Compound enhances SSRI antidepressant’s effects in mice
A synthetic compound is able to turn off “secondary” vacuum cleaners in the brain that take up serotonin, resulting in the “happy” chemical being more plentiful, scientists from the School of Medicine at The University of Texas Health Science Center San Antonio have discovered. Their study, released June 18 by The Journal of Neuroscience, points to novel targets to treat depression.
Serotonin, a neurotransmitter that carries chemical signals, is associated with feelings of wellness. Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressants that block a specific “vacuum cleaner” for serotonin (the serotonin transporter, or SERT) from taking up serotonin, resulting in more supply of the neurotransmitter in circulation in the extracellular fluid of the brain.
Delicate balance
“Serotonin is released by neurons in the brain,” said Lyn Daws, Ph.D., professor of physiology and pharmacology in the School of Medicine. “Too much or too little may be a bad thing. It is thought that having too little serotonin is linked to depression. That’s why we think Prozac-type drugs (SSRIs) work, by stopping the serotonin transporter from taking up serotonin from extracellular fluid in the brain.”
A problem with SSRIs is that many depressed patients experience modest or no therapeutic benefit. It turns out that, while SSRIs block the activity of the serotonin transporter, they don’t block other “vacuum cleaners.” “Until now we did not appreciate the presence of backup cleaners for serotonin,” Dr. Daws said. “We were not the first to show their presence in the brain, but we were among the first show that they were limiting the ability of the SSRIs to increase serotonin signaling in the brain. The study described in this new paper is the first demonstration of enhancing the antidepressant-like effect of an SSRI by concurrently blocking these backup vacuum cleaners.”
Serotonin ceiling
Even if SERT activity is blocked, the backup vacuum cleaners (called organic cation transporters) keep a ceiling on how high the serotonin levels can rise, which likely limits the optimal therapeutic benefit to the patient, Dr. Daws said.
“Right now, the compound we have, decynium-22, is not an agent that we want to give to people in clinical trials,” she said. “We are not there yet. Where we are is being able to use this compound to identify new targets in the brain for antidepressant activity and to turn to medicinal chemists to design molecules to block these secondary vacuum cleaners.”
Selective serotonin reuptake inhibitors (SSRIs) are a type of medicine used to treat depression.
SSRIs can also be used to treat other conditions, such as:
anxiety disorder
obsessive compulsive disorder (OCD)
panic disorder
serious phobias, such as agoraphobia and social phobia
How they work
SSRIs boost levels of a substance called serotonin in the brain. When serotonin is released it helps lift mood.
It is thought people with depression release only small amounts of serotonin. The SSRIs prevent the nerve cells in the brain absorbing serotonin.
Depression is not simply caused by serotonin levels. But a rise in serotonin levels can improve mood and make people more responsive to other types of treatment, such as the talking therapy cognitive behavioural therapy.
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This work was supported by National Institutes of Health Grants R01-MH064489 (L.C.D.), R01-MH093320 (L.C.D., W.K.) and R03-MH086708 (G.G.G.), and a National Alliance for Research on Schizophrenia and Depression Independent Investigator Award (L.C.D.).
Types of selective serotonin reuptake inhibitors
SSRI generic and brand names
Fluoxetine (Prozac)
Fluvoxamine (Luvox)
Sertraline (Zoloft)
Paroxetine (Paxil)
Escitalopram (Lexapro)
Citalopram (Celexa)
Decynium-22 Enhances SSRI-Induced Antidepressant-Like Effects in Mice: Uncovering Novel Targets to Treat Depression Rebecca E. Horton 1 Deana M. Apple 1,2 W. Anthony Owens 1 Nicole L. Baganz 1 Sonia Cano 2 Nathan C. Mitchell 1 Melissa Vitela 1 Georgianna G. Gould 1 Wouter Koek 2,3* and Lynette C. Daws 1,3*
1 Departments of Physiology, 2 Psychiatry, and 3 Pharmacology, University of Texas Health Science Center, San Antonio, Texas 78229-3900
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SSRI Antidepressants, Suicidal Feelings and Young People
Young people taking SSRIs may have increased suicidal thoughts and behaviors. In fact, in 2004, the FDA ordered the strongest safety warning possible known as a black box warning on SSRI and other antidepressants:
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of [drug name] or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need.
Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older.
Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber.
About the UT Health Science Center San Antonio
The University of Texas Health Science Center at San Antonio, one of the country’s leading health sciences universities, ranks in the top 3 percent of all institutions worldwide receiving National Institutes of Health funding. The university’s schools of medicine, nursing, dentistry, health professions and graduate biomedical sciences have produced approximately 28,000 graduates. The $736 million operating budget supports eight campuses in San Antonio, Laredo, Harlingen and Edinburg.
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Will Sansom
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University of Texas Health Science Center at San Antonio