Can Lamotrigine Be Used for Depression?

Lamotrigine is used for depression, but with important caveats about which type of depression, how it is prescribed, and what the evidence actually supports. The U.S. Food and Drug Administration approved lamotrigine for the maintenance treatment of bipolar disorder, where its primary role is preventing the return of depressive episodes rather than lifting someone out of an acute depressive state.¹ For ordinary (unipolar) depression, it has no FDA approval at all. Yet clinicians prescribe it off-label for both situations regularly, and the research picture is more nuanced than the regulatory labels suggest.

What Lamotrigine Is Approved For and What It Is Not

Lamotrigine entered psychiatry through neurology. It was originally developed as an anti-seizure medication and later found to stabilize mood in people with bipolar disorder. The FDA approval it holds in psychiatry is specifically for maintenance therapy in bipolar disorder, meaning its job is to keep someone well once a mood episode has already resolved. Two large 18-month trials demonstrated that lamotrigine delayed the time to relapse, particularly relapse into depression, and this was the basis for the approval.²

It does not have FDA approval for treating an acute episode of bipolar depression. Five placebo-controlled trials were conducted to pursue that approval, and only one showed a clear positive result. The combined evidence was not strong enough to convince regulators.³ Lamotrigine also has no approval whatsoever for unipolar depression, the kind most people mean when they say “depression.” That said, off-label prescribing is common and not inherently reckless. The regulatory picture and the clinical picture are two different things.

The Evidence for Bipolar Depression

The story with acute bipolar depression is frustrating. In those five placebo-controlled trials, lamotrigine did not separate from placebo on primary outcome measures. But when researchers pooled data and looked at secondary measures and more severely depressed subgroups, hints of benefit appeared. In one of those five studies, lamotrigine did outperform placebo on multiple secondary scales including clinician-rated severity and improvement.³ Some researchers suspect the trials had design issues, including high placebo-response rates that made it hard for any drug to show a clear edge. This is a common problem in depression research.

A large network meta-analysis comparing treatments for bipolar depression found that lamotrigine was indeed more effective than placebo at reducing depressive symptoms, alongside better-established options like quetiapine, lurasidone, and the olanzapine-fluoxetine combination.⁴ The catch is that the effect is modest compared to some of those other agents. Quetiapine, for instance, has much more robust acute-phase data. Lamotrigine’s strength tends to show up more in long-term use and in preventing future depressive episodes rather than quickly pulling someone out of one.

A trial that combined lamotrigine with quetiapine in bipolar depression offers an interesting data point. At 12 weeks, the combination showed a trend toward better scores but did not quite reach statistical significance. By 52 weeks, though, the benefit became clear and statistically meaningful.⁵ This pattern fits lamotrigine’s general personality as a medication: its benefits tend to build over time rather than arriving quickly.

Off-Label Use in Unipolar Depression

For people with treatment-resistant unipolar depression, meaning ordinary depression that has not responded to standard antidepressants, lamotrigine sometimes enters the picture as an add-on medication. The evidence here is thinner and comes from smaller studies rather than large definitive trials, but the signals are encouraging.

An open-label study of patients whose depression had not responded to antidepressants alone found that adding lamotrigine produced rapid and substantial improvement across symptom measures, including the core symptoms of depression. Social and occupational functioning improved over six months, and several patients returned to work or school.⁶ A randomized trial directly compared adding lamotrigine versus adding lithium, the traditional gold-standard augmentation strategy. Both groups showed meaningful improvement, with about half of each group achieving at least a partial response. Lamotrigine was better tolerated.⁷

These results are promising, but a crucial caveat applies. These were small, open-label or single-blind studies, not large double-blind trials. Psychiatrists who prescribe lamotrigine for unipolar depression are making a clinical judgment based on limited data combined with the drug’s favorable side-effect profile. It is one of several augmentation strategies, not an established first-line treatment for this purpose.

How Lamotrigine Works in Depression

Lamotrigine does not work the way most antidepressants do. Standard antidepressants target serotonin, norepinephrine, or dopamine systems. Lamotrigine’s main action is on voltage-gated ion channels in the brain, and its key downstream effect appears to be reducing the release of glutamate, the brain’s primary excitatory chemical messenger.⁸ There is growing interest in glutamate’s role in depression, and lamotrigine’s action on this system may explain why it helps some people who do not respond to conventional antidepressants.

The drug also appears to influence brain health in a more gradual way. Animal research has shown that chronic lamotrigine treatment increases levels of BDNF, a protein that supports nerve cell growth and survival, in the frontal cortex and hippocampus. Importantly, lamotrigine restored BDNF levels that had been depleted by chronic stress, a pattern that mirrors what is seen with effective antidepressant treatments.⁹ Increased BDNF and related growth factors have also been observed in the prefrontal cortex after both short-term and long-term lamotrigine treatment in rats.¹⁰ These findings help explain why the drug seems to work better with sustained use.

An intriguing study in healthy volunteers found that a single dose of lamotrigine reduced activity in brain regions involved in emotional processing, including the amygdala, insula, and anterior cingulate cortex, when participants viewed emotional faces.¹¹ This dampening of emotional reactivity aligns with the clinical observation that lamotrigine smooths out mood instability rather than simply elevating mood the way a stimulant might.

The Rash Risk and Why Titration Matters

The most talked-about risk of lamotrigine is skin rash. Most lamotrigine rashes are benign and self-limiting. But in rare cases, the drug can trigger Stevens-Johnson syndrome or toxic epidermal necrolysis, severe immune reactions that cause the skin to blister and peel and can be life-threatening. A systematic review of published cases identified 70 patients with these severe reactions, including three fatalities where patients deteriorated and died within hours of hospital admission.¹² The rarity of these reactions should be underscored, but their severity demands respect.

This is why lamotrigine has one of the slowest dose-escalation schedules in psychiatry. You typically start at a low dose and increase gradually over weeks. A study comparing different titration speeds found that fast dose increases raised the odds of developing any rash by roughly eightfold, while slow titration cut the risk to about a third of the baseline rate.¹³ The same study found that being female and taking valproate at the same time each independently raised rash risk. A separate naturalistic study of over 250 patients with bipolar depression confirmed that slower-than-standard titration significantly reduced rash development, though at the cost of a slower initial response.¹⁴

The practical takeaway: if you are prescribed lamotrigine, the slow ramp-up is not optional caution. It is essential safety practice. And if you stop taking it for more than a few days, you generally need to restart the titration from the beginning rather than resuming your previous dose.

How Lamotrigine Compares to Other Mood Stabilizers

Lamotrigine occupies a distinctive niche. It leans heavily toward preventing depression rather than preventing mania, which makes it somewhat complementary to lithium, the classic mood stabilizer that has stronger evidence for preventing manic episodes. A single-blind study comparing the two head-to-head in bipolar II depression found equivalent improvement in depressive symptoms, but the lithium group reported significantly more side effects.¹⁵

The tolerability advantage is a recurring theme. Safety data from clinical trials indicate that lamotrigine does not appear to destabilize mood or provoke switching into mania, a concern with many antidepressant treatments in bipolar disorder. It also was not associated with weight gain, sexual side effects, or withdrawal symptoms.¹⁶ That combination of features is unusual. Many mood stabilizers and atypical antipsychotics used for bipolar depression cause weight gain, sedation, or metabolic problems that make long-term use difficult.

Cognitive effects deserve special mention. Among mood stabilizers and anticonvulsants used in psychiatry, lamotrigine has a notably better cognitive profile than alternatives like valproate, carbamazepine, and topiramate.¹⁷ Some studies have found it actually improves verbal fluency, working memory, and attention.¹⁸ For people managing bipolar depression who need to function cognitively at work or school, this matters.

Drug Interactions Worth Knowing About

Lamotrigine is metabolized primarily through a process called glucuronidation in the liver, and several commonly used medications interfere with that process. Valproate, another mood stabilizer, slows lamotrigine’s breakdown and roughly doubles its blood levels, which is why the starting dose and titration schedule must be adjusted when the two are taken together. The increased blood levels also raise the rash risk, as the titration data mentioned earlier confirmed.¹³

The interaction with hormonal contraceptives is less widely known but clinically important. Estrogen-containing oral contraceptives speed up lamotrigine’s metabolism and can reduce its blood levels by more than half.¹⁹ This means that starting or stopping birth control pills can significantly alter how much active lamotrigine is circulating. During the pill-free week of a cycle, lamotrigine levels can rise, potentially causing side effects, and during active pill weeks they drop, potentially reducing effectiveness.²⁰ This interaction is relevant to a large portion of lamotrigine users, given that the drug is frequently prescribed to women of reproductive age.

Lamotrigine in Pregnancy

For people who take lamotrigine and become pregnant, or who need mood stabilization during pregnancy, the safety data is relatively reassuring compared to other options in its class. A systematic review and meta-analysis found that in utero exposure to lamotrigine monotherapy was not associated with increased rates of birth defects compared with either healthy controls or disease-matched controls taking no medication.²¹ Rates of miscarriage, stillbirth, preterm delivery, and small-for-gestational-age babies were also not increased. The same analysis found lamotrigine to be significantly less teratogenic than valproic acid, which carries well-documented risks to fetal development.

A large population-based study corroborated this, finding no association between first-trimester lamotrigine use and major birth defects after statistical adjustment, and no dose-response relationship.²² This profile has made lamotrigine one of the preferred mood stabilizers when treatment during pregnancy is necessary. One wrinkle to keep in mind: pregnancy itself alters lamotrigine metabolism, and blood levels tend to drop as pregnancy progresses, so dose adjustments and monitoring are typically needed.

Adolescents and Younger Patients

Lamotrigine does not have FDA approval for bipolar disorder or depression in children or adolescents, and the evidence base in younger populations is limited. What exists is modestly encouraging. A retrospective chart review of 42 adolescents with mood disorders treated with lamotrigine found improvement in about half, with a mean reduction in illness severity scores. About 10% developed a benign rash.²³ An open-label trial in 20 adolescents with bipolar depression reported stronger results: most participants responded, and over half achieved remission by eight weeks, with no serious adverse effects.²⁴

These are small studies without placebo controls, so the findings need to be interpreted cautiously. But in a population where treatment options are limited and many medications carry concerning side effects, lamotrigine is sometimes tried when other approaches have failed. The slow titration protocol applies equally to younger patients, and careful monitoring is essential.

Long-Term Relapse Prevention

Where lamotrigine’s evidence is strongest is in the long game. Its ability to delay the return of depressive episodes in bipolar disorder is the foundation of its FDA-approved use and its most consistent finding across studies. Research has confirmed that lamotrigine has particular efficacy in delaying relapse into depression without increasing cycling between mood states or provoking manic switches.²⁵ This profile makes it especially valuable for the subset of bipolar patients whose illness is dominated by depressive episodes rather than mania.

The absence of manic switching sets lamotrigine apart from conventional antidepressants used in bipolar depression, which can destabilize mood and trigger manic or mixed episodes in some patients. For someone who has experienced antidepressant-induced mania, lamotrigine offers a way to address depression without that risk.

Use in Borderline Personality Disorder

Lamotrigine has attracted interest for managing emotional instability in borderline personality disorder, where mood swings, impulsivity, and intense emotional reactions are core features. A comprehensive review of clinical outcomes found that lamotrigine showed promise in stabilizing mood and reducing emotional dysregulation and impulsivity in these patients.²⁶ An early case series reported dramatic improvements: patients with severe impulsive behaviors, including suicidal behavior and substance abuse, showed robust functional recovery over several months, with some no longer meeting diagnostic criteria for the disorder at one-year follow-up.²⁷

This is an off-label application, and the evidence base consists mostly of small studies and case series. Still, the overlap between the emotional instability of borderline personality disorder and the mood instability of bipolar disorder makes the drug a plausible option. Clinicians sometimes turn to lamotrigine when the depressive and emotionally reactive features of borderline personality disorder are prominent and have not responded to psychotherapy alone.

Epilepsy With Comorbid Depression

People with epilepsy experience depression at substantially higher rates than the general population, and their treatment is complicated by the fact that some antidepressants can lower the seizure threshold. Lamotrigine is already an established anti-seizure medication, so when a patient with epilepsy also has depression, it can serve double duty. A study of patients with epilepsy and comorbid low-to-moderate depressive symptoms found that lamotrigine treatment improved depression scores, and the improvement was maintained when patients were converted from combination therapy to lamotrigine alone.²⁸ For this population, the fact that one medication can address both conditions simultaneously while preserving cognitive function and avoiding weight gain makes it a particularly appealing choice.