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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 toyounger adults. The one-year prevalence of major depression among community-dwelling persons aged 65years or older is approximately 1%; with an approximately 2% prevalence of dysthymic disorder (12,62). Theprevalence is increased in women compared to men. Significant depressive symptoms without a majordepression diagnosis occur in approximately 8-15% of community residents over 65 years of age (33). Elderlypatients hospitalized for a medical illness have an even higher prevalence of depression with a rate of 40% forcombined major and minor depression (60). Dysthymia in elderly outpatients is not uncommon in the elderlyand tends to become chronic (12,44). Compared with major depression it has less associated psychiatriccomorbidity, 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 clinicallysignificant depression occurs in an additional in 30-35% (26,29). The rates of new cases of depression in nursinghomes are striking, with a 14% incidence of major depression over a six-month period. Those at highest risk formajor depression are the cognitively intact nursing home patients who are sickest, most disabled, and mostdependent, compared to cognitively impaired residents (24% versus 10%, respectively). Patients with majordepression 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 alsoassociated 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 presentdepression given by older respondents. The duration of previous depressive episodes and age at depression onsetcannot always be determined reliably, even when structured interviews are used. Greater difficulties may beencountered in patients with minor depression or chronic intermittent depression as well as early onsetdepression (88). Recent data further suggest that the Hamilton Depression Rating Scale, which is the mostwidely used outcome measure in geriatric depression research, may also lack reliability and validity in thispopulation (82).

Compared to early onset geriatric depressives, patients with late-onset depression appear to have less frequentfamily histories of mood disorders, higher prevalence of dementing disorders, more impairment inneuropsychological 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, aswell as chronicity. Sixty percent of elderly patients who recover from an index episode have at least anothersubsequent one; relapse and chronicity occur in up to 40 percent of depressed patients (8). Mortality issignificant, with an annual death rate of about 10%; delusional depression is associated with greater morbidityand mortality than in patients without delusions (43). The rate of completed suicides for older people is over

Pharmacological Treatment Of Depression In Late Life http://www.acnp.org/g4/GN401000141/CH.html

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twice as high as that of the general population (26.5/100,000 in 80- to 84-year olds compared to 12.4/100,000overall (15).

Vascular depression, a depression related to multiple brain infarcts, has been increasingly studied in the geriatricpopulation. 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 bepredicted by coexisting medical illness, high severity of depression, non-melancholic presentation, anddelusions. Depression with reversible dementia is associated with greater 4-fold increased risk of irreversibledementia (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 considerablediagnostic heterogeneity. Consequently, the search for diagnostic biologic markers of depression has beenparticularly important in the elderly. In addition to symptomatic variability from patient to patient (14,86), thereis diagnostic overlap with dementia, as well as the presence of medical illnesses which may obscure thediagnosis (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 doelderly depressed patients without vascular disease (24). Other studies have reported a correlation betweenprefrontal 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 treatingolder patients. The aging process is associated with changes in the pharmacokinetic characteristics ofantidepressant drugs including altered absorption, distribution, metabolism and excretion of medications. Themost 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 flowand enzyme activity. Renal clearance is reduced by the aging process as well as by disease. Although there isgreat individual variability (20,87), these changes are reflected in higher plasma levels and prolonged eliminationhalf-lives.

Studies of tricyclic antidepressant hydroxymetabolites have been of particular relevance to the elderly. It wasinitially assumed that these metabolites, produced by hepatic aromatic hydroxylation, were inactive; currentevidence suggests that they are active and potentially cardiotoxic (see Side Effects, below). Since thesehydroxymetabolites are water soluble, their clearance depends on renal function which is likely to be reduced byage, disease, or medications. Significant age-related elevations of hydroxymetabolites are likely to occur with alltricyclic antidepressants but data in elderly patients have been reported with nortriptyline (40,74,89), anddesipramine (31).

The relationship between antidepressant blood levels and therapeutic response in the elderly is also characterizedby a large degree of inter-individual variation (87). For nortriptyline and desipramine, elderly patients have beenshown to require approximately the same therapeutic plasma levels as young adults, although lower doses mayproduce these levels (16,17,28,37,38,47). Blood levels of imipramine and amitriptyline tend to be higher in the


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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, althoughhigher levels in the elderly are associated with greater side effects (79). Plasma levels of SSRIs have not beencorrelated with therapeutic response in the elderly.

In elderly patients, it has been possible to predict therapeutic daily doses of nortriptyline by measuring theplasma level 24 hours after the administration of a single 50 mg dose of nortriptyline with by measuring theplasma level 24 hours (16,17,76). The usefulness of this technique in clinical treatment settings, however, is notclear.

Elderly patients are more likely to be taking several medications simultaneously, increasing the potential foradverse drug interactions (58). However, there are no data to suggest that there are age-related changes inenzyme 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 theliterature (e.g., 13,30,54,57,61-63,65,67-69,78,80). An NIMH-sponsored consensus conference on depression inthe elderly (53) as well as older recent reviews of all efficacy studies have concluded the following: (1) thebest-studied drug, nortriptyline, produces a 70-80 percent remission rate; (2) SSRI studies tend to show responserates approximately similar to tricyclics. However, only a few studies have been conducted and further data areneeded; (3) there is a remarkable lack of clinical trials for other recently-released or atypically-structuredantidepressants in the elderly population. Although efficacy has been suggested for all of these drugs, theircomparative usefulness with respect to tricyclics or SSRIs is still not clear (45,4,81,66). There are nodouble-blind controlled trials of bupropion in patients exclusively above the age of 65; one trial in a mixed olderage 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 werecommon.

Several metaanalyses of antidepressant treatment in the elderly have also been performed confirming short-termefficacy (32,78). These indicate that drug-placebo differences are only modest (in terms of Hamilton scalepoints), and significant residual symptomatology remain in the drug-treated group. Two more recentmetaanalyses found no clear differences between heterocyclics and serotonergics in efficacy or safety (short-termas well) (41,42).

Morning presystolic orthostatic blood pressure has been shown to shown to correlate inversely with response tonortriptyline 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 oftheir therapeutic efficacy and favorable side-effect profile. Approximately 1500 elderly patients with majordepression have participated in studies of antidepressants (81). Among the SSRIs currently available in theUnited States, fluoxetine has been studied most frequently. Response has been associated with lower levels ofanxiety, somatization, as well as low levels of cognitive and sleep disturbance. However, as with many studiesof SSRIs in the elderly, a high placebo response rate has been noticed (2). Fluoxetine has also been used tosuccessfully treat dysthymia in the elderly (49). Elderly women patients treated with fluoxetine who alsoreceived estrogen replacement showed a substantially greater mean HAM-D percentage improvement thanpatients receiving ERT who were treated with placebo (73). Citalopram given to elderly depressed patientsproduced 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


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elderly. Starting and treatment doses are substantially lower for elderly patients compared with youngerdepressed adults (4). Adequate therapeutic ranges for MAOIs have never been carefully established for olderpatients, and it is possible that some elderly patients may require full therapeutic doses. Monitoring plateletMAO 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 controlledor 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 thosewho did improve, the necessary lithium dose was one-third to one-half that of younger adults. Augmentationwith carbamazepine or thyroid medication has not been systematically studied in geriatric patients.

Side Effects

Common heterocyclic antidepressant side effects that are particularly hazardous in the elderly include orthostatichypotension, sedation, cardiac toxicity, and anticholinergic reactions. Side effects of selective serotonin reuptakeinhibitors 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. Basedon the available data, it is not possible to state whether or not the elderly are more sensitive to these side effectsthan younger patients at therapeutic doses.

Side effects of MAOIs, especially orthostatic hypotension, are common in the elderly. Other side effects includeagitation, insomnia, sedation, hypertensive crisis, weight gain, peripheral neuropathy, exacerbation of cognitivedysfunction, and inhibition of orgasm.

The most serious side effect of heterocyclic antidepressant treatment in older patients is cardiotoxicity. Patientswith preexisting conduction defects present the highest risk. The quinidine-like effects produce sinustachycardia and stabilization of abnormal cardiac rhythms at low plasma drug levels. However, at higher plasmalevels, these effects interfere with cardiac conduction. Serious conduction alterations (including right and leftbundle branch block or partial or complete atrioventricular (AV) block occur at very high or toxic plasma levelsand 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 olderpatients 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 theelderly. A recent report indicates that falls in elderly patients occur in association with SSRI as well as withTCAs (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-fifththat 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 comorbidAlzheimer's disease, as well as the treatment of cognitive impairment associated with late-life depression. Mostdata suggest that cautious treatment using low doses in depressed patients who have mild to moderateAlzheimer's disease may result in transient improvement of both the depression as well as the cognitiveimpairment. SSRIs and other non-anticholinergic drugs are probably preferred (3,50,51,55) since tricyclics may


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add to the existing memory impairment of a demented patient. The SSRI citalopram has been found effective inboth demented and non-demented depressed elderly patients (50). Moreover, citalopram appears to be effectivein the treatment of behavioral disturbances of non-depressed demented patients (51) While specific studies areneeded, these findings suggest that citalopram, and perhaps other SSRIs, may be favored in cognitively impairedpatients both because they treat a broad spectrum of symptoms and because they have limited anticholinergic andhistaminergic 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 ofdepression in the elderly.

Age. Although age 65 is conventionally considered to be the onset of "old age", most published reports includessubjects who are under 65, and the greatest majority of patients are between the ages of 55 and 65. There areonly 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 concomitantphysical illness, and who are not taking medication for concomitant physical disorders. Thus, they represent anatypical sample of depressed elderly patients, most of whom may be suffering from a variety of disorders as wellas taking several medications simultaneously.

Criteria for depression. Virtually all depressed patients in research studies suffer from moderately severedepression as suggested by Hamilton depression rating scores ranging between 18 and 22. There are no studiesof elderly patients with Hamilton scores higher than 30, and only 1 study of delusional (psychotic) depressedelderly patients.

Criteria for therapeutic response. In nearly all studies, therapeutic response consists of a percentage decline ofbaseline rating-scale scores, e.g. 50% from the original score. In elderly subjects, final Hamilton scores are oftengreater than 10. Consequently, patients who were initially the most depressed prior to treatment are still likely tobe depressed at the end of the treatment course (albeit somewhat less so than placebo treated patients). In moststudies, patients are left with significant residual depressive symptoms. No study has asked patients about theirquality of life or the degree to which they felt they had returned to their normal baseline affective status and onlya few studies consider the final depression rating scale to be an outcome criterion.

Conclusions

It is becoming apparent that many of the conclusions regarding antidepressant pharmacology and therapeuticefficacy in the elderly are based on information that has not adequately reflected the heterogeneity of the elderlypatient 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 furtherresearch 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 followingtentative conclusions can be offered:

1. No individual antidepressant is best for elderly patients.

2. Among the tricyclic antidepressants, secondary amines are usually recommended.


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3. Therapeutic blood levels of tricyclics in the elderly are similar to levels required for response in youngerpatients; lower doses may achieve these levels. Elimination half-life of parent compounds, desmethylatedmetabolites, and hydroxymetabolites tend to be prolonged.

4. Tricyclic antidepressants produce water-soluble hydroxymetabolites whose excretion is dependent of renalfunction. These metabolites may produce clinically relevant cardiotoxicity.

5. Selective serotonin reuptake inhibitors may be effective, well tolerated antidepressants in the elderly, but moredata 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 isneither 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 aheterogeneous patient population. The clinical use of these compounds in the elderly may be complicated bynumerous problems.

8. Considerable progress has been made in the treatment on late-life depression. Many elderly will now respondto treatment, and a significant number will actually become well. Late-life depression should be considered to bea 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 youngerpopulations. Because of the numerous potential complications of age, frail health, multiple medical illnesses andtreatments, the effective treatment of late-life depression requires frequent contact with the older patient, dosingflexibility, and attention to the particular needs of this age group.

published 2000


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