Memantine-Related Psychotic Symptoms in a Patient With Bipolar Disorder

Memantine-Related Psychotic Symptoms in a Patient With Bipolar Disorder

To the Editor: Memantine is an N-methyl-D-aspartate (NMDA) receptor agonist. It was recently approved in Europe and the United States for treating dementia and has been shown to reduce clinical deterioration in moderate-to-severe Alzheimer’s disease and in vascular dementia.1

Although memantine has been reported to be useful for psychotic symptoms (delusions and hallucinations) in patients with Alzheimer’s disease,2,3 a few anecdotal reports have noted that it may conversely cause hallucinations and delusions.4,5

Herein, we report the case of a patient with bipolar disorder and Alzheimer’s disease who developed delusions and auditory hallucinations as a result of memantine therapy. Significant resolution of these symptoms occurred once treatment was discontinued. To our knowledge, this report is the first to describe psychotic symptoms in a patient with bipolar disorder and comorbid Alzheimer’s disease as a result of memantine treatment.

Case report. Ms A was a 63-year-old retired teacher who was being followed for DSM-IV-defined bipolar I disorder. She experienced her first manic episode when she was 24 years old. She had been in remission for 3 years with lithium carbonate (900 mg/d), quetiapine (400 mg/d), and lamotrigine (150 mg/d). She was admitted to our clinic in April 2009 with complaints of memory deficits and behavioral disturbances (apathy, lack of inhibitions, untidiness) that had started 7 months before. On clinical mental state examination, she displayed reduced working memory capacity, impaired attention, and anomic aphasia. Results of a physical and neurologic examination, routine blood tests, and electrocardiogram were normal. Results of magnetic resonance imaging of the brain were unremarkable. Neuropsychological assessment revealed moderate dementia (Standardized Mini Mental State Examination6 score: 18/30). Ms A was diagnosed with probable early Alzheimer’s disease (DSM-IV-TR criteria) and was started on treatment with memantine 5 mg twice daily. Her treatment dose was then increased to 10 mg twice daily.

On the fourth day after she began taking memantine, Ms A reported persecutory delusions (she thought that cars were trying to do bad things to her) and auditory hallucinations (of people calling her name). She was readmitted to our clinic shortly after these symptoms were visible to her family members. We discontinued memantine treatment and started treatment with donepezil 5 mg/d. Significant resolution in her psychotic symptoms was noticed at the fifth day of the new treatment regimen. Ms A has been followed for 4 months with no evidence of recurrence of psychotic symptoms.

Memantine is structurally similar to amantadine, an influenza drug used for the treatment of Parkinson’s disease, which has been reported to cause visual hallucinations in patients with Parkinson’s disease.7 Both drugs bind with low affinity to the ion channel phencyclidine site at the NMDA receptor.8 Phencyclidine, an NMDA receptor antagonist with high affinity, induces psychotomimetic effects, including hallucinations, agitation, and delusions.8 The worsening of psychotic symptoms, including visual hallucinations, as a result of memantine treatment in patients with Alzheimer’s disease has been described.4,5

In a few case reports, memantine was found to be useful in treatment-resistant bipolar disorder.9,10 However, our patient developed delusions and auditory hallucinations shortly after beginning memantine therapy. The strict temporal relationship between the use of the drug and the onset of the psychotic symptoms, as well as the resolution once treatment was discontinued, suggests a causal link between the two phenomena. Because the patient was also receiving other drugs for bipolar disorder, another possible explanation is that a drug interaction between memantine and the other drugs might have occurred. However, despite inhibition of cytochrome P450 (CYP) 2B6 activity, inhibition of other CYPs during memantine therapy has been reported to be unlikely.11

Further studies or case reports are required regarding the incidence of these side effects and the underlying mechanisms of action before definitive conclusions can be reached. Clinicians should be vigilant when prescribing memantine for the treatment of coexisting Alzheimer’s disease and bipolar disorder or of treatment-resistant bipolar disorder.

References

1. Winblad B, Jelic V. Treating the full spectrum of dementia with memantine. Int J Geriatr Psychiatry. 2003;18(1):S41-S46. PubMed doi:10.1002/gps.937

2. Cummings JL, Schneider E, Tariot PN, et al. Memantine MEM-MD-02 Study Group. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology. 2006;67(1):57-63. PubMed doi:10.1212/01.wnl.0000223333.42368.f1

3. Wilcock GK, Ballard CG, Cooper JA, et al. Memantine for agitation/aggression and psychosis in moderately severe to severe Alzheimer’s disease: a pooled analysis of 3 studies. J Clin Psychiatry. 2008;69(3):341-348. PubMed doi:10.4088/JCP.v69n0302

4. Huey ED, Dustin IH, Overman GP, et al. Development of subtle psychotic symptoms with memantine: a case report [letter]. J Clin Psychiatry. 2005;66(5):658-659. PubMed doi:10.4088/JCP.v66n0519f

5. Monastero R, Camarda C, Pipia C, et al. Visual hallucinations and agitation in Alzheimer’s disease due to memantine: report of three cases [letter]. J Neurol Neurosurg Psychiatry. 2007;78(5):546. PubMed doi:10.1136/jnnp.2006.096420

6. Molloy DW, Alemayehu E, Roberts R. Reliability of a Standardized Mini-Mental State Examination compared with the traditional Mini-Mental State Examination. Am J Psychiatry. 1991;148(1):102-105. PubMed

7. Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov. 2006;5(2):160-170. PubMed doi:10.1038/nrd1958

8. Postma JU, Van Tilburg W. Visual hallucinations and delirium during treatment with amantadine (Symmetrel). J Am Geriatr Soc. 1975;23(5):212-215. PubMed

9. Teng CT, Demetrio FN. Memantine may acutely improve cognition and have a mood stabilizing effect in treatment-resistant bipolar disorder. Rev Bras Psiquiatr. 2006;28(3):252-254. PubMed doi:10.1590/S1516-44462006000300020

10. Agarwal V, Tripathi A. Memantine in the management of a clinically challenging case of bipolar disorder. Indian J Psychiatry. 2009;51(2):137-138. PubMed doi:10.4103/0019-5545.49455

11. Micuda S, Mundlova L, Anzenbacherova E, et al. Inhibitory effects of memantine on human cytochrome P450 activities: prediction of in vivo drug interactions. Eur J Clin Pharmacol. 2004;60(8):583-589. PubMed doi:10.1007/s00228-004-0825-1

Fatih Canan, MD

[email protected]

Ahmet Ataoglu, MD

Author affiliation: Department of Psychiatry, School of Medicine, Duzce University, Duzce, Turkey. Potential conflicts of interest: None reported. Funding/support: None reported.

doi:10.4088/JCP.09l05802gry

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