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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).
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.
published 2000