Treating Late-Life Depression

Dr. Nelson is professor of psychiatry, director of geriatric psychiatry, and holds the Leon J. Epstein, MD, chair in geriatric psychiatry at the University of California, San Francisco. His research and expertise focus principally on the description and treatment of adult and geriatric depression, as well as the psychopharmacology of antidepressants. Among many accomplishments, Dr. Nelson received the Yale Residents Outstanding Teacher award in 1995 and 2001, and the Distinguished Yale Alumni Award in 2006. He wrote Geriatric Psychopharmacology¹ in 1998. Dr. Nelson was one of the founding members of the American Society of Clinical Psychopharmacology and served as its president from 1999 to 2003.

This interview took place on September 28, 2006, and was conducted by Norman Sussman, MD.

What is late-life depression and how common is it?

Late-life depression generally occurs in people >60 years of age and can present as late-onset or recurrent depression. Older patients appear to have lower rates of depression than younger patients. The Epidemiologic Catchment Area study² first reported that finding years ago, debunking the assumption that older people might have a higher risk of depression. In the National Comorbidity Study, Kessler and colleagues³ also found that the risk of depression in older individuals was actually less than that in mixed-age samples. In the younger samples, the odds ratio showed approximately a two-fold increased risk of depression. It has been suggested that this data points to a cohort effect; patients born more recently are showing higher rates of depression at a young age, whereas the group that is currently elderly represents a generation in which frequency of depression was reduced. That may not be the only explanation, but overall, older patients appear to have a lower rate of depression.

Do older patients present with different symptoms of depression?

Historically, clinicians have suggested that older patients may have more somatic symptoms than younger patients. However, symptoms that are common in younger populations are also present in older patients. In a sample of 752 patients, the nature and frequency of symptoms and treatment response were nearly identical in patients 60–75 years of age compared with samples of 596 younger patients.⁴ The three symptoms that were most frequent and showed the greatest change during treatment in both age categories were depressed mood, loss of interest, and psychic anxiety.

There is a difference in how some older patients come to attention, particularly among the frail elderly or patients in nursing home settings. Those patients may lose the capacity to understand that they are depressed or make their needs clear. They are less apt to come for help themselves, and usually their depression is identified by someone on the nursing staff or in the family who may notice that the individual has lost interest in things or had a change in appetite.

It is possible that the similarity of symptoms in older and younger patients cited above may not adequately reflect the presence of atypical symptoms of depression. The Hamilton Rating Scale for Depression (HAM-D) used in the above studies does not assess atypical symptoms well. Atypical depression is less common in older individuals, and it is possible that reversed vegetative symptoms—eating and sleeping more—are more common in younger adults. In older adults these symptoms are not common.

Do patients with late-life depression have more vascular problems?

Vascular illness can present first with depressive symptoms or later with vascular dementia. There are two key features to this concept, namely, evidence of small-vessel disease on magnetic resonance imaging (MRI) and evidence of executive dysfunction on cognitive testing with neuropsychologic tests. There remains a question of how many people really have vascular disease as a basis of their depression. Using MRI findings, the prevalence will probably be lower than if the syndrome is defined using executive dysfunction. Many people with late-onset depression do not have pronounced vascular disease. Their depression may be related to other medical illness or other stressors.

Does efficacy of the newer antidepressants differ in patients with late-life depression?

In a meta-analysis of placebo-controlled studies of second-generation antidepressants in patients =60 years of age, antidepressants were more effective than placebo but the difference in mean response rates was <10%.⁵ Few studies have addressed differences in treatment effectiveness in younger and older patients. Most of these comparisons were naturalistic and retrospective. Seldom did younger and older patients receive the same antidepressant at similar doses and for similar durations. In a large, 8-week, open-label, naturalistic study of escitalopram in 5,200 patients,⁶ >700 patients were >60 years of age. The older patients received almost identical dose and duration of treatment as the younger group. That is unusual because older patients are generally given lower doses. In this study, both groups received an average 11-mg dose of escitalopram and were treated for approximately 55 days. Response rates at 8 weeks were nearly identical. It should be noted that, as is typical of most clinical trials, while the participants had common medical illnesses, they were not frail elderly or suffering from severe medical illness.

Looking at the controlled studies, there is no evidence to support the superiority of any one antidepressant class over another in treating late-life depression. Some medications may have advantages depending on comorbid conditions. For example, there is evidence in several of the anxiety disorders that the serotonin reuptake inhibitors or other serotonin drugs are more effective than catecholamine drugs. It is sensible to start a patient with a comorbid anxiety disorder on one of the serotonin agents. On the other hand, if an older patient has lost a lot of weight, mirtazapine is a popular choice because it may improve appetite and facilitate weight gain. Bupropion is the least sedating of any of the antidepressants and can be an attractive choice for patients who are already on a variety of medications that cause sedation. There is good evidence that drugs that act on both serotonin and norepinephrine are better for pain, which is a common comorbidity in older people. For patients experiencing pain, venlafaxine and duloxetine may have advantages. Duloxetine also has an indication for use in diabetic neuropathy. Amitriptyline and clomipramine are also effective for treatment of pain but are more anticholinergic and have cardiac safety issues.

Is there a role for psychostimulants or modafinil in treating late-life depression?

Historically, there has been much interest in the use of stimulants in the elderly. Several clinicians have suggested stimulants might be unusually helpful in this group. However, there are no controlled studies of stimulants as monotherapy in late-life major depressive disorder. In older patients who are depressed, stimulants can have rapid effects. Paradoxically, while stimulants are generally thought of as decreasing appetite, appetite improves as depression improves.

Recently, Lavretsky and colleagues⁷ used stimulants to speed up response in older depressed patients while giving citalopram. This was a placebo-controlled trial. Methylphenidate was given at the beginning of treatment and did accelerate response.

I am not aware of any published data about the use of modafinil for depression in the elderly. It has certainly been used to counteract sedation, although whenever this situation occurs it is important to first evaluate carefully whether the other sedating drugs can be reduced before adding a second drug.

Modafinil has been used for augmentation of selective serotonin reuptake inhibitors (SSRIs) in younger patients who had an incomplete response and residual fatigue.⁸ In those patients, modafinil was more effective than placebo. To my knowledge, no equivalent placebo-controlled studies have been conducted in the geriatric group.

Do antidepressants affect suicidal thinking in the elderly?

Three studies^9-11 showed that suicidal thinking and behavior generally decline during antidepressant treatment. There remains the question of whether there is an emergence of new suicidal thinking in some patients. A placebo-controlled study of sertraline using the HAM-D to assess suicidal thinking⁹ found that the number of patients who did show some increase in the rating of suicidal thinking was similar in the placebo and sertraline groups, revealing no evidence of an aggravating effect of the antidepressant.

Self-injurious behavior such as punching one’s fist through a wall or banging one’s head against something—which may or may not actually have any suicidal intent—has been described in younger populations. In the study above there was no evidence of that in older samples in the narrative reports of adverse reactions. That may be a real difference in older patients.

Is electroconvulsive therapy (ECT) more commonly used among the elderly than the rest of the population?

There is a preponderance of older patients recieving ECT. Some older patients may be less able to tolerate aggressive antidepressant treatment, so ECT is viewed as a safer alternative. Some older patients may have refractory depressions that are not responsive to medication. Psychotic depression is one of the key indications for ECT, and it is more common in older patients. These factors explain why ECT appears to be more common in this population.

Should atypical antipsychotics be used to treat depressed elderly?

It has been clear for a long time that antipsychotics are useful for some symptoms of depression. Four of the conventional antipsychotics are Food and Drug Administration-approved for use in depression, although they are seldom used now for that purpose. The older drugs have fallen out of use now because of the risk of tardive dyskinesia and especially since the risk of tardive dyskinesia is even higher in depressed patients. Some of the more severe side-effect or safety issues associated with current atypical antipsychotics may also lead to some hesitancy about their use. They are also much more costly than antidepressants. On the other hand, atypical antipsychotics are preferred for managing certain kinds of symptoms, such as agitation and psychotic depression.

In light of cardiovascular risk, how do you treat the symptom of agitation in late-life depression?

The relationship between increased mortality risk and atypical neuroleptics is not well understood. The pathology that leads to increased risk of stroke is unclear. Vascular disease appears to be a risk factor. Older patients being treated for depression who have pronounced vascular disease are likely to have the same risks as demented patients with vascular disease. On the other hand, effective alternative treatments are limited. Conventional antipsychotics like haloperidol are not any safer. The safety of the antimanic anticonvulsants and the SSRIs, which have both been used for agitation, has not been established in large placebo-controlled trials comparable to the antipsychotic data.

In a practical sense, the key is talking with the family or caregivers about risks, benefits, and alternative treatments. If the behavioral problem is severe enough, usually families appreciate that the clinician is taking action and not ignoring the fact that the symptoms result in suffering. If a treatment improves quality of life, many families are willing to take a small risk.

Is there any role for psychotherapy in the elderly?

Older patients can respond to psychotherapy. Cognitive-behavioral therapy (CBT) and problem-solving therapy (PST) both have a good evidence base in late-life depression. PST may be especially useful in depressed patients with with executive dysfunction. Alexopoulos and colleagues¹² conducted a preliminary study using PST and found it more effective than supportive therapy in this patient group. They are now in their final year of a National Institute of Mental Health-sponsored study looking at PST for patients with executive dysfunction.

The other group that would seem to benefit from some form of psychosocial intervention are patients having their first episode of depression in late life. In these patients it has been hard to show that drugs are better than placebo. Many of those patients are demoralized because of accumulating medical problems. It appears that the nonspecific effects of education, reassurance, attention, and careful monitoring of symptoms and side effects have a positive impact. Placebo-controlled studies suggest that the nonspecific interventions listed above are very important and relatively effective among patients who have their first episode of depression in late life.

How do bipolar patients evolve with respect to the duration, frequency, and severity of mood cycles as they age?

This is a complicated issue. Goodwin and Jamison¹³ provide a good discussion of this topic. They note that it is hard to separate aging from chronicity of the illness. In other words, as patients are getting older, the course of the illness is progressing.

The percentage of people who develop chronic symptoms is relatively low. It is more common, however, for patients to develop impaired functioning. This may be related to the cumulative effect of several episodes of mania or depression, which makes it difficult to maintain employment. Bipolar patients in their late 50s and 60s are less likely to be working, or they are working below the level that they had achieved previously.

However, it is not uncommon for elderly patients in their 80s to be hospitalized for severe manic episodes. Unlike schizophrenia, which seems to diminish in intensity in late life, patients with bipolar disorder continue to be hospitalized for severe episodes. They may be especially difficult to treat because the illness is severe and they may be less able to tolerate the medicines used to treat the illness.

Is there a therapeutic advantage for either combining two antidepressants with different mechanisms or with drugs that have dual mechanisms of action?

Combinations can be useful. For example, it was demonstrated that the combination of fluoxetine (an SSRI) and desipramine (a norepinephrine agent) is more effective than either drug alone in severely depressed inpatients.¹⁴ A placebo-controlled study demonstrated the efficacy of adding mirtazapine to an SSRI.¹⁵ The combination of bupropion and an SSRI is a popular choice. However, none of these studies have been conducted in older patients. Older patients who fail monotherapy trials are likely to need combined treatment. Alternatively, older patients who are experiencing significant social disruption may benefit from antidepressants combined with an evidence-based psychotherapy.

Disclosure: Dr. Nelson is a consultant to or on the advisory boards of Abbott, Biovail, Bristol-Myers Squibb, Corcept, Eli Lilly, GlaxoSmithKline, Orexigen, Organon, Pfizer, Sepracor, and Shire; receives research support from Eli Lilly; and receives lecture honoraria from Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Pfizer, and Wyeth.

References

1. Nelson JC, ed. Geriatric Psychopharmacology. London, UK: Informa Healthcare; 1998.

2. Robins LN, Helzer JE, Weissman MM, et al. Lifetime prevalence of specific psychiatric disorders in three sites. Arch Gen Psychiatry. 1984;41(10):949-958.

3. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095-3105.

4. Nelson JC, Clary CM, Leon AC, Schneider LS. Symptoms of late-life depression: frequency and change during treatment. Am J Geriatr Psychiatry. 2005;13(6):520-526.

5. Nelson JC, Delucchi K, Schneider LS. A meta-analysis of placebo-controlled studies of second generation antidepressants in late life depression. Poster presented at: Annual Meeting of the American College of Neuropsychopharmacology; December 5, 2006; Fort Lauderdale, FL.

6. Rush AJ, Rothschild A. Efficacy and safety profile of escitalopram in the elderly: findings from a naturalistic clinical study of major depressive disorder. Presented at: 17th Annual Meeting of the American Association for Geriatric Psychiatry; February 21-24, 2004; Baltimore, MD.

7. Lavretsky H, Park S, Siddarth P, Kumar A, Reynolds CF 3rd. Methylphenidate-enhanced antidepressant response to citalopram in the elderly: a double-blind, placebo-controlled pilot trial. Am J Geriatr Psychiatry. 2006;14(2):181-185.

8. Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmenttion in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry. 2005;66(1):85-93.

9. Nelson JC, Delucchi K, Schneider LS. Effects of sertraline on suicidal thinking in late life depression. Poster presented at: 46th Annual Meeting of the New Clinical Drug Evaluation Unit; June 13, 2006; Boca Raton, FL.

10. Bruce ML, Ten Have TR, Reynolds CF 3rd, et al. Reducing suicidal ideation and depressive symptoms in depressed older primary care patients: a randomized controlled trial. JAMA. 2004;291(9):1081-1091.

11. Szanto K, Mulsant BH, Houck P, Dew MA, Reynolds CF 3rd. Occurrence and course of suicidality during short-term treatment of late-life depression. Arch Gen Psychiatry. 2003;60(6):610-617.

12. Alexopoulos GS, Raue P, Arean P. Problem-solving therapy versus supportive therapy in geriatric major depression with executive dysfunction. Am J Geriatr Psychiatry. 2003;11(1):46-52.

13. Goodwin FK, Jamison KR. Manic-Depressive Illness. New York, NY: Oxford University Press; 1990.

14. Nelson JC, Mazure CM, Jatlow PI, Bowers MB, Price LH. Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: a double-blind, randomized study. Biol Psychiatry. 2004;55(3):296-300.

15. Carpenter LL, Yasmin S, Price LH. A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. Biol Psychiatry. 2002;51(2):183-188.