![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 14 of 14. This is the beginning of the thread.
Posted by floatingbridge on May 12, 2011, at 3:04:15
Mood Disorders Research Program
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.eduTardive dysphoria: antidepressant-induced chronic depression
Rif S. El-Mallakh, R. Jeannie Roberts, Alan Swann, Anton Surja
abstract
Objectives: A significant fraction of depressed individuals experience inadequate benefit from long-term antidepressant use. This paper investigates the hypothesis that in some individuals persistent use of antidepressants may be prodepressant.
Methods: Literature regarding the effect of long-term use of antidepressants was reviewed by searching PubMed and Ovid data bases with terms: antidepressant tachyphylaxis, treatment-resistant depression, chronic depression, and antidepressant tolerance.
Results: Antidepressant treatment-resistant patients frequently had a positive initial response to antidepressants. When resistance appeared, initial increases in dose or medication changes usually resulted in transient improvement. Eventually, the episodic course of the original depressive illness was replaced with a continuous, unresponsive depressive syndrome. We propose the term tardive dysphoria to describe this phenomenon.
Conclusions: The phenomenon of antidepressant-induced depression, or tardive dysphoria, needs to be experimentally examined in blinded, randomized antidepressant discontinuation studies.
Key words: Antidepressants, Antidepressant adverse effect, Chronic Depression, Major Depressive Disorder, Tachyphylaxis, Tardive Dysphoria.Introduction
Major depressive disorders affect more than 18 million people in the United States and 340 million people worldwide.1,2 It is the number one cause of disability-adjusted life years in developed countries, making it to be the fourth leading cause of disability worldwide.1,3 It has huge financial and social burdens. The economic impact of treatment resistant depression is even greater, with up to $28,000 inpatient and $3700 outpatient per year in America.4 This illness is usually characterised by chronic recurring depressive episodes. The episode may be brief (two to four weeks) or prolonged (more than nine months), but without treatment generally last about seven to nine months.5-7 The recurrence rate of unipolar depression ranges from 50-80%.8-10 With each episode, there is an increasing probability of another episode.11,12 Numerous randomised controlled trials have demonstrated the usefulness of maintenance therapy for the first year after an acute episode.13,14 For this reason, The American Psychiatric Association practice guideline and The NIMH collaborative study group have suggested that maintenance therapy after recovery is needed in the setting of a recurrent major depressive illness.15,16
However, for many patients, initial response may be suboptimal,17 and recurrence of depressive symptoms may occur despite ongoing and optimized antidepressant treatment.18 These patients with treatment resistant depression (TRD) may comprise up to 30% to 50% of people with major depressive illness.18,19
The cause of TRD is unknown, but its prevalence appears to be increasing; a recent meta-analysis found TRD to be a problem in nearly 40% of depressed patients, while in the early 1990s it was reported to affect 10-15% of patients.20,21 If this latter observation is accurate, it would suggest a dynamic process that may be related to environmental, biologic, or clinical factors. For example, changes in social support, fragmentation of nuclear and extended families, or economic or other stressors, may be conspiring to increase the prevalence of depression and its resistance to somatic treatment. The course of major depression itself may be changing due to a multitude of biologic and genetic factors, comparable to those in bipolar illness.22 Alternatively, the loss of efficacy of the antidepressant may be related to clinical issues such as inadequate dosing of antidepressants23 or other problems like antidepressant tolerance.24 However, there are reasons to believe that antidepressant treatment itself may contribute to a chronic depressive syndrome.25,26 We will review mechanisms by which this could occur.Tachyphylaxis
Several authors have described the phenomenon of tachyphylaxis (also known as antidepressant tolerance, antidepressant poop-out, or breakthrough depression).24,27-29 These patients experience a good initial antidepressant response that is lost over time with repeated or continuous antidepressant administration. This phenomenon differs from patients who only have partial response or those who never had a good response to antidepressant treatment. Although the frequency of antidepressant tachyphylaxis is still unclear, up to 80% of patients diagnosed with major depressive disorder will experience a recurrence of depressive episode despite constant maintenance dose of an
antidepressant.12,24,30,31 Attempts to treat these individuals frequently result in poor response.31
The introduction of serotonin reuptake inhibitors (SRIs) in 1988 ushered in a dramatic increase in antidepressant prescriptions. The advantages of this new class of antidepressant (SRI) over the older generation antidepressants such as tricyclics (TCAs) or monoamine oxidase inhibitors (MAOIs) were immediately apparent especially in terms of safety and tolerability. However, subsequent anecdotal and uncontrolled reports of the loss of SRI efficacy emerged after the initial resolution of a major depressive episode.32,33 Loss of antidepressant efficacy has been noted in large studies. In a prospective study, Solomon et al30 found that relapse occurred in 25% of 171 episodes. In a long-term placebo-controlled, blinded maintenance study of fluoxetine in major depression, there was no difference after 62 weeks in subjects who were still euthymic on fluoxetine (11%) or placebo (16%).34 Sharma35 studied 15 patients who had lost response to antidepressants. These patients had failed multiple treatment strategies including augmentation with mood stabilizers and, in some cases, electroconvulsive therapy (ECT). Eleven of his patients had unipolar depression and four had bipolar depression. When antidepressants were discontinued and patients were left on mood stabilizers only, they improved - even those who were diagnosed with unipolar depression.35 Similarly, in a case series of 11 TRD cases, none of the patients had a lasting response to different classes of antidepressants.27
Once initial treatment response is lost, improvement can be elusive. In a two-year prospective study of the naturalistic outcomes of 124 patients with TRD (109 with major depression and 15 with bipolar), only 18.4% responded and 7.8% achieved remission with treatment as usual despite appropriate medication management.36 Patients with TRD who had lost efficacy with an antidepressant might respond to a subsequent exposure, although not always to the extent of the initial response.37 In case reports related to MAOI treatment, patients not only did not respond to subsequent treatment, but also were reported to be more depressed after relapse than they had been before treatment was initiated.38,39
Antidepressant-induced depression:
Giovanni Fava first described the possibility of antidepressant-induced depression in 1994.40 He suggested that antidepressant drug treatment may not be simply a matter of failure to protect against future episodes, but that a neurobiochemical mechanism increasing vulnerability to depression might play a role in this phenomenon and worsen the long-term outcome of the illness.25 El-Mallakh and colleagues41 and Sharma26 subsequently echoed the same hypothesis. Such a process would be expected to decrease subsequent response to treatment and reduce the length of illness-free periods.These assertions are supported by several lines of evidence. In the early days of antidepressant availability, Van Scheyen42 naturalistically followed 84 depressed adults and found that long term treatment with tricyclic antidepressants increased the likelihood of a depressive recurrence. Mildly depressed patients may actually worsen over time when treated with imipramine.43 Anxious patients who do not have a history of a mood disorder may develop depression after treatment with antidepressants for their anxiety disorder.44,45 A recent study found that 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 cyclothymic illness that persisted for one year after antidepressant discontinuation.46 Normal controls receiving antidepressants in research studies were reported to experience depression.47
These effects may be analogous to the observations that antidepressant treatment in bipolar disorder could lead to an increase in manic and depressive episodes.48 An antidepressant-associated chronic irritable depressive (ACID) state has been reported in bipolar and bipolar spectrum patients given long-term antidepressants.49,50 In a case series, we have previously reported that subjects who experience ACID typically had a good initial response to antidepressant treatment. Over time, with ongoing antidepressant use, depressive symptoms would return and improve transiently with dose increase or change of agents, but would ultimately become resistant to antidepressants. However, slow and gradual improvement in depressive symptoms occurred with the discontinuation of antidepressants.
Fava25 speculated that a prodepressant effect of antidepressants may occur by an oppositional model of tolerance in which continued drug treatment may induce processes that are the opposite of what the medication originally produced. In this case, the use of antidepressants may actually make the illness worse and unresponsive to treatment. He believed this process may even cause a worsening of the illness, continue for a period of time after discontinuation of the medication, and may not be reversible.25Tardive dysphoria (TDp)
We propose 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 large fraction of TRD subjects. We specifically define TDp as a chronic treatment resistant depressive state occurring in the setting of ongoing, persistent antidepressant treatment in subjects with a history of a recurrent major depressive disorder who have historically experienced an initial positive response to antidepressant medication (generally with their first exposure). The depressive state is believed to be perpetuated by the maintenance antidepressant and is treated by removing the antidepressant, initiating slow improvement of symptoms. Subjects who ultimately develop TDp frequently have an initial positive response to antidepressants. This initial antidepressant effect is frequently powerful enough to convince both the treating clinician and the patient that antidepressants are beneficial, and thus cements long-term compliance. As frequently occurs in 9-57% of patients, depression recurs despite ongoing antidepressant treatment.24 An increase in dose,51,52 change to alternate antidepressant agent53,54 or adding another antidepressant55 may frequently be effective in reducing these recurrent depressive symptoms in 30-60% of patients. However, despite an initial improvement, some 20% may again relapse within six months.52 Ultimately, 30% to 50% will develop TRD.18,19 Ongoing attempts to treat the depression with antidepressants perpetuate the TRD, and may ultimately make the chronic depression permanent.
One reason for reluctance to investigate TDp more
rigorously is our own reluctance to believe that our treatments may actually be harmful to our patients.40 However, a possible prodepressant effect of long-term antidepressant treatment in major depressive illness is slowly gaining recognition,25,26,41 and is becoming more frequently recognised in bipolar illness.48,49 If TDp is a true phenomenon, what mechanisms might underlie it?
Serotonin transporter polymorphism
Some individuals have a genetic polymorphism in which the promoter region of the serotonin transporter gene has a 44 base insertion or deletion.56,57 The deletion variation is generally labeled the short form or s form of the serotonin transporter and is associated with a 50% reduction in the number of serotonin transporter units expressed in the membrane.58 Subjects with this variant are at a greater risk of experiencing a major depressive illness in the setting of environmental adversity.59-61 Furthermore, when these individuals are treated with an SRI antidepressant, they are either less likely to respond or have delayed response.62-65
It is not clear how this increased risk for depression comes about, but neuroplastic changes may be important. Modification of serotonergic neurotransmission will alter arborization of the dendritic tree of serotonergic neurons.66,67 Specifically, mice that lack the serotonin transporter have fewer serotonergic neurons and reduced serotoninergic function and express more behaviors associated with anxiety and depression.68 Furthermore, treatment of normal mice with the SRI fluoxetine in early life mimicked the behavioral phenotype of mice made genetically deficient for the serotonin transporter.69
A reduction in the number of synaptic serotonin transporters is very similar to the chronic 60-85% blockade of these transporters with SRIs.70,71 This raises the question as to whether possession of the s allele might serve as a model for chronic exposure to an SRI antidepressant. Reducing or eliminating serotonin transporter function in young
SummaryTDp is proposed to occur in individuals who are exposed chronically to potent antagonists of serotonin reuptake pumps. It manifests as a chronic dysphoria that is initially relieved but ultimately unresponsive to antidepressant medication. The incidence or predisposing risk factors are as yet unknown. The potential existence of this phenomenon raises questions as to the current practice recommendations of chronic antidepressant treatment in the setting of a recurrent major depressive illness. Initial investigations of TDp would comprise blinded, randomized antidepressant discontinuation/continuation trials in TRD patients, over at least one year. One would expect that some individuals who discontinue the antidepressant will remain depressed, and that duration of prior antidepressant exposure (briefer) and subject age (younger) would be major predictors of improvement with antidepressant discontinuation. Until such studies are performed the treatment recommendations must remain unchanged, but trials of antidepressant taper and discontinuation for six to 12 months in patients who have failed most other options appear reasonable.
Declaration of Interest: Dr. El-Mallakh has received research support from Forest Pharmaceuticals, Shire; and Bristol Myers Squibb, has received honoraria from Abbott, Astra-Zeneca, Bristol-Myers-Squibb, Glaxo, and Lilly. Dr. Swann has received research support from Myriad pharmaceuticals, PPD Development, and Pfizer Labs; has been a consultant for Abbott and Sanofi Aventis; and has received honoraria from: Abbott, Astra Zeneca, Eli Lilly, Glaxo, Pfizer, and Sanofi Aventis. Drs. Roberts and Surja do not have any disclosures.
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63. Durham LK, Webb SM, Milos PM, Clary CM, Seymour AB. The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorderNext and last article:
Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehyTardive dysphoria: The role of long term antidepressant use in-inducing
3 chronic depression4 Rif S. El-Mallakh ?, Yonglin Gao, R. Jeannie Roberts
5 Mood Disorders Research Program, The University of Louisville Depression Center, Department of Psychiatry and Behavioral Sciences,
6 University of Louisville School of Medicine, Louisville, KY, USA11 Article history:
12 Received 30 May 2010
13 Accepted 12 January 2011
1145 Available online xxxxa b s t r a c t
Background: Treatment-resistant and chronic depression appear to be increasing. The recent identifica- 17
tion of antidepressant tachyphylaxis, the loss of antidepressant efficacy over time, is only a partial expla- 18
nation. This is an emerging evidence that, in some individuals, persistent use of antidepressants may be 19
prodepressant. 20
Methods: A literature search of PubMed utilizing the terms: antidepressant tachyphylaxis, treatment- 21
resistant depression, chronic depression, and antidepressant tolerance was performed, and relevant arti- 22
cles were used. 23
Results: Depressed patients who ultimately become treatment resistant frequently have had a positive 24
initial response to antidepressants and invariably have received these agents for prolonged time periods 25
at high doses. Parallels between this course and tardive dyskinesia are noted. It is proposed that neuro- 26
plastic processes related to dendritic arborization may underlie the treatment resistant depression that 27
occurs in the setting of chronic antidepressant use. Since the prodepressant effect is seen after prolonged 28
antidepressant use, the term tardive dysphoria is proposed. 29
Conclusions: Tardive dysphoria, needs to be considered in studies of treatment resistant depression, and 30
should be examined in blinded, randomized antidepressant discontinuation trials. 3134 Introduction
35 Depressive disorders affect over 6% of Americans and 5% of all
36 humans on the planet [1,2]. It is the number one cause of disabil-
37 ity-adjusted life years in developed countries, and the fourth
38 leading cause of disability worldwide [1,3]. Major depression is
39 usually characterized by chronic recurring depressive episodes,
40 which can be brief (24 weeks) or prolonged (more than 9 months),
41 but average about 79 months [57]. Recurrence risk is high at 50
42 80% [810]. Recurrence is associated with a positive feedback so
43 that with each episode there is an increasing probability of another
44 episode [11,12]. Randomized controlled trials have demonstrated
45 that maintenance antidepressant therapy may reduce relapse in
46 the first year after an acute episode [13,14]. The American Psychiat-
47 ric Association practice guideline and the NIMH collaborative study
group have recommend maintenance therapy for recurrent major 48
depressive illness [15,16]. 49
For many patients recurrence of depressive symptoms may oc- 50
cur despite ongoing antidepressant treatment [17]. When optimi- 51
zation of treatment fails, such patients are noted to have 52
treatment-resistant depression (TRD). TRD may comprise 3050% 53
of people with major depressive illness [17,18]. The cause of TRD 54
is unknown, but its prevalence appears to be increasing. In 2006, a 55
meta-analysis reported that nearly 40% of depressed patients had 56
TRD [19]. However, in the early 1990s it was reported that only 57
1015% of patients had TRD [20]. If this latter observation is true, 58
it would suggest a dynamic process. For example, fragmentation 59
of nuclear and extended families, economic or life style stressors, 60
or even changes in dietary habits may be conspiring to increase 61
the prevalence of depression and its resistance to somatic treat- 62
ment. Additionally, the biological course of major depression itself 63
may be changing due to a multitude of biologic and genetic factors, 64
as may be occurring in bipolar illness [21]. Alternatively, the loss of 65
efficacy of the antidepressant may be related to clinical issues such 66
as inadequate dosing of antidepressants [22] or antidepressant 67
tolerance [23]. There are reasons to believe that antidepressant 68
treatment itself may contribute to a chronic depressive syndrome 69
[24,25]. 70
0306-9877/$ - see front matter 2011 Published by Elsevier Ltd.
doi:10.1016/j.mehy.2011.01.020q Financial support: No extramural support was provided for this work.
? Corresponding author. Address: Mood Disorders Research Program, 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 address: rselma01@louisville.edu (R.S. El-Mallakh).
Q1
Medical Hypotheses xxx (2011) xxxxxx
Contents lists available at ScienceDirect
Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy
YMEHY 6083 No. of Pages 6, Model 5G
24 January 2011
Please cite this article in press as: El-Mallakh RS et al. Tardive dysphoria: The role of long term antidepressant use in-inducing chronic depression. Med Hypotheses (2011), doi:10.1016/j.mehy.2011.01.020
71 Tachyphylaxis
72 Tachyphylaxis (also known as antidepressant tolerance, antide-
73 pressant poop-out, or breakthrough depression) is a condition
74 in which patients experience a good initial antidepressant re-
75 sponse which is lost over time with repeated or prolonged antide-
76 pressant treatment [23,2628]. This phenomenon is distinct from
77 an initial non-response or a partial response. Up to 80% of patients
78 diagnosed with major depressive disorder will experience a recur-
79 rence of depressive episode despite constant maintenance dose of
80 an antidepressant [12,23,29,30]. Attempts to treat these individu-
81 als frequently result in poor response and the rise of TRD [30].
82 Serotonin reuptake inhibiting (SRIs) antidepressants were intro-
83 duced in 1988. They had obvious advantages over previous tricyclic
84 (TCA) or monoamine oxidase inhibiting (MAOI) agents regarding
85 safety and tolerability, and a dramatic increase in antidepressant
86 prescriptions ensued. More recently, there have been several re-
87 ports of the loss of antidepressant efficacy. For example, Solomon
88 et al. [29] found that relapse occurred in 25% of 171 episodes. A
89 long-term placebo-controlled, blinded maintenance study of fluox-
90 etine in major depression, found no difference after 62 weeks in
91 subjects who were still euthymic on fluoxetine (11%) or placebo
92 (16%) [31]. Fifteen patients who had lost their response to antide-
93 pressants failed multiple treatment strategies including augmenta-
94 tion with mood stabilizers and, in some cases, electroconvulsive
95 therapy (ECT) [32]. When antidepressants were discontinued and
96 patients were left on mood stabilizers only, they improved even
97 though most (73%) had unipolar depression [32]. Similarly, in a
98 small case series of 11 TRD cases, none of the patients had a lasting
99 response to different classes of antidepressants [26].
100 Once initial treatment response is lost, subsequent improve-
101 ment is unlikely. If patients with TRD respond to a subsequent
102 antidepressant, the extent of improvement is inferior to the initial
103 response [33]. Patients who lost response to a MAOI not only did
104 not respond to subsequent treatment, but reported greater extent
105 of depression after relapse than before the new treatment was ini-
106 tiated [34,35].
107 Antidepressant-induced depression
108 The possibility of antidepressant-induced depression was intro-
109 duced by Fava [36]. He suggested that a neurobiochemical mecha-
110 nism increasing vulnerability to depression might play a role in
111 this phenomenon and contribute to the observed worsening
112 long-term outcome of major depression [24]. Other authors have
113 also introduced similar ideas [25,37].
114 Several studies support these assertions. Van Scheyen [38]
115 naturalistically followed 84 depressed adults and found that long
116 term treatment with TCAs increased the likelihood of a depressive
117 recurrence. Long term treatment with imipramine is associated
118 with worsening mood in mildly depressed patients [39]. Anxious
119 patients without a history of a mood disorder may develop depres-
120 sion after long-term treatment with antidepressants for their anx-
121 iety disorder [40,41]. In a recent study 27% of patients without any
122 history of a mood disorder who had received antidepressants for
123 an average of 29 months for panic disorder, developed a cyclothy-
124 mic illness that persisted for 1 year after antidepressant discontin-
125 uation [42]. Normal controls receiving antidepressants in research
126 studies were reported to experience depression [43].
127 These effects may be analogous to the observations that antide-
128 pressant treatment in bipolar disorder could destabilize the illness
129 [44]. An antidepressant-associated chronic irritable depressive
130 (ACID) state has been reported in bipolar and bipolar spectrum pa-
131 tients given long-term antidepressants [45,46]. In some of these
132 patients antidepressant discontinuation was associated with slow
and gradual improvement of the depressive symptoms. In a ran- 133
dom assignment study, antidepressant continuation in rapid cy- 134
cling bipolar subjects who achieved remission with initial 135
antidepressant treatment tripled the likelihood of a future depres- 136
sion compared to patients who discontinued the antidepressant 137
over the subsequent year of treatment [47]. 138
Sharma [25] speculated that a prodepressant effect of antide- 139
pressants may occur because continued drug treatment may in- 140
duce processes that are the opposite of what the medication 141
originally produced. He believed this process may even cause a 142
worsening of the illness, continue for a period of time after discon- 143
tinuation of the medication, and may not be reversible [24]. The 144
field of psychiatry is familiar with such a process in the case of tar- 145
dive dyskinesia. 146
Tardive dyskinesia (TD) 147
Tardive dyskinesia (TD) is a hyperkinetic condition that is char- 148
acterized by abnormal involuntary, repetitive, purposeless move- 149
ments that develop in individuals with long-term exposure to 150
potent dopamine 2 (D2) receptor antagonists. The symptoms 151
include tongue protrusion, grimacing, rapid eye blinking, lip smack- 152
ing, pursing, or puckering, choreaform movement of the extremi- 153
ties, as well as other involuntary movements of the head, face, 154
neck and tongue muscles. Movements may be rapid or slow and 155
complicated [48]. They are usually irregular and do not followa pat- 156
tern. This irreversible or slowly reversible neurological disorder typ- 157
ically develops after long-term exposure to antipsychotic 158
medications [49]. Any medication that causes blockade of the D2 159
receptor can theoretically cause TD. More potent D2 antagonism 160
with antipsychotics such as haloperidol or fluphenazine, increase 161
the risk of TD. In general the risk of developing TD is approximately 162
5% per year of exposure to potent D2 blocking agent [50] and ulti- 163
mately affects 1530% of patients on long-term first generation 164
antipsychotics [48]. The risk is higher in the elderly and female pa- 165
tients [51] and doubles if the patient experiences early extrapyrami- 166
dal parkinsonism[52]. There is no specific treatment for TD [53], but 167
withdrawal of the antipsychotic will prevent worsening, and may 168
allow improvement or remission of symptoms over time. Acutely, 169
antipsychotics themselves are effective treatment for TD, tran- 170
siently masking the symptoms, but long-term use may worsen the 171
symptoms. Thus, themost common treatment of tardive dyskinesia 172
is to stop the offending drugs. One third of TD patients remit within 173
3 months of discontinuing the antipsychotic; another one-sixth re- 174
mitwithin 18 months, leaving 50% with continuing symptoms [54], 175
although in some cases, TD may continue to improve over time. 176
It is important to note that early parkinsonismincreases the risk 177
of subsequent TD [53]. Parkinsonism is a bradykinetic movement 178
disorder, while TD is a hyperkinetic disorder. In line with Favas 179
oppositional model, the chronic consequence is the opposite of 180
the acute manifestation. 181
Different explanations have been put forward to explain TD. 182
Most models propose that there is excessive dopaminergic activity. 183
They may occur through D2 receptor supersensitivity, neurochem- 184
ical imbalance with different neurotransmitter systems; neurolep- 185
tic-induced striatal pathological changes; or toxic free radicals 186
that damage neurons and result in persistent anatomical changes 187
[54]. For example, acute administration of haloperidol has been 188
shown to cause an increase in activity of the A9 DA neurons [55] 189
but chronic administration resulted in a significant decrease in 190
activity of these same neurons [56]. However, the time course of 191
TD slow onset after months or years of antipsychotic exposure, 192
and slow resolution after antipsychotic discontinuation, and the 193
increased relative permanence in the elderly [57], strongly sug- 194
gests neuroplastic changes may underlie this disorder. 195
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196 Meshul and Casey [58] have studied the effects of haloperidol
197 on synapses in the caudate, nucleus accumbens and medial pre-
198 frontal cortex. They have shown a change in the postsynaptic den-
199 sities within the caudate nucleus in rats. This structural change
200 involved the increase of the number of perforated synapses. The
201 change is evident following 2 weeks of treatment with haloperidol
202 and returned to baseline after 2 weeks off the medication. In other
203 words, actual anatomical changes took place in the dopamine sys-
204 tem in response to long-term haloperidol administration.
205 Tardive dysphoria (TDp)
206 It is proposed that tardive dysphoria (TDp) is an abnormal dys-
207 phoric state that develops in some predisposed individuals with
208 prolonged antidepressant treatment. Patients with this syndrome
209 may comprise a significant fraction of TRD subjects. TDp is defined
210 as a chronic, frequently treatment resistant, depressive state with
211 onset in the setting of ongoing, persistent antidepressant treat-
212 ment. Antidepressants may be initially administered for any reason
213 (e.g., anxiety or depression), but afflicted subjects with a history of
214 a recurrent major depressive disorder would have historically
215 experienced an initial positive response to antidepressant medica-
216 tion (generally with their first exposure). The depressive state is
217 perpetuated (and possibly worsened) by continuing the antide-
218 pressant. It is believed that SRI antidepressants might be selec-
219 tively associated with the development of TDp. Discontinuation
220 of the antidepressant results in a slow and gradual improvement
221 of the chronic depressive symptoms. However, in some individuals
222 who have experienced TDp for a very prolonged period of time, dis-
223 continuation of antidepressant may not result in reversal of the
224 symptoms. This is superficially similar to TD. Subjects who ulti-
225 mately develop TDp will have frequently had an initial positive re-
226 sponse to antidepressants, helping to cement adherence.
227 Depression recurs in 957%, or perhaps as high as 93% in the effec-
228 tiveness trial STAR D (relapse and dropout of study) [59], of pa-
229 tients despite ongoing antidepressant treatment [23]. In such
230 patients, an increase in dose [60,61], change to another antidepres-
231 sant agent [62,63] or adding another antidepressant [64,65] may
232 be effective in 3060% of patients. However, there is evidence that
233 switch may not be helpful [66], and if patients do respond relapse
234 occurs within 6 months in some 20% [61]. Ultimately, 3050% of
235 such patients will develop TRD [17,18]. In the subset of such pa-
236 tients who have developed TDp, ongoing attempts to treat the
237 depression with antidepressants perpetuate the TRD, and may ulti-
238 mately make the chronic depression permanent.
239 TDp is different from conditioned tolerance [67] in that it is not
240 merely the loss of the drug effect, but viewed as an active process in
241 which a depressive picture is caused by continued administration of
242 the antidepressant. In conditioned tolerance, environmental and
243 behavioral conditional compensatory responses mediate tolerance
244 by in the presence of cues usually associated with the drug [67].
245 Serotonin transporter polymorphism
246 A genetic polymorphism has been identified in which the pro-
247 moter region of the serotonin transporter gene has a 44 base inser-
248 tion or deletion [68,69]. The deletion variation is generally labeled
249 the short form or s form of the serotonin transporter and is asso-
250 ciated with roughly a 50% reduction in the number of serotonin
251 transporter units in the membrane [70]. Subjects with this variant
252 are at a greater risk of experiencing a major depressive illness in
253 the setting of adversity [7173]. Additionally, when these individ-
254 uals are treated with an SRI antidepressant, they are either less
255 likely to respond or have delayed response [7477].
It is not known how this increased risk for depression comes 256
about, but neuroplastic changes may play a role. It is known that 257
modification of serotonergic neurotransmission alters arborization 258
of the dendritic tree of serotonergic neurons [78,79]. Mice that lack 259
the serotonin transporter have fewer serotonergic neurons and re- 260
duced serotoninergic function and express more behaviors associ- 261
ated with anxiety and depression [80]. This phenotype can be 262
mimicked by treatment of normal mice with the SRI fluoxetine in 263
early life. New born mouse pups given fluoxetine for only 1 week 264
express anxiety symptoms as adults [81]. 265
The reduction in the number of synaptic serotonin transporters 266
associated with the short form of the serotonin transporter is very 267
similar to the chronic 6085% blockade of these transporters that 268
occurs with SRI treatment [82,83]. This suggests that the s allele 269
might serve as a model for chronic exposure to an SRI antidepres- 270
sant, particularlywhen administered to young individuals. In young 271
animals, reducing or eliminating serotonin transporter function 272
causes changes in serotoninergic architecture and function and 273
associated increased depressive and anxious behaviors [81,84]. 274
Similar experiments have not been performed in adult animals 275
whose brains are less plastic and have already completed develop- 276
ment. Nonetheless, it would seem likely that chronic treatment 277
with an SRI in adults might result in neuroplastic changes in the 278
serotonin system similar to those seen in the animal experiments. 279
These changes may underlie the observation that tryptophan 280
depletion experiments are much more likely to induce depression, 281
or induce a more severe depression, if the subjects have been tak- 282
ing serotonin reuptake inhibiting drugs [85]. In this case the con- 283
traction of the serotoninergic system removes the reserve, so 284
that depletion is much more likely to cause depression. 285
In humans, chronic exposure to antidepressants might induce 286
neuroplastic changes in the serotonin system similar to those that 287
occur in early development of subjects possessing the short form. 288
This effect might be more pronounced if the antidepressant expo- 289
sure occurred when the brain was more plastic (e.g., younger age), 290
or if the individual already has reduced serotonin transporter func- 291
tion due to a genetic variant such as the short for of the serotonin 292
transporter. These groups might be considered particularly high 293
risk for the development of TDp. 294
Summary 295
A chronic and treatment-resistant depressive state is proposed 296
to occur in individuals who are exposed to potent antagonists of 297
serotonin reuptake pumps for prolonged time periods. Due to the 298
delay in the onset of this chronic depressive state, it is labeled tar- 299
dive dysphoria (TDp). TDp manifests as a chronic dysphoric state 300
that is initially transiently relieved by but ultimately becomes 301
unresponsive to antidepressant medication. Serotoninergic anti- 302
depressants may be of particular importance in the development of 303
TDp. The incidence or predisposing risk factors are as yet unknown, 304
but younger age at onset of antidepressant exposure and genetic 305
underexpression of the serotonin transporter, such as with the 306
short form of the serotonin transporter, may increase the risk of 307
TDp. Investigations attempting to discern the existence of TDp 308
would comprise blinded, randomized antidepressant discontinua- 309
tion/continuation trials in TRD patients, over at least 1 year. As 310
with TD, one would expect that some individuals who discontinue 311
the antidepressant will remain depressed. Subjects more likely to 312
benefit from antidepressant discontinuation would be those who 313
have had a briefer prior exposure to antidepressants, have more 314
neuroplastic potential (e.g., younger and without chronic medical 315
illnesses), and have the long form of the serotonin transporter. Un- 316
til such studies are performed the treatment recommendations 317
must remain unchanged, but clinical trials of antidepressant taper 318
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Please cite this article in press as: El-Mallakh RS et al. Tardive dysphoria: The role of long term antidepressant use in-inducing chronic depression. Med
Hypotheses (2011), doi:10.1016/j.mehy.2011.01.020
319 and discontinuation for 612 months in patients who have failed
320 most other options appear reasonable.
321 Conflict of interest statement
322 This work did not receive extramural support. Dr. El-Mallakh
323 has received research support from Forest Pharmaceuticals, Shire;
324 and Bristol Myers Squibb, and speakers honoraria from Abbott,
325 Astra-Zeneca, Bristol-Myers-Squibb, Glaxo, and Lilly. Drs. Roberts
326 and Gao do not have any disclosures.
327 Uncited reference
328 [4].
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functional changes in the dorsal raphe nucleus of serotonin transporter- 541
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transporter alters emotional behavior in adult mice. Science 544
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[82] Voineskos AN, Wilson AA, Boovariwala A, et al. Serotonin transporter 546
occupancy of high-dose selective serotonin reuptake inhibitors during major 547
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[83] Meyer JH, Wilson AA, Sagrati S, et al. Serotonin transporter occupancy of five 550
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Posted by SLS on May 12, 2011, at 6:23:54
In reply to TDp Journal Article #2 + #3, posted by floatingbridge on May 12, 2011, at 3:04:15
I had thought of this possibility over ten years ago. Intuitively, it made sense to me, but I could not put the pieces of the puzzle together with facts or statistics. I abandoned the idea, having found no support for it in the literature. I did not think of it as being dysphoria, though, but, rather, a change in the trajectory of the original illness. At this point, I would not refute the idea that there is an induction by antidepressants of a dysphoria separate from the depressive illness.
One thing to take into consideration is that a depressive illness can become more robust over time if left untreated. I think this might be inflating the statistical rate of the appearance of a tardive depressive syndrome resulting from extended antidepressant treatment.
Perhaps there is a way to discourage the hypothesized induction of tardive dysphoria using other pharmacological agents. It will be interesting to see if vilazodone (Viibryd), a serotonin reuptake inhibitor and 5-HT1a receptor agonist, possesses a reduced risk of a dysphoric reaction. If 5-HT1a stimulation does not prevent tardive dysphoria, perhaps to attack it from the other angle using pindolol as a 5-HT1a autoreceptor antagonist might work. I need to think about these two opposing effects on neurotransmission more to be able to predict which of the two angles makes more sense.
Linkadge?
- Scott
Posted by Phillipa on May 12, 2011, at 11:32:17
In reply to TDp Journal Article #2 + #3, posted by floatingbridge on May 12, 2011, at 3:04:15
How do you relate this to you will you continue with emsam or discontinue ad's to attempt to heal your brain? Phillipa
Posted by floatingbridge on May 12, 2011, at 11:39:23
In reply to Re: TDp Journal Article #2 + #3 » floatingbridge, posted by Phillipa on May 12, 2011, at 11:32:17
Well, the unedited version in my head reads like what cartoon characters say in thought bubbles when cursing.
The edited version is that I'm rereading the articles because I barely understand them and refrain from any action.
The researchers suggested I be tested for the genetic factor in question, but I haven't looked into that. So, it takes the wind out of my sails a bit, but that happens to me all the time regardless.
I'm incredibly curious about what others make of all this.
fb
Posted by Phillipa on May 12, 2011, at 13:13:45
In reply to Re: TDp Journal Article #2 + #3 » Phillipa, posted by floatingbridge on May 12, 2011, at 11:39:23
I am too as now I feel I should just get off ad's asap? If panic anxiety were my problems why am I on an ad? Boredom? That doesn't cut it to me. To dull the emothions so things don't bother you means a way of hiding like an ostrich to me. I don't want to be an ostrich. That much I know. Phillipa
Posted by floatingbridge on May 12, 2011, at 13:32:09
In reply to Re: TDp Journal Article #2 + #3 » floatingbridge, posted by SLS on May 12, 2011, at 6:23:54
Scott, you might imagine that I'm still trying to work through the science part. This article is timely because I had independently concluded that snri's somehow made me worse. And dysphoric was becoming like a middle name. Those bouts really have lessened, yet depression itself returned both mentally and physically. I think the authors (and I) would agree that
depressive illnesses have their own course, indeed very often and unfortunately worsening over time. So abstinence from treatment is not a desirable option for me. Hence looking at other agents is wise and proactive.In my own situation, I'm hoping that the emsam (segeline) with some track record of neuroprotection is a wise enough choice.
And a question then, (given the lack of a
fuller comprehension): would the scatter-shot less selective maoi's be seen as more acceptable and perhaps have longer efficacy than a more selective yet also perhaps more idiosyncratic agent?And, can people actually be genetically tested? I mean regular people, not millionaires or test subjects.
fb
(The questions aren't just for you Scott, but meant for discussion.)
Posted by floatingbridge on May 12, 2011, at 14:10:02
In reply to Re: TDp Journal Article #2 + #3 » floatingbridge, posted by Phillipa on May 12, 2011, at 13:13:45
Phillipa, I might curse like a sailor in my head, but I'm not panicking. I hope these articles are helpful and somehow affirming. Many of us have asked, suspected, know that depression treatments are very imperfect.
After my initial deflation of attitude, I think that researchers are asking these questions is fabulous. Once again, it shows to me that 'it's not all in my head'.
I never want to sound an alarm. I dislike being alarmed. More, I print this here because a poster, Bob brought it up first. Then it just showed up in my mailbox. I subscribe to a forward thinking medical research journal--well, subscribe to the abstracts.
My own pdoc may find this all very sobering, of course. He's a good guy and uses psychiatry to truly help. I wonder what he will make of this.
Posted by Phillipa on May 12, 2011, at 20:16:26
In reply to Re: TDp Journal Article #2 + #3 » Phillipa, posted by floatingbridge on May 12, 2011, at 14:10:02
FB don't understand it myself. Do you feel the pdoc will read it and respond to you in a productive mannor? Love Phillipa
Posted by floatingbridge on May 12, 2011, at 22:19:29
In reply to Re: TDp Journal Article #2 + #3 » floatingbridge, posted by Phillipa on May 12, 2011, at 20:16:26
There isn't much to be down as I reckon.
He did tell me that word is a rTMS center is planned for our town. Then to get insurance to cover.
I don't know. The reseachers mention that their hypothesis will be painful for many to consider. My pdoc is older. I suspect he feels medicine is a noble profession. He believes in the efficacy of his work. Now, the articles are merely hypothesises. Babies don't have to go out with the bathwater. Yes?
Posted by Bob on May 14, 2011, at 0:11:59
In reply to Re: TDp Journal Article #2 + #3 » floatingbridge, posted by SLS on May 12, 2011, at 6:23:54
>
> Perhaps there is a way to discourage the hypothesized induction of tardive dysphoria using other pharmacological agents. It will be interesting to see if vilazodone (Viibryd), a serotonin reuptake inhibitor and 5-HT1a receptor agonist, possesses a reduced risk of a dysphoric reaction. If 5-HT1a stimulation does not prevent tardive dysphoria, perhaps to attack it from the other angle using pindolol as a 5-HT1a autoreceptor antagonist might work. I need to think about these two opposing effects on neurotransmission more to be able to predict which of the two angles makes more sense.
>
>
> - Scott
Got a nasty migraine yesterday so I reached for the old trusty Axert (almotriptan). Got curious after I saw this post about drugs that affect serotonin receptor subtypes so I looked up the Axert info and discovered that it is a "potent 5-HT1B/1D serotonin agonist". I guess this class of headache drugs don't have beneficial mood effects or I probably would have heard about it by now.Bob
Posted by SLS on May 14, 2011, at 5:29:18
In reply to Re: TDp Journal Article #2 + #3 » SLS, posted by Bob on May 14, 2011, at 0:11:59
> >
> > Perhaps there is a way to discourage the hypothesized induction of tardive dysphoria using other pharmacological agents. It will be interesting to see if vilazodone (Viibryd), a serotonin reuptake inhibitor and 5-HT1a receptor agonist, possesses a reduced risk of a dysphoric reaction. If 5-HT1a stimulation does not prevent tardive dysphoria, perhaps to attack it from the other angle using pindolol as a 5-HT1a autoreceptor antagonist might work. I need to think about these two opposing effects on neurotransmission more to be able to predict which of the two angles makes more sense.
> >
> >
> > - Scott
>
>
>
>
> Got a nasty migraine yesterday so I reached for the old trusty Axert (almotriptan). Got curious after I saw this post about drugs that affect serotonin receptor subtypes so I looked up the Axert info and discovered that it is a "potent 5-HT1B/1D serotonin agonist". I guess this class of headache drugs don't have beneficial mood effects or I probably would have heard about it by now.
I'm afraid that I don't know much about those serotonin receptors. Currently, I don't know of any antidepressant that works on them. However, lithium does target the 5-HT1b receptor, and thus modulates the serotonin system.Linkadge is the best resource for describing the properties of various receptors.
- Scott
Posted by hyperfocus on May 15, 2011, at 17:56:25
In reply to TDp Journal Article #2 + #3, posted by floatingbridge on May 12, 2011, at 3:04:15
I think it could be a possible genuine condition. But our understanding of mental illness is so imperfect and muddled that I'm wont to commit to yet another new label. Even the methodology of studes, as I've written, I find to be completely wrong. Many people who are put on ADs don't need to be and shouldn't because it can make them worse. Especially if you have attendent physical concerns and chronic physical pain like fibro. Many people diagnosed with major depression have co-morbid issues that can worsen with conventional AD treatment. For me personally I struggled to find a theraputic AD response until I started the amitriptyline which has shown to be effective in disssociation and PTSD, ditto risperdal and tianeptine. If I had been in those studies I might have been labelled with TDp. It would be hard for any psych doctor to distinguish the symptoms of chronic dissociation from depression. Certainly I've had prolonged dysphoria and I do feel better sometimes when I stop the drug I'm on, but is this a result of serotonigic drugs or just a completely flawed understanding of what mental illness is? I'd vote the latter. I don't believe we know enough about it currently to be making more labels.
Posted by floatingbridge on May 17, 2011, at 10:05:25
In reply to Re: TDp Journal Article #2 + #3, posted by hyperfocus on May 15, 2011, at 17:56:25
I agree that we don't need more labels, especially alarming ones. I apologize about the thread title. It was an abbreviation of the journal titles.
What interests me most is that, whatever it may be called, some people's distress intensifies during their treatment with some selective agents. For some, this may be seperate from the noted
tendency of depressive illnesses to progress. It's a phenomena patients themselves could sense, but it can be difficult to explain to one's self, let alone a doctor. Especially a doctor who is locked into ssri's/snri's because they are 'the more advanced' (therefore superior) treatments. That doctors are more
widely advised is very important. Not all patients can, in their worst times, advocate for themselves.This could be very important to the treatment of the BPll and nos populations particularly.
I thank these researchers for studying a
commonly observed phenomena and attempting to further a dialogue within the psychiatric community. I think it takes a little hutzpah to publish a paper that offers no solutions and questions the safety of a deeply invested common practice. Yes, the name they coined does scare the pants off patients. I should have caught on sooner. My apologies for that.fb
Posted by floatingbridge on July 25, 2011, at 14:55:08
In reply to TDp Journal Article #2 + #3, posted by floatingbridge on May 12, 2011, at 3:04:15
I am represnting this author's proof for any self-interest and education. I make no claims to hold any opinion or forward any agenda other than self-education and a neutral ability to look at any evidence presented even if it proves ultimately false. I believe above all in neuroplastcity and an individuals's innate will to health. The main author of this article offered me no advice other than to have the 's alle?' checked to even see if I had a chance of fitting into a responder category
To our health! If anyone comments or can elucidate, I'll happily follow the discussion in a quiet fashion, science not being my greatest strength.
fb
> Mood Disorders Research Program
> 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
>
>Tardive dysphoria: antidepressant-induced chronic depression.
>
> Rif S. El-Mallakh, R. Jeannie Roberts, Alan Swann, Anton Surja
>ABSRTACT:
Objectives: A significant fraction of depressed individuals
experience inadequate benefit from long-term antidepressant
use. This paper investigates the hypothesis that in some individuals persistent use of antidepressants may be prodepressant.Methods: Literature regarding the effect of long-term use of
antidepressants was reviewed by searching PubMed and Ovid data bases with terms: antidepressant tachyphylaxis, treatment-resistant depression, chronic depression, and antidepressant tolerance.Results: Antidepressant treatment-resistant patients
frequently had a positive initial response to antidepressants. When resistance appeared, initial increases in dose or medication changes usually resulted in transient improvement. Eventually, the episodic course of the original depressive illness was replaced with a continuous, unresponsive depressive syndrome. We propose the term
tardive dysphoria to describe this phenomenon.Conclusions: The phenomenon of antidepressant-induced depression, or tardive dysphoria, needs to be experimentally examined in blinded, randomized antidepressant
discontinuation studies.Key words: Antidepressants, Antidepressant adverse effect, Chronic Depression, Major Depressive Disorder,
Tachyphylaxis, Tardive Dysphoria.INTRODUCTION:
Major depressive disorders affect more than 18 million people in the United States and 340 million people worldwide.1,2 It is the number one cause of disability-adjusted life years in developed countries, making it to be the fourth leading cause of disability worldwide.1,3 It has huge
financial and social burdens. The economic impact of treatment resistant depression is even greater, with up to$28,000 inpatient and $3700 outpatient per year in America.4 This illness is usually characterised by chronic recurring
depressive episodes. The episode may be brief (two to four weeks) or prolonged (more than nine months), but without treatment generally last about seven to nine months.5-7 The
recurrence rate of unipolar depression ranges from 50-80%.8-10 With each episode, there is an increasing probability of another episode.11,12 Numerous randomised controlled trials have demonstrated the usefulness of maintenance therapy for the first year after an acute episode.13,14 For this reason,The American Psychiatric Association practice guideline and The NIMH collaborative study group have suggested that
maintenance therapy after recovery is needed in the setting of a recurrent major depressive illness.15,16However, for many patients, initial response may be suboptimal,17 and recurrence of depressive symptoms may occur despite ongoing and optimized antidepressant treatment.18 These patients with treatment resistant depression (TRD) may comprise up to 30% to 50% of people
with major depressive illness.18,19The cause of TRD is unknown, but its prevalence appears to be increasing; a recent meta-analysis found TRD to be a problem in nearly 40% of depressed patients, while in the early 1990s it was reported to affect 10-15% of patients.20,21 If this latter observation is accurate, it would suggest a dynamic process that may be related to environmental,
biologic, or clinical factors. For example, changes in social
support, fragmentation of nuclear and extended families, or
economic or other stressors, may be conspiring to increase the prevalence of depression and its resistance to somatic treatment. The course of major depression itself may be changing due to a multitude of biologic and genetic factors, comparable to those in bipolar illness.22 Alternatively, the loss of efficacy of the antidepressant may be related to
clinical issues such as inadequate dosing of antidepressants23 or other problems like antidepressant tolerance.24 However, there are reasons to believe that antidepressant treatment itself may contribute to a chronic
depressive syndrome.25,26 We will review mechanisms by which this could occur.Tachyphylaxis
Several authors have described the phenomenon of tachyphylaxis (also known as antidepressant tolerance, antidepressant poop-out, or breakthrough depression).24,27-
29 These patients experience a good initial antidepressant
response that is lost over time with repeated or continuous antidepressant administration. This phenomenon differs from patients who only have partial response or those who never had a good response to antidepressant treatment. Although the frequency of antidepressant tachyphylaxis is still unclear, up to 80% of patients diagnosed with major depressive
disorder will experience a recurrence of depressive episode
despite constant maintenance dose of an antidepressant.12,24,30,31 Attempts to treat these individuals frequently result in poor response.31The introduction of serotonin reuptake inhibitors (SRIs) in 1988 ushered in a dramatic increase in antidepressant prescriptions. The advantages of this new class of antidepressant (SRI) over the older generation antidepressants such as tricyclics (TCAs) or monoamine
oxidase inhibitors (MAOIs) were immediately apparent especially in terms of safety and tolerability. However, subsequent anecdotal and uncontrolled reports of the loss of
SRI efficacy emerged after the initial resolution of a major depressive episode.32,33 Loss of antidepressant efficacy has been noted in large studies. In a prospective study, Solomon et al30 found that relapse occurred in 25% of 171 episodes. In a long-term placebo-controlled, blinded maintenance study
of fluoxetine in major depression, there was no difference after 62 weeks in subjects who were still euthymic on
fluoxetine (11%) or placebo (16%).34 Sharma35 studied 15
patients who had lost response to antidepressants. These patients had failed multiple treatment strategies including augmentation with mood stabilizers and, in some cases, electroconvulsive therapy (ECT). Eleven of his patients had unipolar depression and four had bipolar depression. When antidepressants were discontinued and patients were left on
mood stabilizers only, they improved - even those who were
diagnosed with unipolar depression.35 Similarly, in a case
series of 11 TRD cases, none of the patients had a lasting response to different classes of antidepressants.27Once initial treatment response is lost, improvement can be elusive. In a two-year prospective study of the naturalistic outcomes of 124 patients with TRD (109 with major
depression and 15 with bipolar), only 18.4% responded and 7.8% achieved remission with treatment as usual despite
appropriate medication management.36 Patients with TRD who had lost efficacy with an antidepressant might respond to
a subsequent exposure, although not always to the extent of the initial response.37 In case reports related to MAOI treatment, patients not only did not respond to subsequent treatment, but also were reported to be more depressed after
relapse than they had been before treatment was initiated.38,39Antidepressant-induced depression:
Giovanni Fava first described the possibility of antidepressant-induced depression in 1994.40 He suggested that antidepressant drug treatment may not be simply a matter of failure to protect against future episodes, but that a neurobiochemical mechanism increasing vulnerability to depression might play a role in this phenomenon and worsen
the long-term outcome of the illness.25 El-Mallakh and collegue Sharma subsequently echoed the same hypothesis. Such a process would be expected to decrease subsequent response to treatment and reduce the length of illness-free periods.These assertions are supported by several lines of evidence. In the early days of antidepressant availability, Van
Scheyen42 naturalistically followed 84 depressed adults and
found that long term treatment with tricyclic antidepressants increased the likelihood of a depressive recurrence. Mildly depressed patients may actually worsen over time when treated with imipramine.43 Anxious patients who do not have a history of a mood disorder may develop depression after
treatment with antidepressants for their anxiety disorder.44,45
A recent study found that 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 cyclothymic illness that persisted for one year after antidepressant discontinuation.46 Normal controls receiving antidepressants in research studies were reported to experience depression.47These effects may be analogous to the observations that antidepressant treatment in bipolar disorder could lead to an increase in manic and depressive episodes.48 An antidepressant-associated chronic irritable depressive (ACID)
state has been reported in bipolar and bipolar spectrum patients given long-term antidepressants.49,50 In a case series, we have previously reported that subjects who
experience ACID typically had a good initial response to
antidepressant treatment. Over time, with ongoing antidepressant use, depressive symptoms would return and improve transiently with dose increase or change of agents,
but would ultimately become resistant to antidepressants. However, slow and gradual improvement in depressive symptoms occurred with the discontinuation of antidepressants.Fava 25 speculated that a prodepressant effect of
antidepressants may occur by an oppositional model of
tolerance in which continued drug treatment may induce processes that are the opposite of what the medication originally produced. In this case, the use of antidepressants may actually make the illness worse and unresponsive to treatment. He believed this process may even cause a worsening of the illness, continue for a period of time after
discontinuation of the medication, and may not be reversible.25Tardive Dysphoria (TDp)
We propose 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 large fraction of TRD subjects. We specifically define TDp as a chronic treatment resistant depressive state occurring in the setting of ongoing, persistent antidepressant treatment in subjects with a history of a recurrent major depressive disorder who have historically experienced an initial positive response to antidepressant medication (generally with their first exposure). The
depressive state is believed to be perpetuated by the maintenance antidepressant and is treated by removing the antidepressant, initiating slow improvement of symptoms. Subjects who ultimately develop TDp frequently have an initial positive response to antidepressants. This initial
antidepressant effect is frequently powerful enough to
convince both the treating clinician and the patient that
antidepressants are beneficial, and thus cements long-term compliance. As frequently occurs in 9-57% of patients, depression recurs despite ongoing antidepressant treatment.24 An increase in dose,51,52 change to alternate antidepressant agent53,54 or adding another antidepressant55 may frequently be effective in reducing these recurrent depressive symptoms in 30-60% of patients.
However, despite an initial improvement, some 20% may
again relapse within six months.52 Ultimately, 30% to 50%
will develop TRD.18,19 Ongoing attempts to treat the depression with antidepressants perpetuate the TRD, and may ultimately make the chronic depression permanent.One reason for reluctance to investigate TDp more
rigorously is our own reluctance to believe that our treatments may actually be harmful to our patients.40 However, a possible prodepressant effect of long-term antidepressant treatment in major depressive illness is slowly gaining
recognition,25,26,41 and is becoming more frequently
recognised in bipolar illness.48,49 If TDp is a true phenomenon, what mechanisms might underlie it?Serotonin transporter polymorphism:
Some individuals have a genetic polymorphism in which the
promoter region of the serotonin transporter gene has a 44 base insertion or deletion.56,57 The deletion variation is
generally labeled the short form or s form of the serotonin transporter and is associated with a 50% reduction in the number of serotonin transporter units expressed in the membrane.58 Subjects with this variant are at a greater risk of experiencing a major depressive illness in the setting of
environmental adversity.59-61 Furthermore, when these
individuals are treated with an SRI antidepressant, they are either less likely to respond or have delayed response.62-65It is not clear how this increased risk for depression comes
about, but neuroplastic changes may be important. Modification of serotonergic neurotransmission will alter
arborization of the dendritic tree of serotonergic neurons.66,67 Specifically, mice that lack the serotonin transporter have fewer serotonergic neurons and reduced serotoninergic function and express more behaviors
associated with anxiety and depression.68 Furthermore, treatment of normal mice with the SRI fluoxetine in early life mimicked the behavioral phenotype of mice made genetically
deficient for the serotonin transporter.69A reduction in the number of synaptic serotonin transporters is very similar to the chronic 60-85% blockade of these transporters with SRIs.70,71 This raises the question as to
whether possession of the s allele might serve as a model for
chronic exposure to an SRI antidepressant. Reducing or eliminating serotonin transporter function in youngSummary:
TDp is proposed to occur in individuals who are exposed
chronically to potent antagonists of serotonin reuptake pumps. It manifests as a chronic dysphoria that is initially relieved but ultimately unresponsive to antidepressant
medication. The incidence or predisposing risk factors are as yet unknown. The potential existence of this phenomenon raises questions as to the current practice recommendations
of chronic antidepressant treatment in the setting of a
recurrent major depressive illness. Initial investigations of TDp would comprise blinded, randomized antidepressant discontinuation/continuation trials in TRD patients, over at
least one year. One would expect that some individuals who discontinue the antidepressant will remain depressed, and
that duration of prior antidepressant exposure (briefer) and subject age (younger) would be major predictors of improvement with antidepressant discontinuation. Until such studies are performed the treatment recommendations must
remain unchanged, but trials of antidepressant taper and discontinuation for six to 12 months in patients who have failed most other options appear reasonable.Declaration of Interest: Dr. El-Mallakh has received research support from Forest Pharmaceuticals, Shire; and Bristol Myers Squibb, has received honoraria from Abbott, Astra-Zeneca, Bristol-Myers-Squibb, Glaxo, and Lilly. Dr. Swann has received research support from Myriad pharmaceuticals, PPD
Development, and Pfizer Labs; has been a consultant for
Abbott and Sanofi Aventis; and has received honoraria from: Abbott, Astra Zeneca, Eli Lilly, Glaxo, Pfizer, and Sanofi
Aventis. Drs. Roberts and Surja do not have any disclosures.References
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Next and last article:Medical Hypotheses
Tardive dysphoria: The role of long term antidepressant use in
inducing 3 chronic depression.Rif S. El-Mallakh, Yonglin Gao, R. Jeannie Roberts
Disorders Research Program, The University of Louisville Depression Center, Department of Psychiatry and Behavioral
Sciences, 6 University of Louisville School of Medicine,
Louisville, KY, US.Article history: Received 30 May 2010. Accepted 12 January 2011
Introduction
Depressive disorders affect over 6% of Americans and 5% of
all humans on the planet [1,2]. It is the number one cause of disabiliity-adjusted life years in developed countries, and the fourth leading cause of disability worldwide [1,3]. Major depression is usually characterized by chronic recurring depressive episodes, which can be brief (24 weeks) or prolonged (more than 9 months), but average about 79 months [57]. Recurrence risk is high at 50-80% [810]. Recurrence is associated with a positive feedback so that with
each episode there is an increasing probability of another
episode [11,12]. Randomized controlled trials have demonstrated that maintenance antidepressant therapy may reduce relapse in the first year after an acute episode [13,14]. The American Psychiat ric Association practice guideline and the NIMH collaborative study group have recommend maintenance therapy for recurrent major 48 depressive illness [15,16]. For many patients recurrence of depressive symptoms may occur despite ongoing antidepressant treatment [17]. When optimization of treatment fails, such patients are noted to have treatment-resistant depression (TRD). TRD may comprise %53 of people with major depressive illness [17,18]. The cause of TRD is unknown, but its prevalence appears to be increasing. In 2006, ammeta-analysis reported that nearly 40% of depressed patients had TRD [19]. However, in the early 1990s it was reported that only 15% of patients had TRD [20]. If this latter observation is true, it would suggest a dynamic process. For example, fragmentation of nuclear and extended families, economic or
life style stressors, or even changes in dietary habits may be conspiring to increase the prevalence of depression and its resistance to somatic treat. Additionally, the biological course of major depression itself may be changing due to a multitude of biologic and genetic factors,mas may be occurring in bipolar illness [21]. Alternatively, the loss of efficacy of the antidepressant may be related to clinical issues such as 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].2011 Published by Elsevier Ltd. doi:10.1016/j.mehy.2011.01.020
Financial support: No extramural support was provided for this work.
Corresponding author. Address: Mood Disorders Research Program, 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 address: rselma01@louisville.edu (R.S. El-Mallakh).Medical Hypotheses xxx (2011) xxxxxx
Contents lists available at ScienceDirectMedical Hypotheses
journal homepage: www.elsevier.com/locate/mehy
24 January 2011Please cite this article in press as: El-Mallakh RS et al. Tardive dysphoria: The role of long term antidepressant use in-inducing chronic depression. Med Hypotheses (2011),
doi:10.1016/j.mehy.2011.01.020_______________
(some random codas)Tachyphylaxis
Tachyphylaxis (also known as antidepressant tolerance, antidepressant poop-out, or breakthrough depression) is a conditio in which patients experience a good initial antidepressant response which is lost over time with repeated
or prolonged antide treatment [23,2628]. This phenomenon is distinct fromman initial non-response or a partial response. Up to 80% of patients diagnosed with major depressive disorder will experience a recurrence of depressive episode despite constant maintenance dose of an antidepressant [12,23,29,30]. Attempts to treat these individuals frequently result in poor response and the rise of TRD [30].Serotonin reuptake inhibiting (SRIs) antidepressants were introduced in 1988. They had obvious advantages over previous tricyclic (TCA) or monoamine oxidase inhibiting (MAOI) agents regarding safety and tolerability, and a dramatic increase in antidepressant prescriptions ensued. More recently, there have been several reports 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-
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 antidepressants failed multiple treatment strategies including augmentation 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 is
unlikely. If patients with TRD respond to a subsequent antidepressant, the extent of improvement is inferior to the
initialbresponse [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 initiated [34,35].Antidepressant-induced depression
The possibility of antidepressant-induced depression was introduced by Fava [36]. He suggested that a neurobiochemical mechanism 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 depression after long-term treatment with antidepressants for their anxiety 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 cyclothymic illness that persisted for 1 year after antidepressant discontinuation [42]. Normal controls receiving antidepressants in research studies were reported to experience depression [43].These effects may be analogous to the observations that antidepressant treatment in bipolar disorder could destabilize the illness [44]. An antidepressant-associated chronic irritable depressive (ACID) state has been reported in bipolar and bipolar spectrum patients given long-term antidepressants [45,46]. In some of these patients antidepressant discontinuation was associated with slow and gradual improvement of the depressive symptoms. In a random assignment study, antidepressant continuation in rapid cycling bipolar subjects who achieved remission with initialmantidepressant treatment tripled the likelihood of a
future depression compared to patients who discontinued the antidepressant over the subsequent year of treatment [47].Sharma [25] speculated that a prodepressant effect of antidepressants may occur because continued drug treatment
may induce processes that are the opposite of what the medicationmoriginally produced. He believed this process may even cause amworsening of the illness, continue for a period of time after discontinuation of the medication, and
may not be reversible [24]. The field of psychiatry is familiar with such a process in the case of tardive dyskinesia.Tardiive dyskinesia (TD)
Tardive dyskinesia (TD) is a hyperkinetic condition that is charterized by abnormal involuntary, repetitive, purposeless movements that develop in individuals with long-term exposure to potent dopamine 2 (D2) receptor antagonists. The symptoms include tongue protrusion, grimacing, rapid eye
blinking, lip smacking, pursing, or puckering, choreaform movement of the extremities, as well as other involuntary movements of the head, face, neck and tongue muscles. Movements may be rapid or slow and complicated [48]. They are usually irregular and do not follow a pattern. This irreversible or slowly reversible neurological disorder typically develops after long-term exposure to antipsychotic
medications [49]. Any medication that causes blockade of the D2 receptor can theoretically cause TD. More potent D2 antagonism 160 with antipsychotics such as haloperidol or fluphenazine, increase the risk of TD. In general the risk of developing TD is approximately 5% per year of exposure to potent D2 blocking agent [50] and ultimately affects 30% of patients on long-term first generation antipsychotics [48]. The risk is higher in the elderly and female pa tients [51] and
doubles if the patient experiences early extrapyramidal parkinsonism[52]. There is no specific treatment for TD [53], but withdrawal of the antipsychotic will prevent worsening, and may allow improvement or remission of symptoms over time. Acutely, antipsychotics themselves are effective treatment for TD, transiently masking the symptoms, but long-term use may worsen the symptoms. Thus, themost common treatment of tardive dyskinesia is to stop the offending drugs. One third of TD patients remit within 3 months of
discontinuing the antipsychotic; another one-sixth remit within 18 months, leaving 50% with continuing symptoms [54], although in some cases, TD may continue to improve over time. It is important to note that early parkinsonism increases the risk of subsequent TD [53]. Parkinsonism is a bradykinetic movement disorder, while TD is a hyperkinetic disorder. In line with Favas' oppositional model, the chronic consequence is the opposite of the acute manifestation.Different explanations have been put forward to explain TD. Most models propose that there is excessive dopaminergic activity. They may occur through D2 receptor supersensitivity, neurochemical imbalance with different neurotransmitter systems; neurolelptic-induced striatal pathological changes; or toxic free radicals that damage neurons and result in persistent anatomical changes [54]. For example, acute administration of haloperidol has been shown to cause an increase in activity of the A9 DA neurons [55], but chronic
administration resulted in a significant decrease in activity of these same neurons [56]. However, the time course of TD slow onset after months or years of antipsychotic exposure, and slow resolution after antipsychotic discontinuation, and the increased relative permanence in the elderly [57], strongly suggests neuroplastic changes may underlie this disorder.R.S. El-Mallakh et al. / Medical Hypotheses xxx (2011) xxxxxx
YMEHY 6083 No. of Pages 6, Model 5G
24 January 2011Please cite this article in press as: El-Mallakh RS et al. Tardive dysphoria: The role of long term antidepressant use in-inducing chronic depression.
Med Hypothosis (2011), doi:10.1016/j.mehy.2011.01.020
Casey [58] have studied the effects of
haloperidol on synapses in the caudate, nucleus accumbens and medial pre- frontal cortex. They have shown a change in the postsynaptic dendrite within the caudate nucleus in rats. This structural change involved the increase of the number of perforated synapses. The change is evident following 2 weeks of treatment with haloperidol and returned to baseline
after 2 weeks off the medication. In other words, actual anatomical changes took place in the dopamine system in response to long-term haloperidol administration.
dysphoria (TDp) It is proposed that tardive dysphoria (TDp) is an abnormal dysphoric state that develops in some predisposed individuals withnprolonged 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. Antidepressants may be initially administered for any reason (e.g., anxiety or depression), but afflicted for subjects who have experienced TDp for a very prolonged period of time, discontinuation of antidepressant may not result in reversal of the symptoms. This is superficially similar to TD. Subjects who positive respond to antidepressants, helping to cement adherence. Depression recurs in 57% 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 60% of patients. However, there is evidence that thevswitch may not always be helpful [66], and if patients do respond relapse occurs within 6 months in some 20% [61]. Ultimately, 50% 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 antidepressants 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 a depressive picture is caused by continued administration of the antidepressant. In conditioned tolerance, environmental andvbehavioral conditional compensatory responses mediate tolerance by in the presence of cues usually associated with the drug [67].Serotonin transporter polymorphism:
A genetic polymorphism has been identified in which the promotor region of the serotonin transporter gene has a 44 base insertion or deletion [68,69]. The deletion variation is generally labeled the short form or s form of the serotonin transporter and is associated with roughly a 50% reduction in the number of serotonenin transporter units in the membrane [70]. Subjects with this variant are at a greater risk of experiencing a major depressive illness in the setting of adversity [7173]. Additionally, when these individuals are treated with an SRI antidepressant, they are either less likely to respond or have delayed response [7477].
It is not known how this increased risk for depression comes
about, but neuroplastic changes may play a role. It is known that modification of serotonergic neurotransmission alters arborization of the dendritic tree of serotonergic neurons [78,79]. Mice that lack the serotonin transporter have fewer serotonergic neurons and reduced serotoninergic function and express more behaviors associated with anxiety and depression [80]. This phenotype can be mimicked by treatment of normal mice with the SRI fluoxetine in early life. New born mouse pups given fluoxetine for only 1 weekbexpress anxiety symptoms as adults [81].The reduction in the number of synaptic serotonin transporters associated with the short form of the serotonin transporter is very similar to the chronic 6085% blockade of these transporters that occurs with SRI treatment [82,83]. This suggests that the s allele might serve as a model for chronic exposure to an SRI antidepressant, particularlywhen administered to young individuals. In young animals, reducing or eliminating serotonin transporter function causes changes in serotoninergic architecture and function and associated increased depressive and anxious behaviors [81,84]. Similar experiments have not been performed in adult animals whose brains are less plastic and have already completed development. Nonetheless, it would seem likely that chronic treatment with an SRI in adults might result in neuroplastic changes in the serotonin system similar to those seen in the animal experiments. These changes may underlie the observation that tryptophan depletion experiments are much more likely to induce depression, or induce a more severe depression, if the subjects have been tak ing serotonin reuptake inhibiting drugs [85]. In this case the contraction of the serotoninergic system removes the reserve, so that depletion is much more likely to cause depression. In humans, chronic exposure to antidepressants might induce changes in the serotonin system similar to those that occur in early development of subjects possessing the short form. This effect might be more pronounced if the antidepressant expo- sure occurred when the brain was more plastic (e.g., younger age), or if the individual already has reduced serotonin transporter function due to a genetic variant such as the short for of the serotonin transporter. These groups might be considered particularly high risk for the development of TDp.
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 tardive dysphoria (TDp). TDp manifests as a chronic dysphoric state that is initially transiently relieved by but ultimately becomes unresponsive to antidepressant medication. Serotoninergic antidepressants 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 discontinution/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 should be considered.R.S. El-Mallakh et al. / Medical Hypotheses xxx (2011)
xxxxxx 3
> YMEHY 6083 No. of Pages 6, Model 5G
> 24 January 2011Conflict of interest statement: This work did not receive extramural support. Dr. El-Mallakh has received research support from Forest Pharmaceuticals, Shire; and Bristol Myers Squibb, and speakers honoraria from Abbott,
Astra-Zeneca, Bristol-Myers-Squibb, Glaxo, and Lilly. Drs. Roberts and Gao do not have any disclosures.
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>
>
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