Biology 103
2003 First Paper
On Serendip

Bipolar disorder, also known as, "manic-depressive illness," is a brain disorder that results in unusual shifts in a person's mood, energy, and ability to function. More than two million American adults (or, about one per cent of the population aged eighteen and older in any given year) are afflicted by this affective disorder (1). Yet, because it cannot be revealed by a blood test or other physiological means, patients may suffer for years before it is properly diagnosed and treated. Fortunately, once one is diagnosed with bipolar disorder, the acute symptoms of the disease can be effectively mitigated by lithium and certain anticonvulsant drugs, the most popular being Depakote (also known as valproate).

However, not all drugs are created equal. The New York Times recently featured an article elucidating that Lithium, the first drug utilized to treat bi-polar disorder, is more conducive to preventing suicide in people who have manic-depressive illness than Depakote, what has become the most commonly prescribed drug (2).. The new study, published in The Journal of the American Medical Association, found that patients taking Depakote were 2.7 times as likely to kill themselves as those taking lithium (2).. Although studies conducted prior to this have concluded that lithium could in fact prevent suicide, this report is the first to compare suicide and attempted suicide rates in lithium and Depakote users (2).

Approximately fifty years ago, lithium "opened the modern era of psychopharmacology (3)." Its therapeutic effect is indeed very rapid. Administered in the form of lithium carbonate, it is most potent in treating the manic phase of a bipolar affective disorder; once the mania is eliminated, depression usually does not ensue (4). Such information is supported by many open studies, and at least ten controlled, double-blind studies. One study proclaimed that mania was reduced by 64 per cent, and depression, 46 per cent (3). The duration of both manic and depressive recurrent episodes was also reduced (by 19 and 32 per cent, respectively).

The most striking impact was found for the hospitalization rate, which fell by 82 per cent (3). This has considerable economic significance, as hospitalization accounts for a major proportion of direct costs in major psychiatric illness. It is important to note that all of this evidence far exceeds the available support for possible alternatives to lithium treatment, including application of anticonvulsant, antipsychotic, or sedative agents. Still, investigators have yet to discover the pharmacological effects of lithium that are responsible for its ability to eliminate mania. Many posit that the drug stabilizes the population of certain classes of neurotransmitter receptors in the brain (particularly serotonin receptors), preventing wide shifts in neural sensitivity, and in turn, influencing mood (4).

Unfortunately, however, some patients cannot tolerate the side effects of lithium, and because of the potential danger of overdose researchers have been searching for alternative medications. This spurred the trend of prescribing Depakote. In a review published by the American Psychiatric Association, valproate (Depakote) was reported to be more efficacious than lithium among manic patients with mixed symptoms (5). Moreover, the side effects were minimal. For example, sedation or gastrointestinal distress were common initially but typically resolved with continued treatment or dose adjustment. Depakote also has a, "wide therapeutic window;" in other words, inadvertent overdose is uncommon, and even intentional overdose is less noxious than an overdose of lithium. Therefore, it is only in rare instances that Depakote is rendered life-threatening. Nevertheless, Dr. Frederick K. Goodwin, the senior author of the study featured in The Journal of the American Medical Association and director of the psychopharmacology research center at George Washington University, argues, "Lithium is clearly being underutilized...the real tragedy is that a lot of young psychiatrists have never learned to use lithium (2)."

Simultaneously, however, Dr. John Leonard, a spokesman for Abbott Laboratories, the maker of Depakote, questioned the findings; he noted that the studies looking back at patients' records were inherently flawed, and not as reliable as studies in which patients were randomly assigned by researchers to take one drug or the other (2). Based on this potentially flawed study, I don't believe that doctors should suddenly stop prescribing Depakote altogether; as aforementioned, there are several benefits to taking Depakote, including a very low-risk of enduring life-threatening side-effects. Yet, based on the fact that lithium has proven successful for so many years, I also agree that it has become underutilized. It is imperative that young physicians are continually taught how and when to prescribe lithium.

I personally believe the solution is that bipolar disorder must be treated on a case-by-case basis. Evidence presented lends itself to this. For example, it was asserted earlier that Depakote is more efficacious in treating manic patients with mixed symptoms. Therefore, if a patient manifests mixed symptoms, Depakote should be more carefully considered. However, if prescribed, the patient should still be monitored for surfacing symptoms of suicide. If these symptoms emerge, his or her Depakote prescription should be discontinued or minimized. Likewise, if lithium is initially prescribed and not effectively treating a particular patient, Depakote, or a combination of these two treatments should be sought.

With regard to treating bipolar disorder, there is indeed a "war on drugs"; however, tenacious monitoring of patients and critical treatment experimentation and evaluation may help physicians soon find peace.

Sources Cited

1. National Institute of Mental Health: Bipolar Disorder
2. New York Times, 9/17/03: An Older Bipolar Drug Is Linked to Fewer Suicides in a Study (Denise Grady)
3. The British Journal of Psychiatry, 2001. Long-term Clinical Effectiveness of Lithium Maintenance Treatment in Types I and II Bipolar Disorders (Leonardo Tondo, MD)
4. Physiology of Behavior (textbook, 7th edition, Neil R. Carlson)
5. American Psychiatric Association. Practice Guidelines for the Treatment of Patients With Bipolar Disorder; Part B: Background Information and Review of Available Evidence