by Narpinder Kaur, MD; Rohit Madan, MD; and Ashish Sharma, MD

Drs. Kaur and Madan are Residents in the Department of Psychiatry, University of Nebraska Medical Center, Omaha, Nebraska; and Dr. Sharma is Associate Professor in the Department of Psychiatry, University of Nebraska Medical Center, Omaha, Nebraska.

Innov Clin Neurosci. 2012;9(11–12):39–41

Funding: There was no funding for the development and writing of this article.

Financial Disclosures: None of the authors have a conflict of interest in the conduct and reporting of this study.

Key words: rasagiline, depression, parkinson’s disease, bupropion, venlafaxine

Abstract: Parkinson’s disease is the second most common neurodegenerative disorder, affecting 1 to 2 percent of people older than 60 years. Recent reviews show that depression is a common and potentially debilitating aspect of Parkinson’s disease, affecting 40 to 50 percent of patients. Depression in Parkinson’s disease is demonstrably different from ordinary major depression in terms of gender ratio, age, symptom profile, comorbidity, and chronicity. Pharmacotherapy for depression in Parkinson’s disease entails special concerns related to side effects and drug-drug interactions. Rasagiline is a novel, potent, and irreversible monoamine oxidase type B (MAO-B) inhibitor that has recently been approved by the Food and Drug Administration for treatment of Parkinson’s disease. Current rasagiline labeling advises the avoidance of coadministration of rasagiline and antidepressants, which is a challenge in itself for patients with co-morbid depression. We present a case of a 58-year-old woman who failed most of the pharmacologic treatments for Parkinson’s disease, including deep brain stimulation, and was recently prescribed rasagiline with good response. She also met the Diagnostic and Statistical Manual, Fourth Edition, Text Revision criteria of major depressive disorder, which was treated with venlafaxine and bupropion. To our knowledge, this is first clinical case report of successful use of a combination of antidepressants and rasagiline in a patient with Parkinson’s disease.


Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting 1 to 2 percent of people older than 60 years. Rasagiline (marketed as Azilect® in the United States) is a novel, potent, and irreversible monoamine oxidase type B (MAO-B) inhibitor, which was recently approved by the United States Food and Drug Administration (FDA) for treatment of PD. Rasagiline inhibits MAO-B more potently than its congener selegiline and has the advantage of once-daily dosing.

The results from pivotal trials[1–3] suggest that rasagiline improves clinical outcomes in patients with early PD and reduces off time in patients treated with levodopa who experience motor fluctuations. Furthermore, subanalysis of these three trials revealed similar efficacy across all age groups both older and younger than 65 years.

Depression is a neuropsychiatric diagnosis that contributes to a high economic burden and plays a significant role in lowering the quality of life for patients with PD.[4] The prevalence of depressive symptoms in PD has been reported to be as low as 2.7 percent and as high as 90 percent, with an average of 35 percent.[5] Current rasagiline labeling advises the avoidance of coadministration of rasagiline and antidepressant,6 which in clinical practice may be difficult.
Here we discuss a case of successful use of rasagiline with a combination of two antidepressants, which to our knowledge has not been reported before.

Case Report

Ms. A, a 58-year-old woman, was diagnosed with PD in 1999. Clinical presentation included masking of facial expressions, decreased blink rate, bradykinesia, gait disturbance, dysarthria, and cogwheel rigidity. Her symptoms were more pronounced on the left side. Over several years, she failed most of the pharmacologic treatments for PD and had implantation of deep brain stimulator (DBS) in 2004.

Her past medical history was significant for morbid obesity (post-gastric bypass surgery), hypertension, and hypothyroidism. Past psychiatric history included major depressive disorder, diagnosed based upon the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR).

In early 2011, she was admitted with worsening of her PD as well as her depressive symptoms, with low mood, crying spells, anhedonia, decreased energy, decreased concentration, insomnia, hopelessness, and worthlessness. She also reported several times that life is not worth living though she denied any active suicidal ideations. Her activities of daily living were affected significantly. Her daily medications included bupropion 150mg, venlafaxine 225mg, thyroxin 50mcg, and tolterodine 4mg with good adherence.

Neurology was consulted, and after discussion with the patient and family, rasagiline 1mg/day was added for PD symptoms. Her bupropion dose was increased to 150mg twice a day and venlafaxine was continued at 225mg/day for her worsening depression.

During the course of treatment with above combination over the period of one year, significant improvement in neurovegetative symptoms of depression was noted. Her mood brightened with increased level of interaction with family members. She no longer expressed hopelessness or death wishes. Clinically, with regards to PD symptoms, some improvement in bradykinesia, rigidity, and reduced “off time” was noted. Overall quality of life was improved, and she has tolerated this therapeutic combination without side effects.


Rasagiline has demonstrated efficacy in early PD and as an adjunctive therapy in advanced PD. It has also shown to be neuroprotective in in-vitro and in-vivo studies.[7] The recently completed ADAGIO study[8,9] suggests a potential disease-modifying effect for rasagiline 1mg/day. Rasagiline is available in 0.5mg and 1mg tablets and is taken once daily. In the pivotal clinical trials (TEMPO, LARGO, PRESTO)[1–3] rasagiline was well tolerated. Rates of discontinuation due to adverse effects were not significantly different from those of placebo.[10] Additionally, based on the known literature, rasagiline has an advantage at the recommended therapeutic dose of 1mg/day of being selective for MOA-B inhibition with no associated clinically significant inhibition of MAO-A, thus eliminating the risk of tyramine sensitivity. Tyramine, an indirectly acting sympathomimetic found in aged cheeses and cured meats, is metabolized by MAO in the gastrointestinal system. A “cheese effect”, or tyramine pressor response, can occur in patients taking nonselective MAOIs (e.g., tranylcypromine, phenelzine) who ingest foods high in tyramine (e.g. aged cheeses and cured meats). Studies also suggested that rasagiline even at 2mg/d does not increase tyramine sensitivity and does not substantially inhibit MAO-A.[6] Also, because the vast majority of MAO in the intestine is the MAO-A isoform, a selective MAO-B inhibitor, such as rasagiline, is not likely to cause this effect.11,12 In the three phase III studies of rasagiline in PD (TEMPO, PRESTO, LARGO),[1–3] there were no specified dietary restrictions and rasagiline was well-tolerated with no reported tyramine pressor reactions. FDA has removed the bolded warning for tyramine.[13]

Routine clinical practice management of depression has always been a challenge in patients taking MAO inhibitors due to risk of adverse events. The development of serotonin syndrome, characterized by acute changes in mental status, autonomic dysfunction, myoclonus, and hyper-refexia, has been described when nonselective MAOIs and selective serotonin reuptake inhibitors (SSRIs) are taken together.[14] This issue was inconclusively addressed in TEMPO[1] and LARGO[2] studies, where a limited number of antidepressants including SSRIs in following doses were permitted: amitriptyline=50 mg/day, trazodone=100 mg/day, citalopram=20 mg/day, sertraline=100 mg/day, and paroxetine=30 mg/day. No adverse interactions were reported.

In the case we present here, we were successfully able to use rasagiline in combination with two antidepressants without any problems. We believe if proper clinical judgment and close monitoring for drug-drug interactions are used when treating PD patients with rasagiline at the currently recommended therapeutic dose of 1mg/day and an antidepressant, the likelihood of serotonin syndrome is low. Education of patients about possible drug interactions and the symptoms associated with serotonin syndrome should always be kept in mind when considering this combination.

1. TEMPO trial Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO study. Arch Neurol. 2002; 59:1937–1943.
2. Rascol O, Brooks DJ, Melamed E, et al. Rasagiline as an adjunct to levodopa inpatients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double blind, parallel-group trial. Lancet. 2005;365:947–954.
3. Parkinson Study Group. A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations. The PRESTO study. Arch Neurol. 2005; 62:241–248.
4. Dowding CH, Shenton CL, Salek, SS. A review of the health-related quality of life and economic impact of Parkinson’s disease. Drugs Aging. 2006; 23(9): 693–721.
5. Reijnders JS, Ehrt U, Weber WE, et al. A systematic review of prevalence studies of depression in Parkinson’s disease. Mov Disord. 2007; 23(2):183–189.
6. Goren T, Adar L, Sasson N, Weiss YM. Clinical pharmacology tyramine challenge study to determine the selectivity of the monoamine oxidase type B (MAO-B) inhibitor rasagiline. J Clin Pharmacol. 2010;50(12):1420–1428.
7. Bar-Am O, Amit T, Youdim MB. Aminoindan and hydroxyaminoindan, metabolites of rasagiline and ladostigil, respectively, exert neuroprotective properties in vitro. J Neurochem. 2007; 103:500–508.
8. Olanow CW, Hauser RA, Jankovic J, et al. A randomized, double-blind, placebo-controlled, delayed start study to assess rasagiline as a disease modifying therapy in Parkinson’s disease (the ADAGIO study): rationale, design, and baseline characteristics. Mov Disord. 2008; 23:2194–2201.
9. Olanow CW, Rascol O, Hauser R. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med. 2009; 361:1268–1278.
10. Parkinson Study Group. A controlled randomized delayed-start study of rasagiline in early Parkinson disease. Arch Neurol. 2004; 61:561–566.
11. Sterling J, Veinberg A, Lerner D, et al. (R)(+)-N-propargyl-1-aminoindan (rasagiline) and derivatives: highly selective and potent inhibitors of monoamine oxidase B. J Neural Transm 1998;52(Suppl):301–305.
12. Youdim MB, Gross A, Finberg JP. Rasagiline [N-propargyl-1R (+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B. Br J Pharmacol. 2001;132:500–506.
13. Azilect (rasagiline tablets) Prescribing Information, Teva Neuroscience, Kansas City, MO. Dec 2009.
14. Richard IH, Kurlan R, Tanner C, et al. Serotonin syndrome and the combined use of deprenyl and an antidepressant in Parkinson’s disease. Neurology. 1997; 48:1070–1077.