Treatment

Bipolar Meds - the Mood Stabilizers

The fine points of mood stabilizers.

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.

Tegretol

At least five small studies have demonstrated the acute antimanic efficacy of Tegretol (carbamazepine), but until 2003 there was no large double blind study. That study shows the drug is effective against mania 70 percent of the time, with the clinical benefit showing at about day 14. Other small studies show the drug to be effective in the prevention of both mania and depression, either alone or in combination with lithium.

For depression, three small controlled cross-over studies found 68 percent responded to Tegretol, with placebo substitution resulting in 50 percent of them relapsing. One small study found 60 percent who stayed on the drug for one year remained stable.

The drug contains a black box warning about risk of agranulocytosis (affecting white blood cells), but that risk is extremely remote.

Tegretol induces the enzyme cytochrome P450 34A, which can affect the metabolism of other drugs and reduce their efficacy, including other psychiatric drugs (see article) and oral contraceptives. Accordingly, those taking concomitant Depakote, Lamictal, Topamax, antipsychotics, benzodiazepines such as Xanax, and tricyclic antidepressants may need to consider raising the doses.

The drug's labeling warns that dual administration of Tegretol and lithium may increase the risk of neurotoxic side effects.

On the reverse side of the coin, the following psychiatric drugs can raise Tegretol levels: Depakote, Luvox, Prozac, and Serzone.

Tegretol more than doubles the risk of major congenital anomalies during the first trimester of pregnancy according to a Hebrew University (Israel) study of 210 women who had taken the drug. The relative risk of congenital anomalies was 2.24 for women in the Tegretol group. Birth weights were also lower and congenital heart defects higher (2.9 percent prevalence vs 0.7 percent). The findings corroborate a 1999 Dutch study.
Trileptal

An analogue of Tegretol, Trileptal (oxcarbazepine) has only just recently attracted the attention of psychiatrists, even though it has been used for treating epilepsy since 1990. The drug is generating a good deal of buzz because it apparently has the benefits of Tegretol without causing the type of drug-drug interactions of its chemical cousin. Two studies were confounded by the fact that patients were also receiving antipsychotics..

Lamictal

Recent studies have established that Lamictal is singularly effective for bipolar depression, without causing the risk of switching a patient into mania. Taking the drug lessens the need to take antidepressants, with their mania-inducing potential as well as their side effects.

The FDA in June 2003 approved Lamictal for the long-term maintenance of Bipolar I to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes). Additionally, the FDA noted that findings for Lamictal maintenance treatment were more robust in bipolar depression. Two studies involving 1,305 bipolar I patients who were stabilized, then put on either lithium, Lamictal, or a placebo for 18 months, found that Lamictal was superior to lithium at delaying time to intervention for a depressive episode while lithium was superior to Lamictal at delaying time to intervention for a manic episode. Fifty-seven percent of Lamictal patients were intervention-free for depression at one year vs 46 percent of lithium patients vs 45 percent of placebo patients. Eighty-six percent of lithium patients were intervention-free for mania at one year vs 77 percent for Lamictal patients vs 72 percent for placebo patients.

Tellingly, the study found intervention for depression was more frequent than for mania by a factor of nearly three to one.

Two trials, however, suggest that Lamictal’s advantage may only be applicable among those who have recently had mania. Among patients recently manic, Lamictal over 18 months resulted in fewer patients requiring intervention for depression (14 percent vs 22 percent for those on lithium vs 30 percent for those on a placebo), but that there was no appreciable difference among those who had been recently depressed (34 percent vs 38 percent vs 30 percent, respectively). By another measure, fewer recently manic patients on Lamictal had Hamilton depression scores greater than 20 (three percent vs 11 percent vs 19 percent) while the numbers were about the same for recently depressed patients ( 22 percent vs 18 percent vs 26 percent).

A 1999 study involving 195 patients found 200 mg/day effective after seven weeks for acute bipolar depression, but manufacturer GlaxoSmithKline did not seek an indication for this phase of the illness, most likely due to the fact that Lamictal needs to be started on a very low dose and increased gradually over six weeks, suggesting the drug will take even longer than that to kick in. Nevertheless, Lamictal is recommended as first-line acute bipolar depression treatment in both the APA Practice Guideline for the Treatment of Patients with Bipolar Disorder and the pioneering TIMA algorithm put out by the state of Texas. Both the APA and TIMA are vague with regard to treating bipolar depression in the maintenance phase. The British Association for Psychopharmacology, on the other hand, says Lamictal has better evidence going for it as maintenance therapy than acute treatment

The drug is also considered safe for rapid-cycling and mania prevention, but is not regarded as particularly strong for acute mania.

The drug has the advantage of low incidence of weight gain, but contains a black box warning about risk of serious rash, which was found in .08 percent of adults receiving Lamictal as initial therapy for bipolar and 0.13 percent for those receiving the drug as adjunctive therapy. The risk of rash is greater in children and adolescents, and is only approved for this group in treating a certain form of epilepsy. The labeling recommends that the drug be discontinued at the first sign of rash and not be restarted unless the potential benefits clearly outweigh the risks.

Owing to risk of serious rash, GSK recommends gradual increases to a full dose, starting at 25 mg/day for the first two weeks, 50 mg/day for weeks three and four, 100 mg/day for week five, and 200 mg/day for week six. This slow dosing suggests why GSK sought an FDA maintenance indication for the drug instead of an acute one.

If also on Depakote, GSK recommends 25 mg every other day for the first week, 25 mg/day for weeks three and four, 50 mg/day for week five, and 100 mg/day for week six.

If also on Tegretol or other enzyme-inducing drugs, the recommended schedule is 50 mg/day for weeks one and two, 100 mg/day in divided doses for weeks three and four, 200 mg/day in divided doses for week five, 300 mg/day in divided doses for week six, and 400 mg/day in divided doses for week seven.

If discontinuing, GSK recommends a gradual taper over two weeks, unless safety concerns require a more rapid withdrawal.

Lamictal is probably the safest of the antiepileptics to take during pregnancy, with manufacturer GSK’s registry of 293 pregnancies through Sept 2002 showing no major birth defects

Neurontin

The benefits of Neurontin (gabapentin) are that it is well-tolerated, the dosage can be adjusted rapidly, adverse effects are usually transient, and it has no known drug interactions. The catch is in a double blind study, the placebo won. The drug is reputed to be effective, however, as an add-on for anxiety, which frequently co-occurs with bipolar.

A scandal broke out over the drug when a whistle-blower notified authorities that Warner-Lambert, now part of Pfizer, aggressively marketed Neurontin for bipolar and other off-label uses, knowing there was no scientific evidence for its efficacy. Individual readers have contacted this writer, however, saying the drug has worked for them, so if you are currently on the medication and it appears to be working then by all means stay on it, or if nothing else has worked the drug may be an option.

Topamax

Topamax (topiramate) is a newer mood stabilizer that is receiving notice for its appetite-diminishing and weight-reducing properties (in one study patients experienced a mean weight loss of six kilograms at the end of one year). It has few interactions with other mood stabilizers, which facilitates its use as adjunctive therapy. Unfortunately, it is not the antimania agent its manufacturer Ortho-McNeil was hoping it would be. After not having any success in its clinical trials, the manufacturer decided not to seek FDA approval for the drug for mania. Five double-blind studies comparing the drug to a placebo and two others comparing it to lithium turned up negative for mania. Three depression studies report conflicting results.

As an add-on, the drug may have a benefit. A study of 56 patients with various types of bipolar who were not responsive to lithium, Depakote, or Tegretol found that 53 reacted well to the drug as an add-on. An article in Bipolar Disorders by Roy Chengappa MD et al of the Western Psychiatric Institute reports that open trials of Topamax suggest a 50 to 60 percent response for refractory mania and a 40 to 50 percent response for refractory depression, mainly as an add-on.

The drug's greatest benefit may lie in treating behaviors and effects that go with bipolar and bipolar meds, including impulsivity, bulimia, binge eating, substance use, PTSD, and obesity. As Susan McElroy MD in her grand rounds lecture at UCLA put it: "I use it in bipolar when managing some of the shmutz that goes with the illness."

For some people, the drug noticeably dulls cognition, which is why it is unofficially known as "Dopamax."

Experimental Meds

Gabatril - There is little evidence of a positive effect.

Zonigran - A 2004 chart review of 40 patients with depression or bipolar found that the drug added to their medication resulted in improvements based on different indicators.

Mirapex - A 2001 pilot study of the Parkinson’s drug pramipexole (Mirapex) found a 58 percent response after six weeks vs 17 percent on the placebo.

Keppra - A 2003 German open study of 10 bipolar patients found that adding the novel anticonvulsant Keppra (levetiracetam) to Haldol resulted in moderate improvements to mania scores during the first two weeks of the study. Symptoms worsened when the drug was discontinued, and improved, with seven of ten responding by day 28, when the drug was recontinued.

A 2004 UCB Pharma open-label trial of 200 bipolar patients (ages five to 69) on the anticonvulsant Keppra found that "efficacy was good in roughly 50 percent of patients and partial in an additional 20 percent." Sedation occurred in nine percent of the sample and was the cause of four percent dropping out.

Updated Feb 10, 2008

Comment to this article