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?