tardive dysphoria | Antidepressants Make Things Worse in the Long Term?

[Duckbruck]

Certain research and studies are showing that long term antidepressant use can cause chronic relapsing depressive episodes, cognitive damage and tardive dysphoria. Is this legit? Is that for real?
:unsure:

[panic_down_under]

Certain research and studies are showing that long term antidepressant use can cause chronic relapsing depressive episodes, cognitive damage and tardive dysphoria. Is this legit? Is that for real?
:unsure:

Can you cite the studies?

There is evidence antidepressants become gradually less effective each time they are discontinues and restarted with the likelihood of them working again dropping by 20-25% at each cycle. Why that is is unknown. It could be tardive dysphoria, it could be one of many other things.

[MyNameIsTerry]

Hi Ian,

I've seen a paper on this before. This may be round about what the OP has seen.

Last I looked it was being a paywall but I had a copy from somewhere so I can upload you the .pdf if you can't get at it?

Tardive dysphoria: The role of long term antidepressant use in-inducing
chronic depression q
Rif S. El-Mallakh ⇑, Yonglin Gao, R. Jeannie Roberts
Mood Disorders Research Program, The University of Louisville Depression Center, Department of Psychiatry and Behavioral Sciences,
University of Louisville School of Medicine, Louisville, KY, USA
Received 30 May 2010
Accepted 12 January 2011

It's an interesting subject and I would also be interested to know what you think.

[panic_down_under]

Hi Ian,

G'day, mate.


Tardive dysphoria: The role of long term antidepressant use in-inducing chronic depression
Rif S. El-Mallakh, Yonglin Gao, R. Jeannie Roberts

It's an interesting subject and I would also be interested to know what you think.

Yeah, I'm aware of the paper and a case report by the same team. The study appears to be more an idea in search of supporting evidence than a definitive explanation and the case study seems more an indictment of the patient's doctors than evidence of tardive dysphoria. They seems to be all there is in the literature so while it is an interesting idea, I want to see more evidence.

Antidepressants do stop working, both with continual use and as a consequence of discontinuing and restarting them. Unfortunately, while the problem is well known, there doesn't seem to be a lot of effort being made to find either the cause, or a solution. These days all the major drug companies have pretty much vacated the mood disorders field and what research and drug development is underway comes mostly from small startups that have no interest in doing fundamental research.

[panic_down_under]

Duckbruck messaged me the following link as he can't yet post them to the forum and asked me to comment on the points raised:


https://www.psychologytoday.com/blog/mad-in-america/201106/now-antidepressant-induced-chronic-depression-has-name-tardive-dysphoria

I've already covered the main tardive dysphoria claim made by El-Mallakh RS paper above.


In subsequent papers, Fava set forth a biological explanation for why this may be so. Psychiatric drugs perturb neurotransmitter pathways in the brain, and in response to that perturbation, the brain undergoes a series of compensatory adaptations in an effort to maintain normal functioning of those systems. In scientific terms, the brain is trying restore its “homeostatic equilibrium.” Fava has dubbed this compensatory response to a psychiatric drug “oppositional tolerance.”

...For instance, a selective serotonin reuptake inhibitor (SSRI) blocks the normal reuptake of serotonin from the synaptic cleft, which is the tiny gap between neurons. Serotonin now stays in the cleft longer than normal, and feedback mechanisms immediately kick into gear. The presynaptic neurons begin putting out less serotonin than usual, while the postsynaptic neurons—the neurons receiving the message—decrease the density of their receptors for serotonin. The drug is acting as an accelerator of serotonergic activity; the brain responds by putting down the brake.


...With antidepressants, the problem may be that patients, because of the “oppositional tolerance” process, end up with a depleted serotonergic system. The postsynaptic neurons end up with a reduced density of receptors for serotonin; in rat studies, long-term treatment with an SSRI led to markedly reduced levels of serotonin in "nine areas of the brain." El-Mallakh, in his paper, details several other ways that exposure to an SSRI may deplete serotonergic function, and notes that in experiments with young animals, such impairments are "associated with increased depressive and anxious behaviors."

Fava, El-Mallakh and the author of the Psychology Today post apparently think antidepressants drive the brain into an unnatural state, however, this doesn't appear to be the case. Indeed, the opposite seems to be true.

It is now well established the anxiety and depression result from atrophy (http://www.americanscientist.org/issues/feature/depression-and-the-birth-and-death-of-brain-cells/99999) of parts of the hippocampal regions of the brain due to chronically high brain stress hormone levels killing neurons and/or by preventing new ones from growing. Antidepressants reverse this by stimulating the growth of new hippocampal neurons (neurogenesis), with the new cells and the strengthening of interconnects forged producing the therapeutic response, not the meds directly.

Those with anxiety and depression also seem to have higher than normal serotonin levels in areas of the brain which mediate these disorders and when stressed serotonin levels spike even higher. Serotonergic antidepressants significantly reduce serotonin synthesis and expression in these areas within a few weeks, in some regions to less than half the baseline concentration, with levels then matching that of controls, i.e. to normal levels. (see my Serotonin - The 'chemical imbalance' myth (http://www.nomorepanic.co.uk/showthread.php?t=193671) for more on this).


As is now well-documented, in the clinical trials of SSRIs, the drugs did not provide a significant clinical benefit compared to placebo for patients with mild-to-moderate depression.

Firstly, I don't necessarily accept that clinical trial data tells us anything useful about antidepressant effectiveness. Most of these trials only run for 4-6 weeks which is often not long enough for the meds to kick-in. Some are also poorly structured and/or conducted. For example of the 35 studies included in the Kirsch I (http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.0050045), 2008 meta-analysis often cited as evidence antidepressants are just expensive placebos, only 4 met FDA criteria for completion rates. In the other 31 too many subjects in both the active drug and placebo arms dropped out (and this is by no means the only problem with the meta-analysis!

Another consideration is that few patients respond adequately to the first antidepressant prescribed. It can take several attempts and some months before the most effective med for a patient is found. So a failure to respond to an antidepressant in a trial does not necessarily mean that the drugs as a group are ineffective. Clinical trials, while important in determining an antidepressant's overall efficacy and safety, can be of limited value at the individual level. Another considerations is some of us. e.g. me, simply need an antidepressant dose at the high end of the therapeutic range to get a good outcome and few trials use near maximum dosing.

Nor does the seemingly lack of superiority to placebo in mild cases mean antidepressants are ineffective, only that patients with low severity will respond positively to any form of treatment, just as mild headaches will often resolve quickly with or without a painkiller, but this doesn't mean aspirin is useless. There is a very valid argument that antidepressants shouldn't be prescribed for milder cases, but they can become severe very quickly, sometimes with unfortunate outcomes, so many GPs err on the side of caution. Many are also poorly equipped to judge the severity of the problem.


In the 1960s, at the start of the antidepressant era, experts in this disorder regularly wrote that depression was an episodic disorder, which could be expected to clear up with time. As Dean Schuyler, head of the depression section at the NIMH explained in a 1974 book, most depressive episodes “will run their course and terminate with virtually complete recovery without specific intervention.” In 1969, George Winokur, a psychiatrist at Washington University, made the same point: “Assurance can be given to a patient and to his family that subsequent episodes of illness after a first mania or even a first depression will not tend toward a more chronic course.”

Yes, acute, once in a lifetime single anxiety and depression episodes do often occur, but chronic conditions which wax and wane with periods of remission that can last months, sometimes years, are at least as likely, and there is no way of knowing if a new case will prove to be a single occurrence, or the first of many. So is antidepressant treatment to be withheld until time reveals which form it is, and how many episodes should someone have to endure before an effective treatment is prescribed? And what are patients in the midst of their first episode supposed to do to ease their suffering? Grin and bear it? Pull themselves together? Self medicate with booze, or illicit drugs? Sure, therapy is a great alternative, but for many it is about as accessible as the Moon, either being too expensive, or with long waiting lists when it is provided at no/low cost by universal health systems (the number of free sessions may also be inadequate) and it can take longer to get a result than with meds.

Is is all well and good to bad mouth antidepressants, but to quote Sigmund Freud writing at the end of a chapter about the inadequacies of his psychoanalysis therapy, "Those who have been following our discussion only out of of therapeutic interest will perhaps turn away in contempt after this admission. ...It may be there are other still undreamed-of possibilities of therapy. But for the moment we have nothing better at our disposal than the technique of psychoanalysis, and for that reason, in spite of its limitations, it should not be despised." (S. Freud, An Outline of Psycho-Analysis, WW Norton & Company, NY, 1949, p62). At least antidepressants do work often enough to make them worth trying. After interviewing all of Freud's surviving patients in the 1960s, the eminent psychologist Hans Eysenck concluded psychoanalysis help not even one of them.

BTW-in one of his studies Eysenck made basically the same case against psychotherapy as the Psychology Today article under discussion has against antidepressants, the more psychotherapy you got, the less likely you were to recover. (https://www.psychologytoday.com/blog/media-spotlight/201305/does-psychotherapy-work)" If Fava, El-Mallakh, Whitaker and Eysenck are to be believed, then maybe pulling yourself together is indeed the best option just as so many of the ignorant have been telling us all these years! :ohmy:

[Duckbruck]

Thanks for the very detailed input :yesyes:



BTW-in one of his studies Eysenck made basically the same case against psychotherapy as the Psychology Today article under discussion has against antidepressants, the more psychotherapy you got, the less likely you were to recover." If Fava, El-Mallakh, Whitaker and Eysenck are to be believed, then maybe pulling yourself together is indeed the best option just as so many of the ignorant have been telling us all these years! :ohmy:

:unsure: