Detailed analysis of medications used to treat bipolar disorder and using bipolar medications for kids, during pregnancy and breastfeeding, and rapid-cycling.

Consider this: There is no bipolar pill, and maybe there will never be. People with bipolar disorder simply represent too small a market (one to two percent of the population) for a pharmaceutical company to take a gamble on investing the $800 million the industry claims takes to get a drug to market, assuming, that is, such a drug ever leaves the lab. Since most new drugs originate from public sector research in the first place, the industry would virtually have to be handed their magic bullet on a silver platter. So it is that the bipolar community must pick and choose from a menu of leftovers designed for other populations - antidepressants, antianxiety medications, antipsychotics, and antiepileptics. Last but not least, there is a common salt.

Lithium

The story begins in an Australian lab in 1949 when John Cade MD, senior medical officer in the Mental Hygiene Department of Victoria, had a hunch that urea would be effective in the treatment of bipolar. He needed an agent to help the substance dissolve in water, which turned out to be lithium. He quickly found the solution had a calming affect on guinea pigs, but further experimentation showed that it was the lithium and not the urea that was the active ingredient. He then tried lithium on human subjects, with eye-popping results.

John Cade's discovery of lithium as a treatment for bipolar disorder may be accidental, but the simple fact that the finding came in a lab demonstrated that at least one person on the planet back then recognized that the illness carried a biological component. In those days, in a world dominated by Freudian psychiatry and the belief that bipolar was an attitude problem, Dr Cade was way ahead of his time. It would take until the 1960s before his findings were applied in Europe and yet another decade before lithium became available in the US.

Lithium can be considered the first of the mood stabilizers - an agent that reduces the severe mood swings characteristic of bipolar - and today it still remains the treatment of first or second choice. It was approved by the FDA for the treatment of mania in the 1970s and until recently was the only drug approved for maintenance therapy.

Early studies reported success rates of up to 80 percent for the treatment of mania, but more recent results show lithium to be effective in about 40 to 50 percent of subjects, perhaps reflecting its wider use on more unwilling patients.

The drug also works moderately well for treating bipolar depression.

Because of its high toxicity, blood levels need to be very carefully monitored. Lithium can be potentially damaging to the kidneys (where it is metabolized) and the thyroid.

Lithium and other mood stabilizers are believed to work through neurotransmitters outside the brain cell, resulting in a molecular series of events that leads through the brain cell's membrane via various ion channels and inside the neuron through signal transduction pathways (which involve a number of chemical chain reactions responsible for a vast array of cellular activities).

Antiepileptics

Depakote (divaloproex sodium or valproate) became the first of the antiepileptics (or anticonvulsants) used for treating mood swings. Like lithium, its discovery was the result of accident. Valproate was initially developed by the Germans in World War II as a butter substitute, then was used as a diluent for other drugs. In 1963, its anticonvulsant properties became apparent when an experimental anticonvulsant was dissolved in valproic acid (thus revealing the true agent). European asylums in the 1960s had large populations of epileptic patients, and when synthesized valproate (Depakote) was given to these patients - voila! - the next mood stabilizer. The first published European reports based on observations came in 1975.

US studies followed a decade later. The drug was applied off-label without FDA approval, but in 1995 it was cleared for treating mania. By analogy, we know that the brains of lab animals become progressively more sensitive to seizures when induced by an electrical current into the hippocampus and amygdala of the brain. After several days, the animals experience spontaneous seizures. This corresponds to the "kindling theory" of bipolar, of a progressive worsening of the illness, if allowed to go untreated. This may explain why drugs that work so well to prevent seizures are also effective in treating bipolar.

Depakote, along with lithium, is a treatment of first choice for bipolar. Like lithium, Depakote is also potentially toxic - especially to the liver where it metabolizes - and requires blood levels to be taken regularly. The drug poses certain risks for young females, and the following warning posted on the website of the NIMH bears quoting in full:

"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."

A University of Toronto study of 38 women found that 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.

This may be prevented however by using oral contraception.

More recently, doctors have been treating their patients with newer antiepileptics, including Lamictal, Tegretol, Trileptal, Neurontin, Felbatol, Gabatril, and Topamax, all (but Lamictal) off-label, and all with the advantage of a benign toxicity profile. The range of choices a patient now has means that there is hope even if several treatments do not work. (Further discussion on these meds in Part II of this series.)

For the acute phase of mania, clinicians like to start patients on a "loading dose," generally in the midrange of therapeutic levels and work up or down, as the case may be. For the newer antiepileptics there is a much wider dose range, reflecting the sad fact that there is still much to learn. For the maintenance phase of treatment, slightly lower doses are recommended. Gradual tapering is standard practice before discontinuation.