Long-term Treatment Response in Bipolar Illness

June 26, 2013 · Posted in Current Treatments, Potential Treatments 
Willem Nolen

Willem Nolen

Willem Nolen, a researcher who has spent 40 years studying unipolar and bipolar disorder, recently retired from his position at Groningen Hospital in the Netherlands. In February, his retirement was celebrated with a symposium where he and other researchers discussed some of their important findings from the last several decades.

Nolen recently published a double-blind randomized study showing that in patients who were initially responsive to monotherapy with quetiapine (Seroquel), continuing the drug (at doses of 300-800mg/night) or switching to lithium were both more effective than switching to placebo over 72 weeks of long-term follow-up.

This study shows that quetiapine, which is only FDA-approved for long-term preventative treatment when used in combination with lithium or valproate (Depakote), also has efficacy when used as monotherapy.

Lithium is Highly Effective in Long-term Prevention

Nolen’s work also adds to an impressive amount of literature showing that lithium is highly effective in long-term prevention. This case is especially noteworthy because lithium was effective even in patients who had initially been selected for their response to quetiapine. (Studies that use this kind of “enriched sample” can only claim that quetiapine has long-term efficacy in those patients who initially respond well to the drug.) The data on lithium are even more impressive since the patients in this study were not enriched for lithium response.

Nolen has also conducted multiple studies of lithium, but optimal doses and target blood levels of the drug remain controversial. The therapeutic range of lithium is usually considered to be 0.6 to 1.2 meq/L, but some have argued that lower levels may still be effective. In a new analysis of those patients in the quetiapine study who were switched to lithium treatment, Nolen found that only lithium levels above 0.6 meq/L produced better results than placebo in long-term prophylaxis.

These data are also consistent with a recent study in the US known as Litmus. Patients who had only partially responded to their usual treatment received an addition of either low-dose lithium (600mg/day) or placebo. These low doses of lithium did not enhance treatment outcomes better than placebo. However, this dose of lithium did reduce the dose of antipsychotics needed to prevent symptoms from breaking through.

Editor’s Note: For good therapeutic effects in bipolar disorder prevention, it appears wise to aim for lithium doses that produce blood levels of at least 0.6meq/L. If a patient cannot achieve this goal because of the emergence of side effects, an argument can still be made for continuing to use lithium even at lower blood levels. In addition to Nolen’s study in which lithium reduced the necessary dose of antipsychotics, there is evidence that low levels of lithium might have positive effects on both cognitive deterioration and suicide. In animals, even blood levels of lithium as low as 0.38 meq/L increased neuroprotective factors such as Bcl-2 in the brain..

Another important message of Nolen’s study was that long-term maintenance treatment is absolutely necessary, as about 90% of patients who were initially successfully treated with quetiapine and then switched to placebo relapsed by the end of the study, and almost all did so within a year. These data parallel the high rate of relapse in patients who stop effective lithium treatment reported by Suppes et al. in 1995.

Stopping effective treatment often leads to episode recurrence and can lead to hospitalization or suicide. Among those who stop effective preventative treatment with lithium, relapse, and begin lithium treatment again, 10 to 15% fail to re-respond as well as they had previously, and some fail to respond at all.

Take home messages:

  1. Lithium levels should be above 0.6 meq/L for a good prophylactic response in bipolar disorder, although lower levels of lithium may have other benefits.
  2. Quetiapine monotherapy is also effective in prophylaxis (although it is only FDA-approved as an adjunct to lithium or valproate).
  3. Consistent, persistent long-term maintenance treatment is required in bipolar disorder. This may sometimes require complicated treatment regimens.
  4. When treatment is effective, stay the course. When it is not, use a daily monitoring system to assess the effectiveness of each new treatment that is introduced until good effects are achieved.


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