Archive for June, 2009

Antiepileptic medications have been a mainstay in the treatment of bipolar illness since the use of valproate in the 1980′s. Since that time other anticonvulsants such as carbamazepine, lamotrigine, and oxcarbazepine have been added to the list that help control the mood fluctuations that occur in bipolar disorder. In January 2008, the FDA issued an alert about patients being treated with antiepileptics:

In the FDA’s analysis, patients receiving antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%).  The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the eleven drugs.  Patients who were treated for epilepsy, psychiatric disorders, and other conditions were all at increased risk for suicidality when compared to placebo, and there did not appear to be a specific demographic subgroup of patients to which the increased risk could be attributed. The relative risk for suicidality was higher in the patients with epilepsy compared to patients who were given one of the drugs in the class for psychiatric or other conditions.

The following is a list of antiepileptic drugs included in the analyses:

• Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)
• Felbamate (marketed as Felbatol)
• Gabapentin (marketed as Neurontin)
• Lamotrigine (marketed as Lamictal)
• Levetiracetam (marketed as Keppra)
• Oxcarbazepine (marketed as Trileptal)
• Pregabalin (marketed as Lyrica)
• Tiagabine (marketed as Gabitril)
• Topiramate (marketed as Topamax)
• Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)
• Zonisamide (marketed as Zonegran)

How did the FDA arrive at this conclusion?

According to their documents, the FDA began receiving reports of the increased risk of suicidality with the anticonvulsants and did a preliminary review that confirmed the possibility. So in 2005, the FDA began analyzing 199 placebo controlled trials of eleven different antiepileptic drugs. The conditions studied in these clinical trials included epilepsy, selected psychiatric illnesses, and other indications, including migraine and neuropathic pain syndromes.  The analysis included 27,863 patients in drug treatment groups and 16,029 patients in placebo groups.  Patients included in the analysis were five years of age or older.  There were 4 completed suicides among patients in drug treatment groups and none among the patients in placebo groups.  There were also 105 reports of suicidal symptoms in the drug treatment groups in comparison to 35 reports of suicidal symptoms in the placebo group.

Overall, 0.43% of the patients in drug treatment groups experienced suicidal behavior or ideation versus 0.22% of the patients in placebo groups, corresponding to an estimated 2.1 per 1000 (95% CI: 0.7, 4.2) more patients in the drug treatment groups who experienced suicidal behavior or ideation than in the placebo treatment groups.  In comparison, the overall suicide risk in a treated bipolar population was found to be 3.66% in the STEP-BD study (Marangell, et al. Prospective Predictors of Suicide and Suicide Attempts, Bipolar Disorders 2006, 8: 566-575). In this analysis, the relative risk for suicidal thoughts or behavior was higher for patients with epilepsy compared to those patients with psychiatric or other disorders.  The higher risk for suicidal behavior or suicidal ideation was observed at one week after starting a drug and continued to at least 24 weeks.  The results were generally consistent among the drugs and were seen in all demographic subgroups. Specifically, there was no clear pattern of risk across age groups. (For more information please go to: http://www.fda.gov/cder/drug/InfoSheets/HCP/antiepilepticsHCP.htm)

The Response

The FDA has placed a warning label on all antiepileptic drugs reflecting this increase risk of suicide, but it did not attach the dreaded black box warning. Since then, numerous groups have weighed in on the FDA’s findings. At a December 2008 meeting of the American Epilepsy Society, two researchers presented evidence that the findings are inconsistent and vary greatly by drug, region, and illness. Still other experts felt that this warning will do more harm than good and that it is too early to make such a broad statement without further research to substantiate the FDA’s claims. A noted psychiatrist, Dr. David Kahn of Columbia University, weighed in by commenting that the risk of suicide in bipolar disorder is far higher in an untreated patient than a treated one, and that both doctor and patient should be aware of the risk of suicidality in bipolar disorder.

What should you take from all of this?

It appears that antiepileptic drugs roughly double the risk of suicidality as compared with placebo. However, the absolute risks are small, and the effect appears more likely in patients treated for epilepsy than for patients with psychiatric illness (although the FDA has yet to publish all the data required to compare these two populations). In our daily practice, we as psychiatrists are always closely monitoring patients for any evidence of suicidality, so any signs and symptoms should be detected early and carefully evaluated. If it appears a medication is contributing to the increased suicidality, it should be discontinued. With this close monitoring of a given patient’s mood state and the small absolute risks found in the FDA’s analysis, we believe the risk associated with prescribing anticonvulsants in bipolar illness is extremely small. That being said, these findings should be discussed with any patient prior to initiating treatment with an antiepileptic medication, and more research is needed to understand the possible link between suicidality and antiepileptics.

This is an excellent overview of bipolar illness and is written for the practicing clinician. It covers bipolar types I and II as well the more subtle “soft” bipolar spectrum disorders.  The comorbid medical, psychiatric and substance abuse problems associated with bipolar illness are examined in detail.  Treatment interventions including pharmacologic, psychotherapeutic, and psychosocial are explained clearly and concisely.  I would highly recommend this book for any clinician, therapist, etc. who works with bipolar patients.  Informed lay people could also benefit from this book as well.

Goodwin and Jamison, 1990
The bible on MDI circa 1990, this book reviews and summarizes all scientific info on all aspects of this disease (genetics, diagnosis, pathophysiology, subtypes, treatment, etc…) Not an easy read and generally, not for the lay public. Unsurpassed reference work.

The long awaited follow-up to the 1990 definitive and comprehensive text has finally been updated.  The second edition not only maintains the overall quality of authorship of the original, it surpasses its forerunner in presenting its data in more succinct and readable form.  The result is the highest level of scholarship wherein dense levels of information are made palatable by simple but elegant synthesis and writing.  As with the first edition, this book is mainly intended for a professional audience. Starting from the beginning, the 2^nd edition adds the subtitle “Bipolar Disorders and Recurrent Depression.”  A subtle but hardly insignificant change.  This shift emphasizes the author’s belief that recurrent affective disorders, regardless of the presence of mania/hypomania, share fundamental diagnostic, etiological and pathophysiologic attributes and that they should rightfully be classified together.  This contrasts with the prevailing American model of diagnostically prying apart mood disorders on the basis of episode polarity.  With this change, Goodwin and Jamison place themselves squarely in the spectrum’ camp of those that see recurrence as the defining essence of bipolarity.

The organization of this text adheres to the same basic layout as the original version.  Chapters are organized sensibly with clinical description and clinical studies preceding and setting the stage for subsequent sections on pathophysiology and treatment. A tribute to its editors, this work does not suffer from the redundancy that is typical of other comprehensive texts.  Summaries of each chapter distill the major points into bite-sized manageable conclusions.  The references are exhaustive and thoroughly up-to-date.

There are, I think, two potential uses for this book.  The easier of the two is as an authoritative reference work.  Used in this fashion, the text provides an accessible place to gain an initial foothold, quickly review a body of literature, or mount a more thorough exploration of virtually any topic in this arena.  When serving this function, the book is a delight:  the right place to go, the best place to start, equally good for both a glancing refresher as an in-depth review.

The second, more challenging role for this work is as an advanced textbook for psychiatrists and psychologists seeking to gain an extensive grounding in the field of recurrent affective disorders.  In this role, both graduate and post-graduate classes could be designed around a complete reading of this book.

The editors strive for an impartial tone in the presentation and summarization of the research findings.  I did not get the sense that they are ideologues nor that they champion certain positions on various controversies in the field.  Their allegiance to disease-specific empiricism (ie, data derived from randomized, controlled trials) is, however, obvious.  This allegiance contributes to an unfortunate constriction in the scope of this work resulting in a failure to include some very relevant psychoanalytic literature on affect and affect regulation, attachment theory and development research on affect.  But perhaps this is too much to expect from any single work.

Concluding summary:  it doesn’t get any better than this.  In terms of modern psychiatric textbooks, this writing sets a new standard for our field.  It will be the new definitive work in this area for years to come.

Responding to the general absence of information for the lay public on the less acute forms of manic depressive illness, this book provides a helpful overview of the symptoms, course and diagnosis of these less well-known bipolar subtypes.  Written in ultra-basic, simple language, by Dr. Jim Phelps, the Corvallis, OR psychiatrist behind the incredibly useful website psycheducation.org, this work is designed to familiarize readers with the characteristics of Bipolar Disorder Type II.  But there is another, larger agenda here:  to present a different diagnostic viewpoint on bipolarity itself, one that emphasizes illness course, and specifically recurrence, as the hallmark of the illness.  This, in contrast to the current American schema, exemplified in DSM IV TR that sees episode polarity, specifically mania/hypomania, as the defining essence of the condition. Dr. Phelps explains in a clear, pain-staking and repetitive fashion the rationale for using recurrence as the defining standard, the implications this has for diagnosis (it vastly broadens the scope of the condition to include all other recurrent mood disorders such as recurrent depression, SAD, PMDD, etc…) and for treatment.  With regard to treatment, Dr. Phelps repeatedly emphasizes the hazards that can occur from both antidepressant monotherapy (using antidepressants alone without a mood stabilizer) and using antidepressants in combination with mood stabilizers.  My only quibble here is that this is presented as fact rather than the actual, active controversy that surrounds this issue today.  In my opinion, we are far from agreement on the appropriate role of antidepressants in the treatment of the bipolar depression.  This aside, Dr. Phelps should be commended for authoring a much-needed and easily understood treatise on the spectrum concept in manic depression.

This book is directed at a lay audience and devotes itself to defining and explaining this most common subtype of bipolar illness. This book is very informative for any patient with bipolar II but also has some serious problems. So, first with the good. Dr. Fieve’s writing is clear and concise, and his patient examples are both interesting and appropriate. He differentiates Bipolar II from Bipolar I quite well and explores all of the aspects of bipolar II. He covers the range from genetics to the critical importance of sleep/biological rhythms to the behavioral disturbances (e.g. substance abuse, hypersexuality) associated with bipolar illness. The second half of the text details the diagnostic and treatment modalities and prepares the patient as to what to expect in that process. Comorbid illnesses, such as ADHD and panic disorder, are also discussed.

My problems with this book come largely from Dr Fieve’s idea that this illness is somehow beneficial to patients. He has even created his own subtype – Bipolar IIB -wherein the “B” stands for beneficial. He makes numerous comments about his patients being the “movers and shakers” in New York City and associates their bipolar II illness with their level of success. I will admit that I have seen some very successful patients in my practice with bipolar II but I believe they succeed despite all of the problems that the illness brings. The second problem occurs in his treatment parameters. He places little importance on psychotherapy and it is depicted as only an adjunct to the appropriate medications. My belief is that the appropriate medications are only the start of treatment, and psychotherapy teaches the patient how to cope with their illness and try to achieve some balance in their life.

I would recommend this book because it is one of the few devoted entirely to Bipolar II, but I have some serious reservations as noted above.

Both literary and scientific, presents info mainly on BPI D/O (but also prodromal and softer forms of illness and their relationship to acute episodes) in accessible form. Beautifully depicts relationship between person’s environment and illness, contextualizes illness in personal history and psychology.

Kay Jamison, 1996.
Mainly biographically based review of the link between artistic genius and creativity and Bipolar Disorder.

Francis Mondimore, M.D. 1999.
Easy-to-understand primer with a nice, basic explanation of normal vs. abnormal mood states and subsequent overview of mania, depression, hypomania and bipolar subtypes. Goes on to review basic pharmacologic and psychotherapeutic treatments although it is now, somewhat dated on both. A good first read.

Quarterly magazine containing scientific and legislative news and
describing people, both famous and otherwise, with bipolar disorder.
1-866-672-3038 and website: http://www.bphope.com/