Antidepressants Make Things Worse in the Long Term

In June 2011, Rif El-Mallakh, MD, et al. published an article, Tardive dysphoria: The role of long term antidepressant use in inducing chronic depression, in Medical Hypotheses.  The article is a thorough and wide-ranging study review.

Here are some quotes from the abstract:

“Treatment-resistant and chronic depression appear to be increasing.”

“Depressed patients who ultimately become treatment resistant frequently have had a positive initial response to antidepressants and invariably have received these agents for prolonged time periods at high doses.” [Emphasis added]

The authors propose the term “tardive dysphoria” to describe this condition.  Tardive means delayed; dysphoria means unhappy or depressed.  The idea is that just as prolonged ingestion of neuroleptics causes tardive dyskinesia, so the prolonged ingestion of antidepressants causes tardive dysphoria.  It’s a nice idea, but the name hasn’t caught on – at least not yet.

The paper by Dr. El-Mallakh et al. is very detailed, and cites 85 references.  The arguments are well-marshaled and compelling.  Here’s a brief summary.

Depression affects about 5% of the world’s population.  Risk of recurrence is high (about 50-80%).  Maintenance antidepressant therapy may reduce the risk of relapse in the first year after an episode.  The APA recommends maintenance therapy for recurrent major depression.  But recurrence of depression is common even among individuals on maintenance therapy.  Recurrences of this sort are called treatment-resistant depression (TRD), the prevalence of which among depressed individuals may be as high as 30-50%.  This prevalence has increased from about 10-15% in the early 1990’s to about 40% in 2006.  Various reasons have been suggested for this increase, but, there “…are reasons to believe that antidepressant treatment itself may contribute to a chronic depressive syndrome.”

The authors provide a great deal of evidence in support of this conclusion.

“Up to 80% of patients diagnosed with major depressive disorder will experience a recurrence of depressive episode despite constant maintenance dose of an antidepressant.”

“Attempts to treat these individuals frequently result in poor response and the rise of TRD.”

“…there have been several reports of the loss of antidepressant efficacy.”

And perhaps most telling:

“A long-term placebo-controlled, blinded maintenance study of fluoxetine [Prozac] in major depression, found no difference after 62 weeks in subjects who were still euthymic [i.e. not depressed] on fluoxetine (11%) or placebo (16%).”

Dr. El-Mallakh et al. point out that individuals who were not initially depressed, but were given antidepressants for other problems (e.g. anxiety), often became significantly depressed.

“In a recent study 27% of patients without any history of a mood disorder who had received antidepressants for an average of 29 months for panic disorders, developed a cyclothymic illness that persisted for 1 year after antidepressant discontinuation.” [Emphasis added]

Also, and perhaps most alarmingly, it is stated:

“In…patients who have developed TDp [tardive dysphoria], ongoing attempts to treat the depression with antidepressants perpetuate the TRD, and may ultimately make the chronic depression permanent.”

The article was published in 2011, and the authors conclude their paper by calling for

“…blinded, randomized antidepressant discontinuation/continuation trials in TRD patients, over at least 1 year.”

They also suggest that

“…clinical trials of antidepressant taper and discontinuation for 6-12 months in patients who have failed most other options appear reasonable.”

Despite this call, I have not been able to find any follow-up research on this matter.

The notion that long-term ingestion of antidepressants leads to chronic, severe depression is not new. The present authors attribute the introduction of the concept to Giovanni Fava, MD, in his editorial Do antidepressant and antianxiety drugs increase chronicity in affective disorders?, Psychotherapy and Psychosomatics, 1994.

They also mention a paper by Verinder Sharma, MD, Treatment resistance in unipolar depression: Is it an iatrogenic phenomenon caused by antidepressant treatment of patients with a bipolar diathesis? Medical Hypotheses, 2006.

Dr. El-Mallakh himself and two other authors, Courtney Waltrip and Christopher Peters, wrote:  Can Long-Term Antidepressant Use Be Depressogenic? as a letter to the editor in the Journal of Clinical Psychiatry in 1999. 

In Anatomy of an Epidemic (2010), Robert Whitaker also addresses this issue (Chapter 8 – An Episodic Illness Turns Chronic).  Robert’s summary on this matter is clear and straightforward:

“We can now see how the antidepressant story all fits together, and why the widespread use of these drugs would contribute to a rise in the number of disabled mentally ill in the United States.  Over the short term, those who take an antidepressant will likely see their symptoms lessen.  They will see this as proof that the drugs work, as will their doctors.  However, this short-term amelioration of symptoms is not markedly greater than what is seen in patients treated with a placebo, and this initial use also puts them onto a problematic long-term course.  If they stop taking the medications, they are at high risk of relapsing.  But if they stay on the drugs, they will also likely suffer recurrent episodes of depression, and this chronicity increases the risk that they will become disabled.  The SSRIs, to a certain extent, act like a trap in the same way that neuroleptics do.” (p 169-170)

So, since at least 1994 – twenty years ago – researchers and commentators have been adducing evidence and arguments that antidepressants, even though they may have been initially successful in altering feelings of depression, when taken for extended periods may actually lead to persistent, treatment-resistant depression.  Discontinuation of the drug sometimes produces a slow and gradual lightening of the mood, but in some cases this does not occur, and the chronic depression can become more or less permanent.

Amazingly, or perhaps I should say predictably, organized psychiatry has not launched a major investigation into this matter, and I can find no indication that any such investigation is in the works.

In fact, the current (2010) APA treatment guidelines for major depressive disorder state:

“During the maintenance phase, an antidepressant medication that produced symptom remission during the acute phase and maintained remission during the continuation phase should be continued at a full therapeutic dose.” [Emphasis added]

Of course, the APA’s guideline will generate more drug sales.  But surely that wouldn’t be a consideration.  Would it?

  • Francesca Allan

    Great article, Phil. Couple of things jumped out at me. First, ” … after 62 weeks in subjects who were still euthymic [i.e. not depressed] on fluoxetine (11%) or placebo (16%)” is actually more than “no effect”; it’s either close to or actually a significant effect of placebo over Prozac, isn’t it? And, I was heartened to see the researcher’s acknowledgement of antidepressant-induced cyclothymia. It’s quite apparent to me, though, that there’s also a very real danger of full-blown mania (even where there is no previous indication of bipolar disorder). I know many people who developed bipolar disorder in exactly this way and in all cases it was written off as a “triggering” of pre-existing disease. I think this explains much of our bipolar boom.

  • Phil_Hickey


    Yes, the placebo apparently outperformed the drug – but I guess not to the point of statistical significance.

    I’m also convinced of the potential to trigger a frankly manic response. This is being increasingly exposed and, I think , is one of the reasons that an SSRI, a
    benzo, and a neuroleptic “cocktail” is becoming increasingly popular.

  • Francesca Allan

    Great. So we’ll give an upper (SSRI), a downer (AP) and a tranq (benzo) all at once. I believe you’re right — this is standard procedure. My psychiatrist wants me on Risperdal for exactly this reason: to reduce the chance of mania, even though my mania is only ever caused by treatment for depression, as clearly indicated in my medical records.

  • Karen

    I am caring for my brother who has TD after years of drugs that weren’t monitored. Now I see young children being prescribed drugs for ADHD. It’s so easy to stick plasters, but eventually they come off. Please slow down, and talk to those who feel low. Look at alternative therapy. Prescribed as a last resort and monitor the drugs rather than repeating prescriptions.

  • Phil_Hickey


    Good advice. “Slow down, and talk to those who feel low.” And, of course – listen

  • I was prescribed antidepressants after a very traumatic incident in my life. I took them for awhile and felt rather as I was in a dream. I decided, after oversleeping and losing my job that I would wean myself off.
    The trauma I suffered still happened. The drugs numbed me temporarily.
    I’ll never take drugs like that again; They don’t work.

  • Rooftree1

    Following a traumatic experience I went through a nightmare 9 months on antidepressants, where initial feelings of hopelessness turned into full on suicidal thoughts and several “cry for help” attempts. It took a spell in a psychiatric hospital where I had space to deal with what I was feeling and understanding people to talk with to wake me up to the fact that the drugs were making me worse. After that epiphany, I “magically” got “better”. The sad thing is my notes will probably say that increasing the dosage worked. I weaned myself off them the moment I was discharged. I still struggle with things, but facing my issues head on without being medicated is how I learn to cope, and it makes me stronger and more confident to face the next battle. Forcing my brain to “feel happy” when it didn’t have the natural stimulus to do so was hurting my brain. All the things I was told would help while I was on the meds – exercise, good diet, routine, friends, etc. only help now I’m not taking the meds. But it’s harder than “before” even though I have dealt with the issues that started it all off. I have accepted I will never feel the way that I did before the medication, and am dealing with it. Without medication. Thank you, this article made sense of a lot of things that didn’t make sense before.

  • Phil_Hickey


    Thanks for sharing your story, which I’m sure will resonate with many other readers. I’m glad to hear that you cam through the nightmare, and I hope things continue to go well for you.

  • T.A. Anderson
    Do we underestimate the benefits of antidepressants? And the article is free.

    Excuse me but LMFAO!!!!

    Authors disclosures: ” MA has received grants or research support from Aristo, Servier, and Bristol-Myers Squibb; honoraria [from] . . . Bristol-Myers Squibb, . . . Servier, Aristo, Viiv, and Gilead; travel grants from . . . Lundbeck, and Servier; and has been a consultant to . . . Bristol-Myers Squibb, Aristo, Merz, and Lundbeck; is or has been a member of advisory boards for Lilly Deutschland, Lundbeck, Otsuka, and Takeda, and has received honoraria for speaking from Bristol-Myers Squibb, Medice Arzneimittel, and Roche Pharma.”

  • Francesca Allan

    I’ll never underestimate the benefits of antidepressants! Within a matter of weeks I went from lying in bed 23/7 to extreme mania. While it wasn’t exactly unpleasant, it was far more harmful and disruptive to my life than depression ever was. Oh, ADs work, all right, if by “work” you mean take a temporary problem and turn it into a permanent disaster.

  • Francesca Allan

    Just like to add that the psychiatric solution was to upgrade me to a diagnosis of bipolar disorder, despite the fact that I had never suffered mania in my life prior to my bad reaction to ADs. The “thinking” was that I must have had bipolar disorder all along and that the ADs had merely “triggered” it. In science, that’s known as unfalsifiable theory, i.e. it’s very poor logic. The more likely scenario was that I reacted very, very badly to the chemical intervention and it should have been stopped immediately. When you eat a lot of chicken and spend half the night throwing up, that’s an indication to quit with the chicken already, not just add more spice to it and eat even more. My cat can figure things out that are beyond the grasp of most psychiatrists.

  • T.A. Anderson

    The absolute worst diagnosticians in all of medicine are the psychiatrists. Even if we accept their Dopey Stigma Manual definitions their diagnosis for many conditions is correct less than 20% of time. This is crazy.

  • Phil_Hickey


    Unbelievable – and yet there it is. And in the Lancet! Thanks for the link.

  • T.A. Anderson

    I am astounded. Kim Kardashian in Vogue, and now this. I am not an expert but it doesn’t seem like the type of article that merits printing in a prestigious journal. It is little more than rhetorical argument. I can do that. I can be funny too , but its hard to beat the humor in the title to that article. Guess they don’t really think we’re such a small minority after all.

  • barry

    If you have done nothing to ascertain whether other factors such as an unhappy marriage are causing chronic stress then it’s no wonder the individual concerned is not improving or getting worse. Like animals in captivity which develop.behavioral problems, a change of environment may be needed. Changing the brain may be barking up wrong tree. Speculations…..

  • Phil_Hickey


    I agree.