Will Memantine Work for Non-Dementia Psychiatric Disorders?

Memantine is a non-competitive glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, approved by the U.S. Food and Drug Administration (FDA) for treatment of Alzheimer's disease and dementia.1 It selectively blocks extra synaptic glutamate activity without psychotomimetic or psychedelic effects and shows relatively little negative interference with normal physiological functions, such as memory and learning and synaptic plasticity.2 Memantine is generally used as treatment for moderate to severe Alzheimer's disease and for other dementias to augment first-line therapy with cholinesterase inhibitors.3

A recently published review by Sani and colleagues looks at current preclinical and clinical evidence for the use of memantine in psychiatric orders other than the dementias.2 Study of memantine for psychiatric disorders emerges from data showing that "dysregulated NMDA transmission could occur in a wide range of psychiatric disorders, hence memantine might find clinical indications in a similarly wide range of conditions"—especially when used as adjunctive therapy for conditions that are treatment-resistant to more standard agents.2

Bipolar Mood Disorders

The rationale for investigating memantine in bipolar disorder (BD) is an accumulating body of evidence pointing to the key role of dopamine in the pathophysiology of BD, the authors state. Mania seems to be associated with increased dopaminergic transmission, while depression seems to be associated with decreased dopaminergic transmission.4 According to the authors, this mechanism might account for antidepressant-induced switching between depression and mania.  Experimental evidence has demonstrated that NMDA glutamate receptors play an important dopamine-enhancing role. Thus, the authors suggest, non-competitive blockade of NMDA receptors should result in anti-manic and mood-stabilizing action. Additionally, memantine appears to possess neuroprotective properties similar to those of lithium.5

Open-label case reports of add-on memantine in BD have yielded "strong" evidence of its utility. It has been "associated with substantial anti-manic and sustained mood-stabilizing effects in treatment-resistant BD." The authors note that these findings need to be replicated in further studies. A randomized, controlled trial investigating memantine in BD is soon to be conducted by their group.

Major Depression

Antidepressant therapy increases dopaminergic transmission, thereby improving symptoms such as anhedonia, loss of motivation, decreased libido, lack of drive, anergia, and psychomotor retardation.2 Therefore it stands to reason that a dopamine-enhancing agent would also have positive effects in ameliorating depression. However, the authors comment, while evidence from animal studies has been promising, evidence of memantine's usefulness in depression is limited, with "conflicting and inconclusive" results from open or double-blind studies.

Schizophrenia and Psychotic Disorders

Biochemical as well as behavioral lines of evidence point to an important role of glutamate dysregulation in several domains of schizophrenia, including psychosis and cognitive functions such as attention, memory, and learning.6 An important rationale for using memantine in schizophrenia comes from data pointing toward neurodegenerative processes in schizophrenia, which imply that neuroprotective agents such as memantine might be helpful. The authors add that the efficacy of memantine in ameliorating cognitive deficits in patients with Alzheimer's disease also points to possible utility in improving cognitive symptoms in schizophrenia.

However, these theoretical underpinnings have not been substantiated by robust findings from double blind studies. "Positive effects were shown in open studies and individual case reports, but these findings were not corroborated by controlled studies," the authors state. But they add that amantadine and memantine, both NMDA antagonists, have shown utility in catatonia, and it may be reasonable to use memantine in "emergency catatonia," when other methods of treatment have failed.