Doctors may be closer to treating major depression in individuals who don’t respond to selective-serotonin re-uptake inhibitors (SSRIs) and selective-serotonin nor epinephrine re-uptake inhibitors (SSNRIs).
Medications prescribed to treat major depression are often those designed to increase the availability of serotonin, dopamine and/or nor epinephrine in the brain, neurotransmitters involved in a number of processes, including mood. Yet patients who don’t respond to those classes of drugs may in fact have an imbalance in another key brain chemical, GABA (gamma-aminobutyric acid).
Depression Not Always Due to Serotonin, Dopamine, Nor Epinephrine Imbalance
Major depression is a complex mood disorder that can be caused by a number of underlying and potentially intertwined biochemical and psychological factors. While some patients respond to serotonin therapies, for others, SSRI’s don’t improve their symptoms or can even make them worse.
Scientists in a study released in 2005, “Corelease of Dopamine and Serotonin from Striatal Dopamine Terminals” found that higher serotonin concentrations caused by SSRIs can “trick” transporters of another key neurotransmitter, dopamine, into retrieving serotonin into dopamine vesicles. This is referred to as “cosignaling” and can lead to a dangerous, even life threatening condition called serotonin syndrome.
In a March 2010 study published in Biological Psychiatry, co-authors Drs. Andrea J. Levinson and Zafiris J. Daskalakis of the Centre for Addiction and Mental Health (CAMH) studied a group of brain chemicals involved in virtually all brain activity, the neurotransmitter GABA. In the study, individuals who were the least likely to respond well to prior depression treatments were also the ones with the lowest level of GABA in their brain.
Depression and GABA
GABA controls the brain’s rhythmic theta waves that allow individuals to feel physically and mentally balanced. They are the electrical brain waves associated with an “in between” mental state, a drowsy, semiconscious, alert yet relaxed dream-like state of mind.
Dr. Ray Sahelian, author of Mind Boosters [St. Martin’s Press, 2000] explains, “GABA is the most important and widespread inhibitory neurotransmitter in the brain. Excitation in the brain must be balanced with inhibition. Too much excitation can lead to restlessness, irritability, insomnia, and even seizures. GABA is able to induce relaxation, analgesia, and sleep.”
GABA creates a sense of well-being and is involved in the production of endorphins, brain chemicals that create feelings of well-being known as the “runners high.” “Endorphins are produced in the brain during physical movement, such as stretching or even sexual intercourse,” explains Dr. Braverman in his book The Edge Effect [Sterling Publishing, 2005]. As endorphins are released, people begin to feel a sense of calm, often referred to as the Endorphin Effect.
A GABA imbalance can be involved in bipolar disorder, schizophrenia, and anxiety disorder but it’s also inherent to a number of critical day to day brain functions. “We apply so many conscious and unconscious perceptions and judgments to our actions at every second, without even realizing that we are doing so,” says Dr. Levinson. “GABA is part of the brain system that allows us to fine-tune our moods, thoughts, and actions with an incredible level of detail,” she says.
The findings on GABA and major depression may explain why electroconvulsive therapy, once thought barbaric, is still the most efficacious therapy for major depressive disorder. “Electroconvulsive therapy may act on GABA brain chemicals in a way that can reset the balance,” says Levinson.
GABA deficiency symptoms
Because GABA is the chief inhibitory neurotransmitter in the brain, it’s involved in an impressive list of regulatory processes in the body. A GABA deficiency can lead to:
- Allergies, light-headedness, restlessness, transient muscle tension or aches;
- Feelings of dread, blurred vision, protein cravings, impulsive attention errors, cold or clammy hands, butterflies in the stomach, feeling of a lump in the throat;
- Dizziness, coughing or choking, temporomandibular joint syndrome, paresthesia (prickling or tingling sensation), phobias;
- PMS, irritable bowel syndrome, night sweats, moderate to severe constipation/diarrhea;
- Tachycardia (rapid heartbeat), mood swings, various mild pain syndromes, various anxiety disorders, hypertension;
- Delusions, unexplained chronic pains, trigeminal neuralgia and other facial pains;
- Short or violent temper, chronic insomnia, neuropathy (nerve pain), fibromyalgia (chronic muscle pain);
- Severe heart arrhythmias, carbohydrate cravings, severe migraines, rage; and
- Severe tinnitus, severe pain, manic depression, seizures.
The implications of the study suggest that targeted drug therapies that include GABA medications may be more effective for patients with major depression than the trial and error approach that relies on serotonin and other neurotransmitter drug therapies.
“We are advancing the goal of a truly personalized medicine,” says study co-author Dr. Daskalakis. “It is intriguing to think that we may soon be able to apply simple brain stimulation to identify which treatments are most likely to help the individual person, eliminating the guesswork. That is, through these findings we may be able to one day determine who is and who is not going to respond to traditional pharmacological approaches to depression.”
Centre for Addiction and Mental Health (2010, March 6). “Critical brain chemical shown to play role in severe depression.” ScienceDaily. Retrieved July 19, 2010, from http://www.sciencedaily.com /releases/2010/03/100301102803.htm
Fu-Ming Zhou, Yong Liang, Ramiro Salas, Lifen Zhang, Mariella De Biasi, and John A. Dani: “Corelease of Dopamine and Serotonin from Striatal Dopamine Terminals” Publishing in Neuron, Volume 46, Number 1, April 7, 2005, pages 65–74. http://www.neuron.org