FDA-Approved Office Lithium Test Expected To Enhance Clinical Care

August 1, 2005

Although lithium is still a first-line treatment for bipolar disorder, many psychiatrists are reluctant to use it due to blood monitoring requirements. The FDA has approved an in-office blood test that allows lithium blood levels to be obtained in minutes. The test is similar to glucose monitoring devices used for diabetes, and experts on BD are hoping it will increase the use of lithium, which has also been shown to lower the suicide rate among patients with this disorder.

Psychiatric Times

August 2005

Vol. XXII

Issue 9

Since the 1970s, lithium (Eskalith, Lithobid) has been a mainstay of treatment for bipolar disorder (BD) and an effective augmentation strategy for treatment-resistant unipolar depression. Lithium, long before lamotrigine (Lamictal), olanzapine (Zyprexa) and aripiprazole (Abilify), received the U.S. Food and Drug Administration's approval for the maintenance treatment of BD. Despite lithium's efficacy, many psychiatrists find regular monitoring of lithium blood levels to be burdensome for their patients and for themselves. But that burden may soon ease. Recently, the FDA approved an office-based test that permits psychiatrists or their clinical staff to obtain a patient's lithium levels in minutes.

Lithium is a benchmark drug, but the amount that is needed to be effective is slightly less than toxic levels, so you have got to monitor levels and keep them in therapeutic ranges, somewhere between 0.4 mEq/L and 1.4 mEq/L, said William Glazer, M.D., president and chief medical officer of ReliaLAB, Inc., the New Jersey company that developed the testing system. This "point-of-care" test is available to psychiatry and can be likened to glucose monitoring devices being used in diabetes care, said Glazer, who is also associate clinical professor at Massachusetts General Hospital and Harvard Medical School.

During a recent press briefing at the 158th Annual Meeting of the American Psychiatric Association in Atlanta, Glazer explained how that test system provides quantitative results from a few drops of blood obtained from a finger stick. The blood is put into a blood separator device. The processed plasma is added to a prefilled reagent cuvette; and the cuvette is placed in a reader to obtain a patient's lithium level. "All of this takes between two and five minutes," he said. "You can do an assessment of your patient on the spot."

At the APA meeting, Glazer et al. (2005) also presented a new research poster on a study of the accuracy and reliability of the test system that replicated findings of a previous study (Glazer et al., 2004). Investigators from Uptown Research Institute in Chicago performed the clinical trials that led to the FDA's approval.

"We have a large number of patients on lithium in our practice. We selected 56 of these patients to have a triangular blood test done," said poster co-author Michael J. Reinstein, M.D., of the Uptown Research Institute. The patients on oral lithium contributed 88 matched data points, for which blood lithium levels were estimated by the instant test and two different laboratories that employed atomic absorption spectrophotometry (Glazer et al., 2005). Reinstein reported that the new office-based test for lithium levels was as accurate as those tests used in commercial laboratories.

Goodwin's Perspective

Also speaking at the press conference, Frederick Goodwin, M.D., a world authority on BD, said he hoped the new test will help lithium "resume its rightful place as one of the major strategies for treating bipolar disorder, pretty much like it is in the rest of the world."

Many practitioners in the United States, Goodwin explained, view lithium as an historic artifact. They do not know how to use the drug or view it as very difficult to use. Goodwin, director of the Center on Neuroscience, Medical Progress and Society and research professor of psychiatry at George Washington University Medical Center, took the APA and psychiatry residency programs to task for failing to adequately educate psychiatrists in lithium's use.

Because lithium does not make any money for anyone, it is an orphan drug, Goodwin said. He asked press conference attendees how long it had been since they had seen an APA program on lithium.

"It is a disgrace to let young guys and gals get out of psychiatry residency programs without knowing how to use lithium or how to use it well enough," Goodwin added. "If I were on accreditation bodies for residencies, I would not accredit them if they allowed residents to graduate without knowing how to administer one of psychiatry's major drugs."

He revealed that he has been an expert witness for families of suicide victims in two lawsuits. "A couple of doctors took people off lithium because they had been convinced that these alternative drugs were just as good or better [than lithium], and they didn't have to do blood levels, so it was more convenient ... Two suicides resulted," he added.

Bipolar disorder is a lethal illness, according to Goodwin, who said that at least 10% of patients with BD die by suicide. "Lithium is the only agent shown now, convincingly, to prevent it," Goodwin said.

He reminded press conference attendees that meta-analyses have shown an eight- to 13-fold difference in the annual risk of suicide between patients with affective disorders (primarily BD) who were treated with lithium compared to those not treated with lithium (Baldessarini et al., 2001; Muller-Oerlinghausen, 2001; Tondo et al., 2001). For example, in a meta-analysis of 22 studies with data permitting estimates of annual rates of suicide in patients mainly with BD, the computed risk of completed suicide was 8.85 times less with long-term lithium treatment than without it (Baldessarini and Tondo, 2003; Tondo et al., 2001).

When lithium was compared to carbamazepine (Equetro, Tegretol) or divalproex (Depakote), it showed a differential effect in preventing suicides, Goodwin said. European investigators have shown lithium to be superior to carbamazepine, according to Goodwin. In a randomized, 30-month, prospective study comparing maintenance treatment with lithium or carbamazepine in 175 patients with BD discharged from psychiatric inpatient units, there were no suicide attempts or suicide deaths in the lithium group compared with nine suicide events in the carbamazepine group (Goodwin et al., 2003; Thies-Flechtner et al., 1996).

Goodwin said he and colleagues reported that among patients treated for BD, the risk of suicide attempt and suicide death was lower during treatment with lithium than during treatment with divalproex (Goodwin et al., 2003). The study compared suicide attempts and completions in 20,638 people ages 14 or older with BD who belonged to two large integrated health plans in Washington state and California. A total of 12,358 had taken divalproex and 11,303 had taken lithium. A few had also used carbamazepine, though the numbers were too small to make sound comparisons.

Fifty-three people committed suicide during the study period; 338 attempted suicide as recorded as a hospital discharge diagnosis; and an additional 642 attempted suicide as recorded by emergency department personnel. Researchers found that the risk of suicide attempt or suicide death was 1.5 to three times higher during periods of treatment with divalproex than during periods of treatment with lithium.

"Remember that suicide is not only a tragic outcome, it is the No.1 reason that psychiatrists are sued," Goodwin warned at the press conference. "So from a risk prevention strategy, for the clinician to not know how to give lithium is a major deficit."

With proper therapeutics, the success rate for treating bipolar disorder is about 70% to 80%, Goodwin said. He acknowledged that some of the newer drugs for BD are "wonderful and fill important niches." Part of the clinician's skill is in knowing which drug is right for a particular patient.

"There are studies now showing that lithium responders are often nonresponders or partial/poor responders to alternatives, and likewise lithium nonresponders are often good responders to the alternatives," Goodwin said.

He explained that patients with classical bipolar disorder (bipolar I disorder without mood-incongruent delusions and without comorbidity) seem to respond best to lithium (Kleindienst and Greil, 2000). Additionally, long-term studies show that patients who get completely well during episodes are lithium responders, Goodwin said. On the other hand, there is evidence that divalproex is superior to lithium for mixed bipolar episodes (Bowden et al., 1994) and some evidence of a better response to carbamazepine or divalproex than lithium among comorbid substance abusers (Goldberg et al., 1999).

The ability to monitor levels in the office has advantages for providing very careful tracking of patients during special circumstances and for possibly increasing adherence to the medication. "Real toxicity is about twice the therapeutic levels of lithium," Goodwin said. "Maintenance levels for bipolar I disorder are in the range of 0.6 mEq/L to 0.8 mEq/L, and for bipolar II [disorder], 0.4 mEq/L to 0.6 mEq/L."

There are specific times, Goodwin said, when he might want to know more about his patients' lithium levels and have the levels monitored frequently. For example, if a patient experiences breakthrough depression, one of the strategies that works well is to increase the lithium levels temporarily. If a patient has started a vigorous exercise program, such as training for the Boston Marathon, Goodwin said he would want to know the effects of sweating on the patient's lithium levels.

Other times to closely monitor lithium levels may include when patients are undergoing surgery and may not be eating a normal diet for several days afterward, when pregnant patients are resuming lithium treatment in the last trimester, and when patients are ill with a fever. Signs of toxicity include tremors, nausea, vomiting, drowsiness, decreased coordination, and possible seizures and coma.

The instant feedback of the new test system is a valuable asset for clinical care, according to Goodwin. If you can sit there with patients in your office, do the finger stick or have your assistant do it, and get a result within a few minutes, you can explain to patients that maybe the reason they are not feeling well is due to too low or too high lithium levels, Goodwin said. "I have had some patients misread lithium side effects [as signs] that they are depressed or slowing down," he added.

The test also strengthens the relationship with the patient and can have a profound impact on compliance. "Compliance, by the way, is the No. 1 reason why otherwise effective drugs don't work," Goodwin said. "In bipolar illness, one-half the patients will not comply [with prescribed treatment]. Blood levels are a compliance monitor and also a psychological reminder of the patient's illness."

Other Viewpoints

James Jefferson, M.D., clinical professor of psychiatry at the University of Wisconsin Medical School and co-director of the Lithium Information Center, added at the press conference that the test system will permit immediate re-test if an "odd" result appears and may encourage patients to stay on the drug who previously might have discontinued it because of inconveniences associated with monitoring.

Bonnie Rosenthal, a member of the Depression and Bipolar Support Alliance who receives lithium for her chronic and recurrent depression, said the new test will help her safeguard her body. Before, she would have to plan her entire day around a lab visit, experience the discomfort of a venous blood draws because she has "roller veins" and wait days to get the results.

"If I am toxic, which has happened more than once, the doctor doesn't get the results for at least 48 hours. Every hour can make a difference as far as kidney damage," she said. "That is damage being done to my body, not to mention how sick I feel."

In August, ReliaLAB plans to start marketing the lithium system starter kit (which includes the machine, 12 patient test packs and an instruction manual). The FDA gave the test a CLIA (Clinical Laboratory Improvements Amendment)-waiver so it can be used in physicians' offices, according to Glazer. The company also has in clinical trials an office-based system for detecting suppressed white blood cell and absolute neutrophil cell levels for use in patients being treated with clozapine (Clozaril).

References

Baldessarini RJ, Tondo L (2003), Suicide risk and treatments for patients with bipolar disorder. [Published erratum JAMA 291(2):186.] JAMA 290(11):1517-1519 [see comment].

Baldessarini RJ, Tondo L, Hennen J (2001), Treating the suicidal patient with bipolar disorder: reducing suicide risk with lithium. Ann N Y Acad Sci 932:24-38; discussion 39-43.

Bowden CL, Brugger AM, Swann AC et al. (1994), Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. [Published erratum JAMA 271(23):1830.] JAMA 271(12):918-924 [see comment].

Glazer WM, Sonnenberg JG, Reinstein M (2005), A novel, "point of care" test for lithium levels. Presented at the 158th Annual Meeting of the American Psychiatric Association. Atlanta; May 26.

Glazer WM, Sonnenberg JG, Reinstein MJ, Akers RF (2004), A novel, point-of-care test for lithium levels: description and reliability. J Clin Psychiatry 65(5):652-655.

Goldberg JF, Garno JL, Leon AC et al. (1999), A history of substance abuse complicates remission from acute mania in bipolar disorder. J Clin Psychiatry 60(11):733-740.

Goodwin FK, Fireman B, Simon GE et al. (2003), Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA 290(11):1467-1473 [see comment].

Kleindienst N, Greil W (2000), Differential efficacy of lithium and carbamazepine in the prophylaxis of bipolar disorder: results of the MAP study. Neuropsychobiology 42(suppl 1):2-10.

Muller-Oerlinghausen B (2001), Arguments for the specificity of the antisuicidal effect of lithium. Eur Arch Psychiatry Clin Neurosci 251(suppl 2):II72-II75.

Thies-Flechtner K, Muller-Oerlinghausen B, Seibert W et al. (1996), Effect of prophylactic treatment on suicide risk in patients with major affective disorders. Data from a randomized prospective trial. Pharmacopsychiatry 29(3):103-107.

Tondo L, Hennen J, Baldessarini RJ (2001), Lower suicide risk with long-term lithium treatment in major affective illness: a meta-analysis. Acta Psychiatr Scand 104(3):163-172 [see comments].