From The Quarterly, Summer 2010
Prozac is one of the so-called SSRI antidepressant drugs, prescribed extensively throughout the world. Others include Lexapro, Zoloft, Celexa and Paxil. How SSRIs work, why they sometimes don’t work, and whether they can be made to work better are vital questions for millions of people with major depression. Answering those questions has been a key goal of Dr. Randy Blakely, a NARSAD Scientific Council member and two-time NARSAD Distinguished Investigator.
“SSRI” stands for selective serotonin reuptake inhibitor. All of the drugs in this class target the system in the brain that regulates the chemical serotonin, a neurotransmitter. Serotonin relays messages from cell to cell, carrying them across tiny gaps called synapses. Normally, after helping to transmit a message, serotonin is “vacuumed” out of the gap and taken back inside the cell that originally released it. This is called “re-uptake” — a process whereby the serotonin is stored until the cell needs to transmit another message, and it is then re-released into the synaptic gap.
Many people with depression benefit from having serotonin linger in the gaps between nerve cells. This is thought to improve the transmission of messages, which in turn correlates in many people with an improvement in mood. But in order to keep serotonin in the synapse, the activity of a molecule called the serotonin transporter, or SERT, must be blocked, at least partially. SERT molecules normally carry serotonin back into nerve cells. Prozac and the other SSRIs bind to SERT molecules, thus inhibiting them from performing the task of sweeping serotonin from the synapse.
Two decades ago, Dr. Blakely identified the gene that directs SERT production. This enabled scientists to begin learning about SERT’s role as a potential risk factor for anxiety, depression and other serotonin-related brain disorders. It also enabled scientists to make models of serotonin deficiency in animals to aid understanding of how antidepressants really work.
Dr. Blakely now believes that SSRIs may be more effective than they need to be in blocking SERT molecules. In many patients, he hypothesizes, too many blocked SERTs may contribute to the side effects of SSRIs and limit their usefulness. He therefore has been stud ying ways of controlling SERT, hoping to develop medications that will permit tweaking its control mechanism. Recently he and colleagues discovered a protein, called the A3 adenosine receptor that can turn the SERT gene “on.” One idea of future treatment is to reduce SERT production by designing a drug to target — and thereby block — the newly discovered receptor.