Table 2.

Human studies on healthy participants.

Author	Aim and Study Design	Number of Participants	Population	Lamotrigine Dose and Root	Ketamine Dose and Root	Tests and Measures	Outcome
Anand et al. 2000 [46]	To test if lamotrigine can reduce neuropsychiatric effects of ketamine Randomized, double blind Mean ± SEM	19, 16 completed the study	Healthy humans	Lamotrigine 300 mg single dose 2 h prior to ketamine	0.26 mg/kg iv in 1 min followed by 0.65 mg/kg for 90 min Four infusions	YMRS HVLT CADSS BPRS	Lamotrigine caused further increase in ketamine-induced mood elevation (YMRS) and decrease in ketamine-induced impairment of learning (HVLT) and dissociative symptoms (CADSS). Significant decrease in ketamine-induced positive and negative symptoms (BPRS) was observed.
Deakin et al. 2008 [47]	To determine the role of increased glutamate release as an effect of ketamine with the use of lamotrigine. Randomized, double blind, placebo controlled, crossover, counter balanced-order trial SD	21, 19 completed the study	Healthy right-handed humans	Lamotrigine, 300 mg, oral, 2 h prior to ketamine	0.26 mg/kg IV in 1 min followed by 0.25 mg/kg/h Single infusion	CADSS BPRS BOLD	Lamotrigine pretreatment resulted in significantly lower BPRS and CADSS scores. Several areas showing BOLD signal responses to ketamine in the ketamine-placebo experiment also showed significantly greater response to ketamine after placebo infusion compared to lamotrigine infusion.
Doyle et al. 2013 [48]	To test the hypothesis if lamotrigine or risperidone can reduce ketamine-induced glutamate release. Randomized, double blind, placebo controlled, crossover trial Least Square Mean (95%CI) Difference (95% CI)	20, 16 completed the study	Healthy humans	Lamotrigine 300 mg oral, or placebo, 4.75 h prior to ketamine	Ketamine 0.12 (mean) mg/kg iv during 1 min followed by 0.31 mg/kg/h Four test days 1control and 3 ketamine infusions, two of which included pretreatment with lamotrigine or risperidone	BOLD	A significant positive and negative BOLD response was revealed to ketamine infusion. For the positively responding regions, pretreatment with lamotrigine resulted in attenuation of the ketamine responses. For the negatively responding regions the attenuating effect of lamotrigine was weak.
Shcherbinin et al. 2015 [49]	To assess the effects of ketamine, risperidone and lamotrigine, on resting brain perfusion Randomized, double blind, placebo controlled, crossover trial Accuracy (%)	20, 16 completed the study Same sample as Doyle et al. (2013) and Joules et al. (2015)	Healthy humans	Lamotrigine 300 mg oral, or placebo, prior to ketamine	Ketamine 0.12 mg/kg iv during 1 min followed by 0.31 mg/kg/h Four test days	Resting brain perfusion	Lamotrigine had no significant effect on resting brain perfusion.
Joules et al. 2015 [50]	To investigate the functional connectivity effects of ketamine with pharmacological magnetic resonance imaging (phMRI) and the potential modulation of these effects by pre-treatment with lamotrigine and risperidone Randomized, double blind, placebo controlled, crossover trial Accuracy (%)	20, 16 completed the study Same sample as [48] and [49].	Healthy humans	Lamotrigine 300 mg oral, or placebo, 4.75 h prior to ketamine	Ketamine 0.12 (mean) mg/kg IV in 1 min followed by approximately 0.31 mg/kg/hb.c Four test days	Functional connectivity	No evidence of a significant modulation effect of the ketamine-induced degree-centrality pattern by lamotrigine

BOLD blood oxygenation level- dependent; BPRS = Brief Psychiatric Rating Scale; CADSS = Clinician-Administered Dissociative States Scale; GBCr = global brain connectivity with global signal regression; HVLT = Hopkins Verbal Learning Test; IDS-C30 = Inventory of Depressive Symptomatology—Clinician Rated; IV = intravenous; MADRS = Montgomery-Asberg Depression Rating Scale; MDD = major depressive disorder; NMDA = N-methyl-d-aspartate; TRD = therapy resistant depression; vPFC = ventral prefrontal cortex; YMRS = Young Mania Rating Scale.