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article on tardive dysphoria #1

Posted by floatingbridge on May 12, 2011, at 2:39:27

One of the researchers kindly shared these copies with me. I had to do an ungodly cut and paste job, so forgive the legibility. If it just palain unreadable, I do not expect anyone to perserve. It was the best a former Luddite could be expected to do.

Department of Psychiatry and Behavioral Sciences
University of Louisville School of Medicine
501 E. Broadway, Suite 340
Louisville, KY 40202 (USA)
Tel. +1 502 852 1124, Fax +1 502 852 5098
E-Mail rselma01 @ louisville.edu
PPS316799.indd 3 15.07.2010 10:54:03

From the Journal Of Psychotherapy & Psychosomatics

Letter to the Editor
We report a case of antidepressant discontinuation in a TRD
patient. He was a 67-year-old white man with onset of major depressive illness at the age of 45. He was homozygous for the short
form of the serotonin transporter. He was treated off and on until
the age of 59 and had been on an antidepressant continuously until
the age of 67. Over the previous 2 years he had been depressed
without any relief by medication or 2 electroconvulsive treatments.
His medications at the time of evaluation included paroxetine
10 mg daily, venlafaxine 75 mg daily and clonazepam 3 mg
daily. His 17-item Hamilton depression score was 22. Over the
subsequent 6 months, he was started on bupropion and then tapered
off all antidepressants, including the bupropion. His Hamilton
depression score dropped to 18. The patient was not satisfied
with his progress and sought another opinion to restart antidepressants.
One year later, on duloxetine 60 mg daily, he continued
to complain of unremitting depression.
A possible prodepressant effect of antidepressants has been
previously proposed. Fava [5, 18] was the first to suggest that an
antidepressant-related neurobiochemical mechanism of increasing
vulnerability to depression might play a role in worsening the
long-term outcome of the illness. Others have also proposed similar
ideas [6, 19] .
Understanding of potential mechanisms of this phenomenon
can be gleaned from observations regarding the short form of the
serotonin transporter (5HTTR) [20] . The short form of the
5HTTR is a 44-base deletion in the promoter of the SLC6A4 gene,
which codes for the 5HTTR protein [20] . This deletion reduces
expression of the 5HTTR protein so that subjects with the short
form express about half as many serotonin reuptake pumps in the
membrane compared to those without the short form [20] . Subjects
with the short form (heterozygotes and homozygotes) are
more likely to become depressed in the setting of adversity than
people with the long form [20] . Additionally, they are less likely to
respond well to antidepressants, with reports of no response, delayed
response, increased side effects and increased rapid cycling
in bipolar individuals [20] .
It is not clear how the increased risk for these changes comes
about, but neuroplastic changes may be important. Modification
of serotonergic neurotransmission alters arborization of the dendritic
tree of serotonergic neurons [21, 22] . For example, mice that
lack the serotonin transporter have fewer serotonergic neurons
and reduced serotonergic function and express more behaviors
associated with anxiety and depression [23] .
Fifty percent expression of the 5HTTR that occurs with the
short form resembles the 6080% serotonin transporter inhibition
that is required for an antidepressant response [24, 25] . It
would be expected that individuals with either genetic reduction
in 5HTTR or prolonged pharmacological blockage of 5HTTR
would reduce serotonergic arborization, and this may play a role
in the increased recurrence of depression in the setting of adversity,
poor antidepressant response, increased side effects and increased
rapid cycling in bipolar individuals. Patients with both
risk factors, i.e. with the short form of the 5HTTR and prolonged
The prevalence of treatment-resistant depression (TRD) appears
to be increasing. A recent meta-analysis found TRD to be a
problem in nearly 40% of depressed patients, a dramatic increase
from the 1990s when it was reported to affect 1015% of patients
[1, 2] . While this difference may be related to differences in how
the studies were performed, if correct, it would suggest a process
in which TRD is occurring in response to environmental, biological
or clinical factors. Psychiatrists do not have control over
environmental factors, but we do have direct control over clinical
factors and hence a duty to examine these. For example, TRD may
be related to inadequate dosing of antidepressants [3] or antidepressant
tolerance [4] . Alternatively, there are reasons to believe
that antidepressant treatment itself may contribute to a chronic
depressive syndrome [5, 6] .
TRD may be related to the phenomenon of tachyphylaxis.
Such patients experience an initial good response to antidepressants
that is lost over time with repeated or continuous antidepressant
administration [4, 79] . Attempts to treat these individuals
frequently results in poor response [10] . While the incidence
of tachyphylaxis is unknown, in a prospective study, Solomon et
al. [11] found that relapse occurred in 25% of 171 episodes.
However, antidepressants may play a more active role in the
recurrence of depression in some of these patients. Even early reports
noted worrisome phenomena. Mildly depressed patients
may actually worsen over time when treated with imipramine
[12] . Anxious patients who do not have a history of a mood disorder
may develop depression after prolonged treatment with antidepressants
for their anxiety disorder [13, 14] . Twenty-seven percent
of patients without any history of a mood disorder who had
received antidepressants for an average of 29 months for panic
disorder developed a cyclothymic illness that persisted for 1 year
after antidepressant discontinuation [15] . Normal controls receiving
antidepressants in research studies were reported to experience
depression [16] .
In a study of 15 subjects (11 with unipolar and 4 with bipolar
illness) with apparent tachyphylaxis, Sharma [17] found that discontinuation
of antidepressants (and continuation of mood stabilizers)
was associated with improvement.
Published online: $ $ $
© 2010 S. Karger AG, Basel
00333190/10/00000000$26.00/0
Accessible online at:
www.karger.com/pps
Psychother Psychosom 316799
DOI: 10.1159/000316799
Antidepressant-Induced Tardive Dysphoria
Rif S. El-Mallakh, Yonglin Gao, Brian T. Briscoe, R. Jeannie Roberts
Department of Psychiatry and Behavioral Sciences, Mood
Disorders Research Program, University of Louisville School of
Medicine, Louisville, Ky. , USA
PPS316799.indd 1 15.07.2010 10:53:55
2 Letter to the Editor
antidepressant exposure, may be particularly vulnerable to antidepressant-
related worsening. In other words, prolonged exposure
to antidepressants can induce neuroplastic changes that result
in the genesis of antidepressant-induced dysphoric symptoms.
We propose the term tardive dysphoria to describe such a
phenomenon.
Tardive dysphoria may be distinguishable from major depressive
disorder by several characteristics. First, tardive dysphoria is
chronic and appears only after prolonged ( 1 1 year) exposure to
an antidepressant. Function is frequently preserved, and disturbances
in appetite and self-care are usually absent. Any loss of
self-esteem or self-confidence is either related to preexisting personality
traits or as a direct consequence of loss of energy. Mood
is dysphoric more than depressed, although many patients do not
make this distinction. The greatest deficits are in interest, energy
and motivation. There is a clear anhedonia. Generally, patients
are able to distinguish that the character of their current tardive
dysphoria symptoms is different from their previous depressive
episodes.
Tapering or discontinuing the antidepressant might reverse
the dysphoric state. Antidepressant discontinuation may not provide
immediate relief. In fact, it is likely that transient symptoms
of withdrawal will occur in the initial 24 weeks following antidepressant
discontinuation or tapering. However, after a prolonged
period of antidepressant abstinence, one may see a gradual
return to the patients baseline.
To stimulate further investigation and research in this area we
propose criteria for a clinical syndrome of tardive dysphoria ( table
1 ).
Conflicts of Interest
This work did not receive any external funding. R.S. El-Mallakh
is in the speakers bureau of AstraZeneca, Bristol Myers
Squibb, GlaxoSmithKline, Eli Lilly, Merck, Novartis and Pfizer.
In the last 5 years, he has received grant funding from Forest Laboratories,
Shire Pharmaceuticals, NARSAD and the National Institute
of Mental Health. None of the other authors have conflicts
of interest to report.
Table 1. P roposed criteria for tardive dysphoria
1 Prolonged (at least 1 year) exposure to a therapeutic dose of a
serotonergic antidepressant.
2 Onset of a chronic or continuous dysphoric state while receiving
a therapeutic dose of a serotonergic antidepressant; the dysphoric
state lacks the episodic nature of major depressive disorder.
3 After the resolution of initial antidepressant withdrawal symptoms
(usually the first 46 weeks following antidepressant dose
reduction or discontinuation)1, the person returns to the baseline
depressive state experienced prior to discontinuation of the
antidepressant. (Note: the period and symptoms of antidepressant
withdrawal should not be considered as part of tardive
dysphoria.)
4 Delayed (after several months) and gradual improvement in
depressive symptoms. (Note: the improvement does not necessarily
need to represent full remission.)
5 At least 7 of the following symptoms or characteristics are present
or absent:
a Depressed or dysphoric mood
b Reduced motivation
c Reduced interest
d Reduced energy
e Reduced pleasure
f Sleep disturbance with common middle insomnia
g Mood or affective lability
h Irritability
i No or minimal disturbance in appetite
j No or minimal disturbance in self-care
1 There is evidence that some patients may experience a protracted
withdrawal of up to 6 months [26].
References
1 Keitner GI, Ryan CE, Solomon DA: Realistic expectations and a disease
management model for depressed patients with persistent symptoms. J
Clin Psychiatry 2006; 67: 14121421.
2 Burrows GD, Norman TR, Judd FK: Definition and differential diagnosis
of treatment-resistant depression. Int Clin Psychopharmacol
1994; 9(suppl 2):510.
3 Hirschfeld RM, Keller MB, Panico S, Arons BS, Barlow D, Davidoff F,
Endicott J, Froom J, Goldstein M, Gorman JM, Marek RG, Maurer TA,
Meyer R, Phillips K, Ross J, Schwenk TL, Sharfstein SS, Thase ME,
Wyatt RJ: The National Depressive and Manic-Depressive Association
consensus statement on the undertreatment of depression. JAMA 1997;
277: 333340.
4 Byrne SE, Rothschild AJ: Loss of antidepressant efficacy during maintenance
therapy: possible mechanisms and treatments. J Clin Psychiatry
1998; 59: 279288.
5 Fava GA: Can long-term treatments with antidepressant drugs worsen
the course of depression? J Clin Psychiatry 2003; 64: 123133.
6 Sharma V: Treatment resistance in unipolar depression: is it an iatrogenic
phenomenon caused by antidepressant treatment of patients with
a bipolar diathesis? Med Hypotheses 2006; 67: 11421145.
7 Lieb J, Balter A: Antidepressant tachyphylaxis. Med Hypotheses 1984;
15: 279291.
8 Cohen B, Baldessarini R: Tolerance to therapeutic effects of antidepressants.
Am J Psychiatry 1985; 142: 489490.
9 Nierenberg AA, Alpert JE: Depressive breakthrough. Psychiatr Clin
North Am 2000; 23: 731742.
10 Posternak MA, Zimmerman M: Dual reuptake inhibitors incur lower
rates of tachyphylaxis than selective serotonin reuptake inhibitors: a
retrospective study. J Clin Psychiatry 2005; 66: 705707.
11 Solomon D, Leon AC, Mueller TI, Coryell W, Teres IJ, Posternak MA,
Judd LL, Endicott J, Keller MB: Tachyphylaxis in unipolar major depressive
disorder. J Clin Psychiatry 2005; 66: 283290.
12 Di Mascio A, Meyer RE, Stifler L: Effect of imipramine in individuals
varying in levels of depression. Am J Psychiatry 1968; 127(suppl):5558.
13 Aronson TA: Treatment emergent depression with antidepressants in
panic disorder. Compr Psychiatry 1989: 30: 267271.
14 Fux M, Taub M, Zohar J: Emergence of depressive symptoms during
treatment for panic disorder with specific 5-hydroxytryptophan reuptake
inhibitors. Acta Psychiatr Scand 1993; 88: 235237.
15 Fava GA, Bernardi M, Tomba E, Rafanelli C: Effects of gradual discontinuation
of selective serotonin reuptake inhibitors in panic disorder
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16 Healy D: Emergence of antidepressant induced suicidality. Prim Care
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PPS316799.indd 2 15.07.2010 10:54:02
Letter to the Editor 3
25 Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ, Ginovart
N, Spencer EP, Cheok A, Houle S: Serotonin transporter occupancy
of five selective serotonin reuptake inhibitors at different doses:
an [ 11 C]DASB positron emission tomography study. Am J Psychiatry
2004; 161: 826835.
26 Briscoe B, El-Mallakh RS: The evidence base for the long-term use of
antidepressants as prophylaxis against future depressive episodes.
Annu Meet Am Psychiatr Assoc, New Orleans, May 2010.
17 Sharma V: Loss of response to antidepressants and subsequent refractoriness:
diagnostic issues in a retrospective case series. J Affect Disord
2001; 64: 99106.
18 Fava GA: Do antidepressant and antianxiety drugs increase chronicity
in affective disorders? Psychother Psychosom 1994; 61: 125131.
19 El-Mallakh RS, Waltrip C, Peters C: Can long-term antidepressant use
be depressogenic? J Clin Psychiatry 1999; 60: 263.
20 Luddington NS, Mandadapu A, Husk M, El-Mallakh RS: Clinical implications
of genetic variation of the promoter region of the serotonin
transporter. Prim Care Companion J Clin Psychiatry 2009; 11: 93102.
21 El-Mallakh RS, Peters C, Waltrip C: Antidepressant treatment and
neural plasticity. J Child Adolesc Psychopharmacol 2000; 10: 287294.
22 Baker MW, Croll RP: Modulation of in vivo neuronal sprouting by serotonin
in adult CNS of the snail. Cell Mol Neurobiol 1996; 16: 561576.
23 Lira A, Zhou M, Castanon N, Ansorge MS, Gordon JA, Francis JH,
Bradley-Moore M, Lira J, Underwood MD, Arango V, Kung HF, Hofer
MA, Hen R, Gingrich JA: Altered depression-related behaviors and
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deficient mice. Biol Psychiatry 2003; 54: 960971.
24 Voineskos AN, Wilson AA, Boovariwala A, Sagrati S, Houle S, Rusjan
P, Sokolov S, Spencer EP, Ginovart N, Meyer JH: Serotonin transporter
occupancy of high-dose selective serotonin reuptake inhibitors during
major depressive disorder measured with [ 11 C]DASB positron emission
tomography. Psychopharmacology (Berl) 2007; 193: 539545.



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URL: http://www.dr-bob.org/babble/20110502/msgs/985130.html