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. Author manuscript; available in PMC: 2015 Aug 1.
Published in final edited form as: Schizophr Res. 2014 May 28;157(0):84–89. doi: 10.1016/j.schres.2014.04.037

Potential Role of the Combination of Galantamine and Memantine to Improve Cognition in Schizophrenia

Maju Mathew Koola a,b,*, Robert W Buchanan c, Anilkumar Pillai d, Katherine J Aitchison e, Daniel R Weinberger f, Scott T Aaronson a,b, Faith B Dickerson a,b
PMCID: PMC4099270  NIHMSID: NIHMS598571  PMID: 24878431

Abstract

The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia projects were designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia. The MATRICS project identified three drug mechanisms of particular interest: dopaminergic, cholinergic, and glutamatergic. As a group, while people with schizophrenia have moderate cognitive impairment, it is the best predictor of long-term outcome. Unfortunately, there are no approved medications for cognitive impairment in this population. Hence, the development of new pharmacological approaches is critical for reducing illness-related disability. The combination of an acetylcholinesterase inhibitor (AChEI) and memantine is more effective than either medication alone to improve cognition in Alzheimer’s dementia. Galantamine is not only an AChEI, but also a positive allosteric modulator of the α4β2 and α7 nicotinic receptors. Hypofunction of N-methyl-D-aspartate (NMDA) receptors has been implicated in the pathophysiology of cognitive symptoms in schizophrenia and hence memantine may positively impact cognition. Memantine decreases the tonic NMDA current and galantamine enhances the action potential mediated by a postsynaptic NMDA current. This results in an increased signal transmission; therefore, a greater signal-to-noise ratio occurs with the combination than memantine alone. Galantamine improves the α-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA)-mediated signaling which could be neuroprotective and may improve memory coding. The combination of galantamine and memantine may be particularly effective in schizophrenia in order to increase the selective cognition enhancement produced by either medication alone. In the future, multitarget-directed ligands may play a role in the treatment of complex diseases like schizophrenia.

Keywords: Schizophrenia, cognitive impairments, galantamine, memantine

Introduction

Cognitive impairments are core features of schizophrenia. The degree of cognitive impairment in individuals with schizophrenia is the best predictor of their long-term outcome. Unfortunately, there are no effective approved medications for this major public health problem. Hence, the development of new pharmacological approaches is critical for reducing illness-related disability. The National Institute of Mental Health (NIMH) funded Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia (TURNS) projects were designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia. The MATRICS project identified three drug mechanisms of particular interest: dopaminergic, cholinergic, and glutamatergic.

The combination of an acetylcholinesterase inhibitor (AChEI) and memantine is more effective than either medication alone to improve cognition in Alzheimer’s dementia (Tariot et al., 2004; Atri et al., 2008; Parsons et al., 2013; Atri et al., 2013). The purpose of this paper is to review evidence suggesting a potential role of the combination of galantamine and memantine to improve cognitive impairments in schizophrenia.

Cholinergic system and cognition in schizophrenia

The cholinergic system is associated with attention, memory, processing speed, and sensory gating (Furey et al., 2000), processes that are impaired in schizophrenia. Postmortem studies have demonstrated alterations in muscarinic receptor and nicotinic receptor availability or expression (Lee et al., 2001). Serum anticholinergic activity in schizophrenia showed a significant association with impaired performance in the MATRICS-based measures of verbal working memory and verbal learning (Vinogradov et al., 2009). The FDA has approved AChEIs for the treatment of Alzheimer’s disease. Several studies have been done to test the efficacy of AChEIs to improve cognitive impairment in schizophrenia.

Donepezil and Rivastigmine are not effective for cognitive dysfunction in schizophrenia

Four Randomized Controlled Trials (RCTs) failed to observe significant cognitive effects of donepezil in this population (Friedman et al., 2002; Tugal et al., 2004; Freudenreich et al., 2005; Fagerlund et al., 2007). Similarly, in another 24-week RCT (N=21) in stable patients with schizophrenia (Sharma et al., 2006), rivastigmine failed to improve cognitive impairment. Finally, in the largest (N=245) RCT to date, donepezil failed to demonstrate any beneficial effects on a comprehensive neuropsychological battery (Keefe et al., 2008).

Galantamine is better than donepezil and rivastigmine

In contrast to other donepezil and rivastigmine, galantamine has some unique pharmacological properties. Galantamine is not only an AChEI, but also a positive allosteric modulator of the α4β2 and α7 nicotinic receptors. The allosteric properties of galantamine could lead directly to increased release of acetylcholine and activation of postsynaptic nicotinic receptors (Samochocki et al., 2003), or act indirectly through its effects on the release of other neurotransmitters, especially glutamate and dopamine Galantamine increases dopaminergic activity and release in the prefrontal cortex in a dose-dependent manner (Schilstrom et al., 2007). Galantamine increased dopamine release in the hippocampus and this effect was associated with improvement in cognition in a mouse model of Alzheimer’s disease (Wang and Moyzis, 2007).

Galantamine shows selective benefits for cognitive impairments

In an RCT with 24 participants with schizophrenia (Lee et al., 2007), galantamine improved performance on the Hopkins Verbal Learning Test recognition subtest, on the Stroop color subtest. These improvements are suggestive of selective benefit for visual recognition. In another RCT (Schubert et al., 2006), galantamine showed improvement in delayed memory and attention in participants with schizophrenia. In a 12-week RCT in 86 participants with schizophrenia, galantamine produced a significant benefit for processing speed and verbal memory. There was some evidence of galantamine improving the alogia subscale of the Scale for the Assessment of Negative Symptoms (Buchanan et al., 2008). Finally, in a 52-week RCT in 32 participants with schizophrenia, who were on long-acting injectable risperidone, social cognition was better in those who received adjunctive galantamine from month six to 12 compared to placebo (Lindenmayer and Khan, 2011). The above studies suggest a potential beneficial effect of galantamine in improving cognition in schizophrenia.

Glutamatergic system and cognitive impairments

A growing body of evidence supports a link between the glutamatergic neurotransmission and schizophrenia (Javitt and Zukin, 1991; Bressan and Pilowsky, 2000; Carlsson et al., 2000; Egerton et al., 2005; Yang and Chen, 2005). Memantine is an non competitive antagonist of N-methyl-D-aspartate (NMDA) glutamatergic receptors, an effect hypothesized to arise from its ability to block the excessive influx of calcium ions through the channel of the activated NMDA receptor (Parsons et al., 2007). Memantine is FDA approved for the treatment of moderate to severe Alzheimer’s dementia. The rationale for using memantine as an adjunctive therapy for people with schizophrenia comes from the circumstantial evidence that the glutamatergic system, and specifically hypofunction of NMDA receptors, is involved in the pathophysiology of positive, negative, and cognitive symptoms (Javitt and Zukin, 1991; Bressan and Pilowsky, 2000; Carlsson et al., 2000; Egerton et al., 2005; Yang and Chen, 2005). Several RCTs have shown improvement in people with schizophrenia receiving first and second generation antipsychotics, when treated with NMDA receptor allosteric agonists at the glycineB site (glycine, D-serine, D-cycloserine, sarcosine) (Coyle et al., 2002; Tsai and Coyle, 2002; Heresco-Levy et al., 2005). However, large multicenter RCTs have failed to demonstrate beneficial effects of glycine or D-cycloserine (glycine-site agonists of NMDA receptors) on negative symptoms or cognition (Buchanan et al., 2007). Paradoxically, NMDA receptor antagonists may also improve symptoms of schizophrenia, as glutamatergic neurons in the prefrontal cortex are inhibited by GABA interneurons acting through the NMDA receptor (Maccaferri and Dingledine, 2002; Homayoun and Moghaddam, 2007). NMDA receptor antagonists have been shown to release this inhibition, producing profound indirect excitation of cortical pyramidal neurons and increased glutamatergic outflow in the cortex (Moghaddam et al., 1997; Homayoun and Moghaddam, 2007).

Memantine for cognitive impairments in schizophrenia

In schizophrenia, an RCT (N=138) of memantine failed to improve cognition (Lieberman et al., 2009). However, this study focused on residual psychopathology (Brief Psychiatric Rating Scale total score ≥26 and individual item ≥4) rather than impaired cognition, used the Brief Assessment of Cognition in Schizophrenia instead of the MATRICS Consensus Cognitive Battery (MCCB) to assess change in cognition, and was a short trial of eight weeks. In a 12-week RCT, memantine did not improve cognition in 26 participants with chronic schizophrenia (Lee et al., 2012). In another 12-week RCT (N=21), memantine as an augmentation treatment significantly (p<0.01) improved cognition in participants with schizophrenia on clozapine (de Lucena et al., 2009). The last two studies used Mini-Mental State Examination to assess cognition. The FDA-NIMH-MATRICS workshop has recommended the MCCB to measure cognition in clinical trials (Buchanan et al., 2005; Green et al., 2008; Kern et al., 2008; Nuechterlein et al., 2008; Kern et al., 2011). Finally, in a meta-analysis of the three RCTs described above (N=186), memantine significantly (p=0.002) improved some cognitive functioning in people with schizophrenia (Kishi and Iwata, 2013).

To summarize, the strategy of cholinergic enhancement and using NMDA antagonists demonstrated only selective benefits. This approach of using only one target has not completely resolved the issue of treating impaired cognition in schizophrenia.

Advantages combining galantamine and memantine

Galantamine increases glutamatergic activity, whereas memantine inhibits it (Santos et al., 2002; Rogawski and Wenk, 2003). Thus, at first glance, the two drugs appear to act in an opposing manner. However, a closer examination of the effects of both medications on the cholinergic and glutamatergic systems reveals that these medications work synergistically (Figure 1) to improve cognitive impairments in people with Alzheimer’s dementia. In addition, it is unlikely that the combination treatment would affect the metabolism of either drug because galantamine is metabolized by cytochrome P450 (CYP) 2D6 and CYP3A4, which are not affected by memantine (Micuda et al., 2004). The use of galantamine and memantine in combination is supported by pharmacodynamic and pharmacokinetic studies (Wenk et al., 2000; Yao et al., 2005; Grossberg et al., 2006). Through the presynaptic α-7 nicotinic acetylcholine receptor (nAChR), galantamine increases glutamate release. Memantine decreases the tonic NMDA current and galantamine enhances the action potential mediated by a postsynaptic NMDA current which results in an increased signal transmission. Therefore, a greater signal-to-noise ratio occurs with the combination than memantine alone. Galantamine improves the α-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA)-mediated signaling which could be neuroprotective and may improve memory coding as shown in Figure 1 (Geerts and Grossberg, 2006). Finally, galantamine potentiates the neuroprotective effect of memantine against NMDA-induced excitotoxicity (Zhao et al., 2006; Lopes et al., 2013). Combination therapy with memantine and AChEIs may have synergistic efficacy in slowing the progression of Alzheimer’s dementia by modulating the glutamatergic and cholinergic neurotransmitter systems (Butterfield and Pocernich, 2003; Parsons et al., 2013).

Figure 1.

Figure 1

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Galantamine may augment the noise suppression of memantine’s glutamatergic action. Galantamine potentiates glutamatergic neurotransmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors.

Reproduced with permission.

Combination is effective in dementia

RCTs with the combination therapy of AChEIs and memantine in Alzheimer’s dementia slowed cognitive decline/improved cognition compared to cholinesterase inhibitor monotherapy (Tariot et al., 2004; Atri et al., 2008; Atri et al., 2013). Functioning improved significantly in the activities of daily living (ADL) (Tariot et al., 2004) and this finding may map on to people with schizophrenia. An effect size of 0.49 and 0.73 for cognition and ADL respectively were shown for combination therapy versus monotherapy at the end of year four (Atri et al., 2008). A clinically significant effect size of 0.2–0.4 were shown in all efficacy domains such as cognition, functioning and global outcome (Atri et al., 2013). In a 2-year, RCT, a combination of galantamine and memantine (compared to galantamine alone or placebo) modified cognitive function in 232 subjects with mild cognitive impairment (prodrome of Alzheimer’s dementia) (Peters et al., 2012). In addition to the pharmacological agents to modulate NMDA function, the NMDA antagonist in the central nervous system could also be a possible target to improve cognitive function. Kynurenic acid is the only NMDA receptor antagonist in the human central nervous system (Stone, 1993; Krystal et al., 1994).

Kynurenine abnormality in Schizophrenia

The kynurenine pathway regulates the synthesis of kynurenic acid (KYNA) by an enzymatic cascade, known as the kynurenine pathway, which is controlled by the immune system. The indoleamine dioxygenase (IDO) activity is associated with the type-1/type-2 immune response (Grohmann et al., 2003). Th-1 or type-1 cytokines, such as interferon (IFN)-γ and interleukin (IL)-2, stimulate the activity of IDO and tryptophan catabolism to kynurenine (Grohmann et al., 2003). Additional evidence supporting this hypothesis is molecular genetics of schizophrenia – genes involved in the glutamatergic system (Collier and Li, 2003). Increased levels of KYNA have been observed in the cerebrospinal fluid of 28 people with schizophrenia compared to 17 healthy controls (Erhardt et al., 2001). KYNA has been identified as a potent antagonist of NMDA receptor and the α-7 nicotinic receptor (Parsons et al., 1997; Hilmas et al., 2001). This antagonism may be associated with cognitive impairment. Stimulation of the cholinergic system down regulates the inflammatory immune response which is known as cholinergic anti-inflammatory pathway (van Westerloo and van der Poll, 2005). Therefore α-7 nicotinic receptor antagonism of KYNA may contribute to the inhibition of this cholinergic anti-inflammatory pathway. Early developmental elevations of brain KYNA was associated with cognitive impairments in adult rats which were reversed with galantamine (Alexander et al., 2013). There is a growing body of evidence that KYNA is associated with cognitive impairments in schizophrenia (Wonodi and Schwarcz, 2010). The combination of galantamine and memantine may decrease KYNA via the α-7 nicotinic and the NMDA receptors resulting in cognitive enhancement as shown in Figure 2 (Wonodi and Schwarcz, 2010).

Figure 2.

Figure 2

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Excess Kynurenic acid (KYNA) is associated with cognitive impairments in schizophrenia. Galantamine and Memantine combination may target α7nACh-R and NMDA-R respectively to decrease KYNA thereby improving cognitive impairments.

Discussion

The common mechanisms of cognitive impairment in schizophrenia and Alzheimer’s dementia are the cholinergic, α-7 nicotinic receptor and glutamatergic systems (Palmer and Gershon, 1990; Nordberg, 1992; Buchanan et al., 2007). To our knowledge, there are no head-to-head clinical trials comparing donepezil or rivastigmine and memantine vs. galantamine and memantine in Alzheimer’s dementia. As mentioned above, in schizophrenia, galantamine, not donepezil or rivastigmine, has shown an efficacy signal for cognitive impairments.

Therapeutic doses of clozapine, olanzapine, and, to a lesser extent, quetiapine are associated with clinically relevant anticholinergic activity (Chew et al., 2006). These antipsychotics are likely to obscure potential cognitive enhancement. In addition, chronic and excessive use of benztropine may worsen cognition and show lack of response to the combination treatment with galantamine and memantine (Wijegunaratne et al., 2014).

The use of combination treatment is playing a major role in the treatment of several other complex pathological conditions such as depression in schizoaffective disorder, bipolar type, posttraumatic stress disorder (PTSD), unipolar and bipolar depression (Koola et al., 2011; Koola et al., 2014). There is evidence that naltrexone and prazosin combination may be effective for PTSD and alcohol use disorder (Qazi et al., in press). An alternative to drug combinations is the use of multitarget-directed ligands (MDTLs) that can hit multiple targets (Cavalli et al., 2008; Simoni et al., 2012). The MDTL of galantamine and memantine has been shown to be potentially useful in Alzheimer’s dementia (Simoni et al., 2012). The advantages of MDTLs include: clinical development is faster because it is easier to understand the pharmacokinetics of a single compound than the combination treatment, hitting multiple targets simultaneously for the synergistic effect leading to improved efficacy, less side effects with more safety and less drug-drug interactions, simplified medication regimen leading to better adherence (Zimmermann et al., 2007; Small and Dubois, 2007; Morphy and Rankovic, 2007; Cavalli et al., 2008; Hopkins, 2008).

Conclusions and Future Directions

To date, similar studies (Tariot et al., 2004; Atri et al., 2008; Peters et al., 2012; Atri et al., 2013) combining AChEI/galantamine and memantine have not been done in schizophrenia. The combination of galantamine and memantine may be particularly effective in schizophrenia to broaden the selective cognition enhancement produced by either medication alone. Development of an effective treatment for cognitive impairments in schizophrenia is a major public health need. The proposed novel dual receptor mechanism targeting cholinergic and glutamatergic systems simultaneously may be molecular targets that are clinically meaningful for the cognitive impairments in schizophrenia. Cognitive enhancement from treatment with the combination of galantamine and memantine may lead to improved functioning in people with schizophrenia. Future RCTs are warranted to integrate the pathophysiology of cognition in schizophrenia with the galantamine and memantine combination treatment. Because of lack of biomarkers, more research is warranted to shed light on the association of biomarkers and cognitive enhancement with treatment interventions.

Acknowledgments

Role of Funding Source

Faith Dickerson is funded by the Grant 07R-1690 from the Stanley Medical Research Institute.

Maju Koola was supported by the NIMH funded 5R13MH064074 to present part of this manuscript at the 2010 APA Research Colloquium for Junior Investigators in New Orleans, LA, May 22–26. We like to thank Robert Schwarcz, PhD for Figure 2 and Robert Freedman, MD for reviewing the manuscript.

Footnotes

Contributors

Maju Koola wrote part of this manuscript under the mentorships of Drs. Juan Bustillo and Robert W. Buchanan for the 2010 American Psychiatric Association (APA) Research Colloquium for Junior Investigators. Maju Koola wrote the first draft of the manuscript. Drs. Scott Aaronson, Katherine Aitchison, Robert Buchanan, Faith Dickerson, Anilkumar Pillai, Daniel Weinberger made significant intellectual contributions in the manuscript preparation.

Conflict of Interest

Dr. Buchanan has served as a DSMB member for Otsuka and Pfizer; has consulted with Abbott; Amgen; Bristol-Meyers Squibb; EnVivo; Omeros; Pfizer and have served on the following Advisory Boards: Amgen; EnVivo; Janssen Pharmaceutical, Inc; NuPathe, Inc.; Pfizer; Roche and Takeda. Other authors declare no conflict of interest.

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