Neuroscience Letters 458 (2009) 122–125 Contents lists available at ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet ACE polymorphism and response to electroconvulsive therapy in major depression Juhani Akseli Stewart a,∗ , Olli Kampman a,c , Martti Huuhka a,b , Sami Anttila a,d , Kaija Huuhka a,b , Terho Lehtimäki a,d , Esa Leinonen a,b a University of Tampere, Medical School, 33014, Tampere, Finland b Tampere University Hospital, Department of Psychiatry, 33380 Pitkäniemi, Finland c Seinäjoki Hospital District, Department of Psychiatry, Seinäjoki, Finland d Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Centre of Laboratory Medicine, Tampere University Hospital, Teiskontie 35, PL 2000, 33521 Tampere, Finland article info Article history: Received 7 March 2009 Received in revised form 8 April 2009 Accepted 25 April 2009 Keywords: Depression Electroconvulsive therapy Antidepressive agents ACE gene polymorphism Pharmacogenetics abstract The angiotensin I-converting enzyme gene (ACE) has been repeatedly suggested as a major gene affecting affective disorders and their treatment, but the study results have been ambiguous so far. The primary purpose of this study was to compare the effects of the ACE genotype distributions and treatment response to electroconvulsive therapy (ECT) in patients with major depressive disorder (MDD). The association in ACE genotypes and the age at onset of depression was also analyzed and these gene distributions were also compared between patients and healthy controls. The study included 119 treatment-resistant MDD patients who were referred to ECT treatment, and 392 voluntary blood donors as controls. All participants were tested for their ACE genotype, and all study patients were evaluated both before and after treatment. The Montgomery–Åsberg Depression Scale (MADRS) was used as a primary efficacy evaluating method. The ACE genotype was not associated in treatment results for MDD. However, younger onset age of primary depression was associated with the I/D genotype in the whole patient group. The finding was partly gender dependent; in male patients the I allele carried a higher risk of earlier depression onset age, while in female patients the higher risk was seen only in the heterozygous I/D allele carriers. Distributions of these genotypes or alleles did not differ between patients and controls. The studied ACE genotype was not associated with ECT results but may be associated with age of onset of the illness in patients with MDD. © 2009 Elsevier Ireland Ltd. All rights reserved. Major depressive disorder is a common mood disorder with a preva- lence of 5% in the adult population, a life-time prevalence of up to 15% and an incidence of 10% for primary care patients and 15% for medical inpatients [24]. MDD can be very disabling for the patient and, as with other mood disorders, MDD often becomes chronic and has a high chance of recurrence [23]. Genetic factors, which may in turn affect neuronal transmission in the central nervous system, seem to have a strong influence on mood disorders and the outcome of their treatment [3,37]. Angiotensin I-converting enzyme (ACE) participates in the body’s renin-angiotensin system (RAS) which mediates extracel- lular volume by catalyzing the conversion of angiotensin I into vasoactive angiotensin II, a potent vasoconstrictor, and by inacti- vating bradykinin, a potent vasodilator [33]. ACE is found not only in a circulating form in the body fluids, but also as a membrane- bound enzyme in endothelial cells and neuro-epithelial cells [3,33]. ∗ Corresponding author. Tel.: +358 44 4155547; fax: +358 3 35516164. E-mail address: juhani.stewart@uta.fi (J.A. Stewart). In neuro-epithelial cells ACE is found in the membranes of post- synaptic neurons [3], especially in the caudate-putamen region, the globus pallidus, the choroid plexus and the substantia nigra [3–5]. ACE degrades several neurotransmitters in the central ner- vous system, for example dopamine, which has been linked to mood regulation and depression [12,14]. Several studies have shown a strong effect of dopamine and the neuroendocrine systems in both pathophysiology and treatment results of major depressive dis- order [2,25,29]. ECT treatment increases dopamine release in the central nervous system, and thus the activity of ACE in the synap- tic membranes of neuro-epithelial cells might affect ECT treatment outcome in MDD [25,27]. However, the exact mechanism for ECT treatment is still unknown. There is no evidence on concurrent effect of antidepressive drugs and ECT [26], but studies have shown that starting an antidepressive medication during ECT treatment may prevent later relapses [35]. The ACE gene insertion/deletion polymorphism is represented by the presence or absence of a 287 bp DNA fragment [8,11]. The D allele of the functional ACE gene insertion/deletion polymor- phism is associated with higher ACE levels and consequently higher 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.04.057