How New Generation Drugs Are Targeting Depression


Ketamine-and-Other-New-Generation-Drugs-for-DepressionTwo years ago, I talked with a prominent psychiatrist about what could be done for all the people who have treatment-resistant depression who do not respond — or only partially respond — to the drugs on the market today.

“We wait for better drugs to come out,” he said.

I wanted a better answer, because my experience with the newer drugs like Zyprexa (olanzapine) — atypical neuroleptics (a type of antipsychotic) that were supposed to treat bipolar disorder with fewer side effects than typical mood stabilizers like lithium and Depakote (divalproex sodium) — proved to be a disaster.

But I am coming around to agree with the psychiatrist.

With better research comes new ways of tackling the beast of depression. As we learn about different systems that may contribute to the illness and the complicated mechanisms of the brain, scientists are thinking differently about drugs to treat depression and bipolar disorder.

A fascinating article published October 15 in The Economist, “Novel Drugs for Depression,” discusses where we’ve been in terms of drug treatment for depression, and the wide road ahead of us. The article is hopeful and exciting.

Depression: More Than a Chemical Imbalance

Drug companies like Pfizer sold the public the simple “chemical imbalance” theory for depression in the late 1980s and 1990s because it’s easy to understand: A shortage of neurotransmitters like serotonin could be replenished with a class of drugs called selective serotonin reuptake inhibitors (SSRIs).

But it’s really not that simple.

In an April 2015 editorial in The BMJ, “Serotonin and Depression: The Marketing of a Myth,” professor of psychiatry David Healy, MD, explained that there was no correlation between serotonin reuptake-inhibiting potency and antidepressant effectiveness, and that the low-serotonin story is a myth to make people feel better that depression is not a weakness.

“There is little question that the role of serotonin in depression was over-emphasized and over-marketed in the 1990s,” explains Ron Pies, MD, professor of psychiatry and behavioral sciences at SUNY Upstate Medical University in Syracuse and author of Psychiatry on the Edge, “though most psychopharmacologists understood that the neurobiology of depression was much more complicated. Indeed, the term ‘SSRI’ is itself a misnomer, since some of these agents also affect other brain chemicals — for example, sertraline has mild effects on dopamine. None of this, however, should be used in service of the equally mythological claim that ‘antidepressants don’t work’ or are ‘no better than a sugar pill.’ This is demonstrably false, at least with respect to moderate-to-severe depression.”

How Effective Are Current Antidepressants?

As it turns out, at standard doses of the most commonly used SSRIs, only one-third of people achieve remission with the first medication prescribed.

According to the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, a project funded by the National Institute of Mental Health, if the first choice of medication does not provide adequate symptom relief, switching to a new drug is effective about 25 percent of the time. Switching from one SSRI to another is almost as effective as switching to a drug from another class.

If the first choice of medication doesn’t provide adequate symptom relief, adding a new drug while continuing to take the first medication is effective in about one in three people. Some research says one-third of people cannot achieve full recovery even after trying multiple options; however, those studies may not be taking into consideration options like monoamine oxidase inhibitors (MAOIs), tricyclics, or Lithium augmentation, which improve chances at achieving remission.

Here’s Where Ketamine-Type Treatments Come In

In another post, I discussed ketamine (Ketalar), which some people are hailing as a miracle drug for depression.

Often referred to as “Special K,” it has been around since the 1960s and is a staple anesthetic in emergency rooms. Ketamine is also an illicit, psychedelic club drug.

In the last 10 years, studies have shown that it can reverse the kind of severe suicidal depression that traditional antidepressants can’t treat — and sometimes in the matter of a few hours.

Ketamine isn’t quite ready for prime time yet because of concerns about safety and long-term effects. One study published in January 2014 in the British Journal of Clinical Pharmacology included among possible side effects psychedelic symptoms (hallucinations and panic attacks), nausea, cardiovascular stimulation, memory defects, and bladder and renal complications.

But given its tremendous success (75 percent) in treating patients who have been resistant to other depression medications, new ketamine-related treatments are emerging.

Esketamine is one such drug. In a study published in September 2016 in Biological Psychiatry, esketamine delivered rapid and significant improvement of depressive symptoms in people who had not responded to current available drugs.

In a double-blind study, the researchers randomly assigned 30 patients to get a placebo, or a lower (0.2 mg/kg) or higher (0.4 mg/kg) dose of esketamine. The patients got two IV doses during the double-blind phase, which was followed by a two-week follow-up phase in which they could receive up to four additional, optional open-label doses.

The earliest antidepressant effect occured just two hours after the first infusion. Within three days, more than 60 percent of patients receiving either dose of esketamine saw improvement in depressive symptoms. The authors compare this response rate to only 37 to 56 percent of patients after 6 to 12 weeks on conventional antidepressants.

Fast-Acting Drugs Aimed at a New Target

As The Economist article explains, drug companies are studying ketamine in hopes of imitating the way it works. According to the article:

Many people think ketamine affects the action of a common neurotransmitter called glutamate by blocking the activity of receptors for this molecule. One hypothesis is that it interacts with a glutamate receptor called NMDA that had never previously been thought to be involved in depression. Several firms are therefore seeking to mimic the effect of ketamine by aiming at the NMDA receptor.

Rapastinel (formerly known as GLYX-13) is an NMDA-blocking drug that is being developed by Allergan, an Irish company. A recent clinical trial showed that a single intravenous dose produced statistically significant reductions in depression scores in people who had failed treatment with other antidepressants.

The results occured within 24 hours and lasted for an average of seven days. The effect of a single dose was nearly twice as great as the effect seen in clinical trials of most conventional antidepressants after four to six weeks of treatment.

The Economist article makes the point that we are far from a neat conclusion about how depression acts in the brain, and that lots of drugs work well even though we don’t know precisely how.

But with ketamine comes a new way of approaching depression that should offer hope to persons not helped by standard antidepressants. Even if the drugs aren’t ready now, we can believe that there may be substantial relief of symptoms at some point in the near future.

Join Project Hope & Beyond, a depression community.


PHOTO CREDIT: Dwight Eschliman/Getty Images

Originally posted on Sanity Break.

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Therese Borchard
I am a writer and chaplain trying to live a simple life in Annapolis, Maryland.

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21 Responses
  1. kdn

    I often wonder if these types of articles are promoted by pharmaceutical companies. Yesterday, I came across a somewhat similar article funded by a pharmaceutical company.
    We need to remember that science does not understand consciousness, and because mental activity is correlated with brain activity, they simply assume that psychological problems are biological abnormalities that somehow need to be treated with a drug.
    Think of it this way: In various organs of our body (such as the heart, liver, spleen, etc.), it is extremely rare that various problems spring up due to biological/physiological abnormalities that happen to suddenly arise from nowhere. But as soon as people display “mental illness,” a biological/physiological problem in the organ brain is presumed to cause it! Psychiatrists completely ignore neuroplasticity/epigenetics – i.e., how the activity of the mind brings about structural changes in the brain.
    I also came across the following academic article: McLaren, N. (2016). Psychiatry as Bullsh*t. Ethical Human Psychology and Psychiatry, 18(1), 48-57. It talks about the illusory theoretical underpinnings of psychiatry, and how current psychiatric trainees and junior psychiatrists blindly accept the methods used in psychiatry because they simply (wrongly) assume that much smarter people before them have somehow sorted out all the details relating to the theories underlying psychiatry!

  2. Susan

    As someone with the label of “treatment resistant depression”, who has been a guinea pig for thirty-some yrs for every psych drug known to mankind, and who still struggles daily with depression and suicidal thoughts, I do NOT believe the answers lie in pharmaceuticals as yet undiscovered. Read Dr. Kelly Brogan”s book, A Mind of Your Own, for starters. Investigate functional medicine. Look into CIRS (Chronic Inflammatory Response Syndrome). I currently am undergoing treatment for CIRS due to mold…who knew mold could affect the brain so badly? (Read Dr. Mary Ackerly’s article “Brain on Fire”.) Depression is a symptom, not a disease. Pharmaceuticals attempt to treat the symptom without solving the root cause. My heart goes out to everyone suffering from depression or any mental illness…please don’t hang your hopes on drugs, rather put your hope in diet/lifestyle/environmental/toxicity interventions.

    1. Linda

      Susan…..your are right on and I agree with you 100%. I’ver taken antIdepressants most of my life and at age 67 I QUIT.

      1. Linda

        Susan…..your are right on and I agree with you 100%. I’ver taken antIdepressants most of my life and at age 67 I QUIT.

        Does anyone know about the Fisher-Wallace equipment?

    2. Barbara Malony

      Susan, my body suffers from major inflammation, and as a result my current physicians believe it is the cause of my Fibromialgia and Chronic Fatigue. An extremely high percentage of those diagnosed with these two conditions also have Depression…and I do. Coincidentally, I am also allergic to mold. I am currently using a powder (added to water or juice) that has been a miracle for the Fibro and CFS. For the 1st time in 25 years, my pain is hugely reduced, and the heavy, crippling fatigue is gone. Email me for info on the supplement, and PLEASE share your own info regarding depression. Many thanks.

      1. laurie bolton

        Hi Barbara, I’m dealing with mold related depression, CFS and CIRS. Lots of brain inflammation.
        What is this powder that is helping you? Thank you

  3. John Diehl

    Therese, thank you for this exciting post, which offers relief and hope. As always, the links and references to other articles and research add immense credibility to your work. You continue to be a bright shining star for me and countless others.

  4. I believe every case of mental illness is unique to that person, and no one treatment can be said to address everyone. So yes, for some people, lifestyle/diet/environmental changes work, and for others medication works, and for people like me, it’s a combination of all the above. For me, it’s yoga, mindfulness, good sleep, diet, cardio exercise, Paxil and Lithium. I get tired of people like Kelly Brogan who state that meds don’t work, and you need to find the root cause. Sounds all well and good, but I spent a decade searching and not finding it, and then gave up and took the meds. And guess what – suicide thoughts gone. Everyone has their path to walk and don’t judge their path just because their path doesn’t work for you.

    1. Stephen Matson

      I’ve been considering lithium augmentation having been on paxil for 12 years. Has that been a good combination for you?

  5. John Diehl

    Other than the glimmer of hope, your most potent citations are:

    “… no correlation between serotonin reuptake-inhibiting potency and antidepressant effectiveness, and that the low-serotonin story is a myth….”


    “There is little question that the role of serotonin in depression was over-emphasized and over-marketed…. Indeed, the term ‘SSRI’ is itself a misnomer….”

    and finally,

    “…lots of drugs work well even though we don’t know precisely how.”

  6. Peter Krug

    Thank-you Therese for your unique and inspirational work. You have been very helpful to me. I have treatment resistant depression dating back to when I was 17 in 1969. I would like to try Ketamine. I have so far been unable. My research indicates that Ketamine treatments for depression are available in many parts of the world. Perhaps more light could be shed in this growing treatment. Peter

  7. Many of my thoughts after reading this article are along the lines expressed in here, there is so much we still do not understand about the brain and mood. I think many are becoming more and more disillusioned with anti-depressants, and certainly the neurotransmitter theory is not the complete picture. Saying that, it is my understanding that SSRI’s do actually replenish serotonin, they increase levels by means of preventing its breakdown, which actually results in a worse deficiency … and more dependence on the medication. So while still not feeling great, people can’t get off. I am excited to see and hopefully be a part of the change towards a deeper understanding of the true causes and the bigger picture of depression and its effective treatments.

  8. Hi, Therese,
    Many thanks for the nice update on treatment of depression, and for the call-out to my own work. My conclusion, after reviewing the literature on antidepressants, was that,

    “Overall, it is fair to say that antidepressant treatment has been somewhat “oversold”—or at least over-marketed—in terms of its acute efficacy and demonstrable effectiveness in long-term prophylaxis. Nevertheless, there is compelling evidence that 1) for the acute treatment of severe depression, antidepressants are superior to placebo; and that (2) for severe melancholic depression, antidepressants are probably superior to both placebo and psychotherapy. It is also likely that during at least the first six months after the index episode of MDD, and perhaps longer, antidepressants provide protection against relapse.”

    Of course, depression is a complex, “bio-psycho-social” problem, and as I often tell patients,
    “Medication is a bridge between feeling awful and feeling better. You still have to move your legs to get across that bridge.” And for most patients, that means working in some type of “talk therapy” as well. Often, psychotherapy alone may be effective for milder cases of depression; and for more severe cases, the combination of medication and psychotherapy often works best.

    By the way, in addition to medications, TMS (transcranial magnetic stimulation) may be effective for some treatment-resistant forms of depression. [1]

    Best regards, and thanks for your fine work, Therese!

    Ronald Pies MD


  9. Peg

    Therese, I happened on an article and interview about a book called On Living by Kerry Egan, which is about her experiences with dying patients in hospice care and she also mentioned that during the birth of her child there were complications and her anesthesiologist gave her ketamine which resulted in postpartum psychosis finally diagnosed months later and which took quite awhile to get over. You might want to Google it and read her story. Peg

  10. Jane Benkendorf

    Thank you and the doctor who provided this information. Lexapro failed me after 9 years and I am
    still looking for a new antidepressant—-going on two years….I do believe there are many factors
    that go into this chronic illness, but with additional funding for research which I intend to advocate
    and also financially support, I hope and pray someday that more people will find long lasting
    remission. My doctor has informed me there will never be a cure, because of all the variables, but
    I would just be satisfied with more options that actually work and can be maintained to help people
    live happy, productive lives. I appreciate all the information you provide on this site.

  11. Vera

    Dear Therese,
    I stumbled upon one of your articles that’s posted on called
    12 Patient-Approved Natural Supplements for depression. (I wasn’t able to find a way to comment there)
    “Here are the 12 natural supplements I take every day for depression:”
    Do you actually take all 12 in one day?
    I currently take Zoloft, Klonopin, and Ambien for insomnia. But, I’m planning to go to a Christian Rehabilitation Center for 9 months and I can’t be on any psychotherapeutic drugs. However, my insomnia has been chronic for a year or so and I’m afraid I won’t be able to sleep without Ambien. I have been on it for at least 6 months. I’m trying to find alternatives to conventional drugs that can be helpful for me. I need to stock up with something beneficial for my depression, anxiety, and insomnia.
    I would love to hear any suggestions from you and also exactly why I asked if you take all 12 in one day. I may need to take that into consideration and start my shopping process.
    Thank you.

  12. Joyce

    I am currently participating in a trial for the drug Rapastinel. As I understand it, this is the last trial required before FDA approval. The drug has been fast-tracked by the FDA because of its effectiveness. My experience has been very positive. I could feel the results within two hours of my first dose. I believe this drug will provide relief to many people. It is hoped that Rapastinel will be approved within the next two years, possibly sooner. I agree that inflammation can contribute to depression, also there is a great deal of evidence that gut health impacts mental health. Other things that can help include exercise, magnesium, turmeric, and vitamin D3. As with most things, I don’t believe that there’s necessarily one solution for everyone. I believe that for some people, the medication will be what they need.

    1. Sean

      Hi Joyce
      If you don’t mind sharing, I am very interested to here about how Rapastinel helped you and what your symptoms were before trying Rapastinel (how long did you have your illness and how bad was it) and what your experience has been since trying it and any side effects?
      Thanks so much.