Skip to main content Accessibility help
×
Home
Hostname: page-component-747cfc64b6-bv7lh Total loading time: 0.255 Render date: 2021-06-16T01:34:24.301Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "metricsAbstractViews": false, "figures": true, "newCiteModal": false, "newCitedByModal": true, "newEcommerce": true }

Nitric Oxide Synthase activity in major depressive episodes before and after antidepressant treatment: Results of a large case-control treatment study

Published online by Cambridge University Press:  11 June 2020

E. Loeb
Affiliation:
INSERM CESP - Equipe ‘Moods’- Univ Paris-Saclay, 94275 Le Kremlin Bicêtre, France Service de Psychiatrie- Hôpital Bicêtre- GH Paris Saclay- APHP, 94275 Le Kremlin Bicêtre, France Faculté de Médecine Paris-Saclay, 94275 Le Kremlin Bicêtre, France
K. El Asmar
Affiliation:
INSERM CESP - Equipe ‘Moods’- Univ Paris-Saclay, 94275 Le Kremlin Bicêtre, France
S. Trabado
Affiliation:
Faculté de Médecine Paris-Saclay, 94275 Le Kremlin Bicêtre, France Inserm U1185 - Univ Paris-Sud, 94275 Le Kremlin Bicêtre, France Service de Génétique moléculaire, Pharmacogénétique et Hormonologie- CHU de Bicêtre- APHP, 94275 Le Kremlin Bicêtre, France
F. Gressier
Affiliation:
INSERM CESP - Equipe ‘Moods’- Univ Paris-Saclay, 94275 Le Kremlin Bicêtre, France Service de Psychiatrie- Hôpital Bicêtre- GH Paris Saclay- APHP, 94275 Le Kremlin Bicêtre, France Faculté de Médecine Paris-Saclay, 94275 Le Kremlin Bicêtre, France
R. Colle
Affiliation:
INSERM CESP - Equipe ‘Moods’- Univ Paris-Saclay, 94275 Le Kremlin Bicêtre, France Service de Psychiatrie- Hôpital Bicêtre- GH Paris Saclay- APHP, 94275 Le Kremlin Bicêtre, France Faculté de Médecine Paris-Saclay, 94275 Le Kremlin Bicêtre, France
A. Rigal
Affiliation:
INSERM CESP - Equipe ‘Moods’- Univ Paris-Saclay, 94275 Le Kremlin Bicêtre, France Service de Psychiatrie- Hôpital Bicêtre- GH Paris Saclay- APHP, 94275 Le Kremlin Bicêtre, France Faculté de Médecine Paris-Saclay, 94275 Le Kremlin Bicêtre, France
S. Martin
Affiliation:
INSERM CESP - Equipe ‘Moods’- Univ Paris-Saclay, 94275 Le Kremlin Bicêtre, France Service de Psychiatrie- Hôpital Bicêtre- GH Paris Saclay- APHP, 94275 Le Kremlin Bicêtre, France Faculté de Médecine Paris-Saclay, 94275 Le Kremlin Bicêtre, France
C. Verstuyft
Affiliation:
INSERM CESP - Equipe ‘Moods’- Univ Paris-Saclay, 94275 Le Kremlin Bicêtre, France Faculté de Médecine Paris-Saclay, 94275 Le Kremlin Bicêtre, France Service de Génétique moléculaire, Pharmacogénétique et Hormonologie- CHU de Bicêtre- APHP, 94275 Le Kremlin Bicêtre, France
B. Fève
Affiliation:
Sorbonne Université-INSERM UMR S_938, Centre de Recherche Saint-Antoine, 75012Paris, France Service d'Endocrinologie- Hôpital Saint-Antoine- APHP, 75012Paris, France Institut Hospitalo-Universitaire ICAN, 75012Paris, France
P. Chanson
Affiliation:
Faculté de Médecine Paris-Saclay, 94275 Le Kremlin Bicêtre, France Inserm U1185 - Univ Paris-Sud, 94275 Le Kremlin Bicêtre, France Service d'Endocrinologie et des Maladies de la Reproduction- CHU de Bicêtre- APHP, 94275 Le Kremlin Bicêtre, France
L. Becquemont
Affiliation:
INSERM CESP - Equipe ‘Moods’- Univ Paris-Saclay, 94275 Le Kremlin Bicêtre, France Faculté de Médecine Paris-Saclay, 94275 Le Kremlin Bicêtre, France Service de Génétique moléculaire, Pharmacogénétique et Hormonologie- CHU de Bicêtre- APHP, 94275 Le Kremlin Bicêtre, France
E. Corruble
Affiliation:
INSERM CESP - Equipe ‘Moods’- Univ Paris-Saclay, 94275 Le Kremlin Bicêtre, France Service de Psychiatrie- Hôpital Bicêtre- GH Paris Saclay- APHP, 94275 Le Kremlin Bicêtre, France Faculté de Médecine Paris-Saclay, 94275 Le Kremlin Bicêtre, France
Corresponding

Abstract

Background

Nitric oxide synthase (NOS) activity, an enzyme potentially involved in the major depressive episodes (MDE), could be indirectly measured by the L-Citrulline/L-Arginine ratio (L-Cit/L-Arg). The aim of this study was: (1) to compare the NOS activity of patients with a MDE to that of healthy controls (HC); (2) to assess its change after antidepressant treatment.

Methods

A total of 460 patients with a current MDE in a context of major depressive disorder (MDD) were compared to 895 HC for NOS activity (L-Cit/L-Arg plasma ratio). L-Arg and L-Cit plasma levels were measured using a MS-based liquid chromatography method. Depressed patients were assessed at baseline, and after 3 and 6 months of antidepressant treatment for depression severity and clinical response.

Results

Depressed patients had a lower NOS activity than HC at baseline [0.31 ± 0.09 v. 0.38 ± 0.12; 95% confidence interval (CI) −0.084 to −0.062, p < 0.0001]. Lower NOS activity at baseline predicted a higher response rate [odds ratio (OR) = 29.20; 95% CI 1.58–536.37; p = 0.023]. NOS activity in depressed patients increased significantly up to 0.34 ± 0.08 after antidepressant treatment (Est = 0.0034; 95% CI 0.0002–0.0067; p = 0.03).

Conclusions

Depressed patients have a decreased NOS activity that improves after antidepressant treatment and predicts drug response. NOS activity may be a promising biomarker for MDE in a context of MDD.

Type
Original Articles
Copyright
Copyright © The Author(s), 2020. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below.

References

Archer, S. (1993). Measurement of nitric oxide in biological models. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology, 7, 349360.CrossRefGoogle ScholarPubMed
Bagby, R. M., Ryder, A. G., Schuller, D. R., & Marshall, M. B. (2004). The Hamilton depression rating scale: Has the gold standard become a lead weight? American Journal of Psychiatry, 161(12), 21632177. http://dx.doi.org/10.1176/appi.ajp.161.12.2163CrossRefGoogle ScholarPubMed
Baranyi, A, Amouzadeh-Ghadikolai, O, Rothenhäusler, H-B, Theokas, S, Robier, C, Baranyi, M, … Meinitzer, A (2015). Nitric oxide-related biological pathways in patients with major depression. ed. A. A. Mongin PloS one 10, e0143397.CrossRefGoogle ScholarPubMed
Benedetto, C., Marozio, L., Neri, I., Giarola, M., Volpe, A., & Facchinetti, F. (2000). Increased L-citrulline/L-arginine plasma ratio in severe preeclampsia. Obstetrics and Gynecology, 96, 395399.Google ScholarPubMed
Bernstein, H.-G., Heinemann, A., Krell, D., Mawrin, C., Bielau, H., Danos, P., … Baumann, B. (2002). Further immunohistochemical evidence for impaired NO signaling in the hypothalamus of depressed patients. Annals of the New York Academy of Sciences, 973, 9193.CrossRefGoogle ScholarPubMed
Bernstein, H. G., Stanarius, A., Baumann, B., Henning, H., Krell, D., Danos, P., … Bogerts, B. (1998). Nitric oxide synthase-containing neurons in the human hypothalamus: Reduced number of immunoreactive cells in the paraventricular nucleus of depressive patients and schizophrenics. Neuroscience, 83, 867875.CrossRefGoogle ScholarPubMed
Boo, Y. C., & Jo, H. (2003). Flow-dependent regulation of endothelial nitric oxide synthase: Role of protein kinases. American Journal of Physiology-Cell Physiology, 285, C499C508.CrossRefGoogle ScholarPubMed
Calabrese, V., Mancuso, C., Calvani, M., Rizzarelli, E., Butterfield, D. A., & Giuffrida Stella, A. M. (2007). Nitric oxide in the central nervous system: Neuroprotection versus neurotoxicity. Nature Reviews Neuroscience, 8, 766775.CrossRefGoogle ScholarPubMed
Cepeda, M. S., Stang, P., & Makadia, R. (2016). Depression is associated with high levels of C-reactive protein and low levels of fractional exhaled nitric oxide: Results from the 2007–2012 national health and nutrition examination surveys. The Journal of Clinical Psychiatry, 77, 16661671.CrossRefGoogle ScholarPubMed
Chanson, P, Arnoux, A, Mavromati, M, Brailly-Tabard, S, Massart, C, Young, J, …VARIETE Investigators (2016). Reference values for IGF-I serum concentrations: Comparison of six immunoassays. The Journal of Clinical Endocrinology & Metabolism 101, 34503458.CrossRefGoogle ScholarPubMed
Chrapko, W., Jurasz, P., Radomski, M. W., Archer, S. L., Newman, S. C., Baker, G., … Le Mellédo, J.-M. (2006). Alteration of decreased plasma NO metabolites and platelet NO synthase activity by paroxetine in depressed patients. Neuropsychopharmacology, 31, 12861293.CrossRefGoogle ScholarPubMed
Chrapko, W. E., Jurasz, P., Radomski, M. W., Lara, N., Archer, S. L., & Le Mellédo, J.-M. (2004). Decreased platelet nitric oxide synthase activity and plasma nitric oxide metabolites in major depressive disorder. Biological Psychiatry, 56, 129134.CrossRefGoogle Scholar
Corruble, E., El Asmar, K., Trabado, S., Verstuyft, C., Falissard, B., Colle, R., … Becquemont, L. (2015). Treating major depressive episodes with antidepressants can induce or worsen metabolic syndrome: Results of the METADAP cohort. World Psychiatry, 14, 366367.CrossRefGoogle ScholarPubMed
Dhir, A., & Kulkarni, S. K. (2011). Nitric oxide and major depression. Nitric Oxide, 24, 125131.CrossRefGoogle ScholarPubMed
Di Massimo, C., Lo Presti, R., Corbacelli, C., Pompei, A., Scarpelli, P., De Amicis, D., … Tozzi Ciancarelli, M. G. (2006). Impairment of plasma nitric oxide availability in senescent healthy individuals: Apparent involvement of extracellular superoxide dismutase activity. Clinical Hemorheology and Microcirculation, 35, 231237.Google ScholarPubMed
Fernández-Cancio, M., Fernández-Vitos, E. M., Imperial, S., & Centelles, J. J. (2001). Structural requirements of benzodiazepines for the inhibition of pig brain nitric oxide synthase. Molecular Brain Research, 96, 8793.CrossRefGoogle ScholarPubMed
Feron, O., Dessy, C., Moniotte, S., Desager, J.-P., & Balligand, J.-L. (1999). Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase. Journal of Clinical Investigation, 103, 897905.CrossRefGoogle ScholarPubMed
Ferreira, F. R., Oliveira, A. M., Dinarte, A. R., Pinheiro, D. G., Greene, L. J., Silva, W. A., … Guimarães, F. S. (2012). Changes in hippocampal gene expression by 7-nitroindazole in rats submitted to forced swimming stress. Genes, Brain, and Behavior, 11, 303313.CrossRefGoogle Scholar
Finkel, M. S., Laghrissi-Thode, F., Pollock, B. G., & Rong, J. (1996). Paroxetine is a novel nitric oxide synthase inhibitor. Psychopharmacology Bulletin, 32, 653658.Google ScholarPubMed
Fitzmaurice, G. M., Laird, N. M., & Shneyer, L. (2001). An alternative parameterization of the general linear mixture model for longitudinal data with non-ignorable drop-outs. Statistics in Medicine, 20(7), 10091021. http://dx.doi.org/10.1002/(ISSN)1097-0258CrossRefGoogle ScholarPubMed
Förstermann, U., Schmidt, H. H., Pollock, J. S., Sheng, H., Mitchell, J. A., Warner, T. D., … Murad, F. (1991). Isoforms of nitric oxide synthase. Characterization and purification from different cell types. Biochemical Pharmacology, 42, 18491857.CrossRefGoogle ScholarPubMed
Furchgott, R. F., & Zawadzki, J. V. (1980). The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature, 288, 373376.CrossRefGoogle ScholarPubMed
García, R. G., Zarruk, J. G., Barrera, C., Pinzón, A., Trillos, E., Arenas, W. D., … López-Jaramillo, P. (2011). Plasma nitrate levels and flow-mediated vasodilation in untreated major depression. Psychosomatic Medicine, 73, 344349.CrossRefGoogle ScholarPubMed
Gielen, S., Adams, V., Linke, A., Erbs, S., Möbius-Winkler, S., Schubert, A., … Hambrecht, R. (2005). Exercise training in chronic heart failure: Correlation between reduced local inflammation and improved oxidative capacity in the skeletal muscle. European Journal of Cardiovascular Prevention and Rehabilitation: Official Journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology, 12, 393400.CrossRefGoogle ScholarPubMed
Higman, D. J., Strachan, A. M. J., Buttery, L., Hicks, R. C. J., Springall, D. R., Greenhalgh, R. M., & Powell, J. T. (1996). Smoking impairs the activity of endothelial nitric oxide synthase in saphenous vein. Arteriosclerosis, Thrombosis, and Vascular Biology, 16, 546552.CrossRefGoogle ScholarPubMed
Ikenouchi-Sugita, A., Yoshimura, R., Hori, H., Umene-Nakano, W., Ueda, N., & Nakamura, J. (2009). Effects of antidepressants on plasma metabolites of nitric oxide in major depressive disorder: Comparison between milnacipran and paroxetine. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 33, 14511453.CrossRefGoogle ScholarPubMed
Ishibashi, T., Yoshida, J., & Nishio, M. (1999). Evaluation of NOx in the cardiovascular system: Relationship to NO-related compounds in vivo. Japanese Journal of Pharmacology, 81, 317323.CrossRefGoogle ScholarPubMed
Jepsen, P., Johnsen, S. P., Gillman, M. W., & Sørensen, H. T. (2004). Interpretation of observational studies. Heart (British Cardiac Society), 90, 956960.CrossRefGoogle ScholarPubMed
Jia, H-M, Feng, Y-F, Liu, Y-T, Chang, X, Chen, L, Zhang, H-W, … Zou, Z-M (2013). Integration of 1H NMR and UPLC-Q-TOF/MS for a comprehensive urinary metabonomics study on a rat model of depression induced by chronic unpredictable mild stress. ed. J. M. Koomen PloS one 8, e63624.CrossRefGoogle Scholar
Karolewicz, B., Szebeni, K., Stockmeier, C. A., Konick, L., Overholser, J. C., Jurjus, G., … Ordway, G. A. (2004). Low nNOS protein in the locus coeruleus in major depression. Journal of Neurochemistry, 91, 10571066.CrossRefGoogle ScholarPubMed
Kelm, M. (1999). Nitric oxide metabolism and breakdown. Biochimica et biophysica acta, 1411, 273289.CrossRefGoogle ScholarPubMed
Kim, Y.-K., Paik, J.-W., Lee, S.-W., Yoon, D., Han, C., & Lee, B.-H. (2006). Increased plasma nitric oxide level associated with suicide attempt in depressive patients. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 30, 10911096.CrossRefGoogle ScholarPubMed
Kleinbongard, P., Dejam, A., Lauer, T., Rassaf, T., Schindler, A., Picker, O., … Kelm, M. (2003). Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals. Free Radical Biology & Medicine, 35, 790796.CrossRefGoogle ScholarPubMed
Knowles, R. G., & Moncada, S. (1994). Nitric oxide synthases in mammals. The Biochemical Journal, 298(Pt 2), 249258.CrossRefGoogle ScholarPubMed
Kudlow, P., Cha, D. S., Carvalho, A. F., & McIntyre, R. S. (2016). Nitric oxide and major depressive disorder: Pathophysiology and treatment implications. Current Molecular Medicine, 16, 206215.CrossRefGoogle ScholarPubMed
Lara, N., Archer, S. L., Baker, G. B., & Le Mell??do, J.-M. (2003). Paroxetine-induced increase in metabolic end products of nitric oxide. Journal of Clinical Psychopharmacology, 23, 641645.CrossRefGoogle ScholarPubMed
Laughlin, M. H., Pollock, J. S., Amann, J. F., Hollis, M. L., Woodman, C. R., & Price, E. M. (2001). Training induces nonuniform increases in eNOS content along the coronary arterial tree. Journal of Applied Physiology, 90, 501510.CrossRefGoogle ScholarPubMed
Li, J., Tang, G., Cheng, K., Yang, D., Chen, G., Liu, Z., … Xie, P. (2014). Peripheral blood mononuclear cell-based metabolomic profiling of a chronic unpredictable mild stress rat model of depression. Molecular BioSystems, 10, 29943001.CrossRefGoogle ScholarPubMed
Lu, Y.-R., Fu, X.-Y., Shi, L.-G., Jiang, Y., Wu, J.-L., Weng, X.-J., … Bao, A.-M. (2014). Decreased plasma neuroactive amino acids and increased nitric oxide levels in melancholic major depressive disorder. BMC Psychiatry, 14, 123.CrossRefGoogle ScholarPubMed
Mayoral-Mariles, A., Cruz-Revilla, C., Vega-Manriquez, X., Aguirre-Hernández, R., Severiano-Pérez, P., Aburto-Arciniega, E., … Guevara-Guzmán, R. (2012). Plasma amino acid levels discriminate between control subjects and mildly depressed elderly women. Archives of Medical Research, 43, 375382.CrossRefGoogle ScholarPubMed
Murray, I. A., Bullimore, D. W., & Long, R. G. (2003). Fasting plasma nitric oxide products in coeliac disease. European Journal of Gastroenterology & Hepatology, 15, 10911095.CrossRefGoogle ScholarPubMed
Rhodes, P. M., Leone, A. M., Francis, P. L., Struthers, A. D., Moncada, S. (1995). The L-arginine: Nitric oxide pathway is the major source of plasma nitrite in fasted humans. Biochemical and Biophysical Research Communications, 209, 590596.CrossRefGoogle ScholarPubMed
Rush, A. J., Trivedi, M. H., Ibrahim, H. M., Carmody, T. J., Arnow, B., Klein, D. N., … Keller, M. B. (2003). The 16-item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): A psychometric evaluation in patients with chronic major depression. Elsevier Inc. Biological Psychiatry, 54, 573583.CrossRefGoogle Scholar
Schmidt, H. H., & Murad, F. (1991). Purification and characterization of human NO synthase. Biochemical and Biophysical Research Communications, 181, 13721377.CrossRefGoogle ScholarPubMed
Selley, M. L. (2004). Increased (E)-4-hydroxy-2-nonenal and asymmetric dimethylarginine concentrations and decreased nitric oxide concentrations in the plasma of patients with major depression. Journal of Affective Disorders, 80, 249256.CrossRefGoogle Scholar
Sethuraman, R., Lee, T.-L., Chui, J.-W., & Tachibana, S. (2006). Changes in amino acids and nitric oxide concentration in cerebrospinal fluid during labor pain. Neurochemical Research, 31, 11271133.CrossRefGoogle ScholarPubMed
Spiacci, A., Kanamaru, F., Guimarães, F. S., & Oliveira, R. M. W. (2008). Nitric oxide-mediated anxiolytic-like and antidepressant-like effects in animal models of anxiety and depression. Pharmacology, Biochemistry, and Behavior, 88, 247255.CrossRefGoogle Scholar
Stuehr, D. J., Kwon, N. S., Gross, S. S., Thiel, B. A., Levi, R., & Nathan, C. F. (1989). Synthesis of nitrogen oxides from L-arginine by macrophage cytosol: Requirement for inducible and constitutive components. Biochemical and Biophysical Research Communications, 161, 420426.CrossRefGoogle ScholarPubMed
Suzuki, H., & Colasanti, M. (2001). Cross-talk between constitutive and inducible nitric oxide synthases. Circulation, 103, E81E81.CrossRefGoogle ScholarPubMed
Suzuki, E., Yagi, G., Nakaki, T., Kanba, S., & Asai, M. (2001). Elevated plasma nitrate levels in depressive states. Journal of Affective Disorders, 63, 221224.CrossRefGoogle ScholarPubMed
Trabado, S., Al-Salameh, A., Croixmarie, V., Masson, P., Corruble, E., Fève, B., … Chanson, P. (2017). The human plasma-metabolome: Reference values in 800 French healthy volunteers; impact of cholesterol, gender and age. PloS one, 12, e0173615.CrossRefGoogle Scholar
Trajković, G., Starčević, V., Latas, M., Leštarević, M., Ille, T., Bukumirić, Z., & Marinković, J. (2011). Reliability of the Hamilton rating scale for depression: A meta-analysis over a period of 49 years. Psychiatry Research, 189, 19.CrossRefGoogle Scholar
Wang, P. S., Simon, G., & Kessler, R. C. (2003). The economic burden of depression and the cost-effectiveness of treatment. International Journal of Methods in Psychiatric Research, 12, 2233.CrossRefGoogle ScholarPubMed
Wegener, G., & Volke, V. (2010). Nitric oxide synthase inhibitors as antidepressants. Pharmaceuticals, 3, 273299.CrossRefGoogle ScholarPubMed
Wiesinger, H. (2001). Arginine metabolism and the synthesis of nitric oxide in the nervous system. Progress in Neurobiology, 64(4), 365391. http://dx.doi.org/10.1016/S0301-0082(00)00056-3CrossRefGoogle ScholarPubMed
Xing, G., Chavko, M., Zhang, L.-X., Yang, S., & Post, R. M. (2002). Decreased calcium-dependent constitutive nitric oxide synthase (cNOS) activity in prefrontal cortex in schizophrenia and depression. Schizophrenia Research, 58, 2130.CrossRefGoogle ScholarPubMed
Yildiz, F., Erden, B. F., Ulak, G., Utkan, T., & Gacar, N. (2000). Antidepressant-like effect of 7-nitroindazole in the forced swimming test in rats. Psychopharmacology, 149, 4144.CrossRefGoogle ScholarPubMed
Yoshino, Y., Ochi, S., Yamazaki, K., Nakata, S., Abe, M., Mori, Y., & Ueno, S. (2015). Antidepressant action via the nitric oxide system: A pilot study in an acute depressive model induced by Arginin. Neuroscience Letters, 599, 6974.CrossRefGoogle Scholar
Yun, H. Y., Dawson, V. L., & Dawson, T. M. (1997). Nitric oxide in health and disease of the nervous system. Molecular Psychiatry, 2, 300310.CrossRefGoogle Scholar
Supplementary material: File

Loeb et al. supplementary material

Table S3

Download Loeb et al. supplementary material(File)
File 40 KB
Supplementary material: File

Loeb et al. supplementary material

Table S1

Download Loeb et al. supplementary material(File)
File 41 KB
Supplementary material: File

Loeb et al. supplementary material

Table S2

Download Loeb et al. supplementary material(File)
File 49 KB

Send article to Kindle

To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Nitric Oxide Synthase activity in major depressive episodes before and after antidepressant treatment: Results of a large case-control treatment study
Available formats
×

Send article to Dropbox

To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

Nitric Oxide Synthase activity in major depressive episodes before and after antidepressant treatment: Results of a large case-control treatment study
Available formats
×

Send article to Google Drive

To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

Nitric Oxide Synthase activity in major depressive episodes before and after antidepressant treatment: Results of a large case-control treatment study
Available formats
×
×

Reply to: Submit a response

Please enter your response.

Your details

Please enter a valid email address.

Conflicting interests

Do you have any conflicting interests? *