Depression

Treatment Options

From 65% to 75% of cases of depression are treatable; depression can be fatal in 15% of cases if it remains untreated. The earlier the intervention in primary care, the earlier the remission. A “watch-and-wait” period of no more than two weeks for bereavement is acceptable. The lesser the intensity of the initial grief reaction, the better the eventual outcome.

Timing is also important in the administration of estrogen for cognitive problems in older women; later administration worsens the problems.

The outcome of comorbid illness is positively correlated with treatment of the underlying depression. Poor functioning, anxiety, and hopelessness predict a poor response; referral to a mental health specialist should be considered.

Watchful waiting in patients with subsyndromal depressive states is not indicated if social support is inadequate or if there is significant impairment of activities of daily living (ADL). Ethical concerns have been raised about the use of placebo in the treatment of depression in the elderly because of the heterogeneity of causes and responses. Most treatment errors are the result of the non-use or misuse of medications, not over-medication. The most recent study of maintenance treatment of depression in the elderly available at this writing demonstrated the superiority of treatment for two years with paroxetine (Paxil) to psychotherapy alone or placebo in lowering relapse rates significantly.

Table 3 Medications for Depression

Drug Daily Dosage Range (mg)* Adverse Effects Interactions
TCAs
Amitriptylinef 25-150 Anticholinergic and cardiac effects, sedation, orthostatic hypotension, weight gain, reduced seizure threshold, increased falling risk Antiarrhythmics:!:, MAOIs:, SSRIs, serotonin syndrome
Desipramine (Norpramin) 25-150 Anticholinergic and cardiac effects, sedation, orthostatic hypotension, weight gain, reduced seizure threshold, increased falling risk Antiarrhythmics:, MAOIs:, SSRIs, serotonin syndrome
Doxepinf (Sinequan) 25-150 Anticholinergic and cardiac effects, sedation, orthostatic hypotension, weight gain, reduced seizure threshold, increased falling risk Antiarrhythmics:, MAOIs:, SSRIs, serotonin syndrome
Imipramine (Tofranil) 25-150 Anticholinergic and cardiac effects, sedation, orthostatic hypotension, weight gain, reduced seizure threshold, increased falling risk Antiarrhythmics:, MAOIs:, SSRIs, serotonin syndrome
Nortriptyline canadian 25-150 Anticholinergic and cardiac effects, sedation, orthostatic hypotension, weight gain, reduced seizure threshold, increased falling risk Antiarrhythmics:, MAOIs:, SSRIs, serotonin syndrome
Protriptyline (Vivactil) 15-50 Anticholinergic and cardiac effects, sedation, orthostatic hypotension, weight gain, reduced seizure threshold, increased falling risk Antiarrhythmics:, MAOIs:, SSRIs, serotonin syndrome
  50-400 Extrapyramidal movement disorders, male sexual dysfunction, endocrine dysfunction MAOIs:
MAOIs
Tranylcypromine sulfate (Parnate) 30 Orthostatic hypotension MAOIs:, meperidine:, vasoconstric­tors:, narcotics:, decongestants:
Phenelzine sulfate(Nardil) 45-60 Orthostatic hypotension MAOIs:, meperidine:, vasoconstric­tors:, narcotics:, decongestants:
SSRIs
Escitalopram oxalate 10-20 GI symptoms, anxiety, somnolence, sexual dysfunction MAOIs:,TCAs, neuroleptics, antihistamines, antiarrhythmics:
Citalopram hydrobro-mide (Canadian Celexa) 20-60 GI symptoms, anxiety, somnolence, sexual dysfunction MAOIs:,TCAs, neuroleptics, antihistamines, antiarrhythmics:
  25-150 GI symptoms, insomnia, anxiety MAOIs:,TCAs, neuroleptics, antihistamines, antiarrhythmics:
Fluoxetine tablet (Generic Prozac) 10-40 Anorexia, agitation, anxiety, GI symptoms, insomnia, weight loss MAOIs:,TCAs, neuroleptics, antiarrhythmics:
Paroxetine HCl 25-35.7 GI symptoms, anxiety, insomnia, fatigue, dry mouth MAOIs:,TCAs, neuroleptics, antiarrhythmics:
Sertraline drug (Zoloft canadian) 25-200 GI symptoms, sexual dysfunction, weight gain, headache MAOIs:,TCAs, neuroleptics, antiarrhythmics:

Many medications are available for the in the elderly (Table 3). Some of these agents are preferred for certain comorbid conditions (Table 4). These drugs may protect against a decrease in gray matter in the elderly, provide neuroprotection, and enhance brain-derived neu-rotrophic factor.

Start low and go slow. Clinicians should use the lowest dosage range, as shown in Table 3, and should maintain this level for several weeks before increasing the dosage if there is no improvement. Adverse drug effects are quite common in older people because of polypharmacy and multiple physical changes, particularly decreased drug-binding proteins; muscle mass; and renal, hepatic, and cardiac function.

Table 4 Treatment Recommendations for Depressed Patients with Comorbid Medical Conditions

Medication of Choice Drugs to Avoid
Neurologic disease
Alzheimer’s dementia SSRIs, nefazodone, venlafaxine TCAs, bupropion, fluoxetine if agitation present
Parkinson’s disease Bupropion, venlafaxine TCAs, MAOIs, SSRIs if co-prescribed with selegiline
Stroke SSRIs, possibly secondary amines TCAs, MAOIs, bupropion
  TCAs, duloxetine MAOIs
Cachexia Sertraline, paroxetine, trazodone, nefazodone,TCAs, venlafaxine fluoxetine
Nausea Bupropion, SSRIs, venlafaxine
Pain (severe with cancer) TCAs, duloxetine MAOIs
Cardiac disease SSRIs, bupropion, nefazodone TCAs, SSRIs with type-1C antiarrhythmics(e.g., encainide, flecainide), venlafaxine in hypertension
MAOI = monoamine oxidase inhibitor; SSRI = selective serotonin reuptake inhibitor;TCA = tricyclic antidepressant.

Care should be taken in selecting an antidepressant medication and determining the dosing guidelines and the length of therapeutic trials. Prudence dictates avoiding drugs with significant anticholinergic side effects, such as tricyclic anti-depressants (TCAs) as well as sedating antidepressants, which may increase the risk of falling. Agents like sertraline (Zoloft, Pfizer), sustained-release bupropion (Wellbutrin SR, Glaxo-SmithKline), and citalopram hydrobromide (Celexa, Forest) are recommended by expert consensus primarily because these agents help avoid many of the common problematic drug interactions.

TCAs are no longer considered first-line therapy for older patients, although they are thought to be equally effective in comparisons with younger populations. Significant anticholin-ergic side effects and problems with adhering to dosage recommendations are the major reasons for the reduced use of TCAs.

Selective serotonin reuptake inhibitors (SSRIs) are the usual first-line drugs, and selective serotonin-norepinephrine re-uptake inhibitors (SNRIs) are usually the first drugs that are substituted when initial monotherapy fails. Although fluoxetine (Prozac, Eli Lilly) was the first SSRI to be approved for geriatric depression, it would be hard to argue with the use of the short-half-life SSRIs as a first-line treatment in this population. Better tolerated than monoamine oxidase inhibitors (MAOIs) and TCAs, SSRIs have a therapeutic response rate approaching 75%. Dropout rates are 50% to 70% for TCAs, and the cost of SSRIs is offset by the need for less intensive in-patient and outpatient care.

Common side effects include agitation, insomnia, fatigue, dry mouth, weight loss, headache, anxiety, nausea, diarrhea, and constipation. Transitory gastrointestinal distress may be reduced by slow titration and by taking the medication with meals. Sexual dysfunction occurs in 15% to 30% of patients taking SSRIs; in these cases, fluvoxamine maleate (e.g., Luvox, Solvay) should be chosen because the incidence of dysfunction is much lower.

Sertraline, citalopram, and escitalopram (Lexapro, Forest) are associated with a low rate of drug-drug interactions; they are available in a wide range of dosages and are well tolerated. Duloxetine (Cymbalta, Eli Lilly) significantly improves arthritis pain in depressed elderly patients and may be useful for depressed patients with associated pain caused by cancer.

Executive dysfunction, anhedonia, and decreased nor-adrenergic tone, characteristic of late-onset depression, may be associated with a poor response to antidepressant therapy, particularly SSRIs. Recently, the syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been identified in 12% to 25% of elderly patients taking SSRIs. Because the integrity of the receptor sites for these agents appears to be a function of serum cholesterol, excessive swings or reductions may affect therapeutic efficacy.

Alternative drugs such as (Organon) and (Wyeth) have been shown to be equal in efficacy to sertraline. Venlafaxine appears to be useful in elderly patients with treatment-resistant depression, but careful blood pressure monitoring is important in patients with preexisting cardiovascular disease. Bupropion, in its extended-release and SR forms, promotes compliance, and its efficacy appears to be equivalent to that of the TCAs and SSRIs.

Although bupropion has been removed from the Canadian and European markets because of associated liver failure, there are no recommended guidelines for the monitoring of liver functions. Sexual dysfunction is less common with mirtazapine, nefazodone.

Modafinil (Provigil, Cephalon) is a wakefulness-promoting agent that can increase noradrenergic tone as an augmentation strategy with fewer side effects (e.g., tachycardia, anxiety, insomnia). As a result, it might be useful in late-onset or resistant depression that does not respond to SSRIs alone.

Despite a generally negative perception of MAOIs among clinicians, these agents are safe and effective in older patients. A period of at least five to seven weeks is required to attain full therapeutic efficacy. Patients may need at least a two-week washout period before starting an MAOI if another psycho-tropic medication (or another drug that may have an adverse interaction with an MAOI) is to be prescribed.

If the patient is being switched from an MAOI to another antidepressant, the two-week washout period is also necessary before the patient begins taking the new antidepressant. The serotonin withdrawal syndrome (e.g., tremor, diarrhea, fever, incoordination, myoclonus, agitation, shivering, mental status changes, hyperreflexia, and diaphoresis) can follow the use of MAOIs with TCAs and SSRIs. A tyramine-free diet is required for patients taking an MAOI.

For the “vascular” type of depression, drugs that improve adrenergic tone (e.g., desipramine [Norpramin, Sanofi-Aventis]) or dopaminergic tone (bromocriptine), or both (amphetamines) are required. Alpha-antagonists such as canadian trazodone (Generic Desyrel, Apothecon), the benzo-diazepines, and dopamine antagonists should be avoided because they impede recovery from ischemic lesions.

Traditional stepwise monotherapy is yielding to augmentation (the addition of a non-FDA-approved or an “off-label” agent with counterdepressive qualities) and combination (the addition of a second FDA-approved antidepressant) strategies (polypharmacy) in the specialty of psychiatry. The use of multiple agents with different variations inherent to individual psychiatric practice has led to polypharmacy as the perceived and probable standard of care. The most commonly used augmentation strategy is the addition of lithium, and the most common combination strategy is the addition.

A cholinesterase inhibitor may be useful if it is added to an antidepressant in cases of mild cognitive impairment and late depression, because the latter may precede the development of Alzheimer’s disease by five years. Low-dose antipsychotic agents and a referral to a specialist are indicated for patients with concomitant psychotic symptoms as well as resistant depression. The medication should be continued for six months after remission. Controversial therapies include the use of mifepristone (Mifiprex, Danco), metyrapone (Meto-pirone, Novartis), and ketoconazole drug (Nizoral canadian, PriCara); also controversial is the role of stress and glucocorticoids with involvement of the amygdala, the H-P-A axis, and related cardiovascular conditions.

After the decision to initiate drug therapy is made, close follow-up is essential. Goals of treatment in depression should include improvement in social and family function, reduced discomfort, and a significant improvement in satisfaction with life in general. One can look to improvement in appetite, sleep patterns, energy, and attitude to determine when treatment responses are adequate. Some patients early in their treatment do, in fact, deteriorate and become progressively agitated. This possibility should be discussed with the patients before therapy has begun and at their follow-up visits.

A partial treatment effect should be evident in three to four weeks, but a full therapeutic response takes months. Six to 12 months is typical for recovery from a severe episode of depression. The first follow-up visits should be scheduled within two weeks. For patients at increased risk (e.g., men living alone), a telephone follow-up can be made after a week of therapy.

Early visits are intended to assess titration and tolerance of medications. The one-month and six-week follow-up visits would be appropriate intervals to access early positive (or negative) responses. Upward dosage adjustments should probably not be made more often than every four to six weeks.

Decisions about continuing treatment should be made in conjunction with the patient after an evaluation of the response to and tolerance of the regimen prescribed. Medication should be continued for at least six months after remission. Medications should probably not be tapered or stopped in the winter because of the high correlation between Seasonal Affective Disorder (SAD) and depression.

Some patients who have done particularly well with treatment may be resistant to tapering or stopping their medications. Exploration of this issue sometimes reveals that they are feeling well for the first time in many years, and the medications should probably be continued indefinitely in this subset of patients. Improved quality-of-life factors (e.g., positive affect, better health status, and a reduction in somatic complaints) predict increased compliance with antidepressant use and a decrease in do-not-resuscitate (DNR) decisions.

Electroconvulsive therapy (ECT) should be considered if depression is severe (i.e., if the patient has suicidal ideation or psychosis or will not eat). After ECT, the patient should be kept on antidepressant medication and mood stabilizers, because relapse approaches 100%. Maintenance ECT may be more cost-effective than maintenance pharmacotherapy in depressed elderly patients who have responded to ECT.

Wellness advice should be offered. Adjunctive therapies like exercise (physical and mental), low-calorie intake, and specific nutrients have all been associated with improved mental and physical health and should be encouraged. Neutraceuticals such as folate may be helpful in increasing the responsiveness to SSRIs in the elderly.

A variety of effective psychotherapies are also available for the management of depression. Primary care physicians can facilitate optimal adherence to treatment by offering continued patient education and by using cognitive behavioral techniques. Other considerations include psychoneuroimmunol-gical and spiritual factors. Regular organized religious or spiritual practices are associated with a lower incidence of depression.

There is little evidence to support transcranial magnetic stimulation, dialectical behavior therapy, light therapy, interpersonal therapy, or St. John’s wort as therapy for depression. Successful treatment is measured in terms of improved quality of life, enhanced functional capacity, enhanced health status (in some cases), and increased longevity.

Experts recommend that patients be referred for specialized geropsychiatric care if they:

  • exhibit psychosis, bipolar disorder, or suicidal ideation.
  • have a complex or uncertain diagnosis.
  • are unresponsive.
  • are intolerant of an adequate trial of first-line treatment.
  • require more than one drug.
  • are candidates for ECT.
  • are severely ill.

Conclusion

Although depression is common, it is not a normal process of aging. It can cause significant morbidity and mortality, and it is both diagnosable and treatable by the primary care physician. Outcomes in the elderly are comparable to those of younger populations, although remission may take longer to achieve. Because the incidence and severity of adverse effects is significant in older adults, careful follow-up is essential.