The medications that are available now to treat bipolar disorder work well in many, less well in some, and not well in a few. Scientists are exploring the underlying brain and body changes that are part of bipolar disorder with a long-term goal of identifying new ways to treat it. Several medications that have shown some promise in the treatment of various aspects of bipolar disorder.
Meds that target the glutamergic pathways
One of the hottest areas of research is in the glutamate system. Glutamate is a neurotransmitter related to excitatory or energizing circuits in the brain. Research increasingly shows a strong correlation between glutamate systems and depression and bipolar disorder. Researchers are looking closely at three meds and a naturally occurring amino acid that affect this system, and preliminary studies show positive results:
Ketamine: This medication is an antagonist of a particular type of glutamate receptor — N-desmethyl aspartate (NDMA). Several studies show that intravenous infusion of ketamine in people with treatment-resistant depression almost immediately reduces depressive symptoms, making it very different from all other antidepressants in use, which take time to work.
How long the antidepressant effects of ketamine last is unclear, but rapid loss of the benefit over the course of one to two weeks is typical. The pattern of response to ketamine seems to be different in bipolar depression compared to unipolar depression. Ketamine has serious downsides though. For one, it's very sedating and can trigger psychotic responses and changes in perception of reality. It also has potential for abuse; it's been used as a street/club drug for many years. So while ketamine's antidepressant benefits are exciting, this medication won't be readily available for clinical use in the immediate future.
Memantine (Namenda): This medicine helps reduce some of the symptoms of early dementia. Like ketamine, it works at the NMDA type of glutamate receptor, reducing glutamate activity there. In some preliminary studies of people with bipolar depression who haven't responded well to more traditional medications, the addition of memantine appears to have been helpful in reducing symptoms. Side effects seem to be minor so far. Further research is needed.
N-acetyl cysteine (NAC): This amino acid has long been used to treat overdoses of acetaminophen (Tylenol). It plays many roles in the body and brain, being a part of at least two biochemical pathways that are thought to be affected in bipolar disorder. It's involved in glutamate transmission and also plays a key role in the synthesis of glutathione — a chemical that helps to reduce oxidative damage to cells. Impaired glutathione function has been found in bipolar disorder. NAC has been studied in mania and bipolar depression and has shown some promising results. Although it's an over-the-counter nutritional supplement, its use for bipolar disorder is best discussed with your prescriber to determine doses and patterns of use that would be right for you.
Riluzole (Rilutek): This medication is currently approved to treat amyotrophic lateral sclerosis (ALS, commonly known as Lou Gehrig's disease). It modulates glutamate transmissions and enhances neuronal plasticity — a variety of cellular events related to the strength and development of circuits between brain cells. In some early studies, riluzole was shown to reduce symptoms in bipolar depression, but it has severe side effects, so it hasn't been considered for use outside of research.
Protein kinase C inhibitors
Researchers have started looking closely at protein kinase C (PKC) as a possible target in treating bipolar, particularly for mania. PKC is actually a group of enzymes (proteins that trigger chemical reactions in the body) that has many functions in the body. In the brain, PKC plays a vital role in coordinating and translating chemical messages from neurotransmitters on the outside of cells into particular chemical reactions inside of cells. Many studies suggest that over-activation of PKC pathways may be related to manic symptoms, and inhibiting the pathways (with PKC inhibitors) reduces mania.
Even though lithium and valproate are very different medications, they're both known to inhibit PKC activity. Exactly how reducing PKC activity reduces manic symptoms is unknown, but some working theories suggest that the process may be related to changing the excitability of neurons and/or to improving the growth and health of neurons over time.
The estrogen inhibitor tamoxifen, used in treating breast cancer, is another potent PKC inhibitor. Increasing evidence indicates that tamoxifen can be used in combination with lithium to reduce manic symptoms if other, more traditional medications aren't working for an individual. Tamoxifen isn't included in the U.S. practice guidelines at this time, but it is included in the Canadian practice guidelines. In studies that tested tamoxifen for treating acute episodes of mania, the treatment was well tolerated, but the studies didn't account for long-term risks and potential side effects of blocking estrogen receptors. These risks and side effects need to be better researched before tamoxifen can be considered a viable option for treating bipolar on a long-term basis.
Verapamil, a medicine used to treat high blood pressure, also inhibits the PKC pathway and has been researched for treating mania with mixed results. It's not considered standard treatment at this time.
Other meds worth mentioning
Here are some other medications that are still quite a way from any regular use, but they give you an idea of the wide range of research being done in this area:
Pramiprexole: This medication is used to treat Parkinson's disease by increasing the effects of dopamine in the brain. Dopamine is one of the neurotransmitters that may be involved in bipolar symptoms. Some studies have looked at this medicine for the treatment of bipolar depression that hasn't responded well to more typical medications. The results of the studies have been inconsistent; more work still needs to be done.
Allopurinol: This medicine is primarily used to treat gout — a disease in which the body produces too much uric acid, which is then deposited in the joints causing severe swelling and pain. Allopurinol treats gout by reducing uric acid levels. People in a manic episode have elevated uric acid levels, so some studies have looked at adding allopurinol to other mood stabilizers to improve symptom relief. Some studies have been positive whereas others have shown no benefit so more research is needed to clarify whether allopurinol may be a valuable addition to the bipolar medicine cabinet.
Scopolamine: Scopolamine is a popular medication on cruise ships, used primarily to treat motion sickness. It works in the cholinergic system (choline is another neurotransmitter), targeting a specific type of choline receptor called the muscarinic receptor. Some research has suggested that depression (both bipolar and unipolar) may have some roots in this system. Studies have looked at using the scopolamine intravenously, injecting it directly into the blood rather than taking it orally, and some evidence shows that it rapidly reduces depressive symptoms. However, the research remains incomplete, and more work needs to be done.