Lamotrigine (Lamictal) is a newer seizure medication now being used with increasing frequency for bipolar disorder.  While it has a higher price, two studies have shown it to be of some benefit, which is better than the gabapentin (Neurontin) and topiramate (Topamax) fiasco where thousands of bipolar patients were given medications that were later tested and found to be of no value for bipolar disorder.  However, lamotrigine is crassly being promoted as a wonder drug for Bipolar depression despite a very small amount of research and despite the largest study showing it to be of no value whatsoever for preventing depression relapse in Bipolar depressed patients.

There is now a very big push by the manufacturer of lamotrigine and their paid academic psychiatrists to promote it as the new preferred drug for bipolar disorder.  Psychiatrists from Case Western (Eur Neuropsychopharmacol. 2004 May;14 Suppl 2:S100-7), Baylor, University of Texas, and the University of British Columbia, all paid with manufacturer funding for doing research for the manufacturer, have been pushing lamotrigine as "ideal" and as a "valuable addition."  Lamotrigine is being pushed by the Texas Department of Human Services in their guidelines as the sole first-line treatment for bipolar, depressed, despite very little supportive research.  The Canadian CANMAT guidelines appear heavily influenced by the University of British Columbia and recommend lamotrigine as one of the first-line treatments for bipolar, depression, even though it was the University of British Columbia own industry-sponsored study that showed that lamotrigine did no better than placebo for such patients.

Lamotrigine is essentially an anti-depressant that has never been adequately compared to any standard anti-depressant for the treatment of bipolar depression.  One study suggests that it is inferior to fluoxetine (Prozac).  Much of the crusade against giving anti-depressants to bipolar patients has been led by psychiatrists who receive heavy funding from the manufacturers of lamotrigine (Lamictal), divalproex (Depakote-SR), and atypical anti-psychotics, manufacturers who stand to gain from cutting back on anti-depressants.  Half of the lamotrigine studies are unpublished (Drug Saf. 2004;27(3):173-84).  I suspect that the reason is that they weren't favorable for the manufacturer.  The cost of lamotrigine is $152/month for 200 mg/day at Walgreens on 11/11/06.  This is much more than many available anti-depressants.  There is no evidence that lamotrigine causes mania any less frequntly than other anti-depressants.  There is no evidence that lamotrigine is a mood stabilizer, i.e., helps prevent both mania and depression.

With divalproex falling out of favor due to a suicide rate 150% higher than lithium and gabapentin and topiramate found worthless, the advertising is now promoting lamotrigine and atypical anti-psychotics as the new preferred treatments.  Of course there is little advertising promoting lithium since it is generic and quite inexpensive.  Unfortunately, there is still very little long-term suicide data on either of these new strategies.  No studies have compared lamotrigine to an anti-depressant for bipolar depression.  I strongly doubt that it is any better, although the lamotrigine manufacturer is the only one who has paid to get specifically approved by the FDA for bipolar depression. 

The manufacturers and their academic psychiatrists have pooled their trial data in order to hide its weaknesses.  They have also "massaged" the data, i.e., scoured it for some little positive findings, e.g. that lamotrigine was effective for those over age 54 or that it improved the self-reported Quality of Life.

Lithium remains the gold standard.  However, for patients needing help for recurrent depressive episodes, using an anti-depressant or lamotrigine is a worthwhile adjunct.  There is no evidence that lamotrigine is superior to anti-depressants for preventing depressive episodes.  Indeed, a large recent study suggests that lamotrigine might be inferior for patients with recurrent depressive episodes, which is the large majority of bipolar patients, since lamotrigine did minimally better than placebos in that study.  Clearly, lamotrigine is no miracle treatment.  Instead, it appears a sometimes useful alternative.

Atypical anti-psychotics like ziprasidone (Geodon), or Abilify are good for those gaining weight on lithium, having other serious side-effects, or having breakthrough mania.  The other atypicals may also be helpful, but they do have a higher rate of side-effects including weight gain and should probably not be the first choices, but rather back-up choices.  Thyroid is an old and forgotten but useful treatment for rapid cycling.  Fish oil, folic acid, exercise, and a healthy diet are also important and should be used in all bipolar patients.  5-HTP might be useful for the depression.

Lamotrigine does have fewer side-effects than some other epileptic medications, such of gabapentin (Neurontin), topiramate (Topamax), and divalproex (Depakote).  It should be taken on an empty stomach since food decreases bioavailablity (Indian J Med Res. 2005 May;121(5):659-64.).

Lamotrigine (Lamictal), Lithium No Better than Placebo for Preventing Recurrent Bipolar Depression in Study:  In a large 18-month DB PC study of 463 recently depressed bipolars paid for by the manufacturer of lamotrigine, neither lamotrigine nor lithium prevented a recurrence of depression significantly better than placebo.  In a smaller group of 175 recently manic patients, lamotrigine since slightly better than lithium and significantly better than placebo (14% vs. 22% vs. 30%) in preventing a recurrence of depression.  No mention was made about which did better at preventing a recurrence of mania. Yatham, Univ. Brit Columbia, International Congress of Biological Psychiatry 2/2004. Ed: Yatham was paid by GlaxoSmithKline for doing the study and, along with several coauthors, has a presumably paid position on the GSK advisory board.  He is quoted on Medscape News as encouraging psychiatrists to use the expensive lamotrigine "for achieving optimal control of both depression and mania." Unfortunately, the report said nothing of mania and, at most, five more patients out of 210 on lithium in the entire study became depressed than the 210 on lamotrigine. The mania study found lithium better. While Yatham speaks of optimal control, the surprising results of the study is how small the impact of medication was over sugar pills.  This study demonstrates that the authors were a long way away from "optimal control." Since Medscape receives money from the drug companies, don't expect them to point out these shortcomings. 

Lamotrigine Did Help Depression a Very Little Bit: In a different report on the above 463 patients, during an 8- to 16-week open-label phase, lamotrigine (titrated to 200 mg/day) was added to current therapy for currently or recently depressed DSM-IV-defined bipolar I outpatients (N = 966) and concomitant drugs were gradually withdrawn. Patients stabilized on open-label treatment (N = 463) were then randomly assigned to lamotrigine (50, 200, or 400 mg/day; N = 221), lithium (0.8-1.1 mEq/L; N = 121), or placebo (N = 121) monotherapy for up to 18 months. Time to intervention for any mood episode was statistically superior (p = .029) for both lamotrigine and lithium compared with placebo-median survival times were 200, 170, and 93 days, respectively (p = .047). Intervention for depression was more frequent than for mania by a factor of nearly 3:1 . The proportions of patients who were intervention-free for depression at 1 year were lamotrigine 57%, lithium 46%, and placebo 45%. Lithium was statistically superior to placebo at prolonging the time to intervention for a manic or hypomanic episode (p = .026). The proportions of patients who were intervention-free for mania at 1 year were lamotrigine 77%, lithium 86%, and placebo 72%. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. Calabrese JR, Bowden CL, Sachs G, Yatham LN, Behnke K, Mehtonen OP, Montgomery P, Ascher J, Paska W, Earl N, DeVeaugh-Geiss J; Lamictal 605 Study Group. Case Western Reserve. J Clin Psychiatry. 2003 Sep;64(9):1013-24. Ed: Less than half of the patients started on lamotrigine were even included in the study.  This seems to screen out a lot of lamotrigine failures.  Its an awful lot of work to achieve a very little bit of benefit. The study seems stacked against lithium. 

Lamotrigine Inferior to Olanzepine/Fluoxetine for Bipolar I Depression: In a 7-week DB PC study of 410 patients with acute bipolar I depression, the manufacturer's drug combination of olanzepine (Zyprexa) and fluoxetine (Prozac)(6/25, 6/50, 12/25, or 12/50 mg/day) did better than lamotrigine (titrated to 200 mg/day). Completion rates were similar (OFC, 66.8% vs. LMG, 65.4%). OFC-treated patients had significantly greater improvement than lamotrigine-treated patients on the Clinical Global Impressions-Severity of Illness scale (primary outcome) (p = .002, effect size = 0.26), Montgomery-Asberg Depression Rating Scale (MADRS) (p = .002, effect size = 0.24), and Young Mania Rating Scale total scores (p = .001, effect size = 0.24). Response rates did not significantly differ between groups when defined as > or = 50% reduction in MADRS score (OFC, 68.8% vs. LMG, 59.7%; p = .073). Time to response was significantly shorter for OFC-treated patients (median days = OFC, 17 vs. LMG, 23; p = .010). There was a significant difference in incidence of "suicidal and self-injurious behavior" adverse events (OFC, 0.5% vs. LMG, 3.4%; p = .037). Somnolence, increased appetite, dry mouth, sedation, weight gain, and tremor occurred more frequently (p < .05) in OFC-treated patients than lamotrigine-treated patients. Weight, total cholesterol, and triglyceride levels were significantly elevated in OFC-treated patients compared with lamotrigine-treated patients (all p < or = .001). Treatment differences were of modest size. A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. Brown EB, et al. Lilly Research Laboratories, Indianapolis. . J Clin Psychiatry 2006 Jul;67(7):1025-33.

Lamotrigine As Good As Citalopram in Tiny Study: In a 12-week DB PC study of just 20 bipolar depressed patients, each treatment group experienced a significant mean reduction in total MADRS scores (citalopram p=0.002; lamotrigine p= 0.001), and there was no significant difference between treatment groups (p=0.78). One out of ten patients in each group experienced a switch to hypomania. Randomized, double-blind pilot trial comparing lamotrigine versus citalopram for the treatment of bipolar depression. Scheffer A, et al. University of Toronto. J Affect Dis 2006 Nov;96(1-2):95-9. Ed: No placebo control and the small size of this study makes it virtually worthless for drawing any conclusions.

Weight Decreased in Obese Bipolars on Lamotrigine and Increased with Lithium: In 18-month randomized studies of lithium vs. lamotrigine, mean changes in weight among obese patients (N=155) at week 52 were -4.2, +6.1, and -0.6 kg with lamotrigine, lithium, and placebo, respectively. Among nonobese patients (N=399), mean changes in weight (kg) at week 52 were -0.5, +1.1, and +0.7 with lamotrigine, lithium, and placebo with no significant differences among groups. Impact of lamotrigine and lithium on weight in obese and nonobese patients with bipolar I disorder. Bowden CL, et al. University of Texas at San Antonio. . Am J Psychiatry 2006 Jul;163(7):1199-201.

Background Information: Lamotrigine's primary action is to modulate voltage-gated sodium channels. Evidence suggests that it decreases glutamate transmission, directly reduces calcium influx, mildly blocks transmitter reuptake, and alters intracellular mechanisms of resting transmitter release. The average half-life of lamotrigine is approximately 24 hours, but decreases to approximately 7.4 hours when used concurrently with phenytoin, and increases to approximately 59 hours with valproic acid. Seven of the 20 clinical trials were randomized, double-blind, and controlled. Existing data are inadequate to evaluate lamotrigine use in major depression. The pooled response rates for patients with depressed, manic, mixed, and rapid cycling bipolar disorder were similar, ranging from 52% to 63%. Adverse effects are infrequent when the drug is used alone, but become more frequent when lamotrigine is combined with other anticonvulsants. While most rashes are mild, approximately 1 in 500 patients develops exfoliative dermatitis. A slow upward dose titration is recommended to reduce the incidence of serious rash, but this may delay the attainment of adequate dosage for 6 weeks. Lamotrigine has positive effects on cognitive function, but occasionally produces insomnia. Lamotrigine costs 2-4 times more than lithium, carbamazepine, and generic valproic acid. Ann Pharmacother 2002 May;36(5):860-73

Maintenance Claimed Successful: 1,315 bipolars in two DB PC studies of lamotrigine vs. lithium vs. placebo maintenance studies for 2 years (this is the same study as above, just a different report). Lamotrigine was primarily effective against depression and lithium was primarily effective against mania. There was no evidence that lamotrigine induced mania/hypomania/mixed states, caused episode acceleration, or destabilised the overall course of illness. Latest maintenance data on lamotrigine in bipolar disorder. Calabrese JR, Vieta E, Shelton MD. Eur Neuropsychopharmacol. 2003 Aug;13 Suppl 2:57-66. Side-effects: Nausea 14%, Insomnia 10%, somnolence 9%, back pain 8%, fatigue 8%, rhinitis 7%, rash 7%, abdominal pain 6%, dry mouth 6%, constipation 5%, vomiting 5%, cough 5%, pharyngitis 5%. During dose escalation, headaches 25%, rash 11%, dizziness 10%, diarrhea 8%.

Lithium Slightly Better at Maintenance, Especially with Mania: In a DB PC study of 175 recovered patients, lithium did slightly better at preventing relapse, especially a 2nd manic episode. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, Montgomery P, Earl N, Smoot TM, DeVeaugh-Geiss J; Lamictal 606 Study Group. U Texas, San Antonio. Arch Gen Psychiatry. 2003 Apr;60(4):392-400. This is a part of the same study as above, too.

Lamotrigine 200 mg/d Better than 50 mg/d: In a DB PC 7 week study of 192 bipolar I depressed patients, lamotrigine was found to be better than placebo by 3 weeks and the 200 mg/day dose more effective. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry. 1999;60:79-88.. 

Lamotrigine Added to Fluoxetine Helped Depression: In a very small DB PC study of 23 Bipolar II or Major Depression who had failed at least one course of antidepressants, all received fluoxetine 20 mg/day and half received lamotrigine 25 mg/day titrated up to 100 mg/day for 6 weeks. HAM-D scores decreased to 9.7 for lamotrigine vs. 14.5 for placebo. CGI-I much improved ratings were 85% for lamotrigine vs. 30% for placebo (p=.013). Univ Melbourne. Barbosa L, Berk M, Vorster M: A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. J Clin Psychiatry 2003;64:403-7. Ed: Because of its higher cost and some side-effects, I think these patients should all have first been treated with fish oil, folic acid, multivitamins with minerals, exercise, bright light, and rTMS. Also, I would not start a two drug treatment after a single failure on another drug. At very least, I would try fluoxetine by itself, and consider thyroid supplementation before trying lamotrigine supplementation. Still, this study is researching a very important area and it is too bad that it was so small.

Lamotrigine Helped, Gabapentin Didn’t in DB: In a small 45-patient DB PC study of 6 weeks each of 35 refractory bipolar patients and 10 refractory unipolar depressed patients, 51% on lamotrigine, 28% on gabapentin, and 21% on placebo had a positive response. NIMH, Clinical predictors of response to lamotrigine and gabapentin monotherapy in refractory affective disorders. Obrocea GV, Dunn RM, Frye MA, Ketter TA, Luckenbaugh DA, Leverich GS, Speer AM, Osuch EA, Jajodia K, Post RM. Biol Psychiatry 2002 Feb 1;51(3):253-60

Lamotrigine Equaled Lithium in Short, Small DB: In a DB study of 30 patients diagnosed Bipolar I manic phase, 4 weeks of treatment with Lithium 400 BID or lamotrigine 25 mg/day for 1 week, 50 mg/day for the 2nd week, then 100 my/day found that improvement was similar. Ichim Annals Clin Psych 00;12:5, S. Africa. 

Lamotrigine Maintenance Somewhat Better in DB: 180 rapid cycling patients, who had been stable for two weeks or more were placed on lamotrigine monotherapy or placebo. 41% of the lamotrigine vs. 26% of the placebo patients were relapse free at 6 months. 80% had depressive and 20% had manic relapses. J Clin Psychiatry 00;61:841 Case Western and Glaxo Wellcome.

Lamotrigine Might Help Prevent Depression in Senior Bipolars: In a retrospective analysis of response to lamotrigine, lithium, and placebo of just the 98 older adults over age 54 from a 588-patient DB PC study for an emerging mood episode (manic/hypomanic/mixed or depressed)(LTG: 33, Li: 34, PBO: 31), mean daily doses were LTG 240 mg and Li 750 mg. LTG significantly delayed time to intervention for any mood episode and for a depressive episode, compared with placebo. Li significantly delayed time to intervention for mania/hypomania/mixed compared with placebo. Back pain and headache were the most common adverse events during LTG treatment; rash: LTG, 3%; Li, 6%; and PBO, 0; no serious rash was reported. The most common adverse events (>10%) during lithium treatment were dyspraxia, tremor, xerostomia, headache, infection, amnesia, dizziness, diarrhea, nausea, and fatigue. Maintenance treatment outcomes in older patients with bipolar I disorder. Sajatovic M, et al. Case University, Cleveland, OH. . Am J Geriatr Psychiatry. 2005 Apr;13(4):305-11. This is still another spin-off of the one lamotrigine study from above.

Seizures: Carbamazepine Slightly Better Though More Side-Effects: In a meta-analysis of 5 randomized trials with 1,384 participants, time to treatment withdrawal significantly improved with lamotrigine compared to carbamazepine (hazard ratio 0.55), while time to first seizure (hazard ratio 1.14) and seizure freedom at 6 months (relative risk 0.92) favor carbamazepine although the results are not significant. Current industry-sponsored trials fail to adequately inform clinical practice and further more clinically relevant trials are needed in which longer-term outcomes are assessed before the place of lamotrigine in the treatment of epilepsy is defined. A meta-analysis of individual patient responses to lamotrigine or carbamazepine monotherapy. Gamble C, et al. University of Liverpool, UK. Neurology 2006 May 9;66(9):1310-7.

Junk Science from the Journal of Affective Disorder: Psychiatrists from the University of Alcala in Spain make the wild claim that there retrospective chart review of just 34 charts of bipolar outpatients treated with lamotrigine as a sole or add-on treatment is able to "evaluate the effectiveness and safety of lamotrigine in bipolar spectrum patients." Clinic notes were used to score the Clinical Global Impression for Bipolar Disorders (CGI-BP-M) scale and to identify manic, hypomanic mixed or depressive relapses. Treatment duration ranged very widely from 6-96 weeks. While only 47% had their depression lift and only 32% remained not depressed in follow-up, they not only just to the conclusion that "lamotrigine was safe and effective" but also that the "effectiveness of lamotrigine was greater for those patients diagnosed with bipolar spectrum disorders other than bipolar I." Lamotrigine for the treatment of bipolar spectrum disorder: a chart review. Montes JM, et al. Universidad de Alcala, Madrid, Spain. . J Affect Disord. 2005 May;86(1):69-73. Ed: Shame on the Journal of Affective Disorder for publishing such dishonest and wild claims of effectiveness.  Such open retrospective chart reviews are even worse that open studies which have already been repeatly shown to be virtually worthless and extremely misleading. I encourage you to email the editors of the journal, Hagop S. Akiskal of the University of California, San Diego, and protest this promotion of junk science. . and Cornelius Katona at the University of Kent in the UK.

More Junk Science from the Journal of Affective Disorder: Psychiatrists at the University of Tennessee treated 24 women with cyclothymic temperament and refractory depression with lamotrigine in a totally uncontrolled study. Eighteen (75%) met DSM-IV criteria for bipolar II disorder. In two thirds of the cases, lamotrigine was add-on therapy to an antidepressant. The only measure of response to therapy was the DSM-IV Global Assessment of Functioning (GAF). The authors claim that 16 (70%) had sustained "responses" instead of sustained improvement, suggesting that all 16 were helped by lamotrigine and that their study was proof of effectiveness. They state, "Robust, sustained responses to lamotrigine monotherapy were seen in 4 patients (17%)," and 12 had a remission of their depression for at least 12 months. Only "seven patients (30%) received no apparent benefit from lamotrigine." They conclude, "Lamotrigine induced prolonged illness remissions in a substantial number of female patients whose symptoms were both complex and refractory." Sustained remission with lamotrigine augmentation or monotherapy in female resistant depressives with mixed cyclothymic-dysthymic temperament. Manning JS, et al. University of Tennessee-Memphis. . J Affect Disord. 2005 Feb;84(2-3):259-66.

Side-Effects

Felt Better on Lamotrigine than Valproate: Adolescent seizure patients. At the end of 8 months of DB treatment, significantly more patients using lamotrigine compared with valproate experienced quality-of-life improvements on the Health Perceptions (42% vs. 15%), Energy/Fatigue (47% vs. 28%), and Social Isolation (35% vs. 16%) subscales of the Quality of Life in Epilepsy-89 (QOLIE-89) questionnaire (P<0.05). Weight gain with valproate. Depression also decreased with lamotrigine on BDI, POMS. Lamotrigine monotherapy improves health-related quality of life in epilepsy: a double-blind comparison with valproate. Chris Sackellares J, Jacqueline Kwong W, Vuong A, Hammer AE, Barrett PS. Epilepsy Behav. 2002 Aug;3(4):376-382

Lamotrigine Withdrawal Reaction: Abrupt stopping of lamotrigine for surgery in 26-year-old led to visual hallucinations, irritability, hyperhydrosis, and tachycardia for several days until symptoms spontaneously resolved. Recommend stopping over 2 weeks when possible. Geliss, Act Neuro Scan 02;105:232

Fewer Fetal Effects with Lamotrigine than Valproate: In a study of 2,000 with epilepsy and 147 pregnancies, the overall risk of malformations among newborns in the AED-exposed group was 3.1% (n = 4). Two children were born with multiple malformations (VPA monotherapy), two children had ventricular septal defects (one oxcarbamazepine (OXC) monotherapy, and one OXC and LTG). The risk of malformations was 2.0% in women treated with LTG and 6.7% in women treated with VPA (NS). Acta Neurol Scand. 2004 Jan;109(1):9-13

Cognitive Side-Effect Less with Lamotrigine vs Carbamazepine: 25 healthy adults DB crossover design with two 10-week treatment periods. Lamotrigine (150 mg/day) or carbamazepine (mean 696 mg/day) adjusted to a dose to achieve midrange standard therapeutic blood levels (mean 7.6 microg/mL). Tested on 40 scales. Direct comparison of the two AED revealed significantly better performance on 19 (48%) variables for lamotrigine but none for carbamazepine. Differences spanned both objective cognitive and subjective behavioral measures, including cognitive speed, memory, graphomotor coding, neurotoxic symptoms, mood factors, sedation, perception of cognitive performance, and other quality-of-life perceptions. Comparison of carbamazepine with the nondrug average: nondrug better on 24 (62%) but none for carbamazepine. Comparison of lamotrigine with nondrug: one (2.5%) variable for nondrug and on one (2.5%) variable for lamotrigine. Differential cognitive and behavioral effects of carbamazepine and lamotrigine. Meador KJ, Loring DW, et al. Neurology. 2001 May 8;56(9):1177-82

Elderly Tolerate Lamotrigine Better than Carbamazepine: In a DB study of 150 elderly patients treated for new seizures, the drop out rate was more than twice as high for carbamazepine, primarily due to rashes and somnolence. Multicentre, double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. The UK Lamotrigine Elderly Study Group. Brodie MJ, Overstall PW, Giorgi L. Epilepsy Res. 1999 Oct;37(1):81-7

Worsening of Psychosis in Schizophrenia with Addition of Lamotrigine: A case report. Chan YC, et al. Ohio State. Schizophr Res. 2005 Aug 4

Fetal Risk: Study Reports No Increase in Birth Defects: The risk of all major birth defects after 414 first-trimester exposures to lamotrigine monotherapy (2.9%) was similar to that in the general population. Neurology. 2005 Mar 22;64(6):955-60.

Recurrent severe aseptic meningitis after exposure to lamotrigine in a patient with systemic lupus erythematosus. Kilfoyle DH, et al. Epilepsia. 2005 Feb;46(2):327-8.