The key findings of the present double-blind, placebo-controlled and randomized trial were that inpatients suffering from OCD improved significantly after 12 weeks with adjuvant memantine to standard SSRI or clomipramine medication as compared with patients with adjuvant placebo. The findings add to the current literature in so far as we were able to show in a double-blind, randomized, and placebo-controlled study design that adjuvant memantine reduces illness in inpatients suffering from OCD.

Following Stewart et al. (2010) and Ghaleiha et al. (2013), we expected symptom improvements in patients suffering from OCD with adjuvant memantine, relative to patients with placebo, and the data did fully support this expectation. In this regard, the present findings do support the most recent, though rather scarce data regarding OCD symptom improvements with NMDA receptor antagonists. Most importantly, while the response of patients in the placebo group, that is, in the SSRI or clomipramine monotherapy, was within the expected range (cf. Goodman et al. 1996; Pigott and Seay 1999), adjuvant memantine led to significantly more full responders (see Table 3). In this respect, the present pattern of results add to the current literature in so far as we were able to demonstrate a successful application of adjuvant memantine as an NMDA receptor antagonist with patients suffering from severe OCD.

Most importantly, as the data indicate (see Table 2; Fig. 1), significant improvements were observed in the target group only after 8 to 12 weeks, suggesting that a time lapse of at least 12 weeks may be necessary to observe marked improvement. Additionally, in contrast to Ghaleiha et al. (2013) who employed a time lapse of 8 weeks and speculated that perhaps the study period was too short to observe greater improvement in the monotherapy group, we note that in the present study after 12 weeks of treatment, no further improvements could be observed in the monotherapy group with standard SSRIs or clomipramine. As a result, based on the present pattern of results, we believe that a monotherapy with standard SSRIs or clomipramine leads to (modest) improvements within the first 8 weeks of treatment, while an add-on therapy with memantine produces increased efficacy but after 12 (or more) weeks. In this regard, unlike the results of Ghaleiha et al. (2013), we propose that adjuvant memantine not only accelerates the monotherapy response, but also affects the overall response rate.

As possible explanations for the favorable effect of memantine on patients suffering from OCD, several lines of evidence suggest an underlying glutamatergic dysfunction in the pathophysiology of OCD (cf. Rosenberg and Keshavan 1998; Saxena et al. 2001; Wu et al. 2012), with, specifically, evidence from cerebrospinal fluid studies. Chakrabarty et al. (2001) investigated cerebrospinal fluid from 21 patients suffering from OCD and 18 controls and showed that irrespective of gender, age or illness history, glutamate concentrations were significantly higher in the OCD as compared with the control group, a pattern of results replicated by the same research team with further patients and controls (Bhattacharyya et al. 2009). Moreover, whereas a balance between direct and indirect pathways in the corticostriatal–thalamocortical circuitry reflects pathophysiologically favorable processes, it is assumed that a hyperactivity of the direct pathway and/or hypoactivity of the indirect pathway leads to a disinhibition of this circuitry with an ultimate effect on compulsions and obsessions (Rosenberg et al. 2000, 2004; Yücel et al. 2008). Specifically, based on proton magnetic resonance spectroscopy, Rosenberg et al. (2000), Starck et al. (2008), and Yücel et al. (2008) were able to show, in patients suffering from OCD, greater left, but not right caudate glutamatergic concentrations, as well as lower anterior cingulate cortex (ACC) glutamate concentrations. Whiteside et al. (2006) reported greater orbital frontal glutamatergic concentrations in patients with OCD as compared with controls. As an overall concept, Rosenberg et al. (2004) claimed that a possible dysregulation of glutamate within cortico-striatal circuitry with reduced glutamate in the ACC, and a glutamate overactivity in the striatum and orbitofrontal cortex may be the underlying glutamatergic process in OCD. Additionally, a broad variety of further glutamate post-synaptic signaling dysfunctions (Ting and Feng 2011) and genetic causes (see Wu et al. 2012 for extensive overview; see Hanna et al. 2005; Hettema et al. 2001; van Grootheest et al. 2005 for results from twin studies) may further explain the development and maintenance of OCD.

Despite the intriguing findings, several limitations warrant against their overgeneralization. First, the sample size is rather small, though we relied more on effect size calculations which, unlike p-values, are unaffected by sample size. Second, other psychological dimensions such as depression and anxiety symptoms were not assessed, and perhaps improvements in OCD were merely a result of decreased symptoms of anxiety and depression. Third, the study design does not allow a deeper consideration of molecular processes. Fourth, likewise, the complex processes of glutamatergic regulations in various areas of the brain were neither directly, nor indirectly measured. In this respect, strictly speaking the fact that memantine as a NMDA receptor antagonist did favorably improve OCD symptoms does not directly prove that our theoretical model of the underlying mechanisms is correct. Rather, it remains possible that the present pattern of results emerged due to other though unassessed molecular, neuronal, and psychological processes (see above and below). Fifth, in this respect, glutamate receptor antagonists are related to an enhancement of 5-HT2A receptor-mediated transmission and, following Carlsson (2001), 5-HT2A agonism leads to reduced glutamatergic transmission while 5-HT receptor activation is related to a reduction of the excitatory effect of glutamate on cellular activity (cf. Saxena and Rauch 2000). As a consequence, as already outlined above, it is also conceivable that the present pattern of results is due to further, though unassessed pathophysiological processes. Sixth, only patients suffering from OCD without further comorbidities were included, leaving it unclear whether memantine add-on might be helpful for patients suffering from OCD and a concomitant broader spectrum of further psychiatric disorders. Notably, whereas it is usual to sample from comorbidity-free populations for highly standardized clinical trials, such patients are the exception rather than the rule within clinical everyday life. Seventh, the sample consisted of patients suffering from severe OCD for the first time in their lives, and it remains unclear to what extent memantine add-on might also be helpful for patients suffering from therapy-resistant and refractory OCD. Eighth, patients had sociotherapeutic events and (psychotherapeutic) contact with psychologists, psychiatrists and hospital nurses though, given that no data were gathered on these aspects, it remains unclear to what extent these sociotherapeutic events and (psychotherapeutic) contact may have favorably influenced the course of illness. However, irrespective of group assignment, all patients had the same opportunities to benefit from sociotherapeutic events and (psychotherapeutic) contacts, and therefore, it seems highly unlikely that data were systematically biased. Ninth, we note that after 8 of the 12 weeks, 11 of the 40 patients had dropped out of the study for different reasons. Therefore, the present findings should be interpreted in the light of the observed attrition rate. Last, no insight into cognitive-emotional processes was gained, leaving it uncertain to what extent psychopharmacological treatment led to new insights and modified behavior for coping with symptoms of OCD. Further double-blind, randomized, and placebo-controlled studies on OCD might include patients suffering from refractory OCD and with additional comorbidities, as well as assessing symptoms of depression and anxiety and, for instance, cognitive-emotional processes.