-blind, randomized, placebo-controlled evaluation. Am J Geriatr Psychiatry 1998;6: 59-66.

5. Nelson JC, Kennedy JS, Pollock BG, et al. Treatment of major depression with nortriptyline and paroxetine in patients with ischemic heart disease. Am J Psychiatry 1999;156:1024-1028.

6. Borson S, McDonald GJ, Gayle T, et al. Improvement in mood, physical symptoms, and function with nortriptyline for depression in patients with chronic obstructive pulmonary disease. Psychosomatics 1992;33:190-201.

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Disability in Geriatric Depression  

George Alexopoulos, MD, Professor of Psychiatry, Weill Medical College of Cornell University, White Plains, NY, and Professor, Weill Graduate School of Medical Sciences of Cornell University, discussed the relationship between depression and disability, reaffirming the point that depression is linked to poor health and disability. Disability needs to be approached therapeutically and concurrently with the depressive syndrome. The World Heath Organization classified disability into three domains: impairment (body structure or function), limitations to instrumental activities of daily living (IADLs), and restrictions in social participation. Dr. Alexopoulos pointed out that every disability case—in any of the three domains—is affected by both personal and environmental factors.

Disability, especially in the elderly, increases the number of hospitalizations and nursing home admissions, and increases mortality and morbidity for specific medical conditions. Disability has been shown to be a predictor of mortality, independent of medical illness burden, and, therefore, needs to be given independent consideration in the patient’s health status assessment.¹ The relationship between disability and depression has been firmly established by research. “In primary care patients, depression has been found to be one of the most important contributors to disability—the only chronic medical condition that was found to have a greater impact on disability was coronary artery disease,” said Dr. Alexopoulos. Presenting the results of an ongoing study by Dr. Bruce at Cornell, the speaker stated that the number of patients with depression increases with increased impairment of activities of daily living (ADLs) or IADLs. Major depression rates are two times higher in patients with disability.

Dr. Alexopoulos and colleagues^2,3 conducted studies to determine the clinical characteristics that are associated with disability in depressed elderly patients. Among the various depressive manifestations, anxiety, depressive ideation, psychomotor retardation, and weight loss were the most likely symptoms to be found in depressed, disabled, elderly patients. Disability was also associated with cognitive dysfunction and medical illness, but all of these clinical variables predicted less than 50% of the variance in disability. Dr. Alexopoulos concluded that, while disability is related to many clinical features of depression, it reflects a broader clinical disturbance with unique prognostic significance. Another area of Dr. Alexopoulos’ research focused on the relationship of cognitive dysfunction to disability. He and his colleagues found that executive dysfunction is an important contributor to disability. Specifically, the impact of depression in causing disability is most pronounced in elderly patients with cognitive dysfunction.³

In another set of studies, Dr. Alexopoulos and colleagues demonstrated that executive dysfunction is associated with poor⁴ and unstable⁵ response of geriatric major depression to antidepressants. These findings were originally observed in patients who were treated either with adequate dosages of a variety of antidepressants or with nortriptyline. Interim analysis of an ongoing study showed very similar findings in a new sample of patients, using citalopram as the antidepressant and a broader assessment battery for executive dysfunction. Dr. Alexopoulos discussed pharmacologic and nonpharmacologic treatment of depression in the elderly. “With improvements in neuroimaging techniques, we may be able to identify the disturbances in the organization of white matter leading to disconnection syndromes clinically expressed as executive dysfunction,” he said. He is currently conducting a study using fractional anisotropy and focusing in areas of the white matter lateral to the anterior cingulate. Dr. Alexopoulos and his associates have found that depressed elderly patients with reduced organization of white matter in both the left and the right sides of the brain were less likely to respond to citalopram than patients with well-organized white matter.

How do these findings affect pharmacotherapy? Dr. Alexopoulos argued, “If you think of depression as a disconnection syndrome between the cortical and the limbic areas, enhancing the function of neurotransmitter systems related to cortical and limbic structures and their connections may be of help. The cortex and the caudate nucleus are under the control of dopamine, acetylcholine, and enkephalins, among other neurotransmitters.” One approach would then be to use dopamine agonists, such as a dopamine-3 receptor agonist, which directly affect the dopamine system. Another approach would be to use drugs that increase dopamine transmission indirectly (eg, alpha-2 receptor antagonists such as mirtazapine). Psychostimulants may also be administered. Cholinesterase inhibitors seem to be effective in the treatment of depression. In addition, there are now opioid antagonists that are available for use.

Nonpharmacologic treatment should be used concurrently with pharmacologic therapy. The speaker suggested that it is critical to develop focused therapies—nonbiological therapies specifically aimed at disability-associated symptoms of depression, such as the previously mentioned anxiety and depressive ideation as well as the disability itself. The idea is to concurrently offer rehabilitation treatment for the disability and a targeted psychotherapy to alleviate the specific depressive symptoms that have been shown to promote disability. “Disability, while it is a domain that requires independent evaluation, has a specific relationship with both cognitive and emotional symptoms of depression. On a theoretical level, this relationship can give insight into brain function, leading to novel pharmacologic interventions. On a clinical level, it can help us develop focused nonbiological treatments that appropriately target the symptoms of depression known to interact with disability and break the spiral of deterioration that they cause,” concluded Dr. Alexopoulos.

References

1. Pahor M, Guralnik JM, Salive ME, et al. Disability and severe gastrointestinal hemorrhage: A prospective study of community-dwelling older persons. J Am Geriatr Soc 1994;42(8):816-825.

2. Alexopoulos GS, Vrontou C, Kakuma T, et al. Disability in geriatric depression. Am J Psychiatry 1996;153(7):877-885.

3. Kiosses DN, Alexopoulos GS, Murphy C. Symptoms of striatofrontal dysfunction contribute to disability in geriatric depression. Int J Geriatr Psychiatry 2000;15(11):992-999.

4. Kalayam B, Alexopoulos GS. Prefrontal dysfunction and treatment response in geriatric depression. Arch Gen Psychiatry 1999;56(8): 713-718.

5. Alexopoulos GS, Meyers BS, Young RC, et al. Executive dysfunction and long-term outcomes of geriatric depression. Arch Gen Psychiatry 2000;57(3): 285-290.