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Adjunctive Memantine Treatment of Schizophrenia: A Double-Blind, Randomized Placebo-Controlled Study
Abstract
Purpose/background:
This double-blind, placebo-controlled clinical trial was designed to assess the efficacy and safety of memantine augmentation to standard regimen of antipsychotic treatment on psychotic symptoms and cognitive function in individuals with chronic schizophrenia for 8 weeks.
Methods/procedures:
Forty stabilized individuals with chronic schizophrenia were randomized in a 1:1 ratio to memantine (20 mg/d) and control (placebo) groups, along with their antipsychotic regimen for 8 weeks. The efficacy of treatment was assessed by the Positive and Negative Syndrome Scale (PANSS) and Brief Assessment of Cognition Scale, and the safety was measured by the Abnormal Involuntary Movement Scale and Barnes Akathisia Rating Scale at baseline and at weeks 4 and 8.
Findings/results:
No significant differences were observed in demographic or clinical variables between both groups at baseline. During the study, all subscales and total scores of PANSS decreased significantly within both groups, except the subscale score in memantine, which was found to be positive. Reduction in general subscale and total scores of PANSS was significantly higher in the control group compared with the memantine group. All subscale scores of the Brief Assessment of Cognition Scale increased significantly only in the memantine group. The increase in the Verbal Memory, Working Memory, Verbal Fluency Letter, and Verbal Fluency Total subscale scores was significantly higher in the memantine group than in the control group. There was no significant difference in the Abnormal Involuntary Movement Scale and Barnes Akathisia Rating Scale scores between the 2 groups during the study.
Implications/conclusions:
This study showed that adjunctive memantine to antipsychotic regimen improved the verbal memory, learning, verbal letter fluency, and working memory without improvement on psychotic symptoms in individuals with chronic schizophrenia.
... Some other studies have evaluated the effect of memantine versus placebo as an adjunctive therapy to a second-generation antipsychotics in terms of reduction of positive, negative and cognitive symptoms; results did not indicate significant differences between the two groups at baseline or after treatment in terms of reduction of positive and general psychopathologic symptoms, whereas cognitive and negative symptoms were positively reduced in the intervention group [52,53]. Hassanpour et al. assessed the efficacy of the add-on therapy with memantine and antipsychotics versus antipsychotics only in schizophrenia patients; the memantine group reported an improvement of cognitive functions such as verbal memory, working memory and verbal fluency [54]. The efficacy of memantine add-on treatment on negative symptoms and neurocognitive performance has been demonstrated in some other recent studies [55][56][57]. ...
... A few studies have reported positive effects on cognition of galantamine and amantadine. [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] Cannabidiol ...
Background
The pharmacological treatment of schizophrenia is currently based on the employment of anti-psychotic medications showing an antagonism of dopaminergic and serotoninergic. 20-40% of patients are drug-resistant or residually symptomatic in the long-term anti-psychotic treatment, and new strategies are needed for improving their functional and cognitive impairment.
Methods
This systematic review summarized the evidences from the literature regarding the newer pharmacological targets proposed for the treatment of psychosis. We included 128 peer-reviewed articles and 5 other relevant sources published from 2002 to 2020 on PubMed EMBASE, The Cochrane Library, Google Scholar.
Results
It has been extensively described the possible role of glutamate and its receptors as targets of the anti-psychotic mechanism of action. Glutamatergic neurotransmission and NMDA receptors hypofunction are involved in the neurobiological explanatory model of psychosis and possibly targeted for the successful treatment of cognitive and residual symptoms. The rResults show an efficacy of D-cycloserine (antagonist at the Glycine site of the NMDA-R) in the treatment of negative symptoms of schizophrenia as well as Memantine (NMDA:- Receptor antagonist) on cognition and psychopathology. It will be also discussed Tthe putative anti-psychotic effect of cannabidiol on positive symptoms and cognition will also be discussed, even if more evidence is required needing more evidences. The action on serotoninergic and GABAergic receptors will be considered as a new pharmacological target, with a possible efficacy of Vabicaserin on symptoms of psychosis. Mynocicline has shown improvements of in cognitive symptoms in schizophrenia as well as Erythropoietin. Oxytocin reported an antipsychotic-like effect and COX-2 inhibitors reported a reduction of positive symptoms of psychosis , above all in the first episode of illness.
Conclusion
This narrative report suggests a promising role of new agents in the treatment of Schizophrenia, even if more research is needed to approve their clinical employment.
... The positive aspect is the patient's good response to the added doses of me mantine. Despite the lack of registered indications for the use of memantine in schizophrenia and inconclu sive scientific reports on the drug's effectiveness in this illness, an attempt was made to initiate treatment with the hope of obtaining a beneficial effect on cognitive functions [14,15]. ...
... Pozytywnym aspektem jest jednak dość dobra odpowiedź pacjenta na dołączoną memantynę. Mimo braku zarejestrowanych wskazań do stosowania me mantyny w schizofrenii oraz niejednoznacznych doniesień naukowych o skuteczności leku w tym schorzeniu, podjęto próbę włączenia leczenia z nadzieją uzyskania korzystnego wpływu na funkcje poznawcze [14,15]. ...
... for both) Memantine, which has a well-established role in preserving cognition in patients with dementia, may also have benefit in schizophrenia, possibly due to its effects on glutamatergic signaling, 5-HT3 inhibition, and activity at nicotinic cholinergic receptors.48 Whereas a previous systematic review 49 of open-label and double-blind trials of memantine concluded that there was no benefit in its use for CIAS, more recent trials and meta-analyses show some potential benefit.24,25,50 In a 2018 meta-analysis of adjunctive antidementia drugs in schizophrenia, Kishi et al19 found a statistically significant improvement in Mini-Mental State Examination (MMSE) scores with memantine 20 mg/d compared with adjunctive placebo. ...
Currently available antipsychotics provide only modest benefit in managing the cognitive and negative symptoms of schizophrenia even though these symptoms are often the most impairing in patients' daily lives. Certain antipsychotics may have slight benefits over others, and several nonpharmacologic and pharmacologic adjunctive treatments have been evaluated in recent clinical trials. Recently published meta-analyses and clinical studies of such treatments are reviewed. Potential strategies to manage cognitive and negative symptoms, including deprescribing of medications that may exacerbate these symptoms, are described using theoretical case examples.
... In addition, many antipsychotic drugs block dopamine receptors in these brain regions, as well as in the nucleus accumbens, resulting in negative symptoms and cognitive dysfunction. The efficacy of memantine in the treatment of learning and cognitive dysfunction and the negative symptoms of schizophrenia has become increasingly clear in recent years, although its effects on hallucinations via dopamine neurotransmission in the nucleus accumbens should be carefully monitored [79,80]. ...
The number of patients with Alzheimer’s disease is increasing annually. Most of these patients are older adults with comorbid physical illnesses, which means that they are often treated with a combination of medications for the disease they have and those for Alzheimer’s disease. Thus, older adults with Alzheimer’s disease are potentially at risk for polypharmacy. In addition, the drug interactions between Alzheimer’s disease medications and those for the treatment of physical illnesses may reduce their efficacy and increase side effects. This article reviews polypharmacy and drug interactions in elderly patients with Alzheimer’s disease, with a focus on psychotropic drugs.
... planowanie, elastyczność, hamowanie i pamięć operacyjna) oraz regulujących nastrój [67]. Przypuszcza się, że lumateperon powoduje poprawę funkcji poznawczych (ze względu na oddziaływanie na transmisję glutaminergiczną poprzez wzmocnienie sygnalizacji receptorów AMPA i NMDA w korze przedczołowej) [75, 81].Wyniki badań przeprowadzonych w ostatnich latach wykazały brak skuteczności substancji, takich jak między innymi wareniklina[155] oraz rywastygmina (podczas stosowania tego leku mogą wystąpić neurologiczne skutki uboczne u chorych na schizofrenię)[156].Należy zwrócić uwagę, że zachodzi konieczność przeprowadzenia dalszych analiz, gdyż dotychczasowe analizy mające na celu potwierdzenie skuteczności leczenia farmakologicznego w zaburzeniach poznawczych, okazywały się niewystarczające do postawienia ostatecznych konkluzji[150].DyskusjaW niniejszej pracy przedstawiono różne metody leczenia schizofrenii (uwzględniające zarówno nowsze terapie, jak i te dostępne od dłuższego czasu). Opracowanie skutecznych terapii w dalszym ciągu stanowi wyzwanie dla badaczy. ...
... Hassanpour et al. conducted a double-blind, randomized, placebo-controlled, 8-week trial to evaluate the efficacy of memantine add-on administration compared to a standard regimen of antipsychotic treatment in patients with chronic schizophrenia. They reported in 2019 that memantine as an adjunct to the antipsychotic regimen demonstrated improvements in working memory (p = 0.007), verbal fluency letter (p = 0.002), and verbal fluency total (p = 0.013) subscales of the Brief Assessment of Cognition Scale compared to the placebo-treated group [32]. Zheng et al. performed a meta-analysis of randomized, double-blind, placebo-controlled trials in patients with schizophrenia. ...
Memantine, an n-methyl-d-aspartate (NMDA) receptor antagonist approved for treating Alzheimer’s disease, has a good safety profile and is increasingly being studied for possible use in a variety of non-dementia psychiatric disorders. There is an abundance of basic and clinical data that support the hypothesis that NMDA receptor hypofunction contributes to the pathophysiology of schizophrenia. However, there are numerous randomized, double-blind, placebo-controlled clinical trials showing that add-on treatment with memantine improves negative and cognitive symptoms, particularly the negative symptoms of schizophrenia, indicating that memantine as adjunctive therapy in schizophrenia helps to ameliorate negative symptoms and cognitive deficits. It remains unclear why memantine does not show undesirable central nervous system (CNS) side effects in humans unlike other NMDA receptor antagonists, such as phencyclidine and ketamine. However, the answer could lie in the fact that it would appear that memantine works as a low-affinity, fast off-rate, voltage-dependent, and uncompetitive antagonist with preferential inhibition of extrasynaptic receptors. It is reasonable to assume that the effects of memantine as adjunctive therapy on negative symptoms and cognitive deficits in schizophrenia may derive primarily, if not totally, from its NMDA receptor antagonist activity at NMDA receptors including extrasynaptic receptors in the CNS.
... Так, в 8-недельном двойном слепом плацебоконтролируемом исследовании F. Hassanpour и соавт. [56], включавшем 40 больных хронической шизофренией, мемантин назначали в дозе 20 мг/сут. Эффективность лечения оценивалась с помощью шкал PANSS и BACS, а безопасность -с применением шкалы оценки аномальных непроизвольных движений (Abnormal Involuntary Movement Scale, AIMS) и шкалы оценки акатизии Барнса (Barnes Akathisia Rating Scale, BARS). ...
According to the instruction approved in the Russian Federation, Akatinol Memantine is indicated for the treatment of all types of dementia regardless of its severity. In addition, data are being accumulated on the use of memantine in a wide range of mental disorders, including schizophrenia, bipolar affective disorder, recurrent depression, obsessive-compulsive disorder, etc.This review is devoted to the analysis of an update on adjuvant therapy with memantine for the above mental disorders. It discusses the precogni-tive and antinegative effects of the drug in schizophrenia on the basis of the data of meta-analyses and double-blind, placebo-controlled studies.
... Schizophrenia substantially affects brain function and manifests as a combination of cognitive dysfunction and psychotic symptoms such as hallucinations, delusions and thinking disorders, causing great harm to the lives of patients. Many approaches to treating schizophrenia exist, such as pharmacotherapy (Hassanpour, Zarghami et al. 2019;Higuchi, Ishigooka et al. 2019, Mizuno et al., 2019, psychotherapy (Hasan, Callaghan et al. 2014), electroconvulsive therapy (Zhao, Jiang et al. 2016), and targeted treatment (Kurita, Holloway et al. 2013;Oxenkrug, van der Hart et al. 2016;Cuomo, Maina et al. 2018). Although effective treatments are available for schizophrenia, many patients are refractory to such interventions. ...
Morita therapy was developed for common mental problems, and our aim was to evaluate the clinical effect of Morita therapy on schizophrenia. The literature was searched in 10 databases, namely, PubMed, Chinese National Knowledge Infrastructure (CNKI), Sinomed, Wanfang, Cochrane Library, UpToDate, Web of Science, Medline, PsycINFO and Embase, from inception to September 4, 2019. Random-effects models were used. For continuous results, the standardized mean differences (SMDs) and 95% confidence intervals (CIs) were calculated to synthesize the effects. Thirty studies were included, with a total of 2651 patients with schizophrenia. Compared to pharmacotherapy alone and standard care alone, Morita therapy plus pharmacotherapy and Morita therapy plus standard care both had significant effects on mental state (pooled effect size = -1.09, 95% CI: -0.35, -0.83), social functioning (pooled effect size = -0.61, 95% CI: -2.30, -0.92) and behavior (pooled effect size = 1.13, 95% CI: 0.75, 1.51). Significant heterogeneity between studies was found for mental state (I² = 89%, p < 0.05) and social functioning (I² = 95%, p < 0.05), but no heterogeneity was found for behavior (I² = 0%, p = 0.84). Morita therapy has positive effects on mental state and social functioning among patients with schizophrenia, but it leads to some problems with behavior among these patients. Most included studies have unclear bias, and the forest plots show high heterogeneity among the results. Thus, Morita therapy cannot be implemented in clinical practice as a feasible strategy, the conclusion has yet to be confirmed, and new trials and future studies are desired.
... Memantine is useful for the treatment of both cognitive deterioration and BDs in AD and other forms of dementia [172,173]. AD patients treated with memantine plus citalopram show improvement in BDs [174]; in combination with antipsychotics, it may improve verbal memory, learning, verbal letter fluency, and working memory with no effect on psychotic symptoms in patients with chronic schizophrenia [175,176]; at a dose of 20 mg/day, it may be effective in patients with obsessive-compulsive disorder [177]; at 10 mg/day, it may be helpful in migraine [178]; and, in combination with naltrexone, it enhances the efficacy of naltrexone in reducing alcohol drinking and craving [179]. Memantine might also be useful in the treatment of punctate and dynamic allodynia by the blockade of the microglia Kir2.1 channel to suppress microglia activation [180], and in combination with dextromethorphan, it may be beneficial in neuropathic pain [181]. ...
Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.
Schizophrenia (SZ) is a deleterious brain disorder affecting cognition, emotion and reality perception. The most widely accepted neurochemical-hypothesis is the imbalance of neurotransmitter-systems. Depleted GABAergic-inhibitory function might produce a regionally-located dopaminergic and glutamatergic-storm in the brain. The dopaminergic-release may underlie the positive psychotic-symptoms while the glutamatergic-release could prompt the primary negative symptoms/cognitive deficits. This may occur due to excessive synaptic-pruning during the neurodevelopmental stages of adolescence/early adulthood. Thus, although SZ is not a neurodegenerative disease, it has been suggested that exaggerated dendritic-apoptosis could explain the limited neuroprogression around its onset. This apoptotic nature of SZ highlights the potential therapeutic action of anti-apoptotic drugs, especially at prodromal stages. If dysregulation of apoptotic mechanisms underlies the molecular basis of SZ, then anti-apoptotic molecules could be a prodromal therapeutic option to halt or prevent SZ. In fact, risk alleles related in apoptotic genes have been recently associated to SZ and shared molecular apoptotic changes are common in the main neurodegenerative disorders and SZ. PRISMA-guidelines were considered. Anti-apoptotic drugs are commonly applied in classic neurodegenerative disorders with promising results. Despite both the apoptotic-hallmarks of SZ and the widespread use of anti-apoptotic targets in neurodegeneration, there is a strikingly scarce number of studies investigating anti-apoptotic approaches in SZ. We analyzed the anti-apoptotic approaches conducted in neurodegeneration and the potential applications of such anti-apoptotic therapies as a promising novel therapeutic strategy, especially during early stages.
Increased Hcy has a toxic effect on nerve cells and can cause hippocampal death and directly damage the body’s cognitive function and memory ability, leading to the occurrence of vascular dementia. Hcy predicts vascular disease and might be a basis for clinical judgment. This article provides a new basis for the prevention and treatment of this disease by exploring the mechanism of action of memantine hydrochloride in diabetic vascular dementia. After grouping, mice walked through the Morris water maze to record the escape latency, and measured the Hcy level of the mice by high performance liquid chromatography. Observing the volume of brain atrophy in mice. GFAPT, APP, and CHAT level in mouse hippocampus was assessed by IHC and CHAT mRNA was detected by RT-PCR. Escape latency, Hcy level (11.46 ±0.74) yiimmol/L, brain atrophy volume (25.21 ±1.21) mm ³ , number of APP positive cells (46.7003±3.2431), number of GFAP positive cells (21.4000 ± 1.8127) were all significantly lower than those of model group. The positive rate of CHAT and the amount of CHAT mRNA in the memantine hydrochloride group was significantly elevated ( P < 0.05) with higher CHAT mRNA than model group and lower than blank group ( P < 0.05). Memantine hydrochloride could reduce the level of Hcy in mice, improve the cognitive function of mice with diabetic vascular dementia by improving the number of GFAP and CHAT positive cells in hippocampus and cortex, and increasing the amount of CHAT mRNA in brain tissue.
Several evidences support the hypothesis that glutamatergic dysfunction may be implicated in the pathogenesis of schizophrenia and in the last few years great interest has been focused on the role of the N-methyl-D-aspartate receptor (NMDAR). Glutamate is the main excitatory neurotransmitter in human CNS and it plays a prominent role in synaptic plasticity, learning, and memory and other cognitive functions. Increasing interest in memantine add-on therapy in schizophrenic patients with negative and cognitive symptoms may suggest that memantine could be a new promising treatment in schizophrenia. The aim of this update was to evaluate clinical data about the memantine effectiveness in schizophrenic patients. Our systematic review of the literature highlights that memantine therapy in schizophrenic patients seems to improve mainly negative symptoms while positive symptoms and cognitive symptoms did not improve significantly.
Rationale
Pro-cognitive agents for chronic psychotic disorders (CPDs) might be detected via experimental medicine models, in which neural targets engaged by the drug predict sensitivity to the drug’s pro-cognitive effects.
Objective
This study aims to use an experimental medicine model to test the hypothesis that “target engagement” predicts pro-cognitive effects of the NMDA antagonist, memantine (MEM), in CPDs.
Methods
MATRICS Consensus Cognitive Battery (MCCB) performance was assessed in CPD (n = 41) and healthy subjects (HS; n = 41) in a double-blind, randomized cross-over design of acute (single dose) MEM (placebo vs. 10 or 20 mg p.o.). Measures of prepulse inhibition (PPI) and mismatch negativity previously reported from this cohort substantiated target engagement. Biomarkers predicting MEM neurocognitive sensitivity were assessed.
Results
Testing confirmed MCCB deficits associated with CPD diagnosis, age, and anticholinergic exposure. MEM (20 mg p.o.) reduced MCCB performance in HS. To control for significant test order effects, an “order-corrected MEM effect” (OCME) was calculated. In CPD subjects, greater age, positive MEM effects on PPI, and SNP rs1337697 (within the ionotropic NMDA receptor gene, GRIN3A) predicted greater positive OCME with 20 mg MEM.
Conclusions
An experimental medicine model to assess acute pro-cognitive drug effects in CPD subjects is feasible but not without challenges. A single MEM 20 mg dose had a negative impact on neurocognition among HS. In CPD patients, age, MEM effects on PPI, and rs1337697 predicted sensitivity to the neurocognitive effects of MEM. Any potential clinical utility of these predictive markers for pro-cognitive effects of MEM in subgroups of CPD patients cannot be inferred without a validating clinical trial.
Background: Augmentation of clozapine with memantine targets altered glutamatergic neurotransmission in schizophrenia and showed beneficial effects on several symptom domains in a small proof-of-concept study. In this second study we report the effects of memantine add-on treatment to clozapine for cognitive disturbances and negative and positive symptoms in schizophrenia.
Method: Patients with clozapine-resistant schizophrenia were randomly assigned to 12 weeks of double-blind adjunctive treatment with memantine (N=26) or placebo (N=26). Crossover occurred after a 2-week placebo wash-out period. Primary endpoints were change from baseline to 12 weeks treatment and 14 weeks to 26 weeks treatment on the Cambridge Neuropsychological Test Automated Battery, Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression Severity Scale. Secondary endpoints were change on the Calgary Depression Scale for Schizophrenia, Yale-Brown Obsessive Compulsive Scale, Health of the Nation Outcome Scales (HoNOS), Manchester Short Assessment of Quality of Life, and Liverpool University Neuroleptic Side-Effect Rating Scale (LUNSERS).
Results: When compared with placebo, memantine improved verbal recognition memory (free recall; ES=0.56), paired associates learning (ES=0.40), PANSS negative subscale score (ES=0.29), and HoNOS symptoms (ES=0.33). Memantine treatment was associated with a higher score on the Allergic Reactions subscale of the LUNSERS (ES=0.44).
Conclusion: In patients with clozapine-resistant schizophrenia, treatment with adjunctive memantine significantly improved visual and verbal memory and negative symptoms without serious adverse effects.
Trial Registration: ISRCTN14760638 (doi: 10.1186/ISRCTN14760638)
We aimed to evaluate the efficacy of memantine add-on in the treatment of primary negative symptoms of patients with stable schizophrenia. In a double-blind placebo-controlled clinical trial, 40 patients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) who were stabilized on risperidone for a minimum of 8 weeks were randomized to either memantine (20 mg) or placebo in addition to risperidone, 6 mg/d, for eight weeks. Assessment was done using the Positive and Negative Syndrome Scale at baseline, week 4, and week 8. The Hamilton Depression Rating Scale and the Extrapyramidal Symptom Rating Scale at baseline and week 8 were used to assess depression and extrapyramidal symptoms, respectively. All 40 patients had at least one postbaseline measurement, and 38 patients completed the trial. Patients in the memantine group showed a significantly greater improvement on negative subscale than the placebo group at end point (P < 0.001). The same effect was observed for the total score (P < 0.001) and the general psychopathology subscale score (P = 0.002). There was no significant difference in reduction of positive symptoms score between the 2 groups (P = 0.757). Changes in the Hamilton Depression Rating Scale and the Extrapyramidal Symptom Rating Scale scores and frequency of adverse effects did not differ between the 2 groups. Our study showed that memantine is a tolerable and efficacious add-on treatment for primary negative symptoms of schizophrenia.
Nicotine addiction is a major public health problem, resulting in primary glutamatergic dysfunction. We measured the glutamate receptor binding in the human brain and provided direct evidence for the abnormal glutamate system in smokers. Because antagonism of the metabotropic glutamate receptor 5 (mGluR5) reduced nicotine self-administration in rats and mice, mGluR5 is suggested to be involved in nicotine addiction. mGluR5 receptor binding specifically to an allosteric site was observed by using positron emission tomography with [(11)C]ABP688. We found a marked global reduction (20.6%; P < 0.0001) in the mGluR5 distribution volume ratio (DVR) in the gray matter of 14 smokers. The most prominent reductions were found in the bilateral medial orbitofrontal cortex. Compared with 14 nonsmokers, 14 ex-smokers had global reductions in the average gray matter mGluR5 DVR (11.5%; P < 0.005), and there was a significant difference in average gray matter mGluR5 DVR between smokers and ex-smokers (9.2%; P < 0.01). Clinical variables reflecting current nicotine consumption, dependence and abstinence were not correlated with mGluR5 DVR. This decrease in mGluR5 receptor binding may be an adaptation to chronic increases in glutamate induced by chronic nicotine administration, and the decreased down-regulation seen in the ex-smokers could be due to incomplete recovery of the receptors, especially because the ex-smokers were abstinent for only 25 wk on average. These results encourage the development and testing of drugs against addiction that directly target the glutamatergic system.
To investigate the effects of memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, on cognitive impairments in patients with chronic schizophrenia.
A 12-week, placebo-controlled trial was conducted to determine the effectiveness of memantine as an adjunctive treatment with conventional antipsychotic medications in 26 patients with chronic schizophrenia. The subjects were evaluated with the Korean version of the Mini-Mental State Examination (K-MMSE), the Positive and Negative Syndrome Scale (PANSS), the Hamilton Rating Scale for Depression (HAM-D), and a standard neuropsychological screening test.
Memantine treatment was not associated with significantly improved cognitive test scores compared with the placebo control treatment. An improvement in the scores on the PANSS negative subscale was noted with memantine, but it was not significant.
Adjunctive memantine treatment did not improve cognitive functioning or affect psychopathology in patients with chronic schizophrenia in the present study. Memantine, however, was tolerated well and did not exacerbate positive symptoms in patients with chronic schizophrenia.
Memantine, an uncompetitive antagonist of glutamate receptors of the N-methyl-D-aspartate type is approved for the treatment of moderate to severe Alzheimer's disease. A growing body of evidence supports a link between the glutamatergic neurotransmission and schizophrenia. The purpose of this study (MEM-MD-29) was to examine the efficacy and safety of memantine as an adjunctive treatment to atypical antipsychotics in patients with persistent residual psychopathology of schizophrenia. In this double-blind, placebo-controlled study, participants were assigned to receive 20 mg/day memantine (n=70) or placebo (n=68), in addition to continuing treatment with atypical antipsychotics, for 8 weeks. The primary efficacy measure was the total score on the Positive and Negative Symptom Scale (PANSS). Secondary measures were positive and negative PANSS scores, PANSS responders, Calgary Depression Scale for Schizophrenia (CDSS), Clinical Global Impression of Severity (CGI-S), Clinical Global Impression of Improvement (CGI-I), and Brief Assessment of Cognition in Schizophrenia (BACS). Missing data were imputed using the last observation carried forward (LOCF) approach. Safety was assessed by means of physical examination, clinical laboratory evaluation, recording of adverse events (AEs), and measures of extrapyramidal symptoms. At end point, total PANSS scores did not differ between the memantine and the placebo group (p=0.570, LOCF). A similar outcome was observed for all secondary measures. The frequency of serious AEs in the memantine vs placebo group was 8.7 vs 6.0%; treatment discontinuations because of AEs occurred in 11.6 and 3.0% of patients in these groups, respectively. Memantine showed no efficacy as an adjunctive therapy in schizophrenia patients with residual psychopathology and was associated with a higher incidence of AEs than placebo.
Memantine is a moderate affinity, uncompetitive NMDA receptor antagonist currently approved for the treatment of moderate to severe Alzheimer's disease (AD). A 24-week, double-blind, placebo-controlled, study (Study 99679) conducted in Europe evaluated the efficacy and tolerability of 20mg/day memantine in patients with mild to moderate AD. Patients were randomised to either memantine or placebo in a 2:1 ratio. Efficacy was primarily assessed as change from baseline in ADAS-cog and CIBIC-plus score. Of 470 patients randomised and treated (memantine, n = 318; placebo, n = 152), 85% and 91% completed the study. Memantine-treated patients showed statistically significant improvement relative to placebo at weeks 12 and 18, and numerical superiority at week 24 on both efficacy scales. The lack of significance at week 24 was attributed to an unexpectedly high placebo response. Memantine was well tolerated with an adverse event profile similar to placebo. The data presented support the efficacy of memantine in mild to moderate AD.
The Schizophrenia Cognition Rating Scale (SCoRS) is an interview-based assessment of cognition that involves interviews with patients and informants. The SCoRS has shown good reliability, validity, and sensitivity to cognitive impairment in schizophrenia, with the advantage of brief administration and scoring time. The present study aimed to test the concurrent validity of the Persian version of the SCoRS. A group of 35 patients with schizophrenia and a group of 35 healthy controls received the Persian-SCoRS in the first session, and a standardized performance-based cognitive battery, the Brief Assessment of Cognition in Schizophrenia (BACS), in the second session.Our results indicated that the Persian version of the SCoRS was sensitive to cognitive impairment in the patients. The Persian SCoRS global rating was significantly associated with the composite score generated from the Persian version of the BACS and predicted functional outcomes as measured by Global Assessment of Functioning (GAF) and World Health Organization Quality of Life (WHO QOL). A Persian version of the SCoRS, an interview based measure of cognition that included informants, is related to cognitive performance and global functioning.
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.
The Brief Assessment of Cognition in Schizophrenia (BACS) is designed for assessment of cognitive function in patients with schizophrenia. Versions of the BACS in English and other languages have been shown to be as sensitive to cognitive dysfunction as a standard test battery, with the advantage of brief administration and scoring time. The present study aimed to test the concurrent validity of the Persian version of the BACS (Persian-BACS).
A group of 50 patients with schizophrenia-spectrum disorders and a group of 50 healthy controls received the Persian-BACS in a first session, and in a second session a standard neurocognitive battery.
Cronbach's alpha for the Persian-BACS was 0.74. All the Persian-BACS subscales weresignificantly correlated with the corresponding standard neurocognitive subscales and the Pearson correlation of the composite scores from the two instruments was 0.71. Moreover, a one-factor solution was found that accounted for 67.9% of the variance. Finally, the Persian-BACS demonstrated high ability to discriminate patients with schizophrenia from healthy controls.
Good psychometric properties of the Persian-BACS suggest that it is a useful tool for assessing cognition in schizophrenic patients with Persian as their primary language.
Verbal fluency is impaired in patients with schizophrenia, but the association with other cognitive domains remains unclear. Forty-seven patients with schizophrenia (DSM-IV) and 47 controls matched by age, gender, years of education, and vocabulary (Wechsler Adult Intelligence Scale-III) were assessed in terms of sociodemographic, clinical, and cognitive variables. Healthy controls performed significantly better than patients with schizophrenia in all cognitive measures. However, the way these cognitive domains were related differed across groups. Semantic fluency (SF) and phonological fluency (PF) were predicted by working memory (WM) in patients with schizophrenia, whereas the predictor in the healthy controls was processing speed (PS). Moreover, after dividing the sample of patients according to their performance on fluency tests, we found that a worse performance on SF or PF was predicted by WM. However, for patients with a better performance on fluency, the pattern was similar to that of healthy controls. Cognition may show a different pattern of interaction in schizophrenia, with less impaired patients showing a closer pattern to healthy controls. Therefore, we suggest that, depending on the severity of cognitive deficits, performance on neuropsychological tests may not reflect the same underlying mechanisms.
Cognitive dysfunction is increasingly considered to be the strongest clinical predictor of poor long-term outcome in schizophrenia. Associations have been found between the severity of cognitive deficits and social dysfunction, impairments in independent living, occupational limitations, and disturbances in quality of life (QOL).
In this cross-sectional study, the relationships of cognitive deficits and treatment outcomes in terms of QOL, needs, and psychosocial functioning were examined in 60 outpatients with schizophrenia who had a duration of illness over 2 years and had been treated with either clozapine or olanzapine for at least 6 months.
The present study suggests that cognitive functioning might be a predictor of work functioning/independent living outcome in stabilized patients with schizophrenia: deficits of visual memory and working memory were negatively associated with occupational functioning, and older patients lived independently and/or in a stable partnership more often. The patients' assessments of QOL and needs for care did not show any significant associations with cognitive functioning.
These findings suggest that cognitive functioning is a key determinant of work functioning/independent living for stable outpatients with schizophrenia.
Schizophrenia is comprised of several debilitating symptoms. Antipsychotics offer an effective treatment for positive symptoms, while the negative signs and cognitive deficits are usually treatment-resistant. It was suggested that glutamate dysregulation may be involved in the neuropathology of schizophrenia, mainly through NMDA dysfunction. We hypothesized that addition of memantine, a weak non-selective NMDA receptor antagonist approved for dementia, to antipsychotics would improve the clinical status of un-remitted schizophrenia patients, notably the negative signs and cognitive deficits.
Seven schizophrenia patients, were included in a six-week open-label study, with weekly increasing dosage (5, 10, 15, 20 mg) of memantine added to their on-going antipsychotic treatment.
We found a significant improvement of the PANSS score (baseline 116.28+/-21.9 vs. 97.86+/-24.48 after six weeks, t=5.98, p<0.001) with the most prominent improvement (21%) in negative signs sub-scale (baseline 40+/-6.38 vs. 31.71+/-7.76 after six weeks, t=5.87, p<0.001). Cognitive status, measured with the Neurobehavioral Cognitive Examination (NCSE) and Clock Drawing Test (CDT) showed no improvement.
Memantine addition to antipsychotic treatment, in schizophrenia patients might improve their clinical status, primarily the negative signs, but not their cognitive deficits. Further research is needed to replicate these observations.