Posts Tagged SSRIs

[WEB PAGE] How New Ketamine Drug Helps with Depression

Yale psychiatrists, pioneers of ketamine research, shed light on new FDA approval

An illustration of a woman suffering from depression who might be helped by esketamine

The FDA approval of esketamine gives doctors another valuable tool in their arsenal against depression—and offers new hope for patients no one had been able to help before. “This is a game changer,” says John Krystal, MD, chief psychiatrist at Yale Medicine and one of the pioneers of ketamine research in the country.

On March 5, the Food and Drug Administration (FDA) approved the first truly new medication for major depression in decades. The drug is a nasal spray called esketamine, derived from ketamine—an anesthetic that has made waves for its surprising antidepressant effect.

Because treatment with esketamine might be so helpful to patients with treatment-resistant depression (meaning standard treatments had not helped them), the FDA expedited the approval process to make it more quickly available. In one study, 70 percent of patients with treatment-resistant depression who were started on an oral antidepressant and intranasal esketamine improved, compared to just over half in the group that did not receive the medication (called the placebo group).

“This is a game changer,” says John Krystal, MD, chief psychiatrist at Yale Medicine and one of the pioneers of ketamine research in the country. The drug works differently than those used previously, he notes, calling ketamine “the anti-medication” medication. “With most medications, like valium, the anti-anxiety effect you get only lasts when it is in your system. When the valium goes away, you can get rebound anxiety. When you take ketamine, it triggers reactions in your cortex that enable brain connections to regrow. It’s the reaction to ketamine, not the presence of ketamine in the body that constitutes its effects,” he says.

And this is exactly what makes ketamine unique as an antidepressant, says Dr. Krystal.

However, as the nasal spray becomes available via prescription, patients have questions: How does it work? Is it safe? And who should get it? Read on for answers.

How do antidepressants work?

Research into ketamine as an antidepressant began in the 1990s with Dr. Krystal and his colleagues Dennis Charney, MD, and Ronald Duman, PhD, at the Yale School of Medicine. At the time (as is still mostly true today) depression was considered a “black box” disease, meaning that little was known about its cause.

One popular theory was the serotonin hypothesis, which asserted that people with depression had low levels of a neurotransmitter called serotonin. This hypothesis came about by accident—certain drugs given to treat other diseases like high blood pressure and tuberculosis seemed to drastically affect people’s moods. Those that lowered serotonin levels caused depression-like symptoms; others that raised serotonin levels created euphoric-like feelings in depressed patients. This discovery ushered in a new class of drugs meant to treat depression, known as selective serotonin reuptake inhibitors (SSRIs). The first one developed for the mass market was Prozac.

But eventually it became clear that the serotonin hypothesis didn’t fully explain depression. Not only were SSRIs of limited help to more than one-third of people given them for depression, but growing research showed that the neurotransmitters these drugs target (like serotonin) account for less than 20 percent of the neurotransmitters in a person’s brain. The other 80 percent are neurotransmitters called GABA and glutamate.

GABA and glutamate were known to play a role in seizure disorders and schizophrenia. Together, the two neurotransmitters form a complex push-and-pull response, sparking and stopping electrical activity in the brain. Researchers believe they may be responsible for regulating the majority of brain activity, including mood.

What’s more, intense stress can alter glutamate signaling in the brain and have effects on the neurons that make them less adaptable and less able to communicate with other neurons.

This means stress and depression themselves make it harder to deal with negative events, a cycle that can make matters even worse for people struggling with difficult life events.

Ketamine—from anesthetic to depression “miracle drug”

Interestingly, studies from Yale research labs showed that the drug ketamine, which was widely used as anesthesia during surgeries, triggers glutamate production, which, in a complex, cascading series of events, prompts the brain to form new neural connections. This makes the brain more adaptable and able to create new pathways, and gives patients the opportunity to develop more positive thoughts and behaviors. This was an effect that had not been seen before, even with traditional antidepressants.

“I think the interesting and exciting part of this discovery is that it came largely out of basic neuroscience research, instead of by chance,” says Gerard Sanacora, MD, PhD, a psychiatrist at Yale Medicine who was also involved in many of the ketamine studies. “It wasn’t just, ‘let’s try this drug and see what happens.’ There was increasing evidence suggesting that there was some abnormality within the glutamatergic system in the brains of people suffering from depression, and this prompted the idea of using a drug that targets this system.”

For the last two decades, researchers at Yale have led ketamine research by experimenting with using subanesthetic doses of ketamine delivered intravenously in controlled clinic settings for patients with severe depression who have not improved with standard antidepressant treatments. The results have been dramatic: In several studies, more than half of participants show a significant decrease in depression symptoms after just 24 hours. These are patients who felt no meaningful improvement on other antidepressant medications.

Most important for people to know, however, is that ketamine needs to be part of a more comprehensive treatment plan for depression. “Patients will call me up and say they don’t want any other medication or psychotherapy, they just want ketamine, and I have to explain to them that it is very unlikely that a single dose, or even several doses of ketamine alone, will cure their depression,” says Dr. Sanacora. Instead, he explains, “I tell them it may provide rapid benefits that can be sustained with comprehensive treatment plans that could include ongoing treatments with ketamine.  Additionally, it appears to help facilitate the creation new neural pathways that can help them develop resiliency and protect against the return of the depression.”

This is why Dr. Sanacora believes that ketamine may be most effective when combined with cognitive behavioral therapy (CBT). CBT is a type of psychotherapy that helps patients learn more productive attitudes and behaviors. Ongoing research, including clinical trials, addressing this idea are currently underway here at Yale.

A more patient-friendly version

The FDA-approved drug esketamine is one version of the ketamine molecule, and makes up half of what is found in the commonly used anesthetic form of the drug. It works similarly, but its chemical makeup allows it to bind more tightly to the NMDA glutamate receptors, making it two to five times more potent. This means that patients need a lower dose of esketamine than they do ketamine. The nasal spray allows the drug to be taken more easily in an outpatient treatment setting (under the supervision of a doctor), making it more accessible for patients than the IV treatments currently required to deliver ketamine.

But like any new drug, this one comes with its cautions. Side effects, including dizziness, a rise in blood pressure, and feelings of detachment or disconnection from reality may arise. In addition, the research is still relatively new. Studies have only followed patients for one year, which means doctors don’t yet know how it might affect patients over longer periods of time. Others worry that since ketamine is sometimes abused (as a club drug called Special K), there may be a downside to making it more readily available—it might increase the likelihood that it will end up in the wrong hands.

Also, esketamine is only part of the treatment for a person with depression. To date, it has only been shown to be effective when taken in combination with an oral antidepressant. For these reasons, esketamine is not considered a first-line treatment option for depression. It’s only prescribed for people with moderate to severe major depressive disorder who haven’t been helped by at least two other depression medications.

In the end, though, the FDA approval of esketamine gives doctors another valuable tool in their arsenal against depression—and offers new hope for patients no one had been able to help before.

To learn more, visit yalemedicine.org.

 

via How New Ketamine Drug Helps with Depression > Stories at Yale Medicine

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[WEB SITE] Prozac vs. Zoloft: What are the differences?

Prozac and Zoloft are common antidepressant drugs. Although they have similar effects on the body, their specific uses, side effects, and dosages are different.

Prozac and Zoloft are both selective serotonin reuptake inhibitors (SSRIs). This class of medication is among the first options for treating major depressive disorder, which people usually call depression.

Fluoxetine is the generic drug name for Prozac, and sertraline is the generic name for Zoloft.

In this article, we discuss the differences between Prozac and Zoloft.

What do they treat?

prozac vs zoloft

Taking either Prozac or Zoloft will increase the levels of serotonin in the brain.

The Food and Drug Administration (FDA) have approved both Prozac and Zoloft for treating:

In addition, the FDA have approved Prozac for the treatment of:

Doctors may also use Zoloft to treat post-traumatic stress disorder (PTSD) and social anxiety disorder.

Some doctors prescribe Prozac for social anxiety disorder in adults, borderline personality disorderRaynaud’s phenomenon, and selective mutism, but the FDA have not approved these uses.

Other SSRIs include:

  • escitalopram (Lexapro)
  • vortioxetine (Trintellix)
  • citalopram (Celexa)
  • fluvoxamine (Luvox)
  • paroxetine (Paxil)
  • vilazodone (Viibryd)

Forms

Both Prozac and Zoloft are available in the forms of a liquid oral solution, a tablet, and a capsule.

The following table lists the different forms of each drug along with the available dosages in milligrams (mg) and milligrams per milliliter (mg/ml).

Prozac Zoloft
Capsule 10 mg, 20 mg, 40 mg, 90 mg 25 mg, 50 mg, 100 mg
Tablet 60 mg 25 mg, 50 mg, 100 mg
Liquid 20 mg/5 ml 20 mg/ml

How to take and dosage

When a person first starts taking antidepressants, they will typically begin on a smaller dosage and increase this over time. Doing this makes it possible to test how well the drug works and monitor its side effects, as the effectiveness and adverse effects can differ among individuals.

American Psychiatric Association guidelines report the following starting dosages and the usual effective dosages when treating MDD:

Prozac Zoloft
Starting dosage 20 mg/day 50 mg/day
Usual effective dosages 20–60 mg/day 50–200 mg/day

Some people may see improvements in their symptoms in the first 1–2 weeks of treatment, whereas it may take 2–4 weeks for others to notice changes.

Some studies have shown that all antidepressants require at least 4–6 weeks before they reach their maximal clinical effectiveness.

There are three phases of MDD therapy:

  • The acute phase. The goal of the acute phase is for the person to recover from depressive symptoms and return to their baseline of functioning. This phase will last about 6–12 weeks.
  • The continuation phase. During the continuation phase, doctors will recommend that people continue treatment for 4–9 months to prevent symptoms from returning.
  • The maintenance phase. Some people may need to continue their medication for longer and complete a maintenance phase. The goal is to protect at-risk people from recurring depressive symptoms.

Doctors will usually recommend a maintenance phase for people with recurrent MDD or chronic depression.

If a person does not have a satisfactory response to medication, the doctor may try increasing the dosage. However, a higher dosage may cause more side effects, so doctors need to evaluate the risks and benefits of increasing it.

Another strategy to increase the effectiveness of the therapy is to add another medicine. A doctor may advise a person to combine Prozac or Zoloft with certain other antidepressants and other types of medication to improve their symptoms.

The doctor will determine which combinations are the most appropriate for each person while keeping in mind the possibility of drug interactions.

Doctors may also adjust medication dosages and regimens for people who are combining medication therapy and psychotherapy.

Side effects

As Prozac and Zoloft are both SSRIs, people may experience similar side effects with these drugs.

Zoloft is more likely than Prozac to cause gastrointestinal tract side effects, such as nausea and diarrhea. Men taking Zoloft may also report more sexual dysfunction side effects, such as failure to ejaculate, than those using Prozac.

However, people taking Prozac more often experience headaches, nervousness, and a lack of energy.

The following table lists the most common side effects of Prozac and Zoloft, which occur in at least 5% of people.

Prozac Zoloft
nausea 22% 26%
diarrhea 11% 20%
constipation 5% 6%
decreased appetite no data available 7%
anorexia 10% no data available
acid reflux 8% 8%
dry mouth 9% 14%
sweating 7% 7%
insomnia 19% 20%
drowsiness 12% 11%
anxiety 12% no data available
agitation no data available 8%
nervousness 13% no data available
dizziness 9% 12%
tremor 9% 9%
headache 21% no data available
weakness/lack of energy 11% no data available
flu-like symptoms 5% no data available
decreased sex drive no data available 6%
failure to ejaculate no data available 8%

Warnings

When people are ready to come off their antidepressant medications, they should do so gradually. Stopping Prozac, Zoloft, or any other antidepressant abruptly can cause discontinuation symptoms.

Discontinuation symptoms may include:

  • dysphoria, or general unease and dissatisfaction
  • irritability
  • agitation
  • dizziness
  • electric shock sensations
  • anxiety
  • confusion
  • headaches
  • lethargy
  • emotional lability, or rapid and exaggerated changes in mood
  • sleeplessness

Several short-term studies have shown that children, adolescents, and young adults under 24 years old have an increased risk of suicidal thoughts and behaviors when taking any antidepressants.

Doctors will monitor people taking Prozac, Zoloft, or any other antidepressant for worsening of depressive symptoms, suicidal thoughts, and unusual behaviors.

People with glaucoma and a history of seizures should use Prozac, Zoloft, and other SSRIs with caution because the drugs can make these conditions worse.

Suicide prevention

  • If you know someone at immediate risk of self-harm, suicide, or hurting another person:
  • Call 911 or the local emergency number.
  • Stay with the person until professional help arrives.
  • Remove any weapons, medications, or other potentially harmful objects.
  • Listen to the person without judgment.
  • If you or someone you know is having thoughts of suicide, a prevention hotline can help. The National Suicide Prevention Lifeline is available 24 hours a day at 1-800-273-8255.

Interactions

SSRIs, including Prozac and Zoloft, have similar drug interactions.

Serotonin syndrome

prozac vs zoloft agitated

Feelings of agitation and restlessness can indicate serotonin syndrome.

Serotonin syndrome is a potentially life-threatening interaction that occurs as a result of combining drugs that increase serotonin in the body.

Doctors should avoid prescribing Prozac, Zoloft, and other SSRIs alongside the following drugs:

  • triptans
  • tricyclic antidepressants (TCAs)
  • fentanyl
  • lithium
  • tramadol
  • tryptophan
  • buspirone
  • amphetamines
  • St. John’s wort
  • monoamine oxidase inhibitors (MAOIs)

Some of the signs and symptoms of serotonin syndrome include:

  • agitation
  • anxiety
  • restlessness
  • disorientation
  • sweating
  • a high body temperature
  • increased heart rate
  • nausea
  • vomiting
  • shaking
  • muscle rigidity
  • overactive reflexes
  • abnormal muscle contractions
  • dilated pupils
  • abnormal eye movements
  • dry mucous membranes
  • flushed skin
  • increased bowel sounds

MAOIs

People cannot take MAOIs, another type of antidepressant, with Prozac, Zoloft, or any other SSRIs because the risk of developing serotonin syndrome is very high.

Anyone taking an MAOI must stop taking it at least 2 weeks before starting SSRI treatment.

QT prolongation

Doctors have reported QT prolongation in people taking Prozac and Zoloft. QT prolongation is a potentially fatal heart rhythm dysfunction.

This heart condition is more common in people who take other drugs that can prolong the QT interval on an electrocardiograph. These include certain antipsychotics, antibiotics, and anti-arrhythmic medications.

Abnormal bleeding

Some people can experience abnormal bleeding when combining Prozac, Zoloft, and other SSRIs with drugs that can increase bleeding, such as:

  • aspirin
  • nonsteroidal anti-inflammatories (NSAIDs)
  • warfarin
  • anticoagulants

Cost

The following table compares the lowest available prices of Prozac and Zoloft:

fluoxetine Prozac sertraline Zoloft
Capsule (30 capsules) 10 mg: $3.00
20 mg: $3.00
40 mg: $3.00
10 mg: $461.85
20 mg: $474.70
40 mg: $947.40
no information available no information available
Tablet (30 tablets) 10 mg: $4.00
20 mg: $26.76
60 mg: $96.35
no information available 25 mg: $3.99
50 mg: $7.17
100 mg: $6.52
25 mg: $313.61
50 mg: $313.61
100 mg: $313.61
Liquid oral solution (1 bottle) 120 ml: $12.81 no information available 60 ml: $25.10 60 ml: $216.18

Can you take Prozac and Zoloft together?

People should not take Prozac and Zoloft together. These drugs are in the same drug class and have the same actions. Taking both drugs will not improve symptoms but can cause additional side effects.

When people are not feeling the intended effects of either Prozac or Zoloft, the doctor may increase the dosage or alter the treatment regimen by adding another antidepressant or antipsychotic drug that has different actions on the brain.

Summary

Prozac and Zoloft are part of the same family of antidepressants, and both raise the levels of serotonin in the brain. Both drugs have FDA approval for the treatment of MDD, and they also have other approved and nonapproved uses.

The safe warnings relating to taking Prozac or Zoloft are similar, as are many of the side effects, although these can vary from person to person. Zoloft may be harsher on the stomach, while Prozac is more likely to cause headaches.

Both drugs are generally effective and safe, but people taking Prozac or Zoloft should follow up with their doctor to discuss their symptoms and side effects to ensure that they are taking the most effective dosage.

If treatment is successful, the doctor will slowly reduce the dosage if possible to eventually stop the medication. People should not abruptly stop taking Prozac or Zoloft.

via Prozac vs. Zoloft: What are the differences?

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[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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[WEB SITE] Low Serotonin, Depression Link a Myth?

The concept that depression is a result of low brain serotonin levels and, therefore, that selective serotonin reuptake inhibitors (SSRIs) are an effective treatment for the disorder is a myth, says a UK psychiatrist.

Moreover, David Healy, MD, professor of psychiatry, Hergest Unit, Bangor, Wales, United Kingdom, believes that SSRIs were a treatment looking for a condition and that doctors and patients were co-opted into the myth by clever marketing, resulting in better treatments being sidelined.

“This history raises a question about the weight doctors and others put on biological and epidemiological plausibility. Does a plausible (but mythical) account of biology and treatment let everyone put aside clinical trial data that show no evidence of lives saved or restored function?,” Dr Healy asks.

“In other areas of life the products we use, from computers to microwaves, improve year on year, but this is not the case for medicines, where this year’s treatments may achieve blockbuster sales despite being less effective and less safe than yesterday’s models,” he adds.

The editorial was published online April 21 in the BMJ.

Doctors, Patients Co-opted

Outlining the history of SSRIs, Dr Healy says that in the 1960s, the notion that serotonin levels are lower in persons with depression was rejected, and SSRIs were shown to be less effective than tricyclic antidepressants. The SSRIs were then marketed as tranquilizers, for which they were equally unsuccessful.

Continue —> Low Serotonin, Depression Link a Myth?.

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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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