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|Neuropsychopharmacology: The Fifth Generation of Progress|
Pharmacological Treatment Of Depression In Late Life
Carl Salzman, Lon S. Schneider, and George Alexopoulos
Major depression is a serious disorder in late life. Although common, it is less frequent in elderly compared to younger adults. The one-year prevalence of major depression among community-dwelling persons aged 65 years or older is approximately 1%; with an approximately 2% prevalence of dysthymic disorder (12,62). The prevalence is increased in women compared to men. Significant depressive symptoms without a major depression diagnosis occur in approximately 8-15% of community residents over 65 years of age (33). Elderly patients hospitalized for a medical illness have an even higher prevalence of depression with a rate of 40% for combined major and minor depression (60). Dysthymia in elderly outpatients is not uncommon in the elderly and tends to become chronic (12,44). Compared with major depression it has less associated psychiatric comorbidity, although it is more closely tied to severe life stresses and medical illness with early age onset (33).
In nursing home residents, major depression has been estimated at approximately 12% while lesser but clinically significant depression occurs in an additional in 30-35% (26,29). The rates of new cases of depression in nursing homes are striking, with a 14% incidence of major depression over a six-month period. Those at highest risk for major depression are the cognitively intact nursing home patients who are sickest, most disabled, and most dependent, compared to cognitively impaired residents (24% versus 10%, respectively). Patients with major depression show increased mortality, with death rates between 1.5 and three times those of other residents (52). Dysphoria in residential care facilities occurs in nearly 20 percent of residents, and is a persistent state also associated with increased medical illness, pain, self-care deficits, and mortality relative to euthymic subjects (26). Interestingly, recent studies have emphasized the lack of reliability in the history of past and present depression given by older respondents. The duration of previous depressive episodes and age at depression onset cannot always be determined reliably, even when structured interviews are used. Greater difficulties may be encountered in patients with minor depression or chronic intermittent depression as well as early onset depression (88). Recent data further suggest that the Hamilton Depression Rating Scale, which is the most widely used outcome measure in geriatric depression research, may also lack reliability and validity in this population (82).
Compared to early onset geriatric depressives, patients with late-onset depression appear to have less frequent family histories of mood disorders, higher prevalence of dementing disorders, more impairment in neuropsychological tests, higher rate of dementia follow-up, and more neurosensory hearing impairment.
As in younger people, the course of depression in the elderly is characterized by exacerbations and remissions, as well as chronicity. Sixty percent of elderly patients who recover from an index episode have at least another subsequent one; relapse and chronicity occur in up to 40 percent of depressed patients (8). Mortality is significant, with an annual death rate of about 10%; delusional depression is associated with greater morbidity and mortality than in patients without delusions (43). The rate of completed suicides for older people is over twice as high as that of the general population (26.5/100,000 in 80- to 84-year olds compared to 12.4/100,000 overall (15).
Vascular depression, a depression related to multiple brain infarcts, has been increasingly studied in the geriatric population. The depression is MORE likely to be associated with a family history of alcohol or drug abuse, functional disability, and anhedonia. The depression itself is likely to be associated with cognitive impairment, but not delusions (see below) (15,34). Depressive syndromes are also frequent in elderly patients with stroke, Parkinson's disease, and dementia (3).
Despite progress in treatment with antidepressant drugs, longitudinal studies indicate significant chronicity (64). Although about 60% of elderly depressed patients remain well at one to six years follow-up, the other 40% show relapse, only partial improvement, chronicity or death (43). Chronicity of depression in the elderly may be predicted by coexisting medical illness, high severity of depression, non-melancholic presentation, and delusions. Depression with reversible dementia is associated with greater 4-fold increased risk of irreversible dementia (7). Depressed mood is associated with a 3-fold increase in dementia (18).
Although depression in the elderly may symptomatically resemble younger life depression, there is considerable diagnostic heterogeneity. Consequently, the search for diagnostic biologic markers of depression has been particularly important in the elderly. In addition to symptomatic variability from patient to patient (14,86), there is diagnostic overlap with dementia, as well as the presence of medical illnesses which may obscure the diagnosis (6). As with young persons, no specific diagnostic test for late-life depression has yet been developed. Vascular depression in the elderly, however, has been associated with greater changes in wave V latency than do elderly depressed patients without vascular disease (24). Other studies have reported a correlation between prefrontal lobe volume and severity of late-life depression (35,36).
Treatment of Depression
Appreciation of the age-associated changes in the bioavailability of antidepressants is important when treating older patients. The aging process is associated with changes in the pharmacokinetic characteristics of antidepressant drugs including altered absorption, distribution, metabolism and excretion of medications. The most clinically significant changes, however, occur in hepatic and renal clearance.
Hepatic clearance of antidepressants is, in general, decreased in the elderly due to reduced hepatic blood flow and enzyme activity. Renal clearance is reduced by the aging process as well as by disease. Although there is great individual variability (20,87), these changes are reflected in higher plasma levels and prolonged elimination half-lives.
Studies of tricyclic antidepressant hydroxymetabolites have been of particular relevance to the elderly. It was initially assumed that these metabolites, produced by hepatic aromatic hydroxylation, were inactive; current evidence suggests that they are active and potentially cardiotoxic (see Side Effects, below). Since these hydroxymetabolites are water soluble, their clearance depends on renal function which is likely to be reduced by age, disease, or medications. Significant age-related elevations of hydroxymetabolites are likely to occur with all tricyclic antidepressants but data in elderly patients have been reported with nortriptyline (40,74,89), and desipramine (31).
The relationship between antidepressant blood levels and therapeutic response in the elderly is also characterized by a large degree of inter-individual variation (87). For nortriptyline and desipramine, elderly patients have been shown to require approximately the same therapeutic plasma levels as young adults, although lower doses may produce these levels (16,17,28,37,38,47). Blood levels of imipramine and amitriptyline tend to be higher in the elderly than in young adults (1,48), but these levels have not clearly been correlated with therapeutic response. Plasma levels of doxepin and trazodone similarly have not been correlated with clinical response, although higher levels in the elderly are associated with greater side effects (79). Plasma levels of SSRIs have not been correlated with therapeutic response in the elderly.
In elderly patients, it has been possible to predict therapeutic daily doses of nortriptyline by measuring the plasma level 24 hours after the administration of a single 50 mg dose of nortriptyline with by measuring the plasma level 24 hours (16,17,76). The usefulness of this technique in clinical treatment settings, however, is not clear.
Elderly patients are more likely to be taking several medications simultaneously, increasing the potential for adverse drug interactions (58). However, there are no data to suggest that there are age-related changes in enzyme function that make the elderly sensitive to these interactions aside from the risks of polypharmacy.
The efficacy of antidepressants for the treatment of late-life depression has been frequently described in the literature (e.g., 13,30,54,57,61-63,65,67-69,78,80). An NIMH-sponsored consensus conference on depression in the elderly (53) as well as older recent reviews of all efficacy studies have concluded the following: (1) the best-studied drug, nortriptyline, produces a 70-80 percent remission rate; (2) SSRI studies tend to show response rates approximately similar to tricyclics. However, only a few studies have been conducted and further data are needed; (3) there is a remarkable lack of clinical trials for other recently-released or atypically-structured antidepressants in the elderly population. Although efficacy has been suggested for all of these drugs, their comparative usefulness with respect to tricyclics or SSRIs is still not clear (45,4,81,66). There are no double-blind controlled trials of bupropion in patients exclusively above the age of 65; one trial in a mixed older age population demonstrated its efficacy and safety (25). In the only study of delusional elderly patients (4), antidepressants were found to be effective in only about 50% of delusional patients, and residual symptoms were common.
Several metaanalyses of antidepressant treatment in the elderly have also been performed confirming short-term efficacy (32,78). These indicate that drug-placebo differences are only modest (in terms of Hamilton scale points), and significant residual symptomatology remain in the drug-treated group. Two more recent metaanalyses found no clear differences between heterocyclics and serotonergics in efficacy or safety (short-term as well) (41,42).
Morning presystolic orthostatic blood pressure has been shown to shown to correlate inversely with response to nortriptyline in some elderly patients (23,75,83). The applicability of this finding in clinical treatment settings, however, is not clear.
SSRI antidepressants have become the most common class of antidepressants given to the elderly because of their therapeutic efficacy and favorable side-effect profile. Approximately 1500 elderly patients with major depression have participated in studies of antidepressants (81). Among the SSRIs currently available in the United States, fluoxetine has been studied most frequently. Response has been associated with lower levels of anxiety, somatization, as well as low levels of cognitive and sleep disturbance. However, as with many studies of SSRIs in the elderly, a high placebo response rate has been noticed (2). Fluoxetine has also been used to successfully treat dysthymia in the elderly (49). Elderly women patients treated with fluoxetine who also received estrogen replacement showed a substantially greater mean HAM-D percentage improvement than patients receiving ERT who were treated with placebo (73). Citalopram given to elderly depressed patients produced a significant improvement in 53 percent without significant side effects (21).
There are no clinical or research data to suggest that one MAOI is therapeutically superior to any other in the elderly. Starting and treatment doses are substantially lower for elderly patients compared with younger depressed adults (4). Adequate therapeutic ranges for MAOIs have never been carefully established for older patients, and it is possible that some elderly patients may require full therapeutic doses. Monitoring platelet MAO inhibition activity as a guide to dosing is of uncertain value.
Stimulants are sometimes used to treat anergia and apathy in non-depressed elderly persons (56). No controlled or methodologically acceptable studies have been conducted to date (4).
Eight reports suggest a modest effect of lithium in augmenting tricyclic antidepressant response in the elderly (summarized in 4). Not all who receive lithium respond with enhanced therapeutic effect; however, and in those who did improve, the necessary lithium dose was one-third to one-half that of younger adults. Augmentation with carbamazepine or thyroid medication has not been systematically studied in geriatric patients.
Common heterocyclic antidepressant side effects that are particularly hazardous in the elderly include orthostatic hypotension, sedation, cardiac toxicity, and anticholinergic reactions. Side effects of selective serotonin reuptake inhibitors do not differ between young and elderly populations; agitation, anxiety, insomnia, sedation, gastrointestinal difficulties, and sexual dysfunction have been reported with all currently available SSRIs. Based on the available data, it is not possible to state whether or not the elderly are more sensitive to these side effects than younger patients at therapeutic doses.
Side effects of MAOIs, especially orthostatic hypotension, are common in the elderly. Other side effects include agitation, insomnia, sedation, hypertensive crisis, weight gain, peripheral neuropathy, exacerbation of cognitive dysfunction, and inhibition of orgasm.
The most serious side effect of heterocyclic antidepressant treatment in older patients is cardiotoxicity. Patients with preexisting conduction defects present the highest risk. The quinidine-like effects produce sinus tachycardia and stabilization of abnormal cardiac rhythms at low plasma drug levels. However, at higher plasma levels, these effects interfere with cardiac conduction. Serious conduction alterations (including right and left bundle branch block or partial or complete atrioventricular (AV) block occur at very high or toxic plasma levels and are reflected in the ECG as prolonged PR, QRS, and QT intervals and T-wave flattening or inversion (19,22,53). These effects have not been reported with trazodone (22). High plasma levels of 10-hydroxy-nortriptyline (39) and 2-hydroxy-desipramine (46) are also associated with cardiac conduction defects in older patients and are reflected in the ECG.
Several comprehensive reviews (72) have concluded that
amitriptyline and imipramine cause significant orthostatic hypotension and probably should be avoided in the elderly. A recent report indicates that falls in elderly patients occur in association with SSRI as well as with TCAs (84). Anticholinergic effects also limit the use of tertiary amine tricyclic antidepressants in the elderly. The anticholinergic properties of paroxetine (the only SSRI which blocks M1 receptors) in the elderly is one-fifth that of nortriptyline when both drugs are given in therapeutic doses (58).
A growing area of clinical and research enquiry has been the treatment of depression in patients with comorbid Alzheimer's disease, as well as the treatment of cognitive impairment associated with late-life depression. Most data suggest that cautious treatment using low doses in depressed patients who have mild to moderate Alzheimer's disease may result in transient improvement of both the depression as well as the cognitive impairment. SSRIs and other non-anticholinergic drugs are probably preferred (3,50,51,55) since tricyclics may add to the existing memory impairment of a demented patient. The SSRI citalopram has been found effective in both demented and non-demented depressed elderly patients (50). Moreover, citalopram appears to be effective in the treatment of behavioral disturbances of non-depressed demented patients (51) While specific studies are needed, these findings suggest that citalopram, and perhaps other SSRIs, may be favored in cognitively impaired patients both because they treat a broad spectrum of symptoms and because they have limited anticholinergic and histaminergic properties.
Problems in Research Methodology Used to Study Antidepressant Effects in the Elderly
Several methodological problems face the clinician who wishes to study the pharmacologic treatment of depression in the elderly.
Age. Although age 65 is conventionally considered to be the onset of "old age", most published reports includes subjects who are under 65, and the greatest majority of patients are between the ages of 55 and 65. There are only 5 studies of depressed patients exclusively 75 and older, and only one study (27) of patients all 80 or older (70).
Medical illness. Elderly patients in randomized clinical trials are usually outpatients without concomitant physical illness, and who are not taking medication for concomitant physical disorders. Thus, they represent an atypical sample of depressed elderly patients, most of whom may be suffering from a variety of disorders as well as taking several medications simultaneously.
Criteria for depression. Virtually all depressed patients in research studies suffer from moderately severe depression as suggested by Hamilton depression rating scores ranging between 18 and 22. There are no studies of elderly patients with Hamilton scores higher than 30, and only 1 study of delusional (psychotic) depressed elderly patients.
Criteria for therapeutic response. In nearly all studies, therapeutic response consists of a percentage decline of baseline rating-scale scores, e.g. 50% from the original score. In elderly subjects, final Hamilton scores are often greater than 10. Consequently, patients who were initially the most depressed prior to treatment are still likely to be depressed at the end of the treatment course (albeit somewhat less so than placebo treated patients). In most studies, patients are left with significant residual depressive symptoms. No study has asked patients about their quality of life or the degree to which they felt they had returned to their normal baseline affective status and only a few studies consider the final depression rating scale to be an outcome criterion.
It is becoming apparent that many of the conclusions regarding antidepressant pharmacology and therapeutic efficacy in the elderly are based on information that has not adequately reflected the heterogeneity of the elderly patient sample, problems in patient selection, wide range of inter-individual variability, concomitant medication, and definition of both depression and treatment response. The NIMH Consensus Conference called for further research on the effect of antidepressants in the elderly, especially in the over 80 age group range.
Considering the numerous methodologic problems of available studies with this population, the following tentative conclusions can be offered:
1. No individual antidepressant is best for elderly patients.
2. Among the tricyclic antidepressants, secondary amines are usually recommended.
3. Therapeutic blood levels of tricyclics in the elderly are similar to levels required for response in younger patients; lower doses may achieve these levels. Elimination half-life of parent compounds, desmethylated metabolites, and hydroxymetabolites tend to be prolonged.
4. Tricyclic antidepressants produce water-soluble hydroxymetabolites whose excretion is dependent of renal function. These metabolites may produce clinically relevant cardiotoxicity.
5. Selective serotonin reuptake inhibitors may be effective, well tolerated antidepressants in the elderly, but more data are needed. No data suggest a therapeutic superiority for one SSRI.
6. Augmentation of tricyclic antidepressant effect may be helpful for some elderly patients, but this effect is neither reliable nor predictable. Further data are required to form definitive conclusions.
7. Monoamine oxidase inhibitors may be therapeutic, but most of the data comes from studies employing a heterogeneous patient population. The clinical use of these compounds in the elderly may be complicated by numerous problems.
8. Considerable progress has been made in the treatment on late-life depression. Many elderly will now respond to treatment, and a significant number will actually become well. Late-life depression should be considered to be a treatable disorder that is carefully but assertively diagnosed and then treated. Once a response has occurred, elderly patients should be maintained on their medication in order to prevent relapse as with younger populations. Because of the numerous potential complications of age, frail health, multiple medical illnesses and treatments, the effective treatment of late-life depression requires frequent contact with the older patient, dosing flexibility, and attention to the particular needs of this age group.