Lamotrigine Is Not Slow: Comments About Its Efficacy in Bipolar Depression

James Phelps, MD

Mood Disorders Program
Samaritan Mental Health, Corvallis, OR.

Dr. Phelps has no conflicts of interest to disclose.

Last updated: May 4, 2018

Lamotrigine has a reputation for being slow because of its long titration period. Lamotrigine was just as fast as the olanzapine/fluoxetine combination (OFC) in a trial sponsored by the manufacturer of OFC, Eli Lilly. Lamotrigine was less effective than OFC in the same study.

In severe bipolar depression, if a patient’s life is at stake, a treatment with robust evidence of efficacy but lower tolerability is preferred. Options include ECT, quetiapine, and olanzapine/fluoxetine combination.

How slow is lamotrigine? You see that patient who has severe depression and you want this to work fast. It has the reputation for being slow because of its long titration, six to eight weeks depending on how you do it. I’ve heard people say: “Well, we don’t use lamotrigine on our inpatient psychiatric unit because it’s too slow” which strikes me as rather ironic. Don’t you start antidepressants on your inpatient psychiatric unit? Well, we all expect that a full trial of an antidepressant to rule whether it’s effective or not can take six or some people would even say eight weeks. So if it makes sense to start an antidepressant on an inpatient unit, it really makes sense to start lamotrigine on an inpatient unit. Nevertheless, it does have this reputation for being slow. In fact, people go on to use something that they think is faster like quetiapine say or even lithium. The irony is that lamotrigine is not so slow to produce a benefit. There was a randomized trial in which it went head to head with olanzapine/fluoxetine combination. The study was sponsored by Eli Lilly who makes the olanzapine/fluoxetine combination. You would expect that maybe they would kind of stack the deck against lamotrigine and they did in a number of interesting ways. Olanzapine/fluoxetine got to start faster. Lamotrigine had to do with its usual titration. Interestingly, even though lamotrigine was always less effective than the olanzapine/fluoxetine combination -it was never as good- it was just as fast as the combination. In other words, the curve of improvement is not quite superimposed on that of olanzapine/fluoxetine combination. It’s parallel to it from the very beginning. So instead of waiting and waiting and waiting and then finally it kicks in, no. The benefits were paralleling the improvement on olanzapine/fluoxetine combination, just not quite as good. So it’s not that slow at least based on that study. I think it makes sense to start lamotrigine where you would think of starting an antidepressant. It’s not that slow.

In severe bipolar depression, if a patient’s life is at stake using a treatment with robust evidence for efficacy instead of lamotrigine would make sense. Electroconvulsive therapy (ECT) may be an option, or maybe quetiapine which can be quite fast, maybe even olanzapine/fluoxetine combination because the evidence for efficacy for those agents is better. Patients in the middle of the mood spectrum can have depressions that are this severe. They likely had these depressions many times before and they face the prospect of having them again unless a treatment is found that will prevent recurrences, in other words, a maintenance agent. Unless the depression is immediately dangerous, to me, it does not make sense to hurry toward a treatment with significant side effects like memory impairment with ECT or metabolic risks with quetiapine or olanzapine and skip over in the process a treatment with few side effects and no established long-term risks. Most patients in my practice prefer to work their way through options starting with those that if they work will be the most tolerable in the long run even if the likelihood of response is lower. If lamotrigine doesn’t work in six weeks when you’ve reached at least 100 mg, okay, then move on.

To summarize, key points here. Lamotrigine is not much slower than antidepressants. But if the patient has dangerous severe symptoms, use something that’s likely to be faster like ECT or olanzapine/fluoxetine combination even though I think lamotrigine is not far behind on that one. And otherwise, patients, again, they tend to choose based on tolerability not speed.



  1. Brown, E. B., McElroy, S. L., Keck Jr, P. E., Deldar, A., Adams, D. H., Tohen, M., & Williamson, D. J. (2006). A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. The Journal of clinical psychiatry, 67(7), 1025-1033.
  2. Phelps, J. R. (2016). A spectrum approach to mood disorders: not fully bipolar but not unipolar: practical management. New York: W. W. Norton & Company.


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