Psychostimulants in the Treatment of Depression in the Older Patient
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Valid July 1 - September 30, 2005. Estimated time: 1 hour
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1. To identify the effect of depression on older patients
2. To describe the use of psychostimulants as an antidepressant
3. To describe the effect of psychostimulants as an augmenting agent for antidepressants
4. To be able to make evidence-based recommendations on the use of psychostimulants in the treatment of depression in older patients
Depression can be particularly devastating in late life, when social supports may be inadequate and comorbid medical illness and polypharmacy can compound severity and delay recovery. Rates of depression are markedly higher among medically ill older persons and nursing home residents, ranging from 9-42%.1 Depression may result from debilitating medical illness and may in turn exacerbate and even cause medical illness, increasing, for instance, the risk of myocardial infarction.2 Depression reduces quality of life, impairing ability to carry out activities of daily living and thereby limiting independence. It increases the risk of suicide, and, indeed, older men have the highest rates of suicide in the United States. The diagnosis of depression may be more difficult in the older person, who usually presents with somatic complaints rather than dysphoric mood.1 Treatment may be more difficult among older patients who, due to altered metabolism, experience a more brittle course on antidepressants. Once treated, older patients still have a higher and more rapid rate of recurrence.3 Despite significant improvements in treatment, prominent limitations of conventional antidepressant therapy remain. They include the delayed onset of therapeutic response and the partial or lack of response in as many as 50% of patients who complete an adequate trial.3 As a result, augmentation strategies have been employed in an attempt to accelerate or enhance response to conventional antidepressant therapy.
Psychostimulants are among the oldest agents in the psychiatric pharmacopeia, having been used in treatments ranging from pathologic fatigue to mania to schizophrenia. Myerson first described the use of amphetamine sulfate in the treatment of depression in 1936.4 Later, agents such as dextro-N-methylamphetamine, dextroamphetamine, methylphenidate, and pemoline were introduced into the pharmacopeia. These drugs are indirect-acting, sympathomimetic agents. They are both dopaminergic and noradrenergic agonists and reuptake inhibitors. Early observations of stimulant response noted the rapid effect on mood and enhancement of motor activity.5 Their mechanism of action in potential treatment of depression, however, remains unclear. Nierenberg et al6 examined the role of dopamine in the development and treatment of depression, and concluded that the evidence for dopaminer gic dysfunction in patients with depression is, at best, mixed. They noted that whereas uncontrolled studies suggested a role for stimulants in treatment-refractory depression, no stimulant-responsive subgroup of patients with depression has been identified. Studies have consistently demonstrated that psycho-stimulants are rarely associated with serious adverse effects. Typical side effects are mild to moderate. They include insomnia, exacerbation of anxiety or agitation, tremor, changes in appetite, palpitations, blurred vision, dry mouth, constipation, and dizziness.
Changes in blood pressure, dysrhythmias, and tachycardia have been reported, although such changes were also noted among patients taking placebo. Of note, cardiovascular complications have not been prominent, even among patients with pre-existing cardiac disease, and side effects are reversible with discontinuation of stimulant. Regarding the potential for abuse, there has been little evidence for habit formation or addiction among patients taking stimulants for depression. Finally, numerous studies have documented the lack of development of tolerance to the beneficial effects of this class of drugs.7
AS AN ANTIDEPRESSANT
Chiarello and Cole5 reviewed the body of literature on the use of psychostimulants in various psychiatric disorders. In reviewing data from the mid-1930s to the mid-1980s pertaining to their use in depression, the authors found mostly poorly designed studies that demonstrated widely variable responses. Although a good number of patients with depression appeared to benefit from treatment, a sizeable number of patients did not. The authors noted a remarkably high placebo effect in the few controlled studies. They concluded that “the available evidence on the efficacy of stimulants in depression is intriguing but clearly insufficient to warrant consideration for FDA approval.” Although clinical experience suggested that a small subgroup of patients with chronic depression benefited from treatment with stimulants, a similar group of patients with depression did not. It was ultimately impossible, given the data available, to accurately determine any subgroup of stimulant-responsive patients with depression.
Satel and Nelson7 critically reviewed 16 studies examining the efficacy of dextroamphetamine and methylphenidate as monotherapy in patients with primary depression. Whereas several uncontrolled studies documented high positive response rates, they also noted similar response rates, some as high as 72%, in the placebo groups of controlled studies. The authors concluded that stimulant drugs demonstrated little advantage over placebo in treatment of depression. The one exception they found was a study conducted by Rickels et al8 that documented the efficacy of methylphenidate 15 mg per day and pemoline 75 mg per day over placebo in the treatment of two of three groups of patients with mild depression who complained of fatigue or apathy. However, in a later study of similar patients, Rickels et al9 found more mixed results. Patients with mild depression who were receiving methylphenidate 30-60 mg per day for 4 weeks reported significantly greater improvements in mood and performance relative to patients receiving placebo. However, physician ratings of improvement found no difference between drug and placebo groups.
In an effort to examine the potential usefulness of stimulants in specific depressed populations, Satel and Nelson7 then examined studies of these drugs in geriatric and medical populations. Among geriatric patients, they found that four of five placebo-controlled studies reported benefits of stimulants over placebo in the treatment of geriatric patients with “senile behavior” and apathy. The authors noted, however, that each of the samples included patients with some form of brain disease or systemic illness who could not be diagnosed as patients with primary depression. Furthermore, the symptoms reported to improve included mental alertness and self-care, which were not necessarily depressive symptoms.
AUGMENTATION OF ANTIDEPRESSANTS
Despite the lack of consistent and compelling data in controlled studies documenting the efficacy of stimulants as monotherapy for the treatment of primary depression, these medications may yet have use in the augmentation of conventional antidepressants in specific populations, particularly given their reported rapid onset of action and relative lack of serious side effects. Stimulants have been studied in trials with monoamine oxidase inhibitors (MAOIs) alone or in combination with tricyclic antidepressants (TCAs) in severely treatment-resistant patients with depression. For example, Fawcett et al10 studied 32 patients with unipolar or bipolar major depression who had remained refractory to conventional therapy, including adequate trials with TCAs and MAOIs alone and in combination. Several of the patients had not responded to augmentation strategies with lithium, thyroid hormone, and bromocriptine. Eleven patients had not responded to electroconvulsive therapy (ECT). Treatment was not blinded, and there was no control group. An MAOI was initiated and titrated to the maximum dose tolerated. If the patient experienced a partial response but could not tolerate further increases in MAOI dose, pemoline or dextroamphetamine were added in low doses and titrated to therapeutic response. Of the 32 patients studied, 78% were considered to have a good response as defined by Clinical Global Impression (CGI) Scale score of 1 or 2 (“very much improved” or “much improved”) over at least 6 months. Thirteen patients tried both combinations of pemoline-MAOI and dextroamphetamine-MAOI after inadequate response with the first combination.
Other augmentation strategies were simultaneously employed, including using TCAs, tetracyclics, lithium, trazodone, alprazolam, and valproic acid. Subcategorization by type and duration of treatment resulted in small cell sizes, so that no statistical analyses could be run. Ultimately, only 12.5% (four patients) maintained a good response. Adverse effects that led to discontinuation included impotence, orthostatic hypotension, elevated blood pressure, and shakiness with pemoline. Memory difficulties, parkinsonian syndromes, and somnambulism were seen with dextroamphetamine. Other side effects included fatigue, unsteady gait, and weight gain, and six patients developed hypomania or mania.
A number of studies have examined the efficacy of stimulant augmentation for the newer antidepressants. In a letter to the editor, Linet11 first documented the use of a selective serotonin reuptake inhibitor (SSRI) with a stimulant. The author reported markedly beneficial effects of augmentation of fluoxetine with d-amphetamine in a 36-year-old man with atypical depression refractory to imipramine, who had already tried augmentation with methylphenidate, triiodothyronine, tryptophan, and L-thyroxine. The patient did not respond to fluoxetine 60 mg per day alone, but when d-amphetamine 45 mg 3 times daily was added, he experienced dramatic and sustained clinical improvement in depressive symptoms without development of tolerance.
Bader et al12 reported a case of a 79-year-old veteran with a history of major depression with psychotic features who had been successfully treated with ECT during World War II. The patient was in complete remission until February 1991, when he relapsed with hopelessness, apathy, and suicidal ideation. Antidepressant trials of doxepin, fluoxetine, maprotiline, bupropion, sertraline, paroxetine, and augmentation with trazodone and haloperidol were unsuccessful. Neuropsychological testing demonstrated mild dementia with depression. Electroconvulsive therapy was initiated, but the patient withdrew consent after one treatment. Venlafaxine was begun and titrated to 75 mg thrice daily. The patient responded only with improvement in appetite and weight gain. After 4 weeks of treatment with venlafaxine, methylphenidate was added and titrated to 10 mg in the morning and 5 mg at noon. Within 5 days of augmentation with methylphenidate, the patient’s mood and activities of daily living improved, although his affect remained flat. The authors were especially attentive to the potential for cardiovascular side effects, but no adverse effects were noted. The patient was doing well at 12-month follow-up.
Masand et al13 reported a case series of seven patients diagnosed with major depressive disorder with and without atypical features, dysthymic disorder, or double depression who were only partially responsive to treatment with second-generation antidepressants. Treatment was augmented with methylphenidate or dextroamphetamine. The authors reported a marked improvement in depressive symptoms in all patients, with notable improvement in apathy and fatigue. Significant limitations of the study included lack of an objective scale to rate improvement, small sample size, and lack of blinding and a control group. Furthermore, patients were diagnosed with various disorders along the depressive spectrum, and several patients had comorbid psychiatric conditions including post-traumatic stress disorder, mixed personality disorder, panic disorder, and trichotillomania, making it difficult to determine the effect of stimulant augmentation of antidepressants in patients with major depressive disorder of similar severity.
In a retrospective case series, Menza et al14 examined the use of a novel psychostimulant in augmenting conventional antidepressant therapy. The authors retrospectively reviewed the charts of seven patients diagnosed with unipolar major depression or bipolar depression who had been successfully treated with modafinil combined with an antidepressant. Modafinil is a novel psychostimulant that has only weak affinity for the dopamine reuptake receptor and does not stimulate dopamine release from the striatum of rodents. It has been found to be 250-fold less potent than amphetamine and has only weak peripheral sympathomimetic action, along with minimal hemodynamic effects. Patients in the study had exhibited only partial or no response to adequate trials of various conventional antidepressants, including bupropion, fluoxetine, citalopram, and trazodone. Modafinil 100-200 mg daily was added. All patients experienced marked improvement in overall well-being and decreased Hamilton Rating Scale for Depression (HAM-D) scores within 1-2 weeks. In particular, the patients experienced improvement in complaints of prominent fatigue. Patients diagnosed with bipolar depression did not experience emergence of agitation, hypomanic or manic symptoms, or psychosis. Interpretation of results was significantly limited by selection bias, as the series of cases was not consecutive, and there was the lack of a control group.
In an open trial, Stoll et al15 examined the use of methylphenidate to augment SSRIs in a subgroup of patients with major depression who remained refractory to treatment. They reported a case series of five patients ranging in age from 27-68 years who had experienced only partial improvement on SSRIs. Methylphenidate 10-40 mg per day was used to augment SSRI treatment. Subjective symptom reduction was reported among all subjects, often within days of initiation of methylphenidate. Beneficial effects appeared robust. The authors reported that none of the subjects developed tolerance once an adequate dose of methylphenidate was achieved. None of the subjects was noted to abuse methylphenidate. Only mild side effects, including a slight decrease in appetite in one patient and overstimulation in another patient, were reported. Interpretation of results was limited by small sample size and the lack of a control group, making it impossible to rule out a placebo effect or the effect of additional time on the SSRIs. Furthermore, four of the five patients had been diagnosed with comorbid psychiatric illnesses including panic disorder, bulimia, attention-deficit hyperactivity disorder (ADHD), dysthymia, and social phobia. Several patients were also taking medications such as nortriptyline and trazodone. In several cases, the doses of SSRIs were also increased.
Lavretsky and Kumar3 followed 10 patients age 68-92 years in an open trial of methylphenidate and citalopram. Nine of the 10 patients were diagnosed with unipolar depression without psychotic features, and one patient was diagnosed with depression due to Parkinson’s disease. Based on clinical presentation and medical need for rapid response, five patients were started on methylphenidate at the same time that citalopram was initiated (designated day 0), two patients received augmentation beginning on day 3 of antidepressant treatment, and three patients began augmentation at 3 weeks, following minimal response to monotherapy. Response was defined as a HAM-D score of lower than 10 and Clinical Global Impressions-Improvement (CGI-I) Scale score of 1 or 2 (“very much improved” or “much improved”), while accelerated or rapid response was defined by such ratings reached by treatment week 2. Remission was defined as HAM-D scores of 10 or lower, and patients were followed up for at least 8 weeks. Rapid response was observed in four patients, all of whom had had methylphenidate started within 3 days of initiating treatment with citalopram. Among the three patients who had augmentation therapy initiated at week 3, two patients improved by week 8, whereas the one patient diagnosed with depression secondary to Parkinson’s disease failed to respond and required ECT. The authors did not note any major side effects, although one patient with history of myocardial infarction was able to tolerate only citalopram 10 mg and methylphenidate 2.5 mg daily due to increased anxiety and palpitations.
Observed side effects included insomnia, anxiety, agitation, and increased blood pressure and heart rate. Five patients required adjunct lorazepam, four of whom had a history of benzodiazepine use for anxiety or insomnia. No patient developed tolerance to methylphenidate. The authors concluded that eight of the 10 patients benefited from augmentation by demonstrating clinically and statistically significant improvement by week 8. The effects of citalopram alone would be expected to be observed by week 8, however, and without a control group it is difficult to know whether response was due to augmentation, increased time of exposure to or increased levels of citalopram, or placebo effect.
In a later study, Lavretsky et al16 followed 11 outpatients 70 years and older who were diagnosed with major depressive disorder and were given a combination of methylphenidate in doses ranging from 5-20 mg per day and citalopram 20-40 mg per day in a 10-week, open-label trial. Methylphenidate was tapered and discontinued during weeks 9 and 10. Nine patients completed the study. Six patients met criteria for accelerated response, which was defined as HAM-D score lower than 10 and CGI-I scale score of 1 or 2 by treatment week 2. An additional two patients responded by week 3, so that only one patient who completed the trial failed to respond. Five of six rapid responders maintained response until week 8. Five of eight responders maintained antidepressant response even after discontinuation of methylphenidate, whereas three patients required re-instatement of methylphenidate secondary to worsening of depressive symptoms. All subjects reported mild-to-moderate side effects including sedation, nausea, anxiety, polyuria, dry mouth, and hypersalivation. Two subjects did not complete the trial, one subject due to side effects after 1 week and another subject due to lack of response at week 3. No patient experienced significant change in blood pressure or heart rate, and tolerance to methylphenidate was not observed.
The authors concluded that the observed reduction in time to response among the rapid responders was dramatic, particularly given the typically observed prolonged onset of action among geriatric patients with depression, and considering the characteristics of the study population (ie, elderly subjects suffering from chronic major depressive disorder refractory to treatment). Interpretation of the results, however, as noted by the authors, is significantly limited by lack of a control group, small sample size, and relatively short duration of trial. Furthermore, methylphenidate inhibits cytochrome P450 enzymes involved in metabolism of citalopram, making it difficult to conclusively determine whether observed accelerated response was due to augmentation by methylphenidate or increased levels of citalopram.
In the only controlled study, Postolache et al17 conducted a randomized, double-blind, placebo-controlled trial in which patients diagnosed with major depression who had received no antidepressant treatment for at least 6 weeks were randomly assigned to active or control group. Patients in the control group received sertraline 50 mg daily and placebo, while patients assigned to active group received sertraline 50 mg daily and methylphenidate 5 mg twice daily in a parallel design. Sertraline dose was increased to 100 mg daily on day 10 in both groups, and methylphenidate was increased to 10 mg twice daily in the active group. Methylphenidate was tapered at the end of week 7. Full response was defined as a 50% reduction in HAM-D score and a HAM-D score of 9 or less. Nine outpatients were enrolled in the study, which was too small for statistical analysis. The authors hypothesized accelerated improvement in patients receiving the combined treatment. However, they found no response by day 7 of the combined treatment, and, indeed, at no point in the 9-week study did patients in the active group demonstrate advantage relative to the control group with regard to decrease in HAM-D score or improvement in global functioning as measured by the Social and Occupational Functioning Assessment Scale (SOFAS). At 9 weeks, two of the four patients receiving sertraline and placebo had fully responded, whereas no patient receiving combined treatment had fulfilled criteria for full response.
Although a few open trials demonstrate benefits for psychostimulants as monotherapy and as augmenting agents to standard antidepressant therapy, these studies are limited by the small sample size and the lack of control groups. The only controlled study examined here did not find any benefit for stimulants in its augmentation of sertraline. This dearth of data is even more conspicuous with older patients with depression, as very few trials have included them. Therefore, although preliminary studies suggest beneficial effects for psychostimulants in the treatment of depression in the older patient (ie, in those who are also medically ill), more rigorous studies need to be conducted before their routine use in this capacity can be recommended.
This project is supported by funds from the Division of State, Community, and Public Health, Bureau of Health Professions (BHPr), Health Resources and Services Administration (HRSA), Department of Health and Human Services (DHHS) under grant number 1 K01 HP 00071-02 and Geriatric Academic Career Award. The information or content and conclusion are those of the author, Rajesh R. Tampi, MD, MS, and should not be construed as the official position or policy of, nor should be any endorsements be inferred by, the BHPr, HRSA, DHHS or the U.S. government.