A focus on memantine 
Memantine may offer clinical improvement in positive and/or negative psychopathology when combined with antipsychotics, as well as improvements in cognitive and/or functional domains. It may also allow for reduction of antipsychotic doses [1]. Memantine is an uncompetitive NMDA antagonist (showing rapid on-and-off kinetics) and is hypothesised to be capable of reducing cortical and prefrontal signal-to-noise patterns, thus improving symptoms [see review]. Research concludes that there is a “low but significant block of NMDA receptors [~ 30% NMDAR occupancy] by memantine at nontoxic therapeutic doses (~20mg/day)” and at clinically relevant concentrations memantine can promote synaptic plasticity, protect against excitotoxicity and preserve or enhance memory whilst lacking cognition impairing and psychotomimetic properties [2,3].
“…memantine preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an uncompetitive, low-affinity, open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission”
Memantine also antagonises α7 nAChRs (more potently than the NMDAR) [4] and acts as a non-competitive antagonist at the 5-HT3 receptor.
Changes in astrocytic glutamate uptake due to chronic administration of memantine have been reported [5].
A Cochrane Review Intervention Protocol [6] concludes:
“Schizophrenia’s traditional models of the causative pathology have focused mainly on the dopamine hypothesis (Olney 1995). It has been suggested that there could be a possible role for other neurotransmitters such as serotonin, acetylcholine and glutamate in treating schizophrenia. This is based on the fact that currently available antipsychotics, both conventional and second generation, leave many symptoms untreated and cause undue side effects (Stone 2007).
Lately, the focus has been on the role of the excitatory neurotransmitter glutamate acting via NMDARs (Bondi 2012). It is therefore imperative to undertake a systematic review of the current studies with a view to establish if memantine with an uncompetitive antagonist action at NMDA receptors could be added to the armoury of drugs for treating schizophrenia.”
A recent study found evidence of possible enhanced cognition and function in patients with chronic psychosis treated with acute doses of memantine:
Memantine Effects on Sensorimotor Gating and Mismatch Negativity in Patients with Chronic Psychosis.
Patients with chronic psychotic disorders (CPD) exhibit deficient sensorimotor gating (measured by prepulse inhibition (PPI) of startle) and mismatch negativity (MMN). In healthy subjects (HS), NMDA antagonists like memantine and ketamine increase PPI, and under some conditions, memantine enhances MMN; these findings present a challenge to understanding the basis for deficient PPI and MMN in psychotic disorders, as reduced NMDA activity is implicated in the pathogenesis of these disorders. Here, we assessed for the first time the effects of memantine on PPI and MMN in CPD subjects. Baseline PPI was measured in HS and patients with a diagnosis of schizophrenia or schizoaffective disorder, depressed type. Subjects (total n=84) were then tested twice, in a double-blind crossover design, comparing either: 1) placebo vs. 10 mg of memantine, or 2) placebo vs. 20 mg memantine. Tests included measures of acoustic startle magnitude and habituation, PPI, MMN, autonomic indices and subjective self-rating scales. Memantine (20 mg) significantly enhanced PPI in CPD subjects, and enhanced MMN across subject groups. These effects on PPI were age-dependent and most evident in older CPD patients, while those on MMN were most evident in younger subjects. The lower dose (10 mg) either had no detectable effect or tended to degrade these measures. The NMDA antagonist, memantine, has dose-dependent effects on preconscious, automatic measures of sensorimotor gating and auditory sensory processing that are associated with enhanced cognition and function in CPD patients. Ongoing studies will determine whether these memantine-induced changes predict acute pro-cognitive or otherwise clinically beneficial effects in CPD patients.
“Memantine in the Treatment of Negative and Cognitive Symptoms” reviews several meta-analyses and finds that current evidence is limited by the lack of consistent results. Memantine is well-tolerated with minimal adverse effects (auditory hallucinations were reported by Lieberman et al.in 4/69 patients). Memantine appears to be safe for use in patients with schizophrenia but cannot be routinely recommended as an adjunctive treatment for negative or cognitive symptoms. Large, adequately powered studies with well-defined, clinically meaningful outcome measures are desired to determine the role of memantine in the treatment of negative and cognitive symptoms of schizophrenia
“Memantine holds great promise as adjunctive therapy for treatment of schizophrenia. Randomized controlled trials, wherein memantine is administered at adequate doses for an adequate period of time to ongoing antipsychotic treatment are required to confirm its efficacy in alleviating symptoms of schizophrenia.”
UPDATE:
BACKGROUND:
Schizophrenia severely influences function and quality of life. The benefit of newer antipsychotics in improving the quality of life in schizophrenia still remains controversial. The aim of the present study is to evaluate the effect of memantine on global function and quality of life in patients with schizophrenia.
MATERIALS AND METHODS:
This was a randomized controlled trial on inpatient cases of schizophrenia in Noor University Hospital, Isfahan, Iran. A number of 64 patients were selected through sequential sampling; patients were randomly allocated in intervention and placebo groups. The intervention group was treated with memantine plus previously administered, stabled-dose, atypical antipsychotic, while the control group received placebo plus previously administered, stabled-dose, atypical antipsychotic. Memantine administration was initiated at 5 mg daily; the dosage was increased at weekly intervals by 5 mg and finally up-titrated to 20 mg daily within 4 weeks. All patients were assessed by means of Global Assessment of Functioning (GAF) and quality of life scale (QLS) initially and every four weeks to the end of the 12th week.
RESULTS:
Analysis of baseline GAF and QLS scores showed no significant differences between the two groups (P = 0.081 and P = 0.225, respectively). GAF and QLS scores increased in both groups; but it was higher in the intervention group. The difference between the two groups was statistically significant. (P < 0.001 and P < 0.001, respectively) memantine was well tolerated, with no significant side effects.
CONCLUSION:
Add-on memantine was significantly effective in improving the global function of patients as well as their quality of life.
See also:
advancingschizophreniatherapeutics 