Table 2.
Lamotrigine
| Source: 1st author, year | Study design |
No. of participants (males) | Population | Drug, dosage, route of administration, time interval with ketamine administration | Ketamine dosage, route of administration and duration | Clinical outcome | Possible mechanism of interaction |
|---|---|---|---|---|---|---|---|
| Abdallah et al. (2017) | Randomized, double-blind, placebo-controlled, crossover trial | 18 (18) | Healthy individuals | Lamotrigine 300 mg oral, or placebo, about 2 h prior to ketaminea | Ketamine 0.23 mg/kg IV in 2 min followed by 0.58 mg/kg for approximately 70 min | Ketamine significantly increased BPRS and CADSS scores but pretreatment with lamotrigine had no significant effect on ketamine-induced increases in BPRS and CADSS scores. Lamotrigine significantly reduced ketamine-induced GBCr surge in clusters of bilateral dorsomedial and left frontolateral prefrontal cortex. Significantly higher GBCr was found in vPFC of TRD patients compared with healthy controls. Ketamine did not significantly reduce vPFC GBCr in TRD patients but did reduce vPFC GBCr in healthy individuals. Following pretreatment with lamotrigine, ketamine showed no significant effects on GBCr in vPFC. | Inhibition of glutamate transmission reduces GBCr in prefrontal cortex. Ketamine induces glutamate level and so increases GBCr in prefrontal cortex. Glutamate release inhibitor lamotrigine reduces glutamate level induced by ketamine and so reduces GBCr and attenuates effect of ketamine. |
| Anand et al. (2000) | Randomized, double-blind, balanced order trial | 19, 16 completed the study (8) | Healthy individuals | Lamotrigine, 300 mg, oral, 2 h prior to ketamine | 0.26 mg/kg IV in 1 min followed by 0.65 mg/kg for 90 min | Lamotrigine led to increase in ketamine-induced mood elevation (measured by YMRS). Led to decrease in ketamine-induced impairment of learning a wordlist (measured by HVLT) and dissociative symptoms (measured by CADSS score. Also a significant decrease in ketamine-induced positive and negative symptoms (measured by BPRS symptom score). | Lamotrigine may reduce hyperglutamatergic consequences of NMDA receptor dysfunction implicated in pathophysiologic processes of neuropsychiatric illnesses. It decreases glutamate release by blocking sodium channels and so reduces increased glutamate levels effectuated by ketamine. |
| Deakin et al. (2008) | Randomized, double-blind, placebo-controlled, crossover, counterbalanced-order trial | 21 (21), 19 completed the study |
Healthy right-handed individuals | Lamotrigine, 300 mg, oral, 2 h prior to ketamine | 0.26 mg/kg IV in 1 min followed by 0.25 mg/kg/hb | After ketamine infusion with lamotrigine pretreatment, BPRS total, thought disorder, activation, and hallucinations scores were significantly lower. Similarly, CADSS total, derealization and depersonalization scores were significantly lower. Several areas showing BOLD signal responses to ketamine in ketamine-placebo experiment also showed significantly greater respons to ketamine after placebo infusion than after lamotrigine infusion. |
Effects of ketamine are mediated by enhanced glutamate release. Glutamate system challenged by ketamine through upstream effect of glutamate on neural activity and this is isolated by glutamate inhibitor lamotrigine. |
| Mathew et al. (2010) | Randomized, double-blind, placebo-controlled, continuation trial | 26 (16) | Medication-free patients with diagnosis of MDD (chronic and/or recurrent) of at least moderate severity, >32 on IDS-C30 and insufficient response to >2 adequate AD trials in current episode. |
Lamotrigine 300 mg oral, or placebo, 2 h prior to ketamine infusion | Ketamine 0.5 mg/kg IV for 40 min | Lamotrigine failed to attenuate mild, transient side-effects associated with ketamine. No difference detected in MADRS scores and no differences on BPRS positive symptoms between lamotrgine and placebo treatment groups. Also no difference in CADSS scores found. | No interaction reported between ketamine and lamotrigine. |
| Doyle et al. (2013) | Randomized, double-blind, placebo-controlled, crossover trial | 20 (20), 16 completed the study |
Healthy individualsSame sample as Joules et al. (2015) and Shcherbinin et al. (2015) | 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 | Significant BOLD response revealed to ketamine infusion including positive and negative responses. For positively responding regions (frontal and thalamic regions), pretreatment with lamotrigine resulted in relatively consistent attenuation of ketamine responses. For negatively responding regions (subgenual cingulate and ventral medial prefrontal cortex), attenuating effect of lamotrigine was weak. Pretreated (lamotrigine) scans dissimilar to placebo scans. Pretreatment with lamotrigine resulted in no significant effect of ketamine on alert-drowsy scale, whereas significant differences remained for muzzy-clear scale. | Lamotrigine produces widespread inhibition of relative blood volume response and produces global attenuation of this positive ketamine response with downstream effects resulting in inhibition of glutamate release and reduces ketamine-induced changes in BOLD signal. |
| Joules et al. (2015) | Randomized, double-blind, placebo-controlled, crossover trial | 20 (20), 16 completed the study Same sample as Doyle et al. (2013) and Shcherbinin et al. (2015) |
Healthy individuals | 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 | Not possible to discriminate lamotrigine from placebo, suggesting similar patterns of degree-centrality. No supportive evidence of significant modulation effect of ketamine-induced degree-centrality pattern by lamotrigine. | No interaction reported between ketamine and lamotrigine. Pretreatment with lamotrigine does not alter ketamine-induced functional connectivity pattern. This suggests that observed changes in connectivity more likely a result of NMDA receptor blockade and possible serotonergic modulation rather than purely modulation of glutamate release. |
| Shcherbinin et al. (2015) | Randomized, double-blind, placebo-controlled, crossover trial | 20 (20), 16 completed the study Same sample as Doyle et al. (2013) and Joules et al. (2015) |
Healthy individuals | Lamotrigine 300 mg oral, or placebo, about 2.5 h prior to ketaminea | Ketamine 0.12 (mean) mg/kg IV in 1 min followed by approximately 0.31 mg/kg/hb,c | Lamotrigine condition not distinguished from placebo for post-infusion scans. Lamotrigine had no significant effect on resting brain perfusion. | No clear interaction of lamotrigine in combination with ketamine on brain perfusion described. |
Abbreviations: AD, antidepressant; 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.
aTime interval uncertain.
bTotal duration of infusion not reported.
cDosage adjusted to a target plasma level of 75 ng/mL in accordance with the subject’s height and weight.