Memantine Treatment for Obsessive-compulsive Disorder and Generalized Anxiety Disorder

Differential Efficacy of Memantine for Obsessive-compulsive Disorder vs. Generalized Anxiety Disorder: an Open-label Trial

The objective of this study was to obtain preliminary open-label data on the efficacy and tolerability of memantine, an anti-glutamatergic medication with a unique pharmacodynamic profile, in individuals with OCD and individuals with GAD. Because glutamatergic hyperactivity in frontal and frontal-subcortical circuits may play a role in the symptomatic expression of OCD, and possibly GAD, agents that reduce glutamatergic neurotransmission should provide unique anti-stress and anti-obsessional benefits. Memantine is a specific, uncompetitive antagonist at the NMDA receptor that blocks sustained activation of the NMDA receptor by high concentrations of glutamate under pathological conditions but rapidly leaves the NMDA channel upon transient physiological activation by low concentrations of glutamate.

Several case reports and an open-label trial have reported efficacy of anti-glutamatergic medications for the treatment of OCD. In an open-label trial of riluzole, a glutamate release inhibitor, seven of 13 adult patients with OCD improved, and five were categorized as treatment responders. Another open trial found riluzole to be effective for four of six children with treatment-refractory OCD. N-acetylcysteine, an agent that likely attenuates glutamate neurotransmission, was effective as an augmentation in one patient with OCD. Two case reports described memantine treatment of OCD. Poyurovsky et al. reported improvement with memantine augmentation in one patient with treatment resistant OCD, while Pasquini and Biondi noted improvement in one OCD patient with checking compulsions but not in one with contamination obsessions. There have been no controlled or open-label trials of memantine in OCD reported thus far.

Few studies have examined the efficacy of anti-glutamatergic agents in GAD. In an open-label trial of riluzole treatment in 18 patients with GAD, twelve patients responded and eight achieved remission. A double-blind, controlled study found that LY354740, a metabotropic glutamate receptor 2/3 (mGlu2/3) agonist, was significantly more effective than placebo for GAD. No studies of memantine in GAD have been reported thus far. We hypothesized that treatment with memantine would result in significant symptom reduction in both OCD and GAD.

Inclusion Criteria:

• The subject is male or female outpatient between 18-64 years old.
• The subject meets DSM-IV criteria for Generalized Anxiety Disorder or Obsessive Compulsive Disorder as determined by the MINI.
• Sexually active female patients of childbearing potential must be practicing at least one or more the following methods of contraception during the study: intrauterine device (IUD), barrier method in combination with a spermicide, oral/hormonal contraception or abstinence. Female patients of childbearing potential must have a negative pregnancy test prior to receiving study drug.
• Written informed consent must be obtained from the subject prior to study participation.
• The subject is in good medical health or with chronic medical conditions which are currently stable.
• No current abuse of alcohol or other substance.
• The subject has a total score of 20 or more on the HARS or YBOCS at screening (for GAD and OCD, respectively)
• The subject has a Clinical Global Impression (CGI) Severity score of 4 or more at screening.

Exclusion Criteria:

• The subject meets DSM-IV criteria for an Axis I diagnosis (other than GAD or OCD) as the primary diagnosis (i.e., schizophrenia, mood disorder, psychosis, anorexia nervosa) as determined by the MINI.
• The subject is clinically judged by the investigator to be at risk for suicide or is acutely suicidal as objectively measured by the MINI and MSE.
• The subject is clinically judged by the investigator to be at risk for homicide or is acutely homicidal as objectively measured by the MINI and MSE.
• The subject has a psychiatric condition that would require inpatient, or partial psychiatric hospitalization.
• Seizure disorders.
• Significant history of medical disease (i.e. cardiovascular, hepatic (e.g. cirrhosis, hepatitis B or C) renal, gynecological, musculoskeletal, neurological, gastrointestinal, metabolic, hematological, endocrine, cancer with a metastatic potential or progressive neurological disorders) which could impair reliable participation in the trial or necessitate the use of medication not allowed by this protocol.
• The subject is pregnant, planning to become pregnant, or nursing. If a subject becomes pregnant, she will be discontinued immediately and followed appropriately.
• Concomitant therapy with another investigational drug, or participation in an investigational drug study within one month prior to entering this study.
• Current psychotherapeutic treatment except for treatment with Specific Reuptake Inhibitor (SSRIs) medications which include: Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft), Luvox (Fluvoxamine), and Citalopram. Potential subjects may remain on one of the SSRI medications provided that he or she has been on a stable dose for at least 4 weeks prior to entering this study; this dose remains stable throughout the remainder of this study; and it can be determined that this medication is not exacerbating the anxiety symptoms.
• History of poor compliance or in the Investigator's judgment patients any subject whose treatment as an outpatient would be clinically contraindicated
• The subject has attempted suicide one or more times within the past twelve months
• The subject has a Structured Hamilton Depression Rating Scale (SIGH-D) score above 38 which suggests a moderate to severe clinical level of depressive symptoms