New insights into treatment-resistant depression

Ann MacDonald

Contributor, Harvard Health

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Only one-third of people with major depression achieve remission after trying one antidepressant. When the first medication doesn’t adequately relieve symptoms, next step options include taking a new drug along with the first, or switching to another drug. With time and persistence, nearly seven in 10 adults with major depression eventually find a treatment that works.

Of course, that also means that the remaining one-third of people with major depression cannot achieve remission even after trying multiple options. Experts are hunting for ways to understand the cause of persistent symptoms. In recent years, one theory in particular has gained traction: that many people with hard-to-treat major depression actually suffer from bipolar disorder. However, a paper published online this week in the Archives of General Psychiatry suggests otherwise—and the findings provide new insights into the nature of treatment-resistant depression.

Researchers at Massachusetts General Hospital (MGH) and colleagues analyzed outcomes for roughly 4,000 participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which was conducted both in primary care and psychiatric settings in order to mimic real-world treatment of major depression. The STAR*D investigators had used a simple questionnaire to ask participants about symptoms characteristic of bipolar disorder (such as mania or hypomania) as well as those suggesting psychosis (the inability to recognize reality, such as false beliefs or false perceptions). All participants initially received the antidepressant citalopram (Celexa), followed by up to three additional treatments as necessary.

The MGH researchers did find that many participants in the STAR*D study had multiple symptoms associated with bipolar disorder rather than major depression. Contrary to common wisdom, however, these symptoms did not significantly worsen chances of attaining remission after taking antidepressants. Instead, the researchers found that participants who said they experienced one or more unusual beliefs or experiences in the past two weeks—symptoms that can indicate psychosis—were significantly less likely than other STAR*D participants to attain remission.

“We found that about one-third of participants in the STAR*D study reported strange or unusual experiences,” explains Dr. Roy H. Perlis, medical director of the Bipolar Clinic and Research Program at MGH and lead author of the paper. “That doesn’t mean that one in three participants were psychotic, but that unusual thinking is common in people with major depression. As such, it is important that clinicians are on the alert for these symptoms, because they are associated with poorer response to antidepressants.”

In recent years, both scientific review papers and continuing medical education courses have advised clinicians to re-evaluate a diagnosis of major depression and instead consider bipolar disorder when a patient does not respond to multiple antidepressants. But Dr. Perlis and others are growing concerned that bipolar disorder is now overdiagnosed as a result. “We were seeing an increasing number of patients diagnosed with bipolar disorder, or bipolar spectrum disorder, simply because they had a family member with bipolar disorder or hadn’t responded well to antidepressants,” says Dr. Perlis. (In a 2008 paper, researchers at Brown University estimated that more than half of bipolar diagnoses might be wrong—partly because clinicians attribute symptoms like agitation or racing thoughts to mania rather than to major depression.)

When people with major depression don’t benefit adequately from a first antidepressant, Dr. Perlis advises that it’s wise to take several steps before deciding on the next treatment:

Review the diagnosis. Major depression can be difficult to diagnose because symptoms vary from one person to the next. “It’s critical to revisit the diagnosis any time a treatment isn’t working, and this should include consideration of bipolar disorder,” Dr. Perlis explained. “Risk factors such as a family history of bipolar disorder certainly increase my concern, and cause me to look even more closely. On the other hand, treatment resistance does not automatically equal bipolar disorder.”

Consider other illnesses. It’s also important to consider whether another medical illness, such as anemia or obstructive sleep apnea, might be causing fatigue and other symptoms of depression.

Consider comorbidities. Major depression frequently occurs in conjunction with other psychiatric disorders, such as anxiety or substance use disorders, which can also affect antidepressant responsiveness. In such cases, it’s important to treat the co-occurring mental health problem in addition to major depression.

Double-check dose. It’s always wise to double-check whether someone is taking the drug at the dose prescribed.

Give it more time. Although the standard advice for patients is to take an antidepressant for six weeks to see if symptoms improve, earlier findings from the STAR*D trial suggest that many people need more time to respond. The STAR*D investigators recommended that people with major depression take an antidepressant for at least eight weeks before considering another strategy.


  1. Cassie Miller

    This problem was being common nowadays especially for children and teens. Depression can lead those youngsters into harming themselves and that is really dangerous so I think parental guidance should be recommended.

  2. Sven Cooke

    Linden Method Review Depression is such a terrible ailment. My father suffered with it for years until his untimely death. He was helped by self help therapy after tiring of drugs. It created a blog to provide information.

  3. mayank

    Hey I’m Mayank,It’s been about a year and a half since I’ve started medication and going to therapy. However, I’ve been depressed for like 3 or 4 years total. I just feel like it will never go away. Just when I’m back on my feet, something else ruins my life. Part of it’s just me, I’m never happy even though I can put on a happy face. My mom thinks I’m doing fine, but I’m not.For me, I don’t think it will ever end. I get by, but that’s about it. I wonder sometimes if it’s worth it. Do we live our lives or do we sit in the bleachers and watch our lives as if in a stadium.

    It sounds like you are doing well right now and I’m happy for you.

  4. librezine

    Thanks for advices. I tried these and had a doctor to avoid depression.

  5. Kate

    Interesting read. Thank you. I recently found out that I’m deprimerad (depressed in swedish) so I’m trying to soak up as much information as I can. I’m also going to double check my anti-depressant dose as I suspect it might be too low.


  6. James

    Thank you so much for the article, I suffer from depression, and my wife has been diagnosed Bipolar. I have done alot of research on how to keep a relationship afloat when there are two mental illnesses that both partners are dealing with I have found alot of help from a few articles on Ezine. The one that I found interesting was called “help, my wife is Bipolar”. Here is the link just incase anyone has any interest thanks again for everything!

  7. Dana

    I see the admonition to keep looking. I’ve been looking for 31 years, but that isn’t easy, it means picked up by an ambulance in my neighborhood after a hypertensive crisis related to an MAOI,it means the stigma of being outed when you can’t work or do anything while getting ECT, like the disabling side effects of some of the many drugs (atypical anti-psychotics are worst for me). I did a clinical trial for VNS and copied a trial, Ketamine. I can’t help but get very angry with Physicians for a couple things:
    1 The stataement “depression is treatable”so my spouse, children and others logically think I must be faking it.
    2. Where are the trials to follow up on promising compounds that looked good once before like prednisone and xyrem?

  8. Frank Lane, M.D.

    Clinical Depression is a seriously disabling condition, a mental illness and, untreated increases the risk of suicide- the ultimate tragic loss of life in a body otherwise healthy enough to reap the full benefits of a fulfilling life. No one should enter the discussion without respect for this illness. It is possible for other medical conditions to present as a clinical depression, such as the hormone imbalance mentioned above, hypothyroidism- which is all the more reason to start the evaluation with a thorough physical exam and screening laboratory tests performed by a physician. As part of the initial visit, every good psychiatrist inquires as to when the patient last had a complete physical examination and they often work closely with an internist and neurologist to rule out other possible medical conditions that might be contributing to the depressive syndrome. Because human beings are ALWAYS dynamic constructs of biological and psychological phenomena, to address only one or the other arena is inadequate when attempting to treat a mental illness. The doctor must hold BOTH in mind as he or she explores the problem, with all it’s dimensions with the patient. Hopefully, they form a working alliance, share observations and knowledge and persist in the endeavor to relieve the suffering. It just so happens that the brain is the most complex and fascinating organ in the human body and we are far from understanding all of it’s functions in health and disease so all parties need to accept this, stay open-minded and continue to study what science can reveal about this problem. Patients need to look for a clinician who seems really interested in them, takes the time to get to know them as a person, and diligently goes about gathering all the necessary information- not someone in a hurry who just throws a new prescription at them every week ( a legitimate clinical trial of any psychoactive medications is almost always 4-6 weeks in duration, and sometimes even longer). The doctor is hoping to have a patient that cares enough about themselves to keep accurate records of WHEN symptoms first appeared, what made them better or worse, what medications they’ve tried… at what dose and for how long, etc. If you cannot forge a comfortable working relationship with your doctor- KEEP LOOKING! Once you find someone that you feel you can work with, stick with it for the long run and be scrupulously honest with them. You only delay finding the best solution to the problem if you withhold information or are deceptive for any reason. Many wonder if their depression is a “punishment” of some sort resulting from their religious beliefs but this is usually another confusion of “cause and effect”. Depression itself imposes a negative self-image on the person suffering from it- they think and say aloud negative things like “you’re just stupid, ignorant, ugly, lazy… etc. etc” and so, it’s no surprise when their religious beliefs incorporate this negative tone, burdening them with guilt and shame. It’s simply part of the illness. That goes away as the patient heals from their depression. Most of all, do not give up in trying to feel better 🙂

  9. paul

    Depression is not to be taken lightly. I know I suffered from it for years. I also noticed that it was worse when I was under stress, which usually coincided with another outbreak of my herpes.

  10. Valerie

    Interesting insight into bipolar depression and depression treatments.

    Medication should be combined with the safe and commonly-touted natural remedies for depression such as exercise, good nutrition and proper hydration. It takes consistent long-term effort, but the result is definitely worth it.

  11. Anonymous

    One of the factors that make depression more prevalent is that we tend to isolate ourselves more. We socialize via the internet, shop via the internet and can work via the internet. Human interaction is getting limited. Being cooped up for so long can make a person not only cranky but depressed too.

  12. Vassiliki

    Great article, thank you! Another (hopefully) interesting one can be found here:
    Depression: the psychological epidemic of our times

    I am eager to read your comments, if any!


  13. PsychPatient

    My observation is that the star*d sounds like yet another poorly designed psychiatric study. Were these symptoms of psychosis and bipolar disorder only manifested once psychiatric medications were administered? Sounds to me like these are effects of the drugs. Antidepressants do not reveal a hidden illness, you are either bipolar or you are not. If you have symptoms of mania after taking an antidepressant, you are merely having a negative reaction to the drug. Psychiatry is nothing but a pseudoscience, a collection of fad diagnosis and fad prescription practices, undeniably influenced by the pharmaceutical industry. The current fad in psychiatry is bipolar diagnosis and the current prescription fad is atypical antipsychotics.
    Etiology in any mental illness is almost completely unknown. SSRi’s don’t work due to the fact that depression probably has nothing to do with monoamines. If monoamines were the answer, than these drugs would have a statistically significant efficacy, which they are clearly don’t. And from what i’ve seen, no one benefits from augmentation therapy, I don’t know one person taking a handful of psych drugs who is doing well and functioning. One of the reasons these studies are bogus is that they are entirely too short to reveal the true nature of these drugs. I believe they are neurotoxins that cause damage over time leading to long term mental disability. You’d have to do a study over the course of several years to have any meaningful data., whereas most studies last only months.
    And where is differential diagnosis in psychiatry?!! How many people get misdiagnosed because psych doctors are too lazy/corrupt/incompetent to take a blood test? How many people get misdiagnosed with depression who really have hypothyroidism or hypogonadism or any other of the numerous causes of mental illness. Depression isn’t a disease but a symptom of which there are many different causes. And there are many treatments that are taken off the table because of profit motive. Face it, many TRD cases respond miraculously to opiates. I would say that if real research was done on opiates, that they would have greater efficacy than any currently prescribed antidepressant. Maybe the chemical imbalance in some people’s depression is that of beta endorphin, not serotonin. Or possibly acetylcholine, or any number of neurotransmitter’s besides the big three of dopamine/norepinephrine/serotonin. But you people will cling to your unproven, ineffective, iatrogenic poisons, and when one doesn’t work, hell, try taking three.

  14. Julie VanValkenburgh

    Good article, thankyou. I have Bipolar Disorder and have ALWAYS had “hard to treat depprsion.” Over the years I have gotten very depressed for long periods of time. Working with my psychiatrist I have tryed MANY different antideppresants and nothing helped. Finally, as a last ditch effort she put me on Nardil (MOA) inhibitor and in three weeks it was like BAMN! Somebody turned the lights on!
    Nardil has worked so well for me that the benefits outweigh the risks of this drug. MAOI’s can potentionaly
    be very dangerious so their are strict guide lines one must follow. there are many foods and medications one must
    not eat or take. The danger is ones blood pressure can get very high if one doesn’t adhere to the diet and medication
    restrictions and can lead to a hypertensive crisis that could cause a stroke and other very serious conditions.
    For that reason Nardil is, I think, rarely prescribed.
    If anyone out there has very hard to treat deppression
    and nothing has worked for you ask your doctor whether he/she thinks this might be a good treatment to try. For me
    anyway it has been a wonder drug and has been very easy for me to follow the dietary and medication restrictions.

  15. Andrew

    Good artcile. Happy Holidays

  16. Charm

    Thanks for such great article. I believe that the one thing the STAR*D study left out is the choice factor. It may not look that way to us but people choose what they want to experience. I don’t think giving people antidepressant and send them on their way is the way to go about it.

    We have start the process of understanding where the depression came from. We need to get deep down to where the person made the choice to experience it. Many time after a patient explore the choice point he or she may realize that they don’t want the disease anymore and get better. All that can happen without drugs administering to them.

    Best Regards,


    • Caroline

      You are uninformed about mental disorders. Leave it to those that are doing the research.

    • Johnni

      I can tell you haven”t experienced clinical depression. People do not choose to become depressed anymore than they choose to have diabetes or high blood pressure. It sounds as if you have been influenced by a book or someone who has no widespread knowledge or experience of the disease. Your comments are degrading to people who are struggling so hard to gain control of their disorder to have someone allege that they “chose” depression. Also, depression is not cured, it is simply controlled. Sometimes better than others. It is a long, hard road.

  17. Jenny

    thanks for the post. depression is getting more and more common due to isolated societies we have nowadays. Would be good to have a treatment that really helps people to get over the depression and living.

  18. gloria mikyska

    the article is most interesting–mental health needs more
    support from the pulic–people need to understand what
    depression can do to those suffering–having a mental health problem doesn’t mean people are mean or weak–it is a brian disORDER and those who suffer should certainly be
    treated like any other human-being—but there is a great deal of stigma out in the world—the mentally ill
    frequently don’t get help—cause of STIGMA & THAT SHOULD
    publically to inform the world that mental health issues are just as important as cancer,diabetes,hypertension etc..

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