Treatment Alternatives for Bipolar Disorder

By Arline Kaplan © 2000 (All Rights Reserved)

In his recent summary of rational treatment alternatives for the bipolar patient, psychiatrist Mark Frye, M.D., presented new data on intravenous valproate (Depacon) and atypical antipsychotics for treating mania. He also discussed mood stabilizers for bipolar depression, for conduct disorder and for mood lability in youth.

Frye, associate director of the Mood Disorders Research Program at the University of California, Los Angeles (UCLA), and West Los Angeles Veterans Affairs Medical Center, spoke about algorithms and new treatments for bipolar and related disorders at the 13th Annual U.S. Psychiatric and Mental Health Congress in San Diego.

He prefaced his discussion of treatments with an alert about the immense economic cost of bipolar disorder and an appeal for improved diagnosis. Frye, describing a recent study, said that Charles Begley, Ph.D., and Alan C. Swann, M.D., of the University of Texas, Houston Health Science Center, estimated a lifetime cost of $24 billion for providing care to all individuals newly diagnosed with bipolar disorder in 1998 or $250,000 each. Average cost per case ranged from $11,720 for persons with a single manic episode to $624,785 for persons with nonresponsive/chronic episodes (Begley et al., 2001).

"If we can identify the illness and aggressively treat it, it is our hope that the burden and cost will decrease," Frye added.

But diagnosis can "often be quite challenging" Frye said, pointing to many patients who are symptomatic for years before the diagnosis of bipolar disorder is made.

One new diagnostic aid, he said, is the recently developed Mood Disorder Questionnaire (MDQ), a self-report, single-page, paper-and-pencil inventory that can be easily and quickly scored by a physician, nurse or trained medical staff assistant (Hirschfeld et al., 2000). When patients answered yes to seven of 13 questions on the MDQ related to manic or hypomanic symptoms, "the ability to correctly identify individuals with bipolar disorder was 73%," Frye said. Additionally, nine out of 10 patients who answered fewer than seven questions were correctly identified as not having a bipolar spectrum disorder.

The MDQ is a preliminary instrument "used to enhance our sensitivity of diagnosing the condition, but not specifically subtype patterns, such as dysphoric, mixed or rapid-cycling," according to Frye who is assistant professor of psychiatry at UCLA School of Medicine.

"We are going to see a lot more of this instrument," he said, "and I think the real punch will be the benefit of using such an instrument in general medicine clinics and in family practice clinics." Prospective patients could also be asked to complete the MDQ before coming to a psychiatrist’s office for an appointment.

Treatment Approaches, Algorithms

Shifting to treatment concerns, Frye said, "The real challenge about bipolar disorder is that we are either treating mania or we are treating depression, but we have always got to keep in mind what the liabilities of treatments might be for the other pole of the illness. When we are treating mania, are we going to be using a medication that actually promotes post-manic depression, or post-manic depressive severity, such as a typical antipsychotic? When we treat bipolar depression, are we going be using a medication, such as a unimodal antidepressant agent, that has a liability for inducing mania or rapid cycling?"

Rational treatment algorithms (e.g., the Practice Guideline for the Treatment of Patients with Bipolar Disorder [American Psychiatric Association, 2000] and the Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder [Sachs et al., 2000]) are important guidelines for clinicians, according to Frye. They are based on well-established controlled data, and on recommendations of individuals who treat many patients with bipolar disorder and have had experience with different types of medications.

In the Expert Consensus Guideline Series, for example, 58 national experts on bipolar disorder completed a survey with different types of patient presentations, and they indicated which treatments they would use as first-line, second-line or alternative strategies.

"The treatment of choice for euphoric mania was lithium [Eskalith, Lithobid] or divalproex sodium [Depakote]; the treatment of choice for dysphoric mania, divalproex; the treatment for psychotic mania, lithium or divalproex, plus an atypical antipsychotics; the treatment for rapid-cycling, currently manic, divalproex. These are guidelines looking at first-line agents, based on well-established controlled data, and important when we think about algorithms in treating patients with bipolar disorder."

Frye then considered the advantages and disadvantages of specific agents. Based on 30 years of American and 50 years of worldwide clinical experience with lithium, clinicians know some patients do well on this agent while others do not.

When categorized by subtypes, patients who tend to be lithium responsive are those who are nonrapid cycling, who have euphoric mania, who have no history of substance abuse, who have a positive family history of lithium response, who have few lifetime episodes and who have a pattern where mania precedes depression, according to Frye.

Bipolar conditions less responsive to lithium, he said, include patients who are rapid-cycling, who have abused substances or are currently substance abusers, who have a negative family history of lithium response, who have more than three episodes and who have a pattern where depression precedes mania (Frye and Altshuler, 1997).

"One of the strongest predictors of lithium nonresponse is the aspect of depressive symptoms in mania," Frye said.

He cited a study by Swann et al. (1997), a secondary analysis of Bowden et al. (1994) study showing that divalproex and lithium were equally efficacious in the treatment of acute mania. When Swann et al. went back to that data set and looked at the presence of depressive symptoms, they found that even modest pretreatment depression-related symptoms were a robust predictor of lithium nonresponse, and were associated with a better response to divalproex.

Frye also shared data from "boutique studies," including one from investigators at the Ludwig-Maximilians University in Munich. Grunze and colleagues (1999) studied the use of intravenous valproate loading in seven inpatients with bipolar I (two with euphoric mania; three, mixed state; two, depressed mood)

"I think it is an important study in showing there are many different ways to treat mania," Frye said. For the five manic patients, intravenous valproate was given at 600 mg and was infused over a 20- to 30-minute time period. Patients were given that dose two or three times per day, depending on their weight. Over a five-day period, the dose was increased as clinically needed. Four of the five patients with mania showed a rapid (usually within 24 hours) and favorable response to intravenous valproate loading, building up sufficient blood levels that were maintained with consecutive oral treatment. Of the two patients with depressed mood, one experienced minor benefits while the other showed no change.

"We typically think of a reduction of 50% [in affective symptomatology] as being identified as a response," Frye said.

For this small study, there was a 75% decrease on the Bech-Rafaelson Mania Rating Scale (BRMAS) in the five manic patients. The intravenous valproate was generally well-tolerated; the only observed side effect was sedation. There were no adverse gastrointestinal effects. Grunze and colleagues also noted that intravenous valproate led to a drastic reduction in and eventual withdrawal of benzodiazepine treatment in two cases.

Another interesting idea, Frye said, comes from a randomized, multicenter, double-blind clinical trial conducted by the European Valproate Mania Study Group (Müller-Oerlinghausen et al., 2000). The results of the trial suggest "that we can decrease the neuroleptic burden of manic patients hospitalized," Frye said, explaining that typical antipsychotics are primarily first-line agents for the treatment of mania in Europe.

In this study, patients who met the International Classification of Diseases (ICD-10) criteria for acute manic episodes were given a fixed dose of 20 mg/kg of body weight of sodium valproate orally in addition to their antipsychotic/neuroleptic, commonly haloperidol (Haldol) or perazine. Over the course of the three-week study period, the clinician was asked to decrease the neuroleptic as clinically indicated. This group was compared to another group that received a neuroleptic and an add-on placebo. The mean neuroleptic dose declined continuously in the valproate group, but only slight variations occurred in the placebo group. The difference was statistically significant in study weeks 2 and 3.

"At the end of the study, …it is very clear that a combination of the antipsychotic and divalproex sodium was associated with a significantly better response than add-on placebo," Frye said. "So this is an example of combination synergy, as well as being able to reduce the neuroleptic burden."

The U.S. Food and Drug Administration’s approval of divalproex sodium, an anticonvulsant, for treatment of manic episodes associated with bipolar disorder spurred researchers to look at other newly approved anticonvulsants as possible mood stabilizers, Frye said.

There are an enormous amount of open-trial data that look promising for gabapentin (Neurontin) as an add-on treatment, Frye said. In 12 open-label studies (N=295), the response rate was 65% (Frye et al., 2000). These were individuals who were on mood stabilizers, but still symptomatic of their illness or intolerant of side effects, and their clinicians were looking at gabapentin as an add-on treatment. The mean daily dose was 2000 mg.

There are, however, two controlled studies involving gabapentin where the results were negative. The first study (Pande et al., 1999), involved 117 outpatients with acute mania who were on lithium and/or divalproex and received either add-on placebo or add-on gabapentin, flexibly dosed between 900 mg/day and 3600 mg/day. In that study, placebo was superior to gabapentin for mood symptom amelioration.

"Our study looked at a different patient population—inpatients [with] refractory affective disorder—and found that gabapentin was ineffective compared to placebo or lamotrigine," Frye said. "So we have a bit of a divide, where we have a large, uncontrolled set of observations looking promising, and a smaller group of studies, more rigorously defined, not confirming mood stabilization properties. So the question is, is this drug really a mood stabilizer, our answer to date would appear to be no [Frye et al., 2000]. Certainly, it is a very effective medication for panic disorder, social phobia, many neuropathic presentations, and we know often our patients can be comorbid with those conditions."

Topiramate (Topamax), FDA-approved as an add-on treatment for epilepsy, was studied in an open trial of 11 acutely manic patients (Calabrese et al., 1998). About one-third of the patients had significantly reduced Young Mania Rating Scale (YMRS) scores at the end of the trial. This open trial set the basis for a controlled study that is currently being evaluated, Frye said.

Another class of medications Frye discussed were the atypical antipsychotics. Olanzapine (Zyprexa) has FDA approval for the treatment of mania. Two placebo-controlled studies show there is a greater reduction in manic symptoms in comparison to placebo. In the first study (Tohen et al., 1999), 48.6% of the acutely manic patients being treated with olanzapine responded, where as only 24.2% of those on placebo responded. In the second study (Tohen et al., 2000), 115 patients with a DSM-IV diagnosis of bipolar disorder, manic or mixed, were randomized to olanzapine (n = 55) or placebo (n = 60). Olanzapine-treated patients demonstrated a higher rate of response compared to placebo-treated patients (65% versus 43%) (p=0.02)

Since both divalproex and olanzapine appear to help in treating mania, Frye said, "What is needed now are comparative studies …addressing efficacy, stabilization, tolerability."

With regard to risperidone (Risperdal), Frye cited a study by Sachs et al. (2000) that compared add-on risperidone (1 mg/day to 6 mg/day), haloperidol (2 mg/day to 12 mg/day) or placebo with open-label lithium or valproate for the management of acute mania. For individuals who were breaking through their mood stabilizer, add-on risperidone was as "good an add-on as haloperidol," Frye said.

Asked about the atypical antipsychotic quetiapine (Seroquel), Frye responded that he was aware of some case reports from Ghaemi (Ghaemi and Katzow, 1999) where it was used for treatment-resistant bipolar disorder.

"The critical, early small-scale impressions are positive," Frye said. "I am aware of one study that is looking at Seroquel in a placebo-controlled way for the treatment of mania."

Bipolar Depression

For the treatment of depression in bipolar disorder, antidepressants have a liability for inducing mania and rapid-cycling, but that is not the case with mood stabilizers, Frye said. This treatment approach is an area of increasing study.

"Treating bipolar depression with a mood stabilizer appears to be quite effective," Frye said. "We have finished a study looking at divalproex sodium versus placebo in a more controlled investigation, and that data is now being analyzed."

Looking at lamotrigine (Lamictal), Frye said, Calabrese et al. (1999) published a study showing that the lamotrigine treatment of non rapid-cycling bipolar type I depression can be very effective. In the double-blind, placebo-controlled study, both lamotrigine at 200 mg/day and at 50 mg/day demonstrated antidepressant efficacy compared with placebo on several measures, such as the 17-item Hamilton Rating Scale for Depression (HAM-D).

(In a double-blind, placebo-controlled prophylaxis study [Calabrese et al., 2000], lamotrigine was a useful treatment for some patients with rapid-cycling bipolar disorder. The differences favoring lamotrigine over placebo were consistently greater for patients with bipolar II than patients with bipolar I—AK)

One of the dilemmas clinicians face, Frye said, is whether to add a second mood stabilizer or add an antidepressant to an initial mood stabilizer in patients with bipolar depression. Young et al. (2000) compared the addition of an antidepressant (paroxetine [Paxil]) versus the addition of a second mood stabilizer for 27 outpatients with bipolar II or II who experienced a major depressive episode while being treated with either lithium or divalproex.

"Half of the group went to a double mood stabilizer combination—receiving both lithium and divalproex sodium. The other group stayed on the mood stabilizer they were on and had paroxetine added on board. What you see over the course of six weeks, is an equal reduction in depressive symptoms. Surprisingly over this short period of time, there was no difference in the induction of mania…a higher dropout rate was noted with the double mood-stabilizer combination."

These kinds of studies need to be for longer duration and need to include rapid-cycling and psychotic patients as subjects, Frye added.

Aggression

Frye emphasized the importance of looking at the use of lithium, anticonvulsants and antipsychotics in nonadult populations for treating disorders possibly related to bipolar disorder.

"We know bipolar illness for many develops prodromally in childhood and adolescents," he said. Malone et al. (2000) looked at the efficacy of lithium in treating children and adolescents who have conduct disorder and were hospitalized because of severe and chronic aggression. At the end of the four-week trial, the researchers concluded, "Lithium is a safe and effective short-term treatment for aggression in inpatients with conduct disorder, although its use is associated with adverse effects."

In the lithium treatment group, 16 of 20 (80%) were responders compared to 6 of 20 (30%) in the placebo group, as rated by the Global Clinical Judgments (Consensus) Scale (GCJCS). Nausea, vomiting and urinary frequency were more frequently associated with lithium than with placebo, but no subject dropped from the study because of the side effects.

Another recent study (Donovan et al., 2000) suggested that divalproex sodium could decrease emotional lability and hostility, Frye said. The study looked at 20 outpatients (aged 10 to 18 years) with a disruptive behavior disorder that met criteria for explosive temper, mood lability and aggressivity. In this randomized, double-blind, crossover study, the groups received either divalproex sodium (750 mg/day to 1500 mg/day) or placebo. The researchers looked at who got better on measures of aggressivity and hostility, such as the Modified Overt Aggression Scale (OAS) and six items from the anger-hostility subscale of the Symptom Checklist-90 (SCL-90).

In the first arm of the study, the response rate was 80% for blinded divalproex sodium, and 0% for placebo.

"After that four-week period, the patient groups switched, and received the alternate study drug. So patients who were on placebo, crossed over to divalproex sodium and had a 86% response rate; the divalproex group crossed over to placebo and had a 25% response rate."

Frye concluded his talk by characterizing the future of treating bipolar disorder as having never looked brighter.

"We are developing more treatments," he said, "and we are finally realizing the importance of studying bipolar depression."

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