Bipolar Depression and Rapid Cycling: The Latest Pharmacologic Strategies

Brown University Child and Adolescent Psychopharmacology Update 13(7):1, 10-12, 2002. © 2002 Manisses Communications Group, Inc.

Posted 07/09/2002
Introduction
Our ability to treat and manage patients with bipolar disorder -- both adequately and inadequately -- was the focus of several well-attended industry symposiums at the recent 155th American Psychiatric Association Annual meeting in Philadelphia. The latest data put the lifetime prevalence of bipolar disorder up to around 6.5 percent, with medical costs of up to $476,000 per year per patient. Astounding figures, and when one adds the fact that about 25 to 50 percent of those diagnosed with bipolar disorder attempt suicide, and that as many as 40 percent are not diagnosed or are misdiagnosed, the picture can look fairly grim for patients and families.
The most exciting of the bipolar disorder symposiums -- "Bipolar depression and rapid cycling: current management strategies" -- attempted to elucidate some of the most telling treatment deficiencies and explore the latest approaches to addressing them. Joseph R. Calabrese, M.D., Director of the Mood Disorders Program at the University Hospitals of Cleveland, and Professor of Psychiatry at Case Western University, chaired the symposium and said that the recognition and treatment of bipolar disorder has improved in recent years. However, he urged attendees to help eradicate the underdiagnosing and misdiagnosing of a disorder that takes such a personal and economic toll.

Presenter Mark A. Frye, M.D., director of the Bipolar Disorder Research Program at UCLA, examined the problem of unmet need more closely.

"Bipolar disorder is commonly unrecognized, hypomania is often overlooked, and bipolar depression is frequently not differentiated from unipolar depression," said Frye. "In one survey of 400 patients, 69 percent of patients with bipolar disorder had not been diagnosed initially, and bipolar disorder was most commonly mistaken for depression, anxiety and schizophrenia. More than one third of respondents had suffered symptoms of bipolar disorder for at least 10 years before they were diagnosed."

Frye also said that current treatment of bipolar disorder is inadequate. Treatment of the disorder as unipolar depression is particularly worrying because antidepressants may destabilize bipolar depression and may even cause mania and/or rapid cycling in some patients.

Joseph F. Goldberg, M.D., Director of the Bipolar Disorders Research Clinic at New York Presbyterian Hospital and Assistant Professor of Psychiatry at Cornell University, addressed the issue of stabilizing mood over long periods. He presented information on current treatment options, ranging from typical mood stabilizers such as lithium (Eskalith and others) and divalproex (Depakote, Depakene) that work from above baseline to help mania, hypomania and mixed episodes, to the newer atypical antipsychotics (see page 8). He also explored the possibilities offered by novel mood stabilizers like lamotrigine (Lamictal), that work from below baseline to help major depressive episodes and subsyndromal depressive symptoms -- a relatively novel concept.

"The three goals of mood stabilizer therapy is to treat manias without causing or worsening them, treat depressions without causing or worsening them and effective prophylaxis for manias and depressions," said Goldberg. "I'm hard pressed to find one agent that does all three of these things in an excellent way," he added.

Goldberg stressed the need to conceptualize mood stabilizers as primary antidepressants, and not just anti-manic drugs. He also recommends using antidepressants when needed for depression and the sustained use of antidepressants to prevent depression.

"Lithium is the only agent approved for long-term treatment of bipolar disorder, but where depression precedes mania, it may not work as well," said Goldberg."lithium prophylaxes mania better than it does depression."

Limitations of the current bipolar pharmacopoeia include:

Drug development in bipolar disorder has primarily focused on mania.

No treatment is specifically indicated by the FDA for bipolar depression.

Bipolar patients usually excluded from antidepressant FDA application studies.

Unimodal antidepressants can destabilize bipolar disorder (i.e., induction of mania or rapid cycling).

Lithium vs. Lamotrigine for Bipolar Depression
Data suggest that lithium will prevent or attenuate depression better if it has been effective first in the mania phase, according to Goldberg. Though results for divalproex and carbamazepine (Tegretol) for depression prophylaxis have been adequate, the most excitement has been generated by recent studies of lamotrigine for both bipolar depression and rapid cycling. Brand new data [Bowden CL, et al.: in press] comparing lamotrigine (LTG; N=69) and lithium (Li; N=58) to placebo (PBO; N=44), found both drugs superior to placebo in time to intervention for depression (LTG vs. PBO, P=0.015; Li vs. PBO, P=0.167; LTG vs. Li, P=0.355) when the index episode was mania.
In a second new open-label double-blind study [Calabrese JR, et al.: submitted for publication 2002] looking at the same comparison where polarity of entry was depression, lithium did not fair as well as lamotrigine in time to intervention for depression (LTG vs. PBO, P=0.047; Li vs. PBO, P=0.209; LTG vs. Li, P=0.434). In both trials, lithium was superior to lamotrigine and placebo in time to intervention for manic and mood episodes.

Goldberg also presented new data on factors associated with antidepressant-induced mania (Goldberg JF, J Clin Psychiatry, in press). Results showed that predictors of antidepressant-induced mania include substance use or dependence and having been on several antidepressant trials, particularly when there was a lack of response.

Rapid Cycling
Robert M. Post, M.D., released new data from two studies looking at the efficacy of lamotrigine for rapid cycling, as well as the use of combination therapy for this subset of patients.
"Although rapid cycling was once viewed as a rare presentation for bipolar disorder, recent data suggest that it may present in as many as 30 to 50 percent of patients," said Post. "We really have to revise our notions about rapid cycling; it is much more prevalent then it used to be and up to one quarter of one recent study sample remained ill three quarters of the time."

Clinical outcomes in rapid cyclers is often poor and these patients may be non-responsive or only partially responsive to lithium, according to Post. Treatment limited to antimanic agents that stabilize mood from above baseline usually only improves hypomania and mania, but not the depression phase, he added.

Newer agents in monotherapy or in combination with typical mood stabilizers may be able to effectively manage patients with rapid cycling. Across nine different studies, lithium has proven less effective in rapid cycling bipolar disorder, and more rapid cycling episodes prior to starting lithium is associated with poor response. Likewise, results have not been stellar for carbamazepine or combination carbamazepine/lithium treatment for rapid cycling.

Efficacy with valproate has been a little better, says Post, but again results for the depression phase of the cycling have been relatively poor. "In one study comparing lithium and valproate in rapid cycling," said Post, "we couldn't get more than 25 percent of the patients well enough to get them into the study -- with our two best drugs!"

Calling this a terrible statement for our field, Post added that most patients are relapsing through monotherapy. He presented data from the two new studies by Bowden et al. and Calabrese et al. mentioned above to offer some hope that lamotrigine might be effective for treating rapid cycling in bipolar I. An earlier study found the drug superior to placebo for rapid cycling in bipolar II patients only.

"Lamotrigine looks like it is better for the depressive side of rapid cycling and it appears to do it without any induction of mania," said Post.

He also noted that topiramate (Topamax) and quetiapine (Seroquel) look promising, but more data is needed.

"We are left with a lot of guesses with these patients and my own bias is to get the patient involved in tracking their own moods," concluded Post. "In the absence of randomized clinical trial data, we must use all these medications as best we can."

Sidebar: Bipolar Depression is the Greatest Unmet Need
Depression is the predominant pole;

typically first presentation of the illness;

episodes are longer and more frequent than mania;

in controlled maintenance studies, patients more commonly relapse into depression than mania.

Persistent early depressive symptoms predict depressive symptoms 15 years later and poor prognosis.

90 percent completed suicides in depression or mixed mania.
[Judd LL, et al.: Arch Gen Psychiatry, in press.]

Sidebar: One Schema for Treatment of Rapid Cyclers
Combination Treatment

Lithium + Valproate (Dysphoric Mania)

Lithium + Carbamazepine/Oxcarbamazepine (Schizoaffective, BPII, Substance Abuse)

Lithium + Lamotrigine (Depressions predominate)
Adjuncts

For Agitation/Insomnia -- 1) Clonazepam or Lorazepam; 2) Gabapentin (Social Phobia, GAD).

For Psychosis -- Atypical Antipsychotic

For Persistent Cycling -- Third Mood Stabilizer
Plus:

Weight Loss -- Topiramate
Cognitive Slowing -- T3/T4 (esp with lithium); Dihydropyridine; Ca++ blocker; Donepezil
Mania -- Third Mood Stabilizer; Atypical Antipsychotic; High-dose Thyroid
Depression -- Lamotrigine; Antidepressants (Bupropion, SSRI, SNRI, Folate, Omega-3 Fatty Acids, High Intensity Light)
Alcoholism -- Naltrexone
Atypical Depression -- MAOI; SNRI + Bupropion
Ultradian Cycling -- Dihydropyridine;Ca++ blocker
Highly Refractory Mania or Depression -- ECT
Post RM; Rapid cycling: clinical presentation and treatment approaches. New research presented at the 155th Annual Meeting of the American Psychiatric Association, Philadelphia, May 2002.