Question from a Member:
“Have you encountered clients stating that lamotrigine (Lamictal) is making their depression worse? I have had quite a few clients tell me this and it has been difficult to parse out if it is their condition worsening or an adverse effect. Some anticonvulsants such as levetiracetam (Keppra) have been known to worsen depression, so it might not be such a wild phenomenon. Thoughts?”
Antiepileptic drugs (AEDs) are well known to be associated sometimes with so-called “psychiatric and behavioral” side effects (Chen et al., 2017).
The Prescribing Information for lamotrigine notes that:
“AEDs [antiepileptic drugs] including [lamotrigine] increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior” (emphases added).
It also notes that:
“Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidalthoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, the emergence of suicidal thoughts or suicidal behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.”
From the above, it may seem that the answer to our Member’s question is clear cut. But it is not so simple.
1. Most of what the Prescribing Information for lamotrigine says about possible psychiatric side effects is about antiepileptic medications in general. That is, these are class warnings mandated for all antiepileptics by the FDA. But, the risk of such side effects is not the same with all antiepileptic medications. The risk of psychiatric side effects is much lower with some antiepileptics, including lamotrigine, than with others; levetiracetam and zonisamide are probably the worst in this regard (Chen et al., 2017). In fact, among antiepileptic drugs, lamotrigine was particularly noted to be associated with a significantly lower risk of depression as an adverse event (Chen et al., 2017).
2. Also, as you might imagine, the problem for mental health clinicians can be that if a person is more depressed or has suicidal ideation, it is hard to know whether it is due to the illness or is a side effect of the medication. Here are some data to illustrate this point:
In clinical trials of lamotrigine as adjunctive treatments in epilepsy, the incidence of psychiatric symptoms that emerged after lamotrigine or placebo was started were:
Depression 4% versus 3%
Anxiety 4% versus 3%
Irritability 3% versus 2%
Unfortunately, adverse events in clinical trials are typically not systematically evaluated and rely on “spontaneous reporting” by the participants (Mago, 2016). But, still, these numbers suggest that patients on placebo also report new-onset depression, anxiety, and irritability. And, the percentage differences between lamotrigine and placebo were small.
Lamotrigine may occasionally be associated with new-onset or worsening depression, anxiety, or irritability though it is much less likely to do that than some other antiepileptic medications, especially levetiracetam and zonisamide.
But, if a patient says that s/he is more depressed/ anxious/ irritable since starting lamotrigine, we can’t assume that it is definitely due to the lamotrigine.
So, while we should definitely be cautious and monitor patients in whom such symptoms emerge, we should think twice before assuming that such symptoms are being caused by lamotrigine.
Other possible psychiatric side effects
Other than depression, anxiety, and irritability, occasional case reports of many different types of psychiatric problems supposedly caused by lamotrigine have been published.
Methodological tip: Case reports have pros and cons. On the one hand, alert clinicians can often spot events and associations that have not been researched or have been missed by larger research studies because they are rare and hard to identify. On the other hand, it is usually hard to be confident from isolated clinical cases that the supposed side effect was really due to the medication to which it is attributed.
But, even with uncertainty about whether lamotrigine was the cause of the supposed side effect and even though these side effects are rare, I thought that it may still be helpful for us to know at the back of our minds that things like this can occur so that we don’t fail to spot them when they do.
Mania (Oflaz et al., 2015; Bhagyalakshmi et al., 2011; Coskun et al., 2009; Moor et al., 2007; Desarkar and Sinha, 2006; Raskin et al., 2006; Margolese et al., 2003)
Psychosis (Brandt et al., 2007; Uher and Jones, 2006))
Obsessive/ Tourette’s symptoms (Alkin et al., 2007; Kuloglu et al., 2009; Kemp et al., 2007)–these appear to be dose-related and reversible (Szmulewicz et al., 2016).
Compulsive gambling (Storrier and Beran, 2014)
Tourette’s symptoms (Seemüller et al., 2006)
Hypersexuality (Grabowska-Grzyb et al., 2006)
“Anger with murderous impulse” (Saito et al., 2014)
Chen B, Choi H, Hirsch LJ, Katz A, Legge A, Buchsbaum R, Detyniecki K. Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy. Epilepsy Behav. 2017 Nov;76:24-31. doi: 10.1016/j.yebeh.2017.08.039. Epub 2017 Sep 18. PMID: 28931473.
Eddy CM, Rickards HE, Cavanna AE. Behavioral adverse effects of antiepileptic drugs in epilepsy. J Clin Psychopharmacol. 2012 Jun;32(3):362-75. doi: 10.1097/JCP.0b013e318253a186. PMID: 22544012.
Ettinger AB. Psychotropic effects of antiepileptic drugs. Neurology. 2006 Dec 12;67(11):1916-25. doi: 10.1212/01.wnl.0000247045.85646.c0. PMID: 17159095.
Mattson RH. Cognitive, affective, and behavioral side events in adults secondary to antiepileptic drug use. Rev Neurol Dis. 2004;1 Suppl 1:S10-7. PMID: 16400290.
Meador KJ, Baker GA. Behavioral and cognitive effects of lamotrigine. J Child Neurol. 1997 Nov;12 Suppl 1:S44-7. doi: 10.1177/0883073897012001101. PMID: 9429130.
Schmitz B. Effects of antiepileptic drugs on mood and behavior. Epilepsia. 2006;47 Suppl 2:28-33. doi: 10.1111/j.1528-1167.2006.00684.x. PMID: 17105456.
Szmulewicz A, Samamé C, Caravotta P, Martino DJ, Igoa A, Hidalgo-Mazzei D, Colom F, Strejilevich SA. Behavioral and emotional adverse events of drugs frequently used in the treatment of bipolar disorders: clinical and theoretical implications. Int J Bipolar Disord. 2016 Dec;4(1):6. doi: 10.1186/s40345-016-0047-3. Epub 2016 Feb 16. PMID: 26879750; PMCID: PMC4754238.
Meador KJ, Loring DW, Vahle VJ, Ray PG, Werz MA, Fessler AJ, Ogrocki P, Schoenberg MR, Miller JM, Kustra RP. Cognitive and behavioral effects of lamotrigine and topiramate in healthy volunteers. Neurology. 2005 Jun 28;64(12):2108-14. doi: 10.1212/01.WNL.0000165994.46777.BE. PMID: 15985582.
Bhagyalakshmi Subodh N, Jayarajan D, Chand PK, Benegal V, Murthy P. Lamotrigine-induced manic switch: a report of 2 cases. Prim Care Companion CNS Disord. 2011;13(1):PCC.10l01034. doi: 10.4088/PCC.10l01034. PMID: 21731838; PMCID: PMC3121206. Not convincing, in my opinion.
Brandt C, Fueratsch N, Boehme V, Kramme C, Pieridou M, Villagran A, Woermann F, Pohlmann-Eden B. Development of psychosis in patients with epilepsy treated with lamotrigine: report of six cases and review of the literature. Epilepsy Behav. 2007 Aug;11(1):133-9. doi: 10.1016/j.yebeh.2007.03.015. Epub 2007 May 7. PMID: 17485241.
Coskun M, Bozkurt H, Zoroglu S. Possible lamotrigine-induced mania in a child with autism spectrum disorder and epilepsy. J Clin Psychopharmacol. 2009 Oct;29(5):508-9. doi: 10.1097/JCP.0b013e3181b6017f. PMID: 19745659.
Desarkar P, Sinha VK. Lamotrigine-induced severe manic switch. Aust N Z J Psychiatry. 2006 Aug;40(8):718. doi: 10.1080/j.1440-1614.2006.01874.x. PMID: 16866770.
Grabowska-Grzyb A, Nagańska E, Wolańczyk T. Hypersexuality in two patients with epilepsy treated with lamotrigine. Epilepsy Behav. 2006 May;8(3):663-5. doi: 10.1016/j.yebeh.2006.01.005. Epub 2006 Feb 13. PMID: 16473556.
Kemp DE, Gilmer WS, Fleck J, Dago PL. An association of intrusive, repetitive phrases with lamotrigine treatment in bipolar II disorder. CNS Spectr. 2007 Feb;12(2):106-11. doi: 10.1017/s1092852900020617. PMID: 17277710.
Kuloglu M, Caykoylu A, Ekinci O, Yilmaz E. Lamotrigine-induced obsessional symptoms in a patient with bipolar II disorder: a case report. J Psychopharmacol. 2009 Nov;23(8):1001-3. doi: 10.1177/0269881108095082. Epub 2008 Aug 21. PMID: 18719043.
Mago R. Adverse Effects of Psychotropic Medications: A Call to Action. Psychiatr Clin North Am. 2016 Sep;39(3):361-73. doi: 10.1016/j.psc.2016.04.005. PMID: 27514294.
Margolese HC, Beauclair L, Szkrumelak N, Chouinard G. Hypomania induced by adjunctive lamotrigine. Am J Psychiatry. 2003 Jan;160(1):183-4. doi: 10.1176/appi.ajp.160.1.183-a. PMID: 12505823.
Moor S, Luty S, Joyce P. Lamotrigine-induced mania in adolescents. Aust N Z J Psychiatry. 2007 Dec;41(12):1013. doi: 10.1080/00048670701689469. PMID: 17999274.
Oflaz S, Yıldızhan E, Tatar ZB, Akyuz F. A case of hypomania with low-dose lamotrigine. Indian J Psychiatry. 2015 Apr-Jun;57(2):217. doi: 10.4103/0019-5545.158207. PMID: 26124534; PMCID: PMC4462797. Involved rechallenge.
Raskin S, Teitelbaum A, Zislin J, Durst R. Adjunctive lamotrigine as a possible mania inducer in bipolar patients. Am J Psychiatry. 2006 Jan;163(1):159-60. doi: 10.1176/appi.ajp.163.1.159-a. PMID: 16390907.
Saito S, Shioda K, Nisijima K. Anger with murderous impulse induced by lamotrigine. Gen Hosp Psychiatry. 2014 Jul-Aug;36(4):451.e1-2. doi: 10.1016/j.genhosppsych.2014.03.008. Epub 2014 Mar 18. PMID: 24736088.
Seemüller F, Dehning S, Grunze H, Müller N. Tourette’s symptoms provoked by lamotrigine in a bipolar patient. Am J Psychiatry. 2006 Jan;163(1):159. doi: 10.1176/appi.ajp.163.1.159. PMID: 16390908.
Selek S, Savas HA. Psychosis, delirium, or manic switch due to lamotrigine? Epilepsy Behav. 2007 Nov;11(3):476; author reply 477. doi: 10.1016/j.yebeh.2007.07.003. Epub 2007 Sep 29. PMID: 17904908.
Selek S, Savas HA. Lamotrigine-induced manic switches have already been reported. Aust N Z J Psychiatry. 2007 Feb;41(2):195. PMID: 17479512.
Storrier S, Beran RG. Compulsive gambling possibly associated with antiepileptic medication. Epilepsy Behav Case Rep. 2014 Jan 8;2:15-6. doi: 10.1016/j.ebcr.2013.11.002. PMID: 25667858; PMCID: PMC4307955.
Uher R, Jones HM. Hallucinations during lamotrigine treatment of bipolar disorder. Am J Psychiatry. 2006 Apr;163(4):749-50. doi: 10.1176/appi.ajp.163.4.749-a. PMID: 16585461.
Copyright © 2020, Simple and Practical Medical Education, LLC. All rights reserved. May not be reproduced in any form without express written permission.
Disclaimer: The content on this website is provided as general education for medical professionals. It is not intended or recommended for patients or other laypersons or as a substitute for medical advice, diagnosis, or treatment. Patients must always consult a qualified health care professional regarding their diagnosis and treatment. Healthcare professionals should always check this website for the most recently updated information.