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Izvirni znanstveni članek 
NARAVOSLOVJE – 
farmacija   
Datum prejema:  
26. december 2015 
ANALI PAZU 
5/ 2016/ 1-2: 6-9  
www.anali-pazu.si 
 
Abstract: The positive effect of memantine on parkinsonism has been reported widely, but 
there have not been reports in the literature of parkinsonism, tremor and bradykinesis, induced by 
memantine, in an Alzheimer's patient, who did not have Parkinson's disease or a history of 
antipsychotic agents. In this case study, we report parkinsonism, tremor and night bradykinesis 
induced by memantine use (5 mg daily) in a 83-year-old Slovenian female patient. After 
memantine discontinuation, suggested by a clinical pharmacist specialist, and switching to 
donepezil 5 mg, the adverse drug reactions disappeared the next day. This case study may serve to 
help clinicians and clinical pharmacists distinguish memantine-induced parkinsonism from more 
serious conditions.  
Keywords: parkinsonism, adverse event , literature review, Alzheimer's disease, clinical 
pharmacy.  
Povzetek: Pozitivni učinki memantina na parkinsonizem so pogosto opisani, a 
parkinsonizem, tremor, bradikinezija povzročeni z memantinom, brez zgodovine zdravljenja z 
antipsihotiki, pri bolniku z Alzheimerjevo boleznijo v literaturi še niso bili opisani. V tej študiji 
primera prikazujemo z memantinom (5 mg dnevno) povzročen parkinsonizem, tremor in 
bradikinezijo pri 83-letni slovenski bolnici. Po ukinitvi zdravljenja z memantinom in uvedbo 
donepezila 5 mg dnevno, svetovano s strani kliničnega farmacevta specialista, so se neželeni 
učinki umaknili naslednji dan. Ta študija primera lahko služi kot pomoč zdravnikom in kliničnim 
farmacevtom v razlikovanju z memantinom povzročenega parkinsonizma od bolj resnih stanj. 
Ključne besede: parkinsonizem, neželeni dogodek, pregled literature, Alzheimerjeva 
bolezen, klinična farmacija.  
Memantine associated with parkinsonism in a 
patient with Alzheimer's disease: A case study 
and the review of the literature 
                                                                                   Matej Štuhec 
Oddelek za klinično farmacijo, Psihiatrična bolnišnica Ormož, Ptujska cesta 33, 2270 Ormož  
Fakulteta za farmacijo, Katedra za biofarmacijo in farmakokinetiko, Univerza v Ljubljani. Aškerčeva 
cesta 7, 1000 Ljubljana 
E-mail: matejstuhec@gmail.si   
Parkinsonizem povzročen z memantinom pri 
 bolniku z Alzheimerjevo boleznijo: Študija 
primera in pregled literature 

MEMANTINE ASSOCIATED WITH PARKINSONISM IN A PATIENT WITH ALZHEIMER'S DISEASE: A CASE... 
|  7 
1. Introduction 
With the aging population and its rapidly increasing 
prevalence, Alzheimer's disease (AD) has become an 
important public health concern in both developed and 
developing countries. Memantine is a non-competitive 
low-affinity antagonist of the N-methyl-D-aspartate 
(NMDA) receptor with a half-life of 70 hours. 
Memantine also has no impact on CYP450 metabolism 
and is not metabolized by CYP450. Its major route of 
elimination is unchanged with kidneys. Addressing the 
issue of interpatient variability in treatment response 
might be of significant importance for the vulnerable 
population taking anti-dementia drugs. (1) Memantine is 
beneficial for AD patients with regards to cognition and 
the Clinical Global Impression. Usually memantine is 
not discontinued due to its adverse effects. (2) In 
addition, memantine is also being investigated as a 
treatment option for a number of different conditions 
and although there are reports of a number of 
psychiatric and neurological adverse effects, it is 
considered to be a generally well-tolerated drug. 
However, there are two case reports of AD patients 
repeatedly losing consciousness after a long-term 
memantine treatment. The adverse effects were resolved 
after memantine discontinuation. This report indicates 
the need for increased caution and careful weighing of 
benefits and risks of prolonged treatment with 
memantine in patients with AD. (3)  
A PubMed search was conducted using the terms 
memantine, AD and adverse effects to identify 
randomized controlled trials and case reports, that 
evaluated the adverse effect for this patient. The 
positive effect of memantine on parkinsonism has been 
reported widely, but there have not been reports in the 
literature of parkinsonism, tremor and bradykinesia, 
induced by memantine, in an Alzheimer's patient, who 
did not have Parkinson's disease or a history of 
antipsychotic agents. This present paper describes the 
first case of memantine related parkinsonism, tremor 
and night bradykinesia with a prompt resolution upon 
the recognition and discontinuation of memantine. 
2. Results and discussion 
An 83-year-old Caucasian Slovenian female was 
admitted to a psychiatric department in July 2013 
because of severe AD (Parkinson's disease and 
dementia with Lewy bodies were excluded previously 
when AD was diagnosed in January 2013).   
In her medical history, she denied using alcohol, 
herbal products and smoking. The patient reported no 
known drug allergies. Her medications before 
hospitalization included lisinopril 10 mg daily, 
donepezil 10 mg daily and escitalopram 10 mg daily 
and she reported good adherence to medication. The 
patient had no history of antipsychotic treatment. She 
did not report previous syncope, palpitations, dyspnea, 
loss of consciousness, sleep disorders or seizures. 
Visual hallucinations also did not occur. Baseline 
laboratory results collected on admission showed a 
normal platelet count, serum creatinine, normal liver 
enzymes, and liver function tests. Her score on the Mini
-Mental State Exam was 15/30, therefore patient was 
switched from donepezil to memantine 5 mg daily and 
titration up to 10 mg daily after 7 days was suggested. 
On the fourth day of treatment with memantine, the 
patient developed generalized parkinsonism with resting 
and postural tremor (without resting tremor) and night 
bradykinesia without behavioral deviations. The patient 
also started complaining of slowness of movement, only 
being able to make small steps when walking, difficulty 
from sitting, disturbance of speech (slurred speech), and 
the development of a mask-like facial expression. All 
other vital signs were normal and serum creatinine was 
not elevated. The patient could no longer walk without 
staff support. On the next morning these symptoms 
continued and the patient was therefore sent to a clinical 
pharmacist. Her medication list included lisinopril 10 
mg daily, memantine 5 mg daily and escitalopram 10 
mg daily without any herbal products. 
The clinical pharmacy service recommended 
stopping the memantine immediately and switching to 
donepezil 5 mg daily. The physician accepted these 
recommendations and cognitive and psychiatric 
symptoms did not worsen when memantine was 
immediately discontinued and an adverse medication 
withdrawal event was not observed. Day after drug 
discontinuation, the patient recovered progressively 
with less severe adverse effects and completely 
recovered in 3 days. On the seventh day after the drugs 
were switched, the patient left the hospital with 5 mg of 
donepezil daily without any symptoms of parkinsonism. 
An adverse effect was determined by a clinical 
pharmacist with the Naranjo probability scale and was 
possibly associated with memantine use (4 points). (4)  
Such a case has not been described in the 
literature. Essential tremor is one of the most common 
and most disabling movement disorders among adults. 
Memantine is a potentially useful drug for treating 
essential tremor, particularly given its neuroprotective 
efficacy. (5) In a systematic review of 889 studies, 
Young and colleagues found memantine had significant 
benefits for AD patients in terms of cognition and the 
Clinical Global Impression. There were no significant 
benefits for AD patients in terms of mental state or 
activities in daily life. Memantine did not significantly 
affect discontinuation, caused by serious adverse events, 
but did increase the risk for somnolence, weight gain, 
confusion, hypertension, nervous system disorders, and 
risk for falls. (2) There have not been reports of 
memantine causing parkinsonism, tremor and night 
bradykinesia without associated polypharmacy, and of 
the adverse effect ceasing after replacing memantine 
with donepezil. We also do not believe that any 

ANALI PAZU, 5/ 2016/ 1-2, str. 6-9                                                                                                       Matej ŠTUHEC 
8  |  
pharmacokinetic and/or pharmacodynamic drug–drug 
interaction could had occurred, which would have led to 
this adverse effect. The relationship between the 
patient's symptoms with the initiation, discontinuation 
and half-life of the memantine suggests that the drug 
had a causal effect. No other medication was changed 
regarding dosage in this time.  
Tremor, dyskinesias, movement disorders, and 
akathisia have been attributed to escitalopram, which 
was continued in this patient. (6) Memantine has no 
impact on CYP450 metabolism and is not metabolized 
by CYP450, therefore it is not expected that memantine 
would alter (increase) escitalopram plasma levels (i.e. 
parkinsonism due to increased plasma levels of 
escitalopram because of pharmacokinetic interaction 
with memantine). (1) In addition, memantine is an 
inhibitor of the cationic renal transporter, and it is not 
known if escitalopram is a substrate of this transporter. 
(1) Although we believe that these hypotheses are not a 
likely reason for the observed effects, this cannot be 
excluded unless escitalopram plasma levels are 
measured before and after memantine. The 
antidepressant escitalopram is metabolized by the 
cytochrome-P450 (CYP) enzymes CYP 2D6, 2C19 and 
3A4. The genetic polymorphisms in CYP2C19 may 
influence escitalopram serum concentrations, which 
may lead to a small additive effect in this case. (7) 
Consequently, small additive effect of escitalopram 
cannot be excluded, although drug-drug 
pharmacokinetic interaction between memantine and 
escitalopram had not occured. However, with use of the 
Naranjo scale, this adverse effect was not associated 
with escitalopram use (0 points). The patient also 
recovered immediately after drug discontinuation, so we 
do not believe that this adverse effect was an adverse 
effect of escitalopram or of a drug-drug interaction. 
One limitation of our case report is that we did not 
rechallenge the patient with memantine and show that 
adverse effects would recur. Obviously, drug 
rechallenge would have established a stronger causal 
relationship between memantine and adverse effects for 
this patient (2 points on Naranjo scale), but we felt it 
would be unethical to do so and risk serious adverse 
effects, especially when alternative drug was readily 
available. We would recommend a rechallenge with 
memantine only in cases where no other options are 
available, such as in a case of a patient with multiple 
drug allergies. These examples show that the response 
of health care professionals to adverse effects varies 
among different cases, but both the conservative 
approach (drug discontinuation) and the approach with 
drug reinitiation may contribute to patient safety. The 
decision for an approach depends primarily on the risk 
of an adverse effect and the availability of alternative 
drugs. The withdrawal of the donepezil therapy may 
have also possibly contributed to the patient's symptoms 
(2 points on Naranjo scale). When donepezil therapy 
was reinitiated after memantine discontinuation, the 
symptoms improved. Therefore, the possiblity of an 
adverse drug withdrawal event should have also been 
considered (2 points for donepezil on Naranjo scale).  
Memantine is an adamantane derivative just as 
amantadine, which has U.S. Food and Drug 
Administration approval for use both as an antiviral and 
an antiparkinsonian drug. Additionally, its effectiveness 
as an antiparkinsonian drug is undetermined, with a 
2003 Cochrane Review concluding that there was 
insufficient evidence in support or against its efficacy 
and safety in the treatment of idiopathic Parkinson's 
disease. (8)  
This case serves to illustrate how clinical pharmacy 
can help ensure a satisfactory clinical outcome and 
prevent a potentially life threatening adverse drug 
reaction. Along with similar case studies, it highlights 
the importance of collaboration between the field of 
clinical pharmacy and psychiatry in successfully 
managing adverse psychotropic drug reactions. (9, 10, 
11, 12) As shown in this case report and in many others, 
the diagnosis of an adverse drug reaction is often 
tentative. Physicians and clinical pharmacists treating 
patients with a psychiatric disorder must carefully 
weigh the risk of developing these potential problems 
against the possibility of relapse of the disorder, should 
the medication be discontinued. 
3. Conclusions 
In conclusion, even though memantine is known to 
be a well-tolerated and safe drug, physicians and 
clinical pharmacists should be aware of the possible risk 
of parkinsonism associated with memantine. 
Substituting memantine with donepezil reversed this 
adverse effect and eliminated it. This specific adverse 
effect has not been previously reported in the medical 
literature. In this report, we identified a case with 
evidence for memantine-induced adverse effects with a 
single agent responsible rather than a pharmacokinetic 
and/or pharmacodynamic drug–drug interaction. It is 
our hope that this report will help alert clinicians and 
pharmacists to the possibility of memantine related 
parkinsonism, tremor and night bradykinesia and serve 
as the impetus for further published case reports and 
clinical studies. 
4. Acknowledgements 
None. 
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