Re: Do antidepressants worsen your depression? » SLS

> I have no doubt that exposure to antidepressants leaves the brain changed in some way. That "poop-out" occurs at all is evidence of this. Perhaps one change involves the downregulation of serotonin autoreceptors.

I have some more quotes from the two articles I mentioned earlier in this thread. (I left some of the contents of the articles out, so it shouldn't be too much to read in one message.) Now I also have quoted the references from part of the articles.

Do you have any comments to the quotes below? I will greatly appreciate any response.

There is increasing awareness of the complex mutual inhibitory effects of different serotonin receptors, particu-larly 5-HT1 and 5-HT2 receptors.89 Berendsen90 has sug-gested that an important function of antidepressants is
to restore a disturbed balance between 5-HT1A, 5-HT1B, and 5-HT2 receptors. It is, therefore, conceivable that a therapeutic action of antidepressant drugs (e.g., down-regulation of postsynaptic 5-HT2 receptors) may, under certain conditions, trigger changes in postreceptor signal transduction, in intraneuronal signaling pathways, or in neuronal architecture that are likely to affect the balance of serotonin receptors. There is preclinical evidence of the
autoregulation of serotonin and its potential effect on neurogenesis. 91,92 Jacobs et al.93 have recently proposed an impairment in neurogenesis as the key pathophysiologic event in depression.

In the same vein, there is increasing awareness of the complex mutual inhibitory effects of different neurotrans-mitter systems that may be affected in depression. 89 Anti-depressant drugs may yield changes in connections or sensitivity to neurotransmitters indirectly related to the
specific actions.

Interactions Between Neurotransmitter Balance and the Hypothalamic-Pituitary-Adrenal Axis

Neurophysiologists have used the term sensitization, as opposed to habituation, to refer to the long-lasting in-crement in response occurring on repeated presentation of a stimulus that reliably elicits a response at its initial pre-sentation. 94 Psychostimulants such as amphetamine and cocaine have been found to induce sensitization. Anti-depressant therapy, however, may also induce time-dependent sensitization.95

There is extensive evidence that the hypothalamic-pituitary-adrenal (HPA) axis, through an action on corticotropin-releasing factor neurons, 96
can modulate both sensitization and tolerance. 97
Of particular interest is the relationship between serotonin receptors and HPA axis. 98 By facilitating 5-HT1 receptormediated neurotransmission, 5-HT2 postsynaptic down-regulation, a pu-tative final common pathway of the actions of different antidepressants, 89 may induce an activation of the HPA axis. This activation, in turn, may unfavorably affect sero-tonin receptor functioning.
99 An example of this interac-tion is provided by the use of specific 5-HT2 receptor an-tagonists (ritanserin and ketanserin) in Cushings disease, which often yields only a temporary decrease in adreno-corticotropic hormone (ACTH) and cortisol secretion, followed by an escape phenomenon. 100

An impressive body of evidence 101,102 supports the concept of an antidepressant mechanism of action that exerts its effects beyond the cell membrane receptors of biogenic amines and leads to enhanced glucocorticoid receptor function and expression. Thus, the phenomena observed with long-term use of serotonin receptor antago-nists in Cushings disease have considerable relevance, particularly considering the fact that long-term treatment with inhibitors of steroid production is unlikely to yield the same phenomenon. 98 It has thus been postulated 98 that long-term treatment with antidepressant drugs in nonendocrine depression, after an initial phase of normal-ization of the HPA axis, may recruit its ACTH-dependent activation, which results in loss of clinical effect. The poor prognosis of remitted patients who still display abnormalities of the HPA axis is in line with this hypothesis. 98

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

Activation of the HPA axis may be permissive for re-peated psychostimulant sensitization. 96 Indeed, the acute and sensitizing effects of amphetamine are diminished by adrenalectomy. There is considerable evidence of cross-
sensitization between psychoactive drugs and environ-mental stressors,104 and such cross-sensitization may be HPA mediated.

Post 105 postulated that both sensitization to stressors and episode sensitization may occur in mood disorders and became encoded at the level of gene expression. In particular, stressors and the biochemical concomitants of the episode can themselves induce the proto-oncogene c-fos and related transcription factors, which then affect
the expression of transmitters, receptors, and neuropep-tides that alter responsiveness in a long-lasting way. 105

Segal et al. 106 extended these possibilities to negative pat-terns of information processing, and Benazzi 107 extended them to residual symptomatology. In this context, antide- pressant drugs may display a protective effect. We cannot
exclude, however, thatthrough an action mediated by the HPA axisthey may also potentiate both sensitization
of stressors and episode sensitization

89. Leonard BE. Serotonin receptors and their function in sleep, anxiety
disorders, and depression. Psychother Psychosom 1996;65:6675

90. Berendsen HG. Interactions between 5-hydroxytryptamine receptor
subtypes. Pharmacol Ther 1995;66:1739

91. Baker MW, Croll RP. Modulation of in vivo neuronal sprouting by
serotonin in the adult CNS of the snail. Cell Mol Neurobiol 1996;16:
561576

92. Diefenbach TJ, Sloley BD, Goldberg JI. Neurite branch development of
an identified serotonergic neuron from embryonic Helisomer: evidence
for autoregulation by serotonin. Dev Biology 1995;167:282293

93. Jacobs BC, Van Praag H, Gage PH. Adult brain neurogenesis and psy-
chiatry: a novel theory of depression. Mol Psychiatry 2000;5:262264

94. Groves PM, Thompson RF. Habituation: a dual-process theory. Psychol
Rev 1970;77:419450

95. Antelman SM, Gershon S. Clinical application of time-dependent
sensitization to antidepressant therapy. Prog Neuropsychopharmacol
Biol Psychiatry 1998;22:6578

96. Koob GF, Cador M. Psychomotor stimulant sensitization: the
corticotropin-releasing factor-steroid connection. Behav Pharmacol
1993;4:351354

97. Ritzmann RF, Colbern DL, Zimmermann EG, et al. Neurohypophyseal
hormones in tolerance and physical dependence. Pharmacol Ther
1984;23:281312

98. Sonino N, Fava GA. CNS drugs in Cushings disease: pathophysio-
logical and therapeutic implications for mood disorders. Progr
Neuropsychopharmacol Biol Psychiatry 2002;26:10111018

99. Van Praag HM. Faulty cortisol/serotonin interplay. Psychiatry Res
1996;65:143157

100. Sonino N, Fava GA, Fallo F, et al. Effect of the serotonin antagonists
ritanserin and ketanserin in Cushings disease. Pituitary 2000;3:5559

101. Holsboer F, Barden N. Antidepressants and the hypothalamic-pituitary-
adrenocortical regulation. End Rev 1996;17:187205

102. Pariante C, Miller AH. Glucocorticoid receptors in major depression.
Biol Psychiatry 2001;49:391404

103. Michelson D, Amsterdam J, Apter J, et al. Hormonal markers of stress
response following interruption of selective serotonin reuptake inhibitor
treatment. Psychoneuroendocrinology 2000;25:169177

104. Stewart J, Badiani A. Tolerance and sensitization to the behavioral
effects of drugs. Behav Pharmacol 1993;4:289312

105. Post RM. Transduction of psychosocial stress into the neurobiology
of recurrent affective disorder. Am J Psychiatry 1992;149:9991010

106. Segal ZV, Williams JM, Teasdale JD, et al. A cognitive science
perspective on kindling and episode sensitization in recurrent affective
disorder. Psychol Med 1996;26:371380

107. Benazzi F. Prevalence and clinical correlates of residual depressive
symptoms in bipolar II disorder. Psychother Psychosom 2001;70:
232238

A genetic polymorphism has been identified in which the pro-moter region of the serotonin transporter gene has a 44 base inser-tion or deletion[68,69]. The deletion variation is generally labeled the short form or s form of the serotonin transporter and is asso-ciated with roughly a 50% reduction in the number of serotonin transporter units in the membrane [70]. Subjects with this variant are at a greater risk of experiencing a major depressive illness inthe setting of adversity[7173]. Additionally, when these individ-uals 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 re-
duced serotoninergic function and express more behaviors associ-
ated 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 week
express 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 antidepres-
sant,particularlywhenadministeredtoyoungindividuals.Inyoung
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 develop-
ment. 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 con-
traction 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
neuroplastic 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 func-
tion 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.

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[72] Wilhelm K, Mitchell PB, Niven H, et al. Life events, first depression onset and 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 negative affectivity and genetically altered serotonin transporter function: evidence of synergism in shaping risk of depression. Arch Gen Psychiatry 2006;63:98996.

[74] Murphy GM, Hollander SB, Rodrigues HE, Kremer C, Schatzberg AF. Effects of
the serotonin transporter gene promoter polymorphism on mirtrazapine and
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[75] 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.
Psychopharmacology (Berlin) 2004;174(4):5259.

[76] Yu YW, Tsai SJ, Chen TJ, Lin CH, Hong CJ. Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepressant response in major depressive disorders. Mol Psychiatry 2002;7:11159.

[77] Pollock BG, Ferrell RE, Mulsant BH, et al. Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 2000;23:58790.

[78] El-Mallakh RS, Peters C, Waltrip C. Antidepressant treatment and neural
plasticity. J Child Adoles Psychopharmacol 2000;10:28794.

[79] Baker MW, Croll RP. Modulation of in vivo neuronal sprouting by serotonin in adult CNS of the snail. Cell Mol Neurobiol 1996;16:56176.

[80] Lira A, Zhou M, Castanon N, et al. Altered depression-related behaviors and
functional changes in the dorsal raphe nucleus of serotonin transporter-
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[81] Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA. Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science
2004;306:87981.

[82] Voineskos AN, Wilson AA, Boovariwala A, et al. Serotonin transporter
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[83] Meyer JH, Wilson AA, Sagrati S, et al. Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB
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[85] Ruhé HG, Mason NS, Schene AH. Mood is indirectly related to serotonin,
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Earlier TRD/anxiety
300 mg tianeptine, 6 X 50 mg successfully since Oct 2009
20 mcg liothyronine
40 mg escitalopram
100 mg trimipramine
50 mg agomelatine
600 mg quetiapine

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