Methylphenidate (Ritalin) and other psychostimulants in adults and the elderly

Monday, March 30, 2015

Executive Summary

This is an abstract of the literature on the use of psychostimulants to treat psychiatric conditions in adults and the elderly. The results are presented primarily in two sections: the first section reports on studies in which psychostimulants, primarily methylphenidate (MPH) were used as first-line therapy or monotherapy. This section is broken down into five tables: randomized controlled trials; open label trials; case series, retrospective chart reviews, and case reports. The subsequent section lists studies of psychostimulants used as adjunctive therapy, usually as add-ons to either conventional antidepressants or the newer SSRIs and SNRIs.

While the mechanism of action of psychostimulants in treating depression or depressive symptoms such as apathy remains speculative, my hypothesis is that the effect of psychostimulants on reducing sleep, and especially reducing REM sleep when given early in the morning, is responsible for improving depressive symptoms. There is a considerable body of literature on the use of sleep deprivation or partial sleep deprivation to treat depression (please see the talks I have given on this topic, eg: http://henry.olders.ca/wordpress/?p=192 ). That MPH is effective at suppressing sleep is briefly discussed in the section “MPH and sleep”.

My clinical impression, after treating hundreds of elderly patients with methylphenidate,  including many at Ste. Anne’s Hospital, is that better results in treating depressive symptoms are obtained by giving the first dose of the medication early in the morning, when it is likely to suppress what would otherwise be the longest period of REM sleep. A later dose of MPH, at 8h for example, is not as effective as a 6h or 6h30 dose.

Several review articles, abstracted in the section “Reviews”, typically emphasize that psychostimulants result in rapid improvement with few side effects.

In conclusion, the scientific literature suggests that methylphenidate and other stimulants have been widely used as first-line treatment for a number of conditions affecting the elderly, and continue to be so used because they are effective and safe. Additionally, these medications find application as add-on treatment, especially in depressions resistant to treatment with traditional or newer generations of antidepressants.

Future studies on the use of psychostimulants should include measurements of their effects on sleep, particularly duration, timing, and REM sleep; and effects on circadian rhythms.

Psychostimulants as adjunctive therapy

MPH and sleep

MPH suppresses REM sleep (Baekeland 1966). MPH reduces total sleep and REM sleep, but does not decrease slow wave sleep (Nicholson and Stone 1980).

Stimulant drugs are effective in the treatment of hypersomnia (Taub 1978).

The time of day when MPH is taken has an important influence on effectiveness in improving depressive symptoms (Swift 1989).

Partial sleep deprivation acts to increase the effect of MPH on subjective fatigue and on attentional performance. It also increase the preference of subjects for taking MPH (Roehrs et al. 1999),

In dementia patients, neither sertraline nor mirtazapine was better than placebo in improving symptoms of depression after 13 weeks of treatment (Banerjee et al. 2011)

MPH keeps people awake (increased mean latency on the Multiple Sleep Latency Test (MSLT) in both sleep deprived and sleep replete conditions) (Bishop et al. 1997)

Reviews

“Psychostimulants have useful antidepressant properties and are usually well tolerated. They may be useful as adjuncts to standard antidepressants in refractory depression, but have particular utility in conditions where a prompt therapeutic effect is desired and where tolerance and dependence are less of a concern. Such conditions include the treatment of depression in terminal illness and in extreme old age.Psychostimulants, although now largely discarded as treatment options for depression, deserve careful consideration as potential therapeutic agents in specific patient subgroups.” (Orr and Taylor 2007)

“173 studies were screened. Five studies on methylphenidate and 1 study on caffeine met inclusion criteria and were included in this review. Two studies were case reports, 2 were open-label trials, and 2 were double-blind, crossover randomized placebo-controlled trials. Three studies were conducted with hypoactive delirium patients and all studies were conducted in an advanced cancer patient population. CONCLUSIONS: The reviewed studies support the use of methylphenidate to improve end-of-life patient cognitive functions, particularly in the case of hypoactive delirium. Caffeine seems to have beneficial effects on psychomotor activity.” (Elie et al. 2010)

“Randomised controlled trials (RCTs) assessing the effectiveness of PS (psychostimulants) were included. The trial population comprised adults of either sex with a diagnosis of depression. …Twenty-four RCTs were identified. The overall quality of the trials was low. Five drugs were evaluated; dexamphetamine, methylphenidate, methylamphetamine, pemoline and modafinil. Modafinil was evaluated separately as its pharmacology is different to that of the other PS. PS were administered as a monotherapy, adjunct therapy, in oral or intravenous preparation and in comparison with a placebo or an active therapy. Most effects were measured in the short term (up to four weeks). Thirteen trials had some usable data for meta-analyses. Three trials (62 participants) demonstrated that oral PS, as a monotherapy, significantly reduced short term depressive symptoms in comparison with placebo (SMD -0.87, 95% CI -1.40, -0.33, with non-significant heterogeneity. A similar effect was found for fatigue. In the short term PS were acceptable and well tolerated. Tolerance and dependence were under evaluated. No statistically significant difference in depression symptoms was found between modafinil and placebo.” (Candy et al. 2008)

“Despite antidepressant therapy of appropriate trial duration and dose optimization, …only 35-40% achieve remission. …18 RCTs reporting on the use of psychostimulants in the treatment of adult patient populations, suffering from moderate-severe depression and having no other concomitant medical illnesses, were included in this review. 14 articles provided results for unipolar depression, two for bipolar depression, whereas two articles presented mixed samples of unipolar and bipolar patients. RESULTS: Five different psychostimulants were evaluated: modafinil, methylphenidate, dexamphetamine, methylamphetamine and pemoline. Two studies examining modafinil demonstrated significant ameliorating characteristics pertaining to symptoms of depression. No clear evidence for the effectiveness of traditional psychostimulants in the therapeutic management of MDD was found. In general the quality of included trials was poor since the majority was of short-term duration, comprising relatively small sample sizes and some, especially older studies, were methodologically flawed.” (Abbasowa et al. 2013)

“A total of 19 controlled trials of methylphenidate in medically ill older adults or patients in palliative care were identified. Unfortunately, their conflicting results, small sample sizes, and poor methodologic quality limited the ability to draw inferences regarding the efficacy of methylphenidate, although evidence of tolerability was stronger. The available evidence suggests possible effectiveness of methylphenidate for depressive symptoms, fatigue, and apathy in various medically ill populations.“ (Hardy 2009)

This review looked at the pharmacology of psychostimulants and their uses in a range of conditions. It looked at both retrospective and prospective studies in depression, medical illness, cancer, fatigue, obsessive-compulsive disorder, drug-induced sedation, hiccups, Parkinson’s disease, epilepsy, incontinence, mania, narcolepsy, pain, opiod-induced respiratory depression, physical disability, traumatic brain injury, and syncope. Psychostimulants were helpful in many of these conditions, although there were differential effects in some cases, eg dextroamphetamine was helpful, but MPH was not, in OCD (Homsi et al. 2000).

A MEDLINE search from 1986 to 1995 was done to identify literature on the use of methylphenidate for depression in the medically ill elderly. The references of articles found were evaluated for other relevant articles. CONCLUSIONS: Depression in the medically ill elderly occurs frequently and is underdetected in part because of the difficulty in diagnosing depression in this population. Methylphenidate has been found to be a safe and effective treatment of depression in the medically ill elderly. A potential advantage of methylphenidate over other antidepressants is its relatively quick onset of action, usually within 2-5 days. (Emptage and Semla 1996)

Survey

All 245 psychiatrists registered in Alberta in Feb 1995 were sent a survey (2 mailings); 230 (94%) responded. 204 out of this group treated adult patients. 95/204 (47%) prescribed psychostimulants; 73/95 (77%) prescribed MPH. 55/95 (58%) prescribed psychostimulants for unipolar depression for 296 patients; 12/95 (13%) for bipolar depression (36 patients), and 4/95 (4.2%) for dementia (17 patients). (Beck et al. 1999)

Side effects

To evaluate MPH-associated symptoms or side effects in frail adults with advanced cancer, data was collected from 2 published prospective cohort series and a phase 2 study of MPH for symptom control in advanced cancer. Initial doses were MPH 5 mg bid at 8h and 12h, titrated up to a maximum of 30 mg/day. 62 patients were enrolled. Fifty completed 7 days of MP with a median age of 69 (range 30-90) years. Thirty-five received MPH 10 mg/day. Most (96%) had improvement in depression and/or fatigue. Among the 62 patients, new symptom prevalence throughout the study was agitation (16%), insomnia (16%), dry mouth (15%), nausea (10%), tremors (6%), anorexia (5%), headache (3%), palpitations (2%), and vomiting (2%). Patients could have more than 1 symptom simultaneously. Seven (11%) withdrew due to MPH S/E. (Lasheen et al. 2010)

Forty percent of bipolar patients treated with psychostimulants for either ADHD or bipolar depression developed mania or hypomania, in a retrospective chart review of patients with bipolar disorder (137 randomly selected patients) evaluated at the Emory Bipolar Disorder Specialty Clinic (Wingo and Ghaemi 2008)

Bibliography

Abbasowa L, Kessing LV, Vinberg M (2013) Psychostimulants in moderate to severe affective disorder: a systematic review of randomized controlled trials. Nord J Psychiatry 67, 369–382.

Adida M, Azorin J-M (2014) Effectiveness of methylphenidate as augmentation therapy after failure of adjunctive neuromodulation for patients with treatment-refractory bipolar depression: a case report. NDT 559.

Ayache DC, Junior RF (2001) Methylphenidate in a patient with depression and respiratory insufficiency. Int J Psychiatry Med 31, 443–449.

Baekeland F (1966) The effect of methyl phenidate on the sleep cycle in man. Psychopharmacologia 10, 179–183.

Banerjee S, Hellier J, Dewey M, Romeo R, Ballard C, Baldwin R, Bentham P, Fox C, Holmes C, Katona C, Knapp M, Lawton C, Lindesay J, Livingston G, McCrae N, Moniz-Cook E, Murray J, Nurock S, Orrell M, O’Brien J, Poppe M, Thomas A, Walwyn R, Wilson K, Burns A (2011) Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial. Lancet 378, 403–411.

Beck C, Silverstone P, Glor K, Dunn J (1999) Psychostimulant prescriptions by psychiatrists higher than expected: a self-report survey. Can J Psychiatry 44, 680–684.

Bishop C, Roehrs T, Rosenthal L, Roth T (1997) Alerting effects of methylphenidate under basal and sleep-deprived conditions. Exp Clin Psychopharmacol 5, 344–352.

Breitbart W, Rosenfeld B, Kaim M, Funesti-Esch J (2001) A randomized, double-blind, placebo-controlled trial of psychostimulants for the treatment of fatigue in ambulatory patients with human immunodeficiency virus disease. Arch Intern Med 161, 411–420.

Bruera E, Driver L, Barnes EA, Willey J, Shen L, Palmer JL, Escalante C (2003) Patient-controlled methylphenidate for the management of fatigue in patients with advanced cancer: a preliminary report. J Clin Oncol 21, 4439–4443.

Camacho A, Ng B (2006) Methylphenidate for {alpha}-interferon induced depression. J Psychopharmacol

Candy M, Jones L, Williams R, Tookman A, King M (2008) Psychostimulants for depression. Cochrane Database Syst Rev CD006722.

Carlson PJ, Merlock MC, Suppes T (2004) Adjunctive stimulant use in patients with bipolar disorder: treatment of residual depression and sedation. Bipolar Disord 6, 416–420.

El-Mallakh RS (2000) An open study of methylphenidate in bipolar depression. Bipolar Disord 2, 56–59.

Elie D, Gagnon P, Gagnon B, Giguere A (2010) [Using psychostimulants in end-of-life patients with hypoactive delirium and cognitive disorders: A literature review]. Can J Psychiatry 55, 386–393.

Emptage RE, Semla TP (1996) Depression in the medically ill elderly: a focus on methylphenidate. Ann Pharmacother 30, 151–157.

Fernandez F, Levy JK, Samley HR, Pirozzolo FJ, Lachar D, Crowley J, Adams S, Ross B, Ruiz P (1995) Effects of methylphenidate in HIV-related depression: a comparative trial with desipramine. Int J Psychiatry Med 25, 53–67.

Galynker I, Ieronimo C, Miner C, Rosenblum J, Vilkas N, Rosenthal R (1997) Methylphenidate treatment of negative symptoms in patients with dementia. J Neuropsychiatry Clin Neurosci 9, 231–239.

Grade C, Redford B, Chrostowski J, Toussaint L, Blackwell B (1998) Methylphenidate in early poststroke recovery: a double-blind, placebo-controlled study. Arch Phys Med Rehabil 79, 1047–1050.

Gurian B, Rosowsky E (1990) Low-dose methylphenidate in the very old. J Geriatr Psychiatry Neurol 3, 152–154.

Hardy JR, Carmont SA, O’Shea A, Vora R, Schluter P, Nikles CJ, Mitchell GK (2010) Pilot study to determine the optimal dose of methylphenidate for an n-of-1 trial for fatigue in patients with cancer. J Palliat Med 13, 1193–1197.

Hardy SE (2009) Methylphenidate for the treatment of depressive symptoms, including fatigue and apathy, in medically ill older adults and terminally ill adults. Am J Geriatr Pharmacother 7, 34–59.

Homsi J, Nelson KA, Sarhill N, Rybicki L, LeGrand SB, Davis MP, Walsh D (2001) A phase II study of methylphenidate for depression in advanced cancer. Am J Hosp Palliat Care 18, 403–407.

Homsi J, Walsh D, Nelson KA (2000) Psychostimulants in supportive care. Support Care Cancer 8, 385–397.

Jansen IH, Olde Rikkert MG, Hulsbos HA, Hoefnagels WH (2001) Toward individualized evidence-based medicine: five “N of 1” trials of methylphenidate in geriatric patients. J Am Geriatr Soc 49, 474–476.

Johnson ML, Roberts MD, Ross AR, Witten CM (1992) Methylphenidate in stroke patients with depression. Am J Phys Med Rehabil 71, 239–241.

Kaplitz SE (1975) Withdrawn, apathetic geriatric patients responsive to methylphenidate. J Am Geriatr Soc 23, 271–276.

Keen JC, Brown D (2004) Psychostimulants and delirium in patients receiving palliative care. Palliat Support Care 2, 199–202.

Lasheen W, Walsh D, Mahmoud F, Davis MP, Rivera N, Khoshknabi DS (2010) Methylphenidate side effects in advanced cancer: a retrospective analysis. Am J Hosp Palliat Care 27, 16–23.

Lavretsky H, Park S, Siddarth P, Kumar A, Reynolds CF (2006) Methylphenidate-enhanced antidepressant response to citalopram in the elderly: a double-blind, placebo-controlled pilot trial. Am J Geriatr Psychiatry 14, 181–185.

Lavretsky H, Reinlieb M, St Cyr N, Siddarth P, Ercoli LM, Senturk D (2015) Citalopram, Methylphenidate, or Their Combination in Geriatric Depression: A Randomized, Double-Blind, Placebo-Controlled Trial. Am J Psychiatry appiajp201414070889.

Lazarus LW, Moberg PJ, Langsley PR, Lingam VR (1994) Methylphenidate and nortriptyline in the treatment of poststroke depression: a retrospective comparison. Arch Phys Med Rehabil 75, 403–406.

Lingam VR, Lazarus LW, Groves L, Oh SH (1988) Methylphenidate in treating poststroke depression. J Clin Psychiatry 49, 151–153.

Little KY (1993) d-Amphetamine versus methylphenidate effects in depressed inpatients. J Clin Psychiatry 54, 349–355.

Lydon E, El-Mallakh RS (2006) Naturalistic long-term use of methylphenidate in bipolar disorder. J Clin Psychopharmacol 26, 516–518.

Macleod AD (1998) Methylphenidate in terminal depression. J Pain Symptom Manage 16, 193–198.

Masand PS, Anand VS, Tanquary JF (1998) Psychostimulant augmentation of second generation antidepressants: a case series. Depress Anxiety 7, 89–91.

Meyers CA, Weitzner MA, Valentine AD, Levin VA (1998) Methylphenidate therapy improves cognition, mood, and function of brain tumor patients. J Clin Oncol 16, 2522–2527.

Nicholson AN, Stone BM (1980) Heterocyclic amphetamine derivatives and caffeine on sleep in man. Br J Clin Pharmacol 9, 195–203.

Orr K, Taylor D (2007) Psychostimulants in the treatment of depression : a review of the evidence. CNS Drugs 21, 239–257.

Padala PR, Burke WJ, Bhatia SC, Petty F (2007) Treatment of apathy with methylphenidate. J Neuropsychiatry Clin Neurosci 19, 81–83.

Padala PR, Burke WJ, Shostrom VK, Bhatia SC, Wengel SP, Potter JF, Petty F (2010) Methylphenidate for apathy and functional status in dementia of the Alzheimer type. Am J Geriatr Psychiatry 18, 371–374.

Padala PR, Petty F, Bhatia SC (2005) Methylphenidate may treat apathy independent of depression. Ann Pharmacother 39, 1947–1949.

Patkar AA, Masand PS, Pae CU, Peindl K, Hooper-Wood C, Mannelli P, Ciccone P (2006) A randomized, double-blind, placebo-controlled trial of augmentation with an extended release formulation of methylphenidate in outpatients with treatment-resistant depression. J Clin Psychopharmacol 26, 653–656.

Roehrs T, Papineau K, Rosenthal L, Roth T (1999) Sleepiness and the reinforcing and subjective effects of methylphenidate. Exp Clin Psychopharmacol 7, 145–150.

Rosenberg PB, Ahmed I, Hurwitz S (1991) Methylphenidate in depressed medically ill patients. J Clin Psychiatry 52, 263–267.

Roy M, Bernier J (1999) A rapid response with psychostimulants in the treatment of depressed persons with medical illnesses. Can J Psychiatry 44, 283–284.

Stoll AL, Pillay SS, Diamond L, Workum SB, Cole JO (1996) Methylphenidate augmentation of serotonin selective reuptake inhibitors: a case series. J Clin Psychiatry 57, 72–76.

Swift RM (1989) Diurnal variation in methylphenidate stimulant response in major depression. J Clin Psychopharmacol 9, 452.

Taub JM (1978) Psychobiology and pathologies of human sleep. Int J Neurosci 8, 153–175.

Wallace AE, Kofoed LL, West AN (1995) Double-blind, placebo-controlled trial of methylphenidate in older, depressed, medically ill patients. Am J Psychiatry 152, 929–931.

Watanabe MD, Martin EM, DeLeon OA, Gaviria M, Pavel DG, Trepashko DW (1995) Successful methylphenidate treatment of apathy after subcortical infarcts. J Neuropsychiatry Clin Neurosci 7, 502–504.

Wingo AP, Ghaemi SN (2008) Frequency of stimulant treatment and of stimulant-associated mania/hypomania in bipolar disorder patients. Psychopharmacol Bull 41, 37–47.

Yennurajalingam S, Palmer JL, Chacko R, Bruera E (2011) Factors associated with response to methylphenidate in advanced cancer patients. Oncologist 16, 246–253.

• ← Dealing with difficult patients
• Choosing a healthy oil for cooking, frying, or baking →