Posts Tagged selective serotonin reuptake inhibitors

[WEB PAGE] Faster-acting antidepressants may soon be a reality

Understanding where antidepressants act is the key to improving their function.

 

Using cutting-edge techniques, researchers have investigated the mechanism by which common antidepressants work, finally pinning down the specific receptors responsible for their action. The findings might pave the way to designing improved, faster-acting antidepressants.

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.”

Paul Greengard

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.

Source: Faster-acting antidepressants may soon be a reality

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[WEB SITE] What if everything we know about treating depression is wrong?

Woman worried, depressed (Shutterstock)

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.

via What if everything we know about treating depression is wrong?.

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[ARTICLE] A Combined Therapeutic Approach in Stroke Rehabilitation: A Review on Non-Invasive Brain Stimulation plus Pharmacotherapy -Full Text PDF

Abstract

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

Full Text PDF

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[ARTICLE] Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery

Abstract

Background

Stroke is the major cause of adult disability. Selective serotonin reuptake inhibitors (SSRIs) have been used for many years to manage depression. Recently, small trials have demonstrated that SSRIs might improve recovery after stroke, even in people who are not depressed. Systematic reviews and meta-analyses are the least biased way to bring together data from several trials. Given the promising effect of SSRIs on stroke recovery seen in small trials, a systematic review and meta-analysis is needed.

Objectives

To determine whether SSRIs improve recovery after stroke, and whether treatment with SSRIs was associated with adverse effects.

Search methods

We searched the Cochrane Stroke Group Trials Register (August 2011), Cochrane Depression Anxiety and Neurosis Group Trials Register (November 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 8), MEDLINE (from 1948 to August 2011), EMBASE (from 1980 to August 2011), CINAHL (from 1982 to August 2011), AMED (Allied and Complementary Medicine) (from 1985 to August 2011), PsycINFO (from 1967 to August 2011) and PsycBITE (Pyschological Database for Brain Impairment Treatment Efficacy) (March 2012). To identify further published, unpublished and ongoing trials we searched trials registers, pharmaceutical websites, reference lists, contacted experts and performed citation tracking of included studies.

Selection criteria

We included randomised controlled trials that recruited stroke survivors (ischaemic or haemorrhagic) at any time within the first year. The intervention was any SSRI, given at any dose, for any period. We excluded drugs with mixed pharmacological effects. The comparator was usual care or placebo. In order to be included, trials had to collect data on at least one of our primary (dependence and disability) or secondary (impairments, depression, anxiety, quality of life, fatigue, healthcare cost, death, adverse events and leaving the trial early) outcomes.

Data collection and analysis

We extracted data on demographics, type of stroke, time since stroke, our primary and secondary outcomes, and sources of bias. For trials in English, two review authors independently extracted data. For Chinese papers, one review author extracted data. We used standardised mean differences (SMD) to estimate treatment effects for continuous variables, and risk ratios (RR) for dichotomous effects, with their 95% confidence intervals (CIs).

Main results

We identified 56 completed trials of SSRI versus control, of which 52 trials (4060 participants) provided data for meta-analysis. There were statistically significant benefits of SSRI on both of the primary outcomes: RR for reducing dependency at the end of treatment was 0.81 (95% CI 0.68 to 0.97) based on one trial, and for disability score, the SMD was 0.92 (95% CI 0.62 to 1.23) (22 trials involving 1310 participants) with high heterogeneity between trials (I2 = 85%; P < 0.0001). For neurological deficit, depression and anxiety, there were statistically significant benefits of SSRIs. For neurological deficit score, the SMD was -1.00 (95% CI -1.26 to -0.75) (29 trials involving 2011 participants) with high heterogeneity between trials (I2 = 86%; P < 0.00001). For dichotomous depression scores, the RR was 0.43 (95% CI 0.24 to 0.77) (eight trials involving 771 participants) with high heterogeneity between trials (I2 = 77%; P < 0.0001). For continuous depression scores, the SMD was -1.91 (95% CI -2.34 to -1.48) (39 trials involving 2728 participants) with high heterogeneity between trials (I2 = 95%; P < 0.00001). For anxiety, the SMD was -0.77 (95% CI -1.52 to -0.02) (eight trials involving 413 participants) with high heterogeneity between trials (I2 = 92%; P < 0.00001). There was no statistically significant benefit of SSRI on cognition, death, motor deficits and leaving the trial early. For cognition, the SMD was 0.32 (95% CI -0.23 to 0.86), (seven trials involving 425 participants) with high heterogeneity between trials (I2 = 86%; P < 0.00001). The RR for death was 0.76 (95% CI 0.34 to 1.70) (46 trials involving 3344 participants) with no heterogeneity between trials (I2 = 0%; P = 0.85). For motor deficits, the SMD was -0.33 (95% CI -1.22 to 0.56) (two trials involving 145 participants). The RR for leaving the trial early was 1.02 (95% CI 0.86 to 1.21) in favour of control, with no heterogeneity between trials. There was a non-significant excess of seizures (RR 2.67; 95% CI 0.61 to 11.63) (seven trials involving 444 participants), a non-significant excess of gastrointestinal side effects (RR 1.90; 95% CI 0.94 to 3.85) (14 trials involving 902 participants) and a non-significant excess of bleeding (RR 1.63; 95% CI 0.20 to 13.05) (two trials involving 249 participants) in those allocated SSRIs. Data were not available on quality of life, fatigue or healthcare costs.

There was no clear evidence from subgroup analyses that one SSRI was consistently superior to another, or that time since stroke or depression at baseline had a major influence on effect sizes. Sensitivity analyses suggested that effect sizes were smaller when we excluded trials at high or unclear risk of bias.

Only eight trials provided data on outcomes after treatment had been completed; the effect sizes were generally in favour of SSRIs but CIs were wide.

Authors’ conclusions

SSRIs appeared to improve dependence, disability, neurological impairment, anxiety and depression after stroke, but there was heterogeneity between trials and methodological limitations in a substantial proportion of the trials. Large, well-designed trials are now needed to determine whether SSRIs should be given routinely to patients with stroke.

Plain language summary

Selective serotonin reuptake inhibitors for stroke recovery

Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that have been in use for many years, mainly for the treatment of mood disorders such as depression. Animal studies have shown that SSRIs may have other direct effects on the brain, such as encouraging the development of new brain cells. If this also occurs in humans, recovery from stroke may be improved. This review brought together the results of 52 trials (4060 participants) of SSRIs in people who had had a stroke in the previous year, to find out whether SSRIs might reduce dependency and disability. The review found promising evidence that SSRIs might improve recovery after stroke, even in patients who were not depressed. Large trials are now needed to confirm or refute these findings, and to determine whether SSRIs increase the risk of side effects such as seizures. If effective, SSRIs would be a low-cost, simple and widely applicable treatment for patients with stroke.

via Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery – The Cochrane Library – Mead – Wiley Online Library.

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WEB SITE: Study Questions Link Between Antidepressants, Miscarriage

…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…

via Study Questions Link Between Antidepressants, Miscarriage: MedlinePlus.

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