Late-life depression

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Late-life depression is an important health issue. According to US data, the prevalence of clinically significant depressive symptoms ranges from 8% to 15% among community-dwelling elderly persons and is about 30% among the institutionalized elderly.1-4 Depression affects an estimated 200,000 people over the age of 65 in Canada.5 Groups at particular risk include in-patients, long-term care residents, and patients with dementia.6 With an anticipated increase in the geriatric population as the baby boomer generation ages, it is important for health care professionals to become familiar with the recognition of the disease and its treatment.

Etiology

The exact etiology of depression remains largely unknown. Theories based on neurotransmitters point to abnormal levels of norepinephrine, serotonin, and dopamine. Research has shown that the time spent depressed is related to reduced hippocampal volume, which could indicate that depression is neurotoxic.7 Antidepressants can stimulate brain-derived neurotrophic factor production and reverse this process,8 and this improved ability to form new neurons, or neurogenesis, is seen with various types of antidepressants.9 These discoveries suggest that medical interventions should start early; appropriate treatment duration and adherence will be important for ensuring positive patient outcomes.

Assessment

Diagnosis of depression is itself a challenge. Depression can profoundly impair a person's ability to function, regardless of his or her age.10 Unfortunately, older patients and health care providers alike may view decreased functioning as a natural consequence of aging and/or concurrent physical illness rather than as a symptom of depression.3

Depressed older patients often present with atypical symptoms, such as anxiety, irritability, delusions (instead of suicidal thoughts), sadness, or feelings of depression.5,11-13 Patients may also appear disoriented, apathetic, and unreactive, and may experience loss of appetite, insomnia, incontinence, or memory problems. Other symptoms to watch for include paranoia, feelings of guilt or sinfulness, and thoughts focused on losses in life, such as people or money.

Standard questionnaires used for diagnosis include the Geriatric Depression Scale (GDS) and the Even Briefer Assessment Scale for Depression (EBAS DEP)14-15; the Cornell Scale for Depression in Dementia is useful for distinguishing cognitive symptoms from dementia.16 Familiarity with these scales will help pharmacists know what to look for and how to engage in information-gathering conversations with patients or caregivers. See box below for common risk factors for depression.12,17

Treatment goals

The goals of treatment for late-life depression include relieving target symptoms, restoring functional ability, and preventing recurrence.

Non-pharmacological therapies

Psychotherapy

Integrated cognitive, behavioural, or interpersonal psychotherapies are useful when patients are dealing with acute stress or cannot tolerate medications. For isolated elderly patients, this may provide a comforting, safe environment for social interaction, but it is not recommended as monotherapy in severe depression.1 In the elderly, unwillingness to see a therapist, physical barriers to getting to appointments, and the expense involved can be deterring factors.

Electroconvulsive therapy

Electroconvulsive therapy (ECT) is safe, effective, and well tolerated in late-life depression.18-19 It is useful in patients with psychotic symptoms or severe melancholy, or in patients who do not respond to medications. Adverse effects include amnesia during ECT and headaches. The relapse rate is high, so patients who respond to ECT can benefit from maintenance antidepressant therapy and/or maintenance ECT.

Pharmacotherapy

Antidepressants are the mainstay of therapy in late-life depression. Physiological changes with age affect pharmacokinetics. Reduced stature, decreased drug metabolism and elimination rates put older patients at greater risk for medication toxicity clue to increased drug concentration and longer half-life. The elderly are also more sensitive to side effects, more likely to have organ damage and/or concomitant illnesses, and more at risk for claig interactions due to polypharmacy.

Sensory impairment (loss of hearing, sight, or dexterity) or cognitive impairment (memory impairment, dementia) can be barriers to adherence. All of these issues need to be considered when choosing an antidepressant. Medication should be selected based on individual response, tolerability, drug interactions, comorbidity, and adherence. Start the dose low - at half the normal adult dose for most agents - and slowly titrate up. Allow up to twice as long (8-12 weeks) to assess response.20 Prolonged use of benzodiazepines in patients with symptoms of agitation or anxiety is not appropriate.

Late-life depression is an important health issue. According to US data, the prevalence of clinically significant depressive symptoms ranges from 8% to 15% among community-dwelling elderly persons and is about 30% among the institutionalized elderly.1-4 Depression affects an estimated 200,000 people over the age of 65 in Canada.5 Groups at particular risk include in-patients, long-term care residents, and patients with dementia.6 With an anticipated increase in the geriatric population as the baby boomer generation ages, it is important for health care professionals to become familiar with the recognition of the disease and its treatment.

Etiology

The exact etiology of depression remains largely unknown. Theories based on neurotransmitters point to abnormal levels of norepinephrine, serotonin, and dopamine. Research has shown that the time spent depressed is related to reduced hippocampal volume, which could indicate that depression is neurotoxic.7 Antidepressants can stimulate brain-derived neurotrophic factor production and reverse this process,8 and this improved ability to form new neurons, or neurogenesis, is seen with various types of antidepressants.9 These discoveries suggest that medical interventions should start early; appropriate treatment duration and adherence will be important for ensuring positive patient outcomes.

Assessment

Diagnosis of depression is itself a challenge. Depression can profoundly impair a person's ability to function, regardless of his or her age.10 Unfortunately, older patients and health care providers alike may view decreased functioning as a natural consequence of aging and/or concurrent physical illness rather than as a symptom of depression.3

Depressed older patients often present with atypical symptoms, such as anxiety, irritability, delusions (instead of suicidal thoughts), sadness, or feelings of depression.5,11-13 Patients may also appear disoriented, apathetic, and unreactive, and may experience loss of appetite, insomnia, incontinence, or memory problems. Other symptoms to watch for include paranoia, feelings of guilt or sinfulness, and thoughts focused on losses in life, such as people or money.

Standard questionnaires used for diagnosis include the Geriatric Depression Scale (GDS) and the Even Briefer Assessment Scale for Depression (EBAS DEP)14-15; the Cornell Scale for Depression in Dementia is useful for distinguishing cognitive symptoms from dementia.16 Familiarity with these scales will help pharmacists know what to look for and how to engage in information-gathering conversations with patients or caregivers. See box below for common risk factors for depression.12,17

Treatment goals

The goals of treatment for late-life depression include relieving target symptoms, restoring functional ability, and preventing recurrence.

Non-pharmacological therapies

Psychotherapy

Integrated cognitive, behavioural, or interpersonal psychotherapies are useful when patients are dealing with acute stress or cannot tolerate medications. For isolated elderly patients, this may provide a comforting, safe environment for social interaction, but it is not recommended as monotherapy in severe depression.1 In the elderly, unwillingness to see a therapist, physical barriers to getting to appointments, and the expense involved can be deterring factors.

Electroconvulsive therapy

Electroconvulsive therapy (ECT) is safe, effective, and well tolerated in late-life depression.18-19 It is useful in patients with psychotic symptoms or severe melancholy, or in patients who do not respond to medications. Adverse effects include amnesia during ECT and headaches. The relapse rate is high, so patients who respond to ECT can benefit from maintenance antidepressant therapy and/or maintenance ECT.

Pharmacotherapy

Antidepressants are the mainstay of therapy in late-life depression. Physiological changes with age affect pharmacokinetics. Reduced stature, decreased drug metabolism and elimination rates put older patients at greater risk for medication toxicity clue to increased drug concentration and longer half-life. The elderly are also more sensitive to side effects, more likely to have organ damage and/or concomitant illnesses, and more at risk for claig interactions due to polypharmacy.

Sensory impairment (loss of hearing, sight, or dexterity) or cognitive impairment (memory impairment, dementia) can be barriers to adherence. All of these issues need to be considered when choosing an antidepressant. Medication should be selected based on individual response, tolerability, drug interactions, comorbidity, and adherence. Start the dose low - at half the normal adult dose for most agents - and slowly titrate up. Allow up to twice as long (8-12 weeks) to assess response.20 Prolonged use of benzodiazepines in patients with symptoms of agitation or anxiety is not appropriate.

Reversible monoamine oxidase inhibitors

Moclobemide, a reversible inhibitor of monoamine oxidase (RIMA), selectively and reversibly blocks the action of monoamine oxidase A (MAO-A), which is responsible for breaking down neurotransmitters. There is less concern associated with tyramine and food restrictions with moclobemide than with irreversible monoamine oxidase inhibitors (MAOIs) (see Other Antidepressants, below) because the MAO-A blockade is reversible, but patients should still be informed to take moclobemide after tyramine-rich meals to minimize the risk.27 Food restrictions are still recommended for high doses or for hypertensive patients. Moclobemide has minimal anticholinergic effects. It is also associated with fewer GI effects and less sexual dysfunction than SSRIs.28

Norepinephrine dopamine reuptake inhibitors

Bupropion, a norepinephrine dopamine reuptake inhibitor (NDRI), blocks the neuronal uptake of dopamine and norepinephrine with negligible effects on serotonin. This different mechanism is advantageous for patients who do not respond to or cannot tolerate the serotonergic agents. Incidence of sexual dysfunction is low. It is available in a slow-release formulation for convenient dosing and improved tolerability. In the elderly, it can also improve focus and attention.12 One disadvantage with bupropion is the increased risk of seizures (4/1000 in doses up to 450 mg/day).29 This incidence of seizures could exceed that of other marketed antidepressants by as much as four-fold.30

Other antidepressants

Older antidepressants such as the tricyclic antidepressants (TCAs) (amitriptyline, imipramine, doxepin), tetracyclics (amoxapine and maprotiline), and the irreversible MAOIs (phenelzine, tranylcypromine) are not recommended in the elderly.

The cyclic antidepressants have strong anticholinergic effects (dry mouth, blurred vision, orthostatic hypotension, constipation, memory impairment, tachycardia) and are not recommended in patients with urinary retention, glaucoma, or ischemic heart disease.31-32 They also increase the risk of falls and hip fractures in the elderly.33

MAOIs are associated with potentially fatal hypertensive crisis when taken with certain drugs or tyramine-containing foods; patients taking them need to follow dietary restrictions and have drug interactions carefully monitored. MAOIs also cause orthostatic hypotension, which is a risk factor for falls in the elderly.

Nortriptyline and desipramine are the preferred agents among the nonselective cyclic antidepressants, mostly because of their comparatively favourable side effect profile. Desipramine is less sedating and has the lowest anticholinergic profile.30 Nortriptyline has a lower incidence of orthostatic hypotension. Trazodone has the drawback of heavy sedation through histamine receptor blockade, so its use is limited; lower doses at bedtime can be used to increase REM sleep.

Over-the-counter supplements

St. John's wort, or hypericin, has been used for more than 15 years as a natural remedy for depression. Its mechanism of action is not completely understood, but it appears to modulate the effects of serotonin, dopamine, and noradrenaline, possibly through reuptake inhibition.34 In clinical studies, it has shown comparable efficacy to other antidepressants in mild to moderate depression. However, it is not indicated for severe depression.35 St. John's wort interacts with a number of drugs, including SSRIs, MAOIs, indinavir, cyclosporine, digoxin, warfarin, and estrogen.34 When used orally in large doses, St. John's wort can lead to severe phototoxic skin reactions.

There is some evidence that 5-hydroxytryptophan (5-HTP) is comparable to fluvoxamine and imipramine. 36-37 It seems to improve symptoms of depression, including in patients with treatment-resistant depression.36,38 The mechanism of action is related to both L-tryptophan and serotonin. In the body, L-tryptophan is converted to 5-HTP, which is then converted to serotonin. 5-HTP side effects are mostly GI-related: heartburn, nausea, vomiting, abdominal pain, and anorexia. Drug interactions could occur with carbidopa, SSRIs, TCAs, and MAOIs.

Many other over-the-counter (OTC) supplements are advertised for depression, including S-adenosylmethionine (SAMe), fish oil, vitamin B, and trace minerals. Pharmacists should take the time to discuss the benefits and risks of these with their patients. OTC supplements may not have clearly marked labels or strict quality control measures, so their safety and efficacy cannot always be guaranteed. Patients should be encouraged to see a qualified health professional before taking any of these supplements.

Management strategies

Pharmacists are in a unique position to help monitor the patient's progress once an antidepressant is selected. It is important that they educate patients about the onset and duration of the medication and remind them not to discontinue therapy abruptly, especially if they begin to feel better, because discontinuation syndrome (insomnia, nausea, imbalance, hyperarousal, flu-like symptoms) can occur. Citalopram, mirtazapine, and bupropion are associated with less risk for this syndrome.39 Issues with intolerance can be dealt with by adjusting administration times or lowering or splitting the dose. If a single agent causes intolerable side effects at full dose, it is possible to use two agents, both at partial doses. Suggesting OTC agents for symptom control, such as using dimenhydrinate for nausea, can be helpful if the antidepressant is otherwise effective.

If a patient is compliant and tolerating the medication but response does not seem adequate, the dose should be increased to the higher end of the dosing range before considering it a treatment failure. If a patient is intolerant or has no response after an appropriate course, another agent can be recommended. A switch can be made to any of the first-line agents recommended for the elderly (Table 1). Among SSRIs, the response rate is 66% after switching to a second SSRI when the first SSRI is poorly tolerated and 48% when the patient is refractory to the first agent.25 First-line agents should be tried before moving to other agents.

If a patient has a partial response after an appropriate course, augmentation with lithium, liothyronine, stimulants (amphetamine, methylphenidate), atypical antipsychotics such as rispericlone, or folic acid may produce additional benefit. If choosing to use combination therapy, recommend two agents with different mechanisms of action. Remind the patient that it will take another four to six weeks for improvement after the initiation of a combination. Mirtazapine and SSRIs, bupropion and SSRIs, and TCAs and SSRIs are combinations that can lead to more rapid onset, higher response rate, or reduced side effects.40 Keep in mind there is added risk of toxicities and drug-drug interactions with combination therapy. Adherence can also become an issue.

Maintenance therapy

The acute phase of major depression lasts at least 8-12 weeks in the elderly.41 If the patient's symptoms lessen during this time and previous level of functioning returns, the medication should be continued for at least six months and then reassessed. The Canadian Psychiatric Association recommends two years as maintenance, since recurrence of symptoms can occur in up to 50% of patients within the first two years.19,42 Grieving-related depression generally lasts at least one year. Patients who have had three or more episodes of major depression or two episodes followed by rapid recurrence, patients who were older at onset of depression (> 60 years), and patients with a family history of mood disorders may need maintenance therapy indefinitely.43

Suicide prevention

Depression is a predictor for suicide. People 65 and over account for a disproportionately high number of suicide deaths when compared to other age groups.5,44-45 The elderly are less likely than younger patients to seek or respond to help for the prevention of suicide.1 As frontline health care professionals, pharmacists need to be on the alert for signs of depression and suicidal ideation. Look for clues, including statements such as "feeling empty," "feeling like no one loves me," or "feeling like life is not worth living"; fatigue; guilt; feelings of worthlessness; and unusual sleeping or eating habits.5 Antidepressants that are easily toxic in overdose, such as the TCAs, should be prescribed in small quantities, and the patient should be monitored closely while receiving them.

Conclusion

Late-life depression is a debilitating illness. Pharmacists have the opportunity to interact with older patients on a regular basis and can help improve the health and quality of life of these patients. As medication experts, pharmacists can help to optimize the patient's therapy by assisting the physician with antidepressant selection, dose titration, drug-interaction checking, adherence monitoring, and patient education.

Pharmacists can also help improve adherence by helping patients manage side effects, identifying potential drug-related problems associated with sedative medications (such as falls), and providing ongoing support. They should encourage the patient or caregiver to discuss any concerns or unusual effects. For many community-dwelling elderly patients, access to and trust in their pharmacist will facilitate their road to recovery from depression.

COMMON RISK FACTORS FOR DEPRESSION
* Prior history of depression
* Poor self-rated health
* Poor functional capacity
* Loss of a spouse
* Social isolation/loneliness
* Chronic medical conditions (anxiety disorders, substance abuse, myocardial infarction, stroke, Parkinson's disease, dementia)
* Perceived negative changes in life

Optimizing therapy

Pharmacists can help to optimize therapy by assisting the physician with antidepressant selection, dose titration, drug-interaction checking, monitoring adherence, and patient education.
Pharmacists can also improve adherence by helping patients manage side effects, identifying possible drug interactions or potential drug-related problems associated with sedative medications (such as falls), and providing ongoing support.