TDp Journal Article #2 + #3

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

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.

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.

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.25

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
Summary

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
1. Murray C, Lopez AD. The global burden of disease. Cambridge, Mass: Harvard University Press, 1996.
2. Keller MB. Issues in Treatment-Resistant Depression. J Clin Psychiatry 2005; 66 (suppl 8): 5-12.
3. Kocsis JH. Recurrent depression: patient characteristics, clinical course, and current recommendations for management. CNS Spectrums 2006; 11:12 (Suppl 15): 6-11.
4. Crown WH, Finkelstein S, Berndt ER, Ling D, Poret AW, Rush AJ, Russell JM. The impact of treatment resistant depression on health care utilization and costs. J Clin Psychiatry 2002; 63:963-971.
5. Angst J. The course of affective disorders. Psychopathology 1986; 19 (suppl 2): 47-52.
6. American Psychiatric Association. Diagnostic and statistical manual of mental disorders . Fourth Edition. Washington, DC: American Psychiatric Press, 2000:339-342.
7. Posternak MA,Solomon DA, Leon AC, Mueller TI, Shea MT, Endicott J, Keller MB. The naturalistic course of unipolar major depression in the absence of somatic therapy. J Nerv Mental Dis 2006; 194:324-329.
8. Coryell W, Endicott J, Keller M. Outcome of patients with chronic affective disorder: a five-year follow up. Am J Psych 1990; 147: 1627-1633.
9. Hirschfield RMA. Guidelines for the long-term treatment of depression. J Clin Psychiatry 1994; 55(12 suppl): 61-69.
10. Thase M, Sullivan L. Relapse and recurrence of depression: a practical approach for prevention. CNS Drugs 1995; 4(4): 261-277.
11. Solomon DA, Keller MB, Leon AC, Mueller TI, Lavori PW, Shea MT, Coryell W, Warshaw M, Turvey C, Maser JD, Endicott J. Multiple recurrences of major depressive disorder. Am J Psychiatry 2000; 157:229-233.
12. Bockting CL, Spinhoven P, Koeter MWJ, Wouters LF, Schene AH, Depression Evaluation Longitudinal Therapy Assessment Study Group. Prediction of recurrence on recurrent depression and the influence of consecutive episodes on vulnerability for depression: a 2-year prospective study. J Clin Psychiatry 2006; 67:747-755.
13. Reynolds CF 3rd, Frank E, Perel JM, Imber SD, Cornes C, Miller MD, Mazumdar S, Houck PR, Dew MA, Stack JA, Pollock BG, Kupfer DJ. Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years. JAMA 1999; 281: 39-45.
14. Keller MB, Kocsis JH, Thase ME, Gelenberg AJ, Rush AJ, Koran L, Schatzberg A, Russell J, Hirschfeld R, Klein D, McCullough JP, Fawcett JA, Kornstein S, LaVange L, Harrison W. Maintenance phase efficacy of sertraline for chronic depression: a randomized controlled trial. JAMA 1998; 280: 1665-1672.
15. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry 2000; 157 (suppl 4): 1-45.
16. Prien RF, Kupfer DJ, Mansky PA,Small JG, Tuason VB, Voss CB, Johnson WE. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders: report of the NIMH collaborative study group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination. Arch Gen Psychiatry 1984; 41:1096-104
17. Fava M, Davidson KG. Definition and epidemiology of treatment resistant depression. Psychiatr Clin North Am 1996; 19: 179-200.
18. Thase ME, Rush AJ. Treatment-resistant depression; in Bloom RE, Kupfer DJ (eds): Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press, Ltd, 1995: 1081-1097.
19. Shelton RC, Tollefson GD, Tohen M, Stahl S, Gannon KS, Jacobs TG, Buras WR, Bymaster FP, Zhang W, Spencer KA, Feldman PD, Meltzer HY. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001; 158: 131-134.
20. Keitner GI, Ryan CE, Solomon DA. Realistic expectations and a disease management model for depressed patients with persistent symptoms. J Clin Psychiatry 2006; 67:1412-1421.
21. Burrows GD, Norman TR, Judd FK. Definition and differential diagnosis of treatment-resistant depression. Int Clin Psychopharmacol 1994; 9 (Suppl 2): 5-10.
22. Surja AAS, El-Mallakh RS. Fertility and childhood bipolar disorder. Med Hypotheses 2007; 69(3):587-589.
23. Hirschfeld RM, Keller MB, Panico S, Arons BS, Barlow D, Davidoff F, Endicott J, Froom J, Goldstein M, Gorman JM, Marek RG, Maurer TA, Meyer R, Phillips K, Ross J, Schwenk TL, Sharfstein SS, Thase ME, Wyatt RJ. The National Depressive and Manic-Depressive Association consensus statement on the undertreatment of depression. JAMA 1997; 277:333-340.
??
Ir J Psych Med 2011; 28(1): ??-??
24. Byrne SE, Rothschild AJ. Loss of antidepressant efficacy during maintance therapy: possible mechanisms and treatments. J Clin Psychiatry 1998; 59:279-288.
25. Fava GA. Can long-term treatments with antidepressant drugs worsen the course of depression? J Clin Psychiatry 2003; 64:123-133.
26. Sharma V. Treatment resistance in unipolar depression: Is it an iatrogenic phenomenon caused by antidepressant treatment of patients with a bipolar diathesis? Med Hypotheses 2006; 67:1142-1145.
27. Lieb J, Balter A. Antidepressant tachyphylaxis. Med Hypotheses 1984; 15:279-291.
28. Cohen B, Baldessarini R. Tolerance to therapeutic effects of antidepressants. Am J Psychiatry 1985; 142:489-490.
29. Nierenberg AA, Alpert JE. Depressive breakthrough. Psychiatr Clin North Am 2000; 23(4):731-742.
30. Solomon D, Leon AC, Mueller TI, Coryell W, Teres IJ, Posternak MA, Judd LL, Endicott J, Keller MB. Tachyphalaxis in unipolar major depressive disorder. J Clin Psychiatry 2005; 66:283-290.
31. Posternak MA, Zimmerman M. Dual reuptake inhibitors incur lower rates of Tachyphylaxis than selective serotonin reuptake inhibitors: a retrospective study. J Clin Psychiatry 2005; 66:705-707.
32. Goldberg JF, Sacks MH, Kocsis JH. Attenuation of response to serotonin reuptake inhibitors (letter). Am J Psychiatry 1995; 152:954.
33. Diamond B, Hamner M, Sunde D. Possible tolerance to the antidepressant, anti-obsessive-compulsive, and analgesic effects of fluoxetine (abstract). Biol Psychiatry 1989; 25:155A.
34. Reimherr FW, Amsterdam JD,Quitkin FM, Rosenbaum JF, Fava M, Zajecka J, Beasley CM Jr, Michelson D, Roback P, Sundell K. Optimal length of continuation therapy in depression. Am J Psychiatry 1998; 155:1247-1253.
35. Sharma V. Loss of response to antidepressants and subsequent refractoriness: diagnostic issues in a retrospective case series. J Affect Disord 2001; 64:99-106.
36. Dunner DL, Rush AJ, Russell JM, Burke M, Woodard S, Wingard P, Allen J. Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression. J Clin Psychiatry 2006; 67(5):688-695.
37. Lieb J. Antidepressant tachyphlaxis. J Clin Psychiatry 1990; 51:36.
38. Mann JJ. Loss of antidepressant effect with long-term monoamine oxidase inhibitor treatment without loss of monoamine oxidase inhibition. J Clin Psychopharmacol 1983; 3:363-366.
39. Donaldson S. Tolerance to Phenelzine and subsequent refractory depression: three cases. J Clin Psychiatry 1989; 50:33-35.
40. Fava GA. Do antidepressant and antianxiety drugs increase chronicity in affective disorders? Psychother Psychosom 1994; 61(3-4):125-131.
41. El-Mallakh RS, Waltrip C, Peters C. Can long-term antidepressant use be depressogenic? J Clin Psychiatry 1999; 60:263.
42. Van Scheyen JD. Recurrent vital depressions. Psychiatr Neurol Neurochir 1973; 76:93-112.
43. Di Mascio A,Meyer RE, Stifler L. Effect of imipramine in individuals varying in levels of depression. Am J Psychiatry 1968; 127 (Suppl):55-58.
44. Aronson TA. Treatment emergent depression with antidepressants in panic disorder. Compr Psychiatry 1989: 30:267-271.
45. Fux M, Taub M, Zohar J. Emergence of depressive symptoms during treatment for panic disorder with specific 5-hydroxytryptophan reuptake inhibitors. Acta Psychiatr Scand 1993;88:235-237.
46. Fava GA, Bernardi M, Tomba E, Rafanelli C. Effects of gradual discontinuation of selective serotonin reuptake inhibitors in panic disorder with agoraphobia. Int J Neuropsychopharmacol 2007; 10:835-838.
47. Healy D. Emergence of antidepressant induced suicidality. Prim Care Psychiatry 2000; 6:23-28.
48. El-Mallakh RS, Karippot A. Chronic depression in bipolar disorder. Am J Psychiatry 163:1137-1341, 2006
49. El-Mallakh RS, Karippot A. Antidepressant-associated chronic irritable dysphoria (ACID) in bipolar disorder: a case series. J Affect Disord 2005; 84:267-272.
50. Akiskal HS, Mallya G. Criteria for the soft bipolar spectrum: treatment implications. Psychopharmacol Bull 1987; 23, 68-73.
51. Fava M, Rappe SM, Pava JA, Nierenberg AA, Alpert JE, Rosenbaum JF. Relapse in patients on long-term fluoxetine treatment: response to increased fluoxetine dose. J Clin Psychiatry 1995; 56:52-55.
52. Schmidt ME, Fava M, Zhang S, Gonzales J, Raute NJ, Judge R. Treatment approaches to major depressive disorder relapse, part I: Dose increase. Psychother Psychosom 2002; 71:190-194.
53. Poirier MF, Boyer P. Venlafaxine and paroxetine in treatment-resistant depression: double-blind, randomized comparison. Br J Psychiatry 1999; 175:12-16.
54. Thase ME, Blomgren SL, Birkett MA, Apter JT, Tepner RG. Fluoxetine treatment of patients with major depressive disorder who failed initial treatment with sertraline. J Clin Psychiatry 1997; 58:16-21.
55. Maes M, Vandoolaeghe E, Densnyder R. Efficacy of treatment with trazadone in combination with pindolol or fluoxetine in major depression. J Affect Disord 1996; 41:201-210.
56. Heils A, Teufel A, Petri S, Seemann M, Bengel D, Balling U, RiedererP, Lesch KP. Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene. J Neural Transm 1995; 102:247-254.
57. Heils A, Teufel A, Petri S, Stober G, RiedererP, Bengel D, Lesch KP. Allelic variation of human serotonin trasporter gene expression. J Neurochem 1996; 66:2621-2624.
58. Lesch KP, Bengel D, Heils A, sabol SZ, Greenberg BD, Petri S, Benjamin J, M_ller CR, Hamer DH, Murphy DL. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274:1527-1531.
59. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003; 301:386-389.
60. Wilhelm K, Mitchell PB, Niven H, Finch A, Wedgwood L, Scimone A, Blair IP, Parker G, Schofield PR. Life events, first depression onset and the serotonin transporter gene. Br J Psychiatry. 2006; 188:210-215.
61. Jacobs N, Kenis G, Peeters F, Deron C, Vlietinck R, van Os J. Stress-related negative affectivity and genetically altered serotonin transporter function: Evidence of synergism in shaping risk of depression. Arch Gen Psychiatry 2006; 63:989-996.
62. Murphy GM, Hollander SB, Rodrigues HE, Kremer C, Schatzberg AF. Effects of the serotonin trasporter gene promoter polymorphism on mirtrazapine and paroxetine efficacy and adverse events in geriatric major depression. Arch Gen Psychiatry 2004; 61:1163-1169.
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 disorder

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

4 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, USA

11 Article history:
12 Received 30 May 2010
13 Accepted 12 January 2011
1145 Available online xxxx

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. 31

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.2011.01.020

? 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
Q2
2 R.S. El-Mallakh et al. / Medical Hypotheses xxx (2011) xxxxxx
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
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
R.S. El-Mallakh et al. / Medical Hypotheses xxx (2011) xxxxxx 3
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
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].
329 References
330 [1] Murray C, Lopez AD. The global burden of disease. Cambridge, Mass: Harvard
331 University Press; 1996.
332 [2] Keller MB. Issues in treatment-resistant depression. J Clin Psychiatry
333 2005;66(Suppl. 8):512.
334 [3] Kocsis JH. Recurrent depression: patient characteristics, clinical course, and
335 current recommendations for management. CNS Spectrums 2006;11(12 Suppl.
336 15):611.
337 [4] Crown WH, Finkelstein S, Berndt ER, et al. The impact of treatment resistant
338 depression on health care utilization and costs. J Clin Psychiatry
339 2002;63:96371.
340 [5] Angst J. The course of affective disorders. Psychopathology 1986;19(Suppl.
341 2):4752.
342 [6] American Psychiatric Association. Diagnostic and statistical manual of mental
343 disorders. 4th ed. Washington, DC: American Psychiatric Press; 2000. p. 339
344 42.
345 [7] Posternak MA, Solomon DA, Leon AC, et al. The naturalistic course of unipolar
346 major depression in the absence of somatic therapy. J Nerv Mental Dis
347 2006;194:3249.
348 [8] Coryell W, Endicott J, Keller M. Outcome of patients with chronic affective
349 disorder: a five-year follow up. Am J Psych 1990;147:162733.
350 [9] Hirschfield RMA. Guidelines for the long-term treatment of depression. J Clin
351 Psychiatry 1994;55(Suppl. 12):619.
352 [10] Thase M, Sullivan L. Relapse and recurrence of depression: a practical approach
353 for prevention. CNS Drugs 1995;4(4):26177.
354 [11] Solomon DA, Keller MB, Leon AC, et al. Multiple recurrences of major
355 depressive disorder. Am J Psychiatry 2000;157:22933.
356 [12] Bockting CL, Spinhoven P, Koeter MWJ, Wouters LF, Schene AH. Depression
357 Evaluation Longitudinal Therapy Assessment Study Group: prediction of
358 recurrence on recurrent depression and the influence of consecutive
359 episodes on vulnerability for depression: a 2-year prospective study. J Clin
360 Psychiatry 2006;67:74755.
361 [13] Reynolds 3rd CF, Frank E, Perel JM, et al. Nortriptyline and interpersonal
362 psychotherapy as maintenance therapies for recurrent major depression: a
363 randomized controlled trial in patients older than 59 years. JAMA
364 1999;281:3945.
365 [14] Keller MB, Kocsis JH, Thase ME, et al. Maintenance phase efficacy of sertraline
366 for chronic depression: a randomized controlled trial. JAMA
367 1998;280:166572.
368 [15] American Psychiatric Association. Practice guideline for the treatment of
369 patients with major depressive disorder (revision). Am J Psychiatry
370 2000;157(Suppl. 4):145.
371 [16] Prien RF, Kupfer DJ, Mansky PA, et al. Drug therapy in the prevention of
372 recurrences in unipolar and bipolar affective disorders: report of the NIMH
373 collaborative study group comparing lithium carbonate, imipramine, and a
374 lithium carbonateimipramine combination. Arch Gen Psychiatry
375 1984;41:1096104.
376 [17] Thase ME, Rush AJ. Treatment-resistant depression. In: Bloom RE, Kupfer DJ,
377 editors. Psychopharmacology: the fourth generation of progress. New York,
378 NY: Raven Press, Ltd.; 1995. p. 108197.
379 [18] Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for
380 treating resistant major depression. Am J Psychiatry 2001;158:1314.
381 [19] Keitner GI, Ryan CE, Solomon DA. Realistic expectations and a disease
382 management model for depressed patients with persistent symptoms. J Clin
383 Psychiatry 2006;67:141221.
384 [20] Burrows GD, Norman TR, Judd FK. Definition and differential diagnosis of
385 treatment-resistant depression. Int Clin Psychopharmacol 1994;9(Suppl.
386 2):510.
387 [21] Surja AAS, El-Mallakh RS. Fertility and childhood bipolar disorder. Med
388 Hypotheses 2007;69(3):5879.
389 [22] Hirschfeld RM, Keller MB, Panico S, et al. The National Depressive and Manic-
390 Depressive Association consensus statement on the undertreatment of
391 depression. JAMA 1997;277:33340.
[23] Byrne SE, Rothschild AJ. Loss of antidepressant efficacy during maintenance 392
therapy: possible mechanisms and treatments. J Clin Psychiatry 393
1998;59:27988. 394
[24] Fava GA. Can long-term treatments with antidepressant drugs worsen the 395
course of depression? J Clin Psychiatry 2003;64:12333. 396
[25] Sharma V. Treatment resistance in unipolar depression: is it an iatrogenic 397
phenomenon caused by antidepressant treatment of patients with a bipolar 398
diathesis? Med Hypotheses 2006;67:11425. 399
[26] Lieb J, Balter A. Antidepressant tachyphylaxis. Med Hypotheses 400
1984;15:27991. 401
[27] Cohen B, Baldessarini R. Tolerance to therapeutic effects of antidepressants. 402
Am J Psychiatry 1985;142:48990. 403
[28] Nierenberg AA, Alpert JE. Depressive breakthrough. Psychiatr Clin North Am 404
2000;23(4):73142. 405
[29] Solomon D, Leon AC, Mueller TI, et al. Tachyphalaxis in unipolar major 406
depressive disorder. J Clin Psychiatry 2005;66:28390. 407
[30] Posternak MA, Zimmerman M. Dual reuptake inhibitors incur lower rates of 408
Tachyphylaxis than selective serotonin reuptake inhibitors: a retrospective 409
study. J Clin Psychiatry 2005;66:7057. 410
[31] Reimherr FW, Amsterdam JD, Quitkin FM, et al. Optimal length of continuation 411
therapy in depression. Am J Psychiatry 1998;155:124753. 412
[32] Sharma V. Loss of response to antidepressants and subsequent refractoriness: 413
diagnostic issues in a retrospective case series. J Affect Disord 414
2001;64:99106. 415
[33] Lieb J. Antidepressant tachyphlaxis. J Clin Psychiatry 1990;51:36. 416
[34] Mann JJ. Loss of antidepressant effect with long-term monoamine oxidase 417
inhibitor treatment without loss of monoamine oxidase inhibition. J Clin 418
Psychopharmacol 1983;3:3636. 419
[35] Donaldson S. Tolerance to phenelzine and subsequent refractory depression: 420
three cases. J Clin Psychiatry 1989;50:335. 421
[36] Fava GA. Do antidepressant and antianxiety drugs increase chronicity in 422
affective disorders? Psychother Psychosom 1994;61(34):12531. 423
[37] El-Mallakh RS, Waltrip C, Peters C. Can long-term antidepressant use be 424
depressogenic? J Clin Psychiatry 1999;60:263. 425
[38] Van Scheyen JD. Recurrent vital depressions. Psychiatr Neurol Neurochir 426
1973;76:93112. 427
[39] Di Mascio A, Meyer RE, Stifler L. Effect of imipramine in individuals varying in 428
levels of depression. Am J Psychiatry 1968;127(Suppl.):558. 429
[40] Aronson TA. Treatment emergent depression with antidepressants in panic 430
disorder. Compr Psychiatry 1989;30:26771. 431
[41] Fux M, Taub M, Zohar J. Emergence of depressive symptoms during treatment 432
for panic disorder with specific 5-hydroxytryptophan reuptake inhibitors. Acta 433
Psychiatr Scand 1993;88:2357. 434
[42] Fava GA, Bernardi M, Tomba E, Rafanelli C. Effects of gradual discontinuation of 435
selective serotonin reuptake inhibitors in panic disorder with agoraphobia. Int 436
J Neuropsychopharmacol 2007;10:8358. 437
[43] Healy D. Emergence of antidepressant induced suicidality. Prim Care 438
Psychiatry 2000;6:238. 439
[44] El-Mallakh RS, Karippot A. Chronic depression in bipolar disorder. Am J 440
Psychiatry 2006;163:1137341. 441
[45] El-Mallakh RS, Karippot A. Antidepressant-associated chronic irritable 442
dysphoria (ACID) in bipolar disorder: a case series. J Affect Disord 443
2005;84:26772. 444
[46] Akiskal HS, Mallya G. Criteria for the soft bipolar spectrum: treatment 445
implications. Psychopharmacol Bull 1987;23:6873. 446
[47] Ghaemi SN, Ostacher MM, El-Mallakh RS, et al. Antidepressant discontinuation 447
in bipolar depression: a Systematic Treatment Enhancement Program for 448
Bipolar Disorder (STEP-BD) randomized clinical trial of long-termeffectiveness 449
and safety. J Clin Psychiatry 2010;71(4):37280. 450
[48] Khot V, Wyatt RJ. Not all that moves is tardive dyskinesia. Am J Psychiatry 451
1991;148:6616. 452
[49] Elliot KJ, Lewis S, El-Mallakh RS, et al. The role of parkinsonism and 453
antiparkinsonian therapy in the subsequent development of tardive 454
dyskinesia. Ann Clin Psychiatry 1994;6:197203. 455
[50] Kane JM, Woerner M, Weinhold P, Wegner J, Kinon B. A prospective study of 456
tardive dyskinesia development: preliminary results. J Clin Psychopharmacol 457
1982;2:3459. 458
[51] Woerner MG, Alvir JMJ, Saltz BL, Lieberman JA, Kane JM. Prospective study of 459
tardive dyskinesia in the elderly: rates and risk factors. Am J Psychiatry 460
1998;155:15218. 461
[52] Tenback DE, van Harten PN, Slooff CJ, van Os J. Evidence that early 462
extrapyramidal symptoms predict later tardive dyskinesia: a prospective 463
analysis of 10,000 patients in the European Schizophrenia Outpatient Health 464
Outcomes (SOHO) study. Am J Psychiatry 2006;163:143840. 465
[53] Soares-Weiser K, Fernandez HH. Tardive dyskinesia. Semin Neurol 466
2007;27:15969. 467
[54] Jeste DV, Dolder CR. Medication-induced movement disorders. In: Tasman A, 468
Kay J, Lieberman JA, editors. Psychiatry. West Sussex, England: Wiley; 2003. p. 469
16668. 470
[55] Bunney BS, Grace AA. Acute and chronic haloperidol treatment: comparison of 471
effects on nigral dopaminergic cell activity. Life Sci 1978;23:171527. 472
[56] Chiodo LA, Bunney BS. Typical and atypical neuroleptics: differential effects of 473
chronic administration on the activity of A9 and A10 midbrain dopaminergic 474
neurons. J Neurosci 1983;3:160719. 475
[57] Kane JM. Tardive dyskinesia circa 2006. Am J Psychiatry 2006;163(8):13168. 476
Q3
4 R.S. El-Mallakh et al. / Medical Hypotheses xxx (2011) xxxxxx
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
477 [58] Meshul CK, Casey DE. Regional, reversible ultrastructural changes in rat brain
478 with chronic neuroleptic treatment. Brain Res 1989;489:33846.
479 [59] Pigott HE, Leventhal AM, Alter GS, Boren JJ. Efficacy and effectiveness of
480 antidepressants: current status of research. Psychother Psychosom
481 2010;79(5):26779.
482 [60] Fava M, Rappe SM, Pava JA, Nierenberg AA, Alpert JE, Rosenbaum JF. Relapse in
483 patients on long-term fluoxetine treatment: response to increased fluoxetine
484 dose. J Clin Psychiatry 1995;56:525.
485 [61] Schmidt ME, Fava M, Zhang S, Gonzales J, Raute NJ, Judge R. Treatment
486 approaches to major depressive disorder relapse, part I: dose increase.
487 Psychother Psychosom 2002;71:1904.
488 [62] Poirier MF, Boyer P. Venlafaxine and paroxetine in treatment-resistant
489 depression: double-blind, randomized comparison. Br J Psychiatry
490 1999;175:126.
491 [63] Thase ME, Blomgren SL, Birkett MA, Apter JT, Tepner RG. Fluoxetine treatment
492 of patients with major depressive disorder who failed initial treatment with
493 sertraline. J Clin Psychiatry 1997;58:1621.
494 [64] Maes M, Vandoolaeghe E, Densnyder R. Efficacy of treatment with trazadone in
495 combination with pindolol or fluoxetine in major depression. J Affect Disord
496 1996;41:20110.
497 [65] Blier P, Ward HE, Tremblay P, Laberge L, Hébert C, Bergeron R. Combination of
498 antidepressant medications from treatment initiation for major depressive
499 disorder: a double-blind randomized study. Am J Psychiatry 2010;167:2818.
500 [66] Bschor T, Baethge C. No evidence for switching the antidepressant: systematic
501 review and meta-analysis of RCTs of a common therapeutic strategy. Acta
502 Psychiatr Scand 2010;121(3):1749.
503 [67] Siegel S, Baptista MA, Kim JA, McDonald RV, Weise-Kelly L. Pavlovian
504 psychopharmacology: the associative basis of tolerance. Exp Clin
505 Psychopharmacol 2000;8(3):27693.
506 [68] Heils A, Teufel A, Petri S, et al. Functional promoter and polyadenylation site
507 mapping of the human serotonin (5-HT) transporter gene. J Neural Transm
508 1995;102:24754.
509 [69] Heils A, Teufel A, Petri S, et al. Allelic variation of human serotonin transporter
510 gene expression. J Neurochem 1996;66:26214.
511 [70] Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a
512 polymorphism in the serotonin transporter gene regulatory region. Science
513 1996;274:152731.
514 [71] Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression:
515 moderation by a polymorphism in the 5-HTT gene. Science 2003;301:3869.
516 [72] Wilhelm K, Mitchell PB, Niven H, et al. Life events, first depression onset and
517 the serotonin transporter gene. Br J Psychiatry 2006;188:2105.
[73] Jacobs N, Kenis G, Peeters F, Deron C, Vlietinck R, van Os J. Stress-related 518
negative affectivity and genetically altered serotonin transporter function: 519
evidence of synergism in shaping risk of depression. Arch Gen Psychiatry 520
2006;63:98996. 521
[74] Murphy GM, Hollander SB, Rodrigues HE, Kremer C, Schatzberg AF. Effects of 522
the serotonin transporter gene promoter polymorphism on mirtrazapine and 523
paroxetine efficacy and adverse events in geriatric major depression. Arch Gen 524
Psychiatry 2004;61:11639. 525
[75] Durham LK, Webb SM, Milos PM, Clary CM, Seymour AB. The serotonin 526
transporter polymorphism, 5HTTLPR, is associated with a faster response time 527
to sertraline in an elderly population with major depressive disorder. 528
Psychopharmacology (Berlin) 2004;174(4):5259. 529
[76] Yu YW, Tsai SJ, Chen TJ, Lin CH, Hong CJ. Association study of the serotonin 530
transporter promoter polymorphism and symptomatology and antidepressant 531
response in major depressive disorders. Mol Psychiatry 2002;7:11159. 532
[77] Pollock BG, Ferrell RE, Mulsant BH, et al. Allelic variation in the serotonin 533
transporter promoter affects onset of paroxetine treatment response in late- 534
life depression. Neuropsychopharmacology 2000;23:58790. 535
[78] El-Mallakh RS, Peters C, Waltrip C. Antidepressant treatment and neural 536
plasticity. J Child Adoles Psychopharmacol 2000;10:28794. 537
[79] Baker MW, Croll RP. Modulation of in vivo neuronal sprouting by serotonin in 538
adult CNS of the snail. Cell Mol Neurobiol 1996;16:56176. 539
[80] Lira A, Zhou M, Castanon N, et al. Altered depression-related behaviors and 540
functional changes in the dorsal raphe nucleus of serotonin transporter- 541
deficient mice. Biol Psychiatry 2003;54(10):96071. 542
[81] Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA. Early-life blockade of the 5-HT 543
transporter alters emotional behavior in adult mice. Science 544
2004;306:87981. 545
[82] Voineskos AN, Wilson AA, Boovariwala A, et al. Serotonin transporter 546
occupancy of high-dose selective serotonin reuptake inhibitors during major 547
depressive disorder measured with [11C]DASB positron emission tomography. 548
Psychopharmacology (Berlin) 2007;193(4):53945. 549
[83] Meyer JH, Wilson AA, Sagrati S, et al. Serotonin transporter occupancy of five 550
selective serotonin reuptake inhibitors at different doses: an [11C]DASB 551
positron emission tomography study. Am J Psychiatry 2004;161(5):82635. 552
[84] Gaspar P, Cases O, Maroteaux L. The developmental role of serotonin: news 553
from mouse molecular genetics. Nat Rev Neurosci 2003;4(12):100212. 554
[85] Ruhé HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, 555
norepinephrine and dopamine levels in humans: a meta-analysis of 556
monoamine depletion studies. Mol Psychiatry 2007;12(4):33159. 557

* and whoever gazes at the stars will never again be quite alone...

c-ptsd & attendant health concerns

TDp Journal Article #2 + #3

Thread

Post a new follow-up

Notify the administrators

Start a new thread