Depression affects millions worldwide, and finding effective treatment can be a significant challenge. While some individuals find relief with oral antidepressants, many do not. Increasingly, people are turning to an alternative option: intravenous (IV) ketamine. Originally used as an anesthetic, ketamine is now gaining recognition for its potential as a rapid and safe antidepressant. Over the years, researchers have extensively studied how ketamine affects brain activity, including its interaction with another antidepressant, lamotrigine. Commonly used as an adjunctive treatment in bipolar disorder and treatment-resistant depression, lamotrigine has garnered attention in the context of ketamine therapy.
Some clinics recommend stopping lamotrigine during ketamine treatment due to concerns that lamotrigine may attenuate the antidepressant effects of ketamine. Lamotrigine is known to inhibit the release of glutamate, a neurotransmitter crucial for ketamine's antidepressant action. By reducing glutamate release, lamotrigine might diminish ketamine's efficacy and the duration of its effects. However, there is not robust evidence supporting this view, and stopping lamotrigine can potentially risk mood destabilization. Moreover, other studies suggest that lamotrigine might augment the effects of ketamine, enhancing their combined efficacy in treating mood disorders.
Here’s what you need to know about the combination of ketamine and lamotrigine for treating depression.
Lamotrigine, marketed under the brand name Lamictal among others, is an anticonvulsant medication primarily used to treat epilepsy and bipolar disorder. It helps prevent and control seizures and mood episodes by stabilizing nerve cells in the brain and reducing the release of the excitatory neurotransmitter glutamate. Although the exact mechanism of action is not fully understood, lamotrigine is believed to exert its effects through several pathways. It blocks certain channels in nerve cells, making them less likely to release excessive amounts of glutamate and aspartate, thereby calming the nerve cells and reducing seizures and mood swings. By lowering the amount of glutamate released, lamotrigine diminishes overactive signals in the brain, helping to manage seizures and mood instability.
Lamotrigine is indicated for several conditions. For epilepsy, it treats partial-onset seizures, primary generalized tonic-clonic seizures, and generalized seizures associated with Lennox-Gastaut syndrome, either as monotherapy or adjunctive therapy. In bipolar disorder, it is used for maintenance treatment to delay mood episodes in adults. Additionally, lamotrigine is used off-label for bipolar depression, borderline personality disorder, neuropathic pain, and schizoaffective disorder due to its mood-stabilizing properties and potential benefits in these conditions.
This systematic review, including 17 animal and human studies, examines the potential of combining ketamine and lamotrigine for treating mood disorders, particularly bipolar depression. Key findings suggest several benefits of this combination therapy. Firstly, ketamine and lamotrigine together lowered proinflammatory cytokines and reduced oxidative damage in the hippocampus, indicating a synergistic anti-inflammatory effect. Secondly, lamotrigine mitigated cognitive and sensorimotor impairments, as well as ketamine-induced dissociative symptoms, thereby improving overall tolerability. Additionally, lamotrigine decreased ketamine craving in rats, suggesting potential anti-craving properties. Lastly, while evidence is limited, some studies suggest that lamotrigine may enhance ketamine's antidepressant effects, with case reports indicating mood improvements and resolution of suicidal ideation in patients with bipolar depression.
Another preliminary study aimed to investigate the efficacy of serial ketamine/esketamine treatments with or without continued lamotrigine therapy among patients with treatment-resistant depression (TRD). Similarly, the study found insufficient evidence that lamotrigine attenuates the antidepressant response to ketamine. Response and remission rates with ketamine/esketamine were similar regardless of lamotrigine use, and no significant difference in dissociative symptoms (CADSS scores) was observed, though there was a trend towards lower scores among lamotrigine users.
Lastly in one recent study, researchers focused on how ketamine and lamotrigine influence the anterior cingulate cortex (ACC), a critical brain region involved in emotional and cognitive processing. The study involved 75 healthy participants who underwent brain scans before, during, and after ketamine administration. Participants were divided into three groups: one receiving a placebo, one receiving ketamine, and the third receiving lamotrigine followed by ketamine. When participants were pretreated with lamotrigine, the reduction in activity in the subgenual and pregenual ACC was less pronounced. Twenty-four hours post-administration, ACC activity returned to baseline levels; however, differences persisted between the groups, suggesting that lamotrigine influences the lasting effects of ketamine.
We have administered thousands of ketamine infusions and treated hundreds of patients, many of whom are taking at least one psychotropic medication, including lamotrigine. Our clinic's recommendation is to hold the morning dose of lamotrigine if approved by the patient’s prescribing physician. However, many patients have opted to continue taking lamotrigine alongside their infusions. Clinically, we have not observed any significant interactions between lamotrigine and ketamine. In fact, the vast majority of patients have experienced positive results from ketamine infusions, despite the potential for interaction. This leads us to believe that if this phenomenon exists, it is clinically insignificant or, at the very least, quite rare.
Upon close review of high-quality studies, evidence suggests that lamotrigine interferes with glutamatergic neurotransmission, potentially reducing the acute effects of ketamine. However, it is not clear how this may impact ketamine’s antidepressant action. Some animal studies suggest that combining ketamine and lamotrigine might have a synergistic antidepressant effect, possibly due to neuroplasticity and anti-inflammatory mechanisms. However, human studies have not conclusively demonstrated enhanced antidepressant effects from this combination, although some evidence indicates it can reduce side effects.
To fully evaluate the efficacy and safety of this treatment for depression, more extensive randomized controlled trials with larger sample sizes, multiple ketamine infusions, and longer follow-up periods are necessary. While the rapid antidepressant effects of ketamine are well-established, further research is needed to identify interventions that can interfere with, enhance, or prolong these effects. Continued investigation into the interactions between ketamine and lamotrigine is essential, as current evidence presents mixed results on their combined use.
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By exploring and understanding these new frontiers in depression treatment, we can bring hope and healing to many more individuals affected by this challenging condition.
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