Topiramate No Value for Bipolar Disorder

Topiramate (Topamax) has been found more beneficial than placebos in double-blind studies for chronic headaches (Cephalalgia. 2003 Oct;23(8):820-4), partial-onset seizures (Drugs Today (Barc). 1999 Jan;35(1):49-57), episodic migraines (CNS Spectr. 2003 Jun;8(6):428-32), partial epilepsy (Acta Neurol Scand. 2003 Jul;108(1):9-15), of minor benefit for obesity (Obes Res. 2003 Jun;11(6):722-33; Only 2.6% placebo vs. 5-6% on topiramate after 24 weeks), alcoholism (Lancet. 2003 May 17;361(9370):1677-85), binge eating (Am J Psychiatry. 2003 Feb;160(2):255-61), and essential tremor (Neurology. 2002 Jul 9;59(1):132-4).  However, in almost all of these studies it was compared to a placebo rather than some alternative treatment.  A double-blind study for seizures found it no better than carbamazepine or valproate, although it is much more expensive than carbamazepine and had more side-effects than either carbamazepine or valproate (Acta Neurol Scand. 2003 Mar;107(3):165-75).

The problem is that thousands of psychiatrists were prescribing topiramate for bipolar patients before a single double-blind study was ever being done!  Now that double-blind research has proven topiramate worthless for bipolars, thousands of psychiatrists are still prescribing it. This is not evidence-based medicine.  There is no scientific evidence that topiramate is of any value in treating bipolar disorder.  Open trials and so-called single blind trials are not evidence.  While the authors of these trials always say that double-blind studies should be done, tens of thousands of patients end up being given a treatment before there is any evidence that it is of value.  The manufacturer Johnson & Johnson has now done four double-blind studies as of June, 2005, all of which found no benefit and all of which have been suppressed, i.e. the authors have not been allowed to publish the negative results.  Human beings are being treated worse than guinea pigs, since at least guinea pigs are part of a scientific study, whereas giving patients topiramate in open trials or simple clinical practice does not further science.  Federal prosecutors investigated Johnson & Johnson about it sales and marketing practices of promoting Topamax for illegally bipolar disorder (Knight Ridder 12/15/03).

There are now at least five out of five unpublished double-blind studies proving that topiramate is of no benefit for the treatment of mania (Ann Gen Psychiatry. 2005 Feb 16;4(1):5).  None of these studies has ever been published, but the manufacturer continues to fund, conduct, and get published open-label "studies" falsely claiming that the studies show that topiramate "can reduced the severity of manic and depressive symptoms" (Canad J Psychiatry. 2005 June).

In the meantime, we have numerous good, scientifically proven medications to choose from without experimenting on our patients: lithium (the gold standard for bipolar disorder), carbamazepine, valproate, six atypical anti-psychotics, and a number of traditional anti-psychotics in addition to add-on anti-depressants, fish oil, folate, and thyroid medication for bipolar depression.  In my opinion and in the opinions of at least a few researchers not working for drug companies, open trials are not research and should rarely ever be published.  (The exception would be for large open trials with randomization to placebo or active comparators and objective rather than subjective measures, e.g. blood glucose levels, chest x-rays, etc. or in cases where blinding is impossible, e.g. randomizing to two different types of psychotherapy.)

Topiramate causes a high rate of side-effects, although the industry's paid researchers minimize these, e.g. calling the side-effects "generally mild" (Renu Kotwal, Univ. Cincinnati, Medscape 11/10/03).  In the PDR, where the industry lays out the facts to try to protect itself against lawsuits, out of 1,757 adult seizure patients, an amazing 28% discontinued topiramate because of the side-effects.  Psychiatric side-effects are particularly common and include: psychomotor slowing (16%), memory problems (10%), fatigue (17%), language problems (7%), confusion (8%), sleepiness (16%), difficulty concentrating (9%), loss of appetite (7%), depression (6%), dizziness (8%), nervousness (12%), and staggering (8%)(percentages are increases above placebo levels).  Symptomatic kidney stones develop in 1.5%, usually causing tremendous pain and hospitalization.

Suicide attempts were impressively increased in the company's own research with 13 attempts in 3999 patient-years vs. 0 attempts in 1430 patient-years on placebo.  One was a completed suicide.  Since December, 2003, suicide attempts are now listed as a "frequent" side-effect, i.e. occurring in at least 1% of patients (added 12/03 to FDA required labelling).  Depression in considerably increased in people taking Topamax when compared to placebo (13% vs. 3% at the top dosage).

Grossly Irresponsible Promotion of Topiramate (Topamax) for Bipolars by University of Toronto and Canadian Journal of Psychiatry: In a highly-biased, manufacturer-funded, open-label report of 16 weeks of topiramate added to the treatments of 109 bipolar patients treated by 17 different psychiatrists (80% depressed, only 3% manic and 8% hypomanic), by the end of the 16 weeks, depression and manic symptoms had decreased. Three of the four authors are employees of the manufacturer. Only the head of the Mood Psychopharmacology Unit at the University of Toronto, Dr. McIntyre, is not an employee, although the university received funding for this study.  The authors conclude with the totally unsupported claim that, "Adjunctive topiramate treatment can reduce the severity of manic and depressive symptoms, as well as reducing tremor and weight in outpatients with BD I or II." Incredibly, the study was approved by Health Canada and various "ethics" boards.  The authors do note that four [unpublished (i.e. suppressed), manufacturer-financed] placebo- and comparator-controlled trials conducted in patients with acute mania have failed to support the efficacy of topiramate as a monotherapy in bipolar disorder and are on file with the manufacturer, Johnson & Johnson. Open-label adjunctive topiramate in the treatment of unstable bipolar disorder. McIntyre RS, et al. University Health Network, Toronto, Ontario. . Can J Psychiatry. 2005 Jun;50(7):415-22. Ed: Shame on Health Canada and the so-called Canadian "ethics" committees.  This open trial could have served no purpose other than to falsely promote topiramate for bipolar disorder, which was the manufacturer's sole intent.  If the manufacturer really wanted to determine benefit, they would have funded yet another double-blind trial.  If open trials are truly needed before embarking on double-blind research, Health Canada and the ethics boards should prohibited publication of the results.  After all, Johnson and Johnson has prohibited publication of their own results of scientific, double-blind studies showing unfavorable outcomes, so there should be nothing wrong with the responsible governmental bodies prohibiting the publication of unscientific studies which do harm to the public welfare. 

Topiramate Said to Fail in DB Study Not Yet Published: There are negative, as yet unpublished, controlled studies on topiramate for mania. RW Licht, Acta Psychiatrica Scand 2003;419:108 (suppl pg 13), although in three open trial reports, researchers claimed benefit (J Clin Psychiatry 2001;62:464-8; Biol Psychiatry 2000;47:1025-33; J Clin Psychopharm 2001;21:340-2). Ed: Open trials are virtually worthless due to their high rate of false positive findings.

Topiramate Claimed Effective is Small, Poorly Designed Study: In a 6-week DB study of 74 acutely bipolar manic patients, all were given risperidone and half were given either divalproex (Depakote) or topiramate (Topamax). The Young Mania Rating Scale, and Clinical Global Impression were reduced by 68% and 57% for topiramate plus risperidone group  vs. 64% and 58% for divalproex plus risperidone group (DVPG). Weight increased 3.6% with DVPG vs. decreasing 0.5% with Topamax. The authors claimed, "Topiramate was effective and tolerable for treating acute mania." Topiramate and divalproex in combination with risperidone for acute mania: a randomized open-label study. Bahk WM, Shin YC, et al. The Catholic University of Korea, Seoul, South Korea. Prog Neuropsychopharmacol Biol Psychiatry. 2005 Jan;29(1):115-21. Ed: The authors' claim of topiramate effectiveness is unfounded.  The anti-psychotic by itself could easily have accounted for all of the decrease in mania.  Without a group taking risperidone alone, this study is of very little scientific value.  Also, with the high suicide rate on divalproex, divalproex is hardly a good comparator.

Topiramate Impairs Cognitive Function: In a study of 22 seizure patients treated with topiramate (TPM), TPM was associated with declines in fluency, attention/concentration, processing speed, language skills, and perception; working memory but not retention was affected. As the two studies used an opposite order of testing on versus off TPM, the results clearly show a performance decrement while patients are taking TPM, without respect to which condition is tested first. McGill University. The effects of adjunctive topiramate on cognitive function in patients with epilepsy. Lee S, Sziklas V, Andermann F, Farnham S, Risse G, Gustafson M, Gates J, Penovich P, Al-Asmi A, Dubeau F, Jones-Gotman M. Epilepsia. 2003 Mar;44(3):339-47

Psychosis Can Be a Side-Effect: Two men ages 33 and 43 receiving treatment for epilepsy, and one woman age 31 with mild mental retardation and psychotic episodes, psychotic symptoms emerged soon after the introduction of topiramate. These symptoms were associated with agitation/aggressive behavior and significant weight loss. Psychotic symptomatology gradually disappeared after discontinuation of topiramate without the administration of an antipsychotic. Treatment with topiramate can be associated with neuropsychiatric side-effects such as cognitive impairments, deficits in word finding, and incidental psychotic decompensation. Psychosis following treatment with topiramate. Verhoeven WM, Boermans JA, et al. Vincent van Gogh Instituut voor Psychiatrie, Venray, Netherlands. Ned Tijdschr Geneeskd. 2002 Nov 2;146(44):2093-5.

Topiramate No Weight Gain: Retrospective chart evaluation of 214 on mood stabilizers found 8% weight gain with lithium, 8.5% with valproate, and 0.7% weight loss with topiramate. Clin Ther 2002 Oct;24(10):1576-84

Topiramate Less Weight Gain: Used as mood stabilizer and for binge-eating (Shapira, J Clin Psychiatry 2000;61:368). May cause weight loss (Ghaemi, Harvd Rev Psychiatry 2000;8:1). Cognitive impairment and kidney stones do occur.

Topiramate: "Successful" in Open Trial Resistant Bipolar: 34 bipolars resistant to lithium, carbamazepine, or valproate. 11 depressed, 17 manic, 3 hypo, 3 mixed. 11 on anti-depressant, 13 antipsychotic. All at least 2 mood stabilizers without success. Topiramate 100-400mg/d (aver 202) for 6 months. 56% improved > 1point on CGI-S. 15 relapsed. Only one d/c due to paresthesia, anxiety. 10 lost weight. Vieta, J Clin Psychoph 02;22:431, Barcelona. (Ed: Remember open trials are of little value due to the high rate of observer bias).

Suicide: Case Report: Topiramate-induced suicidality. Abraham G. Can J Psychiatry. 2003 Mar;48(2):127-8.