El-Mallakh, 2011 Tardive dysphoria: The role of long term antidepressant use in inducing chronic depression

[Altostrata]

Again, this study based on a survey of the literature cannot take into account the misdiagnoses of antidepressant withdrawal syndrome for "chronic depression."

 

Med Hypotheses. 2011 Jun;76(6):769-73. Epub 2011 Apr 2.

 

Tardive dysphoria: The role of long term antidepressant use in inducing chronic depression.

 

El-Mallakh RS, Gao Y, Jeannie Roberts R.

 

Source

 

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.

 

Abstract at http://www.ncbi.nlm.nih.gov/pubmed/21459521 Full text here.

 

BACKGROUND:

 

Treatment-resistant and chronic depression appear to be increasing. The recent identification of antidepressant tachyphylaxis, the loss of antidepressant efficacy over time, is only a partial explanation. This is an emerging evidence that, in some individuals, persistent use of antidepressants may be prodepressant.

 

METHODS:

 

A literature search of PubMed utilizing the terms: antidepressant tachyphylaxis, treatment-resistant depression, chronic depression, and antidepressant tolerance was performed, and relevant articles were used.

 

RESULTS:

 

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. Parallels between this course and tardive dyskinesia are noted. It is proposed that neuroplastic processes related to dendritic arborization may underlie the treatment resistant depression that occurs in the setting of chronic antidepressant use. Since the prodepressant effect is seen after prolonged antidepressant use, the term tardive dysphoria is proposed.

 

CONCLUSIONS:

 

Tardive dysphoria, needs to be considered in studies of treatment resistant depression, and should be examined in blinded, randomized antidepressant discontinuation trials.

 

 

-------SELECTIONS FROM THE PAPER--------

 

Depressive disorders affect over 6% of Americans and 5% of all humans on the planet....

 

For many patients recurrence of depressive symptoms may occur despite ongoing antidepressant treatment. When optimization of treatment fails, such patients are noted to have treatment-resistant depression (TRD). TRD may comprise 30–50% of people with major depressive illness. The cause of TRD is unknown, but its prevalence appears to be increasing. In 2006, a meta-analysis reported that nearly 40% of depressed patients had TRD. However, in the early 1990s it was reported that only 10–15% of patients had TRD....There are reasons to believe that antidepressant treatment itself may contribute to a chronic depressive syndrome....

 

Tachyphylaxis (also known as antidepressant tolerance, antidepressant ‘‘poop-out’’, or ‘‘breakthrough depression’’) is a condition in which patients experience a good initial antidepressant response which is lost over time with repeated or prolonged antidepressant treatment....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....

 

Once initial treatment response is lost, subsequent improvement is unlikely. If patients with TRD respond to a subsequent antidepressant, the extent of improvement is inferior to the initial response. Patients who lost response to a MAOI not only did not respond to subsequent treatment, but reported greater extent of depression after relapse than before the new treatment was initiated....

 

It is proposed that tardive dysphoria (TDp) is an abnormal dysphoric state that develops in some predisposed individuals with prolonged antidepressant treatment. Patients with this syndrome may comprise a significant fraction of TRD subjects. TDp is defined as a chronic, frequently treatment resistant, depressive state with onset in the setting of ongoing, persistent antidepressant treatment....The depressive state is perpetuated (and possibly worsened) by continuing the antidepressant. It is believed that SRI antidepressants might be selectively associated with the development of TDp. Discontinuation of the antidepressant results in a slow and gradual improvement of the chronic depressive symptoms. However, in some individuals who have experienced TDp for a very prolonged period of time, discontinuation of antidepressant may not result in reversal of the symptoms.....

[cinephile]

These are all GOLD alto! I especially like the newest one -- looks like Whitaker's work is FINALLY bearing fruit! Can I get a big "told ya so?" from everyone on this forum?

[summer]

This makes total sense to me also...

 

On second thought I have a question - what could be the difference between dealing with depression which is ongoing, has returned or relapse, and the symptoms of withdrawal?

[Altostrata]

In withdrawal, the state of your nervous system and overall neurochemical balance is abnormal.

 

In natural depression, if your overall health is good, your nervous system and neurochemical balance are also healthy.

 

The theory that depression indicates an imbalance or disease in the brain is a myth.

[Nadia]

In withdrawal, the state of your nervous system and overall neurochemical balance is abnormal.

 

In natural depression, if your overall health is good, your nervous system and neurochemical balance are also healthy.

 

The theory that depression indicates an imbalance or disease in the brain is a myth.

 

I wonder what causes depression, then? I can't remember now where I read that maybe it doesn't have to do with neurotransmitter levels, but rather with how neuron receptors work. God, it could be anything... the limbic system is such a complicated thing.

 

Allopathic medicine just ignores how we are complex ecosystems and goes at everything with a hatchet. All my years of taking ADs, though I feel in so many ways I truly did cope with life in a healthier way because of them, were just wishful thinking that this wasn't going to have a down-side in the future. At most I thought the meds would make me permanently less sensitive, and I actually thought that was a good thing. I just wanted to be able to function like everyone else. It really disturbs me how sickly involved drug companies are in health practices and in studies. Organizations like the FDA should be protecting us, but instead they are pretty much bought out by the pharmaceutical industry. I knew this, and yet my desire to be a normally functioning individual blinded me anyway.

[Altostrata]

I guess we all wanted to believe we could take a pill, like a vitamin, to cure our problems.

 

I remember way back when I rationalized it as "all they do is add serotonin, that's a natural hormone, it's no big deal."

 

Of course, all that serotonin imbalance thing was a huge lie.

 

Moods do not depend on serotonin or even neurological actions solely in the brain. The entire body is involved, there's even feedback from the gut. Memories and attitudes are extremely important.

 

Relearning cognitive framing has been shown to be more effective than drugs on depression and anxiety.

[Nadia]

Yes... the appeal of the magic solution. Why eat well if you can just take a pill to lower your cholesterol? So tempting... but in the end, there's no such thing as a free lunch.

 

I totally bought into the chemical imbalance thing. It seemed to make so much sense. Alas.

[areyouthere]

 

 

Relearning cognitive framing has been shown to be more effective than drugs on depression and anxiety.

 

Like it!

[aza]

 

 

 

Relearning cognitive framing has been shown to be more effective than drugs on depression and anxiety.

 

Like it!

 

Cognitive therapy allowed me to overcome my anxiety. And without drugg therapy.

[LoveandLight]

The last statement that scares me, that is what I'm trying to get at in my thread in symptoms. But there is no way of knowing which 'camp' I'll be in until I'm off and that scares me too. Is there any research that anyone has found that natural remedies may help reverse if that indeed, is the case.

[degen12]

The theory that depression indicates an imbalance or disease in the brain is a myth.

 

I don't think it's that simple. The brain is not separate from the body, and nor is it separate from the mind. I agree that antidepressants aren't the answer. They can't protect you from sh*tty life circumstances, and they can't cure physical illness. Depression can be construed as a physical illness. I don't think it's possible to separate the two. Psychology and disease may lead to the same biological underpinnings that lead to depressive behaviour.

 

Full text for this review is available.

 

1. Nat Rev Neurosci. 2008 Jan;9(1):46-56.From inflammation to sickness and depression: when the immune system subjugatesthe brain.Dantzer R(1), O'Connor JC, Freund GG, Johnson RW, Kelley KW.Author information: (1)Integrative Immunology & Behavior, Department of Animal Sciences, College ofAgricultural, Consumer and Environmental Sciences, University of Illinois,Urbana-Champaign, Illinois 61801, USA. dantzer@uiuc.eduIn response to a peripheral infection, innate immune cells producepro-inflammatory cytokines that act on the brain to cause sickness behaviour.When activation of the peripheral immune system continues unabated, such asduring systemic infections, cancer or autoimmune diseases, the ensuing immunesignalling to the brain can lead to an exacerbation of sickness and thedevelopment of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physicallyill people. Inflammation is therefore an important biological event that mightincrease the risk of major depressive episodes, much like the more traditionalpsychosocial factors.PMCID: PMC2919277PMID: 18073775  [PubMed - indexed for MEDLINE]

 

Here is the study regarding anti-inflammatory drugs. Full text is also available.

 

1. JAMA Psychiatry. 2014 Dec 1;71(12):1381-91. doi:10.1001/jamapsychiatry.2014.1611.Effect of Anti-inflammatory Treatment on Depression, Depressive Symptoms, andAdverse Effects: A Systematic Review and Meta-analysis of Randomized ClinicalTrials.Köhler O(1), Benros ME(2), Nordentoft M(2), Farkouh ME(3), Iyengar RL(4), MorsO(1), Krogh J(2).Author information: (1)Research Department P, Aarhus University Hospital, Risskov, Denmark2LundbeckFoundation Initiative for Integrative Psychiatric Research, iPSYCH, AarhusUniversity Hospital, Risskov, Denmark. (2)Mental Health Centre Copenhagen,University of Copenhagen, Copenhagen, Denmark. (3)Zena and Michael A. WeinerCardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York5Peter Munk Cardiac Centre and the Heart and Stroke Richard Lewar Centre ofExcellence, University of Toronto, Toronto, Ontario, Canada. (4)Zena and Michael A. Weiner Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York6School of Medicine, St George's University, St George's, Grenada.IMPORTANCE: Several studies have reported antidepressant effects ofanti-inflammatory treatment; however, the results have been conflicting anddetrimental adverse effects may contraindicate the use of anti-inflammatoryagents.OBJECTIVE: To systematically review the antidepressant and possible adverseeffects of anti-inflammatory interventions.DATA SOURCES: Trials published prior to December, 31, 2013, were identifiedsearching Cochrane Central Register of Controlled Trials, PubMed, EMBASE,PsychINFO, Clinicaltrials.gov, and relevant review articles.STUDY SELECTION: Randomized placebo-controlled trials assessing the efficacy and adverse effects of pharmacologic anti-inflammatory treatment in adults withdepressive symptoms, including those who fulfilled the criteria for depression.DATA EXTRACTION AND SYNTHESIS: Data were extracted by 2 independent reviewers.Pooled standard mean difference (SMD) and odds ratios (ORs) were calculated.MAIN OUTCOMES AND MEASURES: Depression scores after treatment and adverseeffects.RESULTS: Ten publications reporting on 14 trials (6262 participants) wereincluded: 10 trials evaluated the use of nonsteroidal anti-inflammatory drugs(NSAIDs) (n = 4258) and 4 investigated cytokine inhibitors (n = 2004). The pooledeffect estimate suggested that anti-inflammatory treatment reduced depressivesymptoms (SMD, -0.34; 95% CI, -0.57 to -0.11; I2 = 90%) compared with placebo.This effect was observed in studies including patients with depression (SMD,-0.54; 95% CI, -1.08 to -0.01; I2 = 68%) and depressive symptoms (SMD, -0.27; 95%CI, -0.53 to -0.01; I2 = 68%). The heterogeneity of the studies was not explainedby differences in inclusion of clinical depression vs depressive symptoms or use of NSAIDs vs cytokine inhibitors. Subanalyses emphasized the antidepressantproperties of the selective cyclooxygenase 2 inhibitor celecoxib (SMD, -0.29; 95%CI, -0.49 to -0.08; I2 = 73%) on remission (OR, 7.89; 95% CI, 2.94 to 21.17;I2 = 0%) and response (OR, 6.59; 95% CI, 2.24 to 19.42; I2 = 0%). Among the 6studies reporting on adverse effects, we found no evidence of an increased numberof gastrointestinal or cardiovascular events after 6 weeks or infections after 12weeks of anti-inflammatory treatment compared with placebo. All trials wereassociated with a high risk of bias owing to potentially compromised internalvalidity.CONCLUSIONS AND RELEVANCE: Our analysis suggests that anti-inflammatorytreatment, in particular celecoxib, decreases depressive symptoms withoutincreased risks of adverse effects. However, a high risk of bias and highheterogeneity made the mean estimate uncertain. This study supports aproof-of-concept concerning the use of anti-inflammatory treatment in depression.Identification of subgroups that could benefit from such treatment might bewarranted.PMID: 25322082  [PubMed - in process]

 

Depression may lead to a vicious inflammatory cycle.

 

1. BMC Med. 2012 Jun 29;10:66. doi: 10.1186/1741-7015-10-66.Depression and sickness behavior are Janus-faced responses to shared inflammatorypathways.Maes M(1), Berk M, Goehler L, Song C, Anderson G, Gałecki P, Leonard B.Author information: (1)Maes Clinics @ TRIA, Piyavate Hospital, 998 Rimklongsamsen Road, Bangkok10310, Thailand. dr.michaelmaes@hotmail.comIt is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complexinduced by infections and immune trauma and mediated by pro-inflammatorycytokines. It is an adaptive response that enhances recovery by conserving energyto combat acute inflammation. There are considerable phenomenologicalsimilarities between sickness behavior and depression, for example, behavioralinhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic(fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. Inclinical depression, however, a transition occurs to sensitization ofimmuno-inflammatory pathways, progressive damage by oxidative and nitrosativestress to lipids, proteins, and DNA, and autoimmune responses directed againstself-epitopes. The latter mechanisms are the substrate of a neuroprogressiveprocess, whereby multiple depressive episodes cause neural tissue damage andconsequent functional and cognitive sequelae. Thus, shared immuno-inflammatorypathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology.Inflammation may provoke a Janus-faced response with a good, acute side,generating protective inflammation through sickness behavior and a bad, chronicside, for example, clinical depression, a lifelong disorder with positivefeedback loops between (neuro)inflammation and (neuro)degenerative processesfollowing less well defined triggers.PMCID: PMC3391987PMID: 22747645  [PubMed - indexed for MEDLINE]

 

CBT, or "cognitive framing", as you call it, is certainly effective, but it can be a way to lie yourself to happiness in the same way that SSRIs are a way to "I don't care" yourself to happi... la la land.

 

If my life sucks, which it does, I can go to a therapist who practices CBT and have him "reframe" my outlook on my life so that it seems good, but in the end, it still sucks. (Says the back of my mind, but outlook on life is subjective, although I can't help but make seemingly objective evaluations of my own.)

 

The reasons why people are depressed usually aren't hard to find. I prefer psychoanalytic therapy, but all talk therapy, regardless of mode, has been shown to improve depression. CBT is the most well studied. Hell, I recently read about dance therapy for depression.

[degen12]

Discontinuation of the antidepressant results in a slow and gradual improvement of the chronic depressive symptoms.

 

Having been on an SSRI since age 7, this brings me sorely needed hope. Thank you for finding this article and posting it.

[LoveandLight]

Funny, selective reading. I chose to focus on the gloomier aspect and totally disregarded the above quote.

[Altostrata]

degen, is it possible that when people feel unwell, even if only vaguely, that might affect mood?

[degen12]

degen, is it possible that when people feel unwell, even if only vaguely, that might affect mood?

 

Almost certainly, even if they don't know it.

 

The factors that affect mood are so numerous and layered that it's futile to try and pin it down to one thing. Of course that's what drug companies and their researchers are trying to do. I posted some studies that try and connect inflammation and sickness behaviour to depression. It's definitely interesting to read but trying to create a "unifying theory" for depressive behaviour is impossible. There will be no E=mc² . Heck, how your mother fared during her pregnancy can affect susceptibility to almost anything.

[Altostrata]

That's exactly how all those studies finding a correlation between inflammation and "depression" are confounded -- no one is sure which came first, the inflammation or the "depression."

 

In addition, "depression" is so sloppily defined and diagnosed that no one knows what was called "depression" in those studies. They usually use multiple-choice quizzes to identify "depression," but these have a host of problems.

[westcoast]

I love that word, "prodepressant."

But what about all those people who comment on drug stories in the newspaper (nytimes.com, etc) saying "effexor and lithium saved my life!" It's so complicated. Some might be shills, of course.

[Altostrata]

Some people like the effects of psychiatric drugs. They are psychoactives, after all.

[WiggleIt]

OMG this is obviously a credible conclusion. I don't think there is a need for "trials."

 

Recreational drug and alcohol use leads to chronic depression. They are psychoactive and alter the same stuff in the brain as psych meds; therefore psych meds pose the same risks.

 

It would be cruel and unusual to subject people to trials of these meds. This is one situation where I believe the research conclusions can be made based on common sense.

 

If we were talking about cancer or some other kind of illness, I'd be all for clinical trials, but I think there is enough evidence here that a reasonable causal conclusion can be made.

[WiggleIt]

ESPECIALLY now that so many psych meds are being prescribed off-label to patients with no history of depression prior to meds. THERE'S the evidence.

 

Honestly, I'm developing such a disrespect for medical science.

[westcoast]

Some people like the effects of psychiatric drugs. They are psychoactives, after all.

good point. Also, as someone pointed out, the folks who say that Effexor is saving their lives might have discontinued and gone nuts, and not known it was withdrawal.

[jimmy555]

This is worrying ,so it becomes permanent ?

 

Discontinuation of the antidepressant results in a slow and gradual improvement of the chronic depressive symptoms. However, in some individuals who have experienced TDp for a very prolonged period of time, discontinuation of antidepressant may not result in reversal of the symptoms.