Does N-methyl-D-aspartate (NMDA) receptor modulation affect emotional processing? Implications for novel antidepressant treatments

Conventional antidepressants have a relatively slow onset of action, requiring a number of weeks before clinical improvement in depressive symptoms is apparent. The delay in onset of action of antidepressants may result in patients suffering increased morbidity due to the persistence of depressed mood and associated symptomatology. More recently, animal and human studies suggest that N-methyl-D-aspartate (NMDA) receptors may participate in the pathophysiology of depression and play an important role in effective pharmacological treatment. Indeed, several NMDA receptors antagonists, such as ketamine, lanicemine and nitrous oxide (N2O) have been shown to produce an antidepressant effect within hours in some clinical trials. Another group of drugs, acting at the glycine site of the NMDA receptor, have also shown potential as antidepressant agents.
The cognitive neuropsychological model of antidepressant drug action proposes that in the early stage of conventional antidepressant treatments the primary effect of antidepressants is to modify negative biases in the processing of emotional information. However, there have been no systematic studies to identify how NMDA-targeting antidepressants may change emotional processing in humans. Thus, this thesis aimed to investigate the effects of different NMDA receptor ligands on emotional processing in both depressed patients and healthy participants using a combination of behavioral and neuroimaging approaches. The first study assessed the effects of single doses of lanicemine and ketamine on neural and behavioural measures of emotional processing in depressed patients, 24 hours post infusion. It was found that ketamine did not show the broad range of effects on emotional processing seen with conventional antidepressants but instead significantly increased the error rate for recognizing facial expression as positive, and also produced higher false positive memory intrusions in the emotional recall task. Lanicemine only showed a trend for better recognition of facial expression across all emotions and did not produce positive shifts in any emotional processing tasks (Chapter 2). Furthermore, a single dose of ketamine increased brain activation in the right dorsolateral prefrontal cortex region during negative self-referential processing (Chapter 3).
The second study assessed the effects of a single dose of N2O 24 hours post infusion using behavioural measures of emotional processing in treatment-resistant depressed (TRD) patients. It was found that N2O did not change the processing of emotions in TRD patients compared to those in the placebo group (Chapter 4).
The third study was designed to assess the effects of an acute dose of an NMDA receptor glycine site, partial agonist D-cycloserine (DCS), on autobiographical memory, emotional processing and stress response in healthy volunteers. Relative to placebo, DCS enhanced autobiographical memory specificity at 3 and at 24 hours post treatment. DCS also increased positive bias in emotional word categorisation and subsequent free recall at 3 hours; however, this effect did not extend to other emotional processing tasks (chapter 5). In addition, further investigation on the effects of DCS on stress responses (chapter 6) found no effect of DCS on psychophysiological changes and self-reported mood and anxiety in an acute psychosocial stress paradigm.
These findings suggested that NMDA receptor targeting antidepressants showed early effects on emotional processing in the absence of subjective improvement in mood symptoms, though the changes seen differ from those observed with conventional antidepressants. These findings are important for understanding the therapeutic action of NMDA receptor targeting antidepressants in the treatment of depression and stress-related disorders and also for the ability of DCS to augment psychological treatment in patients with anxiety and depression. This thesis also outlines the challenges and future research directions for better understanding the cognitive neuropsychological mechanisms underlying the effects of NMDA receptor drugs in depression. This could have implications for the development of antidepressants with an early onset of clinical action.

Keywords: antidepressant
emotional processing
NMDA
Advisor: Capitão, L
Harmer, C
Cowen, P