Int J Psychiatry Clin Pract 2014; 18: 261–264. © 2014 Informa Healthcare ISSN 1365-1501 print/ISSN 1471-1788 online. DOI: 10.3109/13651501.2014.941880
ORIGINAL ARTICLE
Effects of electroconvulsive therapy on plasma levels of neuroactive steroids in inpatients with major depression
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Şenol Turan1, Abdullah Yıldırım2, Cana Aksoy-Poyraz1, Murat Bolayırlı3 & Mert Savrun1 1
Department of Psychiatry, Medical School of Cerrahpasa, Istanbul University, Istanbul, Turkey, Department of Psychiatry, Bakırkoy Research and Training State Hospital , Istanbul, Turkey, and 3 Department of Medical Biochemistry, Medical School of Cerrahpasa, Istanbul University, Istanbul, Turkey
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2
Abstract Objectıve. Neuroactive steroids (NAS) are neuroactive molecules that have been shown to be associated with various psychiatric disorders. There are some inconclusive findings about the alteration in neuroactive steroid levels after the treatment of depression and ECT is still one of the most effective treatment choices for treatment resistant depression. Thus, we aimed to investigate the alterations of several NAS in plasma after ECT in inpatients with treatment resistant depression. Methods. In this study we enrolled 19 consecutive patients, 12 female and 7 male inpatients with major depression, who were not responding to medication, for whom ECT was Indicated, and were not taking any antidepressant treatment for at least a week prior to enrolment. We measured plasma progesterone, testosterone, pregnenolone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate, and estradiol levels before and after ECT. Results. The mean age of the participants was 38.3 ⫾ 9.4 years. The mean plasma neuroactive steroid levels were insignificant between baseline and post ECT in patients with treatment resistant depression. Conclusıons. ECT does not seem to influence plasma neuroactive steroid levels in patients with treatment resistant depression. Additionally, plasma dehydroepiandrosterone and pregnenolone levels might be associated with improvement in depressive symptoms after ECT. Key words: Neuroactive steroid, depression, ECT, dehydroepiandrosterone, pregnenolone (Received 10 April 2014; accepted 2 July 2014)
Introduction The involvement of neuroactive steroids (NAS) in the underlying mechanisms of pathophysiology, course, and treatment of depression has been debated for the last two decades. The data from preclinical studies have shown that some NAS have antidepressant like features in forced swimming test in experimental animal models of depression (Khisti et al. 2000; Urani et al. 2001; Maayan et al. 2005). Pregnenolone is derived from cholesterol and is the main precursor molecule for NAS which is converted into three physiologic pathways resulting NAS including: pregnenolone sulfate, progesterone, dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S), testosterone, estradiol (Maayan et al. 2005; Eser et al. 2006). Pregnenolone is suggested to reduce subjective depressive ratings in normal human beings (Meieran et al. 2004). In addition, pregnenolone has been found decreased in cerebro-spinal fluid (CSF) of depressed individuals which has been turned to normal levels after using antidepressants (Romeo et al. 1998; Uzunova et al. 1998). Progesterone may be produced by 3 β-hydroxysteroid dehydrogenase that might serve as precursor 3α-reduced NAS of which the concentrations Correspondence: Şenol Turan, MD, Specialist, Department of Psychiatry, Medical School of Cerrahpasa, Istanbul University, Turkey. Tel: ⫹ 90 212 4143000-22183, Fax: ⫹ 90 212 473 26 34, E-mail: senolturan81@ yahoo.com.tr
in CSF have generally been informed lower in patients with depression (Rupprecht 2003; Baghai et al. 2005). The association between depression and DHEA and DHEA-S is still inconclusive. However, the increased plasma level of DHEA-S (Maayan et al. 2000; Assies et al. 2004) has been found as a possible precursor in inpatients with psychotic depression who were nonresponsive to electroconvulsive therapy (ECT) (Maayan et al. 2000) and the possible antidepressant effect of DHEA (Maurice et al. 1996; Wolkowitz et al. 1999; Kurita et al. 2013) have been reported in several studies. DHEA and DHEA-S are the main precursors of estrogen and testosterone in peripheral tissues. Receiving estrogen in postmenopausal phase (Palinkas and BarrettConnor 1992) or replacement of lower testosterone in men or women (McHenry et al. 2014) is related with improvement in depressive mood. In literature there are some inconclusive findings about the alteration in NAS level after the treatment of depression of which some of them have been investigated non-pharmacological treatments such as repetitive transcranial magnetic stimulation (Padberg et al. 2002), sleep deprivation (Schule et al. 2003), and ECT (Baghai et al. 2005). ECT is still one of the most effective treatment choices for treatment resistant depression. Although plasma NAS changes are not essential in recovery of depression after non-pharmacological treatment, this proposal seems to be debatable (Dubrovsky 2006). Thus, in this study, we aimed
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to investigate the alterations of several NAS in plasma after ECT in inpatients with treatment resistant depression. Here we hypothesized that there would be significant changes among pregnenolone, progesterone, DHEA, DHEA-S, estradiol, and testosterone levels after ECT in inpatients with treatment resistant depression. Secondly, there would be some significant correlations between changes in abovementioned NAS level and response to ECT.
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Methods Participants A total of 20 treatment resistant depressed inpatients (13 women and 7 men) were included in this open-label prospective study. However, one female patient was excluded from the study, because of the development of mania after third ECT session. The participants were recruited from inpatients with major depression who have not responded to medication and for whom ECT was indicated in Cerrahpasa Medical School, during the period from January to September 2010. The inclusion criteria were as follows: i) ⬎ 18 and ⬍ 60 years old, ii) meeting the criteria of major depression according to Diagnostic and Statistical Manual of Mental Disorders IV, Text Revision, (APA, 2000), iii) indication for ECT as treatment resistance and/or suicide attempt, iv) at least drug free for 1 week and no ECT administration for 6 months. The exclusion criteria were as follows: i) depression due to general medical condition (i.e., endocrine pathologies such as hypothyroidism or Cushing Disease, cerebrovascular events, vasculitis, etc.) or drug use for such conditions (antihypertensive, anti-arrhythmic, NSAIDs, etc.), iii) previous or current any axis 1 disorder other than depression (related with substance/alcohol use, generalized anxiety, schizophrenia, etc.,), iv) women in menopause, being pregnant, or receiving contraceptives. Psychological assessment After filling out a socio-demographic inquiry, all patients were assessed according to Hamilton Depression Rating Scale (HAM-D) prior to ECT and after all ECT sessions have been completed. Hamilton depression rating scale The severity of the depressive symptoms was evaluated with the Hamilton Depression Rating Scale (Hamilton 1960) that is consisted of 17 sub-items. The Turkish availability and reliability is performed by Akdemir et al. (1996). Electroconvulsive therapy procedure The ECT procedure was performed as in our previous study (Bayar et al. 2009). ECT was performed between 8:00 h and 11:00 h. All patients were asked to fast for at least 6 h; none of them was wearing dentures, contact lenses, or jewelry; and all were wearing hospital clothing. The procedure room was equipped with a defibrillator and drugs necessary for cardiopulmonary resuscitation. Technical procedures were performed according to the standard routines of the laboratory. Electrodes were placed bilaterally on the temporal areas for electrical stimulus conduction. Propofol 1 mg/kg was
Int J Psychiatry Clin Pract 2014;18:261–264
administered as a short-acting anesthetic; atropine was not used as a preanesthetic because it influences heart rate and could mask possible bradyarrhythmias during the procedure. Curarization was done with succinylcholine (0.5 mg/kg). The Guedel airway was used to optimize oxygen ventilation with a mask and Ambu bag during the convulsive crisis; a protective device was placed between the dental arches. The ECT device has waves of the fixed, biphasic, and short-pulse type. The electrical charges ranged from 250 to 350 milli-Coulombs, and the current ranged from 550 to 800 milli-Amperes with a frequency of 0.5–2.0 seconds. Seizure was considered effective when lasting more than 20 seconds. Blood pressure, ECG tracing, and oxygen saturation index were monitored before and during each convulsive seizure because ventilation was not interrupted during convulsion. After the seizures, all patients remained under medical and nursing care until complete recovery. Blood sample for NAS level The blood samples were collected at baseline and post treatment when patients reached remission. Blood samples for progesterone (normal range for women: 0.75–20 ng/ml and for men: ⬍1.2 ng/ml), testosterone (normal range for women (w): ⬍2.2 ng/ml and for men (m): 3–20 ng/ml), pregnenolone (for w: 0.31–3.8 ng/ml and m: 0.38–3.5 ng/ ml), DHEA (for w: 1–12 ng/ml and m: 3–11 ng/ml), DHEA-S (for w: 0.46–2.75 μg/ml and m: 0.39–4.63 μg/ml), and estradiol (for w: 15–400pg/ml and m: ⬍100pg/ml) were drawn in the morning around 08:00 A.M. from a fore arm vein of the participants at the end of an overnight fasting period for at least 8 hours. Tubes with 5-milliliter capacity and containing EDTA were used to collect blood. Then, the blood was carefully and immediately (in a few seconds) transferred from these tubes to centrifuge tubes. After the centrifuge process at 3000 rpm for 15 min, the serum was obtained and stored at ⫺80°C until the time of enzyme linked immunosorbent assay (ELISA). The study was performed in accordance with the Declaration of Helsinki and International Conference on Harmonisation/Good Clinical Practice guidelines. All patients who participated in the study provided written informed consent, and the study has received full Local Research Ethics Committee approval. Statistical analysis Statistical analysis was performed with SPSS for Windows version 16.0 (SPSS Inc, Chicago, Il, USA). The frequencies and means ⫾ SD of data were given in the text. The baseline and post treatment data on serum NAS levels were compared with Wilcoxon Signed Rank test in total group and in women or men patients. Correlations among plasma NAS levels and HAM-D were made by Spearman Correlation Test. A p value less than 0.05 was considered as statistically significant. Results The study included 19 inpatients with treatment resistant depression (12 were women while 7 of them were men). The
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DOI: 10.3109/13651501.2014.941880
mean age of the participants was 38.3 ⫾ 9.4 years. Seventeen of the participants were married while two of them were single. The socio-demographic features of the participants were shown in Table I. The baseline depression score according to HAM-D was 23.9 ⫾ 3.3 points and that was decreased to 11.7 ⫾ 5.9 points after ECT (p ⬍ 0.01). The mean plasma NAS levels were insignificant between baseline and post treatment in patients with treatment resistant depression according to progesterone level (0.66 ⫾ 0.66 ng/ml vs 1.21 ⫾ 1.98 ng/ml and p ⫽ 0.53), testosterone level (2.44 ⫾ 2.11 ng/ml vs 3.37 ⫾ 3.30 ng/ml, p ⫽ 0.40), pregnenolone level (7.13 ⫾ 6.71 ng/ml vs 11.11 ⫾ 8.83 ng/ml, p ⫽ 0.18), DHEA level (18.63 ⫾ 11.22 ng/ml vs 22.76 ⫾ 12.34 ng/ml, p ⫽ 0.31), DHEA-S level (2.49 ⫾ 2.09 μg/ml vs 2.51 ⫾ 1.20 μg/ml, p ⫽ 0.28), and estradiol level (97.15 ⫾ 60.953pg/ml vs 99.68 ⫾ 54.42pg/ml, p ⫽ 0.72) (Table II). Additionally, we have investigated the alterations in NAS levels between baseline and post ECT among women and men inpatients with treatment resistant depression. There were no significant changes in plasma NAS levels (i.e., progesterone, testosterone, pregnenolone, DHEA, DHEA-S, estradiol) between baseline and after ECT among women inpatients with treatment resistant depression (p ⬎ 0.05 for all). The only significant change between baseline and post ECT was DHEA-S level (p ⫽ 0.05) while the rest of them have remained to be insignificant (p ⬎ 0.05) (Table III). The correlations between baseline and post plasma NAS levels and HAM-D scale were insignificant while there was a negative correlation between plasma pregnenolone level (p ⫽ 0.016, r ⫽ ⫺ 0.545) and plasma DHEA level (p ⫽ 0.014, r ⫽ ⫺ 0.552) and HAM-D mean scores post ECT. Discussion In the current study, no changes have been detected in plasma NAS levels after ECT in treatment resistant depression which was contrary to predictions of our hypothesis. In several clinical and preclinical studies, besides improvement in depressive symptoms, alterations in plasma NAS after antidepressant treatments have been reported (Romeo et al. 1998; Uzunova et al. 1998; Uzunova et al. 2004).
38.3 ⫾ 9.4 Gender Women/Men Education: Primary Middle High school Marital status Married Single Occupational status Unemployed Worker Servant House-wife
HAM-D Progesterone Testosterone Pregnenolone DHEA DHEA-S Estradiol
Baseline n ⫽ 19 (mean ⫾ SD)
Post ECT n ⫽ 19 (mean ⫾ SD)
p
23.9 ⫾ 3.3 0.66 ⫾ 0.66 2.44 ⫾ 2.11 7.13 ⫾ 6.71 18.63 ⫾ 11.22 2.49 ⫾ 2.09 97.15 ⫾ 60.95
11.7 ⫾ 5.9 1.21 ⫾ 1.98 3.37 ⫾ 3.30 11.11 ⫾ 8.83 22.76 ⫾ 12.34 2.51 ⫾ 1.20 99.68 ⫾ 54.42
⬍0.001 0.53 0.40 0.18 0.31 0.28 0.72
However, no alterations have been shown in the plasma NAS levels of clinically remitted depressive patients after non-pharmacological treatments such as transcranial magnetic stimulation (Padberg et al. 2002), partial sleep deprivation (Schule et al. 2003), or ECT (Baghai et al. 2005). Thus, although a substantial improvement in the depressive symptoms with both pharmacological and/or nonpharmacological treatments have been reported, we considered that the unchanged plasma NAS level after ECT in our study might be due to paracrine effect of NAS (Dubrovsky 2006). In the current study, we have revealed some significant correlations between plasma NAS levels and improvement in HAM-D scores after ECT in treatment resistant depressive patients. Plasma pregnenolone and DHEA levels were negatively correlated with mean HAM-D scores. In a double blind study about the treatment of depression, a significant decrement has been found in HAM-D scores after receiving DHEA (Wolkowitz et al. 1999). Thus, we suggested that DHEA is related with improvement in depressive symptoms in patients who were under ECT. In addition, plasma DHEA and DHEA-S were higher in baseline in depressive patients than healthy controls in a study by Maayan et al. (2000) in which higher plasma DHEA-S levels were suggested to be related with nonresponsiveness to ECT. Therefore, having a healthy control group in our study would be more informative about the relationship between DHEA and treatment response. Likewise, Table III. The alterations of clinical and laboratory data in women and men inpatients.
Table I. The socio-demographic features of the patients.
Age (mean ⫾ SD)
Table II. The baseline and post ECT clinical assessment and laboratory data of among total groups.
n
%
12/7
63.2/36.8
12 5 2
63.2 26.3 10.5
17 2
89.5 10.5
4 1 4 10
21.1 5.3 21.1 52.6
Women n ⫽ 12 Men n ⫽ 7
Baseline (mean ⫾ SD)
Post ECT (mean ⫾ SD)
HAM-D
23.5 ⫾ 2.5 24.5 ⫾ 4.5 0.71 ⫾ 0.75 0.57 ⫾ 0.50 1.04 ⫾ 0.40 4.84 ⫾ 1.58 7.85 ⫾ 8.27 5.91 ⫾ 2.66 18.33 ⫾ 11.89 19.14 ⫾ 10.85 2.80 ⫾ 2.56 1.96 ⫾ 0.74 111.12 ⫾ 68.46 71.14 ⫾ 36.09
10.9 ⫾ 5.2 13.1 ⫾ 7.0 1.58 ⫾ 2.45 0.57 ⫾ 0.24 2.14 ⫾ 3.58 5.47 ⫾ 1.06 11.00 ⫾ 8.93 11.32 ⫾ 9.35 21.55 ⫾ 13.27 24.85 ⫾ 11.25 2.04 ⫾ 0.92 3.32 ⫾ 1.25 96.33 ⫾ 58.68 111.05 ⫾ 50.10
Progesterone Testosterone Pregnenolone DHEA DHEA-S Estradiol
p ⬍0.001 0.01 0.44 0.53 0.44 0.31 0.47 0.31 0.67 0.32 0.67 0.05 0.71 0.13
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we have revealed a negative correlation between plasma pregnenolone level and HAM-D scores after ECT. In previous research, it was found that the pregnenolone level was lower in the CSF and plasma of patients with depression, and it reached normal ranges after antidepressant treatment (Romeo et al. 1998; Uzunova et al. 1998; Strohle et al. 1999). Thus, our finding of negative correlation between plasma pregnenolone and HAM-D score is in line with these studies. There are several limitations of this study. Small sample size and lack of healthy comparison groups are important limitations while interpreting our negative and/or positive findings. Plasma NAS is suggested to be different among genders (Ozsoy et al. 2008), thereby comparing NAS in female/male patients with depression after ECT would be more informative. In conclusion, ECT does not seem to influence plasma NAS levels in patients with treatment resistant depression. Additionally, serum DHEA and pregnenolone levels might be associated with improvement in depressive symptoms after ECT. Key points • • •
No changes have been detected in plasma NAS levels after ECT in treatment resistant depression. Plasma DHEA and pregnenolone levels might be associated with improvement in depressive symptoms after ECT. ECT is an effective treatment modality of treatment resistant depression.
Acknowledgement The study team would like to thank all the patients that have made this study possible. Also, we would like to thank the members of the Scientific Research Projects Coordination Unit of Istanbul University Statement of interest The authors declare that they have no conflicts of interest in the research. This study was funded by the Scientific Research Projects Coordination Unit of Istanbul University. References Akdemir A, Orsel S, Dağ I, Türkçapar H, Işcan N, Ozbay H. 1996. The Turkish validity and reliability of Hamilton Depression Rating Scale and its use in clinical practice. Journal of Psikiyatri Psikoloji Psikofarmakoloji 4:251–259 (in Turkish). American Psychiatric Association. 2000. Diagnostic and Statistical Manual of Mental Disorders IV, Text Revision (DSM-IV-TR). Assies J, Visser I, Nicolson NA, Eggelte TA, Wekking EM, Huyser J, et al. 2004. Elevated salivary dehydroepiandrosterone-sulfate but normal cortisol levels in medicated depressed patients: preliminary findings. Psychiatry Res 128:117–122. Baghai TC, di Michele F, Schule C, Eser D, Zwanzger P, Pasini A, et al. 2005. Plasma concentrations of neuroactive steroids before and after electroconvulsive therapy in major depression. Neuropsychopharmacology 30:1181–1186. Bayar R, Emul M, Turan S, Zerdali H, Salihoglu T, Duran A, et al. 2009. Electrocardiographical P wave changes after electroconvulsive therapy in patients with schizophrenia: a preliminary study. J ECT 25:26–30. Dubrovsky B. 2006. Neurosteroids, neuroactive steroids, and symptoms of affective disorders. Pharmacol Biochem Behav 84:644–655.
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Eser D, Schule C, Baghai TC, Romeo E, Uzunov DP, Rupprecht R. 2006. Neuroactive steroids and affective disorders. Pharmacol Biochem Behav 84:656–666. Hamilton M. 1960. A rating scale for depression. J Neurol Neurosurg Psychiatry. 23:56–62. Khisti RT, Chopde CT, Jain SP. 2000. Antidepressant-like effect of the neurosteroid 3 alpha-hydroxy-5alpha-pregnan-20-one in mice forced swim test. Pharmacol Biochem Behav 67:137–143. Kurita H, Maeshima H, Kida S, Matsuzaka H, Shimano T, Nakano Y, et al. 2013. Serum dehydroepiandrosterone (DHEA) and DHEAsulfate (S) levels in medicated patients with major depressive disorder compared with controls. J Affect Disord 146:205–212. Maayan R, Morad O, Dorfman P, Overstreet DH, Weizman A, Yadid G. 2005. The involvement of dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) in blocking the therapeutic effect of electroconvulsive shocks in an animal model of depression. Eur Neuropsychopharmacol 15:253–262. Maayan R, Yagorowski Y, Grupper D, Weiss M, Shtaif B, Kaoud MA, et al. 2000. Basal plasma dehydroepiandrosterone sulfate level: a possible predictor for response to electroconvulsive therapy in depressed psychotic inpatients. Biol Psychiatry 48: 693–701. Maurice T, Roman FJ, Privat A. Modulation by neurosteroids of the in vivo (⫹)-[3H] SKF-10,047 binding to sigma 1 receptors in the mouse forebrain. 1996. J Neurosci Res 46: 734–743. McHenry J, Carrier N, Hull E, Kabbaj M. 2014. Sex differences in anxiety and depression: Role of testosterone. Front Neuroendocrinol 35:42–57. Meieran SE, Reus VI, Webster R, Shafton R, Wolkowitz OM. 2004. Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation. Psychoneuroendocrinology 29: 486–500. Ozsoy S, Esel E, Hacimusalar Y, Candan Z, Kula M, Turan T. 2008. Acute and chronic effects of electroconvulsive therapy on neuroactive steroids in patients with major depressive disorder. Turk Psikiyatri Derg 19:341–348. Padberg F, di Michele F, Zwanzger R, Romeo E, Bernardi G, Schule C, et al. 2002. Plasma concentrations of neuroactive steroids before and after repetitive transcranial magnetic stimulation (rTMS) in depression. Neuropsychopharmacology 27:874–878. Palinkas L, Barret-Connor E. 1992. Estrogen use and depressive symptoms in postmenopausal women. Obstet Gynecol 80: 30–36. Romeo E, Strohle A, Spaelleta G, di Michele F, Herman B, Holsboer F. 1998. Effects of antidepressant treatment on neuractive steroids in major depression. Am J Psychiatry 155:910–913. Rupprecht R. 2003. Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties. Psychoneuroendocrinology 28:139–168. Schule C, di Michele F, Baghai T, Romeo E, Bernardi G, Zwanzger R. 2003. Influence of sleep deprivation on neuroactive steroids in major depression. Neuropsychopharmacology 28:577–581. Strohle A, Romeo E, Hermann B, Pasini A, Spalletta G, di Michele F, et al. 1999. Concentrations of 3 alpha-reduced neuroactive steroids and their precursors in plasma of patients with major depression and after clinical recovery. Biol Psychiatry 45:274–277. Urani A, Roman FJ, Phan VL, Su TP, Maurice T. 2001. The antidepressant-like effect induced by sigma(1)-receptor agonists and neuroactive steroids in mice submitted to the forced swimming test. J Pharmacol Exp Ther 298:1269–1279. Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, et al. 1998. Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci 95:3239–3244. Uzunova V, Wrynn AS, Kinnunen A, Ceci M, Kohler C, Uzunov DP. 2004. Chronic antidepressants reverse cerebrocortical allopregnanolone decline in the olfactory-bulbectomized rat. Eur J Pharmacol 486:31–34. Wolkowitz OM, Reus VI, Keebler A, Nelson N, Friedland M, Brizendine L, Roberts E. 1999. Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry 156: 646–649.
ORIGINAL ARTICLE
Effects of electroconvulsive therapy on plasma levels of neuroactive steroids in inpatients with major depression
informahealthcare.com/ijpcp
Şenol Turan1, Abdullah Yıldırım2, Cana Aksoy-Poyraz1, Murat Bolayırlı3 & Mert Savrun1 1
Department of Psychiatry, Medical School of Cerrahpasa, Istanbul University, Istanbul, Turkey, Department of Psychiatry, Bakırkoy Research and Training State Hospital , Istanbul, Turkey, and 3 Department of Medical Biochemistry, Medical School of Cerrahpasa, Istanbul University, Istanbul, Turkey
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2
Abstract Objectıve. Neuroactive steroids (NAS) are neuroactive molecules that have been shown to be associated with various psychiatric disorders. There are some inconclusive findings about the alteration in neuroactive steroid levels after the treatment of depression and ECT is still one of the most effective treatment choices for treatment resistant depression. Thus, we aimed to investigate the alterations of several NAS in plasma after ECT in inpatients with treatment resistant depression. Methods. In this study we enrolled 19 consecutive patients, 12 female and 7 male inpatients with major depression, who were not responding to medication, for whom ECT was Indicated, and were not taking any antidepressant treatment for at least a week prior to enrolment. We measured plasma progesterone, testosterone, pregnenolone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate, and estradiol levels before and after ECT. Results. The mean age of the participants was 38.3 ⫾ 9.4 years. The mean plasma neuroactive steroid levels were insignificant between baseline and post ECT in patients with treatment resistant depression. Conclusıons. ECT does not seem to influence plasma neuroactive steroid levels in patients with treatment resistant depression. Additionally, plasma dehydroepiandrosterone and pregnenolone levels might be associated with improvement in depressive symptoms after ECT. Key words: Neuroactive steroid, depression, ECT, dehydroepiandrosterone, pregnenolone (Received 10 April 2014; accepted 2 July 2014)
Introduction The involvement of neuroactive steroids (NAS) in the underlying mechanisms of pathophysiology, course, and treatment of depression has been debated for the last two decades. The data from preclinical studies have shown that some NAS have antidepressant like features in forced swimming test in experimental animal models of depression (Khisti et al. 2000; Urani et al. 2001; Maayan et al. 2005). Pregnenolone is derived from cholesterol and is the main precursor molecule for NAS which is converted into three physiologic pathways resulting NAS including: pregnenolone sulfate, progesterone, dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S), testosterone, estradiol (Maayan et al. 2005; Eser et al. 2006). Pregnenolone is suggested to reduce subjective depressive ratings in normal human beings (Meieran et al. 2004). In addition, pregnenolone has been found decreased in cerebro-spinal fluid (CSF) of depressed individuals which has been turned to normal levels after using antidepressants (Romeo et al. 1998; Uzunova et al. 1998). Progesterone may be produced by 3 β-hydroxysteroid dehydrogenase that might serve as precursor 3α-reduced NAS of which the concentrations Correspondence: Şenol Turan, MD, Specialist, Department of Psychiatry, Medical School of Cerrahpasa, Istanbul University, Turkey. Tel: ⫹ 90 212 4143000-22183, Fax: ⫹ 90 212 473 26 34, E-mail: senolturan81@ yahoo.com.tr
in CSF have generally been informed lower in patients with depression (Rupprecht 2003; Baghai et al. 2005). The association between depression and DHEA and DHEA-S is still inconclusive. However, the increased plasma level of DHEA-S (Maayan et al. 2000; Assies et al. 2004) has been found as a possible precursor in inpatients with psychotic depression who were nonresponsive to electroconvulsive therapy (ECT) (Maayan et al. 2000) and the possible antidepressant effect of DHEA (Maurice et al. 1996; Wolkowitz et al. 1999; Kurita et al. 2013) have been reported in several studies. DHEA and DHEA-S are the main precursors of estrogen and testosterone in peripheral tissues. Receiving estrogen in postmenopausal phase (Palinkas and BarrettConnor 1992) or replacement of lower testosterone in men or women (McHenry et al. 2014) is related with improvement in depressive mood. In literature there are some inconclusive findings about the alteration in NAS level after the treatment of depression of which some of them have been investigated non-pharmacological treatments such as repetitive transcranial magnetic stimulation (Padberg et al. 2002), sleep deprivation (Schule et al. 2003), and ECT (Baghai et al. 2005). ECT is still one of the most effective treatment choices for treatment resistant depression. Although plasma NAS changes are not essential in recovery of depression after non-pharmacological treatment, this proposal seems to be debatable (Dubrovsky 2006). Thus, in this study, we aimed
262
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to investigate the alterations of several NAS in plasma after ECT in inpatients with treatment resistant depression. Here we hypothesized that there would be significant changes among pregnenolone, progesterone, DHEA, DHEA-S, estradiol, and testosterone levels after ECT in inpatients with treatment resistant depression. Secondly, there would be some significant correlations between changes in abovementioned NAS level and response to ECT.
Int J Psych Clin Pract Downloaded from informahealthcare.com by Nyu Medical Center on 02/15/15 For personal use only.
Methods Participants A total of 20 treatment resistant depressed inpatients (13 women and 7 men) were included in this open-label prospective study. However, one female patient was excluded from the study, because of the development of mania after third ECT session. The participants were recruited from inpatients with major depression who have not responded to medication and for whom ECT was indicated in Cerrahpasa Medical School, during the period from January to September 2010. The inclusion criteria were as follows: i) ⬎ 18 and ⬍ 60 years old, ii) meeting the criteria of major depression according to Diagnostic and Statistical Manual of Mental Disorders IV, Text Revision, (APA, 2000), iii) indication for ECT as treatment resistance and/or suicide attempt, iv) at least drug free for 1 week and no ECT administration for 6 months. The exclusion criteria were as follows: i) depression due to general medical condition (i.e., endocrine pathologies such as hypothyroidism or Cushing Disease, cerebrovascular events, vasculitis, etc.) or drug use for such conditions (antihypertensive, anti-arrhythmic, NSAIDs, etc.), iii) previous or current any axis 1 disorder other than depression (related with substance/alcohol use, generalized anxiety, schizophrenia, etc.,), iv) women in menopause, being pregnant, or receiving contraceptives. Psychological assessment After filling out a socio-demographic inquiry, all patients were assessed according to Hamilton Depression Rating Scale (HAM-D) prior to ECT and after all ECT sessions have been completed. Hamilton depression rating scale The severity of the depressive symptoms was evaluated with the Hamilton Depression Rating Scale (Hamilton 1960) that is consisted of 17 sub-items. The Turkish availability and reliability is performed by Akdemir et al. (1996). Electroconvulsive therapy procedure The ECT procedure was performed as in our previous study (Bayar et al. 2009). ECT was performed between 8:00 h and 11:00 h. All patients were asked to fast for at least 6 h; none of them was wearing dentures, contact lenses, or jewelry; and all were wearing hospital clothing. The procedure room was equipped with a defibrillator and drugs necessary for cardiopulmonary resuscitation. Technical procedures were performed according to the standard routines of the laboratory. Electrodes were placed bilaterally on the temporal areas for electrical stimulus conduction. Propofol 1 mg/kg was
Int J Psychiatry Clin Pract 2014;18:261–264
administered as a short-acting anesthetic; atropine was not used as a preanesthetic because it influences heart rate and could mask possible bradyarrhythmias during the procedure. Curarization was done with succinylcholine (0.5 mg/kg). The Guedel airway was used to optimize oxygen ventilation with a mask and Ambu bag during the convulsive crisis; a protective device was placed between the dental arches. The ECT device has waves of the fixed, biphasic, and short-pulse type. The electrical charges ranged from 250 to 350 milli-Coulombs, and the current ranged from 550 to 800 milli-Amperes with a frequency of 0.5–2.0 seconds. Seizure was considered effective when lasting more than 20 seconds. Blood pressure, ECG tracing, and oxygen saturation index were monitored before and during each convulsive seizure because ventilation was not interrupted during convulsion. After the seizures, all patients remained under medical and nursing care until complete recovery. Blood sample for NAS level The blood samples were collected at baseline and post treatment when patients reached remission. Blood samples for progesterone (normal range for women: 0.75–20 ng/ml and for men: ⬍1.2 ng/ml), testosterone (normal range for women (w): ⬍2.2 ng/ml and for men (m): 3–20 ng/ml), pregnenolone (for w: 0.31–3.8 ng/ml and m: 0.38–3.5 ng/ ml), DHEA (for w: 1–12 ng/ml and m: 3–11 ng/ml), DHEA-S (for w: 0.46–2.75 μg/ml and m: 0.39–4.63 μg/ml), and estradiol (for w: 15–400pg/ml and m: ⬍100pg/ml) were drawn in the morning around 08:00 A.M. from a fore arm vein of the participants at the end of an overnight fasting period for at least 8 hours. Tubes with 5-milliliter capacity and containing EDTA were used to collect blood. Then, the blood was carefully and immediately (in a few seconds) transferred from these tubes to centrifuge tubes. After the centrifuge process at 3000 rpm for 15 min, the serum was obtained and stored at ⫺80°C until the time of enzyme linked immunosorbent assay (ELISA). The study was performed in accordance with the Declaration of Helsinki and International Conference on Harmonisation/Good Clinical Practice guidelines. All patients who participated in the study provided written informed consent, and the study has received full Local Research Ethics Committee approval. Statistical analysis Statistical analysis was performed with SPSS for Windows version 16.0 (SPSS Inc, Chicago, Il, USA). The frequencies and means ⫾ SD of data were given in the text. The baseline and post treatment data on serum NAS levels were compared with Wilcoxon Signed Rank test in total group and in women or men patients. Correlations among plasma NAS levels and HAM-D were made by Spearman Correlation Test. A p value less than 0.05 was considered as statistically significant. Results The study included 19 inpatients with treatment resistant depression (12 were women while 7 of them were men). The
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DOI: 10.3109/13651501.2014.941880
mean age of the participants was 38.3 ⫾ 9.4 years. Seventeen of the participants were married while two of them were single. The socio-demographic features of the participants were shown in Table I. The baseline depression score according to HAM-D was 23.9 ⫾ 3.3 points and that was decreased to 11.7 ⫾ 5.9 points after ECT (p ⬍ 0.01). The mean plasma NAS levels were insignificant between baseline and post treatment in patients with treatment resistant depression according to progesterone level (0.66 ⫾ 0.66 ng/ml vs 1.21 ⫾ 1.98 ng/ml and p ⫽ 0.53), testosterone level (2.44 ⫾ 2.11 ng/ml vs 3.37 ⫾ 3.30 ng/ml, p ⫽ 0.40), pregnenolone level (7.13 ⫾ 6.71 ng/ml vs 11.11 ⫾ 8.83 ng/ml, p ⫽ 0.18), DHEA level (18.63 ⫾ 11.22 ng/ml vs 22.76 ⫾ 12.34 ng/ml, p ⫽ 0.31), DHEA-S level (2.49 ⫾ 2.09 μg/ml vs 2.51 ⫾ 1.20 μg/ml, p ⫽ 0.28), and estradiol level (97.15 ⫾ 60.953pg/ml vs 99.68 ⫾ 54.42pg/ml, p ⫽ 0.72) (Table II). Additionally, we have investigated the alterations in NAS levels between baseline and post ECT among women and men inpatients with treatment resistant depression. There were no significant changes in plasma NAS levels (i.e., progesterone, testosterone, pregnenolone, DHEA, DHEA-S, estradiol) between baseline and after ECT among women inpatients with treatment resistant depression (p ⬎ 0.05 for all). The only significant change between baseline and post ECT was DHEA-S level (p ⫽ 0.05) while the rest of them have remained to be insignificant (p ⬎ 0.05) (Table III). The correlations between baseline and post plasma NAS levels and HAM-D scale were insignificant while there was a negative correlation between plasma pregnenolone level (p ⫽ 0.016, r ⫽ ⫺ 0.545) and plasma DHEA level (p ⫽ 0.014, r ⫽ ⫺ 0.552) and HAM-D mean scores post ECT. Discussion In the current study, no changes have been detected in plasma NAS levels after ECT in treatment resistant depression which was contrary to predictions of our hypothesis. In several clinical and preclinical studies, besides improvement in depressive symptoms, alterations in plasma NAS after antidepressant treatments have been reported (Romeo et al. 1998; Uzunova et al. 1998; Uzunova et al. 2004).
38.3 ⫾ 9.4 Gender Women/Men Education: Primary Middle High school Marital status Married Single Occupational status Unemployed Worker Servant House-wife
HAM-D Progesterone Testosterone Pregnenolone DHEA DHEA-S Estradiol
Baseline n ⫽ 19 (mean ⫾ SD)
Post ECT n ⫽ 19 (mean ⫾ SD)
p
23.9 ⫾ 3.3 0.66 ⫾ 0.66 2.44 ⫾ 2.11 7.13 ⫾ 6.71 18.63 ⫾ 11.22 2.49 ⫾ 2.09 97.15 ⫾ 60.95
11.7 ⫾ 5.9 1.21 ⫾ 1.98 3.37 ⫾ 3.30 11.11 ⫾ 8.83 22.76 ⫾ 12.34 2.51 ⫾ 1.20 99.68 ⫾ 54.42
⬍0.001 0.53 0.40 0.18 0.31 0.28 0.72
However, no alterations have been shown in the plasma NAS levels of clinically remitted depressive patients after non-pharmacological treatments such as transcranial magnetic stimulation (Padberg et al. 2002), partial sleep deprivation (Schule et al. 2003), or ECT (Baghai et al. 2005). Thus, although a substantial improvement in the depressive symptoms with both pharmacological and/or nonpharmacological treatments have been reported, we considered that the unchanged plasma NAS level after ECT in our study might be due to paracrine effect of NAS (Dubrovsky 2006). In the current study, we have revealed some significant correlations between plasma NAS levels and improvement in HAM-D scores after ECT in treatment resistant depressive patients. Plasma pregnenolone and DHEA levels were negatively correlated with mean HAM-D scores. In a double blind study about the treatment of depression, a significant decrement has been found in HAM-D scores after receiving DHEA (Wolkowitz et al. 1999). Thus, we suggested that DHEA is related with improvement in depressive symptoms in patients who were under ECT. In addition, plasma DHEA and DHEA-S were higher in baseline in depressive patients than healthy controls in a study by Maayan et al. (2000) in which higher plasma DHEA-S levels were suggested to be related with nonresponsiveness to ECT. Therefore, having a healthy control group in our study would be more informative about the relationship between DHEA and treatment response. Likewise, Table III. The alterations of clinical and laboratory data in women and men inpatients.
Table I. The socio-demographic features of the patients.
Age (mean ⫾ SD)
Table II. The baseline and post ECT clinical assessment and laboratory data of among total groups.
n
%
12/7
63.2/36.8
12 5 2
63.2 26.3 10.5
17 2
89.5 10.5
4 1 4 10
21.1 5.3 21.1 52.6
Women n ⫽ 12 Men n ⫽ 7
Baseline (mean ⫾ SD)
Post ECT (mean ⫾ SD)
HAM-D
23.5 ⫾ 2.5 24.5 ⫾ 4.5 0.71 ⫾ 0.75 0.57 ⫾ 0.50 1.04 ⫾ 0.40 4.84 ⫾ 1.58 7.85 ⫾ 8.27 5.91 ⫾ 2.66 18.33 ⫾ 11.89 19.14 ⫾ 10.85 2.80 ⫾ 2.56 1.96 ⫾ 0.74 111.12 ⫾ 68.46 71.14 ⫾ 36.09
10.9 ⫾ 5.2 13.1 ⫾ 7.0 1.58 ⫾ 2.45 0.57 ⫾ 0.24 2.14 ⫾ 3.58 5.47 ⫾ 1.06 11.00 ⫾ 8.93 11.32 ⫾ 9.35 21.55 ⫾ 13.27 24.85 ⫾ 11.25 2.04 ⫾ 0.92 3.32 ⫾ 1.25 96.33 ⫾ 58.68 111.05 ⫾ 50.10
Progesterone Testosterone Pregnenolone DHEA DHEA-S Estradiol
p ⬍0.001 0.01 0.44 0.53 0.44 0.31 0.47 0.31 0.67 0.32 0.67 0.05 0.71 0.13
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we have revealed a negative correlation between plasma pregnenolone level and HAM-D scores after ECT. In previous research, it was found that the pregnenolone level was lower in the CSF and plasma of patients with depression, and it reached normal ranges after antidepressant treatment (Romeo et al. 1998; Uzunova et al. 1998; Strohle et al. 1999). Thus, our finding of negative correlation between plasma pregnenolone and HAM-D score is in line with these studies. There are several limitations of this study. Small sample size and lack of healthy comparison groups are important limitations while interpreting our negative and/or positive findings. Plasma NAS is suggested to be different among genders (Ozsoy et al. 2008), thereby comparing NAS in female/male patients with depression after ECT would be more informative. In conclusion, ECT does not seem to influence plasma NAS levels in patients with treatment resistant depression. Additionally, serum DHEA and pregnenolone levels might be associated with improvement in depressive symptoms after ECT. Key points • • •
No changes have been detected in plasma NAS levels after ECT in treatment resistant depression. Plasma DHEA and pregnenolone levels might be associated with improvement in depressive symptoms after ECT. ECT is an effective treatment modality of treatment resistant depression.
Acknowledgement The study team would like to thank all the patients that have made this study possible. Also, we would like to thank the members of the Scientific Research Projects Coordination Unit of Istanbul University Statement of interest The authors declare that they have no conflicts of interest in the research. This study was funded by the Scientific Research Projects Coordination Unit of Istanbul University. References Akdemir A, Orsel S, Dağ I, Türkçapar H, Işcan N, Ozbay H. 1996. The Turkish validity and reliability of Hamilton Depression Rating Scale and its use in clinical practice. Journal of Psikiyatri Psikoloji Psikofarmakoloji 4:251–259 (in Turkish). American Psychiatric Association. 2000. Diagnostic and Statistical Manual of Mental Disorders IV, Text Revision (DSM-IV-TR). Assies J, Visser I, Nicolson NA, Eggelte TA, Wekking EM, Huyser J, et al. 2004. Elevated salivary dehydroepiandrosterone-sulfate but normal cortisol levels in medicated depressed patients: preliminary findings. Psychiatry Res 128:117–122. Baghai TC, di Michele F, Schule C, Eser D, Zwanzger P, Pasini A, et al. 2005. Plasma concentrations of neuroactive steroids before and after electroconvulsive therapy in major depression. Neuropsychopharmacology 30:1181–1186. Bayar R, Emul M, Turan S, Zerdali H, Salihoglu T, Duran A, et al. 2009. Electrocardiographical P wave changes after electroconvulsive therapy in patients with schizophrenia: a preliminary study. J ECT 25:26–30. Dubrovsky B. 2006. Neurosteroids, neuroactive steroids, and symptoms of affective disorders. Pharmacol Biochem Behav 84:644–655.
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