New findings on how ketamine acts against depression
The discovery that the anaesthetic ketamine can help people with severe depression has raised hopes of finding new treatment options for the disease. Researchers at Karolinska Institutet have now identified novel mechanistic insights of how the drug exerts its antidepressant effect. The findings have been published in the journal Molecular Psychiatry.
According to the World Health Organization, depression is a leading cause of disability worldwide and the disease affects more than 360 million people every year.
The risk of suffering is affected by both genetics and environmental factors. The most commonly prescribed antidepressants, such as SSRIs, affect nerve signalling via monoamines in the brain.
However, it can take a long time for these drugs to help, and over 30 percent of sufferers experience no relief at all.
The need for new types of antidepressants with faster action and wider effect is therefore considerable.
An important breakthrough is the anaesthetic ketamine, which has been registered for some years in the form of a nasal spray for the treatment of intractable depression.
Relieves depressive symptoms quickly
Unlike classic antidepressants, ketamine affects the nerve signalling that occurs via the glutamate system, but it is unclear exactly how the antidepressant effect is mediated. When the medicine has an effect, it relieves depressive symptoms and suicidal thoughts very quickly.
However, ketamine can cause unwanted side effects such as hallucinations and delusions and there may be a risk of abuse so alternative medicines are needed.
The researchers want to better understand how ketamine works in order to find substances that can have the same rapid effect but without the side effects.
Explains ketamine’s effects
In a new study, researchers at Karolinska Institutet have further investigated the molecular mechanisms underlying ketamine’s antidepressant effects. Using experiments on both cells and mice, the researchers were able to show that ketamine reduced so-called presynaptic activity and the persistent release of the neurotransmitter glutamate.
“Elevated glutamate release has been linked to stress, depression and other mood disorders, so lowered glutamate levels may explain some of the effects of ketamine,” says Per Svenningsson, professor at the Department of Clinical Neuroscience, Karolinska Institutet, and the study’s last author.
When nerve signals are transmitted, the transmission from one neuron to the next occurs via synapses, a small gap where the two neurons meet.
The researchers were able to see that ketamine directly stimulated AMPA receptors, which sit postsynaptically, that is, the part of the nerve cell that receives signals and this leads to the increased release of the neurotransmitter adenosine which inhibits presynaptic glutamate release.
The effects of ketamine could be counteracted by the researchers inhibiting presynaptic adenosine A1 receptors.
“This suggests that the antidepressant action of ketamine can be regulated by a feedback mechanism. It is new knowledge that can explain some of the rapid effects of ketamine,” says Per Svenningsson.
In collaboration with Rockefeller University, the same research group has also recently reported on the disease mechanism in depression.
The findings, also published in the journal Molecular Psychiatry, show how the molecule p11 plays an important role in the onset of depression by affecting cells sitting on the surface of the brain cavity, ependymal cells, and the flow of cerebrospinal fluid.
(Image caption: Mutations in the GABA-A receptor cause a temporary imbalance between GABA signaling (yellow) and glutamate signaling (blue) in the brain. Homeostatic down regulation of glutamate signaling rebalances the system at a lower level and can lead to depression. Treatment with ketamine restores both GABA and glutamate levels to normal. Credit: Penn State University)
New research demonstrates the effectiveness of ketamine to treat depression in a mouse model of the disease and brings together two hypotheses for the cause of depression. The research, led by Bernhard Lüscher, professor of biology and of biochemistry and molecular biology at Penn State University, is in press and was published in the September 15, 2016 print edition of the journal Biological Psychiatry.
“Depression is the second most expensive health problem that we face worldwide, but this fact is not very well known because there is a stigma attached to depression and people don’t like to talk about it,” said Lüscher. “About 17 percent of Americans will be treated for depression at some point in their lives, but there are limited treatment options and about one-third of patients do not respond to these treatments.”
Lüscher and his colleagues generated a mouse model for depression by introducing a mutation into a gene that codes for one of the subunits of a receptor for GABA – the second most abundant chemical used by nerve cells in the brain to communicate. GABA functions mainly to reduce the activity of nerve cells. The receptor mutation results in a reduction in GABA signaling of about 15 to 20 percent and mimics reductions in GABA signaling seen in patients with depression. The mice that have the mutation exhibit traits associated with depression, such as reduced pleasure seeking, and they become normal again following treatment with antidepressant medications.
“You can think of GABA as acting like the brakes of a car – its function is to slow activity in nerve cells,” said Lüscher. “Its counterpart is glutamate, another signaling chemical in the brain that acts as the accelerator of nerve-cell activity. When we reduced the function of GABA in our mice, we were surprised to see that the level of glutamate was also reduced. This result suggests that the brain has mechanisms that maintain a balance between the brakes and the accelerator to prevent brain activity from going out of control, a state we refer to as homeostasis.”
The researchers treated the mice with low doses of ketamine, an experimental antidepressant drug known to act by transiently blocking a major class of glutamate receptors in nerve cells. “Treatment with ketamine not only normalized the behavior and brought glutamate receptor levels back up to normal in our mice, but GABA function also was restored,” said Lüscher. Importantly, the effects of ketamine were only observed in mice with the receptor mutation where nerve signaling was defective, and not in normal mice. “Our results bring together the hypothesis that depression results from deficits in GABA signaling and the hypothesis that depression results from deficits in glutamate signaling. We showed that the depression-like behavior in our mice results from the reduction of both GABA and glutamate, and importantly, that both can be restored with a single dose of ketamine.”
The researchers plan to use their mouse model to better understand how ketamine functions to develop safer alternatives. “Ketamine has many advantages over currently used antidepressant medications,” said Lüscher. “It acts quickly and has long lasting effects, but it is addictive and can induce psychosis, so we hope to use our model to better understand how ketamine works biochemically. We can then begin to develop ketamine-like drugs without the unwanted side effects.”
What are antidepressants? How do antidepressants work? Do I need antidepressants? Antidepressants or therapy? Well if you’ve ever had any of these questions, then you should watch this video. In this video I’m talking you through what antidepressants are, how antidepressants work with the brain, and when you may need antidepressants versus just therapy. I’m lucky enough to be joined by my friend and neuroscientist Ben Rein, Ph.D. from Stanford University, because as you know, I am not a neuroscientist!
Dietary pattern and food choice may play a role in the treatment and prevention of brain-based disorders, particularly depression
❕ Many nutrients are implicated in the pathophysiology of depression, for instance: the long-chained omega-3 fatty acids, B-vitamins, zinc, magnesium, and vitamin D. Deficiencies of these nutrients can cause depressive symptoms
Nutrients such as the long-chained omega-3 fatty acids, zinc, magnesium, and several phytonutrients promote the expression of Brain-Derived Neurotropic Factor (BDNF) and thus influence neuroplasticity
Antidepressant nutrients are folate, iron, long-chain omega-3 fatty acids (EPA, DHA), magnesium, potassium, selenium, thiamine, vitamin A, vitamin B6, vitamin B12, vitamin C, and zinc
Antidepressant plant food with high antidepressant food score
▫️ watercress
▫️ spinach
▫️ mustard, turnip, or beet greens
▫️ lettuces (red, green, romaine)
▫️ swiss chard
▫️ fresh herbs
▫️ chicory greens
▫️ pummelo
▫️ peppers (bell, serrano, or jalapeno)
▫️ kale or collards
▫️ pumpkin
▫️ dandelion greens
▫️ cauliflower
Antidepressant animal food with high antidepressant food score
▪️ oyster
▪️ liver and organ meats (spleen, kidney, or heart)
▪️ poultry giblets
▪️ clam
▪️ mussels
Gut health is critical for brain health. Eat healthily, stay healthy ☝
psa to everyone on antipsychotics during the summertime
some antipsychotics can make you more susceptible to heat exhaustion because they make it so your body cannot regulate your body temperature correctly. I learned this the hard way last summer, I got really nasty heat exhaustion while on a high dose of quetiapine. so check if your meds react badly to heat, and if they do, please be sure to wear your sunscreen, have light cover ups on or with you, wear a hat, and stay hydrated! be safe
especiallyduloxetineandclozapine,know the signs of dehydration,take cooling breaks if you have to be in the sun
duloxetine is commonly branded in the USA as Cymbalta.
Note: many anti-bipolar meds are also antipsychotics. I found a list of psychotropic meds that can increase risk of heat exhaustion here:
Can personally confirm that Latuda/Lurasidone can also mess with your heat response and lead to heat exhaustion if you aren’t careful, like I wasn’t.
fuck the french education system, we’re 1900 ppl in my year 460 will make it into medicine next year
got admitted to the psych ward twice, got stitches
changed treatments and shrinks numerous amounts of times
dude im tired i fail at everything i cant study i cant stay healthy i cant function normally unless im doped up, even then gotta take my anxios or brain go :
i hate taking antidepressants and antipsychotics bc they make me feel like i’ve been hit by a truck at full speed and soooo numb and tired but when i don’t take them i still feel numb and tired but with less hours of sleep
that’s literally all the difference they make antidepressants and antipsychotics just help me kind of sleep so if that’s all it does and nothing about my mood like IT SHOULD then i should just take sleeping pills instead lmfao they’re cheaper and more available
Despite these wild times, I am still on track to publish my first book. It’s an incredible and difficult experience, writing about your own life, and remaining honest forces you to confront yourself on many levels.
So I ran out of antidepressants/anxiety tablets a week ago and it feels like i’m awake for the first time in months, but I have however noticed that I have been struggling to sleep again and I am getting worked up about the silliest of things again. I’m unsure what to do, should I go back to the doctors or stay of them as I actually feel awake and not like some zombie that is just passing through the motions in life, so far luckily I haven’t had any major downers which is a plus but it will probley happen at some point Just really unsure on what to do.
has anyone had any experiences with SNRIs? I’ve been prescribed many SSRIs and it’s been decided they don’t work for me. I have an appointment tomorrow to switch off Lexapro to some SNRI(possibly Effexor) but I’ve been reading lots of reviews and I’m not sure what to expect
Hey. If you are currently taking or considering taking medication for depression/anxiety/other mental health things, first of all: I’m with you. I feel for you and I wish you the best success at getting better and feeling like yourself again.
We’ve seen flashes of what it looks like to detox from Heroin on TV. But they never show detox from CymbaltaorEffexor. And those guys have a nasty detox too.
Disclaimer 1: This post is notanti-medication. It’s not meant to scare you out of taking them. If they help you - take them! It’s just here to help answer questions you might have, such as “Are my new tremors related to the medication I’m taking?” or “Why have I been dizzy for three weeks?”
There is no shame in taking medication for your mental health.
Disclaimer 2:I am not a doctor. Always always always consult your medical professionals. This is only meant to add some knowledge to your vocabulary of things to ask that your doctor might not mention.
I’m giving examples from Effexor because that’s what I know, but the general principles in this post apply to any psychiatric drug.
Below is an incomplete list of withdrawal symptoms from coming off of VenlafaxineakaEffexorakaViepax (the check marks are ones I have experienced):
brain shivers
agitation✅
anxiety✅
confusion
mania
mood swings
anorexia
impaired coordination✅
dizziness✅
fatigue✅
lethargy✅
headaches✅
night tremors
tremor✅
sensory disturbances✅
electric shock-like sensations
vomiting
vertigo✅
sweating
diarrhea
dry mouth✅
… the list goes on. Anything could be a side effect. Nightmares. Loss of appetite. Muscle aches. Sleep disruption. A completely whacked sleep schedule.
I’m posting this because people should know.
First of all,
NEVER STOP TAKING A MEDICATION WITHOUT CONSULTING A DOCTOR.
Second of all, even if you are on a regular dose of Venlafaxine, you might still have some withdrawal symptoms.
Third of all, if you suddenly start having these symptoms, you deserve to know that it could be caused by your medication.
Now, you might be wondering why anyone would ever take this drug if there are so many side effects and such horrible withdrawal? And that’s a fair question. And the answer is that sometimes it’s worth it. Venlafaxine does help with anxiety and depression and their side effects, such as brain fog. It can restore someone to functionality enough that they are not incapacitated by their mental illness. Sometimes it’sworth the side effects if it means you can have a job, take care of yourself and your loved ones, enjoy a drink with friends, feel emotions, drive, etc.
There is no shame in taking medication for your mental health.
There is no shame in taking medication for your mental health.
There is no shame in taking medication for your mental health.
And sometimes it’ll work for a little while and then stop. And if you go to the doctor with just your symptoms, they’ll take a thousand and one tests and conclude that nothing is wrong with you. And you’ll be caught in a loop of asking yourself, What is wrong with me? Is this my life? Am I just…like this now? And that can be terrifying in itself.
So spread the word. Make sure people who are taking or considering taking this drug know what symptoms might be connected to it. It could save a lot of time wondering why we suddenly have extra headaches or get random shivers when it’s not cold outside.
Knowledge is power. Advocate for yourself. Make your psychiatric prescriber inform you of the possible side effects and symptoms you might experience from the medication they just gave you. If you are a highly sensitive person like me, let your doctors know that.
I am going through withdrawal right now. If you are too, I feel for you. If you are screaming into the void of a medical system wondering why you have a zillion symptoms and perfect test results, my heart is with you. You are not alone in this.
for The Small Bow Sometimes when my boyfriend texts me to tell me he’s on his way home from work, I type back, “my legs are broken.” I don’t know why I insist on this code when we both know what it means.
I have been under mental health services since I was a young teen,
I have suffered trauma,
I have suffered loss,
I have been sectioned,
I have starved myself,
I have been in hospital hooked up to machines,
I have used emergency services endlessly,
I have seen multiple therapists,
I have cried myself to sleep,
I have spent a year in a specialist hospital,
I have pushed people away,
I have lived a life not worth living at times.
BUT….
Today I was discharged PROPERLY from mental health services
I had a CPA today where I was able to say I no longer need services. After 10 years of consistent input from services I can finally say I feel human again. I feel happy and content with myself.
I still have down days and I’m on medication but that’s part of life. I can handle what life throws at me and I have goals and plans I want to achieve.
I can see a career I know I will be good at and I am making plans towards that goal,
I am saving for a house,
I am volunteering,
I am getting fitter,
I am getting back into sport,
I am seeing friends,
I have a beautiful niece,
I have a good support network,
I enjoy learning,
I am growing,
I am surviving,
I have passion and motivation,
I am enjoying life
Looking back I am so grateful to those who stood by me. The people who picked me up, the people who never stopped loving me. The people who held me whilst I sobbed, who ran to me late at night, who sat in A&E with me, who put up with my misery, who called me to check I was okay.
I CANNOT THANK YOU ENOUGH - I love you ❤️
I cannot believe all I have been through, I can say I am proud of what I’ve survived. I never thought I would see the day I say goodbye to services. I want to cry and smile all in one, so that’s what I’m going to do
Was supposed to talk to my midwife tomorrow about getting put back on antidepressants and anxiety meds. And now I’ve gotten a call that she won’t be there and I have to reschedule.
So I saw a really interesting post about figuring out who you were before your depression and how to be that person again after you start to gain some control over your depression. Reading that explained a lot about how I’m feeling right now. I’ve been on 40mg Lexapro for about 2 weeks now and I’m definitely seeing a difference in myself, however I’m having a hard time getting comfortable with myself. Like this person that I am now; clearer, quieter, mind, much more care free, over all happier person, is someone I am VERY unfamiliar with. This person is someone I haven’t seen since I was about 9 years old. So I’m really unsure how I should feel about this, whether it’s the real me or just the medication. Either way this person is a stranger.
I never thought that my mental illness defined me as a person but it’s all I’ve known for nearly 90% of my life. Moving into these uncharted waters is extremely unnerving.
Your brain is a network of billions of neurones, all somehow connected to each other. At this very second, millions of impulses are being transmitted through these connections carrying information about what you can see and hear, as well as your emotional state. It’s an incredibly complex system but sometimes things go wrong. Despite extensive research, we are still not certain on the biology that underlies mental illnesses- including depression. However, we have come pretty far in developing effective treatments.
