Que disent les tables de la LOI pour les bipolaires ? Vous devrez utiliser un thymorégulateur à chaque phase de la maladie. (enlevez la barbe, 30 kilog de muscle, rajoutez 2 fossettes, changez l'oeil impératif en persuasif  et vous aurez reconnu qui ?)

Quel est le niveau de "stabilisation" induit par les thymorégulateurs et comment est-il véçu ?. La première priorité pour les médecins (et la famille !) est de ne plus revivre ces cycles infernaux excitation maniaque (ou hypomanie pour certains) suivis de dépression.  C'est extraordinaire de voir pour la première fois un malade reprendre petit à petit une vie normale après avoir été "stabilisé". Mais le(la) malade ressent la "stabilisation" comme un arasement, un rabotage de ses capacités cognitives et mémorielles. C'est pour une grande part une illusion, due au souvenir de la manie qui accélère tous les processus. Mais ce n'est pas qu'une illusion. Les thymorégulateurs fixent le "rythme" des processus mentaux à un niveau un peu plus bas qu'avant la maladie (sauf le lamictal, parait-il). Un travail de recherche (Gualtieri,Johnson 23 aout 2006) fait le point objectif sur les effets cognitifs.    En plus de "forcer" le niveau moyen de l'humeur, les thymorégulateurs limitent l'amplitude des micro-variations de l'humeur. Le(la) stabilisé a une impression d'indifférence par rapport à son environnement, d'émoussement émotionnel. Il y a là encore une part d'illusion : le(la) stabilisé se souvient des moments ou ses réactions étaient immédiates et clouaient le bec des autres.  Il se souvient moins des moments ou ses réactions immédiates blessaient son entourage.

Keywords: bipolar disorder, treatment-resistant, antimanic agents, antidepressants, bipolar depression, medication combinations

Correspondence: Dr M Gitlin, Geffen School of Medicine at UCLA, 300 UCLA Medical Plaza, Suite #2200, Los Angeles, CA 90095, USA. E-mail: mgitlin@mednet.ucla.edu
Received 30 November 2005; Accepted 4 December 2005; Published online 24 January 2006.

Despite the remarkable increase in medications validated as effective in bipolar disorder, treatment is still plagued by inadequate response in acute manic or depressive episodes or in long-term preventive maintenance treatment. Established first-line treatments include lithium, valproate and second-generation antipsychotics (SGAs) in acute mania, and lithium and valproate as maintenance treatments. Recently validated treatments include extended release carbamazapine for acute mania and lamotrigine, olanzapine and aripiprazole as maintenance treatments. For treatment-resistant mania and as maintenance treatments, a number of newer anticonvulsants, and one older one, phenytoin, have shown some promise as effective. However, not all anticonvulsants are effective and each agent needs to be evaluated individually. Combining multiple agents is the most commonly used clinical strategy for treatment resistant bipolar patients despite a relative lack of data supporting its use, except for acute mania (for which lithium or valproate plus an SGA is optimal treatment). Other approaches that may be effective for treatment-resistant patients include high-dose thyroid augmentation, clozapine, calcium channel blockers and electroconvulsive therapy (ECT). Adjunctive psychotherapies show convincing efficacy using a variety of different techniques, most of which include substantial attention to education and enhancing coping strategies. Only recently, bipolar depression has become a topic of serious inquiry with the dominant controversy focusing on the place of antidepressants in the treatment of bipolar depression. Other than mood stabilizers alone or the combination of mood stabilizers and antidepressants, most of the approaches for treatment-resistant bipolar depression are relatively similar to those used in unipolar depression, with the possible exception of a more prominent place for SGAs, prescribed either alone or in combination with antidepressants. Future work in the area needs to explore the treatments commonly used by clinicians with inadequate research support, such as combination therapy and the use of antidepressants as both acute and adjunctive maintenance treatments for bipolar disorder.

Csutora P, Karsai A, Nagy T, Vas B, L Kovács G, Rideg O, Bogner P, Miseta A
Lithium induces phosphoglucomutase activity in various tissues of rats and in bipolar patients.
Int J Neuropsychopharmacol. 2005 Nov 1;1-7.
Phosphoglucomutase catalyses the reversible conversion of glucose-6-P and glucose-1-P. Lithium is a potent inhibitor of phosphoglucomutase in vitro, however, it is not known if phosphoglucomutase was significantly inhibited by Li+ in Li+-treated bipolar patients. Here, we demonstrate that phosphoglucomutase inhibition by chronic Li+ treatment causes alterations of glucose-phosphate levels in various tissues of rats. Also, phosphoglucomutase inhibition results in compensatory elevation of phosphoglucomutase activity in rat tissues and in leukocytes isolated from Li+-treated bipolar patients. The increase of uninhibited phosphoglucomutase activity in leukocytes of Li+-treated bipolar patients is due to the increased expression of the PGM1 gene.

Dmitrzak-Weglarz M, Rybakowski JK, Suwalska A, S?opie? A, Czerski PM, Leszczy?ska-Rodziewicz A, Hauser J
Association studies of 5-HT(2A) and 5-HT(2C) serotonin receptor gene polymorphisms with prophylactic lithium response in bipolar patients.
Pharmacol Rep. 2005 Nov-Dec;57(6):761-5.
Lithium is one of the most commonly used drugs in the prophylaxis and treatment of bipolar disorder. The mechanisms of mood stabilization by lithium incorporate its effect on serotonergic neurotransmission. This paper investigates a relationship between response to lithium prophylaxis and polymorphisms in two genes: T102C of 5-HT(2A) receptor and G68C (Cys23Ser) of 5-HT(2C) serotonin receptor gene. Genotypes were estimated in 92 bipolar patients (39 males and 53 females) who have been taking lithium for at least 5 years. The patients were classified as excellent responders, partial responders and non-responders to lithium. The obtained results suggest that these polymorphisms may not be related to the degree of prophylactic lithium response.

Adjunctive Lamotrigine as a Possible Mania Inducer in Bipolar Patients

SERGEY RASKIN, M.D., ALEXANDER TEITELBAUM, M.D., JOSEF ZISLIN, M.D. and RIMONA DURST, M.D.
Jerusalem, Israel

To the Editor: Lamotrigine is currently being used to treat bipolar and unipolar mood disorders. We report three cases in which lamotrigine acted as a possible hypomania/mania inducer, although it was used in addition to other mood stabilizers. These are probably the first such reported cases besides one report of hypomania induced by adjunctive lamotrigine in antidepressant treatment (1).

Ms. A, a 41-year-old woman, suffered from bipolar I affective disorder. She was stabilized with 1700 mg/day of valproic acid. She then began to develop depressive symptoms. Lamotrigine was added to valproic acid as a mood stabilizer, with an elevating effect (2). After 2 days of 50 mg/day of lamotrigine, Ms. A reported an improvement in her mood. This made her decide to increase her dosage to 100 mg/day. Within 1 week of lamotrigine treatment, she became hyperactive and agitated, needed no sleep, and spent money without judgment. The lamotrigine was stopped, resulting in rapid remission within 2–3 days of Ms. A’s iatrogenic mania.

Mr. B, a 32-year-old man, had bipolar I disorder. He was stabilized with 750 mg/day of carbamazepine, along with 600 mg/day of quetiapine. He then began having episodes of rapid mood changes from euphoria to depression, with grandeur delusions and suicidal ideation. There was no improvement when quetiapine was increased to 800 mg/day. Lamotrigine was then added, 25 mg at bedtime, and elevated to 200 mg at bedtime within a week because of Mr. B’s serious condition; he continued treatment with carbamazepine and quetiapine. A typical manic episode developed within 48 hours. A decrease in his lamotrigine dosage to 50 mg/day resulted in abatement of his mania symptoms within 1 week.

Mr. C, a 29-year-old man, had been diagnosed with schizoaffective disorder at the age of 16. For years, he had been stabilized with 1500 mg/day of lithium. However, he started to develop hypomanic symptoms. Quetiapine, 400 mg/day, was added to the lithium. This resulted in amelioration of his hypomanic signs but a propensity toward depression. It was thought that lamotrigine added to lithium and quetiapine would stabilize him without a manic explosion. Lamotrigine was gradually elevated to 200 mg/day over 3 weeks; Mr. C manifested manic symptoms toward the end of the fourth week. A gradual reduction of his lamotrigine dosage until cessation over 3 weeks resulted in parallel disappearance of his manic symptoms.

These cases highlight the possibility of lamotrigine acting as a quick antidepressant, even when added to other mood stabilizers. Our clinical impression is that the provocation of mania is related to the titration rate and dosage. Thus, special caution should be taken when prescribing lamotrigine together with valproate because the latter decreases the clearance of lamotrigine.

References

1 Margolese HC, Beauclair L, Szkrumelak N, Chouinard G: Hypomania induced by adjunctive lamotrigine (letter). Am J Psychiatry 2003; 160:183–184[Free Full Text]

2. Sporn J, Sachs G: The anticonvulsant lamotrigine in treatment-resistant manic-depressive illness. J Clin Psychopharmacol 1997; 17:185–189[CrossRef][Medline]

Incidence and Time Course of Subsyndromal Symptoms in Patients With Bipolar I Disorder: An Evaluation of 2 Placebo-Controlled Maintenance Trials
Mark A. Frye, M.D.; Lakshmi N. Yatham, M.D.; Joseph R. Calabrese, M.D.; Charles L. Bowden, M.D.; Terence A. Ketter, M.D.; Trisha Suppes, M.D., Ph.D.; Bryan E. Adams, Ph.D.; and Thomas R. Thompson, M.D.
J Clin Psychiatry 2006;67:1721-1728

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Background: Subsyndromal symptoms in bipolar disorder can cause significant functional impairment and are associated with relapse.

Method: In this post hoc analysis from 2 randomized, double-blind, 18-month, placebo-controlled maintenance trials for bipolar I disorder (both trials were conducted between August 1997 and August 2001 and used DSM-IV criteria), the incidence, time course, and impact of pharmacotherapy on subsyndromal symptoms were examined.

Results: Subsyndromal symptoms occurred in approximately 25% of all visits. Compared with placebo (54.8%), a significantly higher mean percentage of visits in remission were observed with lamotrigine treatment (63.0%, p = .020) but not with lithium treatment (60.0%, p = .165). The median time to onset of subsyndromal symptoms for lamotrigine (N = 223), lithium (N = 164), and placebo (N = 188) was 15, 15, and 9 days, respectively. Compared with placebo, both lamotrigine and lithium significantly delayed the time from randomization to onset of subsyndromal symptoms (p = .046, lamotrigine vs. placebo; p = .033, lithium vs. placebo; p = .763, lamotrigine vs. lithium) and the time from onset of subsyndromal symptoms to subsequent mood episode (p = .037, lamotrigine vs. placebo; p = .023, lithium vs. placebo; p = .845, lamotrigine vs. lithium). Agreement between the polarities of the first-observed subsyndromal symptom and subsequent intervention for mood episode was statistically significant (p < .001).

Conclusion: Subsyndromal symptoms are common during maintenance treatment and appear to be associated with relapse into an episode of the same polarity. Both lithium and lamotrigine delayed the onset of subsyndromal symptoms and the time from onset of subsyndromal symptoms to subsequent relapse. Further study to assess whether treatment intervention can minimize subsyndromal symptoms or prevent relapse is encouraged.

---

Received Jan. 23, 2006; accepted April 11, 2006. From the Mood Disorders Research Program, University of California at Los Angeles (Dr. Frye); the Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada (Dr. Yatham); the Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio (Dr. Calabrese); the Department of Psychiatry, University of Texas Health Science Center at San Antonio (Dr. Bowden); the Stanford University School of Medicine, Stanford, Calif. (Dr. Ketter); the University of Texas Southwestern Medical Center, Dallas (Dr. Suppes); GlaxoSmithKline, Research Triangle Park, N.C. (Dr. Thompson); and Clinforce, Research Triangle Park, N.C. (Dr. Adams). Dr. Adams is now with GlaxoSmithKline, Research Triangle Park, N.C.

GlaxoSmithKline funded the studies described in this article.

Financial disclosure for all authors appears at the end of this article.

Corresponding author and reprints: Mark A. Frye, M.D., Department of Psychiatry and Psychology, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905 (e-mail: mfrye@mayo.edu).

The Latest Mania: Selling Bipolar Disorder

David Healy, PLos Medecine April 11, 2006

Funding: The author received no specific funding to write this article.

Competing Interests: DH has been a speaker, consultant, or clinical trialist for Lilly, Janssen, SmithKline Beecham, Pfizer, Astra-Zeneca, Lorex-Synthelabo, Lundbeck, Organon, Pierre-Fabre, Roche, and Sanofi. He has also been an expert witness in ten legal cases involving antidepressants and suicide or homicide and one case involving the patent on olanzapine (Zyprexa). None of these interests played any part in the submission or preparation of this paper.

Citation: Healy D (2006) The Latest Mania: Selling Bipolar Disorder. PLoS Med 3(4): e185 DOI: 10.1371/journal.pmed.0030185


Copyright: © 2006 David Healy. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

David Healy is at the North Wales Department of Psychological Medicine, Cardiff University, Cardiff, Wales, United Kingdom. E-mail: healy_hergest@compuserve.com

One of the most famous direct-to-consumer television adverts for a drug begins with a vibrant woman dancing late into the night. A background voice says, “Your doctor probably never sees you when you feel like this.” The advert cuts to a shrunken and glum figure, and the voiceover now says, “This is who your doctor usually sees.” Cutting again to the woman, in active shopping mode, clutching bags with the latest brand names, we hear: “That's why so many people with bipolar disorder are being treated for depression and not getting any better—because depression is only half the story.” We see the woman again depressed, looking at bills that have arrived in the post before switching to seeing her again energetically painting her apartment. “That fast- talking, energetic, quick tempered, overdoing it, up-all-night you,” says the voiceover, “probably never shows up at the doctor's office, right?”

No drugs are mentioned. But viewers are encouraged to log onto www.bipolarawareness.com, which takes them to a Web site called “Bipolar Help Center,” sponsored by Lilly Pharmaceuticals, the makers of olanzapine (Zyprexa). The Web site contains a “mood disorder questionnaire” (http://www.bipolarhelpcenter.com/resources/mdq.jsp). In the television advert, we see our heroine logging onto www.bipolarawareness.com and finding this questionnaire. The voice encourages the viewer to follow her example: “Take the test you can take to your doctor, it can change your life….getting a correct diagnosis is the first step in treating bipolar disorder. Help your doctor to help you.”

This advert markets bipolar disorder. The advert can be read as a genuine attempt to alert people who may be suffering from one of the most debilitating and serious psychiatric diseases—manic-depressive illness. Alternatively, the advert can be read as an example of what has been termed disease mongering [1]. Whichever it is, it will reach beyond those suffering from a mood disorder to others who will as a consequence be more likely to see aspects of their personal experiences in a new way that will lead to medical consultations and in a way that will shape the outcome of those consultations. Adverts that encourage “mood watching” risk transforming variations from an emotional even keel into potential indicators of latent or actual bipolar disorder. This advert appeared in 2002 shortly after Lilly's antipsychotic olanzapine had received a license for treating mania. The company was also running trials aimed at establishing olanzapine as a “mood stabilizer,” one of which was recently published [2].

Mood Stabilization

From the 1950s on, the depressions of manic-depressive illness have been treated with antidepressants and the manias with antipsychotics or lithium. Lithium was the only agent thought to be prophylactic against further episodes of manic-depressive illness [3]. But lithium was not originally referred to as a mood stabilizer. The term “mood stabilizer” had barely been heard of before 1995 when Abbott Laboratories got a license for using the anticonvulsant sodium valproate (Depakote) for treating acute mania [4].

After 1995, there was a dramatic growth in the frequency with which the term “mood stabilizer” appeared in the title of scientific articles (see Figure 1). By 2001, more than a hundred article titles a year featured this term. Repeated reviews make it clear that the academic psychiatric community still has not come to a consensus on what the term “mood stabilizer” means [5–7]. But this lack of consensus did not get in the way of the message that patients with bipolar disorders needed to be detected and once detected needed mood stabilizers, and perhaps should only be given these drugs and not any other psychotropic drugs [8,9].
Figure 1. Articles Elicited by Medline Using the Mesh Term “Mood Stabilizer”

The growth of awareness of mood stabilization was sensational.

The first group of drugs to colonize this new mood stabilizer niche was anticonvulsants. Anticonvulsants are beneficial in epilepsy and were until recently widely thought to be beneficial by quenching the increased risk of succeeding epileptic fits brought about by fits that have gone before. Robert Post in the 1980s suggested that anticonvulsants might stabilize moods by a comparable quenching of the kindling effect of an episode of mood disorders on the risk of further episodes [10]. It was this idea that provided a pharmacological rationale for treatment of bipolar disorders that was so attractive to pharmaceutical companies, and, in their hands, the growth of awareness of mood stabilization and of bipolar disorders was sensational.

Bipolar disorders entered the DSM (Diagnostic and Statistical Manual of Mental Disorders) in 1980. At the time, the criteria for bipolar I disorder (classic manic-depressive illness) involved an episode of hospitalization for mania. Since then, the community-based disorders bipolar II disorder, bipolar disorders NOS (not otherwise specified), and cyclothymia have emerged. With their emergence, estimates for the prevalence of bipolar disorders have risen from 0.1% of the population having bipolar I disorder (involving an episode of hospitalization for mania) [11] to 5% or more when the definition of bipolar disorders includes the aforementioned community disorders [12]. A range of academic institutions has also grown more interested in the condition.

There has always been a rationale to using antipsychotics in bipolar disorders, as they are effective in acute manic states [13,14]. However, no companies making antipsychotics had previously sought a license for prophylaxis against bipolar disorders. Against a background of epidemiological studies indicating that the prevalence of bipolar disorders might be greater than previously thought [15,16], and growing academic interest in the condition, Lilly, Janssen, and Astra-Zeneca, the makers of the antipsychotics olanzapine, risperidone, and quetiapine (Seroquel), respectively, marched in on the new territory to market these drugs for prophylaxis of bipolar disorder. This, in turn, greatly expanded the number of companies with an interest in making the “bipolar market.” There was, however, no consensus on a theoretical rationale that would lead the average clinician to think these three drugs might “quench” the propensity to further affective episodes, as opposed to simply assist in the management of acute manic states.

But the increased prevalence estimates were based on community surveys that had no clear disability criterion, while acute treatment trials of antipsychotics for mania, and prophylactic trials of lithium for manic-depressive illness, have for the most part been conducted on bipolar I disorder. This necessarily raises the prospect that increased efforts to detect and to treat people risks crossing the line where the benefits of treatment outweigh its risks.

Along with this expansion in prevalence estimates came new journals, Bipolar Disorders (http://www.blackwellpublishing.com/journal.asp?ref=1398-5647) and the Journal of Bipolar Disorders (published by Lippincott, Williams, and Wilkins), a slew of bipolar societies, and annual conferences, many heavily funded by pharmaceutical companies. There is a growing amount of patient Web site and patient support materials that in the case of Zyprexa state that “bipolar disorder is often a lifelong illness needing lifelong treatment; symptoms come and go, but the illness stays; people feel better because the medication is working; almost everyone who stops taking the medication will get ill again and the more episodes you have, the more difficult they are to treat” [17]. Information available from Janssen (the makers of Risperdal) states “medicines are crucially important in the treatment of bipolar disorders. Studies over the past twenty years have shown beyond the shadow of doubt that people who receive the appropriate drugs are better off in the long term than those who receive no medicine” [18].
What Lies Beneath

There is, however, much less evidence than many might think to support these claims for the prophylactic drug treatment of manic-depressive illness (bipolar I). And there is almost no evidence to support such claims in the case of whatever community disorders (bipolar II, bipolar NOS, cyclothymia) are now being pulled into the manic-depressive net by the lure of bipolar disorder.

With the possible exception of lithium for bipolar I disorder, there are no randomized controlled trials to show that patients with bipolar disorders in general who receive psychotropic drugs are better in the long term than those who receive no medicine [19]. This may stem in part from difficulties in conducting trials on psychotropic drugs that last more than a few weeks in conditions as complex as manic-depressive illness. One short-term, randomized, placebo-controlled trial (in which patients were only followed for up to 48 weeks) that some see as a basis for claiming that olanzapine may be prophylactic in bipolar disorder [2] has been regarded by others as indicating that this drug produces a withdrawal-induced decompensation when stopped [20]. Even in the case of lithium, there is some dispute over what has been demonstrated [19], with the best evidence stemming from large open studies in dedicated lithium services rather than from randomized trials [21].

This evidence of benefit for one agent (lithium) and possible benefit for one more (olanzapine) must be weighed against two harms associated with use of antipsychotics: (1) a consistent body of evidence indicates that regular treatment with antipsychotics in the longer run increases mortality [22–26]; and (2) there is evidence that in placebo-controlled trials of antipsychotics submitted in application for schizophrenia licenses there is a statistically significant excess of completed suicides on active treatment [27]. A range of problems associated with antipsychotics, from increased mortality to tardive dyskinesia, never show up in the short-term trials aimed at demonstrating treatment effects in psychiatry.

But aside from these hazards, there are also grounds to question whether the treatment effects that some think have been demonstrated in bipolar disorder trials translate into therapeutic efficacy. If use of these agents based on demonstrated effects leads on to efficacy, admissions for bipolar disorder might be expected to fall, but the evidence for this is difficult to find. In North Wales before the advent of modern pharmacotherapy, patients with bipolar I disorder had on average four admissions every ten years. In contrast, against a background of a constant incidence of bipolar I disorder, and dramatic improvements in service provision, bipolar I patients show a 4-fold increase in the prevalence of admissions despite being treated with the very latest psychotropic medications [11]. This is not ordinarily what happens when treatments “work,” but quite often is what happens when treatments have effects.

The selling of bipolar disorder stresses that the disorder takes a fearsome toll of suicides. And indeed the controversy surrounding the provocation of suicide by antidepressants has been recast by some as a consequence of mistaken diagnosis. If the treating physician had only realized the patient was bipolar, they would not have mistakenly prescribed an antidepressant. Because of the suicide risk traditionally linked to patients with bipolar disorders who needed hospitalisation, most psychiatrists would find it difficult to leave any person with a case of bipolar disorder unmedicated. Yet, the best available evidence shows that unmedicated patients with bipolar disorder do not have a higher risk of suicide.

Storosum and colleagues analyzed all placebo-controlled, double-blind, randomized trials of mood stabilizers for the prevention of manic/depressive episode that were part of a registration dossier submitted to the regulatory authority of the Netherlands, the Medicines Evaluation Board, between 1997 and 2003 [28]. They found four such prophylaxis trials. They compared suicide risk in patients on placebo compared with patients on active medication. Two suicides (493/100,000 person- years of exposure) and eight suicide attempts (1,969/100,000 person-years of exposure) occurred in the group given an active drug (943 patients), but no suicides and two suicide attempts (1,467/100,000 person-years of exposure) occurred in the placebo group (418 patients). Based on these absolute numbers from these four trials, I have calculated (see Figure S1 showing calculation, and see Figure 2) that active agents are most likely to be associated with a 2.22 times greater risk of suicidal acts than placebo (95% CI 0.5, 10.00).
Figure 2. Author's Graph of p-Value Function Based on Data in [30]

(Illustration: Sapna Khandwala)

The Bipolar Future

Until recently the general clinical wisdom was that it was very rare for manic-depressive illness to have an onset in the preteen years. But there is now a surge of diagnoses of bipolar disorder in American children [29,30], even though these children do not meet the traditional criteria for bipolar I disorder (from the Diagnostic and Statistical Manual of Mental Disorders) [31]. The mania for pediatric bipolar disorder hit the front cover of the American edition of Time in August 2002, which featured nine-year-old Ian Palmer and a cover title Young and Bipolar, with a strapline, why are so many kids being diagnosed with the disorder, once known as manic-depression?

A recent book, The Bipolar Child [32], brings out the extent of the current mania. Published in 2000, this book sold 70,000 hardback copies in six months in the US. As the Star Telegram reported in July 2000 [33], The Bipolar Child made all the difference to Heather Norris, whose mother, after reading it, challenged her physician to correct Heather's diagnosis from ADHD, treatment of which had made her daughter worse, to the correct diagnosis of bipolar disorder. As a result, Heather, at the age of two, became the youngest child in Tarrant County, Texas, to have a diagnosis of bipolar disorder. The Star Telegram article noted that “along with the insurance woes, lack of treatment options and weak support systems that plague most families with mentally ill children, parents of the very young face additional challenges. Finding the proper diagnosis for treatment is a nightmare because of scant research into childhood mental illness and the drugs that combat them.”

If we consider adults alone for a moment, there is already the potential for creating an “epidemic” of bipolar disorder, because people are being diagnosed with the condition based on operational criteria that depend upon subjective judgements (rather than an objective criterion of disability, such as hospitalization or being off work for a month). The potential is compounded in the pediatric domain by the fact that the diagnosis is based on caregiver reports with little scope in most clinical practice for critical scrutiny of the social forces that may lead to these reports. Experts that appear willing to go so far as to accept the possibility that the first signs of bipolar disorder may be patterns of overactivity in utero [32] can only further compound these problems. If the resulting diagnoses were provisional, aimed at researching the natural history of childhood irritability, rather than reaching diagnoses that lead on to pharmacotherapy, there might be little problem. However, drugs such as Zyprexa and Risperdal are now being used for preschoolers in America with little questioning of this development [31].

Far from research bringing a skeptical note to bear on clinical enthusiasm, it appears to be adding fuel to the fire. What might once have been thought of as sober institutions, such as Massachusetts General Hospital, have run trials of Risperdal and Zyprexa on children with a mean age of four years old [34,35]. Massachusetts General Hospital in fact recruited trial participants by running its own television adverts featuring clinicians and parents alerting parents to the fact that difficult and aggressive behavior in children aged four and up might stem from bipolar disorder. This does more than recruit patients with a clear disorder; it suggests that everyday behavioral difficulties may be better seen in terms of a disorder. Given that bipolar disorder in children is all but unrecognised outside the US, it seems likely that a significant proportion of these children will not meet conventional DSM criteria for bipolar I disorder. And given that it is all but impossible for a short-term trial of sedative agents in pediatric states characterized by overactivity not to show some rating scale changes that can be regarded as beneficial, the outcomes of this research are likely to appear to validate the diagnosis and increase the pressure for treatment.

Several years after Heather Norris was diagnosed with bipolar disorder, the rationale for mood stabilization was greatly weakened by the results of the largest-ever randomized trial of immediate versus deferred anticonvulsant therapy for people who had experienced a single seizure [36]. The trial found that although immediate antiepileptic drug treatment reduces the occurrence of seizures in the next 1–2 years, such treatment does not affect long-term remission in individuals with single or infrequent seizures. The use of psychotropic medication for bipolar disorders was based on an analogy with epilepsy, rather than on demonstrations of proven clinical benefits over the long term or on the basis of a correction of a known pathophysiology. The absence of a solid theoretical or empirical basis for using psychotropic medication as “mood stabilizers” raises questions as to what lies in store for the Heather Norris's and others of this world exposed to these complex psychotropic agents from such a young age.
Supporting Information

Figure S1. Episheet Showing Author's Relative Risk Calculation, Based on Data in [30]


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  18. De Hert M, Thys E, Magiels G, Wyckaert S (2005) Anything or nothing. Self-guide for people with bipolar disorder. Commentary by P. Grof. Antwerp: Uitgeverij Houtekiet. p 35.
  19. Harris M, Chandran S, Chakroborty N, Healy D (2003) Mood stabilizers: The archaeology of the concept. Bipolar Disord 5:446–452. Find this article online
  20. Ghaemi NS (2005) Uses and abuses of evidence based medicine in psychiatry. American Psychiatric Association meeting; Atlanta Symposium 37A; May 2005; Atlanta, Georgie, United States. Evidence based psychiatry. What it is and what it is not. Available: http://www.mobiltape.com and http://www.psych.org/edu/other_res/lib_archives/archives/meetings/2005saps.cfm. Accessed 6 March 2006.
  21. Tondo L, Baldessarini RJ, Floris G (2001) Long-term clinical effectiveness of lithium maintenance treatment in types 1 and 11 bipolar disorders. Br J Psychiatry 178:184–190 Supplement 41. Find this article online
  22. Joukamaa M, Heliovaara M, Knekt P, Aromaa A, Raitasalo R, et al. (2006) Schizophrenia, neuroleptic medication and mortality. Br J Psychiatry 188:122–127. Find this article online
  23. Healy D (2006) Neuroleptics and mortality: A 50-year cycle: Invited commentary on… schizophrenia, neuroleptic medication and mortality. Br J Psychiatry 188:128. Find this article online
  24. Brown S, Inskip H, Barraclough B (2000) Causes of the excess mortality of schizophrenia. Br J Psychiatry 177:212–217. Find this article online
  25. Mortensen PB (2003) Mortality and physical illness in schizophrenia. In: Murray R, Jones P, Susser E, editors. The epidemiology of schizophrenia Cambridge: Cambridge University Press. pp 275–287.
  26. Osby U, Correia N, Brandt L, et al. (2001) Mortality and causes of death in schizophrenia in Stockholm County, Sweden. Schizophr Res 45:21–28. Find this article online
  27. Healy D (2004) Shaping the intimate. Influences on the experience of everyday nerves. Soc Stud Sci 34:219–245. Find this article online
  28. Storosum JG, Wohlfarth T, Gispen de Wied CC, Linszen DH, Gersons BP, et al. (2005) Suicide-risk in placebo controlled trials of treatment for acute manic episode and prevention of manic-depressive episode. Am J Psychiatry 162:799–802. Find this article online
  29. Findling RL, Kowatch RA, Post RM (2003) Pediatric bipolar disorder. A handbook for clinicians London: Martin Dunitz.
  30. Isaac G (2001) Bipolar not ADHD. Unrecognized epidemic of manic-depressive illness in children Lincoln (Nebraska): Writers Club Press. (http://www.iuniverse.com) 102 p.
  31. Harris J (2005) The increased diagnosis of juvenile “bipolar disorder,” what are we treating? Psychiatr Serv 56:529–531. Find this article online
  32. Papolos D, Papolos J (2000) The bipolar child. New York: Random House. 416 p.
  33. Brooks K (2000 July 19) Families with mentally ill children confront health care shortcomings, undeserved stigma of “bad parenting.”. Fort Worth Star-Telegram: 1.
  34. Mick E, Biederman J, Dougherty M, Aleardi M (2004) Comparative efficacy of atypical antipsychotics for pediatric bipolar disorder [abstract]. Acta Psychiatr Scand 110:29. Find this article online
  35. Mick E, Biederman J, Aleardi M, Dougherty M (2004) Open trial of atypical antipsychotics in pre-schoolers with bipolar disorder [abstract]. Acta Psychiatr Scand 110:29. Find this article online
  36. Marson A, Jacoby A, Johnson A, Kim L, Gamble C, et al. (2005) Immediate versus deferred antiepileptic drug treatment for early epilepsy and single seizures: A randomised controlled trial. Lancet 365:2007–2013. Find this article online

The Newest Mania: Seeing Disease Mongering Everywhere

S. Nassir Ghaemi, July 25, 2006

Emory University Atlanta, Georgia, United States of America

Funding: The author received no specific funding for this article.

Competing Interests: SNG has received research grants and honorariums from GlaxoSmithKline, Pfizer, AstraZeneca, and Abbott Laboratories, and is on the advisory boards of GlaxoSmithKline and Pfizer.

Citation: Ghaemi SN (2006) The Newest Mania: Seeing Disease Mongering Everywhere. PLoS Med 3(7): e319 DOI: 10.1371/journal.pmed.0030319

Copyright: © 2006 S. Nassir Ghaemi. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

(E-mail: nghaemi@emory.edu)

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I feel compelled to comment on your article on bipolar disorder by my friend and colleague David Healy [1]. I respect Dr. Healy both as a historian of psychopharmacology and psychiatry and as a psychopharmacology researcher. I have been impressed by his historical scholarship over the years in bringing out the economic and social aspects of the rise of psychopharmacology. I think his specific critiques about the likely overuse of antidepressants in the West in recent years, as well as the influence of the pharmaceutical industry, have been valid in many respects. I also find the PLoS Medicine's April 2006 series of articles on disease mongering not unconvincing, especially as it relates to new potential diagnoses like adult attention deficit hyperactivity disorder. Yet I must take exception to the inclusion of bipolar disorder with such newfangled entities.

Mania and melancholia have been well described since antiquity, and the current notions about the diagnosis of bipolar disorder (even the broader notions of the “bipolar spectrum”) are fully present in the writings of Esquirol and Kraepelin. It seems highly unlikely that they were markedly influenced by the pharmaceutical industry. To accept the drift of this collection of articles, one would have to suppose that Arataeus of Cappadocia was heavily influenced by pharmaceutical marketing in the 1st century a.d.

Of course, the possibility of overdiagnosis of bipolar disorder exists, often influenced by the pharmaceutical industry, but this in no way means that the diagnosis itself is invalid, nor does it counteract the much larger empirical evidence that bipolar disorder has been highly underdiagnosed (rather than the minimal empirical evidence that it is overdiagnosed) in the antidepressant era [2]. Dr. Healy seems to emphasize the issue in children, where indeed more uncertainty exists, but the overall impression of the article does not do justice to the reality that this illness has a long history of description and much more evidence of nosological validity (based on description, genetics, course, and biological data) [3] than such newcomers as adult attention deficit hyperactivity disorder and restless legs syndrome. Perhaps we should be on the lookout for the newest mania: seeing disease mongering everywhere.

References

1. Healy D (2006) The latest mania: Selling bipolar disorder. PLoS Med 3:e185 DOI: 10.1371/journal.pmed.0030185. Find this article online
2. Ghaemi SN, Ko JY, Goodwin FK (2002) “Cade's disease” and beyond: Misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder. Can J Psychiatry 47:125–134. Find this article online
3. Robins E, Guze SB (1970) Establishment of diagnostic validity in psychiatric illness: Its application to schizophrenia. Am J Psychiatry 126:983–987. Find this article online

The Best Hysterias: Author's Response to Ghaemi

David Healy, July 25, 2006

1 Cardiff University Bangor, United Kingdom

Funding: The author received no specific funding for this article.

Competing Interests: DH has speaker, research, or expert witness links with all major pharmaceutical companies.

Citation: Healy D (2006) The Best Hysterias: Author's Response to Ghaemi. PLoS Med 3(7): e320 DOI: 10.1371/journal.pmed.0030320

Copyright: © 2006 David Healy. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

(E-mail: healy_hergest@compuserve.com)

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Nassir Ghaemi has helped raise the profile of this truly debilitating disorder [1], but he is wrong on the history of bipolar disorder. First, mental disease entities are a recent construct. No disease resembling bipolar disorder was described before 1854 in Paris, and the links between folie circulaire described then and modern bipolar disorder are tenuous. Second, for the Greeks, mania referred to any overactive insanity, and melancholia to any underactive state. The majority of manias were probably delirious states. The melancholias may have been anything from Parkinson disease to hypothyroidism. Third, Emil Kraepelin's manic-depressive insanity (1899) was a very different disorder to bipolar disorder, which only arose in the late 1960s. If bipolar disorder can be clearly traced back to the Greeks, the fact that American physicians so rarely made the diagnosis before 1970—when lithium was introduced in the United States—is hard to explain. Kraepelin's likely response to recent proposals that we recognize and distinguish between bipolar 1, 2, 2.5, 3, 3.5, 4, 5, and 6 and bipolar spectrum disorders would probably not be printable.

Disease mongering is not the creation of diseases de novo, as in the restless legs syndrome Dr Ghaemi cites, descriptions of which go back to antiquity. As so aptly defined by David Menkes at the Conference on Disease Mongering in Newcastle in 2006, disease mongering is where the interests of the seller of a nostrum, who sells by emphasizing the existence of and risks of some condition, in fact outweigh the likely benefits from the proposed remedy to those affected by the putative condition. It shades into hucksterism and it was associated with Harley Street long before modern pharmaceutical companies. But companies now bring an industrial efficiency to this practice, and where physicians were once a bulwark of scepticism against any trading on credulousness, they are now the most cost-effective marketing tool companies have.

Mongering applies to conditions from mild elevations of blood pressure or lipids, to bone thinning. No one argues hypertension or hypercholesterolaemia are not real or that in malignant cases these conditions do not constitute valid targets of treatment. But malignant cases are rare. In cases that are not malignant, when the likely intervention is with a toxic compound rather than a proposed alteration of lifestyle, there is or should be a boundary.

Psychiatry was once plagued by “boundary violations”, where physicians exploited the dependence of their patients. All the indications are that we are now in a new era of drug-related boundary violations. There is perhaps nowhere in medicine where this is more obvious than in the case of bipolar disorders, with adults treated with bizarre cocktails and children put on some of the most lethal drugs in medicine.

Making it clear that the term “mood stabilizer” is itself an advert and that the notion of bipolar disorder can be viewed as an instance of rebranding does not deny the reality of anything. The key concerns are not reality in this sense, but rather when to treat. As the history of hysteria shows, the best pseudo-convulsions come from patients with convulsive disorders, and the most realistic somatization from patients with other real disorders. Patients conform their presentations to the interests of their doctors. Drug companies know this. Patients deserve physicians alert to such possibilities. In the current welter of bipolar presentations, one worry is that patients with severe manic-depressive disorder will lose out. Another is that research on this most difficult of disorders will be invalidated by a dilution by patients with other problems. A final worry is that when the marketing caravan moves on, manic-depressive illness will be left once more under-resourced, and researchers will have one less lever to pull as they have “had their chance”.

Reference

1. Ghaemi SN (2006) The newest mania: Seeing disease mongering everywhere. PLoS Med 3(7):e319 DOI: 10.1371/journal.pmed.0030319. Find this article online

Questionable Advertising of Psychotropic Medications and Disease Mongering

Jeffrey R. Lacasse, Jonathan Leo , Florida State University Tallahassee, Florida, United States of America,  Lincoln Memorial University Harrogate, Tennesseee, United States of America, July 25, 2006

Funding: The authors received no specific funding for this article.

Competing Interests: The authors have declared that no competing interests exist.

Citation: Lacasse JR, Leo J (2006) Questionable Advertising of Psychotropic Medications and Disease Mongering. PLoS Med 3(7): e321 DOI: 10.1371/journal.pmed.0030321

Copyright: © 2006 Lacasse and Leo. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

(E-mail: jeffreylacasse@comcast.net)

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David Healy raises intriguing questions regarding the rapid increase in bipolar diagnoses and the use of “mood stabilizing” medications [1]. Although this phenomenon is multifactorial, surely consumer advertising has played a role.

A widely disseminated advertising campaign for aripiprazole (Abilify) claimed that it worked in the brain “like a thermostat to restore balance” [2]. Interestingly, the Abilify product Web sites for schizophrenia and bipolar disorder both used virtually identical explanations to describe both neuropathology and the drug's mechanism of action. Print advertisements promoting aripiprazole for bipolar disorder claimed: “When activity of key brain chemicals is too high, Abilify lowers it…. When activity of key brain chemicals is too low, Abilify raises it” [3].

Since the product information insert approved by the United States Food and Drug Administration (FDA) lists the mechanism of action as “unknown” [4], this advertisement is debatable. It is further questionable whether the complexities of treating bipolar disorder (with its unknown etiology and well-known heterogeneity in response to treatment) are accurately portrayed as a reliable, mechanical thermostat. However, consumers are likely to find such advertisements compelling.

Regarding unipolar depression, we recently argued [5] that antidepressant manufacturers commonly advertise their products by claiming that depression is caused by a lack of serotonin and that selective serotonin reuptake inhibitors normalize this deficiency, a claim not congruent with the peer-reviewed literature or FDA-approved product information. We have not received any academic objections to our article, but several prominent psychiatrists have affirmed our conclusions. For instance, Wayne Goodman, Chair of the FDA Psychopharmacological Advisory Committee, admitted that the serotonergic theory of depression is a “useful metaphor”—and one that he never uses within his own psychiatric practice [6].

The presentation of metaphorical explanations as scientific consensus in consumer advertising has not been publicly addressed by the relevant professional associations. In fact, we observe that a cooperative relationship exists between industry and medical facilities, even highly esteemed ones: the Mayo Clinic Web site on depression, sponsored by Wyeth Pharmaceuticals (makers of venlafaxine) explains the treatment of depression via the serotonin metaphor [7].

Such bioreductionistic and highly arguable advertisements for psychiatric treatments imply much about the disorder they are licensed for. As Dr. Healy suggests, consumers who view such advertisements are likely to characterize their problems in a manner congruent with industry promotion and to request well-advertised pharmaceuticals as treatment. At a bare minimum, increased medicalization will result; in some cases, disease mongering may indeed be an appropriate characterization.

Such consumer advertising is only possible in the absence of vigorous government regulation [8] or outcry from professional associations. We hypothesize that their combined silence significantly contributes to the process of disease mongering.

References

1. Healy D (2006) The latest mania: Selling bipolar disorder. PLoS Med 3:e185 DOI: 10.1371/journal.pmed.0030185. Find this article online
2. Otsuka America Pharmaceutical. (2006 January 17) Abilify consumer advertising website. Available: http://dtca.net/Pics/ABILIFY%20CACHE.htm. Accessed 7 June 2006.
3. Otsuka America Pharmaceutical. (2005 November 28) How Abilify is thought to work [advertisement]. People. Available: http://dtca.net/Pics/aripadvert.jpg. Accessed 7 June 2006.
4. Otsuka America Pharmaceutical. (2005 December) Abilify: Full product information. Rockville (Maryland): Otsuka America Pharmaceutical. Available: http://www.bms.com/cgi-bin/anybin.pl?sql=select%20PPI%20from%20TB_PRODUCT_PPI%20where%20PPI_SEQ=101&key=PPI. Accessed 5 June 2006.
5. Lacasse JR, Leo J (2005) Serotonin and depression: A disconnect between the advertisements and the scientific literature. PLoS Med 2:e392 DOI: 10.1371/journal.pmed.0020392. Find this article online
6. Anonymous. (2005 November 12) Television adverts for antidepressants cause anxiety. New Scientist. Available: http://www.newscientist.com/article/mg18825252.500.html. Accessed 22 April 2006.
7. Mayo Clinic. (2006) Video: Antidepressants: How they relieve depression. Mayo Clinic. Available: http://www.mayoclinic.com/health/antidepressants/MM00660. Accessed 22 April 2006.
8. Mintzes B (2006) Disease mongering in drug promotion: Do governments have a regulatory role? PLoS Med 3:e198 DOI: 10.1371/journal.pmed.0030198. Find this article online

Confessions of a Disease Monger

James Phelps, July 25, 2006,  Co-Psych.com, PsychEducation.org

Funding: The author received no specific funding for this article.

Competing Interests: Disease monger (see http://www.psycheducation.org/start/Funding.htm).

Citation: Phelps J (2006) Confessions of a Disease Monger. PLoS Med 3(7): e314 DOI: 10.1371/journal.pmed.0030314

Copyright: © 2006 James Phelps. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

(E-mail: jimp@psycheducation.org)

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I am a disease monger. I teach primary care doctors how to identify bipolar disorder. Worse yet, I take money from pharmaceutical companies for doing so. I use it to subsidize my practice so that I can treat patients with no insurance, or little money, who now account for over a third of my patients—in part because the pharmaceutical companies have drained so much money out of the health-care system. Ironic, isn't it?

My Web site PsychEducation.org (http://www.psycheducation.org) is number one on Google for searches on “bipolar II.” See if you think it looks like disease mongering. Hundreds of people have written thanking me for explaining bipolar II and the concept of a bipolar spectrum, indicating that this new perspective really helps them understand their long-standing symptoms. To my immediate recall, none have complained about being led astray by an overbroad interpretation of bipolarity.

Notice that, just like Mr. Moynihan, one of the guest editors of your April 2006 series of articles on disease mongering [1], I could be mongering even now, as I too have a new book. At least I'm not trying to attract attendees to my conference. Tricky, isn't it. Has there been an oversimplification in this analysis?

(PsychEducation.org earned an Honorable Mention Moffic Award for Ethical Practice in Community Psychiatry, 2005.)

Reference

1. Moynihan R, Henry D (2006) The fight against disease mongering: Generating knowledge for action. PLoS Med 3:e191 DOI: 10.1371/journal.pmed.0030191. Find this article online

Comparative Neurocognitive Effects of 5 Psychotropic Anticonvulsants and Lithium

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17406176
Posted 08/23/2006   MedGenMed. 2006 Aug 23;8(3):46.

C. Thomas Gualtieri, MD; Lynda G. Johnson, PhD

Context:
 Many of the new antiepileptic drugs have psychiatric indications, and most are prescribed by psychiatrists for patients with mood disorders, even when a specific indication is absent. Epileptic drugs as a whole, even the newer ones, are known to affect cognition, sometimes in untoward ways. Research on the neurocognitive effects of antiepileptic drugs, however, has been done exclusively in normal volunteers and in patients with seizure disorders.

Method: A naturalistic, cross-sectional study was conducted on patients who were taking 1 of 5 different antiepileptic drugs or lithium (LIT). Cognitive status was measured by a computerized neurocognitive screening battery, CNS Vital Signs (CNSVS).

Subjects: One hundred fifty-nine patients with bipolar disorder, aged 18-70 years, were treated with carbamazepine (CBZ) (N = 16), lamotrigine (LMTG) (N = 38), oxcarbazepine (OCBZ) (N = 19), topiramate (TPM) (N = 19), and valproic acid (VPA) (N = 37); 30 bipolar patients were treated with LIT.

Results: Significant group differences were detected in tests of memory, psychomotor speed, processing speed, reaction time, cognitive flexibility, and attention. Rank-order analysis indicated superiority for LMTG (1.8) followed by OCBZ (2.1), LIT(3.3), TPM (4.3), VPA (4.5), and CBZ (5.0).

Conclusion: The relative neurocognitive effects of the various psychotropic antiepileptic drugs in patients with bipolar disorder were concordant with those described in the seminal literature in normal volunteers and patients with epilepsy. LMTG and OCBZ had the least neurotoxicity, and TPM, VPA, and CBZ had the most. LIT effects on neurocognition were intermediate. Choosing a mood-stabilizing drug with minimal neurocognitive effects may enhance patient compliance over the long term.

Readers are encouraged to respond to George Lundberg, MD, Editor of MedGenMed, for the editor's eye only or for possible publication via email: glundberg@medscape.net

Antiepileptic drugs (AEDs) exercise suppressant effects on neuronal excitability, and thus can cause cognitive impairment.[1,2] The neurocognitive effects of AEDs, when they occur, have diverse presentations. They may be general, for example, cognitive blunting or psychomotor slowing, or they may be specific. Memory and attention are especially vulnerable to AED neurotoxicity. Cognitive effects of AEDs, when and if they occur, tend to be dose-related. They are more likely to occur when more than 1 AED is prescribed concomitantly.[3,4]

Although AEDs are prescribed with increasing frequency to patients with psychiatric disorders, very little has been written on the subject of AED-related cognitive impairment in these patients. Many of the new drugs that have been approved by the US Food and Drug Administration (FDA) as mood stabilizers are also AEDs (eg, VPA, CBZ, and LMTG). In bipolar disorder, AEDs are useful alternatives for patients who cannot tolerate or who fail to respond to LIT or antipsychotic drugs.[3,5–17] Because the therapeutic efficacy of LIT, VPA, CBZ, and LMTG is roughly equivalent, physicians who treat patients with mood disorders may encounter difficulty in selecting one drug over another.

The comparative effects on cognition of the psychotropic AEDs would be an area of interest if they were a factor in the decision to choose one drug over another. In the treatment of bipolar disorder, for example, a drug that spares cognition would be preferred to one that doesn't. Bipolar patients are particularly sensitive to perceived drug side effects, and selecting the right drug always tends to improve compliance.

Studies of AED effects on neurocognition have been conducted almost exclusively in normal volunteers and patients with epilepsy. In these studies, CBZ and VPA were demonstrated to be superior to diphenylhydantoin (DPH),[4,18–23] although neither CBZ nor VPA is entirely free of negative cognitive effects.[21,24] These negative effects were more apparent when CBZ and VPA were compared with the newer AEDs.[25] New AEDs, such as gabapentin, levetiracetam, LMTG, tiagabine, and OCBZ, appear to be better tolerated than DPH, CBZ, and VPA, and their toxicity profiles in neuropsychological tests tend to be benign.[24,26] The only new AEDs that possess significant negative cognitive effects are TPM and zonisamide (ZON), which have diffuse cognitive effects that are similar to the older AEDs, as well as specific effects on language.[3,24] The epilepsy literature indicates that there is a spectrum of neurotoxicity among the AEDs.

We thought that it would be interesting to see whether patients with psychiatric disorders expressed a similar pattern of response to the psychotropic AEDs. To address this question, we analyzed a clinical series of 129 bipolar patients who had been successfully treated with one of the modern AEDs, and who had been evaluated with a neurocognitive test battery.
   
Methods and Materials

This was a cross-sectional, naturalistic study of neurocognitive performance in patients with bipolar disorder who had responded satisfactorily to one of the following mood-stabilizing drugs: CBZ (N = 6), LMTG (N = 38), LIT (N = 30), OCBZ (N = 19), TPM (N = 19), and VPA (N = 37). LIT, of course, is neither a new mood stabilizer nor an AED. Data from LIT-treated patients were included for purposes of comparison. (None of the bipolar patients in our clinic database were treated with DPH, and very few were on ZON.)

Subjects
The subjects of this investigation were patients with bipolar affective disorder. They were all outpatients at the North Carolina Neuropsychiatry Clinics in Chapel Hill and Charlotte, North Carolina. They had been treated with one of the mood-stabilizing drugs listed above, and had achieved, in the judgment of their treating doctors, an optimal clinical response. The patients who were selected for this investigation had been on a stable dose of drug for at least 4 weeks.

Cognitive Evaluation
Patients' neurocognitive performance was measured on a computerized battery of tests, CNS Vital Signs (CNSVS). CNSVS is a PC-based neurocognitive screening battery composed of 7 familiar neuropsychological tests: verbal and visual memory, finger tapping, symbol-digit coding, the Stroop test, the shifting attention test, and the continuous performance test. The test battery is self-administered in the clinic on a computer, and takes about 30 minutes.

The tests in the CNSVS battery are reliable (test-retest, r = 0.65-0.88).[27] Normative data from 500 normal subjects, aged 10-89 years, indicate typical performance differences by age and sex.[28] Concurrent validity was established in studies comparing the CNSVS battery with conventional neuropsychological tests.[29,30]

The CNSVS tests are reported as raw test scores from the individual tests (15 “primary variables,” eg, correct responses, errors, and reaction time). The 7 tests in turn generate 5 “domain scores,” empirically derived by factor analysis. These are memory (derived from and verbal and visual memory), psychomotor speed (from finger tapping and symbol-digit coding), reaction time (Stroop test), cognitive flexibility (Stroop test and shifting attention test), and complex attention (Stroop test, shifting attention test, and continuous performance test). (“Cognitive flexibility” is an executive control function.) These are reported as standard scores (z scores standardized to a mean of 100 and a standard deviation of 15).

The average of the z scores for 5 domains generates a summary score, which is reported as a standard score (the Neurocognition Index [NCI]). This is similar to an IQ score on the Wechsler Adult Intelligence Scale (WAIS) or the Stanford-Binet, which is generated by averaging the z scores of the various subtests.

Method
The CNSVS database contains records from more than 2000 patients with neurologic and/or psychiatric disorders. The database was scanned for patients who met the following criteria: primary diagnosis, bipolar affective disorder; age, 18-70 years; no comorbid neurologic conditions or cognitive disorders (eg, dementia or brain injury); monotherapy with CBZ, LMTG, LIT, OCBZ, TPM, and VPA; stable doses maintained for at least 4 weeks; no other centrally acting drugs.

An independent chart review affirmed the diagnosis (by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR] criteria) and established that the treating clinician considered the patient to be a positive responder to the medication. No further medication changes were recommended or contemplated. All of the patients were tested within a 14-month period (July 2003-August 2004).

CNSVS generates 15 primary scores, 5 domain scores, and 1 composite score. Group differences were assayed by multivariate analysis, taking as covariates patient age, race, and sex. If a multiple analysis of variance (MANOVA) indicated significant group differences, pairwise t tests were done to determine the source of the difference.

   
Results

Table 1 shows data from the 159 patients, their age, medication and dose, and test scores. Immediately below the row “age,” is the NCI, the 5 domain scores, followed by the 15 raw test scores. Summary data are expressed graphically in Figures 1 and 2.
Table 1    Table 1
One Hundred Fifty-Nine Patients on Mood Stabilizers and Mean Test Scores
Figure 1    Figure 1
Cognitive effects of 6 mood stabilizers.
Figure 2    Figure 2
Neurocognition Index.

Group differences were apparent for the summary cognitive score, the NCI, for 3 domains – psychomotor speed, cognitive flexibility, and complex attention – and for the following tests: visual memory, coding, Stroop reaction time and errors, shifting attention test correct and errors, and continuous performance test errors. Pairwise statistics for the NCI indicated significant differences between LMTG and CBZ (t = 3.00, P = 004), LMTG and LIT (t = 2.01, P = .043), LMTG and TPM (t = 2.41, P = .019), and LMTG and VPA (t = 2.17, P = .03) – but not among any of the other drugs.

When the scores of the LMTG patients were compared with those of patients on the other 5 mood stabilizers, significant differences were observed in the NCI (t = 2.59, P < .01), reaction time (t = 1.96, P = .05), cognitive flexibility (t = 3.06, P = .003), and complex attention (t = 2.44, P = .016).

The relative ranks of the test and domain scores for the 6 mood stabilizers are given in Table 2. LMTG ranked first in the NCI and in 4 of the 5 domain scores (Kendall's W = 0.68, chi square = 23.9, P = .0002), and first or second in 10 of the 15 test scores (Kendall's W = 0.46, chi square = 34.8, P < .0001).
Table 2    Table 2
Rank-Order Analysis

This analysis suggests that in terms of neurocognitive effects, LMTG performs best, followed – in order – by OCBZ, LIT, TPM, VPA, and then CBZ. It also suggested 2 clusters of AEDs: LMTG and OCBZ, with low toxicity; and TPM, VPA, and CBZ, with high toxicity. LIT stands by itself in-between, with “medium” toxicity. Collapsing the cohort into 3 groups, we observed even more dramatic differences (Table 3, Figure 3).
Table 3    Table 3
Multivariate Analysis of Drugs With High, Medium, and Low Neurotoxicity
Figure 3    Figure 3
Cognitive effects of antiepileptic drugs divided into 3 groups.
   
Discussion

We present the spectrum of AED cognitive effects, from studies of normal volunteers and epilepsy patients, and the rank order of AEDs/mood stabilizers from our clinical series of bipolar patients.

The results were virtually the same. The older AEDs, CBZ and VPA, and the new one, TPM, had the most cognitive toxicity. LMTG and OCBZ had the least, and LIT was in the middle. The various psychotropic anticonvulsants exercised cognitive effects on patients with bipolar disorder, for better or worse, just as they would in normal volunteers and patients with epilepsy.

The relative neurocognitive effects of AEDs in epileptic patients were difficult to establish because of the inherent difficulty of evaluating small drug-related differences in patients with a brain disorder, many of whom already have cognitive impairments. Epilepsy, by itself, is sometimes associated with blunting of motor performance, cognitive ability, or other aspects of personality. It can be difficult to dissociate drug effects in epileptic patients from the psychological effects of the disease for which the drugs were originally prescribed. The measures of attention, memory, motor performance, and processing speed that are most commonly used in neurocognitive studies are also known to be negatively affected in epileptic populations not receiving drugs.[18,31,32]

The major psychiatric disorders are also associated with cognitive impairment. Patients with bipolar disorder tend to be impaired in measures of attention, memory, and executive control functions.[33] In fact, their cognitive deficits often persist even when they are euthymic.[34,35] This is true even of the best clinical responders, “patients in excellent clinical remission and who reported good social adaptation.[36]”

Cognitive studies of neuropsychiatric patients are prone, therefore, to at least a degree of ambiguity.[37,38] Nevertheless, regardless of a formidable signal/noise problem, a pattern has emerged. The literature suggests that AEDs that are predominantly GABAergic (barbiturates, benzodiazepines, VPA, gabapentin, tiagabine, and vigabatrin) are relatively sedating, and associated with fatigue, cognitive blunting, and weight gain. Drugs whose action is predominantly glutamatergic (eg, felbamate and LMTG) are associated with activation, weight loss, antidepressant effects, and cognitive sparing.[39] This pattern is consistent with results of the present investigation. In terms of cognitive effects, LMTG, for example, is clearly superior to VPA. VPA, despite its mood-stabilizing effects, is prone to negative cognitive effects in various dimensions – learning, memory, attention, and motor speed.[21,24]

That LMTG has a favorable cognitive profile in patients with epilepsy (and normal volunteers) has been established in a relatively large number of studies.[40] LMTG is structurally unrelated to the other anticonvulsants. In direct comparisons to DPH, phenobarbital, and CBZ, it has little cognitive or behavioral toxicity, but rather positive effects on “quality of life” and patient perceptions.[41–44] Even in mentally retarded people, LMTG is said to have “impressive” behavioral effects (less lethargy, reduced hyperactivity, improved social interactions, more appropriate speech, and less irritability).[45] The neurocognitive effects of LMTG in this study were apparent in visual memory, psychomotor speed, reaction time, cognitive flexibility, and sustained attention.

Data from this clinical series of bipolar patients suggested that OCBZ is only marginally inferior to LMTG. This, too, is consistent with data from epileptic patients. In patients with seizure disorders, OCBZ is better tolerated than its parent compound, CBZ. In patients with newly diagnosed epilepsy, and in normal subjects, neurocognitive performance on OCBZ is superior to CBZ.[40,46]

Studies in epileptic patients and normal volunteers indicated that TPM has the potential for diffuse cognitive toxicity, similar to that of CBZ and VPA. Psychomotor slowing is the most common cognitive complaint in patients treated with TPM.[47,48] It has been associated with significant declines in measures of attention and fluency, processing speed, language, perception, and working memory.[26,49,50] In one series, “the majority of the side effects were related to behavioral and cognitive difficulties.[51]”

The results of this investigation indicated that in patients with bipolar disorder, LMTG, and to a lesser degree, OCBZ, are relatively “clean” drugs, at least in terms of cognitive toxicity. The study authors acknowledge the weakness of the study, primarily its cross-sectional approach. A prospective study with a random assignment of patients would obviously be the preferred method. Nevertheless, the fact that our observations are consistent with a substantial literature in epilepsy patents and normal controls supports the validity of the patterns described.

In the epilepsy literature, it is noted that AEDs with a proclivity to cognitive toxicity tend to be less well tolerated by patients, and are more likely to induce behavioral side effects. This clinical series did not generate data to address issues, such as quality of life, or patients' subjective experience of cognitive impairment. If, however, it is fair to extrapolate from one patient group to another, lower rates of compliance with medications that have cognitive side effects should occur in bipolar patients as well. This would be an interesting question to pursue in bipolar patients.

One problem with laboratory studies of cognition in neuropsychiatric patients is that small but statistically significant differences in cognitive test scores may not be meaningful to patients or impressive to prescribing physicians. This is the problem of “clinical salience.” What, exactly, is the significance of small differences, such as those that we have discerned? The illustration in Figure 4 addresses that point with respect to patients' reaction time. There are 5 reaction time measures in CNSVS, in the Stroop test, the continuous performance test, and the shifting attention test. If we compare the reaction times of patients in the “low-toxicity” group (LMTG and OCBZ) with patients in the “high-toxicity” group (CBZ, TPM, and VPA), there is an average difference of 75 mseconds in favor of the former (Figure 4).
Figure 4    Figure 4
Reaction time.

What is the importance of a 75-msecond difference? It is only about 7 ft, in a car traveling 60 mph. Figure 4, however, indicates that the reaction time difference is more or less constant in every kind of mental operation measured in these 3 tests, from simple reaction time on the Stroop test to the speed-accuracy calculation that is necessary on the shifting attention test. What is the cumulative impact, then, of a 75-msecond difference when it is attached to every mental operation that a person executes during the course of a day?

Patients with bipolar disorder, as epileptic patients, are prone to mild cognitive impairment simply by virtue of their illness. When prescribing medications for such patients, one ought to attend to the relative effects that the drugs have on their cognitive status.

Readers are encouraged to respond to George Lundberg, MD, Editor of MedGenMed, for the editor's eye only or for possible publication via email: glundberg@medscape.net
    
Notes

Funding Information

This research was funded by North Carolina Neuropsychiatry, PA, in Chapel Hill and Charlotte. No external support was sought or received on behalf of this research.
    
All author affiliations

C. Thomas Gualtieri, North Carolina Neuropsychiatry Clinics, Chapel Hill, North Carolina; CNS Vital Signs, LLP, Chapel Hill, North Carolina Email: tg@ncneuropsych.com.

Lynda G. Johnson, North Carolina Neuropsychiatry Clinics, Chapel Hill, North Carolina.
   
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