Clinical Indications of Memantine in Psychiatry-Science or Art?

Abstract

Background

Memenatine is USFDA approved for dementia of Alzheimer’s disease. Apart from this indication, trend of its use in psychiatry is on the rise addressing a multitude of disorders.

Study question

Memantine remains one of only few psychotropic drugs with antiglutamate activity. This might impart it a therapeutic potential in treatment-resistant major psychiatric disorders characterized by neuroprogression. We reviewed memantine basic pharmacology and its diversifying clinical indications while examining the extant evidence.

Methods

EMBASE, Ovid MEDLINE, PubMed, Scopus, Web of Science, and Cochrane Database of Systemic Reviews were searched for all relevant studies up to date of November, 2022.

Results

Sound evidence supports use of memantine for major neuro-cognitive disorder due to Alzheimer’s disease and severe vascular dementia, obsessive-compulsive disorder, treatment-resistant schizophrenia, and, ADHD. Modicum evidence supports use of memantine for PTSD, GAD and pathological gambling. Less compelling evidence is present for use in catatonia. No evidence supports use for core symptoms of autism spectrum disorder.

Conclusions

Memantine is an important addition to the psychopharmacological armamentarium. Level of evidence supporting the use of memantine in these off-label indications is highly variable, and hence, sound clinical judgment is necessary for its proper use and placement in real-life psychiatric practice and psychopharmacotherapy algorithms.

Introduction

Memantine is USFDA-approved for moderate to severe Alzheimer’s dementia. Apart from this only legitimate indication, trend of use of memantine off-label in psychiatry is on the rise addressing a multitude of disorders. Suffice to mention autism; catatonia; OCD; bipolar mood disorder; treatment-resistant schizophrenia; ADHD; binge-eating disorder; PTSD; substance use disorder; pathological gambling; and generalized anxiety disorder, just to name few.

This overview is intended to shed light on memantine unique pharmacological portfolio and these diverse indications whilst examining the extant evidence.

Methods

Electronic search for articles on psychiatric uses of lamotrigine using the EMBASE, Ovid MEDLINE, PubMed, Scopus, Web of Science, and Cochrane Database of Systemic Reviews databases from their inception to November, 2022. Key words were MEMANTINE AND PSYCHIATRIC USES. Inclusion criteria consisted of any clinical trial, retrospective review, or case report of use of mamantine in clinical psychiatric practice. Studies already included in previously mentioned reviews were excluded to avoid duplication and redundancy.

Pharmacology

Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that selectively blocks the excitotoxic effects of glutamate while preserving physiological transmission for normal cellular function.

Memantine shows linear pharmacokinetics when given at normal therapeutic doses. It is well absorbed after an oral dose, showing an absolute bioavailability of about 100%. Its maximum concentrations are reached in about 3–7 h (Tmax).

Memantine is mainly metabolized to three inactive compounds which are subjected to renal excretion. In vitro studies have discarded cytochrome P450 involvement in memantine’s metabolism. Memantine’s elimination half-life (T1/2) is 60–100 h.¹

Dementia

Memantine is FDA-approved for moderate to severe Alzheimer’s dementia. Majority of patients treated for dementia end up on a combination of memantine and ACE-i, usually donepezil (a combo of memantine ER and donepezil 10 mg is commercially marketed as Namzaric®). As a cognitive enhancer, it is used as well off-label for dementia of any type or severity. A Cochrane Database Systematic Review by McShane² et al. demonstrated a small clinical benefit of memantine on cognitive and behaviour/mood domains, in vascular dementia, but not on clinical global rating or ADLs. This effect was amplified for moderate-to-severe vascular dementia compared to mild-to-moderate vascular dementia. For Parkinson’s disease dementia and dementia with Lewy bodies, a small clinical benefit on clinical global rating and behaviour/mood domains was shown as was the case with Fronto-temporal dementia. In AIDS-related dementia complex, cognitive gains, on mamantine, could be demonstrated.

Autism Spectrum Disorder

It has been hypothesised that memantine may be effective in reducing the core symptoms of autism as well as some comorbidities such as hyperactivity and language difficulties. A Cochrane Database Systematic Review by Brignell³ et al. failed to demonstrate a clear evidence for difference between memantine and placebo with respect to severity of core symptoms of autism nor on language, memory, adaptive behaviour, hyperactivity or irritability.

Catatonia

Neurobiological underpinnings of catatonia basically involve cortical GABA deficiency and glutamate excitotoxicity.⁴ Benzodiazepines and electro-convulsive therapy (ECT) are the treatment modalities of choice in catatonia irrespective of underlying causation. When these fail, NMDA antagonists, like memantine, have been successfully deployed.⁵ Such case reports abound in literature including pediatric population with great tolerability.⁶ Memantine, has been also successfully trialled for catatonia-delirium presentations⁷ (e.g. in neuro-covid).

Obsessive-Compulsive Disorder

Glutamate and GABA are highly expressed in neurocircuity underlying OCD. Agents with anti-glutamate actions, like memantine, have been found successful as adjunctive treatment for OCD in 2 RCTs from Iran.⁸ A recent systematic review and meta-analysis by Modarressi⁹ et al. showed that OCD patients receiving memantine augmentation were 3.61 times more likely to respond to treatment than those receiving placebo and concluded that memantine 20 mg/d augmentation of first-line agents for a period of at least 8 weeks is a safe and effective intervention for moderate to severe OCD.

Bipolar Mood Disorder

Clinical use of memantine as a mood-stabilizer has been widely described in literature.¹⁰ It was suggested that memantine by blocking NMDA receptors prevents the up and down regulation of mesolimbic dopamine D2 receptors and the neurodegeneration that results from excessive glutamatergic neurotransmission during mania which might underlie the following depressive phase. Moreover, a recent RCT¹¹ attested to the potential of add-on memantine to attenuate inflammation and improve cognition in middle- to old-aged BP-II patients. (vide infra)

Treatment-Resistant Schizophrenia

Several lines of evidence supports the hypothesis that glutamatergic dysfunction may be implicated in the pathogenesis of schizophrenia. Many RCTs have examined the therapeutic potential of memantine for TR schizophrenia.¹² These RCTs have been meta-analyzed by at least 2 groups of authors. Results were pretty the same. Memantine (20 mg/d for 6–12 weeks) augmentation of antipsychotic treatment was found to attenuate the severity of negative symptoms and improve cognitive functioning; in both regards, the effect was large. Memantine was also associated with a small but statistically significant reduction in general psychopathology. Whereas memantine did not significantly attenuate positive symptom, depression, total psychopathology, and global illness ratings, it was also not associated with an increased risk of individual adverse events, discontinuation due to adverse events, or all-cause discontinuation.¹³

ADHD

Literature is consistent on the effectiveness of stimulant medications, whether methylphenidate or amphetamine-based, with effect sizes of 0.8–1.1, as well as behavioural interventions for the management of the core symptoms of ADHD. Nonetheless, 20–35% of subjects in clinical trials show inadequate response that could be attributed in part to dose-limiting side effects of medications or disorder severity or complexity.¹⁴

An RCT found significant and substantial improvements with memantine monotherapy in adults with respect to inattention, impulsivity, self-esteem issues and ADHD total index.¹⁵ A small double-blind study of 12 weeks of memantine adjuventia to stimulants showed an evidence of benefit with respect to certain executive functions in adults with ADHD. One study found beneficial effects of 20 mg memantine/day in children with ADHD with acceptable side effects. Another RCT in children with ADHD found a weaker effect with slightly higher side effects compared to methylphenidate.¹⁶

Binge-Eating Disorder

Several studies have shown that memantine can significantly correct the binge-like eating behavior in human and animal models. Long term NMDAR antagonism by memantine increases weight loss in obese mice induced by high fat diet. Memantine decreases food intake without inducing abdominal discomfort and anxiety, suggesting that this compound would be a good candidate drug for obesity control. However, the molecular mechanism and brain circuit involved in the regulation of weight loss by memantine need further study.¹⁷

PTSD

A 12-week open-label clinical trial to examine the efficacy and safety of memantine, in the treatment of civilian women with PTSD.¹⁸ Mean PDS total scores decreased from 32.3 ± 9.7 at baseline to 12.2 ± 7.9 at endpoint, which was statistically significant with a large effect; intrusion, avoidance, hyperarousal symptoms were all significantly improved from baseline to endpoint. Six patients (out of 13 initially enrolled) no longer fulfilled the diagnostic criteria of PTSD at endpoint. Memantine was well tolerated. This is quite interesting given the fact that a lifetime diagnosis of PTSD has been associated with a doubling of the risk of developing dementia later in life.¹⁹

Substance Use Disorders

Memantine is a unique glutamatergic medication with proven ability to attenuate drug NMDA receptor addiction in preclinical models. However, clinical translational studies are inconsistent.

Memantine’s clinical effects are generally attributed to its ability to transiently block NMDA receptors and reduce glutamatergic over-stimulation. While this mechanism could be effective in relieving drug-induced hyperglutamatergic states such as acute alcohol withdrawal, it may not be effective in hypoglutamatergic conditions such as cocaine or nicotine withdrawal.²⁰

Neuroprotection

Memantine at a clinically relevant dose markedly increased BDNF mRNA levels in the limbic cortex, and this effect was more widespread and pronounced at higher doses. Effects of memantine on BDNF mRNA were also reflected in changes in BDNF protein levels. Moreover, memantine induced isoforms of the BDNF receptor trkB. Taken together, these data suggest that the neuroprotective properties of memantine could be mediated by the increased endogenous production of BDNF in the brain.²¹ Moreover, the neuroprotective effect of memantine might be as well related to increasing levels of cells with active caspase-3 and active caspase-9, and hence, improving caspase-dependent apoptosis in the aging brain.²²

Pathological Gambling

A pilot study has demonstrated that pharmacological manipulation of the glutamate system, with memantine, may target both gambling and cognitive (flexibility) deficits and impulsive decision-making in pathological gambling (PG).²³ A related agent, amantadine, was shown to decrease PG symptoms among PG individuals with Parkinson’s disease in a double-blind, placebo-controlled trial.²⁴

Generalized Anxiety Disorder

Memantine may be an effective augmentation agent in patients with treatment-resistant anxiety as shown in a study comprising 15 consecutive partially responding anxious patients treated with adjunctive memantine for 10 weeks. Memantine was dosed 5–20 mg/day (mean dose of 14 mg/d) and resulted in clinically relevant reduction in anxiety symptoms when compared to baseline. Forty percent of patients achieved remission (HAM-A ⩾ 7). Memantine also improved sleep quality. Typical adverse events included nausea and headache.²⁵

Fibromyalgia

Neuropathic pain stems from an injury to the nervous system which, in turn, leads to increased glutamate production- the major excitatory neurotransmitter in the CNS with resultant excitatory neurotransmission through postsynaptic receptors. This ultimately culminates into excitotoxic cell death and is thus responsible for spasticity along with manifestations of acute pain, thereby progressing to chronic neuropathic pain. Simultaneously, NMDA mediates the release of substance P from the dorsal horn, leading to central sensitization by facilitating synaptic changes, and also increases the release of glutamate via presynaptic receptors. This gives kudos to memantine use to address neuropathic pain, like fibromyalgia.^26,27

Conclusion

This overview has casted some light on memantine pharmacological portfolio as a pluripotent agent with panoply of off-label uses especially in treatment-resistant major psychiatric disorders. It remains one of only few psychotropic drugs with anti-glutamate activity. Glutamate excitotoxicity lies at the core of many neuropsychiatric disorders and is strongly tied to neuroprogression and treatment-resistance. This might explain, at least in part, the utility of agents like memantine in these cases. Having said so, the hitherto level of evidence supporting the use of memantine in all these indications is highly variable (Table 1), and, hence, sound clinical acumen, manipulating all other viable treatment options at hand, would dictate its judicious and proper use and placement in real-life psychiatric practice and psychopharmacotherapy algorithms. Sound evidence supports use of memantine for major neuro-cognitive disorder due to Alzheimer’s disease and severe vascular dementia, obsessive-compulsive disorder, treatment-resistant schizophrenia, and, ADHD. Modicum evidence supports use of memantine for PTSD, GAD and pathological gambling. Less compelling evidence is present for use in catatonia. No evidence supports use for core symptoms of autism spectrum disorder.

Table 1. Memantine Uses in Psychiatry.

Indication		Level of Evidence*
Dementia**  - Alzheimer’s Disease  - Vascular Autism Catatonia OCD Bipolar Mood Disorder Schizophrenia–TR ADHD Binge-eating disorder PTSD Substance Use Disorder Pathological Gambling Generalized Anxiety Disorder		Level I (Positive) Level I (Positive) Level I (Negative) Level II-3 (Positive) Level I (Positive) Level III (Positive) Level I (Positive) Level I (Positive) Level III (Positive) Level II-1 (Positive) Level III (Positive) Level II-1 (Positive) Level II-1(Positive)

*USPSTF rankings (1998).

• Level I: Evidence obtained from at least one properly designed randomized controlled trial.

• Level II-1: Evidence obtained from well-designed controlled trials without randomization.

• Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.

• Level II-3: Evidence obtained from multiple time series designs with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence.

• Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

**Only FDA Indication.