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Why Do Antidepressants Take So Long to Work?

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Kate wanted to die. She remembers the moment the psychiatrist said “the antidepressant isn’t going to work right away. Can you promise to be here next week and not kill yourself?”

“I told her no,” Kate says. “I couldn’t promise my doctor I’d make it a week. That’s how bad my life had to be before I got help. When you’re struggling to stay alive every single day, and then your doctor tells you it’s going to take two to six weeks before the medications they give you are going to work, it’s devastating.” To make matters worse, after those weeks, the drug didn’t work. Kate went through five different anti-depressants over the course of six months before confirming that none of them worked. The debilitating disorder kept her out of school for extended periods of time.

The National Center for Health Statistics estimates more than one in 10 Americans over the age of 12 took antidepressants between 2005 and 2008, the last time period for which the data are available. The rate of antidepressant use increased 400 percent from 1998 to 2008.

Traditional antidepressants go after serotonin transporter proteins. These regulatory proteins take serotonin back into the nerve cell after it has been released in the process of signaling other neurons. Antidepressants keep the transporters from performing this function.

Although nowadays, most scientists feel that serotonin release and reuptake are fairly normal in depressed patients, many scientists nonetheless believe the changes in serotonin signaling caused by antidepressants, induces the alleviation of symptoms, says Gary Rudnick, professor of pharmacology at Yale School of Medicine.

Still, antidepressants stop the process of serotonin transporters sucking up released serotonin fairly quickly, so researchers don’t understand why it takes weeks for the medications to take effect, Rudnick says. Scientists believe the behavioral effects of antidepressants may be due to other changes that occur as a reaction to the changed serotonin levels. However, researchers don’t know what reactions include, and therefore cannot create medications that target them directly.

Targeting proteins

A large portion of depression research is associated with trying to ascertain the role of neurogenesis, the process by which the brain generates new neurons. Researchers have noticed that the hippocampus of a depressed person’s brain tends to be smaller than average. Some researchers hypothesize that a problem with neurogenesis causes both the small hippocampus as well as depression; others caution that the causal arrow may be reversed, with a small hippocampus leading to problems with neurogenesis and depression.

“Chronic [or long term] antidepressant treatment will actually increase levels of neurogenesis,” says Julie Blendy, a neuroscientist and pharmacologist at the Perelman School of Medicine at the University of Pennsylvania. Chronic treatment will also increase levels of the protein CREB, known to play a role in the long-term effects of anti-depressants.

To test the effectiveness of CREB, Blendy got rid of the protein in mice. Of course, CREB doesn’t work in a vacuum, and another protein CREM upregulated (increased) in order to compensate for the missing CREB. Interested in the effects of CREM, Blendy upregulated CREM without touching CREB, and found the antidepressants acted much quicker. This new development, published in The Journal of Neuroscience in August 2013, suggests that identifying CREM targets would be better than attempting to identify CREB targets.


An increasingly popular antidepressant solution involves Ketamine, more popularly known as the illicit drug ‘Special K.’ Ketamine has been shown to be effective in bipolar and depressed patients who have not responded to other antidepressants. The drug works in just two hours.

The use of ketamine as an antidepressant has been called the first true development in the field of antidepressant research in 50 years, for it targets an entirely different part of the brain than traditional antidepressants. Instead of focusing on serotonin, norepinephrine or dopamine neurotransmitters, ketamine focuses on a glutamate neurotransmitter. Glutamate accounts for more than 90 percent of all synapses in the human brain, which makes it the most prevalent of all neurotransmitters.

Further studies need to be done in order to figure out how patients can use the drug without experiencing dangerous side effects, such as severe inflammation of the bladder and addiction. Abundant research also needs to be done to further Blendy’s work. Although she and her team of researchers have shown that CREM is a promising target for antidepressants, targeting that protein with a new drug will be a whole new challenge.

Editor’s note (11/15/13): This blog was edited after its original posting to correct an erroneous description of the effects of antidepressants on serotonin levels in the brain.

About the Author: Julianne Chiaet writes about science and technology.  Follow her on Twitter @JuliChiaet


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  1. 1. kebil 10:56 pm 11/12/2013

    Julia – I have used weekly doses of dextromethorphan, a drug that acts via the same mechanism of action as ketamine, to combat depression. I was first diagnosed with Major Depression when I was 19, but it really started in my teens. I am 38 years old now. I have a degree in pharmacy, worked in the mental health field for years, did two years of post-graduate work in neuropharmacology, and have come to realize that this is the only treatment that truly works for me.

    I know that there are lots of people who abuse dextromethorphan for its dissociative effects, just as they misuse ketamine. THe secret is finding the correct dose. For me it is 210 to 280mg two or three times on Sundays, spread out over about a total of 12 hours. It relieves any lapses into depression as well as keeps depression at bay.

    I have tried all the conventional techniques, and never had much success. Intensive talk therapy helped me greatly with learning coping skills and dealing with things like excessive rumination and learning to avoid negative thought patterns, and the dextromethorphan helps for those feelings that just come out of nowhere and slowly drag a person down by slowly chilling a persons soul.

    Dextromethorphan and ketamine both work by blocking the NMDA receptor gated calcium ion channel, a channel of key importance in the production of LTP and in memory, as well as being on of the main excitatory switches in the brain. These NMDA blocking drugs have a multitude of effects that can be very different, and each seems to kick in at a different dose level – essentially the blockers act as different drugs depending on the dose, with reports of their being between three to five “plateaus”, I believe it is the second or third plateaus that is the most effective for me, above that it is mostly psychedelic, below that it is mildly recreational or something else.

    I am going back to school in January to finish my Masters degree in Pharmacy, and then possibly a PhD and then research (no clinical work for me, I stay away from handling real drugs). I would love to talk to you more about this if you wanted to.

    Link to this
  2. 2. levi_gadye 4:49 pm 11/15/2013

    Nice article summing up why Americans consume so many SSRIs, but continue to get more depressed. I have an update though!

    There was a recent, remarkable advance with a drug that is similar to ketamine, but lacks ketamine’s side effects. The drug is called lanicemine – intermittent injection of this drug provided immediate relief of depression for weeks for over 100 patients, and didn’t cause any serious side-effects. I recently wrote up a blog post for the Berkeley Science Review describing this story. NMDA receptors and glutamate are looking more and more attractive as targets for anti-depressants as new studies roll out.

    Sorry for the self-plug, but it’s super exciting that the field is building off of ketamine’s promise for treating such a widespread, and hard-to-treat, disorder.

    Thanks again for your post! The public needs to be informed by science, and not pharmaceutical companies, regarding important topics like mental illness.

    Levi Gadye
    Helen Wills Neuroscience Institute
    University of California, Berkeley

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  3. 3. vapur 4:51 pm 11/15/2013

    Maybe because the placebo effect hasn’t taken over, that the patient hasn’t given their full faith yet to the drug. Once they start feeling the effects, then it makes it easier to accept that it’s working.

    Link to this
  4. 4. rshoff2 5:33 pm 11/15/2013

    I’m with Kebil and Levi on this. And thank you both for pursuing such real life science!!

    Link to this
  5. 5. jct405 8:23 am 11/16/2013

    Remember the TV commercials characterizing depression as “imbalances” in serotonin levels? As if an SSRI was merely a method for restoring one’s serotonin “deficit?” Depressed? Oh, your serotonin levels are low. Here take this serotonin pill. All will be better. Now, out of my office. Next! To this day physicians cluelessly, with no basis whatsoever, promote SSRI’s and fail to track their patients’ response. Tort reform. I am all for it. When can these hapless addicts to Madison Avenue spin be sued out of practice and away from their prescription pads forever? The complexity of neuropharm is so out of their league that they are a menace.

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  6. 6. kienhua68 11:29 am 11/16/2013

    It did take, for me at least, about a year to gain the full benefit of the antidepressant Sertraline. You have to stay with it until your body adjusts.

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  7. 7. tuned 12:01 pm 11/16/2013

    “Antidepressants” are a rotten answer to depression, especially “clinical”.
    The depressed brain is not making enough of the serotonin, etc. usually. Drugs that end up forcing the brain to dump it’s supply makes a “high”, sure. Then the supply has run out for awhile and the crashes are ferocious, even suicidal. Most any addiction is like that also.
    The answer must be (for now) introducing REAL serotonin, endorphin, et al. from OUTSIDE to make up the difference.
    That is the body’s own natural “feel good” so accept nothing less.
    The best final answer is of course for genetic engineering to fix the problems.

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  8. 8. Iahmad 12:30 pm 11/17/2013

    Excellent article. We are still searching for an effective treatment for depression. Something which is as effective as ketamine (rapid onset of action on resistant depression) without its unwanted effect. Serotonin hypothesis has produced best whatever could be achieved through that mechanism. We need to look at radically different mechanism. Basic science has provided multiple new avenues to explore. Many of us are committed to bring safe and effective treatment to patients in near future.
    Ishtiyaque Ahmad, PhD

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  9. 9. Looie 12:23 pm 11/18/2013

    It probably isn’t the full explanation, but one interesting possibility relates to the influence of serotonin on sleep. People with severe depression usually have disrupted circadian rhythms, and sleep either too little (the most common case) or too much. Serotonin modulates the ability of light to control the circadian rhythm — it makes light feel brighter, so to speak. Depressed people who take SSRIs often don’t experience an improvement in mood for weeks, but they frequently experience an improvement in sleep very rapidly — furthermore the improvement in sleep is a strong predictor of whether a mood improvement will eventually occur.

    Best regards, Bill Skaggs

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  10. 10. RedRoseAndy 9:18 am 11/21/2013

    Sleep experts say that most mental illness is due to poor, or little, sleep. To get the sleep you get at the coast when the wind blows in from the sea just heat salt water in an oil burner overnight. In just five nights insomnia is cured, and this takes with it all symptoms of mental illness. Sound too dangerous? Then heat the salt water during the day to simulate a walk by the sea side.

    Link to this
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  12. 12. pharmaceuticals 5:28 am 10/18/2014

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