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Effect of electroconvulsive therapy on brain 5-HT2 receptors in major depression

  • Lakshmi N. Yatham (a1), Peter F. Liddle (a2), Raymond W. Lam (a1), Athanasios P. Zis (a1), A. Jon Stoessl (a3), Vesna Sossi (a3), Michael J. Adam (a4) and Thomas J. Ruth (a4)...
Abstract
Background

Brain serotonin2 (5-hydroxytryptamine2; 5-HT2) receptors were considered potential targets for therapeutic efficacy of electroconvulsive therapy (ECT), but pre-clinical studies showed that electroconvulsive shock up-regulates 5-HT2 receptors in contrast to antidepressant medications, which down-regulate brain 5-HT2 receptors. Positron emission tomography (PET) studies in individuals with depression confirmed that antidepressant medications reduce brain 5-HT2 receptors, but the effects of ECT on these receptors in individuals with depression are unknown.

Aims

To determine if a course of ECT alters brain 5-HT2 receptors in individuals with depression and whether such changes correlate with improvement in symptoms.

Method

Fifteen people with major depression, refractory to antidepressant therapy and referred for a course of ECT, had an [18F]setoperone scan during baseline drug-free washout period and another after a course of ECT. We assessed changes in brain 5-HT2 receptors with ECT and their relationship to therapeutic outcome.

Results

Widespread reduction in brain 5-HT2 receptors was observed in all cortical areas with changes slightly more prominent in the right hemisphere. There was a trend for correlation between reduction in brain 5-HT2 receptors in right parahippocampal gyrus, right lingual gyrus and right medial frontal gyrus, and improvement in depressive symptoms.

Conclusions

Unlike in rodents, and similar to antidepressants, ECT reduces brain 5-HT2 receptors in individuals with depression. The ability of ECT to further down-regulate brain 5-HT2 receptors in antidepressant non-responsive individuals may explain its efficacy in those people with antidepressant refractory depression.

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Corresponding author
Lakshmi N. Yatham, Professor of Psychiatry, Vice Chair for Research and International Affairs, UBC Department of Psychiatry, The University of British Columbia, UBC Hospital, 2255 Wesbrook Mall, Vancouver, BC, V6T 2A1, Canada. Email: yatham@exchange.ubc.ca
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Declaration of interest

None.

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References
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1 Kellar, KJ, Cascio, CS, Butler, JA, Kurtzke, RN. Differential-effects of electroconvulsive shock and anti-depressant drugs on serotonin-2 receptors in rat-brain. Eur J Pharmacol 1981; 69: 515–8.
2 Peroutka, SJ, Snyder, SH. Long-term anti-depressant treatment decreases spiroperidol-labeled serotonin receptor-binding. Science 1980; 210: 8890.
3 Eison, AS, Yocca, FD, Gianutsos, G. Effect of chronic administration of antidepressant drugs on 5-HT2-mediated behavior in the rat following nor-adrenergic or serotonergic denervation. J Neural Transm Gen Sect 1991; 84: 1932.
4 Blackshear, MA, Sandersbush, E. Serotonin receptor sensitivity after acute and chronic treatment with Mianserin. J Pharmacol Exp Ther 1982; 221: 303–8.
5 Yatham, LN, Liddle, PF, Dennie, J, Shiah, IS, Adam, MJ, Lane, CJ, et al. Decrease in brain serotonin-2 receptor binding in patients with major depression following desipramine treatment: a positron emission tomography study with fluorine-18-labeled setoperone. Arch Gen Psychiatry 1999; 56: 705–11.
6 Meyer, JH, Kapur, S, Eisfeld, B, Brown, GM, Houle, S, DaSilva, J, et al. The effect of paroxetine on 5-HT2A receptors in depression: an [F-18]setoperone PET imaging study. Am J Psychiatry 2001; 158: 7885.
7 Mischoulon, D, Dougherty, DD, Bottonari, KA, Gresham, RL, Sonawalla, SB, Fischman, AJ, et al. An open pilot study of nefazodone in depression with anger attacks: relationship between clinical response and receptor binding. Psychiatry Res 2002; 116: 151–61.
8 Meyer, JH. Applying neuroimaging ligands to study major depressive disorder. Semin Nucl Med 2008; 38: 287304.
9 Blin, J, Sette, G, Fiorelli, M, Bletry, O, Elghozi, JL, Crouzel, C, et al. A method for the in-vivo investigation of the serotonergic 5-HT2 receptors in the human cerebral-cortex using positron emission tomography and F-18 labeled setoperone. J Neurochem 1990; 54: 1744–54.
10 Crouzel, C, Guillaume, M, Barre, L, Lemaire, C, Pike, VW. Ligands and tracers for PET studies of the 5-HT system – current status. Nucl Med Biol 1992; 19: 857–70.
11 First, MB, Spitzer, RL, Gibbon, M, Williams, JBW. Structured Clinical Interview for DSM–IV–TR Axis I Disorders: Research Version, Patient Edition (SCID–I/P). Biometrics Research, 2002.
12 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM–IV). APA, 1994.
13 Hamilton, M. Citation classic – a rating-scale for depression. Curr Contents Clin Pract 1981; 33: 18.
14 Williams, JBW, Link, MJ, Rosenthal, NE, Terman, M. Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders version (SIGH-SAD). New York State Psychiatric Institute, 1988.
15 Yatham, LN, Liddle, PF, Shiah, IS, Scarrow, G, Lam, RW, Adam, MJ, et al. Brain serotonin2 receptors in major depression: a positron emission tomography study. Arch Gen Psychiatry 2000; 57: 850–8.
16 Shiah, IS, Yatham, LN, Srisurapanont, M, Lam, RW, Tam, EM, Zis, AP. Does the addition of pindolol accelerate the response to electroconvulsive therapy in patients with major depression? A double-blind, placebo-controlled pilot study. J Clin Psychopharmacol 2000; 20: 373–8.
17 Petit-Taboue, MC, Landeau, B, Barre, L, Onfroy, MC, Noel, MH, Baron, JC. Parametric PET imaging of 5HT(2A) receptor distribution with F-18-setoperone in the normal human neocortex. J Nucl Med 1999; 40: 2532.
18 Desjardins, AE, Kiehl, KA, Liddle, PF. Removal of confounding effects of global signal in functional MRI analyses. Neuroimage 2001; 13: 751–58.
19 Worsley, KJ. Local maxima and the expected euler characteristic of excursion sets of chi(2), F and T fields. Adv Appl Probab 1994; 26: 1342.
20 Friston, KJ, Frith, CD, Liddle, PF, Frackowiak, RSJ. Comparing functional (Pet) images – the assessment of significant change. J Cerebr Blood F Met 1991; 11: 690–9.
21 Genovese, CR, Lazar, NA, Nichols, T. Thresholding of statistical maps in functional neuroimaging using the false discovery rate. Neuroimage 2002; 15: 870–8.
22 Logan, J, Fowler, JS, Volkow, ND, Wang, GJ, Ding, YS, Alexoff, DL. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cerebr Blood F Metab 1996; 16: 834–40.
23 Klimek, V, Zak-Knapik, J, Mackowiak, M. Effects of repeated treatment with fluoxetine and citalopram, 5-HT uptake inhibitors, on 5-HT1A and 5-HT2 receptors in the rat brain. J Psychiatry Neurosci 1994; 19: 63–7.
24 Kellar, KJ, Stockmeier, CA. Effects of electroconvulsive shock and serotonin axon lesions on beta-adrenergic and serotonin-2 receptors in rat-brain. Ann NY Acad Sci 1986; 462: 7690.
25 Vetulani, J, Lebrecht, U, Pilc, A. Enhancement of responsiveness of the central serotonergic system and serotonin-2 receptor density in rat frontal-cortex by electroconvulsive treatment. Eur J Pharmacol 1981; 76: 81–5.
26 Strome, EM, Clark, CM, Zis, AP, Doudet, DJ. Electroconvulsive shock decreases binding to 5-HT2 receptors in nonhuman primates: an in vivo positron emission tomography study with [F-18]setoperone. Biol Psychiatry 2005; 57: 1004–10.
27 Mayberg, H, Goldapple, K, MacIntosh, AR. Is there a final common pathway mediating depression remission? The functional neuroimaging evidence. Biol Psychiatry 2002; 51: 78S.
28 Mayberg, H. Towards a neural systems model of depression: evidence of dysfunctional limbic-cortical circuits. Clin Neuropsychol 2003; 17: 85–6.
29 D'haenen, H, Bossuyt, A, Mertens, J, Bossuyt-Piron, C, Gijsemans, M, Kaufman, L. SPECT imaging of serotonin-2 receptors in depression. Psychiatry Res 1992; 45: 227–37.
30 Biver, F, Wikler, D, Lotstra, F, Damhaut, P, Goldman, S, Mendlewicz, J. Serotonin 5-HT2 receptor imaging in major depression: focal changes in orbito-insular cortex. Br J Psychiatry 1997; 171: 444–8.
31 Schotte, A, Maloteaux, JM, Laduron, PM. Characterization and regional distribution of serotonin S2-receptors in human brain. Brain Res 1983; 276: 231–5.
32 Mintun, MA, Sheline, YI, Moerlein, SM, Vlassenko, AG, Huang, YY, Snyder, AZ. Decreased hippocampal 5-HT2A receptor binding in major depressive disorder: in vivo measurement with [F-18]Altanserin positron emission tomography. Biol Psychiatry 2004; 55: 217–24.
33 Meyer, JH, McMain, S, Kennedy, SH, Korman, L, Brown, GM, DaSilva, JN, et al. Dysfunctional attitudes and 5-HT2 receptors during depression and selfharm. Am J Psychiatry 2003; 160: 90–9.
34 Bhagwagar, Z, Hinz, R, Taylor, M, Fancy, S, Cowen, P, Grasby, P. Increased 5-HT2A receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [C-11] MDL 100,907. Am J Psychiatry 2006; 163: 1580–7.
35 Tarazi, FI, Zhang, KH, Baldessarini, RJ. Long-term effects of olanzapine, risperidone, and quetiapine on serotonin 1A, 2A and 2C receptors in rat forebrain regions. Psychopharmacol 2002; 161: 263–70.
36 Tohen, M, Vieta, E, Calabrese, J, Ketter, TA, Sachs, G, Bowden, C, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003; 60: 1079–88.
37 Calabrese, JR, Keck, PE, Macfadden, W, Minkwitz, M, Ketter, TA, Weisler, RH, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry 2005; 162: 1351–60.
38 Burnet, PWJ, Chen, CPLH, McGowan, S, Franklin, M, Harrison, PJ. The effects of clozapine and haloperidol on serotonin-1A, -2A and -2C receptor gene expression and serotonin metabolism in the rat forebrain. Neuroscience 1996; 73: 531–40.
39 Tohen, M, Goldberg, JF, Arrillaga, AMGP, Azorin, JM, Vieta, E, Hardy-Bayle, MC, et al. A 12-week, double-blind comparison of olanzapine vs haloperidol in the treatment of acute mania. Arch Gen Psychiatry 2003; 60: 1218–26.
40 Yatham, LN, Liddle, PF, Shiah, IS, Lam, RW, Adam, MJ, Zis, AP, et al. Effects of rapid tryptophan depletion on brain 5-HT(2) receptors: a PET study. Br J Psychiatry 2001; 178: 448–53.
41 Mamo, D, Sedman, E, Tillner, J, Sellers, EM, Romach, MK, Kapur, S. EMD 281014, a specific and potent 5HT2 antagonist in humans: a dose-finding PET study. Psychopharmacol (Berl) 2004; 175: 382–8.
42 Elfving, B, Bjornholm, B, Knudsen, GM. Interference of anaesthetics with radioligand binding in neuroreceptor studies. Eur J Nucl Med Mol Imaging 2003; 30: 912–5.
43 Chow, TW, Mamo, DC, Uchida, H, Graff-Guerrero, A, Houle, S, Smith, GS, et al. Test-retest variability of high resolution positron emission tomography (PET) imaging of cortical serotonin (5HT2A) receptors in older, healthy adults. BMC Med Imaging 2009; 9: 12.
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Effect of electroconvulsive therapy on brain 5-HT2 receptors in major depression

  • Lakshmi N. Yatham (a1), Peter F. Liddle (a2), Raymond W. Lam (a1), Athanasios P. Zis (a1), A. Jon Stoessl (a3), Vesna Sossi (a3), Michael J. Adam (a4) and Thomas J. Ruth (a4)...
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Effect of electroconvulsive therapy on brain 5-HT2 receptors in major depression

Dr Osama Hammer, Psychiatrist
11 August 2010

I read the study by Lakshmi N et al with great interest, AS I can seein this study which it shows clear and valuable information .The findings of this study taken in conjunction with the findings of previous studies of the effects of antidepressants on brain 5-HT2 receptors, consolidates the role of brain 5-HT2 receptors in mediating the antidepressant effects and may put to rest the controversy over the last four decades. Historically Electroconvulsive therapy (ECT) is a useful yet controversialmode of treatment. Despite being in use for over 70 years, its mechanism of action is still not clearly understood. Also Various theories on MOA ofECT have been proposed over the years. These have included looking at psychological, neuro physiological, neuro chemical, neuro endocrine, and neuro peptides mechanisms. Although ECT well established as safe and effective, some basic questions about ECT remain unanswered. What is the necessary and/or sufficient therapeutic component - the Generalised seizure or the postictal slow-wave state? What is the effective seizure - only a generalised/grandmal or a circum-scribed one limited to one set of neurons/region? If the latter is true, seizures with specific localisation(e.g., the limbic structures or ventral striatum or frontal cortex) might be sufficiently therapeutic, while seizures in other locations (e.g. motor, parietal or occipital cortex) might constitute unwanted action/sideeffects. Which of the myriad post-ECT biochemical alterations in the CNS and periphery, individually or in combination, reflect the therapeutic effect? And lastly, why and how does ECT alleviate signs and symptoms of major depression; surprisingly this issue appears to have drawn only a limited scientific attention and there is a paucity of published studies focusing on biochemical/molecular effects of ECT in Depression. In our study here Brain serotonin ( 5-HT2) receptors were considered potential targets for therapeutic efficacy of (ECT), but pre- clinical studies showed that electroconvulsive shock up-regulates 5-HT2 receptors in contrast to antidepressant medications, which down-regulate brain 5-HT2 receptors. PET studies in individuals with depression confirmed that antidepressant medications reduce brain 5-HT2 receptors, but the effects of ECT on these receptors in individuals with depression are unknown.it was concluded in this study that Unlike in rodents, and similar to antidepressants, ECT reduces brain 5-HT2 receptors in individuals with depression and the ability of ECT to further down- regulate brain 5-HT2 receptors in antidepressant non-responsive individuals may explain its efficacy in those people with antidepressant refractory depression ,this result is consistent with BANFF, ALBERTA in his research 2002 using PET shows that ECT and antidepressant therapy have similar effects on the brain's 5-HT2 receptors. The findings run contrary to this belief, according to Lakshmi N. Yatham, MD, of the Mood Disorders Clinical Research Unit, University of British Columbia, Canada. His team's aim was to determine the role 5-HT2 receptors play in relieving the symptoms of depression and the mechanisms of action in ECT in regulating those receptors. The study's finding is important, Dr. Yatham said, because animal studies previously showed antidepressants and ECT to influence 5-HT2 receptors in opposite directions -- with ECT up-regulating the receptors and antidepressants down-regulating them. Dr. Yatham said that little research has been done to determine whether the same effects occur in humans. As such, the researchers studied the effects of ECT, using PET scans to assess effects on 5-HT2 receptors. Dr. Yatham and colleagues had conducted a similar study of the effects of desipramine (Norpramine, Pertofrane) on 5-HT2 receptors over a four- to six-week period.In the new study, 16 patients who had been diagnosed with major depression and had been referred for ECT underwent two PET scans -- one before and another after treatment. Patients had to be 10 days drug free before the start of the study. Researchers used [18F] setoperone as a ligand to measure receptor activity. After treatment, the patients showed significant decreases in 5-HT2-receptor binding in several cortical areas -- the left occiptal gyrus, the right curneus and the left insula. "The important thing is that this shows that ECT down regulates 5-HT2 receptors in depressed patients in the same way that antidepressants do, which may explain why [those] treatments produce symptom relief," Dr. Yathsam said, adding that his earlier study found the same results following treatment with either desipramine or paroxetine. I personally believe that further studies are needed, to look at longer-term effects of either ECT or antidepressants on 5-HT2 receptor changes and to better understand why those changes occur. References Abrams R, Taylor MA, Volavka J. ECT-induced EEG asymmetry and therapeutic response in melancholia: relation totreatment electrode placement. Am J Psy-chiatry, 1987; 144: 327-329. Abrams R, Taylor MA. Diencephalic stimulation and the effects of ECT in endogenous depression. Br J Psy- chiatry. 1976; 129: 482-5. ... More

Conflict of interest: None Declared

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Support for the investigation of 5-HT receptor modulation in vivo, in humans.

Samuel P Leighton, Medical Student
28 June 2010

Dear sir, we welcome further insight into the role of brain 5-HT2 receptors in major depression. However, we have some points requiring clarification.

Firstly, it is difficult to make statistically significant inferencesfrom the data (p=<0.05) because of the small sample size, especially with regards to the suspected correlation between changes in [18F]setoperone binding and the change in Hamilton Rating Scale for Depression score. As the authors state that they have conducted methodologically similar studies in the past1, would a power calculation have been feasible in order to establish the minimum sample size required?

The authors point to previous pre-clinical studies which suggest thatlong-term antidepressants down-regulate 5-HT2 receptors, with an opposite effect being observed following electroconvulsive therapy (ECT). However, research in this field is conflicting, with some groups reporting up-regulation of 5-HT2 receptors following chronic antidepressant administration.2,3 At present, the majority of research into the role of 5-HT2 receptor modulation in depression is carried out in rats. Such conflicting results suggest that the rat is a poor model in which to address the role of receptor modulation in depression. Moreover, studies in rodents are mainly ex-vivo. This is an important methodological difference from those in humans, and may present a confounding factor for results interpretation. Therefore, we strongly agree with the authors thatfuture work must address this topic in vivo, in humans.

Given this, however, we must question the efficacy of [18F]setoperonePET scans in evaluating changes in brain 5-HT2 receptor density by proxy. Cortical extra-cellular serotonin is increased following long-term SSRI treatment and many groups highlight this as crucial to their therapeutic efficacy, perhaps through its predominantly inhibitory action on cortical glutamatergic neurotransmission via the 5-HT1A receptor.2 Elegant work by Zimmer et al highlights the effect of endogenous serotonin levels on the binding of PET radio-ligand to 5-HT receptors. Specifically, they show that [18F]MPPF specific-binding to the 5-HT1A receptor is down-regulated following a fenfluramine-induced serotonin increase.4 Accordingly, we suggest that in analysing the effect of ECT on brain 5-HT2 receptor density, the change in 5-HT2 binding potential (BPND) cannot be taken as directly related to a change in receptor density without first consideringthe effect of ECT on endogenous serotonin levels. For if, like SSRIs, ECT results in increased extra-cellular serotonin, this could independently down-modulate BPND without any change in receptor density.2,4

Finally, we note large differences in the length of depressive symptoms, previous anti-depressant medication and indeed number of ECTs participants received. We acknowledge that such variations are largely unavoidable because of the heterogeneous nature of major depression and its treatment. However, such confounders can make global interpretation ofresults precarious. One participant received only five ECTs which, at the stated rate of three times weekly, would mean his treatment was concluded in under two weeks. Is such a short time course compatible with transcriptional/translational modulation of 5-HT receptors? The Deakin hypothesis, explaining the delayed therapeutic effect of antidepressants, suggests that such receptor regulation occurs over a period of at least two to three weeks.5

References:1.Yatham LN, Liddle PF, Dennie, J, Shiah IS, Adam MJ, Lane CJ, et al. Decrease in brain serotonin-2 receptor binding in patients with major depression following desipramine treatment: a positron emission tomographystudy with fluorine-18-labeled setoperone. Arch Gen Psychiatry 1999; 56: 705-11.

2.Celada P, Puig MV, Amargós-Bosch M, Adell A, Artigas F. The therapeuticrole of 5-HT1A and 5-HT2A receptors in depression. Rev Psychiatr Neurosci 2004; 29 (4): 252-65.

3.Sato H, Skelin I, Diksic M. Chronic buspirone treatment decreases 5-HT1B receptor densities and the serotonin transporter but increases the density of 5-HT2A receptors in the bulbectomized rat model of depression: an autoradiographic study. Brain Res 2010; doi:10.1016/j.brainres.2010.05.054.

4.Zimmer L, Mauger G, Le Bars D, Bonmarchand G, Luxen A, Pujol JF. Effectof endogenous serotonin on the binding of the 5-h T1A PET ligand 18F-MPPF in the rat hippocampus: kinetic beta measurements combined with microdialysis. J Neurochem 2002; 80 (2): 278-86.

5.Deakin JFW. 5 –HT, antidepressant drugs and the psychosocial origins ofdepression. J Psychopharmacol 1996; 10: 31-38.
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Reduction of 5HT2 receptors following ECT - Relevance of the findings are far from clear

Rajeev Krishnadas, Clinical lecturer in psychological medicine
14 June 2010

Dear Editor,

In their study recently published in the journal, Yatham et al, show that a course of ECT decreases 5HT2 binding in individuals with depression. 1 The relevance of this decrease in 5HT2 binding to antidepressant mechanism of action remains far from clear.

In their study, a course of ECT seems to have reduced brain 5HT2 receptor binding by upto 6.7% in the region of maximum effect. As the authors rightly note, this is less that what has been shown with antidepressant medications by the same group. 2 The authors claim that this difference between treatments is possibly attributable to the fact that reductions related to ECT were superimposed on prior reductions associated with previous treatments, inspite of the fact that the patient population in the present study consisted of those who were refractory to antidepressant therapy and had undergone a washout period.

A recent meta-analysis conducted by the UK ECT Review group showed that ECT had a significantly greater antidepressant effect compared to medication therapy (13 trials; n=760). The effect size favoring ECT was large: 0.8 (95% confidence intervals [CI], 0.3-1.3); this means that the mean post-treatment depression score in ECT- treated patients was almost astandard deviation less than the mean of the whole sample. 3 So if the degree of 5HT2 reduction was significantly related to the decrease in symptoms, then clearly treatment with ECT should have shown a greater reduction in 5HT2 binding compared to antidepressants. In the present study, even though there was a significant improvement in depression scores in the population following treatment, correlation of the decrease in depressive symptoms with this “additional” reduction in 5HT2 binding showed only a trend towards significance after correction for multiple analysis. Is it possible that the small effect seen in this population maybe due to the fact that the population consisted of patients with treatment refractory depression?

It should however be noted that 5HT2A desensitisation can occur with or without receptor downregulation, this includes other mechanisms like receptor-effector uncoupling due to receptor phosphorylation and arrestin binding.4 These other mechanisms may also account for the small reduction of receptor binding inspite of the significant improvement in depressive symptoms seen in this study.

In their discussion, by comparing the effects of ECTs, with that of antidepressants and antipsychotics, the authors assume that the possible mechanisms of actions of these diverse treatments are similar. In case ofantidepressants/antipsychotics, it can be assumed that the downregulatory effects are either due to an agonist effect (due to the increase in extracellular serotonin) or due to an antagonistic effect (due to receptorblockade). However, in the case of ECTs, it still remains unclear if the reduction in binding is due to agonism or antagonism or due to mechanisms that are independent of 5HT2 receptor binding.

There are other factors that may be potential confounders in this study. The authors rightly note the effect of age, as this variable seems to have a floor effect on downregulation of 5HT2 receptors. In addition, the wide range of disease duration of the sample make the population heterogenous. As suggested earlier, the findings are also restricted to patients who are treatment refractory. Further factors that may need to beconsidered in the future may include the average dose of ECTs and the effect of bilateral electrode placement considering the fact that bilateral ECT seem to have a slightly greater antidepressant effects compared to unilateral ECT - effect size - small: 0.3 (95% CI, 0.2-0.5) and high dose ECT have been shown to have a greater antidepressant effect than low dose ECT - effect size - 0.6 (95% CI, 0.3-0.8) .

References

1. Yatham LN, Liddle PF, Lam RW, Zis AP, Stoessl AJ, Sossi V, et al. Effect of electroconvulsive therapy on brain 5-HT2 receptors in major depression. Br J Psychiatry 2010 196: 474-479.

2. UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta- analysis. Lancet 2003; 361: 799-808.

3. Yatham LN, Liddle PF, Dennie J, Shiah IS, Adam MJ, Lane CJ, et al.Decrease in brain serotonin-2 receptor binding in patients with major depression following desipramine treatment: a positron emission tomographystudy with fluorine-18-labeled setoperone. Arch Gen Psychiatry 1999; 56: 705 –11

4. Tobin AB. Phosphorylation of phospholipase C-coupled receptors. Pharmac Therapeutics 1997;75:135 – 51.
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