Bipolar Meds - the Mood Stabilizers: The fine points of mood stabilizers
by John McManamy
http://www.mcmanweb.com/mood-stabilizers.html
What little we know about mood stabilizers should be considered an international scandal. Compared to antidepressants, for example, controlled studies are very few. Much of our knowledge comes from small open-label studies, many which conflict with one another, and trial and error on patients.
A treating physician is dealing with a bewildering array of layered symptoms rather than a disease as we know it. New research is telling us more about what goes on inside the skull, but "there is not a good theory of mood regulation in the brain," in the words of Steven Hyman MD, former director of the NIMH.
Lithium
According to a review of the literature by Mark Bauer MD of Brown University, lithium is the only true mood stabilizer, with published studies proving its efficacy in all phases of bipolar treatment, including acute (initial phase) mania and mania prevention, and acute depression and depression prevention. This ability to be all things at once holds out the promise of a simplified one-drug treatment for those fortunate enough to respond.
On the flip side, as an augmenter the drug can boost the performance of another drug.
These days, due to lack of drug companies promoting the drug and the extra care doctors must use in prescribing it, other medications have become more popular, though it still remains a first choice option on all the treatment guidelines.
More than 65 percent of patients with classical symptoms adequately respond to this common salt. That response rate drops to about 40 percent, however, for rapid-cyclers, patients with mixed states, those who are substance dependent, and people with co-occurring disorders. It works for psychotic highs, but other mood stabilizers may work better. These response rates are lower than reported a generation ago, but Frederick Goodwin MD, co-author of the definitive book on bipolar, at a seminar at the 2002 APA annual meeting, said there may be a selection bias in the newer studies, as the university clinics where these studies are done tend to get the sickest patients.
Lithium also tends to work better in patients who have few mood episodes. Lithium, along with Clozaril, is also the only drug proven effective against suicide. A Zurich cohort study that tracked patients over 40 years found a 50 percent reduction in overall mortality and a 29 percent lower suicide rate among lithium users. A 2003 multi-center study of 20,638 bipolar patients over eight years found that those on lithium experienced one-third to one half the suicidality compared to Depakote users (10.8 vs 31.8 emergency department suicide attempts per 1000 person years, 4.2 vs 10.5 suicide attempts resulting in hospitalization per person years, and 0.7 vs 1.7 suicide deaths per person years).
Fifty-five percent of patients develop a resistance to lithium after three years, and only an estimated one-third of those on lithium remain episode-free for two years.
In an article in the BJP, Leonardo Tondo et al of the University of Cagliari (Italy) report on how they treated 360 patients with just lithium and followed them over an average of 14.3 years, including 8.3 before treatment and six years during treatment. The patient population included an even sampling of all bipolar types, including mixed and rapid-cyclers. The study found that lithium treatment reduced mania by 64 percent and depression by 46 percent. The duration for mania was reduced by 19 percent and for depression 32 percent. Time spent ill was reduced by 56 percent overall, and the hospitalization rate fell by 82 percent. Nevertheless, only 29 percent of the patients in the study achieved complete remission.
Bipolar II patients fared best, with only minor differences among the other bipolar groups. The study also found that treatment response did not significantly deteriorate on resumption of lithium after discontinuation.
For bipolar depression, seven crossover studies have established a response rate of 64 to 100 percent to lithium, with one study showing little benefit. A number of small studies comparing lithium to the tricyclic imipramine showed uniform improvement. Numerous studies have found lithium more effective at preventing mania than depression. As an add-on to Tegretol, 6 of 13 patients improved in one open-label study.
Lithium has a lag in its effect, taking a few days to begin, and two to eight weeks to approach its full benefit, making lithium monotherapy risky for all but the mildest cases of mania in the early going.
Because of lithium's toxicity, regular blood levels are required, with risk to both the kidneys and the thyroid (the latter which can be off-set by adding a thyroid agent). The modern therapeutic window for lithium is 0.6 to 1.0 milliequivalents per liter (mEq/l), lower than the recommended 0.8 to 1.2 mEq/l of the past. Dehydration resulting from say a fever may raise lithium levels while sodium and caffeine may lower levels.
To avoid dehydration, ample water is recommended, though parched patients hardly need reminding.
A retrospective study of 114 patients on lithium for four to 30 years found 24 showed excessive blood creatinine levels associated with renal failure. Dr Goodwin stated he was not interested in levels but in changes. If one level is 20 percent above the other, a nephrologist should be consulted, but, according to Jeffrey Jefferson MD, founder of the Lithium Information Center in Madison, at the APA same symposium, the nephrologist needs to understand the patient can’t just quit lithium.
For pregnant women, the risk of fetal heart defects, especially Ebstein’s anomaly, is .05 percent in the first trimester, 10 to 20 times that of the general population. As a general rule, it is advisable to get back on lithium for the second and third trimesters, but one needs to discuss fully the risks vs benefits with one's physician.
As well as dry mouth, a common side effect of lithium is tremors, sometimes of Parkinson's dimensions. Tremor can be alleviated by reducing the dose, reducing caffeine, adding a beta-blocker, using a slow-release preparation, or changing to a bedtime dose.
Other common complaints are gastrointestinal (nausea, diarrhea), cognitive impairment, and weight gain (up to 13 pound over eight weeks in one study).
One theory of mania is that the ion channels that penetrate the brain cell's membrane open too wide, resulting in increased ion flow to the inside of the neuron. According to Stephan Stahl in Antipsychotics and Mood Stabilizers (Cambridge University Press, 2002), lithium may reverse these actions by acting through G proteins, neurotransmitters, and "second messenger systems" (also called signal transduction pathways) to regulate these channels. Recent studies on rats have found lithium grows new cells in the hippocampus and may protect brain cells, suggesting the drug may play a role in repairing the physical damage to the brain caused by manic or depressive or psychotic episodes.
Depakote
Because of lithium's shortcomings in treating rapid-cycling, mixed episodes, and mania complicated by co-occurring disorders, Depakote (divalproex sodium) is the treatment of choice here. It is also as effective as lithium for treatment in the acute stage and maintenance stage of mania, and is also effective for patients with co-occurring substance use. The drug may be administered in high doses to quickly stabilize those with acute mania, and can be used synergistically with lithium, Tegretol, and atypical antipsychotics.
Five placebo-controlled studies have found Depakote achieves a response (ie at least a 50 percent reduction in symptoms) for acute manic episode 48 to 80 percent of the time. In the two trials submitted to the FDA, Depakote was effective in treating acute mania 48 to 53 percent of the time. A 1997 study found the drug comparable to lithium for mania, with the added benefit of successful results in patients with 10 or more episodes (the same study found lithium failed at this threshold).
For depression, a small study found no difference between the Depakote and placebo groups after eight weeks. A two-year study comparing lithium and Depakote found there was no significant difference in efficacy, but the Depakote group had fewer dropouts (10 percent vs 25 percent). Depakote added to lithium or lithium added to Depakote resulted in similar improvements in one study, comparable to Paxil as an add-on, but with fewer dropouts in the Paxil group.
Like lithium, Depakote takes time to achieve its full effect. One recent study found few patients on lithium or Depakote had a return to normal functioning within three weeks. A 2003 Abbott Laboratories pooled analysis of 348 manic patients found those on high doses of Depakote from the outset (oral loading) did better at days five, seven, eight, and 10 than those on the standard gradual dose, and fared the same as those on Zyprexa, with better tolerability than Zyprexa. Oral loading was at 20 or 30 mg/kg/day, equating to between 1,300 mg to 2000 mg/day for a 150-pound individual vs standard dosing at 750 mg/day in divided doses that is gradually increased.
Because of its toxicity, regular blood tests are required. The drug's packaging carries black box warnings about the risk of damage to the liver, neural tube defects to the fetus (three to eight percent during the first trimester), and pancreatitus (very remote). The labeling also advises that Tegretol can double the clearance of Depakote, which means raising its dose accordingly, if taking both drugs together. The labeling additionally advises that doses of Lamictal need to be lowered if taken with Depakote.
Depakote is also a notorious weight-gainer (57 percent of patients in one study gained more than 8.8 pounds during treatment). Those who are put on either this drug or lithium are advised to immediately replace their Ben and Jerry's with non-fat frozen yogurt and find other low-fat or non-fat alternatives at once. Do not, however, rush out to replace your Coke with Diet Coke, or sugar with NutraSweet. One study has found those with mood disorders experienced bad reactions to the artificial sweetener aspartame (see article).
Unfortunately, doctors more often than not neglect to remind their patients of this distressing weight gain side effect, possibly in the mistaken belief that ballooning into Brunehilda's or Santa's cast-offs is a minor consideration in the overall mania and depression scheme of things. Not everyone gains weight on Depakote -and some even drop pounds - but it is advisable to plan ahead lest you find yourself in the distressing situation of trying to shed the equivalent of six unwanted ten-pound sacks of potatoes.
Both aspirin and Depakote have blood-thinning effects, so you should probably consider a different pain-killer or check with your doctor. Like lithium, the drug is known to cause tremors.
The NIMH warning quoted in Part I is worth repeating here:
"According to studies conducted in Finland in patients with epilepsy, valproate may increase testosterone levels in teenage girls and produce polycystic ovary syndrome in women who began taking the medication before age 20. Increased testosterone can lead to polycystic ovary syndrome with irregular or absent menses, obesity, and abnormal growth of hair. Therefore, young female patients taking valproate should be monitored carefully by a physician."
The University of Toronto study also bears repeating, where half of those on Depakote reported menstrual abnormalities vs 15 percent among lithium users. Those taking Depakote had higher levels of male sex hormones, with half the overweight women with menstrual abnormalities having hyperandrogenism.
And again, that oral contraceptives may prevent this.
Depakote and the other antiepileptics are thought to act outside the brain cell on the neurotransmitters GABA and glutamate, which in turn regulate the ion channels leading into the brain cell (these include sodium, calcium, chloride, and potassium), and result in some inside-the-cell activity in the form signal transduction pathway business. Like lithium, Depakote has been found to grow new brain cells in rats and have neuroprotective properties
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Bipolar Disorder - Comparison of Medications