CHAPTER 32—DEPRESSION AND OTHER MOOD DISORDERS
Criteria from the fourth edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-IV ) are generally used for diagnosis in the United States. Criteria required to diagnose major depression are described in Table 32.1. In contrast to previous diagnostic schema, a DSM-IV diagnosis is not hierarchical; that is, having one diagnosis does not exclude the presence of another. Thus, an elderly person with a major depression may also meet criteria for a comorbid anxiety disorder.
Although aging does not appear to markedly affect the overall phenomenology of major depression, some differences between younger and elderly depressed patients have been reported. Older patients are more preoccupied with somatic symptoms and report depressed mood and guilty preoccupations less frequently. This tendency contributes to the syndrome of masked depression, in which a major depression may be hidden because of a patient’s greater preoccupation with physical health concerns rather than with feelings of sadness. Among patients who do not acknowledge sustained feelings of sadness, the demonstration of the second gateway symptom, a persistent loss of pleasure and interest in previously enjoyable activities (anhedonia), is necessary for a diagnosis of major depression. The gateway symptoms are particularly important in primary care settings and have been found to identify most medically ill patients who also meet full diagnostic criteria. Furthermore, the gateway symptoms are less likely to overlap with those of a medical illness.
The diagnosis of major depression in older persons is complicated by the overlap among symptoms of major depression with those of physical illness. Examples of this and other complicating factors are listed in Table 32.2. Furthermore, patients with serious medical illness may be preoccupied with thoughts about death or feel worthless because of concomitant disability. The DSM-IV criteria require that the symptoms are not direct physiologic effects of a general medication condition or medication used to treat it, but this distinction based on cause may be difficult to make reliably. Alternative diagnostic criteria have been suggested for medical patients, including an inclusive approach that counts all symptoms regardless of cause. Inclusive approaches result in the highest prevalence rates. Furthermore, a depressed person’s thoughts about death and worthlessness appear to differ from those of a patient with a serious medical illness. In depression, these thoughts are not based on a realistic assessment of prognosis or overall self-worth. The self-assessment of depressed patients is influenced by the feelings of sadness or guilt that accompany the disordered mood. The alternative diagnosis of mood disorder due to a general medical condition should be used for patients with depression that appears to result directly from a specific medical condition, such as hypothyroidism.
The recognition of psychotic depression has particular relevance to primary care clinicians. Patients with psychotic depression have sustained irrational beliefs in association with their depression. Although this severe form of major depression is most common among elderly patients requiring inpatient psychiatric admission, patients with psychotic depression may be seen in primary care settings when the irrational belief focuses on somatic symptoms or an imagined physical condition.
A diagnosis of mania requires a distinct period of persistently elevated mood lasting for 1 or more weeks and three additional symptoms that may include inflated self-esteem or grandiosity, hypersexuality, increased activity, decreased need for sleep, pressured speech, racing thoughts or flight of ideas, and distractibility. Grandiose or paranoid delusions may be present. Although the criteria for diagnosing bipolar disorder in geriatric patients are identical to those for younger adults, some differences in phenomenology have been noted. Elderly patients with bipolar disorder are more likely to have an admixture of depression that may present as irritability. Pressured speech that tends to go off on tangents is common, although the severity of thinking disturbance is less pronounced than in young adults and flight of ideas is less common. Hypersexuality and grandiosity may be present but are less prominent as well.
Elderly patients with bipolar disorder may also suffer from the depressive phase of this cycling illness. Although there have been few studies of late-life bipolar depression, the presentation of late-life bipolar depression is similar to that of unipolar major depression.
Approximately 50% of patients with late-life depression are having recurrences of episodes that began in early adulthood; in such cases a history of prior depressions assists patients and clinicians to recognize the diagnosis. However, 50% of elderly depressed patients are suffering their first episode. Despite the associations between late-onset depression and chronic medical illness, disability, and psychosocial stresses, most episodes develop without an identifiable precipitant. Because late-onset depression is less likely to run in families than typical recurrent depression, a positive family history is less useful for establishing a diagnosis. Awareness that late-onset depression commonly develops “out of the blue” requires that clinicians rely on diagnostic criteria. Clinicians should include as part of their management an explanation to patients that new-onset depression may occur without an identifiable cause.
Medical disorders that may imitate depression are particularly important to consider in elderly patients because of the increased vulnerability of this population to physical illnesses. Hyperthyroidism merits special consideration, because older hyperthyroid patients may present atypically with apathy and diminished energy that may mimic depression. Apathy may accompany other medical conditions as well. Apathy is experienced as an absence of feeling or of not caring and differs from having feelings of sadness. Although apathy may be commonly associated with the gateway symptom of anhedonia, apathy may also occur in persons who retain a capacity for experiencing pleasure. The distinction of apathy from true depression becomes particularly important among patients with Parkinson’s disease, carcinoma of the pancreas, and dementia, because depressive syndromes that occur commonly in these disorders are responsive to conventional antidepressants.
Major depression may be prodromal for a progressive dementia such as Alzheimer’s disease or may develop after the onset of cognitive decline. Differentiation may be confounded because depression is commonly accompanied by symptoms of impaired concentration, lack of motivation, and somatic preoccupations that are also associated with dementia. An older person with depression may both report symptoms of memory loss and poor concentration and be unable to perform simple cognitive tests without having a progressive dementia. Differentiation from dementia requires evidence that the cognitive impairment is not present consistently, developed concurrently with the onset of depression, and reverses with improvement in mood. Conversely, patients with true dementia may have symptoms that imitate depression. These include loss of interest, apathy, psychomotor retardation, and disrupted sleep. A diagnosis of major depression requires the presence of at least one gateway symptom and the persistence of symptoms for at least 2 weeks; approximately 20% of patients with early Alzheimer’s disease meet these criteria
Studies have described a syndrome of “vascular” or “executive dysfunction” depression that is associated commonly with anhedonia and the absence of guilty preoccupations. The syndrome is thought to result from prefrontal and subcortical lesions due to microinfarcts and should be distinguished from the more classical poststroke depression. These patients tend to have a late age of onset, risk factors for vascular disease, prefrontal or subcortical white matter hyperintensities on T2 weighted magnetic resonance imaging, and evidence of neuropsychologic deficits in functions requiring initiation. Execution of tasks requiring planning and shifting cognitive sets is impaired. Patients with vascular or executive dysfunction depression meet the full DSM-IV criteria but may have a diminished response to standard pharmacotherapies.
Bereavement following the loss of a spouse or another close relationship is common among elderly persons. The most disturbing symptoms of bereavement are generally time-limited and resolve within 2 months. Feelings of sadness, disturbed sleep, and diminished appetite are common in uncomplicated bereavement. Fourteen percent of bereaved persons develop a major depression within 2 years of the loss. However, bereaved older persons appear to develop depressive syndromes or full major depression at lower rates than do younger bereaved adults.
Symptoms indicating that bereavement has evolved into a full major depression include morbid preoccupations with guilt or death beyond transient thoughts that would be expected in association with the loss. Also, bereavement is not associated with marked functional impairment.
The treatment stages for major depression can be conceptualized as follows: acute treatment to reverse the current episode, continuation treatment to prevent a relapse of that episode, and prophylaxis or maintenance treatment to prevent a future recurrence. Continuation treatment to stabilize the recovery involves continuing antidepressant therapy for an additional 6 months. Maintenance treatment is provided to patients with recurrent depression for 3 years or longer. The duration of maintenance therapy should be based on the frequency and severity of previous episodes. Psychotherapy, pharmacotherapy with antidepressants, and electroconvulsive therapy (ECT) are effective treatments for depression in older persons.
Initiatives have been developed to increase the likelihood that patients with major depression treated in primary care settings will receive antidepressant treatment that is adequate in dose and duration. The increased attention to this problems results from findings that most elderly patients prefer being treated for their depressions by their primary care physicians, even though depression has been underrecognized and undertreated in this setting. Also, studies have shown that the majority of patients who are prescribed antidepressants by their primary care physicians do not obtain refills of their initial prescription. Educational programs and the use of depression nurse specialists have been developed to increase recognition and treatment intensity. Of note, primary care patients have been shown to demonstrate response rates to antidepressant treatment that are comparable to those of patients seen in mental health settings.
Research demonstrating the efficacy of psychotherapy for major depression in older adults has relied on treatments that are both individualized and standardized, including cognitive-behavioral therapy, interpersonal psychotherapy, and, most recently, problem-solving therapy. The latter was developed in primary care settings. Problem-solving therapy involves working with the patient to identify real life difficulties that are causing distress and providing guidance to help the patient address them. The treatment is delivered generally in six to eight meetings spaced 1 to 2 weeks apart. Cognitive and interpersonal psychotherapy are also time-limited and highly structured. Ongoing research using psychotherapy for the treatment of minor depression has been promising, with efficacy demonstrated particularly in persons who have suffered a loss. Also, caregivers of older persons may develop minor or major depressive syndromes that benefit from psychotherapy. Psychotherapy may be combined with an antidepressant, and the combination has been associated with a longer period of remission following recovery from the acute episode. Research with younger adults suggests that the effectiveness of psychotherapy alone may be limited to patients with mild to moderately severe forms of major depression.
All approved antidepressants are effective treatments of major depression in older adults. The choice of agents depends, therefore, on a particular patient’s comorbid medical conditions and both the side-effect profile of the antidepressant and the individual patient’s sensitivity to these effects. Potential interactions with other medications a patient is taking should be considered. Table 32.4 provides guidelines for selection from among approved antidepressants; the guidelines are based on the discussion of specific therapies in the sections that follow.
Although methylphenidate and other psychostimulants have been used to treat major depression for decades, controlled data demonstrating their efficacy are lacking. However, these agents may have a role in reversing the apathy and lack of energy seen in some patients with dementia or disabling medical conditions. Benzodiazepines may be useful temporary adjuncts to treat anxiety symptoms associated with a major depression, but older persons are particularly sensitive to the adverse cognitive effects of these medications, and prolonged use may lead to dependency.
Nortriptyline and desipramine, the secondary amine metabolites of imipramine and amitriptyline, are the most appropriate tricyclic antidepressants for use in older persons. These medications are effective in the most severe forms of depression but are associated with greater side effects and potential risks than newer classes of medications. Tricyclics are unique among the antidepressants in that relationships between concentrations and efficacy have been clearly established. For nortriptyline, therapeutic response is associated with blood levels between 50 and 150 ng/mL and for desipramine, levels above 120 ng/mL. Over 60% of patients with nonpsychotic major depression or with depression that is not associated with dementia respond within 6 weeks to levels in these ranges. Of interest, relationships of blood level to response are more variable in patients who have depression that occurs in the context of dementia. Although 5% of the population requires lower dosing because of the absence of the enzyme required to metabolize secondary amine tricyclics, most patients achieve target concentrations at doses of 50 to 75 mg per day of nortriptyline and 100 to 150 mg per day of desipramine.
The potential for side effects due to the anticholinergic and sedative properties of tricyclics limits their use in older patients. These medications are particularly inappropriate for patients who are sensitive to constipation, who have conditions or treatments that cause orthostatic hypotension, and for men with benign prostatic hyperplasia. Also, tricyclic antidepressants have a quinidine-like effect that delays ventricular conduction. Among patients with a pretreatment first-degree heart block, 10% may develop a second-degree block during treatment. Patients with a bundle branch blocked or prolonged QTc interval are at risk for developing a ventricular arrhythmia. Also, patients with ischemic heart disease are more likely to develop cardiovascular side effects during treatment with nortriptyline than with a selective serotonin-reuptake inhibitor (SSRI).
SSRIs and tricyclic antidepressants are comparably effective for treating mild to moderate major depression, but SSRIs are better tolerated. Controversy continues about whether the most severe melancholic form of depression that generally requires treatment in a psychiatric hospital responds better to a secondary amine tricyclic antidepressant. Melancholic patients typically suffer from marked appetite and weight loss, diurnal mood variation that is worse in the morning, early morning awakening, and either retardation of motor movement or agitation.
Recommended doses for older adults are 10 to 40 mg of citalopram, fluoxetine, or paroxetine. These doses are somewhat lower than those used for younger adults because of the somewhat decreased metabolism associated with aging. The recommended target dose for sertraline ranges from 50 to 100 mg in most cases.
Although the SSRIs are generally free of severe side effects, a small proportion of elderly patients develop hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion during SSRI treatment, particularly at higher doses. Some patients may be unable to tolerate SSRIs because of a tendency to become highly anxious or agitated. This reaction appears to be more common in older persons. Beginning at lower doses may reduce the incidence of anxiety with activating SSRIs such as fluoxetine and may decrease the gastrointestinal side effects of nausea or diarrhea that occur with other SSRIs. Sexual side effects occur commonly with all SSRIs, and many elderly patients prefer treatment with another medication to avoid them. Although SSRIs have been associated with mild weight loss initially, long-term use with many of these medications has been associated with weight gain. Pseudoparkinsonism and other movement disorders may occur, particularly if these medications are used in combination with other drugs that block dopamine (eg, metoclopramide).
Much has been written about potential drug interactions with SSRIs. These medications inhibit various P-450 hepatic cytochrome isoenzymes that metabolize most medications. Fluoxetine and paroxetine are potent inhibitors of the P-450 2D6 isoenzyme responsible for the metabolism of most psychiatric medications, in addition to dextromethorphan, codeine, and metoprolol. Sertraline is a weak inhibitor of both the 2D6 and 3A4 isoenzymes. Thus, downward dose adjustment of medications such as tricyclic antidepressants and risperidone is appropriate if used with these SSRIs. Inhibition of 2D6 can decrease the analgesic effects of codeine (and related compounds) and tramadol by preventing their conversion to their active metabolites, morphine and O-desmethyltramadol. Evidence for a clinically significant effect due to inhibition of 2D6 metabolism of metoprolol metabolism is lacking. Nefazodone is a potent inhibitor of the P-450 3A4 isoenzyme that metabolizes medications such as alprazolam, astemizole, cyclosporin, and erythromycin. Fluvoxamine, an SSRI used to treat obsessive-compulsive disorder, is approved as an antidepressant in Europe. Fluvoxamine inhibits both the 3A4 and 1A2 systems. Because P-450 1A2 is required to metabolize theophylline, olanzapine, and phenacetin, concurrent use of fluvoxamine may result in marked increases in marked concentrations of these medications.
SSRIs are known to be tightly protein bound. For this reason, they may displace warfarin from binding sites and increase the anticoagulant effects of this medication. Careful monitoring of prothrombin times or another suitable index of blood clotting is indicated following the introduction of an SSRI to patients being treated with warfarin.
SSRIs have been considered particularly safe for older persons to use because these antidepressants do not cause orthostatic hypotension, arrhythmias, or marked sedation. However, evidence indicates that nursing-home residents treated with SSRIs are at increased risk for falling and suffering hip fractures. It is not clear whether these findings are due to patient selection in that patients considered at greatest risk for falling may be treated with SSRIs preferentially. Alternatively, SSRIs may contribute to falls by causing a subtle balance disturbance or pseudoparkinsonism in vulnerable patients.
Bupropion is generally safe and well tolerated when used at recommended doses. Bupropion has been associated with a 0.4% risk of seizures, which is much higher when recommended doses are exceeded. Although the precise mechanism of action is unknown, bupropion appears to act through increasing the activity of dopamine and norepinephrine. This mechanism may explain the activating property of bupropion and the recommendation that dosing of the short-acting form be completed by mid-afternoon to avoid insomnia. Long-acting bupropion has a smaller seizure risk and is less likely to cause insomnia. Doses are increased gradually by the use of a twice-a-day regimen to achieve target doses of 150 to 300 mg of the short-acting form, although doses as high as 450 mg are used in young adults. The dose range of sustained-release bupropion is between 200 and 300 mg per day, and doses below 300 mg can be given as a single daily dose. Although systematically obtained data are unavailable, older patients may be more vulnerable to developing anxiety, a tremor, or myoclonus at doses at the high end of the approved therapeutic range.
Venlafaxine acts as an SSRI at lower doses while also inhibiting the reuptake of norepinephrine at the high end of the therapeutic range of 75 to 225 mg per day. Venlafaxine is available in short-acting and extended-release forms. Venlafaxine is effective for both generalized anxiety and major depression and may treat both effectively at doses between 75 and 150 mg per day. A dose-response relationship for severe depression has been demonstrated, and patients with melancholia may require doses of 225 mg per day or greater. Initial dosing should use gradual increases to minimize the early side effect of nausea. The noradrenergic properties of higher doses may explain the association between doses of 225 mg and higher with hypertension. Patients requiring doses at the high end of the therapeutic range should have blood-pressure monitoring. Paradoxically, this side effect does not occur in patients with preexisting hypertension that is being controlled by treatment with a β-blocker. Venlafaxine, like other SSRIs, has been associated with decreased sexual functioning. Venlafaxine should be discontinued by gradual tapering to avoid the risk of flu-like discontinuation symptoms.
Nefazodone has SSRI properties as well as being a 5-HT2 antagonist. In addition to being approved as an antidepressant, nefazodone is thought to reduce anxiety. In young adults, the antidepressant response to nefazodone has been shown to be dose related, with greatest response rates occurring in the range of 300 to 500 mg per day given by twice-a-day dosing. However, older persons may have difficulty tolerating the sedative side effects of nefazodone at this dose range. As described above, nefazodone is a potent inhibitor of the P-450 3A4 system and must be used cautiously in patients being treated with other medications metabolized by this isoenzyme. Nefazodone treatment is not associated with sexual side effects or insomnia.
Mirtazapine is a norepinephrine, 5-HT2, and 5HT3 antagonist. The total daily dosage is 15 to 45 mg. Mirtazapine may be given as a single bedtime dose and is available in sublingual form, which may be useful for patients who have difficulty swallowing. Bedtime administration uses the sedative side effects of mirtazapine to help patients sleep. Mirtazapine is also associated with increased appetite and weight gain. This side-effect profile has contributed to the use of mirtazapine before bed in nursing-home residents with depression and dementia who demonstrate nighttime agitation and weight loss. Paradoxically, weight gain may be less severe at higher doses.
The monamine oxidase inhibitors (MAOIs) are effective antidepressants that have been in use for nearly half a century. Phenelzine, used at target doses of 30 to 45 mg per day, tranylcypromine, used at doses of 30 to 40 mg per day, and isocarboxacid at 30 mg per day, are the three MAOIs currently available in the United States. Orthostatic hypotension is a common side effect of MAOIs and may increase the risk of falling among older patients. Ingestion of a food product rich in tyramine or taking a pressor amine such as one used in over-the-counter cold remedies during MAOI therapy can cause a life-threatening hypertensive crisis. Use of MAOIs with an SSRI or meperidine can cause a fatal serotonin syndrome associated with delirium and hyperthermia.
Psychotic depression is generally resistant to standard antidepressant regimens. Aggressive pharmacotherapy is required, with best results obtained in young adults when high doses of antidepressants and antipsychotic medications are combined. However, the effectiveness of combination treatment for older patients with psychotic depression remains uncertain. Available evidence suggests that most elderly patients who have depression with pronounced psychotic features either cannot tolerate adequate doses of conventional medications or do not respond to them. Therefore, ECT has become the standard treatment for late-life psychotic depression. (See also the discussion of ECT in the section on mania.)
Approximately 60% of patients with major depression demonstrate a robust response to treatment within 6 weeks. An additional 15% to 25% of patients who have begun to improve achieve remission if treatment is continued for an additional 4 to 6 weeks. Older patients may take longer than young adults to respond to SSRIs and perhaps to other antidepressants. Some published studies using SSRIs have reported 6-week response rates of 40% that increase to more than 60% when treatment is extended to 12 weeks. As in the treatment of young adults, improvement at 2 to 4 weeks is indicative of whether a particular patient will respond fully.
Lithium carbonate, methylphenidate, or triiodothyronine combined with a secondary amine tricyclic has been used to treat patients who fail to respond to one of the monotherapies. However, empirical data supporting these combinations are scant, particularly in older persons. Consideration should be given initially to whether another diagnosis is present. The options of switching to an antidepressant from another class or consulting with a geriatric psychiatrist are more appropriate than initiating combination treatments that have not been studied systematically.