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Re: Do antidepressants worsen your depression?

Posted by doxogenic boy on October 22, 2013, at 12:55:10

In reply to Do antidepressants worsen your depression?, posted by doxogenic boy on October 22, 2013, at 12:46:02

> There is some research that indicates that antidepressants worsen depression for some antidepressant users.


Today, more people than ever before get antidepressants for depression, and still there are a lot more patients with treatment-resistant depression. Could it be that the antidepressants make patients treatment-resistant, and do they get better if they stop taking their antidepressants?

Below are two more articles which show that long-term use of antidepressants may worsen depression. (I have mentioned them is this message before:
http://www.dr-bob.org/babble/20130930/msgs/1052513.html ).


http://www.madnessradio.net/files/tardivedysphoriadarticle.pdf

I have quoted parts of this study below. When I leave out something is use this: "[...]".

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

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

Article history:
Received 30 May 2010
Accepted 12 January 2011

Abstract

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.

[...]

For many patients recurrence of depressive symptoms may oc-
cur despite ongoing antidepressant treatment [17]. When optimi-
zation of treatment fails, such patients are noted to have
treatment-resistant depression (TRD). TRD may comprise 3050%
of people with major depressive illness [17,18]. 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 [19]. However, in the early 1990s it was reported that only
1015% of patients had TRD [20].

[...]

Alternatively, the loss of efficacy of the antidepressant may be related to clinical issues suchas inadequate dosing of antidepressants [22 or antidepressant tolerance [23]. There are reasons to believe that antidepressant
treatment itself may contribute to a chronic depressive syndrome [24,25].

Tachyphylaxis

Tachyphylaxis (also known as antidepressant tolerance, antide-
pressant poop-out, or breakthrough depression) is a condition
in which patients experience a good initial antidepressant re-
sponse which is lost over time with repeated or prolonged antide-
pressant treatment [23,2628]. This phenomenon is distinct from
an initial non-response or a partial response. Up to 80% of patients
diagnosed with major depressive disorder will experience a recur-
rence of depressive episode despite constant maintenance dose of
an antidepressant [12,23,29,30]. Attempts to treat these individu-
als frequently result in poor response and the rise of TRD [30].

[...]

More recently, there have been several re-
ports of the loss of antidepressant efficacy. For example, Solomon
et al.[29] found that relapse occurred in 25% of 171 episodes. A
long-term placebo-controlled, blinded maintenance study of fluox-
etine in major depression, found no difference after 62 weeks in
subjects who were still euthymic on fluoxetine (11%) or placebo
(16%) [31]. Fifteen patients who had lost their response to antide-
pressants failed multiple treatment strategies including augmenta-
tion with mood stabilizers and, in some cases, electroconvulsive
therapy (ECT)[32]. When antidepressants were discontinued and
patients were left on mood stabilizers only, they improved even
though most (73%) had unipolar depression [32]. Similarly, in a
small case series of 11 TRD cases, none of the patients had a lasting
response to different classes of antidepressants
[26].

Once initial treatment response is lost, subsequent improve-
ment is unlikely. If patients with TRD respond to a subsequent
antidepressant, the extent of improvement is inferior to the initial
response[33]. 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 ini-
tiated[34,35].

Antidepressant-induced depression

The possibility of antidepressant-induced depression was intro-
duced by Fava[36]. He suggested that a neurobiochemical mecha-
nism increasing vulnerability to depression might play a role in
this phenomenon and contribute to the observed worsening long-term outcome of major depression[24]. Other authors have also introduced similar ideas
[25,37].

Several studies support these assertions. Van Scheyen
[38] naturalistically followed 84 depressed adults and found that long
term treatment with TCAs increased the likelihood of a depressive
recurrence. Long term treatment with imipramine is associated
with worsening mood in mildly depressed patients [39]. Anxious
patients without a history of a mood disorder may develop depres-
sion after long-term treatment with antidepressants for their anx-
iety disorder[40,41]. 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 disorder, developed a cyclothy-
mic illness that persisted for 1 year after antidepressant discontin-
uation [42]. Normal controls receiving antidepressants in research
studies were reported to experience depression [43].

[...]

Tardive dysphoria (TDp)

It is proposed that tardive dysphoria (TDp) is an abnormal dys-
phoric 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 treat-
ment. Antidepressants may be initially administered for any reason
(e.g., anxiety or depression), but afflicted subjects with a history of
a recurrent major depressive disorder would have historically
experienced an initial positive response to antidepressant medica-
tion (generally with their first exposure).

The depressive state is
perpetuated (and possibly worsened) by continuing the antide-
pressant. It is believed that SRI antidepressants might be selec-
tively 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, dis-
continuation of antidepressant may not result in reversal of the
symptoms. This is superficially similar to TD. Subjects who
ultimately develop TDp will have frequently had an initial positive
response to antidepressants, helping to cement adherence. Depres-
sion recurs in 957%, or perhaps as high as 93% in the effectiveness
trial STAR*D (relapse and dropout of study) [59], of patients
despite ongoing antidepressant treatment [23]. In such patients,
an increase in dose [60,61], change to another antidepressant agent
[62,63] or adding another antidepressant [64,65] may be effective
in 3060% of patients. However, there is evidence that switch may
not be helpful [66], and if patients do respond relapse occurs with-
in 6 months in some 20% [61]. Ultimately, 3050% of such patients
will develop TRD [17,18].

In the subset of such patients who have
developed TDp, ongoing attempts to treat the depression with anti-
depressants perpetuate the TRD, and may ultimately make the
chronic depression permanent. TDp is different from conditioned tolerance
[67] in that it is not merely the loss of the drug effect, but viewed as an active process in which adepressive picture is caused by continued administration of the antidepressant. In conditioned tolerance, environmental and behavioral conditional compensatory responses mediate tolerance
by in the presence of cues usually associated with the drug [67].

[...]

Summary
A chronic and treatment-resistant depressive state is proposed
to occur in individuals who are exposed to potent antagonists of
serotonin reuptake pumps for prolonged time periods. Due to the
delay in the onset of this chronic depressive state, it is labeled tar-
dive dysphoria (TDp). TDp manifests as a chronic dysphoric state
that is initially transiently relieved by but ultimately becomes
unresponsive to antidepressant medication. Serotoninergic anti-
depressants may be of particular importance in the development of
TDp.

The incidence or predisposing risk factors are as yet unknown,
but younger age at onset of antidepressant exposure and genetic
underexpression of the serotonin transporter, such as with the
short form of the serotonin transporter, may increase the risk of
TDp. Investigations attempting to discern the existence of TDp
would comprise blinded, randomized antidepressant discontinua-
tion/continuation trials in TRD patients, over at least 1 year. As
with TD, one would expect that some individuals who discontinue
the antidepressant will remain depressed.

Subjects more likely to benefit from antidepressant discontinuation would be those who have had a briefer prior exposure to antidepressants, have more
neuroplastic potential (e.g., younger and without chronic medical
illnesses), and have the long form of the serotonin transporter.
Until such studies are performed the treatment recommendations
must remain unchanged, but clinical trials of antidepressant taper and discontinuation for 612 months in patients who have failed
most other options appear reasonable.

Quote end.

-------------------------------------
-------------------------------------


http://www.madinamerica.com/wp-content/uploads/2011/11/Can-long-term-treatment-with-antidepressant-drugs-worsen-the-course-of-depression.pdf

I quote parts of the article below.

Can Long-Term Treatment With Antidepressant Drugs Worsen the Course of Depression?

Giovanni A. Fava, M.D.

[...]

Results:
A number of reported clinical find-
ings point to the following possibilities: very un-
favorable long-term outcome of major depression
treated by pharmacologic means, paradoxical
(depression-inducing) effects of antidepressant
drugs in some patients with mood and anxiety
disturbances, antidepressant-induced switching
and cycle acceleration in bipolar disorder, occur-
rence of tolerance to the effects of antidepressants
during long-term treatment, onset of resistance
upon rechallenge with the same antidepressant
drug in a few patients, and withdrawal syndromes
following discontinuation of mood-elevating
drugs. These phenomena in susceptible individu-
als may be explained on the basis of the opposi-
tional model of tolerance. Continued drug treat-
ment may recruit processes that oppose the initial
acute effects of a drug and may result in loss of
clinical effect. When drug treatment ends, these
processes may operate unopposed, at least for
some time, and increase vulnerability to relapse.

[...]

(J Clin Psychiatry 2003;64:123133)
Received June 21, 2001; accepted Aug. 8, 2002. From the Department
of Psychiatry, State University of New York at Buffalo, Buffalo; and the
Affective Disorders Program, Department of Psychology, University of
Bologna, Bologna, Italy.

[...]
Corresponding author and reprints: Giovanni A. Fava, M.D.,
Dipartimento di Psicologia, Viale Berti Pichat 5, 40127 Bologna, Italy.

[...]
The most common conviction among re-
searchers and clinicians has probably been the recognition
of the chronic nature and increasing incidence of depres-
sive illness. 4

However, we seem to forget and do not want to entertain another possibility: the likelihood that antide-pressant drugs may be depressogenic, at least in some
cases. 14


[...]

Fux et al.36 observed the emergence of depres-
sive symptoms in 7 (9%) of 80 patients during the treat-
ment of panic disorder with fluvoxamine. These patients
had no history of mood disorder, and no symptoms of
depression were present before treatment with fluvox-
amine. The symptoms abated when fluvoxamine was dis-
continued and a tricyclic antidepressant or clonazepam
was prescribed, and they reappeared when fluoxetine
was administered. Fux et al. 36 suggest the possibility of
a vulnerability among some panic disorder patients to a
noradrenergic-serotonergic imbalance caused by selec-
tive serotonin reuptake inhibitors (SSRIs).

The question that arises is whether such paradoxical
phenomena may affect only a few individuals or are
manifestations of a subtle, but general effect. The results
of a recent randomized controlled trial comparing
cognitive-behavioral therapy (CBT), imipramine, or their
combination for panic disorder 37 point to the possibility
of a general effect in panic disorder. Six months after
treatment discontinuation, response rates were 41% for
CBT plus placebo, compared with 26% for CBT com-
bined with imipramine. A relationship between use of
antidepressant drugs and increased relapse risk of panic
disorder has been reported by other investigators, 3840
and depression was found to occur during the follow-up of
patients receiving tricyclic antidepressants for panic dis-
order. 41

Another intriguing phenomenon involves the con-
cept of a therapeutic window, which was originally ap-
plied to nortriptyline, 42 but was subsequently described
with SSRI therapy. 4347
The possibility of paradoxical or no effects occurring above a certain dosage would be in line with the phenomena described with patients with
affective disorders and healthy controls.

[...]

In the early 1980s, Kukopulos et al. 50,51 observed how treat-
ment by antidepressant drugs may contribute to changes
of course from unipolar to bipolar illness and to an in-
creased frequence of cyclicity. Cycle acceleration has
been subsequently confirmed by other investigators. 48

Kukopulos et al. 50,51 deserve credit in raising the possi-
bility that antidepressant-induced mania is not simply a
temporary and fully reversible phenomenon, but may trig-
ger complex biochemical mechanisms of illness deterio-
ration. A case of tricyclic-induced mania in a 60-year-old
woman with a long-standing history of unipolar depres-
sion (that was followed by rapid cycling refractory to
lithium) illustrates the hormonal implications of such
mechanisms. 52

[...]

Tolerance to Antidepressant Drugs

The return of depressive symptoms during mainte-
nance antidepressant treatment was found to occur in 9%
to 57% of patients in published trials. 54

Possible explana-
tions include pharmacologic tolerance, loss of placebo
effect, increase in disease severity, change in disease
pathogenesis, accumulation of a detrimental metabolite,
unrecognized rapid cycling, and prophylactic inefficacy.
54

Several clinical observations point to the existence of
tolerance phenomena during antidepressant treatment.
24,55 Some data point to dispositional (pharmacokinetic) toler-
ance, which reduces the concentration of a drug. For in-
stance, patients who relapsed while on fluoxetine treat-
ment (20 mg/day) responded to an increased dosage of the
same drug (40 mg/day).56

Other studies, however, suggest the likelihood of pharmacodynamic processes that change sensitivity to the drug. Mann 57 observed loss of antidepres-
sant effect with long-term monoamine oxidase (MAO) inhibitor treatment without loss of MAO inhibition. Lieb and Balter 58 described the development of tolerance to an-
tidepressant effects that was refractory to dosage increase.


[...]

Donaldson 69 described 3 patients with major depres-
sion who relapsed while on phenelzine treatment and de-
veloped a severe chronic depression that was refractory
to other treatments. The phenomenon of resistance was
analyzed in a study of 122 patients who, after initially
responding to fluoxetine, were assigned to placebo. About
half of the patients relapsed. After reinitiation of med-
ication, 38% of the patients either did not respond or ini-
tially responded but again relapsed. 70 Similar results were obtained after discontinuation of an SSRI in obsessive-
compulsive disorder. 71

The few data available thus indicate that when drug
treatment is reinstituted, the patient may not respond to
the same antidepressant that improved depressive symp-
toms the first time. The prevalence of this resistance that
ensues varies. Patients who respond to reinstitution of the
same antidepressant drug may display a subsequent loss
of therapeutic effect. 70

This suggests that resistance and loss of clinical effects may be related and share a common mechanism. Episodes that are simply classified as respon-
ding poorly to antidepressant drugs 72 may underlie the
phenomena described here (previous successful response
to antidepressant drugs). This issue is currently neglected,
but it is worthy of research attention.

[...]

We know that discontinuation of antidepressant drugs
may trigger hypomania or mania 81,82 despite adequate con-
comitant mood-stabilizing treatment. 83 Furthermore, mood shifts to euthymia or hypomania are not rare events in patients withdrawn from medication because of a lack of efficacy. 84

Mood elevation may also occur with anti-
depressant dose decrease,85
and patients who failed to re-
spond to mood stabilizers in combination with antide-
pressant drugs may improve on discontinuation of the
antidepressant drugs. 86

These data suggest a relationship between antidepressant drug discontinuation and cycle acceleration in bipolar disorder. 83
In unipolar depression,withdrawal phenomena may be associated with recur-
rence acceleration.

[...]

The opposi-
tional model of tolerance, 87 however, seems to entail sev-
eral important implications. According to this model, con-
tinued drug treatment may recruit processes that oppose
the initial acute effects of a drug or of receptor alterations.

This model may explain the onset of tolerance in some
patients. Use of antidepressant drugs may also propel the
illness to a more malignant and treatment-unresponsive
course, as was suggested in bipolar disorder.
When drug treatment ends, oppositional processes may
operate for some time, resulting in appearance of with-
drawal symptoms and increased vulnerability to relapse.

As Baldessarini 20 remarks, the assumption that such
physiologic processes will readjust after a withdrawal
phase is not supported by current awareness in the field of
drug dependence. Several months may be necessary (or
the processes may even have an irreversible connotation),
as has been found with, for instance, the sex-specific re-
sidual effects of cannabis on visuospatial memory. 88

[...]

Activation of hormonal markers of stress response fol-
lowing discontinuation of SSRI has been described
103 and thus may lead to increased vulnerability to relapse in sus-
ceptible individuals.

[...]

Researchers thus should demonstrate that the com-
bination of psychotherapy and pharmacotherapy is infe-
rior in terms of relapse prevention to psychotherapy
alone.


In a controlled trial study, [114] patients with recurrent
depression were allocated to 3 groups: short-term and
maintenance (2 years) treatment with antidepressant
drugs, CBT in the short-term and maintenance phases,
and antidepressant use in the short-term phase and CBT
for maintenance. Cognitive therapy displayed a similar
prophylactic effect to maintenance medication. The long-
term outcome of the group receiving both short-term
and maintenance treatment with cognitive therapy was
slightly better than that of the group who received phar-
macotherapy followed by psychotherapy. 114

Furthermore, an additive effect of combination therapy has been shown
only with the more complex depressive disorders.
115 How-ever, all results may be affected by the presence of pa-
tients who were previously treated with antidepressant
drugs.

[...]

It is conceivable that, once drug treatment has
been discontinued, despite substantial clinical improve-
ment in anxiety symptoms during active treatment, pa-
tients treated with antidepressant drugs may suffer from
episodes of major depression more than patients treated
with placebo or benzodiazepines.

[...]

Antidepressant drugs were developed for and found to
be effective in the treatment of major depressive epi-
sodes.6 In recent years, their use has been extended to
maintenance and prevention. 31 However, treatments that
are effective in the acute phase of illness are not necessar-
ily the most suitable for postacute and residual phases or
maintenance. 3 Different antidepressant drugs may yield a differential rate of tolerance in the long term, with par-ticular reference to the HPA axis.98

[...]

Are withdrawal phenomena simply bothersome and
self-limiting reactions, or are they a manifestation of
an increased vulnerability to relapse once drug treatment
has been discontinued? There is evidence that certain
SSRIs are more likely to induce withdrawal reactions than
others. 78,79

According to the oppositional tolerance model,
this would mean that they also facilitate (or fail to protect
from) relapse once they are discontinued. This effect
could explain the high rate of relapse on switching from
an SSRI to placebo, which may be different from one drug
to another and be demonstrated by follow-up studies.

[...]

Yet, at present, the opposi-
tional tolerance model applied to antidepressant drugs
may provide room for a number of clinical phenomena
that would otherwise lack explanation. We should be
aware that we are stretching the original indications (ma-
jor depressive episodes) of drugs of modest efficacy
135 to include prevention of relapse, anxiety disorders, and de-
moralization. Antidepressant drugs may speed improve-
ment and change the boundary between responders and
nonresponders.

However, when we prolong treatment to more than 6 to 9 months, we may recruit different phenomena, such as tolerance, episode acceleration, and paradoxical effects. 136 Commonly shared clinical assump-
tions (the longer the antidepressant drug treatment, the
better; the higher the dosage, the better) are challenged by
research evidence. It is time to switch gears in depression
research and start tackling the basic issues concerned with
long-term treatment of depression.

End quote.

Have you experienced tardive dysphoria/worsening of depression because of antidepressants, as described above?

- doxogenic


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Earlier TRD/anxiety
300 mg tianeptine, 6 X 50 mg successfully since Oct 2009
20 mcg liothyronine
40 mg escitalopram
100 mg trimipramine
50 mg agomelatine
600 mg quetiapine


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URL: http://www.dr-bob.org/babble/20130930/msgs/1052785.html