Posts Tagged Antidepressant

[BLOG POST] Antidepressants help us understand why we get fatigued during exercise

In general, the term ‘fatigue’ is used to describe any exercise-induced decline in the ability of a muscle to generate force. To identify the causes of fatigue, it is common to examine two divisions of the body that might be affected during exercise. The central component of fatigue includes the many nerves that travel throughout the brain to the spinal cord. The peripheral component predominantly reflects elements in the muscle itself. If there is a problem with either of these components, the ability to contract a muscle might be compromised. For many years, there has been suggestion that central fatigue is heavily influenced by neurotransmitters that get released in the central nervous system (such as dopamine and serotonin). However, little research has been performed in this area.

Serotonin is a chemical that can improve mood, and increasing the amount of serotonin that circulates in the brain is a common therapy for depression. However, serotonin also plays a vital role in activating neurons in the spinal cord which tell the muscle to contract. With the correct amount of serotonin release, a muscle will activate efficiently. However, if too much serotonin is released, there is a possibility that the muscle will rapidly fatigue. Recent animal studies indicate that moderate amounts of serotonin release, which are common during exercise, can promote muscle contractions (Cotel et al. 2013). However, massive serotonin release, which may occur with very large bouts of exercise, could further exacerbate the already fatigued muscle (Perrier et al. 2018).

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants. These medications keep serotonin levels high in the central nervous system by stopping the chemical from being reabsorbed by nerves (reuptake inhibition). Instead of using SSRIs to relieve symptoms of depression, we used them in our recent study (Kavanagh et al. 2019) to elevate serotonin in the central nervous system, and then determine if characteristics of fatigue are enhanced when serotonin is elevated. We performed three experiments that used maximal voluntary contractions of the biceps muscle to cause fatigue in healthy young individuals. Our main goal was to determine if excessive serotonin limits the amount of exercise that can be performed, and then determine which central or peripheral component was compromised by excessive serotonin.

WHAT DID WE FIND?

Given that SSRIs influence neurotransmitters in the central nervous system, it was not surprising that peripheral fatigue was unaltered by the medication. However, central fatigue was influenced with enhanced serotonin. The time that a maximum voluntary contraction could be held was reduced with enhanced serotonin, whereby the ability of the central nervous system to drive the muscle was compromised by 2-5%. We further explored the location of dysfunction and found that the neurons in the spinal cord that activate the muscle were 4-18% less excitable when fatiguing contractions were performed in the presence of enhanced serotonin.

SIGNIFICANCE AND IMPLICATIONS

The central nervous system is diverse, and the fatigue that is experienced during exercise is not just restricted to the brain. Instead, the spinal cord plays an integral role in activating muscles, and mechanisms of fatigue also occur in these lower, often overlooked, neural circuits. This is the first study to provide evidence that serotonin released onto the motoneurones contributes to central fatigue in humans.

PUBLICATION REFERENCE

Kavanagh JJ, McFarland AJ, Taylor JL. Enhanced availability of serotonin increases activation of unfatigued muscle but exacerbates central fatigue during prolonged sustained contractions. J Physiol. 597:319-332, 2019.

If you cannot access the paper, please click here to request a copy.

KEY REFERENCES

Cotel F, Exley R, Cragg SJ, Perrier JF. Serotonin spillover onto the axon initial segment of motoneurons induces central fatigue by inhibiting action potential initiation. Proc Natl Acad Sci U S A. 110:4774-4779, 2013.

Perrier JF, Rasmussen HB, Jørgensen LK, Berg RW. Intense activity of the raphe spinal pathway depresses motor activity via a serotonin dependent mechanism. Front Neural Circuits. 11:111, 2018.

AUTHOR BIO

Associate Professor Justin Kavanagh is a researcher and lecturer at Griffith University. His team explores how the central nervous system controls voluntary and involuntary movement, and he has particular interests in understanding how medications can be used to study mechanisms of human movement.

via Antidepressants help us understand why we get fatigued during exercise – Motor Impairment

 

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[WEB PAGE] Excitatory magnetic brain stimulation reduces emotional arousal to fearful faces, study shows

February 6, 2018

A new study in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging looks at the modulation of emotion in the brain

A new study published in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging reports that processing of negative emotion can be strengthened or weakened by tuning the excitability of the right frontal part of the brain.

Using magnetic stimulation outside the brain, a technique called repetitive transcranial magnetic stimulation (rTMS), researchers at University of Münster, Germany, show that, despite the use of inhibitory stimulation currently used to treat depression, excitatory stimulation better reduced a person’s response to fearful images.

The findings provide the first support for an idea that clinicians use to guide treatment in depression, but has never been verified in a lab. “This study confirms that modulating the frontal region of the brain, in the right hemisphere, directly effects the regulation of processing of emotional information in the brain in a ‘top-down’ manner,” said Cameron Carter, M.D., Editor of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, referring to the function of this region as a control center for the emotion-generating structures of the brain. “These results highlight and expand the scope of the potential therapeutic applications of rTMS,” said Dr. Carter.

In depression, processing of emotion is disrupted in the frontal region of both the left and right brain hemispheres (known as the dorsolateral prefrontal cortices, dlPFC). The disruptions are thought to be at the root of increased negative emotion and diminished positive emotion in the disorder. Reducing excitability of the right dlPFC using inhibitory magnetic stimulation has been shown to have antidepressant effects, even though it’s based on an idea-that this might reduce processing of negative emotion in depression-that has yet to be fully tested in humans.

Co-first authors Swantje Notzon, M.D., and Christian Steinberg, Ph.D, and colleagues divided 41 healthy participants into two groups to compare the effects of a single-session of excitatory or inhibitory magnetic stimulation of the right dlPFC. They performed rTMS while the participants viewed images of fearful faces to evoke negative emotion, or neutral faces for a comparison.

Excitatory and inhibitory rTMS had opposite effects-excitatory reduced visual sensory processing of fearful faces, whereas inhibitory increased visual sensory processing. Similarly, excitatory rTMS reduced participants’ reaction times to respond to fearful faces and reduced feelings of emotional arousal to fearful faces, which were both increased by inhibitory rTMS.

Although the study was limited to healthy participants, senior author Markus Junghöfer, Ph.D., notes that “…these results should encourage more research on the mechanisms of excitatory and inhibitory magnetic stimulation of the right dlPFC in the treatment of depression.”

 

via Excitatory magnetic brain stimulation reduces emotional arousal to fearful faces, study shows

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[WEB SITE] Ketamine – More Than a Recreational Drug.

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Ketamine was first introduced in 1962. It was initially presented as a fast acting general anesthetic, being widely used as a battlefield anesthetic in the 1970s. Ketamine is considered a dissociative anesthetic – it creates an altered state of consciousness, distorting the perception of sound and vision, and producing a feeling of detachment from oneself and from the environment which provides pain relief, sedation, and amnesia.

In the clinic, ketamine is mainly used for starting and maintaining anesthesia. Given its fast sedative action, it is frequently used in emergency situations. Its main effects usually begin within five minutes of injection and last up to 25 minutes.

But ketamine can have some impactful psychological side-effects as the medication wears off, such as agitation, confusion, or hallucinations. The latter is the main reason for its use as a drug of abuse or recreational drug. Ketamine began to be illicitly consumed in the 1970s and, nowadays, it is equally known for its medical and recreational use. Ketamine can produce illusions or hallucinations that are enhanced by environmental stimuli, which explains its popularity as a club drug.

Ketamine is still used in medical contexts as an anesthetic, although its use has become less common and more restricted. However, in recent years, a new use for ketamine has been emerging.

Ketamine as an antidepressant drug

Recent studies have shown that ketamine has fast antidepressant actions in patients with major depressive disorder, even in those with the most treatment-resistant forms of depression. Major depressive disorder is a highly disabling condition with limited treatment options that are often ineffective. The onset of depression is poorly understood but it is thought to derive from a combination of neurochemical factors and triggering life events, such as overwhelming stress. Potential neurochemical factors include defects in the major neurotransmitters of the central nervous system, glutamate and GABA.

Glutamate is the major excitatory neurotransmitter in the central nervous system. Experimental studies in animal models of depression have associated glutamate with depression, showing that there may be altered levels of glutamate receptors; increased glutamate concentrations have also been found in the brains of patients with major depressive disorder. Since ketamine acts by blocking the action of the NMDA glutamate receptors, this is a likely mechanism for its fast action in depression.

Indeed, a single dose of ketamine has been shown to be able to normalize the activity of glutamate receptors. Importantly, the effects of ketamine occurred only at low doses, indicating that these antidepressant effects can occur without the psychological side effects associated with high doses of ketamine.

GABA, on the other hand, is the major inhibitory neurotransmitter in the central nervous system. It has also been associated with depression – mice with an impairment of GABAergic transmission exhibit behavioral signs that mimic the emotional patterns of depression, which supports the view of a causal link between GABAergic neurotransmission and depression. Major depressive disorder has been linked to reduced levels of GABA and GABA receptors, and to reduced expression of glutamic acid decarboxylase, an enzyme that converts glutamate to GABA.

These two effects may seem contradictory, but these deficits in the GABAergic system may actually lead to increased glutamate concentrations. However, some studies have also reported reduced rather than increased brain levels of glutamate. This has led to the hypothesis that depression may actually be associated with a dynamic balance between changes in GABAergic and glutamatergic transmission. The mechanisms underlying this possible relationship were mostly unknown, but a new study published on the journalBiological Psychiatry sheds light on this subject.

A matter of balance

A stable and regular functioning of neural networks relies on an ability to maintain a balance between inhibitory and excitatory neurotransmission. In the mentioned study, and with the goal of understanding how the balance between GABA and glutamate levels may be linked to depression, the consequences of GABAergic deficits on glutamatergic synapses were investigated. It was found that mice with depression associated with GABAergic deficits also showed reduced expression and function of glutamate receptors.

A decrease in the number and activity of glutamatergic synapses was also found. Treatment with a sub-anesthetic dose of ketamine led to a lasting normalization of glutamate receptor levels and glutamatergic synapse function. These results indicate that depression in mice with impaired GABAergic neurotransmission involves a balancing reduction of glutamatergic transmission that can be normalized for a prolonged period of time by the rapidly acting antidepressant ketamine.

This study thereby establishes the link between the GABAergic and glutamatergic deficits described for depression, and suggests that it may be caused by a dysregulation of the equilibrium mechanisms that act to restore the balance of excitation and inhibition. It is possible that conditions of chronic or repeated stress, which may trigger the development of depression, may do so by affecting the balance between GABA and glutamate levels, or by impairing the mechanisms that could restore that balance. Indeed, chronic stress has been shown to decrease the production of glutamate receptors and to render GABAergic inhibition ineffective.

This work also reinforced the antidepressant efficacy of ketamine. However, ketamine will always have a huge drawback due to its drug-of-abuse properties. The use of other NMDA glutamate receptor antagonists without the side-effects of ketamine has been tested with promising results, leading to similar effects as those obtained with ketamine. Here may lay the answer.

References

Garcia, L., Comim, C., Valvassori, S., Réus, G., Stertz, L., Kapczinski, F., Gavioli, E., & Quevedo, J. (2009). Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats Progress in Neuro-Psychopharmacology and Biological Psychiatry, 33 (3), 450-455 DOI:10.1016/j.pnpbp.2009.01.004

Hashimoto, K., Sawa, A., & Iyo, M. (2007). Increased Levels of Glutamate in Brains from Patients with Mood Disorders Biological Psychiatry, 62 (11), 1310-1316 DOI: 10.1016/j.biopsych.2007.03.017

Ionescu, D., Luckenbaugh, D., Niciu, M., Richards, E., Slonena, E., Vande Voort, J., Brutsche, N., & Zarate, C. (2014). Effect of Baseline Anxious Depression on Initial and Sustained Antidepressant Response to Ketamine The Journal of Clinical Psychiatry, 75 (09) DOI: 10.4088/JCP.14m09049

Jansen, K. (2011). A Review of the Nonmedical Use of Ketamine: Use, Users and Consequences Journal of Psychoactive Drugs, 32 (4), 419-433 DOI:10.1080/02791072.2000.10400244

Li, N., Lee, B., Liu, R., Banasr, M., Dwyer, J., Iwata, M., Li, X., Aghajanian, G., & Duman, R. (2010). mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science, 329 (5994), 959-964 DOI:10.1126/science.1190287

Luscher, B., Shen, Q., & Sahir, N. (2010). The GABAergic deficit hypothesis of major depressive disorder Molecular Psychiatry, 16 (4), 383-406 DOI:10.1038/mp.2010.120

Morgan, C., Curran, H., & , . (2012). Ketamine use: a review Addiction, 107 (1), 27-38 DOI: 10.1111/j.1360-0443.2011.03576.x

Niciu, M., Ionescu, D., Richards, E., & Zarate, C. (2013). Glutamate and its receptors in the pathophysiology and treatment of major depressive disorderJournal of Neural Transmission, 121 (8), 907-924 DOI: 10.1007/s00702-013-1130-x

Ren, Z., Pribiag, H., Jefferson, S., Shorey, M., Fuchs, T., Stellwagen, D., & Luscher, B. (2016). Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine TreatmentBiological Psychiatry DOI: 10.1016/j.biopsych.2016.02.009

Image via Unsplash / Pixabay.

Source: Ketamine – More Than a Recreational Drug | Brain Blogger

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[WEB SITE] Ways to Treat Depression That Aren’t Antidepressants

Feb. 27, 2015 — There may be hope for hard-to-treat depression as scientists explore novel ways to help people who have the often crippling condition.

Recently, a number of studies have suggested the benefits of Botox, ketamine, and certain sometimes-unexpected means of treating depression.

“I’m excited in general, and I’m curious,” says Peter D. Kramer, MD, author of Listening to Prozac and Against Depression.

Each year, around 16 million U.S. adults battle major depression. Many of them benefit from antidepressants. But as many as a third get depressive symptoms despite medication. And side effects, which can include weight gain, nausea, and insomnia, are troublesome for some patients. That leaves many people with depression searching for alternatives.

But if Kramer is hopeful about the newer, novel ways to treat the condition, he’s also cautious. The studies backing those treatments aren’t conclusive, and none of the approaches have been approved by the FDA to treat depression (though some, such as ketamine, have been approved for other uses).

“Things are merely hopeful until they are demonstrated [safe and effective],” Kramer says. “It’s always hard to tell what’s going on, but it’s a very interesting time, and I think some of them will come through.”

Here’s a closer look at what might be used to help treat depression in years to come.

Ketamine. Already in use in certain clinics and in some emergency departments around the country, ketamine is an anesthetic most often used during surgery. It’s given through an IV, and it quickly eases symptoms of depression, often in a matter of hours. The benefit is temporary, though.

One recent study found it to be very good at helping curb suicidal thoughts in severely depressed people. But it’s expensive, still experimental as a depression treatment, and can cause hallucinations and other side effects.

“Some people are very uncomfortable with the side effects,” says Alan Manevitz, MD, a psychiatrist who specializes in treatment-resistant depression at Lenox Hill Hospital in New York City.

Nitrous oxide, or laughing gas. This is an anesthetic commonly used by dentists. A small study published last December reports that nitrous oxide improved depression symptoms within less than 2.5 hours.

Continue–> Ways to Treat Depression That Aren’t Antidepressants.

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WEB SITE: Depression: Effects on Your Sex Life and How to Increase Libido

How to keep your sex life — and relationship — alive when you’re dealing with depression.

…Chronic depression affects every part of daily life, including sex. It curbs sex drive, yet sex can boost your mood and is important for relationships. And some depression medicines can curb your libido.

Breaking this cycle can be hard.

How to get out of this funk?…

via Depression: Effects on Your Sex Life and How to Increase Libido.

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WEB SITE: More Than the Blues

To understand depression, think of standing in a pool with the water level up to your lower lip. Moving through the pool is difficult because of the resistance from the water. It’s tiring, like the fatigue often associated with depression. Further, any little wave threatens to overwhelm you so you seek to avoid small ripples and get terrified about even the thought of a big splash coming your way…

via More Than the Blues.

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