Expert Consensus Guidelines:
Medication Treatment of Bipolar Disorder

(August 12, 2000) -- The joke is, "If you have two psychiatrists, you will get three conclusions," says Gary Sachs, M.D. Such is not the case with the recently published Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder 2000. (See related article on "Consensus Guidelines Applied in NIMH Project" on page 5-Ed.)

The level of consensus among the experts is extraordinary, said Sachs, who is director of Partners Bipolar Treatment Center at Massachusetts General Hospital and one of the guidelines' editors. On 89% of the issues, he explained, there is consensus about what the first-line treatments are. Additionally, consensus exists about how to handle a manic patient and what to do if someone has rapid cycling or bipolar depression.

HealthyPlace.com Radio Treatment Guidelines for Bipolar Disorder: Part I and Part II listen with realplayer. audio table of contents here.

"That really is heartening, because it means we can speak to our patients, their family members and the general public with greater confidence," he said, adding that people familiar with the literature are "speaking with one voice."

The 2000 medication guidelines-an update of the first guidelines (Kahn et al., 1996)-were based on reviews of the medical literature and a survey of experts. Funding for the project was provided through unrestricted educational grants from several pharmaceutical companies. The guidelines were assembled under the direction of the editors: Sachs of Harvard Medical School; David J. Printz, M.D., and David A. Kahn, M.D., of Columbia University; and Daniel Carpenter, Ph.D., and John P. Docherty, M.D., of Comprehensive NeuroScience Inc.

"Years of experience are behind the guidelines, and physicians can rely on this tool to provide up-to-date information," said Docherty in a press statement. Docherty is also adjunct professor of psychiatry at Weill Medical College of Cornell University.

The survey asked about 1,276 options for psychopharmacologic interventions in 48 specific clinical situations. Fifty-eight experts on bipolar treatment and clinical research completed the two-hour survey. Questions focused on broad strategies, such as classes of medication, and then delved into tactics, such as specific medication selection and dosing. A modified RAND Corporation format was used to ascertain consensus.

Major Recommendations

The experts favor proven treatments-the mood stabilizers. "In every phase of the illness, the expert consensus speaks very strongly to the fact that you treat bipolar patients with mood stabilizers," said Sachs, assistant professor of psychiatry at Harvard Medical School. "We are seeing fewer physicians who say, 'Yeah, if this was a depressed bipolar patient, I would give them the antidepressant alone.'"

HealthyPlace.com Radio Treatment of Bipolar Disorder Patients in the Young and Middle Adult Years The most effective treatments. Bipolar during pregnancy and other important issues. Presentation from the Fourth International Conference on Bipolar Disorder. Treating the Complex Patient Difficulty and how to treat patients with serious cases of bipolar including those with multiple diagnosis'. Presentation from the Fourth International Conference on Bipolar Disorder. listen with realplayer. audio table of contents here.

Divalproex (Depakote) (especially for mixed or dysphoric subtypes) and lithium are the cornerstone choices among the mood stabilizers for both acute and preventive treatment of mania.

"Regardless of which is selected first, if monotherapy fails, the next recommended intervention is to use these agents in combination," the experts agree. "The combination can then serve as the foundation on which other medications are added, if needed. Carbamazepine [Tegretol] is the leading alternative mood stabilizer for mania. Expert opinion regards other new anticonvulsants as second-line options (e.g., if the previously mentioned mood stabilizers fail or are contraindicated)."

For milder depression, the experts agree:

A mood stabilizer, especially lithium, may be used as monotherapy. Divalproex and lamotrigine [Lamictal] are other first-line choices. For more severe depression, a standard antidepressant should be combined with lithium or divalproex. Bupropion [Wellbutrin], selective serotonin reuptake inhibitors (SSRIs), and venlafaxine [Effexor] are preferred antidepressants and should be tapered 2 to 6 months after remission. Divalproex monotherapy is recommended for initial treatment of either depression or mania with rapid cycling.

According to Sachs, the experts also agree that bipolar disorder should be treated as a chronic illness.

"It looks like the percentage that would start patients on prophylactic treatment and leave them on that treatment long-term is increasing," he said.

Adjunctive use of antipsychotics is recommended for mania or depression with psychosis and possibly in nonpsychotic episodes. "It is very clear that we have moved away from conventional antipsychotics and on to the atypical antipsychotics," Sachs said.

Atypical antipsychotics such as olanzapine (Zyprexa) and risperidone (Risperdal) are rated as first-line agents for adjunctive treatment of mania. Atypical antipsychotics are also rated as first-line agents for combined treatment of psychotic depression. The experts noted, however, that in more severe cases of mania another first-line option is to change the antipsychotic to clozapine [Clozaril].

Electroconvulsive therapy (ECT), according to Sachs, is regarded by the experts as an appropriate treatment in some instances. "The desire is to reserve ECT for treatment failures, even though it is clearly an acceptable choice under certain clinical circumstances, like when the patient is acutely suicidal or has multiple medical complications," he said.

The experts were also asked about their preferred first-line medications when comorbidity is present. The most frequent conditions comorbid with bipolar disorder, Sachs explained, are anxiety disorders, such as panic disorder or obsessive-compulsive disorder; substance abuse; so-called disruptive behavior disorders, such as attention-deficit/hyperactivity disorder and oppositional defiant disorder; and, among women, posttraumatic stress disorder (PTSD) and eating disorders.

Some preferred first-line treatments are divalproex or gabapentin (Neurontin) for comorbid panic disorder; divalproex for comorbid PTSD; divalproex or lithium for alcohol abuse; and divalproex for other substance abuse.

While there was consensus on most of the major clinical decisions in the guidelines, there was not a clear-cut consensus on some issues, including how frequently to monitor labs and what to do in situations where patients have gained a lot of weight, Sachs said.

For weight gain associated with mood stabilizers, the experts prefer to continue the present medication and attempt weight loss through diet or exercise. Adding topiramate (Topamax) or switching to a different mood stabilizer are second-line options. No consensus exists on whether dose reduction is helpful.

HealthyPlace.com Radio How Does Lithium Compare to Other Treatments in the Management of Bipolar Disorder? Bipolar expert, Frederick K. Goodwin, M.D. compares the traditional treatment of Lithium to newer atypical antipsychotics and other medications for bipolar disorder. Use of Anticonvulsants in Bipolar Disorder Presentation from the Fifth International Conference on Bipolar Disorder. Non-adherence with Mood Stabilizers: Prevalence, Predictors and Prognosis Why patients don't take their bipolar medications as prescribed and the results of non-adherence. listen with realplayer. audio table of contents here.

For weight gain associated with an atypical antipsychotic, their preference is to "switch to another atypical antipsychotic or attempt dose reduction. Many experts also consider adding topiramate as an option. Lowering the dose of a concomitantly administered mood stabilizer or switching to molindone [Moban] are considered less likely to be helpful." There was only modest support, with either type of medication, for the use of appetite suppressants or thyroid hormone.

There was also some caution among the experts about using some of the newer treatments, such as lamotrigine, gabapentin and topiramate. Lamotrigine, for example, received low second-line ratings as an initial treatment for mania, reflecting the preliminary nature of the evidence of its efficacy (Calabrese et al., 1999) and the need for slow titration of dosage to minimize the risk of rashes. Similarly, gabapentin was rated mostly as a third-line choice, also due to the lack of high-quality research (Letterman and Markowitz, 1999).

The survey also explored the experts' opinions about using novel treatments for patients with treatment-resistant mania or treatment-resistant bipolar depression. The experts recommended using the novel treatments only as an adjunct to other treatment, not by themselves.

"Omega-3 fatty acids are a good example of that," Sachs said. "Doctors seem perfectly willing to consider omega-3, but it is not the first choice at any time for bipolar patients alone. The same is true for St. John's wort and many other alternatives. We worry quite a bit both about the possibility of missing the benefit of something like omega-3 or St. John's wort…[and about] the possibility that the so-called naturalistic fallacy may lead patients to seek and accept treatment that might be harmful."

Sachs also pointed out that the expert consensus guidelines would be suitable for primary care physicians and other health care professionals involved in the care of patients who have bipolar disorder.

"The format in which [the guidelines] were published includes some extremely simple flowcharts that you can look at and within a couple of seconds have an idea of what might be the reasonable choice for your patient today," he said. "It would be a wonderful thing for public health if every primary care doctor as well as general psychiatrist had a sense of what are the one or two first-step things to do with a bipolar patient who is manic or depressed, and how to manage relapse prevention…For most of the patients that we see, knowing how to use [divalproex] and lithium, knowing how to use at least two of the atypical antipsychotics, and knowing how to use a couple of the first-line antidepressants would be sufficient. The guidelines are pretty clear on how to stage those treatments and where you might go if those treatments don't work for your patient. The guidelines are on a Web site www.psychguides.com."

Guidelines for Patients

In order for the family and patient to take an active role in treatment decisions, Sachs said, the guidelines recommend "appropriate training and education." Working with Ruth Ross, M.A., of Ross Editorial, Sachs, Printz and Kahn created Treatment of Bipolar Disorder: A Guide for Patients and Families as a companion piece to the guidelines.

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When asked what he hoped the guide for families would achieve, Sachs said, "I would like it to be that if the treating psychiatrist isn't familiar with the guideline, the patient or family member might be. When the psychiatrist prescribes the medication, which might be approved for a different indication, and the pharmacist says, 'You don't have epilepsy, and you don't really need to be taking this drug,' the patient will say, 'No, this is a drug that really is appropriate for my illness.' [Patients] will know…rather than discarding the prescription or having their confidence in treatment undermined."

Written in everyday language, the guide for patients and families answers some of the most commonly asked questions about bipolar disorder: What are the symptoms of bipolar disorder? What are the different patterns of bipolar disorder? Why is it important to diagnose and treat bipolar disorder as early as possible? What medications are used to treat bipolar disorder?

Copies of the guide can be obtained by contacting the National Alliance for the Mentally Ill at (800)950-NAMI or the National Depressive and Manic-Depressive Association at (800) 82-NDMDA.

The guidelines editors also wanted to make it easy for the psychiatrist or clinic to provide the guide to patients and their families.

"If you have copies of the guide for patients and families, you can hand it to them. While they are in the waiting room, they can just look at it, take it home with them and make copies for whomever they would like to see it. I hope that it will prove useful," Sachs said.

References

Calabrese JR, Bowden CL, McElroy SL et al. (1999), Spectrum of activity of lamotrigine in treatment-refractory bipolar disorder. Am J Psychiatry 156(7):1019-1023.

Kahn DA, Carpenter D, Docherty JP et al. (1996), The expert consensus guideline series: treatment of bipolar disorder. J Clin Psychiatry 57(suppl 12a):1-88.

Letterman L, Markowitz JS (1999), Gabapentin: a review of published experience in the treatment of bipolar disorder and other psychiatric conditions. Pharmacotherapy 19(5):565-572.

Sachs GS, Printz DJ, Kahn DA et al. (2000), The expert consensus guideline series: medication treatment of bipolar disorder 2000. Postgrad Med Special Report April:1-104.

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