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Effects of memantine added to risperidone on the symptoms of schizophrenia: A randomized double-blind, placebo-controlled clinical trial
Author’s Accepted Manuscript Effects of memantine added to risperidone on the symptoms of schizophrenia: A randomized doubleblind, placebo-controlled clinical trial Robabeh Mazinani, Mohammadreza Khodaei
Somayeh
Nejati, www.elsevier.com/locate/psychres
PII: DOI: Reference:
S0165-1781(16)30358-4 http://dx.doi.org/10.1016/j.psychres.2016.09.028 PSY9962
To appear in: Psychiatry Research Received date: 27 February 2016 Accepted date: 20 September 2016 Cite this article as: Robabeh Mazinani, Somayeh Nejati and Mohammadreza Khodaei, Effects of memantine added to risperidone on the symptoms of schizophrenia: A randomized double-blind, placebo-controlled clinical trial, Psychiatry Research, http://dx.doi.org/10.1016/j.psychres.2016.09.028 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Effects of memantine added to risperidone on the symptoms of schizophrenia: A randomized double-blind, placebo-controlled clinical trial
Robabeh Mazinania,*, Somayeh Nejatia,b,*, Mohammadreza Khodaeia a
Department of Psychiatry, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran b
Substance Abuse and Dependence Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran [email protected] [email protected] *
Corresponding authors: Department of Psychiatry, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
Abstract The “glutamate hypothesis of schizophrenia” has changed attitudes in the development of new medications. This study aimed to evaluate the effects of 20 mg of memantine per day (as a NMDA receptor antagonist) added to risperidone among male patients with schizophrenia. In a randomized placebo-controlled, double-blind clinical trial, 46 adult male patients with schizophrenia were evaluated in both intervention and control groups at weeks 0, 6 and 12. The positive and negative symptoms scale and the mini mental status examination were used to assess positive, negative and cognitive symptoms and general psychopathology. The mean age of the patients was 44.8 for the intervention group and 45.3 for the control group, and the mean times since diagnosis were 23.5 and 25.7 years in the intervention and the control group, respectively. Positive and general psychopathologic symptoms showed no significant differences between the two groups at baseline or after treatment; while negative symptoms improved significantly in the intervention group at week 12. Cognitive function was also significantly improved in the intervention group at weeks 6 and 12. Memantine is supported as an effective adjunct treatment to improve negative and cognitive symptoms in patients with schizophrenia.
Keywords: Memantine, Positive and negative symptoms, Cognitive function
1. Introduction
Schizophrenia is the most severe and debilitating of the functional psychiatric disorders. The life-time prevalence of schizophrenia is almost 1%, and these patients occupy 50% of hospital beds in psychiatric hospitals (Sadock, 2007). Current antipsychotic drugs mainly affect positive
symptoms but tend to be less effective in ameliorating negative symptoms
(Sharma and Harvey, 2000). Negative symptoms persist over the course of illness and may become resistant to drug treatment (Lavoie et al., 2008). Neurocognitive deficits are also a core component of
schizophrenia that may precede the onset of positive symptoms; the
negative effects of cognitive impairment on social function, problem-solving skills, and ability to find stable employment tend not to be dramatically affected by available medications (Sadock, 2007). Hence, many studies have focused on finding new treatments for the alleviation of negative symptoms (e.g., Andreasen, 1982; Sharma and Harvey, 2000). A number of brain regions have been reported to be involved in schizophrenia, such as the pre-frontal cortex, hippocampus and thalamus; also of note is that a range of chemical neurotransmitter interactions have been hypothesized to affect the pathogenesis of the disease (Sadock, 2007). The “glutamate hypothesis of schizophrenia” for example, suggests that the function of N-methyl-d-aspartate (NMDA) receptors is compromised in this disorder. NMDA receptors play a major role in the formation of complex behaviors as well as in neural pathways (Silver et al., 2005; Beneyto and Meador-Woodruff, 2008). In this hypothesis, hyper-stimulation of NMDA receptors with glutamate is thought to lead to high intracellular concentrations of
calcium, nitric oxide and catalytic enzymes that specifically increase
protease activity, leading to neuronal damage and cell death (Lavoie et al., 2008). The glutamate hypothesis has stimulated efforts to develop new treatment regimens targeting NMDA receptors (Schaefer et al., 2007). Amantadine and memantine, two approved treatment options for Alzheimer’s disease that are non-selective NMDA receptor antagonists, have been considered as potential medications for schizophrenia. Although some evidence
suggest promising effects, controversies surround the effects of these medications in the treatment of schizophrenia (Egerton et al., 2005; Silver et al., 2005; Schaefer et al., 2007; Beneyto and Meador-Woodruff, 2008; De Lucena et al., 2009; Lieberman et al., 2009; Lee et al., 2012; Kishi and Iwata, 2013; Rezaei et al., 2013). Memantine, as a non-selective NMDA receptor antagonist, has had few side effects, and a meta- analysis of eight studies shows the positive effects of memantine on cognitive functions and negative symptoms among patients with schizophrenia (Kishi and Iwata, 2013). The current study aimed to evaluate the effects of memantine added to risperidone in the treatment of
schizophrenia among male patients residing in an academic hospital in Iran.
2. Methods and Materials 2.1. Study design This study was designed as a randomized, placebo-controlled, parallel-group, double-blind trial. Recruitment of the patients was carried out from September to December 2014. The intervention began in December 2014; patients allocated to intervention received low-dose memantine and risperidone for 3 to 4 weeks, after which increased dosages were initiated and continued for 12 weeks. The study was completed in 9 months (September 2014 to April 2015). 2.2. Participants All patients diagnosed with schizophrenia in the age range of 18 to 55 years were recruited from different wards of an academic hospital. We conducted semi-structured psychiatric interviews for DSM-IV Axis I disorders to confirm diagnoses. From 238 patients with confirmed diagnoses, 112 were eligible to enter the trial. Inclusion criteria for this study were
as follows: patients had been diagnosed at least for 2 years, had not used a long-term antipsychotic drug for the last 1 month, were not in an acute phase, and had consented to participate. Exclusion criteria were as follows: patients were excluded if they had received electroconvulsive therapy in the last 2 weeks, had other Axis I diagnoses, had a history of using illicit drugs in the past 6 months, had other neurologic or organic disorders (e.g., renal, hepatic disease), needed to receive other drug regimens, or reported clinically significant adverse effects. All patients were males. 2.3. Intervention After initiation of daily risperidone (4 to 6 mg) for 3 to 4 weeks, patients according to random number table and based on number of medical records were allocated to receive either a tablet of memantine or a placebo table with the same shape. Patients in the intervention group received memantine at an initial dose of 5 mg/daily (2 tablets per day); dose increments continued for 4 weeks until reaching an effective dosage of 20 mg/daily for another 12 weeks. Patients in the control group received a placebo capsules twice daily. Nurses providing medication in this study and participating patients were both unaware of the content of the capsules and the sequence of allocation.
2.4. Outcomes The primary outcome measures were changes in negative and positive symptoms, general psychopathology, and cognitive symptoms. A well-trained psychologist without knowledge of treatment assignment (memantine vs. placebo) completed the Positive and Negative Syndrome Scale (PANSS) and the Mini-Mental Status Examination (MMSE). These parameters were measured at baseline, 6 weeks, and 12 weeks after initiation of treatment.
The secondary
outcome measures included all analyses that checked for correlations
between response to treatment and patient age or time since first diagnosis.
2.5. Sample size calculation and random allocation For the purpose of sample size calculation, utilizing Cohen’s table and the standard formulations with a power of 80% (β=20%) and confidence level of 95% (α=0.05), the number of patients in each group was calculated to be 18. With an expected attrition rate of 20%, appropriate sample size was estimated to be 23. For random allocation, specific envelopes containing letters A (control) and B (intervention) were distributed among all participants who completed the initial assessment and provided written consent for participation. 2.6. Statistical analysis Means and percentages were used to report continuous and categorical variables, respectively. Paired t-tests were used for analysis of scores of different scales at different time points in the study. A general linear model repeated measures model was employed to evaluate the interaction of time × treatment for PANSS and MMSE scores between the two groups, with the study groups (memantine vs. placebo) as the between-subject variable and study measurements as the within-subject factor (time). If Mauchly’s test of sphericity was non-significant, Greenhouse-Geisser correction for degrees of freedom was performed. Pearson and Spearman correlation
coefficients were calculated to check for potential
correlation between response to treatment and general patient characteristics. Level of significance was defined as <0.05. The Statistical Package for the Social Sciences (IBM Inc.) version 16.0 was used for all analyses.
2.7. Ethical considerations The protocol was approved by the Ethics Committee of the University of Social Welfare and Rehabilitation Sciences, and all steps were in line with the declaration of Helsinki. Either the patient or his legal guardian would provide written consent after explanation of the main objectives of the study. They clearly understood their right to withdraw at any time in the course of the study. All patients were re-assured regarding the confidentiality of their medical records utilized for the purposes of the present study. The study has been registered on the Iranian Registry of Clinical Trials under number 24817. 3. Results In total, 112 patients with a primary diagnosis of schizophrenia were recruited, of whom 66 declined participation in the trial. From the remaining 46 patients, only 36 completed the study course and were included in final analysis. The participant flow is illustrated in Fig. 1.
Assessed for eligibility (n= 112)
Excluded (n= 66) ¨ Not meeting inclusion criteria (n= 0) ¨ Declined to participate (n= 66) Randomized (n=46)
Allocated to intervention (n= 23) Received allocated intervention (n=19) Did not receive allocated intervention (Declined further participation) (n= 4)
Lost to follow-up (give reasons) (n=1) Discontinued intervention (due to adverse drug reactions) (n= 1)
Allocated to control (n= 23) Received allocated intervention (n= 20) Did not receive allocated intervention (Declined further participation) (n=3)
Lost to follow-up (give reasons) (n=2) Discontinued intervention (non-compliance) (n= 2)
Analysed (n=18) Excluded from analysis (n=0)
Analysed (n=18) Excluded from analysis (n= 0)
Fig. 1. Flow diagram of trial participants
3.1. General characteristics and baseline scores General and demographic characteristics of participants, as well as their PANSS and MMSE scores at baseline, are shown in Table 1. History of schizophrenia in first degree relatives was present in 10 participants in the intervention group and 12 participants in the control group. The two groups were matched based on their age and duration of treatment (p=0.8 and p=0.3, respectively).
Table 1. General characteristics of all participants at baseline Intervention group (n=23)
Control group (n=23)
Mean (SD1)
Mean (SD)
Age (years)
44.8 (6.6)
45.3 (6.2)
p>0.5
Age at onset of illness (years)
21.3 (6.8)
19.6 (2.8)
p>0.5
Duration since 1st diagnosis (years)
23.5 (8.3)
25.7 (5.4)
p>0.5
Variable
1
Standard deviation
p
Table 2. PANSS and MSSE scores of all participants after 12 weeks Intervention group (n=23)
Control group (n=23)
Mean (SD)
Mean (SD)
Positive symptoms score
12.7 (4.8)
15.5 (6.3)
p>0.05
Negative symptoms score
15.1 (4.8)
20.6 (5.2)
p<0.05
General psychopathology score
37.1 (7.4)
36.8 (8.7)
p>0.05
MMSE score
28.2 (1.6)
24.9 (3.0)
p<0.05
Variable
p
3.2. Inter-group comparisons
Based on PANSS scores, the intervention group had significantly improved with reference to negative symptoms by 12 weeks after the initiation of memantine; while no changes in positive symptoms were reported. MMSE scores also showed significant changes after week 12 in the intervention group (Table 3). Table 3. Comparison of intervention and control groups regarding PANSS and MMSE scores at baseline, week 6 and week 12 Scores
Item scale
Intervention group Mean (SD)
Control group Mean (SD)
Time (weeks)
Time (weeks)
0
6
12
0
6
P-value2
12
0
6
12
Positive symptoms
14.4 (5.4)
13.4 (5.2)
12.7 (4.8)
16.1 (6.2)
15.9 (6.3)
15.5 (6.3)
0.3
0.1
0.09
Negative symptoms
19.4 (5.4)
17.4 (5.1)
15.1 (4.8)
18.9 (5.3)
19.5 (5.3)
20.6 (5.2)
0.7
0.2
0.003
2
Level of significance: p < 0.05
General psychopathology
40.6 (8.7)
38.6 (7.9)
37.1 (7.4)
38.0 (8.3)
37.5 (8.3)
36.8 (8.7)
0.3
0.6
MMSE
26.3 (2.8)
28.0 (2.0)
28.2 (1.6)
25.2 (2.7)
25.0 (2.9)
24.9 (3.0)
0.2
0.001 <0.001
0.9
3.3. Repeated measures analyses
Muchly’s test of sphericity indicated that the assumption of sphericity had been violated [
2
(2)= 10.984, p-value=0.004], and therefore a Greenhouse-Geisser correction test was used to compare difference in positive symptoms. Repeated measures analysis of variance (ANOVA) testing for positive symptoms indicated a significant effect of the time×treatment interaction in the intervention group [ (1.336)=20.150, p=0.001] (Fig.2). Corresponding analyses for 2
negative symptoms [ (df:2)=84.667, p<0.001], general psychopathology [ (2)=57.185, 2
2
p<0.001], and MMSE scores [ (1.082)=40.478, p=0.001] indicated a significant effect for 2
the time×treatment interaction in the intervention group. Changes in different sub-scale scores are illustrated in the intervention group compared with the control group (Fig. 2).
a. mean scores for general psychopathology
b. mean scores for cognitive symptoms (MMSE)
41.3 40. 38.8 37.5 36.3 35. 33.8
30. 28.8 27.5 26.3 25. 23.8 22.5 Week 0
Week 6
Memantine
Week 12
Control
Week 0
Week 6
Memantine
Week 12
Control
c. mean scores for positive symptoms
d. mean scores for negative symptoms
17.
26.3
12.8
21. 15.8
8.5
10.5
4.3
5.3
0.
0. Week 0
Week 6
Memantine
Week 12
Control
Week 0
Week 6
Memantine
Week 12
Control
Fig. 2 Time×treatment interactions for a) general psychopathology, b) cognitive symptoms, c) positive symptoms, and d) negative symptoms in the intervention and control groups
3.4. Correlation analyses We found no significant correlation (Pearson’s correlation) between age, time since initial diagnosis, and family history with any of the subscale scores at week 12 (Table 3).
Table 3. Correlations between age, time since initial diagnosis, family history, negative symptoms score, and MMSE score Demographic variable
Pearson correlation (2-tailed significance) Negative symptom score
MMSE score
Age (years)
0.116 (0.647)
0.131 (0.606)
Duration since 1st diagnosis
0.208 (0.407)
-0.52 (0.837)
Family history
0.464 (0.052)
-0.075 (0.768)
4. Discussion
The present study indicates that memantine (20 mg/twice daily) added to risperidone (4 to 6 mg/daily) can improve negative symptoms as well as cognitive function among patients diagnosed with schizophrenia. The current findings confirm previous studies that demonstrated the effectiveness of NMDA receptor antagonists in relationship to negative
symptom and MMSE scores (Schaefer et al., 2007; De Lucena et al., 2009). The limited effects of new generation anti-psychotics on negative symptoms of schizophrenia that adversely influence the quality of life of patients can be enhanced by adjunctive treatment with drugs like memantine. There is evidence that NMDA receptor antagonists have beneficial effects on positive as well as negative symptoms (De Lucena et al., 2009; Koola et al., 2014); however, our findings showed no statistically significant improvements in positive symptoms or general psychopathology in the intervention group compared with the control group. Impaired cognition is another debilitating component of schizophrenia. Our results illustrate that memantine added to risperidone is associated with improved cognition. Nevertheless, previous investigations have been inconsistent in this regard (Lee et al., 2012; Koola et al., 2014). therapy,
However, most recent studies have suggested the promise of combination drug including with drugs other than memantine. Acetylcholine esterase inhibitors,
for example, may have synergistic effects on symptoms not generally improved by antipsychotics (Koola et al., 2014; Geerts et al., 2015). Some evidence also suggest that the synergistic effects may enable clinicians to prescribe lower dosages of antipsychotics and hence may lead to reduced levels of side effects (John et al., 2014; Shim and Nadeem, 2014). We also suggest that widely used measurement scales such as the MMSE can help in timely and precise evaluation of patients’ cognitive level. Utilization of more comprehensive tools that require expert personnel can impose barriers in clinical trials and negatively impact interpretation of findings. Participants in this study constituted a homogeneous sample of hospitalized male patients who had been diagnosed for at least 2 years. The homogeneity of the studied sample and close supervision of medication use in a hospital setting are among the main strengths of the
study. The longer treatment period compared with previous studies also provides a more comprehensive background for further analysis of findings. Different symptom sub-scales (including the ones measured by the PANSS), cognition and correlations between sub-scales and general characteristics were also collected and analyzed to address the limitations of previous studies that had inconsistent results. The high rates of attrition after the initial session for patient selection may be seen as a limiting factor concerning the generalizability of our findings, but the final sample size was consistent with initial power calculations.
The promising effects of memantine on negative symptoms and cognitive function in schizophrenia can lead to a paradigm shift in development of treatment guidelines. The observed effects in our study can add to the existing evidence on the benefits of this drug category (NMDA receptor antagonists). Although, demographic characteristics did not prove to have been correlated with drug effects, longer-term observations of patients receiving memantine can
provide valuable confirmatory information about the efficacy and potential
adverse effects of adjunctive memantine administration in schizophrenia. Conflict of interest None.
Acknowledgement The authors thank the personnel of the Razi Hospital for their kind cooperation and support. The RCT was financially supported by the University of Social Welfare and Rehabilitation Sciences.
References Andreasen, N.C., 1982. Negative symptoms in schizophrenia: definition and reliability. Arch. Gen. Psychiatry 39 (7), 784-788.
Beneyto, M., Meador-Woodruff, J.H., 2008. Lamina-specific abnormalities of NMDA receptorassociated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder. Neuropsychopharmacology 33 (9), 2175-2186. De Lucena, D., Fernandes, B.S., Berk, M., Dodd, S., Medeiros, D.W., Pedrini, M., et al., 2009. Improvement of negative and positive symptoms in treatment-refractory schizophrenia: a doubleblind, randomized, placebo-controlled trial with memantine as add-on therapy to clozapine. J. Clin. Psychiatry 70 (10), 1478-1423. Egerton, A., Reid, L., McKerchar, C.E., Morris, B.J., Pratt, J.A., 2005. Impairment in perceptual attentional set-shifting following PCP administration: a rodent model of set-shifting deficits in schizophrenia. Psychopharmacology 179 (1), 77-84. Geerts, H., Roberts, P., Spiros, A., 2015. Assessing the synergy between cholinomimetics and memantine as augmentation therapy in cognitive impairment in schizophrenia. A virtual human patient trial using quantitative systems pharmacology. Front. Pharmacol..6, 198. John, J., Lukose, A., Manjunath, S., 2014. Off-label use of memantine as adjunctive treatment in schizophrenia: a retrospective case series study. Pharmacopsychiatry 47 (6), 202-209. Kishi, T., Iwata, N., 2013. NMDA receptor antagonists interventions in schizophrenia: meta-analysis of randomized, placebo-controlled trials. J. Psychiatr. Res. 47 (9), 1143-1149. Koola, M.M., Buchanan, R.W., Pillai, A., Aitchison, K.J., Weinberger, D.R., Aaronson, S.T., et al., 2014. Potential role of the combination of galantamine and memantine to improve cognition in schizophrenia. Schizophr. Res. 157 (1), 84-89. Lavoie, S., Murray, M.M., Deppen, P., Knyazeva, M.G., Berk, M., Boulat, O., et al., 2008. Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients. Neuropsychopharmacology 33 (9), 2187-2199. Lee, J. G., Lee, S.W., Lee, B.J., Park, S.W., Kim, G.M., Kim, Y.H., 2012. Adjunctive memantine therapy for cognitive impairment in chronic schizophrenia: a placebo-controlled pilot study. Psychiatry Investig. 9 (2), 166-173. Lieberman, J.A., Papadakis, K., Csernansky, J., Litman, R., Volavka, J., Jia, X.D., et al., 2009. A randomized, placebo-controlled study of memantine as adjunctive treatment in patients with schizophrenia. Neuropsychopharmacology 34 (5), 1322-1329. Rezaei, F., Mohammad-Karimi, M., Seddighi, S., Modabbernia, A., Ashrafi, M., Salehi, B., et al., 2013. Memantine add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: randomized, double-blind, placebo-controlled study. J. Clin. Psychopharmacol. 33 (3), 336-342. Sadock, B., 2007. Kaplan & Sadock’s Synopsis of Psychiatry, 10th ed. Lipincott Willoams & Wilkins, Philadelphia. Schaefer, M., Leopold, K., Hinzpeter, A., Heinz , A., Krebs, M., 2007. Memantine-associated reversal of clozapine-induced weight gain. Pharmacopsychiatry 40 (4), 149-151. Sharma, T., Harvey, P.D., 2000. Cognitive enhancement as a treatment strategy in schizophrenia, in: Sharma, T., Harvey, P.D. (Eds.), Cognition in Schizophrenia. Impairments, Importance, and Treatment Strategies. Oxford University Press, Oxford, pp. 286-302. Shim, S.S., Nadeem, R., 2014. Are NMDA receptor antagonists beneficial in the treatment of schizophrenia? J. Psychiatr. Res. 51, 19-20. Silver, H., Goodman, C., Knoll, G., Isakov, V., Modai, I., 2005. Schizophrenia patients with a history of severe violence differ from nonviolent schizophrenia patients in perception of emotions but not cognitive function. J. Clin. Psychiatry 66 (3), 300-308.
Highlights
A
Antipsychotics have been helpful in improving negative symptoms of schizophrenia
Understanding the role of neurotransmitters in the pathogenesis of schizophrenia has led to the development of new drugs
Memantine can significantly improve negative and cognitive symptoms among patients with schizophrenia
Adjunct treatment with NMDA receptor antagonists can be considered as a useful addition to standard care in the future
Somayeh
Nejati, www.elsevier.com/locate/psychres
PII: DOI: Reference:
S0165-1781(16)30358-4 http://dx.doi.org/10.1016/j.psychres.2016.09.028 PSY9962
To appear in: Psychiatry Research Received date: 27 February 2016 Accepted date: 20 September 2016 Cite this article as: Robabeh Mazinani, Somayeh Nejati and Mohammadreza Khodaei, Effects of memantine added to risperidone on the symptoms of schizophrenia: A randomized double-blind, placebo-controlled clinical trial, Psychiatry Research, http://dx.doi.org/10.1016/j.psychres.2016.09.028 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Effects of memantine added to risperidone on the symptoms of schizophrenia: A randomized double-blind, placebo-controlled clinical trial
Robabeh Mazinania,*, Somayeh Nejatia,b,*, Mohammadreza Khodaeia a
Department of Psychiatry, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran b
Substance Abuse and Dependence Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran [email protected] [email protected] *
Corresponding authors: Department of Psychiatry, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
Abstract The “glutamate hypothesis of schizophrenia” has changed attitudes in the development of new medications. This study aimed to evaluate the effects of 20 mg of memantine per day (as a NMDA receptor antagonist) added to risperidone among male patients with schizophrenia. In a randomized placebo-controlled, double-blind clinical trial, 46 adult male patients with schizophrenia were evaluated in both intervention and control groups at weeks 0, 6 and 12. The positive and negative symptoms scale and the mini mental status examination were used to assess positive, negative and cognitive symptoms and general psychopathology. The mean age of the patients was 44.8 for the intervention group and 45.3 for the control group, and the mean times since diagnosis were 23.5 and 25.7 years in the intervention and the control group, respectively. Positive and general psychopathologic symptoms showed no significant differences between the two groups at baseline or after treatment; while negative symptoms improved significantly in the intervention group at week 12. Cognitive function was also significantly improved in the intervention group at weeks 6 and 12. Memantine is supported as an effective adjunct treatment to improve negative and cognitive symptoms in patients with schizophrenia.
Keywords: Memantine, Positive and negative symptoms, Cognitive function
1. Introduction
Schizophrenia is the most severe and debilitating of the functional psychiatric disorders. The life-time prevalence of schizophrenia is almost 1%, and these patients occupy 50% of hospital beds in psychiatric hospitals (Sadock, 2007). Current antipsychotic drugs mainly affect positive
symptoms but tend to be less effective in ameliorating negative symptoms
(Sharma and Harvey, 2000). Negative symptoms persist over the course of illness and may become resistant to drug treatment (Lavoie et al., 2008). Neurocognitive deficits are also a core component of
schizophrenia that may precede the onset of positive symptoms; the
negative effects of cognitive impairment on social function, problem-solving skills, and ability to find stable employment tend not to be dramatically affected by available medications (Sadock, 2007). Hence, many studies have focused on finding new treatments for the alleviation of negative symptoms (e.g., Andreasen, 1982; Sharma and Harvey, 2000). A number of brain regions have been reported to be involved in schizophrenia, such as the pre-frontal cortex, hippocampus and thalamus; also of note is that a range of chemical neurotransmitter interactions have been hypothesized to affect the pathogenesis of the disease (Sadock, 2007). The “glutamate hypothesis of schizophrenia” for example, suggests that the function of N-methyl-d-aspartate (NMDA) receptors is compromised in this disorder. NMDA receptors play a major role in the formation of complex behaviors as well as in neural pathways (Silver et al., 2005; Beneyto and Meador-Woodruff, 2008). In this hypothesis, hyper-stimulation of NMDA receptors with glutamate is thought to lead to high intracellular concentrations of
calcium, nitric oxide and catalytic enzymes that specifically increase
protease activity, leading to neuronal damage and cell death (Lavoie et al., 2008). The glutamate hypothesis has stimulated efforts to develop new treatment regimens targeting NMDA receptors (Schaefer et al., 2007). Amantadine and memantine, two approved treatment options for Alzheimer’s disease that are non-selective NMDA receptor antagonists, have been considered as potential medications for schizophrenia. Although some evidence
suggest promising effects, controversies surround the effects of these medications in the treatment of schizophrenia (Egerton et al., 2005; Silver et al., 2005; Schaefer et al., 2007; Beneyto and Meador-Woodruff, 2008; De Lucena et al., 2009; Lieberman et al., 2009; Lee et al., 2012; Kishi and Iwata, 2013; Rezaei et al., 2013). Memantine, as a non-selective NMDA receptor antagonist, has had few side effects, and a meta- analysis of eight studies shows the positive effects of memantine on cognitive functions and negative symptoms among patients with schizophrenia (Kishi and Iwata, 2013). The current study aimed to evaluate the effects of memantine added to risperidone in the treatment of
schizophrenia among male patients residing in an academic hospital in Iran.
2. Methods and Materials 2.1. Study design This study was designed as a randomized, placebo-controlled, parallel-group, double-blind trial. Recruitment of the patients was carried out from September to December 2014. The intervention began in December 2014; patients allocated to intervention received low-dose memantine and risperidone for 3 to 4 weeks, after which increased dosages were initiated and continued for 12 weeks. The study was completed in 9 months (September 2014 to April 2015). 2.2. Participants All patients diagnosed with schizophrenia in the age range of 18 to 55 years were recruited from different wards of an academic hospital. We conducted semi-structured psychiatric interviews for DSM-IV Axis I disorders to confirm diagnoses. From 238 patients with confirmed diagnoses, 112 were eligible to enter the trial. Inclusion criteria for this study were
as follows: patients had been diagnosed at least for 2 years, had not used a long-term antipsychotic drug for the last 1 month, were not in an acute phase, and had consented to participate. Exclusion criteria were as follows: patients were excluded if they had received electroconvulsive therapy in the last 2 weeks, had other Axis I diagnoses, had a history of using illicit drugs in the past 6 months, had other neurologic or organic disorders (e.g., renal, hepatic disease), needed to receive other drug regimens, or reported clinically significant adverse effects. All patients were males. 2.3. Intervention After initiation of daily risperidone (4 to 6 mg) for 3 to 4 weeks, patients according to random number table and based on number of medical records were allocated to receive either a tablet of memantine or a placebo table with the same shape. Patients in the intervention group received memantine at an initial dose of 5 mg/daily (2 tablets per day); dose increments continued for 4 weeks until reaching an effective dosage of 20 mg/daily for another 12 weeks. Patients in the control group received a placebo capsules twice daily. Nurses providing medication in this study and participating patients were both unaware of the content of the capsules and the sequence of allocation.
2.4. Outcomes The primary outcome measures were changes in negative and positive symptoms, general psychopathology, and cognitive symptoms. A well-trained psychologist without knowledge of treatment assignment (memantine vs. placebo) completed the Positive and Negative Syndrome Scale (PANSS) and the Mini-Mental Status Examination (MMSE). These parameters were measured at baseline, 6 weeks, and 12 weeks after initiation of treatment.
The secondary
outcome measures included all analyses that checked for correlations
between response to treatment and patient age or time since first diagnosis.
2.5. Sample size calculation and random allocation For the purpose of sample size calculation, utilizing Cohen’s table and the standard formulations with a power of 80% (β=20%) and confidence level of 95% (α=0.05), the number of patients in each group was calculated to be 18. With an expected attrition rate of 20%, appropriate sample size was estimated to be 23. For random allocation, specific envelopes containing letters A (control) and B (intervention) were distributed among all participants who completed the initial assessment and provided written consent for participation. 2.6. Statistical analysis Means and percentages were used to report continuous and categorical variables, respectively. Paired t-tests were used for analysis of scores of different scales at different time points in the study. A general linear model repeated measures model was employed to evaluate the interaction of time × treatment for PANSS and MMSE scores between the two groups, with the study groups (memantine vs. placebo) as the between-subject variable and study measurements as the within-subject factor (time). If Mauchly’s test of sphericity was non-significant, Greenhouse-Geisser correction for degrees of freedom was performed. Pearson and Spearman correlation
coefficients were calculated to check for potential
correlation between response to treatment and general patient characteristics. Level of significance was defined as <0.05. The Statistical Package for the Social Sciences (IBM Inc.) version 16.0 was used for all analyses.
2.7. Ethical considerations The protocol was approved by the Ethics Committee of the University of Social Welfare and Rehabilitation Sciences, and all steps were in line with the declaration of Helsinki. Either the patient or his legal guardian would provide written consent after explanation of the main objectives of the study. They clearly understood their right to withdraw at any time in the course of the study. All patients were re-assured regarding the confidentiality of their medical records utilized for the purposes of the present study. The study has been registered on the Iranian Registry of Clinical Trials under number 24817. 3. Results In total, 112 patients with a primary diagnosis of schizophrenia were recruited, of whom 66 declined participation in the trial. From the remaining 46 patients, only 36 completed the study course and were included in final analysis. The participant flow is illustrated in Fig. 1.
Assessed for eligibility (n= 112)
Excluded (n= 66) ¨ Not meeting inclusion criteria (n= 0) ¨ Declined to participate (n= 66) Randomized (n=46)
Allocated to intervention (n= 23) Received allocated intervention (n=19) Did not receive allocated intervention (Declined further participation) (n= 4)
Lost to follow-up (give reasons) (n=1) Discontinued intervention (due to adverse drug reactions) (n= 1)
Allocated to control (n= 23) Received allocated intervention (n= 20) Did not receive allocated intervention (Declined further participation) (n=3)
Lost to follow-up (give reasons) (n=2) Discontinued intervention (non-compliance) (n= 2)
Analysed (n=18) Excluded from analysis (n=0)
Analysed (n=18) Excluded from analysis (n= 0)
Fig. 1. Flow diagram of trial participants
3.1. General characteristics and baseline scores General and demographic characteristics of participants, as well as their PANSS and MMSE scores at baseline, are shown in Table 1. History of schizophrenia in first degree relatives was present in 10 participants in the intervention group and 12 participants in the control group. The two groups were matched based on their age and duration of treatment (p=0.8 and p=0.3, respectively).
Table 1. General characteristics of all participants at baseline Intervention group (n=23)
Control group (n=23)
Mean (SD1)
Mean (SD)
Age (years)
44.8 (6.6)
45.3 (6.2)
p>0.5
Age at onset of illness (years)
21.3 (6.8)
19.6 (2.8)
p>0.5
Duration since 1st diagnosis (years)
23.5 (8.3)
25.7 (5.4)
p>0.5
Variable
1
Standard deviation
p
Table 2. PANSS and MSSE scores of all participants after 12 weeks Intervention group (n=23)
Control group (n=23)
Mean (SD)
Mean (SD)
Positive symptoms score
12.7 (4.8)
15.5 (6.3)
p>0.05
Negative symptoms score
15.1 (4.8)
20.6 (5.2)
p<0.05
General psychopathology score
37.1 (7.4)
36.8 (8.7)
p>0.05
MMSE score
28.2 (1.6)
24.9 (3.0)
p<0.05
Variable
p
3.2. Inter-group comparisons
Based on PANSS scores, the intervention group had significantly improved with reference to negative symptoms by 12 weeks after the initiation of memantine; while no changes in positive symptoms were reported. MMSE scores also showed significant changes after week 12 in the intervention group (Table 3). Table 3. Comparison of intervention and control groups regarding PANSS and MMSE scores at baseline, week 6 and week 12 Scores
Item scale
Intervention group Mean (SD)
Control group Mean (SD)
Time (weeks)
Time (weeks)
0
6
12
0
6
P-value2
12
0
6
12
Positive symptoms
14.4 (5.4)
13.4 (5.2)
12.7 (4.8)
16.1 (6.2)
15.9 (6.3)
15.5 (6.3)
0.3
0.1
0.09
Negative symptoms
19.4 (5.4)
17.4 (5.1)
15.1 (4.8)
18.9 (5.3)
19.5 (5.3)
20.6 (5.2)
0.7
0.2
0.003
2
Level of significance: p < 0.05
General psychopathology
40.6 (8.7)
38.6 (7.9)
37.1 (7.4)
38.0 (8.3)
37.5 (8.3)
36.8 (8.7)
0.3
0.6
MMSE
26.3 (2.8)
28.0 (2.0)
28.2 (1.6)
25.2 (2.7)
25.0 (2.9)
24.9 (3.0)
0.2
0.001 <0.001
0.9
3.3. Repeated measures analyses
Muchly’s test of sphericity indicated that the assumption of sphericity had been violated [
2
(2)= 10.984, p-value=0.004], and therefore a Greenhouse-Geisser correction test was used to compare difference in positive symptoms. Repeated measures analysis of variance (ANOVA) testing for positive symptoms indicated a significant effect of the time×treatment interaction in the intervention group [ (1.336)=20.150, p=0.001] (Fig.2). Corresponding analyses for 2
negative symptoms [ (df:2)=84.667, p<0.001], general psychopathology [ (2)=57.185, 2
2
p<0.001], and MMSE scores [ (1.082)=40.478, p=0.001] indicated a significant effect for 2
the time×treatment interaction in the intervention group. Changes in different sub-scale scores are illustrated in the intervention group compared with the control group (Fig. 2).
a. mean scores for general psychopathology
b. mean scores for cognitive symptoms (MMSE)
41.3 40. 38.8 37.5 36.3 35. 33.8
30. 28.8 27.5 26.3 25. 23.8 22.5 Week 0
Week 6
Memantine
Week 12
Control
Week 0
Week 6
Memantine
Week 12
Control
c. mean scores for positive symptoms
d. mean scores for negative symptoms
17.
26.3
12.8
21. 15.8
8.5
10.5
4.3
5.3
0.
0. Week 0
Week 6
Memantine
Week 12
Control
Week 0
Week 6
Memantine
Week 12
Control
Fig. 2 Time×treatment interactions for a) general psychopathology, b) cognitive symptoms, c) positive symptoms, and d) negative symptoms in the intervention and control groups
3.4. Correlation analyses We found no significant correlation (Pearson’s correlation) between age, time since initial diagnosis, and family history with any of the subscale scores at week 12 (Table 3).
Table 3. Correlations between age, time since initial diagnosis, family history, negative symptoms score, and MMSE score Demographic variable
Pearson correlation (2-tailed significance) Negative symptom score
MMSE score
Age (years)
0.116 (0.647)
0.131 (0.606)
Duration since 1st diagnosis
0.208 (0.407)
-0.52 (0.837)
Family history
0.464 (0.052)
-0.075 (0.768)
4. Discussion
The present study indicates that memantine (20 mg/twice daily) added to risperidone (4 to 6 mg/daily) can improve negative symptoms as well as cognitive function among patients diagnosed with schizophrenia. The current findings confirm previous studies that demonstrated the effectiveness of NMDA receptor antagonists in relationship to negative
symptom and MMSE scores (Schaefer et al., 2007; De Lucena et al., 2009). The limited effects of new generation anti-psychotics on negative symptoms of schizophrenia that adversely influence the quality of life of patients can be enhanced by adjunctive treatment with drugs like memantine. There is evidence that NMDA receptor antagonists have beneficial effects on positive as well as negative symptoms (De Lucena et al., 2009; Koola et al., 2014); however, our findings showed no statistically significant improvements in positive symptoms or general psychopathology in the intervention group compared with the control group. Impaired cognition is another debilitating component of schizophrenia. Our results illustrate that memantine added to risperidone is associated with improved cognition. Nevertheless, previous investigations have been inconsistent in this regard (Lee et al., 2012; Koola et al., 2014). therapy,
However, most recent studies have suggested the promise of combination drug including with drugs other than memantine. Acetylcholine esterase inhibitors,
for example, may have synergistic effects on symptoms not generally improved by antipsychotics (Koola et al., 2014; Geerts et al., 2015). Some evidence also suggest that the synergistic effects may enable clinicians to prescribe lower dosages of antipsychotics and hence may lead to reduced levels of side effects (John et al., 2014; Shim and Nadeem, 2014). We also suggest that widely used measurement scales such as the MMSE can help in timely and precise evaluation of patients’ cognitive level. Utilization of more comprehensive tools that require expert personnel can impose barriers in clinical trials and negatively impact interpretation of findings. Participants in this study constituted a homogeneous sample of hospitalized male patients who had been diagnosed for at least 2 years. The homogeneity of the studied sample and close supervision of medication use in a hospital setting are among the main strengths of the
study. The longer treatment period compared with previous studies also provides a more comprehensive background for further analysis of findings. Different symptom sub-scales (including the ones measured by the PANSS), cognition and correlations between sub-scales and general characteristics were also collected and analyzed to address the limitations of previous studies that had inconsistent results. The high rates of attrition after the initial session for patient selection may be seen as a limiting factor concerning the generalizability of our findings, but the final sample size was consistent with initial power calculations.
The promising effects of memantine on negative symptoms and cognitive function in schizophrenia can lead to a paradigm shift in development of treatment guidelines. The observed effects in our study can add to the existing evidence on the benefits of this drug category (NMDA receptor antagonists). Although, demographic characteristics did not prove to have been correlated with drug effects, longer-term observations of patients receiving memantine can
provide valuable confirmatory information about the efficacy and potential
adverse effects of adjunctive memantine administration in schizophrenia. Conflict of interest None.
Acknowledgement The authors thank the personnel of the Razi Hospital for their kind cooperation and support. The RCT was financially supported by the University of Social Welfare and Rehabilitation Sciences.
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Highlights
A
Antipsychotics have been helpful in improving negative symptoms of schizophrenia
Understanding the role of neurotransmitters in the pathogenesis of schizophrenia has led to the development of new drugs
Memantine can significantly improve negative and cognitive symptoms among patients with schizophrenia
Adjunct treatment with NMDA receptor antagonists can be considered as a useful addition to standard care in the future