When were Harvard, Duke, UCLA, Stanford, Canadian, Italian, and Spanish academic psychiatrists all wrong? When they published open trial reports promoting gabapentin (Neurontin) as useful for almost every known psychiatric condition!
Federal prosecutors are investigating Topamax manufacturer Johnson & Johnson in regards to possible illegal marketing practices in promoting Topamax. (Knight Ridder 12/15/03). The manufacturer of Neurontin is being sued by a former employee alleging illegal marketing practices. The FDA has put out a warning against many of the "off-label" uses of gabapentin.
Since the 1960's, scientifically-oriented physicians have known that they can't trust their own impressions on what works because personal biases can affect any of us. This is the reason why double-blind studies are considered essential to the practice of scientific psychiatry (the popular new expression is "evidence-based medicine").
I remember a study from the 1970s that went over all of the medicines touted by different academic physicians as helping in the treatment of alcoholism in various published articles in academic journals. Of 89 studies reviewed, an amazing 95% of the articles published about "open trials," where the doctor knew what medicine he was giving the patients and vice versa, reported that the medications were of at least some value in treating alcoholism, often considerable value. However, when the more scientific reviewer looked at somewhat later "double-blind studies," where neither the doctor nor the patient knew what medicine (or placebo) was being given, and which were done with the same exact medicines as those used in the open trials, only 6% of the studies found any evidence of benefit! 95% vs. 6%! (M. Pattison, Am J Psychiatry. 1977 Mar;134(3):261-6). Most of the medicines were worthless for treating alcoholism and yet numerous academic physicians had been fooled by trusting their own impressions.
You would think that the field of medicine has gotten wiser since the 1950's. But, in the year 2001, thousands of psychiatrists, like lemmings, began using gabapentin, a new and expensive patented seizure medication, for the treatment of mania in bipolar disorder and many other psychiatric disorders including alcoholism, panic disorder, agitation in the elderly, anxiety disorders, obsessive-compulsive disorder, PTSD, alcohol withdrawal, cocaine dependence, schizophrenia, and schizo-affective disorder. According to a survey by Psychiatric Drug Alerts of over 1000 practicing psychiatrist subscribers, gabapentin had become the third most popular anti-manic agent after lithium and divalproex (Depakote). This practice was based not on double-blind research, but only a huge number of "open trial" reports by big name psychiatrists affiliated with major medical schools in the U.S., Canada, Italy, and a couple other countries.
In the survey in April, 2001, the over 1000 psychiatrists responded: "After 1st line treatment (e.g. lithium/depakote), I use adjuvant antiepileptic drugs": Yes (92%): No (8%). "The next drug I use is": gabapentin (Neurontin) 30%, lamotrigine (Lamictal) 23%, topiramate (Topamax) 19%, carbamazepine (Tegretol) 15%, an atypical antipsychotics 6%.
Sadly, after double-blind research studies were finally done, gabapentin was been found to be worthless for treating bipolar disorder, probably worthless for depression and only of slight value for social phobia! While gabapentin scored 100% in way over 40 open trials, it is only one for six (16%) in the double-blind studies of psychiatric patients listed on PubMed as of October 8, 2003. The one success was the very minimal benefit over placebo in the treatment of social phobia. Yet, in 2001 there were large numbers of double-blind trials showing that a sizeable number of other medications can help bipolar disorder. It's not that other and better alternatives were not available.
In my opinion, to have 30% of the psychiatrists in America experimenting on their patients with a drug that has never been found helpful for the condition being treated in at least one double-blind study is wrong. I would go further. To give a patient a medication that has never been shown to be of value in a double-blind study requires signed informed consent. The consent should explain that there is no scientific evidence that the medication is of any benefit in treating the disorder. The current situation is unethical. Who is to blame? I don't think individual practicing psychiatrists with a limited knowledge of and appreciation for the scientific method can be held responsible. The pharmaceutical industry, certain academic psychiatrists, certain academic institutions (Stanford, Harvard, and Duke especially), the FDA, certain politicians, and President George W. Bush all share the blame. The American Psychiatric Association is also to blame.
The truth is that much of academic psychiatry has become seriously corrupted by the pharmaceutical industry. The same is probably true of the entire field of medicine. Many, probably most, physician offices are littered with crass advertising for expensive patented medicines. Many physicians are fed and paid by the drug pushers. I know for a fact that in 2003 many psychiatrists in the Omaha-Council Bluffs area have met monthly for dinner and one of the psychiatrists on a rotating basis gives a presentation for which he or she receives a handsome stipend. All of the costs are picked up by drug manufacturers! That's corrupt.
The pharmaceutical manufacturer of gabapentin is currently in court on a lawsuit by a former employee reporting the various tactics that the company used to illegally promote off-label sales based on poor quality, open trial reports. Pharmaceutical companies now employee one sales rep for every seven doctors in America! Free samples have increased to $11.9 billion in 2002, a 140% increase from 1996. Of course, free samples are provided only for expensive patent-protected medications. Very few physicians spend their own money to have low-cost generic samples available, but I think they should.
For medical journals to publish huge numbers of open trials, often funded by the drug's manufacturer, is wrong. Perhaps, the first open trial finding evidence of possible benefit, if cautiously worded so as not to suggest proof of benefit, is OK. But not dozens and dozens of these open trial "puff pieces." Of course, many medical journals also receive large incomes from drug company advertising and many of the reviewers for medical journals are working for these same companies. Many, but not all, of the academic psychiatrist authors of these open trial studies receive money from the pharmaceutical manufacturers.
For medical reviewers to allow the exaggerated wording that is common in these open trial articles, claiming that the medications "caused" the improvement, an effect impossible to establish in an open trial, is wrong. There is something seriously wrong with academic psychiatry in the 21st century. And patients too often pay the price. And the rest of us end up helping foot the bill for over-priced medicines that are no better, or even worse in the case of gabapentin, than other worthwhile alternatives.
Harvard Psychiatrist Claims Gabapentin Helpful for Many Conditions Based on Open Trial: 15 of 50 patients were said to be "helped" in a poor quality open trial study as add-on med. The author claimed it was of moderate to marked effectiveness. 70% had side-effects especially sedation with 16% stopping the medicine due to them. Nasser Ghaemi, Harvard, J Clin Psychiatry 10/98, 426-9; Used for anxiety, social phobia, panic disorder, aggressive behavior and substance abuse withdrawal (Pharmacother 1999; 19:565). Dr. Ghaemi did report at the APA Convention in 1999 that gabapentin was found to be no better than sugar pills for treating type I bipolar disorder in a double-blind study. But in 2001, (see below) he wrote that it was of considerable benefit to manic patients based on a very small number of manic patients in an open trial!
Italian University Psychiatrist Claims Gabapentin Helps Bipolar Aggression at APA Convention Based on Open Study: Open study 900-1200mg/d well tolerated with "good response." Hardoy, University of Florence, APA 5/30/98 Toronto. Half-life 5-7 hr.
UCLA Psychiatrist Claim Gabapentin Benefits Large Numbers of Depressed and Manic in Open Study: UCLA claimed 78% of manics benefited and 100% of depressives! Gabapentin in the acute treatment of refractory bipolar disorder. Altshuler LL, Keck PE Jr, McElroy SL, Suppes T, Brown ES, Denicoff K, Frye M, Gitlin M, Hwang S, Goodman R, Leverich G, Nolen W, Kupka R, Post R. Bipolar Disord 1999 Sep;1(1):61-5.
Harvard Psychiatrists Claim Gabapentin Markedly Effective for Depressed and Manic in Very Small Open Study: A Harvard/Cambridge studied only 21 out-patients but claimed gabapentin was markedly effective for 43% of depressed and relieved 57.5% of depressive symptoms in the 10 depressed patients and a 43.7% decrease in manic symptoms in the 11 manic patients. Gabapentin treatment of the non-refractory bipolar spectrum: an open case series. Ghaemi SN, Goodwin FK. J Affect Disord 2001 Jul;65(2):167-71. Ed: The great precision of calculating decreases in symptoms to the tenth of a percentage based on so few patients gives the false impression of scientific reliability. Such a misuse of statistics is ludicrous. The use of wording in an open trial of "markedly effective," when there can be no scientific evidence of effectiveness in an open trial, is seriously misleading and grossly irresponsible.
Italian University Psychiatrists: Gabapentin Claimed Effective for Refractory Bipolars in Open Trial especially for Anxiety & Depression; Also Good for Panic Disorder and Alcoholism!: The University of Pisa in an open trial of 42 refractory bipolars put on gabapentin for 8 weeks report 41.9% responders. "The results of the present study replicate prior studies indicating that GBP is an effective and well tolerated treatment in a large proportion of bipolar patients who are resistant to traditional mood stabilizers." Effectiveness of adjunctive gabapentin in resistant bipolar disorder: is it due to anxious-alcohol abuse comorbidity? Perugi G, Toni C, Frare F, Ruffolo G, Moretti L, Torti C, Akiskal HS. J Clin Psychopharmacol 2002 Dec;22(6):584-91
Spanish University Psychiatrists: Gabapentin Said to Have Good Results with Bipolars Based on Very Small Open Trial: Only 22 patients is an open trial. And only 16 completers. 50% improved 2 steps on CGI. "Gabapentin may be a useful drug for the add-on treatment of bipolar patients with poor response to other mood stabilizers. Gabapentin may improve depressive residual symptoms such as irritability, social withdrawal or anxiety. These results should be confirmed in randomized clinical trials." Univ. Barcelona, Adjunctive gabapentin treatment of bipolar disorder. Vieta E, Martinez-Aran A, Nieto E, Colom F, Reinares M, Benabarre A, Gasto C. Eur Psychiatry 2000 Nov;15(7):433-7. (Ed.: The call for randomized trials is a sop thrown in. These studies should never be published since their data is totally worthless and yet it influences large numbers of practicing psychiatrists.)
Gabapentin Called Effective in an Amazing 91% of Bipolar Teens and Adults in Open Study: Psychiatry Drug Alerts (10/97 pg 74) in reviewing an open retrospective study writes, "Gabapentin was effective in patients with bipolar disorder who had failed trials of other drugs." 73 teens and adult bipolars not successful with a mood stabilizer given 200-3500mg/d. Six stopped due to side-effects (2) or worse mood (4). 100% of 67 others reportedly successful in stopping cycling with activities, moods, behaviors returning to normal. The authors write gabapentin could become a major agent in the treatment of bipolar disorder. Ryback R, et al: Gabapentin in bipolar disorder (letter). J Neuropsychiatry 97;9:301.
Gabapentin Supposedly Helped 8 of 9 in Open Trial: Psychiatry Drug Alerts (10/97, pg 75) writes, "Adjunctive gabapentin resulted in clinical improvement in 8 of 9 patients with bipolar disorder whose symptoms had responded inadequately to standard agents." All had been given one standard mood stabilizer but continued to have manic or mixed (8) symptoms, 6 called rapid cycling Only one "had a marked response to gabapentin) the first month and 6 had moderate responses. After 3 more months, another had moderate improvement. The mood stabilizers were reduced or stopped in five. However, five of the 9 stopped gabapentin. McElroy S, et al: A pilot trial of adjunctive gabapentin in the treatment of bipolar disorder. Annals of Clin Psyc 97;9:99-103 U Cinn.
Canadian University Psychiatrists: Gabapentin Supposedly Had Anti-Depressant Effects Based on Very Small Open Trial: 6 week open trial of 15 bipolars, 10 of whom were rapid cyclers. According to Psychiatry Drug Alerts, "Three patients had a marked response to gabapentin" 50% decrease in HAM-D. 5 supposedly responded partially. One patient got worse. The Alerts concluded "gabapentin had moderate antidepressant effects" Young L, et al: Acute treatment of bipolar depression with gabapentin. Biol Psychiatry 97;42:851-3, McMaster Univ. Funded by Medical Research Council of Canada. (Ed: In fact, in an open trial you can never conclude that there was a "marked response to gabapentin," but only "a marked improvement while on gabapentin" with a word of caution that no one should assume cause-effect.)
Gabapentin in PTSD Improvement: Open trial 30 patients said 77% showed moderate or greater improvement in sleep and decreased nightmares. Gabapentin in PTSD: a retrospective, clinical series of adjunctive therapy. Hamner MB, Brodrick PS, Labbate LA. Ann Clin Psychiatry 2001 Sep;13(3):141-6
Gabapentin Case Report Helps Dementia Aggression & Anxiety: "It has a favorable adverse effect profile in the elderly, which makes it an attractive alternative to standard therapies, including benzodiazepines and neuroleptics.... This case suggests that gabapentin is a reasonable alternative therapy for patients whose behavioral symptoms do not respond to conventional agents." Gabapentin for treatment of behavioral and psychological symptoms of dementia. Miller L J. Ann Pharmacother 2001 Apr;35(4):427-31. (Ed: Recommending a treatment based on a single case treated in an open trial seems misguided. Even publishing such a report seems misguided.)
University of Toronto Psychiatrist Says Gabapentin Possible Role in Dementia Based on Very Small Open Trial: Open "prospective" trial 12 patients 8 weeks with only 2 improving more than minimally. U Toronto. Effectiveness of gabapentin for the treatment of behavioral disorders in dementia. Herrmann N, Lanctot K, Myszak M. J Clin Psychopharmacol 2000 Feb;20(1):90-3
Gabapentin Said Helpful in Open Trial of Bipolar Spectrum: U Cagliari. 10 patients, open trial, very poorly defined. Adjunctive gabapentin in patients with intellectual disability and bipolar spectrum disorders. Carta MG, Hardoy MC, Dessi I, Hardoy MJ, Carpiniello B.
Gabapentin Promoted for Depression: 37% response rate (10 pt). "gabapentin may be of adjunctive benefit in the management of treatment-resistant depression." Adjunctive gabapentin in treatment-resistant depression: a retrospective chart review. Brown Univ: Yasmin S, Carpenter LL, Leon Z, Siniscalchi JM, Price LH. J Affect Disord 2001 Mar;63(1-3):243-7
Duke Psychiatrist Claims Gabapentin Extensively Studied for Social Phobia: "Controlled trials and/or anecdotal reports have shown SSRIs and anticonvulsants to be effective treatments for the symptoms of panic disorder and social phobia. However, although SSRIs are emerging as a leading treatment for generalized social phobia, it is not at all clear whether they can benefit nongeneralized social phobia. Their side-effect profile, while a marked improvement over earlier antidepressant drugs, still can cause significant discomfort. The anticonvulsants are now emerging as a very important group of drugs in the anxiety disorders, with gabapentin having been the most extensively studied in social phobia." Panic disorder and social phobia: current treatments and new strategies. Davidson JR, Connor KM, Sutherland SM. Cleve Clin J Med 1998;65 Suppl 1:SI39-44; discussion SI45-7; also see J Clin Psychiatry 2001;62 Suppl 1:50-3 (Ed: In fact, I could only find one single double-blind study of gabapentin treating social phobia and that was funded by the manufacturer. Admittedly, I only searched on PubMed, but it is extremely unlikely that any "extensively studied" medication would have only one study on PubMed.)
Gabapentin Said to Help in Open Trial by Stanford Psychiatry: 12-week trial of open GBP (mean dose 1725 mg/day) added to stable doses of mood stabilizers or atypical antipsychotics in 22 (10 women, mean age 38.4 years) depressed [28-item Hamilton Depression Rating Scale (HDRS) >18] bipolar (10 bipolar I, 12 bipolar II) disorder outpatients. Mean illness duration was 18.6 years; current depressive episode duration was 18.0 weeks. HDRS ratings decreased 53% from 32.5 ± 7.7 at baseline to 16.5 ± 12.8 at week 12 (p < 0.0001). Well tolerated, Stanford, Wang, Bipolar Disorder 02;4:296
Gabapentin Reportedly Helpful in 40 out of 40 Published Open Trial: Italian University of Caligari psychiatrists reviewing gabapentin bipolar research through June, 2002, says gabapentin still beneficial although 50% of the four double-blind trials he found concluded it did no better than sugar pills. His words "Among the innovative third generation mood stabilizing anticonvulsants, gabapentin (GBP) seems to have a broad spectrum of efficacy..." seems to puff up gabapentin and go far beyond any real research findings. The clinical use of gabapentin in bipolar spectrum disorders. Carta MG, Hardoy MC, Hardoy MJ, Grunze H, Carpiniello B. J Affect Disord. 2003 Jun;75(1):83-91
University of Trieste & Drugs and Aging Journal Continue Publishing Highly Irresponsible Articles: Another unbelievably poor quality and unethical report was published in December, 2003, claiming gabapentin was "efficacious" for elderly demented patients based on an open trial of only 20 patients. For instance, the authors write, "Gabapentin appeared to be efficacious and well tolerated" and "gabapentin provides significant and sustained efficacy in terms of behaviour, with associated reductions in caregiver burden." Gabapentin for the treatment of behavioural alterations in dementia : preliminary 15-month investigation. Moretti R, Torre P, Antonello RM, Cazzato G, Bava A. Drugs Aging. 2003;20(14):1035-40
Gabapentin No Value for Bipolars in DB; Placebo did Better!: DB PC using gabapentin 900-3600mg/d add-on to patients not well enough controlled on lithium, valproate, or both. Placebo patients actually did slightly better! Parke-Davis, Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Gabapentin Bipolar Disorder Study Group. Pande AC, Crockatt JG, Janney CA, Werth JL, Tsaroucha G. Bipolar Disord 2000 Sep;2(3 Pt 2):249-55
Gabapentin No Value for Bipolars in DB, Lamotrigine Helps: DB PC 45 patients 6 weeks each. 51% lamotrigine, 28% gabapentin, 21% placebo 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
Gabapentin No Value for Unipolars or Bipolars in DB, Lamotrigine Helps: DB PC 31 refractory unipolar and bipolar patients all given 6 week trial of lamotrigine, gabapentin, and placebo. NIMH, Frye MA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol 2000 Dec;20(6):607-14
Gabapentin No Value in DB for Panic Disorder: Parke-Davis DB PC found no difference with a p=0.606! The drug company's "researchers" did a post-hoc analysis to tease out supposed benefits for patients with higher PAS (Panic & Agoraphobia Scale) scores (p<.04). Placebo-controlled study of gabapentin treatment of panic disorder. Pande AC, Pollack MH, Crockatt J, Greiner M, Chouinard G, Lydiard RB, Taylor CB, Dager SR, Shiovitz T. J Clin Psychopharmacol 2000 Aug;20(4):467-71
Gabapentin Helps Social Phobia a Little in DB: 69 pt 14 weeks DB PC 600-3600mg/d. p<0.05 only. Parke-Davis manufacturer study. Treatment of social phobia with gabapentin: a placebo-controlled study. Pande AC, Davidson JR, Jefferson JW, Janney CA, Katzelnick DJ, Weisler RH, Greist JH, Sutherland SM. J Clin Psychopharmacol 1999 Aug;19(4):341-8
Gabapentin Worthless for Alcohol Withdrawal in DB: A good German University of Essen DB PC study of 61 alcoholic patients going through alcohol withdrawal. Gabapentin was tested at 400mg qid as an add-on to clomethiazole. Treatment of acute alcohol withdrawal with gabapentin: results from a controlled two-center trial. Bonnet U, Banger M, Leweke FM, Specka M, Muller BW, Hashemi T, Nyhuis PW, Kutscher S, Burtscheidt W, Gastpar M. J Clin Psychopharmacol. 2003 Oct;23(5):514-9.
Use Off Label Only if Solid Research Support: Other unscientific uses besides bipolar supported only by open trials include complex regional pain syndrome, attention deficit disorder, trigeminal neuralgia, and alcohol withdrawal syndrome. The author states, "Off-label use of gabapentin for indications not approved by the FDA should be reserved for cases where there is solid research support (e.g., diabetic neuropathy and prophylaxis of frequent migraine headaches). Managed care pharmacists should develop programs to restrict the use of gabapentin to these specific evidence-based situations." Examination of the evidence for off-label use of gabapentin. Mack A. J Manag Care Pharm. 2003 Nov-Dec;9(6):559-68
There is research on seizures, restless legs syndrome, neuropathic pain, and hot flashes to show that gabapentin does help a number of disorders in double-blind studies, just not psychiatric patients.