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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Am J Geriatr Pharmacother. Author manuscript; available in PMC 2010 February 1.
Published in final edited form as:
PMCID: PMC2738590
NIHMSID: NIHMS111715

Methylphenidate for Treatment of Depressive Symptoms, Apathy, and Fatigue in Medically Ill Older Adults and Terminally Ill Adults

Susan E. Hardy, MD, PhD*

Abstract

Background

Depressive symptoms, apathy, and fatigue are common symptoms among medically ill older adults and patients with advanced disease, and are associated with morbidity and mortality. Methylphenidate has been used to treat these symptoms because of its rapid effect.

Objective

To review the literature regarding the efficacy and safety of methylphenidate to treat depressive symptoms, apathy, and fatigue in medically ill older adults and in palliative care.

Methods

English-language articles presenting systematic reviews, clinical trials, or case series describing use of methylphenidate to treat depressive symptoms, fatigue, or apathy in medically ill older adults or in palliative care were identified. The keywords “methylphenidate” and either “depressive”, “depression”, “fatigue”, or “apathy” were used to search the Cochrane Database, MEDLINE, PsycINFO, and International Pharmaceutical Abstracts. Included articles addressed depressive symptoms, apathy, or fatigue in 1) older adults (generally age 65 years or older), particularly those with comorbid medical illness; 2) adult patients receiving palliative care; and 3) adults with other chronic illnesses. We excluded articles regarding 1) treatment of depression in healthy young adults; 2) treatment of bipolar disorder or attention-deficit hyperactivity disorder; and 3) treatment of narcolepsy, chronic fatigue syndrome and related disorders.

Results

19 controlled trials of methylphenidate in medically ill older adults or in palliative care were identified. Unfortunately, their conflicting results, small size, and poor methodologic quality limit our ability to draw inferences regarding the efficacy of methylphenidate, although the evidence of its safety is stronger. The available evidence suggests possible effectiveness of methylphenidate for depressive symptoms, fatigue, apathy, and cognitive slowing in various medically ill populations.

Conclusions

In the absence of definitive evidence of effectiveness, trials of low-dose methylphenidate in medically ill adults suffering from depression, apathy, or fatigue with monitoring for response and adverse effects are appropriate.

Keywords: methylphenidate, depression, apathy, fatigue, older adults, palliative care, medically ill

INTRODUCTION

Depressive symptoms, apathy, and fatigue are common symptoms among medically ill older adults and patients with advanced disease. A quarter of hospitalized older adults meet criteria for major depression.1 Among patients with advanced disease receiving palliative care, the prevalence of major depression is approximately 15%, with clinically significant depressive symptoms present in 30%.2 Among acutely ill hospitalized older adults, depressive symptoms are associated with mortality, disability, and poor health status.3, 4 An association between depressive symptoms and poor recovery has been reported in a variety of illnesses, including hip fracture and other injuries, acute myocardial infarction, and stroke.5, 6 Depressive symptoms affect older adults ability to participate in rehabilitation and other aspects of their care, leading to adverse outcomes.7-9

Since their introduction in the 1930s, psychostimulants such as amphetamine and methylphenidate have been used in the treatment of depression. Methylphenidate, a piperadine derivative, is a central nervous system stimulant FDA-approved for treatment of attention deficit hyperactivity disorder and narcolepsy.10 It is a chiral drug with four entantiomers; most clinical preparations contain both d- and l-threo entantiomers, although only the d-threo entantiomer is clinically active.11 Dexmethylphenidate contains only the d-threo entantiomer and is twice as potent as standard methylphenidate at the same dose. Although methylphenidate's mechanism of action is not completely understood, it is known to bind to the dopamine transporter in the presynaptic cell membrane, blocking dopamine reuptake and increasing extracellular dopamine levels.12 The highest area of methylphenidate uptake in humans is the striatum, where dopamine enhances the signal to noise ratio and increases salience of a stimulus and motivation for goal-directed behavior.11 Methylphenidate also inhibits norepinephrine reuptake and (weakly) serotonin reuptake.13

While the use of methylphenidate in depression declined with the introduction of tricyclic antidepressants in the 1950s and selective serotonin reuptake inhibitors in the 1980s, interest in methylphenidate as an antidepressant has persisted, particularly in the settings of medical illness and palliative care.12 The rapid onset is particularly attractive in these settings. Despite the long history of methylphenidate use in the treatment of depressive symptoms, fatigue, and apathy, there is little definitive evidence to support its use. We review the literature regarding the efficacy and safety of methylphenidate to treat these symptoms in medically ill older adults and in patients receiving palliative care.

MATERIALS AND METHODS

Data Sources

English-language articles presenting systematic reviews, clinical trials, or case series describing use of methylphenidate to treat depressive symptoms, fatigue, or apathy in medically ill older adults or in the palliative care setting were identified. The first step in data collection was a search in the Cochrane Database of Systematic Reviews (through 2008 Issue 3) using the keywords “methylphenidate” and either “depressive”, “depression”, “fatigue”, or “apathy”. These search terms were also used to identify individual articles in MEDLINE (1950 to July 2008), PsycINFO (1806 to July 2008) and International Pharmaceutical Abstracts (1970 to July 2008). The references of all pertinent articles (including review articles) were also searched for eligible articles.

Selection Criteria

Articles were included if they addressed depressive symptoms, apathy, or fatigue in 1) older adults (defined as age 65 years or older, although some articles with lower age cutoffs were included), particularly those with comorbid medical illness; 2) adult patients receiving palliative care or with terminal illness; and 3) in adult patients with other chronic medical illnesses. We excluded articles regarding 1) treatment of depression in adults younger than 65 without comorbid illness; 2) treatment of bipolar disorder or attention-deficit hyperactivity disorder; and 3) treatment of narcolepsy, cataplexy, chronic fatigue syndrome and related disorders. We also excluded articles assessing psychological response to methylphenidate in healthy adults or other non-clinical populations. Because of the relative paucity of evidence, we examine case series and case reports in addition to controlled trials.

RESULTS

Systematic Reviews

Two recent Cochrane reviews have addressed the use of psychostimulants for depression14 and pharmacologic treatment for cancer-related fatigue.15 The review of psychostimulants for depression was limited to randomized controlled trials and identified only 24 trials, 10 of which involved methylphenidate. They report that the trials were small and of poor quality, and conclude that “few clinically relevant conclusion can be drawn.” Six of these trials were studies of younger outpatients without major medical comorbidity, and thus were not included in this review. The two trials with more than 100 participants showed positive effects of methylphenidate,16, 17 while the other four, all with 60 or fewer participants, showed no significant difference between methylphenidate and placebo.{Mattes, 1985 #3101; Patkar, 2006 #3102; Robin, 1958 #3103; Postolache, 1999 #3027} Three positive studies are described later in this review.{Fernandez, 1995 #2942; Lee, 2005 #2985; Wallace, 1995 #3052} The final study found that a single dose of intravenous methylphenidate improved mood in depressed patients without Parkinson's disease, but not in those with Parkinson's disease.{Cantello, 1989 #3104} Overall, these studies leave a mixed picture of the potential role of methylphenidate in depression treatment, with more positive results in older adults and the chronically ill. Two randomized controlled trials of methylphenidate18, 19 were included in the cancer-related fatigue review and are described below (Table 2). Combining the trials they found evidence that methylphenidate was significantly better than placebo for the treatment of cancer-related fatigue.

Table 2
Controlled trials of methylphenidate in terminal illness and palliative care

Controlled Trials

Medically Ill Older Adults

The characteristics of the 13 controlled trials evaluating the use of methylphenidate in medically ill older adults are presented in Table 1.20-32 All of the trials were small (between 1 and 70 participants) and compared methyphenidate with placebo. Seven trials, 20, 22, 24, 27, 29, 30, 32 including two “N-of-1” trials,27, 29 were crossover trials and six21, 23, 25, 26, 28, 31 were parallel comparisons. Most of the trials provide limited methodologic details, limiting our ability to assess the validity of the individual trials. Of the 11 trials20-24, 26-28, 30, 32 in which statistical significance was evaluated (or could be calculated from data provided), seven23, 24, 26-28, 30, 32 reported positive results for at least one outcome. Studies specifically measuring depressive symptoms or apathy23, 24, 26-28, 30-32 were more likely to be positive (7/8) than those measuring other outcomes20-22 (0/3).

Table 1
Controlled trials of methylphenidate in medically ill older adults.

In addition to using methylphenidate as monotherapy, several more recent studies have used methylphenidate in combination with a standard antidepressant to accelerate or enhance the response to the standard agent. Cases reporting the effectiveness of methylphenidate in achieving therapeutic response in patients with inadequate response to standard antidepressants, have been in the literature since the 1960s.33-36 After two prospective uncontrolled trials of older adults (aged 70 years or older) showing response to the combination of citalopram and methylphenidate within 2 weeks in a majority of patients,37, 38 a small randomized, double-blind trial comparing citalopram and methylphenidate to citalopram and placebo found responses (defined as a Hamilton Depression Rating Scale score less than 10) in 5/6 patients receiving methylphenidate compared to 0/6 receiving placebo (p=0.04).39 However, a controlled trial of sertraline and methylphenidate in younger adults found no benefit.40

Terminal Illness and Palliative Care

Methylphenidate has been used in palliative care to treat fatigue, depression and opiate-associated sedation, to potentiate the analgesic effect of opiates, and to improve cognitive function.10, 41, 42 The characteristics of the 6 controlled trials evaluating the use of methylphenidate in terminal illness and palliative care are presented in Table 2.18, 19, 43-46 Methylphenidate improved fatigue in 4/6 studies19, 43, 44, 46 and cognition in 2/2 studies. 44Lower, 2005 #2989

Other Chronic Medical Illnesses

Methylphenidate has been used as a treatment for depression, cognitive symptoms, and fatigue in a wide variety of chronic medical conditions, including HIV and AIDS, stroke, and traumatic brain injury.47 Studies of methyphenidate in HIV patients have mixed results, but generally suggest some benefit for depressive symptoms (2 of 3 studies),48-50 fatigue (1 of 1 study),51 and cognitive deficits (2 of 3, with the third suggesting benefit in the subgroup with the greatest impairment).49, 50, 52 Studies of methylphenidate in traumatic brain injury suggest benefit for cognition, particularly attention, (4 of 6 studies),53-58 but not for behavioral symptoms (2 of 6 studies).53, 55-59 Studies suggest a beneficial effect of methylphenidate on fatigue associated with Parkinson's disease,60 sarcoidosis,61 and possibly α-interferon treatment.62

Case Series and Case Studies

Medically Ill Older Adults

The characteristics of 2 prospective uncontrolled trials63, 64 and 9 retrospective complete case series65-74 of medically ill older adults treated with methylphenidate are presented in Table 3. A prospective trial of 10 post-stroke rehabilitation patients with major depression reported a response rate of 40%,63 while the retrospective series reported response rates between 33% and 83% for depressive disorders.65-74 One series of medically ill adults reported response rates overall71 and in those aged 65 years or older;72 response rates among older adults (n=25) were lower than for younger adults (n=19), although this result was not statistically significant (89% versus 68%, p=0.15). A prospective trial of methylphenidate for negative symptoms such as anhedonia and psychomotor retardation in patients with Alzheimer's disease or vascular dementia64 reported significant improvement in symptoms scores, but did not provide response rates. Reports of successful uses of methylphenidate in the literature include treatment of lethargy and depressive symptoms in mechanically ventilated patients who are difficult to wean,75, 76 treatment of anorexia in apathetic, severely demented nursing home residents,77, and treatment of depressive symptoms in patients up to 106 years of age.78

Table 3
Prospective uncontrolled trials and retrospective complete case series: medically ill older adults

Terminal Illness and Palliative Care

The characteristics of 11 prospective uncontrolled trials44, 79-88 and 2 retrospective complete case series89, 90 of palliative care patients treated with methylphenidate are presented in Table 4. Among patients with depressive disorders, response rates ranged from 73% to 81%81, 84, 89, 90 except in a study of hospice inpatients by Macleod with a 27% response rate.85 Macleod noted that 54% of the patients in his study died within 6 weeks, and that only one of these patients response, suggesting that methylphenidate may not be effective or may require higher doses in the last weeks of life. Response rates for opiate-induced somnolence or sedation ranged from 80% to 88%,44, 79 and for fatigue from 38% to 82%.80, 83, 88 Two studies demonstrated significant improvements in cognitive function.82, 86 Methylphenidate has been succesully used to treat hypoactive delirium in the terminally ill in several case reports.91, 92

Table 4
Prospective uncontrolled trials and retrospective complete case series: terminal illness and palliative care

Other Chronic Medical Illnesses

There are numerous cases in the literature reporting successful use of methylphenidate for depression and cognitive symptoms in HIV/AIDS,93, 94 intensive care patients with respiratory failure,95, 96 and other chronic illnesses.97-99 Cases of apathy independent of depression successfully treated with methylphenidate are also reported.100-103

Guidelines/Treatment Algorithms

Methylphenidate is recommended as a potential treatment in guidelines or treatment algorithms for major depression in advanced cancer,104-106 augmentation therapy in geriatric depression,107 and neurobehavioral sequelae of traumatic brain injury.108 In their treatment algorithm for depression in advanced cancer,{Nakano, 1999 #3009; Okamura, 2008 #3013} Nakano and colleagues recommend methyphenidate alone or in combination with other drugs, particularly for older patients experiencing lethargy or fatigue. They base this recommendation on a single RCT{Wallace, 1995 #3052} and several uncontrolled studies. Passik and colleagues{Passik, 2002 #3019} describe successful implementation of a treatment algorithm in oncology clinics which recommended fluoxetine in combination with methylphenidate for depressed patients with prominent fatigue. Oshima and Higuchi{Oshima, 1999 #3016} recommend methylphenidate as augmentation therapy in geriatric major depression, based on observational studies. These algorithms and recommendations for methylphenidate use in depression are based on relatively weak evidence. In a thorough and evidence-based guideline for the treatment of neurobehavioral sequellae of traumatic brain injury,{Neurobehavioral Guidelines Working Group, 2006 #3011} the Neurobehavioral Guidelines Working Group recommended methylphenidate for the treatment of deficits in attention and processing speed based on two well-designed randomized controlled trials, three prospective studies, and three retrospective studies.

Tolerability and Adverse Reactions

Most studies suggest that methylphenidate is well tolerated in the medically ill, the terminally ill, and older adults (see Tables 1--4).4). Adverse effects occur in 0% to 90% of patients on methylphenidate, with the majority of studies reporting rates between 5% and 30%; most adverse effects are mild and resolve with discontinuation of therapy. Most controlled studies showed no difference in adverse events between methylphenidate and placebo.18, 20-23, 28, 30-32, 43, 45, 46, 55-58, 60, 61, 109 Herrmann and colleagues24 reported significantly more adverse effects on methylphenidate versus placebo in patients with apathy in Alzheimer's disease, with two patients developing severe delirium. Lower and colleagues19 found high rates of adverse events in cancer patients taking either methylphenidate or placebo (90% versus 78%, p=0.08); nausea, dry mouth, dizziness, and jitteriness were more common in the methylphenidate group. Breitbart and colleagues51 found that AIDS patients receiving methylphenidate experienced significantly more adverse effects than those receiving placebo, particularly hyperactivity or jitteriness. In patients receiving methylphenidate, adverse effects were no more frequent than in patients receiving desipramine48 or nortriptyline68, and were less frequent than in patients receiving sertraline.54 While standard antidepressants have been associated with increased risk of falls,110, 111 older adults improved in mobility, gait variability, and executive function after a single dose of 20mg of methylphenidate.112

The most common adverse effects reported are agitation or restlessness, sinus tachycardia or palpitations, delirium or confusion, and insomnia. Both hypertension and hypotension have been reported in older adults on methylphenidate, although both are relatively infrequent. One serious but uncommon adverse effect was arrhythmia,65, 113-115 which was reversible with discontinuation in all cases. Cases have been published reporting multiple strokes in a 63 year old woman treated for hyperactivity with methylphenidate,116 and auto-immune hepatitis in a 57 year old liver transplant patient which resolved after methylphenidate was discontinued.117 Two case series of patients taking methylphenidate for 12 to 54 months found no evidence of adverse effects or development of dependence.99, 118 Steibel119 reports two cases of patients with end stage renal disease treated with methylphenidate with no evidence of clinical toxicity or elevated drug levels. Two case series of adult epilepsy patients and brain injured patients with seizure disorders showed no increase in seizure rates with methylphenidate treatment.120, 121

In 2007, the FDA required new warnings in psychostimulant labeling regarding reports of serious cardiovascular events, including sudden death, stroke, and myocardial infarction in children and adults using stimulants for attention deficit hyperactivity disorder. A comprehensive review of clinical data on over 500,000 individuals prescribed psychostimulants is currently underway.{, #3105} Between 1992 and 2004, sudden death was reported to the FDA in 2 adults and 11 children taking methylphenidate. Over a five year period from 1999 to 2003, there were 11 spontaneous reports of serious nonfatal cardiovascular or cerebrovascular adverse events in adults taking methylphenidate, including syncope, hypertension, chest pain, heart failure, myocardial infarction, arrhythmia, mitral valve prolapse, and stroke.{, #3107} In a six-week study of adults aged 19 to 60 years with attention deficit hyperactivity disorder treated with an average of 1.1 mg/kg/day of methylphenidate, close clinical monitoring including electrocardiography revealed small but statistically significant increases in pulse (7 beats per minute, p< .001), but not in systolic or diastolic blood pressure (both increased 2mm Hg, p=.10 and p=0.6 respectively). On electrocardiography, there were slight increases in ventricular rate (7 beats per minute, p<.001) and QTc interval( .007s, p<.01). There were no symptoms or adverse events referable to the cardiovascular system.{Spencer, 2005 #3106} While these were relatively young and healthy patients, the average dose (82 ± 22 mg/day) was much higher than the maximum dose I would recommend for older adults (20 mg/day). In a study of fatigued geriatric rehabilitation patients, heart rate increased 5−10% with methylphenidate doses of 20mg/day and was unchanged with placebo.{Larsson, 1988 #2979} Among the 24 participants in this study, 10 had pacemakers or were taking a beta-blocker or digoxin and none experienced cardiovascular side effects. Among the 31 patients aged 65 and older who received methylphenidate augmentation in Lavretsky and colleagues studies,{Lavretsky, 2003 #2980; Lavretsky, 2001 #2982; Lavretsky, 2006 #2981} only one subject experienced a fluctuation of greater than 10% in heart rate or blood pressure, and this responded to dosage adjustments of his antihypertensives. These studies included participants with hypertension, coronary artery disease, and cerebrovascular disease.

In medical illness and palliative care, malnutrition and weight loss are often major problems. An anorexigenic effect of methylphenidate would limit its usefulness in these populations. Several early trials of methylphenidate in institutionalized chronically-ill older adults reported stable weights compared to placebo on doses of 20−60mg per day for 4−8 weeks.21, 22, 28 In a trial of methylphenidate for cancer-related fatigue, self-rated appetite improved in both the methylphenidate and placebo groups (with no significant difference between them), and appetite improved significantly from baseline for the methylphenidate group.18 In a trial of methylphenidate for HIV-associated depression, patients taking methylphenidate were more likely to report weight loss than those taking desipramine (2/8 versus 0/12, p=0.14). Maletta and colleagues report three cases of methylphenidate used to reverse anorexia in apathetic, severely demented nursing home patients; in all three cases weight loss stabilized or reversed and no changes in blood pressure or evidence of delirium occurred.77 Among 25 medical and surgical inpatients treated with methylphenidate, no anorexia was observed and appetite improved in many patients.72

Drug-Drug Interactions

Methylphenidate should not be used in patients receiving monoamine oxidase inhibitors due to risk of hypertensive crisis and serotonin syndrome, although there are case reports of successful concomitant use.122 Although in vitro studies have shown increased levels of tricyclic antidepressants when administered with methylphenidate,123 an observational study in children showed no significant interaction between methylphenidate and despiramine levels.124 In healthy adults, administration of quinidine, a potent cytochrome P450 2D6 inhibitor, with methylphenidate had no effect on the pharmacokinetics of methylphenidate or its metabolites, suggesting that tricyclic antidepressants and other P450 2D6 inhibitors should not interact with methylphenidate.125 However, caution should still be used when combining methylphenidate and tricyclic antidepressants. Perhaps because selective serotonin reuptake inhibitors are metabolized in the liver while 80% of methylphenidate is metabolized extrahepatically, there are no reports of interactions for the combination.123 Methylphenidate has been reported to inhibit the metabolism of some antidepressants,123 while anticonvulsants have been reported to decrease the effectiveness of methylphenidate secondary to induction of cytochrome P450 3A4-mediated methylphenidate metabolism.126 Overall, administration of methylphenidate with anticonvulsants appears safe with careful monitoring.127 Methylphenidate may also increase warfarin levels through inhibition of warfarin metabolism.126

DISCUSSION

Despite the long history of methylphenidate use in older adults and the medically ill, the data to support such use is of relatively poor quality. None of the clinical trials in older adults had more than 70 participants, and many, particularly those published before the CONSORT guidelines were adopted, had substantial methodologic flaws. Controlled trials in palliative care, HIV/AIDS, stroke, and traumatic brain injury are more recent and tended to be of higher quality, but still gave mixed results. The weight of the evidence suggests possible effectiveness of methylphenidate for depressive symptoms, fatigue, apathy, and cognitive slowing in a variety of medically ill populations. Strong evidence of effectiveness would require a well designed randomized, controlled trial with adequate power.

Evidence for the safety of methylphenidate in the medically ill is considerably stronger than for effectiveness. Evidence from both controlled clinical trials and the extensive case series that have been published indicate a very low risk of serious adverse effects. Although a causal link has not been determined, there have been reports of sudden unexplained death, stroke, and myocardial infarction in adults receiving usual dosages of stimulants for the treatment of ADHD.126 No published reports of deaths attributable to methylphenidate in adults were identified. Methylphenidate appears to be at least as safe and well tolerated as standard antidepressants in the medically ill.

Given the safety of methylphenidate, trials of methylphenidate in medically ill adults suffering from depression, apathy, or fatigue with monitoring for response and adverse effects are appropriate. I would recommend initial dosing of 5mg methylphenidate with breakfast, or 2.5mg in patients who are frail or have significant cardiovascular disease, increasing by 2.5−5mg every one to two days in divided doses at breakfast and lunch if well tolerated and not effective to a maximum dose of 20−30mg/day. If ineffective after three days on the maximum dose, methylphenidate should be tapered and discontinued. Blood pressure and pulse should be monitored before and during methylphenidate therapy. It would be prudent to monitor the INR or drug levels in patients receiving warfarin or anticonvulsants. The optimal duration of therapy in patients who respond to methylphenidate is unclear. In patients with acute or subacute illness, the medication can be tapered once the condition has stabilized. While most studies have demonstrated little evidence of habituation to the effects of methylphenidate, it is possible that doses may need to be increased in long-term therapy to maintain effectiveness.

CONCLUSIONS

Depressive symptoms, fatigue, and apathy are common symptoms among medically ill older adults, patients receiving palliative care, and chronically ill adults. Methylphenidate has long been used in these populations because of its benign adverse effect profile and the rapid response to treatment. In the absence of definitive evidence of effectiveness, trials of methylphenidate in medically ill adults suffering from depression, apathy, or fatigue with monitoring for response and adverse effects are appropriate.

ACKNOWLEDGMENTS

Dr. Hardy is supported by the Pittsburgh Claude D. Pepper Older Americans Independence Center (P30AG-024827) and the Hartford Foundation. She would like to thank Dr. Joseph Hanlon for his thoughtful review of the manuscript.

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