CABF Ask The Expert: How Do Drugs Used to Treat Bipolar Disorder Work?
Barbara Geller, M.D.
By: Dorie Geraci, M.S., R.N., Medication Safety Team Leader & CABF Board Member

CABF asked Barbara Geller, M.D., Chair of the CABF Scientific Advisory Council and Professor of Psychiatry at Washington University School of Medicine at St. Louis, MO:

How Do Drugs Used to Treat Bipolar Disorder Work?

A Brief Overview
Exactly how these medications work is not yet known. An analogy may be helpful. When antibiotics are given for "strep" throat, the white blood cell count goes down. If we did not know about "germs", we might be investigating how white blood cells cause "strep". Similarly, we know some of the actions of drugs but do not yet know precisely which, if any, of these actions are the ones related to recovery.

Lithium affects a number of systems in the body. Notably, it is very neuroprotective in animal models, possibly by working at intracellular signaling pathways, i.e., pathways involved in brain cell (neuronal) functioning. Neuroprotective means that animals given brain toxins have less damage to their brain cells if lithium is also given. In humans, there is some evidence from neuroimaging studies that lithium may also be neuroprotective as it may increase brain compounds that are associated with enhanced brain functioning. Lithium also acts on the serotonin system, which may account for its anti-depressive properties.

Anticonvulsants affect systems involved with how cells signal one another to either increase or inhibit cell activity. The compound involved in increasing activity of brain cells is called glutamate and the compound involved in inhibiting activity is called GABA (gamma amino butyric acid). There is evidence that anticonvulsants either decrease glutamate activity or increase GABA actions, which makes sense for compounds that work on seizures. Anticonvulsants have also been found to have some neuroprotective properties.

Antipsychotics work on a number of substances that modulate brain cell functioning. Typical (older) antipsychotics (such as Haldol, Thorazine) work on the dopamine system by interfering with the actions of dopamine at the point where dopamine attaches to brain cell surfaces. Although there is a relationship between the amount of interference with dopamine and the clinical effectiveness of this class of drugs, it is not yet known exactly why this is the case. But, too much dopamine is a hallmark of many psychotic states, including taking PCP (phencyclidine, a classified hallucinogen) and schizophrenia. The newer, or atypical antipsychotics, also act at serotonin sites. Risperdal acts very much like typical antipsychotics and is prone to the neurological side effects (parkinsonism, tardive dsykinesia) seen with the typicals. Other atypicals have less propensity to produce neurological side effects, but as a class most (all but Abilify and Geodon) have a much higher rate of severe obesity with its attendant cardiovascular and metabolic problems. Most importantly, all of the atypicals are very new to the market so that their longer term side effects cannot yet be known. (Click here to view the FDA Indications for Adult Use Medications for Bipolar Disorder.) This class of medications have also been found to be neuroprotective. Antipsychotics have also been found to have some neuroprotective properties.


Are any Drugs FDA Approved for Childhood Bipolar Disorder?

Although approved for use in children age 2 and older, lithium was "grandfathered in" by the FDA in 1970. Its approval was not based on controlled studies as currently required by the FDA. Medications in the anticonvulsant class, however, have been used for childhood seizures so that pediatric safety data has been evaluated.


Why are adult medications used to treat pediatric bipolar disorder?

When the Food and Drug Administration (FDA) approves a new drug, it also approves the instructions for the labeling based on data submitted by the drug company that show the drug worked better than a sugar pill in at least two studies. Clinical trials usually study adults. and therefore the labeling is for adult use only, making many drugs "off label" for children. Physicians are allowed to prescribe "off label" if the medication is given to a different age group, such as prescribing a medication FDA approved for adults to children.

Many of the most commonly used drugs in adults across medicine have never been studied in children. Studies in children require the assent of the child, which is usually no problem as these forms are written in age appropriate language. The more difficult problem in conducting studies of children is simply the complexity, as both parents and the little patients need to be interviewed and need to be included in the procedures. Thus, studies of the child age group are substantially more expensive than those in adults. However, interest of manufacturers in conducting studies on children was enhanced by congressional action (the Best Pharmaceuticals for Children Act) that provides six months more of exclusivity on a drug studied for the pediatric age population. This means drug manufacturers have an additional six months during which generics cannot be made and this is a financial windfall for these corporations and thus a big incentive to study the medication in the pediatric age group.

Therefore, to treat severe, chronic, non-self limiting illnesses, such as bipolar disorder, physicians must use their best judgement and must educate families about the risks and benefits of drugs useful in adults. Then both physician and family can make the decision about what is best to use for a particular child.


Is there any current research exploring the efficacy and adverse reactions of these psychotropic drugs in children with bipolar disorder?

There are currently a number of ongoing studies supported both by NIMH and by manufacturers that are specifically aimed at the child and adolescent population.