Posts Tagged selective serotonin reuptake inhibitors
Depression is characterized by persistent low mood and feelings of hopelessness, and it is one of the most common mental disorders in the United States. In 2014, there were an estimated 15.7 million U.S. adults who experienced at least one major depressive episode, representing around 6.7 percent of the country’s adults.
Treatments for depression generally include talking therapies in conjunction with medication. The class of drugs most commonly prescribed is selective serotonin reuptake inhibitors (SSRIs), and these include brands such as Prozac and Zoloft.
SSRIs can help some people with depression, but they are not perfect; not everyone responds well to them, and side effects including nausea, insomnia, agitation, and erectile dysfunction can be unpleasant.
Also, SSRIs can take some time to kick in; although some people might feel some benefit within hours or even minutes, most people do not feel the full antidepressant effect until they have been taking the drugs for weeks or even months.
How do SSRIs work?
In the brain, messages are sent between neurons by releasing neurotransmitters into a gap between the cells, or the synapse. Serotonin is one such neurotransmitter. It is released from the first neuron and binds to receptors on the second neuron.
Normally, once serotonin has been released into the synapse and relayed its message, the majority is reabsorbed into the first nerve cell for reuse at a later date. SSRIs prevent serotonin from being reabsorbed. In this way, they ensure that serotonin hangs around in the synapse for a longer time, exerting more of an effect.
Although SSRIs have been known to medical science since the 1950s, their exact mechanism is not understood. This is because there are at least 1,000 types of neuron that can be influenced by a surge in serotonin, and some of these neurons may be excited, while others might be inhibited.
The mixed response is because there are 14 subtypes of serotonin receptor throughout the body and any single nerve could have a cocktail of receptor types. Teasing out which receptor subtype is playing the most significant role has proven challenging.
The role of the dentate gyrus
A group of scientists from Rockefeller University in New York City, NY, recently set out to take a closer look at the action of SSRIs on a particular type of nerve cell. The team was headed up by Lucian Medrihan and Yotam Sagi, both research associates in the Laboratory of Molecular and Cellular Neuroscience, and Paul Greengard, Nobel laureate.
Their findings were recently published in the journal Neuron.
“Many different types of synapses throughout the brain use serotonin as their neurotransmitter. An issue of major importance has been to identify where in the myriad of neurons the antidepressants initiate their pharmacological action.”
The team concentrated on a group of cells in the dentate gyrus (DG). According to the authors, they chose the DG because previous work has established that “SSRI treatment promotes a variety of synaptic, cellular, and network adaptations in the DG.”
Specifically, the team investigated cholecystokinin (CCK)-expressing neurons within the DG. These neurons were of interest because they are heavily influenced by neurotransmitter systems that are associated with mood disorders, such as depression.
Finding the right receptor
Using a technique called translating ribosome affinity purification, the team were able to identify the serotonin receptors on CCK cells. Sage explains, “We were able to show that one type of receptor, called 5-HT2A, is important for SSRIs’ long-term effect, while the other, 5-HT1B, mediates the initiation of their effect.
The next step in the study involved efforts to mimic SSRIs’ effects by manipulating CCK neurons in mice. They used chemogenetics to switch nerve cells on or off and implanted tiny electrodes inside the mouse brains.
The findings were clear. When the CCK neurons were inhibited, the pathways important for the mediation of SSRI responses lit up. In other words, the scientists had recreated a Prozac-like effect without using the drug.
To back up these findings, the team used behavioral experiments in a pool and observed swimming patterns. Again, silencing the CCK neurons created behavior that was similar to that displayed by the mice that had been given SSRIs: they swam for longer with increased vigor.
According to the researchers, understanding the importance of the DG and the specific cells important for treating depression will help to design faster-acting, more effective antidepressants with fewer side effects.
The work was carried out using techniques that would have been impossible just 5 years ago, and the studies that follow are likely to improve our understanding even further.
A study is challenging the relationship between depression and an imbalance of serotonin levels in the brain, and brings into doubt how depression has been treated in the U.S. over the past 20 years.
Researchers at the John D. Dingell VA Medical Center and Wayne State University School of Medicine in Detroit have bred mice who cannot produce serotonin in their brains, which should theoretically make them chronically depressed. But researchers instead found that the mice showed no signs of depression, but instead acted aggressively and exhibited compulsive personality traits.
This study backs recent research indicating that selective serotonin reuptake inhibitors, or SSRIs, may not be effective in lifting people out of depression. These commonly used antidepressants such as Prozac, Paxil, Celexa, Zoloft, and Lexapro, are taken by some 10% of the U.S. population and nearly 25% of women between 40 and 60 years of age. More than 350 million people suffer from depression, according to the World Health Organization, and it is the leading cause of disability across the globe.
The study was published in the journal ACS Chemical Neuroscience. Donald Kuhn, the lead author of the study, set out to find what role, if any, serotonin played in depression. To do this, Kuhn and his associates bred mice who lacked the ability to produce serotonin in their brains, and ran a battery of behavioral tests on them. In addition to being compulsive and extremely aggressive, the mice who could not produce serotonin showed no signs of depression-like symptoms. The researchers also found, to their surprise, that under stressful conditions, the serotonin-deficient mice behaved normally.
A subset of the mice who couldn’t produce serotonin were given antidepressant medications and they responded in a similar manner to the drugs as did normal mice. Altogether, the study found that serotonin is not a major player in depression, and science should look elsewhere to identify other factors that might be involved. These results could greatly reshape depression research, the authors say, and shift the focus of the search for depression treatments.
The study joins others in directly challenging the notion that depression is related to lower levels of serotonin in the brain. One study has shown that some two-thirds of those who take SSRIs remain depressed, while another study has even found them clinically insignificant.
Critics of common antidepressants claim they’re not much better than a placebo, yet may still have unwanted side effects.
SSRIs started to become widely used in the 1980s. Their introduction was heralded by the psychiatric community as a new era where safer drugs that directly targeted the causes of depression would become the standard. While SSRIs aren’t more effective than the older antidepressants, such as tricyclics and monoamine oxidase inhibitors, they are less toxic.
An earlier study by the National Institute of Mental Health found that two out of three patients with depression don’t fully recover using modern antidepressants.
These results “are important because previously it was unclear just how effective (or ineffective) antidepressant medications are in patients seeking treatment in real-world settings,” said James Murrough, a research fellow at the Mount Sinai School of Medicine Mood and Anxiety Disorders Program.
[ARTICLE] A Combined Therapeutic Approach in Stroke Rehabilitation: A Review on Non-Invasive Brain Stimulation plus Pharmacotherapy -Full Text PDF
Stroke is a leading cause of disability in the United States. Available treatments for stroke have only a modest effect on motor rehabilitation and about 50-60% of stroke patients remain with some degree of motor impairment after standard treatment.
Non-invasive brain stimulation (NIBS) techniques have been proposed as adjuvant treatments to physical therapy for motor recovery after stroke. High frequency rTMS and anodal tDCS can be delivered over the affected motor cortex in order to increase cortical excitability and induce brain plasticity with the intention to enhance motor learning and achieve functional goals in stroke patients. Similarly, low frequency rTMS and cathodal tDCS can be delivered to the unaffected motor cortex to reduce interhemispheric inhibition and hinder maladaptive plasticity.
The use of several drugs such as amphetamines, selective serotonin reuptake inhibitors (SSRIs), levodopa and cholinergic agents have been also proposed to enhance the motor function. Given that both NIBS and pharmacotherapy might provide some treatment effect independently for motor rehabilitation in stroke and with the rationale that they could work in a synergistic fashion, we believe that a combined therapy- NIBS plus pharmacotherapy- can lead to better outcomes than one or the other alone. In this paper we review the literature that support the potential use of a combined approach in stroke recovery and present the studies that have already investigated this idea
…Some studies have found that women who use common antidepressants early in pregnancy face a raised risk of miscarriage, but new research suggests the link might be better explained by the depression, rather than the drugs that treat it…