Researchers Sharon A. Murphy, MD, and Douglas Woodruff, MD, psychiatrists in private practice in Baltimore, Maryland presented their findings at the 160th annual meeting of the American Psychiatric Association (APA). Their work is based a particular technique called cell membrane potential. They propose that use of this technique may help medical professionals clearly identify attention deficit hyperactivity disorder (ADHD), bipolar disorder, and possibly major depressive disorder.
According to investigators, this physiologic property of cells differs among these disorders and is also differentiated from that seen in healthy controls. This is an interesting theory which has some credibility from years of previous research on manic and depressed persons. To extrapolate this theory to ADHD persons is intriguing.
The theory is a little complex, so I’ll attempt to simplify it. Cells contain energy. In that regard, they are like little batteries. If you attach a voltmeter to two terminals of a battery, a voltage difference will be measured across the two terminals. If you have a battery tester that lights up, you’re actually testing the voltage difference between the positive and negative ends of the battery. Since a cell is like a battery, if you attach a voltmeter to measure voltage across the cell membrane (outside of a cell) you’ll find that the inside of the cell has a negative voltage (measured in millivolts; mV) with respect to the outside of the cell (which is referenced as 0 mV).
If the cell is at rest, it is termed the resting membrane potential. By convention, the potential outside the cell is arbitrarily defined as zero. There exists an excess of negative charges inside the membrane because it is filled with many potassium (K+) and organic ions. Thus, the potential difference across the membrane is expressed as a negative value. The resting membrane potential is disrupted when net flux of ions (charged particles) moves into or out of the cell. Ions flow through various channels constructed of proteins to traverse the cell membrane. These are called, ion channels. Sodium and potassium are known as electrolytes – substances that conduct electrical activity that play a vital role in the normal functioning of the nervous system. There is a higher concentration of sodium outside the nerve cell and a higher concentration of potassium inside. The sodium pump is a process that maintains the normal distribution of sodium and potassium.
The researchers maintain that when cells are placed in a potassium-free buffer, the assay used in their test, cells are stressed. Abnormal regulation of ion distribution and variability in the functioning of the sodium-potassium pump within cells is known to be associated with bipolar I disorder and may also be a hallmark of ADHD, according to Drs. Murphy and Woodruff. I had heard of malfunctioning neuronal sodium-potassium pumps being associated with bipolar I disorder or ADHD, but not blood cells, so this intrigued me.
“While using the membrane potential assay to identify bipolar I disorder, we were intrigued by data that suggested this membrane potential test is also sensitive to presumed malfunctioning of the sodium-potassium pump in ADHD,” the authors reported.
Here’s the theory upon which the researchers are presumably basing their work: Any factor that alters the sodium or potassium pump in a neuron likely alters the neuron’s capacity to respond to stimuli basically affecting the functioning of the neurons. This may then affect the central nervous system and human behavior. Various studies over many years have demonstrated that depressed and manic patients may exhibit disturbances in the distribution of sodium and potassium (pump problems). Some research indicates patients with psychotic depression and mania had higher levels of intracellular sodium. The hypothesis is that manic and depressed people may have a highly excitable (hyperexcitable) central nervous system due to the excess sodium levels. They are treated successfully with lithium salts which greatly reduce intracellular sodium and so may reduce central nervous system hyperexcitability.
Murphy and Woodruff recruited 273 subjects, of whom 123 were controls. Within that group, 55 were identified by the blood work assay as having bipolar I disorder, and 95 were identified as having ADHD. The assay consists of fluorescence intensity of the membrane potential dye in patients’ blood cells. I would truly enjoy seeing fluorescence intensity of membrane potential dye. Fluorescence intensity is widely used in the manner in which the researchers used it. However, fluorescence intensity is a relative measurement which depends on instrument characteristics. This means that different fluorescence measuring instruments or even the same fluorescence instrument produce different data at different times. Additionally, turbidity (similar to muddy water) or the presence of colored compounds in the sample further complicate the interpretation of the measurements.
After all was said and done, the researchers used clinical response to medication to see if their diagnoses were correct. If the patients responded well, then the researchers concluded they were right! I’ve seen many medical practitioners perform this reverse diagnosis; concluding a child has ADHD if he responds well to ADHD medication.
Seems rather ridiculous. Both their methodology and their conclusions seem quite a stretch given the technology they’re working with.
Murphy and Woodruff claim that their test gives “a very clear and distinct difference among the controls, people with ADHD, and people with bipolar I disorder.” The average membrane potential ratio was 0.8, and the average ratio for ADHD was 1.1; the mean ratio in controls was 0.9
Essentially, I have five primary arguments against this type of test presenting any conclusive evidence:
- It is curious that the researchers used blood cells rather than neurons as previous research upon which their theory is based was produced from neural cell examination.
- Fluorescence is a relative measurement that varies with each measuring instrument and is highly susceptible to the most minor variations in the substance being measured.
- Using a reverse diagnosis to verify one’s test data is suspect.
- Their data don’t seem statistically significant, but since they didn’t provide their standard deviation, one cannot determine significance.
- Extrapolation to ADHD from bipolar I is quite a stretch.
Again, the Holy Grail of ADHD is to find that true biological marker that absolutely defines the disorder. We haven’t been able to find it for mania, depression, etc. for the past 50 years. I doubt we’ll find one for ADHD for a variety of reasons, but that’s another chapter unto itself.