Significant outcomes
• Memantine may decrease platelet 5-HT levels in Alzheimer's disease (AD) patients with pseudobulbar affect (PBA) and may worsen neuropsychiatric symptoms, especially aggression/agitation and irritability in those patients.
• The clinical importance of memantine sigma ligand properties could be revealed through these outcome findings.
Limitations
• The study had to be prematurely stopped.
• The results are therefore presented as case controls and the findings are based on a limited number of patients.
Introduction
AD is a progressive neurodegenerative disorder manifested by progressive decline in cognition and function, and the emergence of a variety of behavioural disturbances (Reference Cummings and Cole1). Neuropsychiatric symptoms associated with AD include agitation and aggression; psychosis; mood abnormalities, including depression, irritability and lability, anxiety; apathy; and other behavioural alterations, including disinhibition, wandering, pacing, rummaging and alterations in sleep and appetite (Reference Mega, Cummings, Fiorello and Gornbein2).
PBA, also called involuntary emotional expression disorder (IEED), is a syndrome characterised by involuntary episodes of crying or laughing that typically occur suddenly and appear to be independent or in excess of any eliciting stimulus or the prevailing mood (Reference Cummings, Arciniegas and Brooks3), and is seen in a significant number of patients with AD with reported prevalence rates from 10% (Reference Lieberman and Benson4), 18% (Reference Tanaka and Sumitsuji5) and up to 39% (Reference Starkstein, Migliorelli and Tesón6).
There are anatomic and functional changes in neurotransmitter systems associated with decline in cognition and development of neuropsychiatric symptoms. Cholinergic pathways are best known, but also other neurotransmitter systems including serotoninergic and glutamatergic are important (Reference Selkoe7).
The role of 5-HT in AD was investigated in post-mortem brain studies, positron emission tomography studies, neuroendocrine and pharmacotherapy studies, and also in clinical studies looking at putative peripheral markers of serotonin activity (Reference Lanctôt, Herrmann and Mazzotta8). Blood platelets have been proposed as an easy obtainable limited peripheral model for some processes in the central serotonergic neurons (Reference Camacho and Dimsdale9). The studies on platelet 5-HT concentration in AD yielded inconsistent results. The increased (Reference Meszaros, Borsiczky and Mate10), decreased (Reference Kumar, Sevush, Kumar, Ruiz and Eisdorfer11) or unaltered (Reference Mimica, Muck-Seler, Pivac, Mustapic and Folnegovic-Smalc12) platelet 5-HT concentrations were observed in AD, and furthermore no relation between platelet 5-HT concentrations and the presence of psychotic features in AD patients were found (Reference Mimica, Muck-Šeler and Pivac13).
The use of citalopram was associated with greatly reduced irritability without sedation in a group of behaviourally disturbed AD patients (Reference Siddique, Hynan and Weiner14), and it has also been described that citalopram was effective in treating IEED in post-stroke patients (Reference Andersen, Vestergaard and Riis15).
Memantine, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, with moderate affinity and rapid voltage-dependent kinetics, which regulates elevated concentrations of glutamate (Reference Parsons, Danysz and Quack16), is approved by the US Food and Drug Administration (US FDA) and by the European Medicines Agency for the treatment of moderate to severe AD. The efficacy and tolerability of memantine have been described in a number of placebo-controlled studies, with significant benefits in global, cognitive, functional and behavioural domains, particularly aggression/agitation, irritability/lability, delusions and hallucinations, compared with placebo (Reference Van Dyke, Tariot, Meyers and Malca Resnick17,Reference Gauthier, Loft and Cummings18).
Dextromethorphan (DM) is another uncompetitive NMDA ionotropic glutamate receptor antagonist. On the basis of studies that support effectiveness in patients with underlying amyotrophic lateral sclerosis (Reference Brooks, Thirsted and Appel19) or multiple sclerosis (Reference Panitch, Thisted and Smith20), DM in combination with quinidine (DM/Q) recently became the only drug (Nuedexta) approved by the US FDA for treating PBA characterised by sudden outbursts of involuntary emotional displays. DM is also a sigma-1 receptor agonist; however, the mechanism of its action on improving PBA remains uncertain and it has never been studied in patients with AD (Reference Torella, Pellicano and Bowery21,Reference Rogawski22).
As memantine possesses similar NMDA glutamate receptor activity as DM, we hypothesised that memantine also improves PBA owing to stabilisation of glutamatergic neurotransmission. To exclude the action on improving PBA via serotoninergic neurotransmission, platelet serotonin concentrations were measured.
Aims of the study
Although memantine possesses similar NMDA glutamate receptor activity compared with DM, the effectiveness on PBA has not been studied yet. In the present study, we intended to evaluate the efficacy of memantine on PBA in patients with AD.
Materials and methods
Patients were enrolled and treated between October 2008 and December 2011 at University Psychiatric Hospital Ljubljana in a prospective, double-blind, case-control study.
The study protocol and consent forms were approved by the institutional review boards and The National Medical Ethics Committee of the Republic of Slovenia. Informed consent of the patients and their caregivers was obtained following the principles outlined in the Declaration of Helsinki.
The entry criteria for study included clinical diagnosis of AD according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) (23) and clinical diagnosis of probable or possible AD according to the National Institute of Neurological and Communicative Disorders and Stroke/AD and related disorders association (NINCDS–ADRDA) criteria (Reference Mckhann, Drachman, Folstein, Katzman, Price and Stadlan24). Patients were included if they met recently proposed diagnostic criteria for IEED (Reference Cummings, Arciniegas and Brooks3) and scored 2 or 3 on item 2 (assessing the frequency of crying episodes), item 13 (assessing loss of voluntary control of emotions during episode) and item 18 (assessing distress and embarrassment associated with the episodes) of the pathological laughter and crying scale (PLACS) (Reference Robinson, Parikh, Lipsley, Starkstein and Price25) with a total score ⩾13.
PLACS is an interviewer-rated instrument that measures the severity of IEED symptoms (higher scores indicating greater severity), and has been validated in stroke patients. The scale begins with two screening questions asking whether the respondent has experienced laughing or crying episodes, following by 16 items (eight assessing pathological laughter and eight pathological crying), which are scored from 0 to 3 points (Reference Robinson, Parikh, Lipsley, Starkstein and Price25).
In addition, we were observing other behavioural changes assessed with Neuropsychiatric Inventory (NPI) (Reference Cummings, Mega, Gray, Rosenberg-Tompson, Carusi and Gornbein26) and the Overt Aggression Scale-Modified (OAS-M) (Reference Coccaro, Harvey, Kupsaw-Lawrence, Herbert and Bernstein27). Furthermore, we were measuring the platelet serotonin (5-hydroxytryptamine, 5-HT) concentrations. Global cognitive abilities were assessed with Slovenian version of mini mental state exam (MMSE) (Reference Rakusa, Granda, Kogoj, Mlakar and Vodusek28).
Patients with prior or current history of major psychiatric disturbances, coexistent systemic disease or abnormal hematological, hepatic and renal function tests that would interfere with interpretation of the results of the study were excluded. Patients were not allowed to take antidepressants, and the treatment with other drugs must have been established at least 1 month before enrolment and had to be maintained at a constant dose throughout the study.
Patients were to be excluded from the study if disruptive side effects or worsening of psychiatric or other medical condition were noticed.
Effects of memantine were compared with efficiency of citalopram.
Memantine or citalopram was administered randomly, each for 10 weeks (including titration) with a 6-week washout period. Dosing of memantine initiated at 5 mg daily and titrated up in weekly steps of 5 mg daily to a final dose of 20 mg daily. Citalopram final dose was also 20 mg. Memantine and citalopram tablets are of the same colour and size and were administered crushed. The person administering drugs to the patients also took blood samples for measuring platelet 5-HT levels before and after taking memantine. He was excluded from the evaluating process. The assessors and the patients were blind to the study drug.
Blood samples for measuring platelet 5-HT levels were taken in the morning and the heparinised plasma samples were assayed at Institute of Clinical Chemistry and Biochemistry, University Medical Center Ljubljana.
Blood samples were collected in the tubes containing EDTA. Platelet-rich plasma was obtained after centrifugation at 1000 g, and the concentration of platelets in plasma samples was measured using Coulter Hmx hematology analyser (Beckman Coulter Inc., Brea, CA, USA). Platelets were separated from plasma by centrifugation and stored at −20°C until analysis.
After thawing, the material was dispensed in saline and centrifuged. The concentration of serotonin was measured in supernatant using ELISA (GenWay Biotech Inc., San Diego, CA, USA). The results were expressed as the amount (pmol) of serotonin in 109 platelets.
The primary efficacy variables were based on the change in the PLACS score and number of episodes of involuntary crying or laughing per week. Second efficacy variable was change in platelet 5-HT concentrations after taking memantine and the additional efficacy variables were changed on the NPI and OAS-M. The assessments were obtained before and after the study drug was administered.
The comparison between the groups was made by paired t-test. The level of significance was set at p < 0.05.
Results
Four patients (two women and two men) from 75 to 81 years of age (average 78 ± 2.9) were included before premature stop of study. All but one already had severe cognitive decline with MMSE 4 to 20 (average 10 ± 6.8).
All four included patients were diagnosed having PBA with PLACS total score ranging from 14 to 30 (average 20.8 ± 7.6), with predominated crying episodes (only one woman having both crying and some laughing episodes). Two patients (one woman and one man) expressed verbal and physically aggressive behaviour assessed with OAS-M total score 9 and 52, respectively (average 30.5 ± 30.4). Neuropsychiatric disturbances were observed in three patients ranging from 6 to 15 total score on NPI (average 11 ± 4.6), one including irritability/lability and the other two also expressing agitation/aggression and aberrant motor behaviour (wandering and rummaging).
Both memantine and citalopram decreased the number of episodes of involuntary emotional expression per week as well as PLACS total scores (p < 0.05; Table 1). No deterioration of behavioural symptoms and aggressiveness was noticed in patients receiving citalopram. Crucial behavioural changes occurred in three out of four patients taking memantine. Three patients became more aggressive, assessing with a significant increase on OAS-M total scores to an average of 3.5 times higher scores compared with the initial value. One of them was without previous aggressive behaviour. NPI total scores were significantly increased for 114% of the initial value on average (p < 0.05). In those three patients, irritability and aberrant motor behaviour (wandering and rummaging) became more expressed, and furthermore lability of quickly alternating mood changes, disinhibition and alterations in appetite occurred (two patients expressed binge eating and overeating and one patient disregarding to eat). In the woman with coexisting involuntary episodes of crying and laughing episodes, behavioural chances did not occur (Table 1).
Table 1 Summary of efficacy results
ID = patients’ identification number.
d_NPI = change (difference) of scores on Neuropsychiatric Inventory Scale after taking the study drug.
d_OAS-M = change (difference) of scores on Overt Aggression Scale-Modified after taking the study drug.
d_PLACS = change (difference) of scores on Pathological Laughter and Crying Scale after taking the study drug.
d_eIEE/w = change (difference) in number of episodes of involuntary emotional expression (crying or laughing) per week after taking the study drug.
d_5HT = change (difference) of platelet serotonin concentration after taking memantine.
*p < 0.05 (paired t-test); **not significant (p > 0.05).
Therefore, by all ethical means, we were forced to stop our study because of deterioration of behavioural symptoms and our results were presented as a case controls
Memantine crucially decreased platelet 5-HT concentration in three out of four patients to an average 73% of initial value [from an average 617 ± 538 to an average 165 ± 20 pmol/(109 platelets); p < 0.05].
Discussion
Memantine alleviated involuntary emotional expression in our study; however, severe deterioration of other behavioural symptoms in AD patients with PBA was noticed, although memantine is known to generally improve behavioural disturbances in patients with AD, particularly aggression/agitation and irritability/lability (Reference Van Dyke, Tariot, Meyers and Malca Resnick17,Reference Gauthier, Loft and Cummings18).
Three patients became more aggressive, of those one without previous aggressive behaviour. In all three patients, irritability and aberrant motor behaviour (wandering and rummaging) became more expressed, and furthermore lability of quickly alternating mood changes, disinhibition and alterations in appetite occurred (two patients expressed binge eating and overeating and one patient disregarding to eat) without any mentioned preexisting disturbances.
In two out of three described patients, changes of mood and alternations in appetite coincided with a significant drop of platelet 5-HT concentration, which is known to have an important role in mood disturbances and aggressive behaviour (Reference Lanctôt, Herrmann and Mazzotta8). In the woman with coexisting involuntary episodes of crying and laughing, behavioural changes did not occur, although the platelet 5-HT drop was reported.
Besides its action on glutamatergic neurotransmitter system, memantine acts also as a non-competitive antagonist at the 5-HT3 receptor (Reference Rammes, Rupprecht, Ferrari, Zieglgänsberger and Parsons29), as well as inhibit the reuptake of both 5-HT and dopamine in mouse forebrain (Reference Onogi, Ishigaki and Nakagawasai30). It was also described that memantine was as effective as escitalopram in reducing the baseline level of depression and anxiety in major depressive disorder in patients with comorbid alcohol dependence (Reference Muhonen, Lönnqvist, Juva and Alho31). To determine the overall effect of memantine on serotoninergic neurotransmitter system, platelet 5-HT concentration was measured. The vast extent of decrease of 5-HT concentration in our patients may explain the deterioration of behavioural symptoms.
The significant platelet 5-HT concentration drop and behavioural disturbances could be explained by sigma receptor ligands modulating 5-HT neurotransmission. In an in vivo study on animal models, Bermack and Debonnel found that the sigma ligands induce a significant effect on the firing activity of 5-HT neurons of the dorsal raphe nucleus (DRN), which was increased by more than 50%. The sigma ligands demonstrated the fast onset of action, producing increased serotoninergic activity in the DRN after only 2 days of treatment. Throughout their findings they were suggesting that sigma agonists have the potential to produce a fast onset of antidepressant effect, which could be mediated locally in the DRN, or indirectly via feedback loops (Reference Bermack and Debonnel32).
The behavioural changes in our patients occurred quickly in less than 1 week after taking low doses (5–10 mg/day) of memantine, which is similar to the rapid onset of action seen in the studies by Bermack and Debonnel. This furthermore supports the suggestion that behavioural changes in our patients could be due to the mechanism of action via sigma receptors sites that modulates serotoninergic transmission. As memantine's sigma properties have not been clearly revealed yet, our research findings support Stahl's description of memantine having sigma-antagonism properties (Reference Stahl33), according to the modulation of serotoninergic transmission.
Sigma ligands can also modulate NMDA-mediated glutamatergic neurotransmission via sigma-1 receptors (in a bell-shaped dose-response curve manner) (Reference Bermack and Debonnel32). By recent data based on the DM mechanism of action, the main role for improving IEED is stabilising glutamatergic activity via NMDA receptors antagonism and sigma-1 receptors agonism (Reference Brooks, Thirsted and Appel19,Reference Panitch, Thisted and Smith20).
In our study, memantine decreased platelet 5-HT concentration and had a crucial effect on behavioural changes, but it had a beneficial effect on PBA. That finding excludes regular pathways via serotoninergic neurotransmitter system in PBA and supports the importance of glutamatergic neurotransmitter system and sigma receptors. Citalopram's potency for the subtypes of sigma receptors has been proved in research on rat brain (Reference Narita, Hashimoto, Tomitaka and Minabe34), giving possible explanation of its effect on improving PBA, regardless of its action on serotoninergic pathways. Reports on citalopram's efficiency on improving PBA, with relatively low doses, within few days after the initiation of treatment (Reference Andersen, Vestergaard and Riis15,Reference Van Watum35,Reference King and Reiss36), much sooner than it would be expected for an antidepressant effect, already suggested that this improvement must be because of some other pathways than those via 5-HT receptors, and supports the possibility of the mechanism of action via sigma receptor agonism. On the other hand, the improvement of neurobehavioural changes in AD patients in <12 weeks after treatment with memantine given in maximum therapeutic doses has not been observed; however, there were no studies on AD patients with PBA (Reference Parsons, Danysz and Quack16–Reference Gauthier, Loft and Cummings18). As in our study memantine has shown the alleviation of PBA, improving of PBA could be explained by the mechanism of action similar to DM, which is stabilising glutamatergic neurotransmission by NMDA receptors antagonism and sigma-1 receptors agonism.
Memantine's benefit on improving PBA supports the data that indicate that the main mechanism of pathophysiology PBA refers to glutamatergic neurotransmission, possible via sigma agonism (Reference Brooks, Thirsted and Appel19,Reference Panitch, Thisted and Smith20). Although memantine is effective in many patients with AD, our finding suggests that there may be some subgroups of AD patients with specific behavioural symptoms and specific underlying neuroanatomical disruption in which memantine lacks favourable outcome.
Our study was planned as a double-blind, cross-over study. Owing to a premature ending, findings are based only on a limited number of case-controlled patients. More investigations should be made to reveal the cause of our findings and strengthen our suggestions of memantine's action.
Acknowledgements
The authors thank Prof. Milan Skitek, Eur. Clin. Chem. for approving the implementation of the biochemical analysis carried out on Institute of Clinical Chemistry and Biochemistry, University Medical Center Ljubljana which provided the material and needed equipment.
Authors’ contributions
Tatjana Prokšelj's contribution as the first author includes the conception and design of the study, analysis and interpretation of all data, drafting the article and the final approval for the version to be published.
Aleš Jerin's contribution refers to laboratory measurements of platelet 5-HT concentration regarding the design of the methodology, revealing the data and drafting this part of the article.
Aleš Kogoj's contribution refers to the mentorship of the great value helping in making conception and study design, critically revising the data interpretations and overall revising the article for the final approval of the version to be published with important intellectual content.
Potential conflicts of interest
All authors have no potential conflicts of interest to declare.
