Low tumor necrosis factor-α levels predict symptom reduction during electroconvulsive therapy in major depressive disorder
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Brain and Behavior. 2018;8:e00933.Պ | Պ1 of 8 https://doi.org/10.1002/brb3.933 wileyonlinelibrary.com/journal/brb3 SIGNIFICANT OUTCOMES These findings support the role of cytokines, especially TNFα, in depression. ECT decreased TNFα levels during each ECT session. Low TNFα levels during the first ECT session predict symptom reduction after the treatment. LIMITATIONS The number of patients is relatively small. TNFα levels of normal controls were not available. Plasma TNFα levels may be affected by anesthesia during ECT series. !;1;b;7ĹƑƏo;l0;uƑƏƐƕՊ | Պ !;bv;7ĹƑƏ;1;l0;uƑƏƐƕՊ | Պ 11;r|;7ĹƑƐ;1;l0;uƑƏƐƕ ĹƐƏĺƐƏƏƑņ0u0ƒĺƖƒƒ ORIGINAL RESEARCH Low tumor necrosis factorα levels predict symptom reduction during electroconvulsive therapy in major depressive disorder Annamari Sorri1,2 Պ|Պ-bf-࢜u;m|-v|-1,2Պ|ՊѴѴb-lrl-m2,3Պ|Պ-b;_|bl࢜hb4Պ|Պ bmm-fuhtbv|1Պ|Պ-|b$o_bl--1Պ|Պ-ub࢜l࢜Ѵ࢜bm;m5Պ|Պ;-obѴ-m;m5Պ|Պ Esa Leinonen1,2 $_bvbv-mor;m-11;vv-u|b1Ѵ;m7;u|_;|;ulvo=|_;u;-|b;ollomv||ub0|bomb1;mv;ķ_b1_r;ulb|vv;ķ7bv|ub0|bom-m7u;ruo71|bombm-ml;7blķ provided the original work is properly cited. šƑƏƐѶ$_;|_ouvĺ Brain and Behaviorr0Ѵbv_;70)bѴ;;ubo7b1-Ѵvķm1ĺ 1;r-u|l;m|o=v1_b-|uķ$-lr;u; University Hospital, Tampere, Finland 2;r-u|l;m|o=v1_b-|uķ"1_ooѴo= Medicine, University of Tampere, Tampere, Finland 3;r-u|l;m|o=v1_b-|uķ";bm࢜fohbovrb|-Ѵ bv|ub1|ķ";bm࢜fohbķbmѴ-m7 4;r-u|l;m|o=;uovu];uķ;uoѴo]-m7 Rehabilitation, Tampere University Hospital, Tampere, Finland 5$_;llmor_-ul-1oѴo]!;v;-u1_ Group, Faculty of Medicine and Life "1b;m1;vķ&mb;uvb|o=$-lr;u;-m7$-lr;u; University Hospital, Tampere, Finland Correspondence mm-l-ub"ouubķ;r-u|l;m|o=v1_b-|uķ Tampere University Hospital, Tampere, Finland. Email: [email protected] Funding information Competitive Research Funding of Tampere &mb;uvb|ovrb|-Ѵķu-m|ņ-u7l0;uĹ 9U029 Abstract Objective: Changes in the tumor necrosis factorα (TNFα) have been associated with l-fou7;ru;vvb;7bvou7;uŐőĺbm7bm]v1om1;umbm]|_;;==;1|vo=;Ѵ;1|uo1omѴsive therapy (ECT) on the TNFα level have been contradictory. The aim was to examine the immediate and longterm changes in the TNFα level and their associations with vlr|olu;71|bombmr-|b;m|vb|_7ubm]$ĺ MethodĹ$_;v|7bm1Ѵ7;7ƒƏr-|b;m|vb|_ĺ$_;bu$α levels were meas- u;7-|0-v;Ѵbm;-m7Ƒ-m7Ɠ_u-=|;u|_;=buv|ķ=b=|_-m7Ѵ-v|$v;vvbomĺ;ru;vvb; vlr|olv ;u; -vv;vv;7 b|_ |_; om|]ol;uŊv0;u] ;ru;vvbom !-|bm] "1-Ѵ; Ő!"őĺ Results: The TNFα level decreased from baseline to the 2and 4hr measurements. There was a correlation between the first ECT session TNFα levels and the relative vlr|olu;71|bom-11ou7bm]|o|_;!"v1ou;-=|;u|_;$v;ub;vĺo|_|_;=buv| (baseline) ECT and 4hr TNFα levels were lower in responders than in nonresponders. Conclusion: ECT consistently induced a decrease in the TNFα level after each studied v;vvbomĺѴo$α level at the first ECT appeared to predict a symptom reduction. These findings suggest that TNFαlb]_|_-;-uoѴ;bm|_;r-|_o];m;vbvbm-m7 in the mechanism of action of ECT. +)!" cytokine, electroconvulsive therapy, major depressive disorder, seizure
Ƒo=ѶՊ | ՊՊՍ SORRI ET AL. ƐՊ|Պ$!&$ Electroconvulsive therapy (ECT) is considered to be the most effi1-1bov|u;-|l;m|=ouv;;u;l-fou7;ru;vvb;7bvou7;uŐőŐ& ECT Review Group, 2003). Thus, the main indications for ECT are se- ;u;rv1_o|b1-m7|u;-|l;m|u;vbv|-m1;bmr-|b;m|vb|_ Ől;ub1-mv1_b-|ub1vvo1b-|bomķƑƏƏƐőĺo;;uķ|_;l;1_-mbvlo= action of ECT remains obscure. Tumor necrosis factorα (TNFα) is a proinflammatory cytokine that has been considered to be expressed in the brain only in response to pathological stimuli. However, TNFα as well as some other cytokines have recently been found to play an active role in neural plasticity and m;uo];m;vbvŐ_-buo-ķ-1_-7oŊ(b;bu-ķķş-mfbķƑƏƏƖĸ+bulb- ş ov_;mķ ƑƏƐƐőĺ$_; 1|ohbm; _ro|_;vbv o= 7;ru;vvbom ruorov;v that activation of the inflammatory system, which results in increased production of proinflammatory cytokines, contributes to the patho- ];m;vbv o= Ő-;vķ ƐƖƖƔőĺ m -mbl-Ѵ lo7;Ѵvķ 1|ohbm; -1|b-- tion has produced depressive symptoms, a decreased hippocampal oѴl;ķ-m7ľvb1hm;vv0;_-bouĿŐmmķ"b;u]b;Ѵķş7;;-u;r-bu;ķ ƑƏƏƔĸ ov_;m ;|-Ѵĺķ ƑƏƏѶĸ -vomķ 1vh;uķ ş ;ѴѴ;ķ ƑƏƐƒőĺ llmo|_;u-rb|_bm|;uѴ;hbmŊƑoubm|;u=;uomŊα is reportedly associated with cognitive impairment and a depressed mood as well as fa- |b];ķvѴ;;r7bv|u0-m1;vķbuub|-0bѴb|ķ-m7Ѵovvo=-rr;|b|;Őom-11ouvo ;|-ѴĺķƑƏƏƐķƑƏƏƑĸ-ruomķ!--7ķş-m|;uķƑƏƏƐĸ-ruom;|-Ѵĺķ ƑƏƏƐĸb;r;ubmhķ)bѴѴ;m0ubm]ķşoķƑƏƏƏőĺ(-11bm;vķ_b1_-1|-v1- tokine inducers, also cause a depressed mood in healthy individuals (Harrison et al., 2009). Proinflammatory cytokines such as TNFα are associated with the actions of moodrelevant neurotransmitters, including the mono- -lbm;vķ 0 7b==;u;m| r-|_-v ŐbѴѴ;uķ -Ѵ;|b1ķ ş !-bvomķ ƑƏƏƖőĺ However, the reported associations between TNFα -m7 ou ECT are inconsistent due to different methodologies and variations bmv|7rorѴ-|bomvĺm-77b|bomķ0o|_rѴ-vl--m7v;ul$α lev- ;Ѵv_-;0;;mu;rou|;7ĺ";;u-Ѵl;|-Ŋ-m-Ѵv;v_-;u;;-Ѵ;7l-uhedly higher concentrations of TNFα in depressed individuals than in _;-Ѵ|_1om|uoѴvŐoѴ-|b;|-ѴĺķƑƏƐƏĸoѴ7vlb|_ķ!-r-rou|ķşbѴѴ;uķ ƑƏƐѵĸ-m]ş;;ķƑƏƏƕĸbķoķş-hķƑƏƐƑőĺo;;uķv|7ies with no association with changes in the TNFα level and symp- |olvo=_-;0;;mr0Ѵbv_;7Ő--r-hovhbķ-|_b;ķ0l;b;uķ Ѵ;mbvķ ş bbl࢜hbķ ƑƏƐƔĸ -uѴob1ķ ";uu;||bķ (uhb1ķ -u|bm-1ķş -u1bmhoķƑƏƐƑĸ+oomķblķ;;ķomķş blķ ƑƏƐƑőĺ$_bv-vvo1b-|bom _-v 0;;m t;v|bom;7 bm - u;1;m| l;|-Ŋ-m-Ѵvbv Őmbvl-mķ !-bm7u-mķub==b|_vķş;u-ѴbķƐƖƖƖőĺ|_-v-Ѵvo0;;m_ro|_;vb;7 that the pathophysiological mechanisms of various subtypes of lb]_|7b==;u=uolom;-mo|_;ub|_u;vr;1||o7vu;]Ѵ-|bom o=|_;bllm;Ŋbm=Ѵ-ll-|ouvv|;lŐ-l;uv;|-ѴĺķƑƏƐƒőĺm;u;- port suggested that atypical depression is associated with an elevated TNFα Ѵ;;Ѵ Ő-m;Ѵb7;ķ -||;bķ );v|ubmķ$u࢜vhl-mŊ;m7ķ ş um7bmķ ƑƏƐƐőĺ Ѵ;-|;7 $α levels have also been associated b|_vb1b7;-||;lr|v-m77bvvo1b-|b;vlr|olvŐ00-vbķovv;bmbķ o7-00;umb-ķ v_u-=bķ ş h_om7-7;_ķ ƑƏƐƑĸ bbh ;|-Ѵĺķ ƑƏƐƓőĺ The nonsteroidal antiinflammatory drug celecoxib reportedly has -0;m;=b1b-Ѵ;==;1|bmr-|b;m|vb|_-v-m-7f-m|l;7b1-|bom Őh_om7-7;_;|-ѴĺķƑƏƏƖĸ-u]-u;|-ѴĺķƑƏƐƓĸুѴѴ;u;|-ѴĺķƑƏƏѵőĺ 77b|bom-ѴѴķ1;Ѵ;1ob0u;71;7|_;$α level after an ECT series in r-|b;m|vb|_0broѴ-u7bvou7;uŐ-m|;uķĽommouķ-vomķş;ѴѴ;ķ 2011). |_-v0;;mru;vl;7|_-|$α, through its induction of indoleambm;ƑķƒŊ7bo];m-v;Őőķ-1|b-|;v|_;hmu;mbm;r-|_-ķ_b1_bv 1omvb7;u;7|o0;-vvo1b-|;7b|_bm=Ѵ-ll-|bom-m77;ru;vvbomĺ catabolizes tryptophan into neuroactive kynurenine metabolites such as quinolic acid and 3hydroxy kynurenine. These tryptophan metabolites are neurotoxic because they are able to generate oxidative radicals and act as NmethylNaspartate receptor agonists (Haroon, !-bvomķ ş bѴѴ;uķ ƑƏƐƑĸ -;vķ b_-Ѵo-ķ 0;u-ķ ş !bm];Ѵķ ƑƏƐƑĸ "1_-u1ķ umoķ 1_ovhbķ ş )ķ ƑƏƐƑőĺ mo|_;u l;|-0oѴb|; o= kynurenine, kynurenic acid, is considered to have neuroprotective ruor;u|b;vŐ-uoom;|-ѴĺķƑƏƐƑĸbm|şblķƑƏƏƒőĺ|_-v0;;mv]- ];v|;7|_-|bmr-|b;m|vb|_7;ru;vvbomķ-1|b-|bomo=1oѴ7|um the kynurenine pathway toward the generation of neurotoxic metabolites (Guloksuz et al., 2015). ECT was recently reported to increase the levels of kynurenic acid, referring to the fact that ECT can alter the balance of the kynurenine pathway toward a neuroprotective course Ő"1_b;Ѵ;u ;|-Ѵĺķ ƑƏƐѵőĺ u|_;ulou;ķ $ 1-m u;rou|;7Ѵ 7;1u;-v; quinolic acid levels in patients with treatmentresistant depression Ő;v|-7ķ$pmv;|_ķ"|p;mķ&;Ѵ-m7ķşhuv|ķƑƏƏƒőĺѴ|o];|_;uķ|_;v; findings imply that the mechanism of action of ECT is partly associated with the kynurenine pathway, which is induced by TNFα. "ol;v|7b;v_-;-77u;vv;7|_;-vvo1b-|bom0;|;;m$α and $Őbuv|ķ"rb|;uķb00omķş)bѴѴb-lvķƐƖƖѵĸѴb|l-m;|-ѴĺķƑƏƐƐĸ Hestad et al., 2003; Rotter et al., 2013; Rush et al., 2016; Zincir, |uhķbѴ];mķ1bķş+hv;ѴbuķƑƏƐѵőĺmƑƏƏƒķ;v|-7;|-ѴĺŐѴb|l-m et al., 2011) reported a decrease in the TNFα level in patients with -Ѵom]b|_1Ѵbmb1-Ѵblruo;l;m|7ubm]-m7-=|;u-m$v;ub;vķ whereas another study revealed a rapid increase in the TNFα level after a single ECT session but no longterm change during the ECT v;ub;vŐ!o||;u;|-ѴĺķƑƏƐƒőĺ|_;uv|7b;v_-;=om7mo1_-m];bm|_; TNFα level during or after the ECT series (First et al., 1996; Hestad ;|-ѴĺķƑƏƏƒĸ,bm1bu;|-ѴĺķƑƏƐѵőĺu;1;m|v|7u;;-Ѵ;7-7;1u;-v;bm the TNFα level during and after an ECT series, although the baseline TNFα level before ECT was lower in patients than in controls (Rush et al., 2016). ƐĺƐՊ|Պblvo=|_;v|7 The causality of the TNFα level and ECT as well as the association between changes in the TNFα level and symptoms during ECT are contradictory. The aim of this study was to examine the changes in the plasma level of TNFα and their possible associations with symp- |olu;71|bombmr-|b;m|vb|_-||_u;;7b==;u;m|v;vvbomv7ubm] an ECT series. These sessions were included to study the immediate and longterm effects of ECT on the TNFα level during an ECT series. TNFα was measured from plasma (instead of serum) in order to avoid artifact production of TNF alpha during the sampling procedure/clot- |bm]ruo1;vvŐ7;-];uķou1b;uķ!bfh;uvķu-hh;mķş";=;u|Ŋ-u]oѴbvķ 2009).
ՊՍՊ | Պƒo=Ѷ SORRI ET AL. ƑՊ|Պ$!$" ƑĺƐՊ|ՊѴbmb1-Ѵ1_-u-1|;ubv|b1v ou|Ŋmbm;r-|b;m|vb|_v;;u;ourv1_o|b1_o;u;1omv;1|b;Ѵ -7lb||;7 =ou $ |o |_; ;r-u|l;m| o= v1_b-|uķ Tampere University Hospital were asked to participate in this study. Thirteen of these 49 patients declined, and six patients withdrew from the study. Therefore, the study group comprised 30 patients ŐƐƑ=;l-Ѵ;ķƐѶl-Ѵ;őĺm-7lbvvbomķ|_;"|u1|u;7Ѵbmb1-Ѵm|;ub; =ou"Ŋ(bvou7;uvŐl;ub1-mv1_b-|ub1vvo1b-|bomķƐƖƖƓő-v 1om71|;7 |o 1om=bul |_; 7b-]movbv bm ;-1_ r-|b;m|ĺ ѴѴ r-|b;m|v =Ѵ=bѴѴ;7 |_; "Ŋ( 7b-]mov|b1 1ub|;ub- =ou Őom|]ol;u ş Åsberg, 1979), and 14 of them had psychotic symptoms. Nine pa- |b;m|vv==;u;7=uol-=buv|;rbvo7;o=ķ-m7|_;-vu;- current in 21 patients. Patients with bipolar depression and major psychiatric disorders o|_;u |_-m ;u; ;1Ѵ7;7ĺ -|b;m|vb|_ ruo]u;vvb; ou]-mb1 brain disorders, epilepsy, inflammatory or autoimmune diseases, and alcohol or other substance abuse were also excluded from the study. Patients who had undergone ECT within 3 months prior to entry into the study were not included. The mean age of the patients was 57.1 years (standard deviation [SD], 17.7; range, 25–85 years). The patients underwent constant psychotropic drug treatment throughout the entire ECT period (Table 1). Twentyeight patients in the study were taking a combination of at least two psychotropic medications, and only two were un7;u]obm]lomo|_;u-rĺ;mo7b-;rbm;v;u;7bv1om|bm;7ƐƏ_ouv before ECT to avoid any effects on the seizure threshold. The severity of depression was quantified by the Montgomery- v0;u] ;ru;vvbom !-|bm] "1-Ѵ; Ő!"ő Őom|]ol;u şܲv0;u]ķ 1979) in addition to the TNFα level before the first and after the fifth and last ECT session. ѴѴr-|b;m|vruob7;7ub||;mbm=oul;71omv;m|ĺ$_bvv|77;vb]m was reviewed and approved by the Tampere University Hospital Ethics Committee. ƑĺƑՊ|ՊѴ;1|uo1omѴvb;|_;u-r ;=ou;|_;=buv|$v;vvbomķ-l;7b1-Ѵ_bv|ou-vo0|-bm;7-m7- physical examination with routine blood examination and electrocardiogram was performed. ECT was administered three times a ;;hb|_-1omv|-m|Ŋ1uu;m|ķ0ub;=ŊrѴv;7;b1;Ő$vr$ul ƔƏƏƏ ĸ$ourĺķ-h;v;]oķ!ķ&"őĺ$_;v;bu;|_u;v_old was titrated during the first treatment, and subsequent treatments were administered at 1.5 times the seizure threshold for bilateral $ĺ";bu;vo=ƻƑƔvbm7u-|bomom;Ѵ;1|uo;m1;r_-Ѵo]u-r_;u; 7;;l;7-7;t-|;ĺ=|_;7u-|bom -vv_ou|;uķ- u;v|blѴ-|bom-v All patients (n = 30) Female patients (n = 12) Male patients (n = 18) ]; Mean ± SD 57.1 ± 17.7 71.1 ± 12.2 45.2 ± 17.0 Range 25–85 45–85 25–79 Total number of ECTs Mean ± SD 10.4 ± 3.6 10.8 ± 4.3 8.2 ± 3,6 Range 5–17 5–17 5–13 Psychotic symptoms 14 7 7 buv|;rbvo7;o= 94 5 !;1uu;m| 21 13 8 m|b7;ru;vv-m|v ""! 93 6 "! 12 5 7 Mirtazapine 12 6 6 ruorbom 41 3 m|brv1_o|b1v ";1om7];m;u-|bom antipsychotics 28 11 17 Conventional neurolepts 1 0 1 mboѴ|b1v ;mo7b-;rbm;v 21 8 13 Pregabalin 2 2 0 vrbuom; 10 1 ""!ķ";Ѵ;1|b;v;uo|ombmu;r|-h;bm_b0b|ouĸ"!ķ";uo|ombm-m7mou;rbm;r_ubm;u;r|-h;bm_b0b|ouĺ $ƐՊPsychotropic medications of r-|b;m|vb|_7ubm]|_;$v;ub;v
Ɠo=ѶՊ | ՊՊՍ SORRI ET AL. performed during the same treatment session with a 50% increase in the stimulus intensity. ƑĺƒՊ|Պm;v|_;vb- m;v|_;vb- -v bm71;7 b|_ l;|_o_;b|-Ѵ Őbmb|b-Ѵ 7ov; o= Ɛl]ņ kg), and muscle relaxation was achieved with succinylcholine (initial dose of 0.5 mg/kg). The patients were ventilated with 100% oxygen until resumption of spontaneous respiration. Physiological monitoring during the treatment included pulse oximetry, blood pressure, electrocardiography, onechannel electroencephalography and elec- |uolo]u-r_ĺѴѴr-|b;m|v;u;|u;-|;7b|_v|-m7-u70bѴ-|;u-ѴŐ0bfrontotemporal) ECT. The number of treatments ranged from 5 to 17 (10.4 ± 3.6 [mean ± SD]). ECT treatment was discontinued on the basis of clinical judgment if the patient was either in remission Ő!"v1ou;o=ƽƐƏőķoumo=u|_;ublruo;l;m|-vu;1ou7;77ubm]|_;Ѵ-v||o$v;vvbomvĺm=b;r-|b;m|vķ|_;=b=|_$v;vvbom was the last (not included in the last ECT session data). ƑĺƓՊ|ՊѴoo7v-lrѴbm] $_;0Ѵoo7v-lrѴbm]-vv|ub1|Ѵv|-m7-u7b;7ĺѴoo7-v7u-m0;- fore ECT (baseline) and 2 and 4 hr after ECT at the first, fifth, and Ѵ-v|v;vvbomvķ-m7$Ŋ|u;-|;7rѴ-vl--vv;r-u-|;7-m7v|ou;7-| ƴѶƏŦ m|bѴ -m-Ѵ;7ĺ $_; 1om1;m|u-|bom o= $α was determined by enzymelinked immunosorbent assay with commercial reagents Ő -m|bhbm;"ĸ!ş"v|;lvuor;ķ|7ĺķ0bm]7omķ&őĺ$_;7;- tection limit and interassay coefficient of variation were 0.25 pg/ml and 3.3%, respectively. ƑĺƔՊ|Պ"|-|bv|b1-Ѵl;|_o7v r-bu;7Ŋv-lrѴ;ttest was used to analyze changes between the TNFα level at different measurement points: baseline vs. 2 hr, baseline vs. 4 hr, and 2 hr vs. 4 hr. The relationships between the TNFα level and vlr|olu;71|bom-11ou7bm]|o|_;!"-v;ѴѴ-vo|_;u1Ѵbmb1-Ѵ -ub-0Ѵ;v;u;;-lbm;7b|_"r;-ul-mĽvu_o7;|o|_;vh;;77bv- |ub0|bombm|_;!"u;vromv;u-|;-ub-0Ѵ;ĺolr-ubvomv0;|;;m u;vrom7;uvĽ-m7momu;vrom7;uvĽ$α levels were performed using the Mann–Whitney Utest because of the nonnormal distribution of the TNFαѴ;;Ѵvĺom=;uuomb1ouu;1|bom-vv;7bm|_;1ouu;Ѵ-|bom calculation by setting the limit of statistical significance to 0.05/9, |_-|bvķ07bb7bm]0|_;ml0;uo=|;v|vĺm-ѴѴo|_;u|;v|vķ|_;Ѵ;;Ѵ of significance was set at p < ĺƏƔĺ"r;-ul-mĽv1ouu;Ѵ-|bom1o;==b1b;m|v were used in the exploratory analyses for selecting statistically significant or trend level (p < .1) correlating explanatory variables for the regression model to predict dichotomized response, in addition to the bm1Ѵ7;71om=om7bm]-ub-0Ѵ;v-];-m7];m7;uĺѴo]bv|b1u;]u;vvbom lo7;Ѵ-vv;7|oru;7b1|-7b1_o|olb;7u;vromv;ĺm|_;lo7;Ѵķ TNF alpha baseline value, number of ECT treatments, gender, and age ;u;v;7-v;rѴ-m-|ou-ub-0Ѵ;vĺ77vu-|bovŐ!ő-m7ƖƔѷ1om=b7;m1;bm|;u-ѴvŐő;u;1-Ѵ1Ѵ-|;7=ou1o-ub-|;vĺ"|-|bv|b1-Ѵ-m-Ѵv;v ;u;r;u=oul;7b|_|_;"|-|bv|b1-Ѵ-1h-];=ou|_;"o1b-Ѵ"1b;m1;v Ő"""ő;uvbomƑƑĺƏĺ ƒՊ|Պ!"&$" The plasma levels of TNFα during ECT series are presented in Table 2. These levels consistently decreased from baseline (before ECT) to 2 hr during the first (p < .001), fifth (p < .001), and last (p = .007) ECT sessions. The plasma TNFα level also decreased from baseline to 4 hr during every ECT session (p < .001, p < .001, and p = .001, respectively). No significant changes were found in the TNFα level between the 2and 4hr measurements. When comparing the baseline TNFα level among the first, fifth, and last ECT sessions, no significant changes were found in the whole study group (Figure 1). ubou |o |_; =buv| $ v;vvbomķ |_; l;-m !" v1ou; -v 31.6 ± 7.2 (mean ± SD), and that after the ECT series was 11.3 ± 7.5. ||_;;m7o=|_;v|7ķƑƑo=ƒƏr-|b;m|vv_o;7-|Ѵ;-v|-ƔƏѷ 7;1u;-v;bm!"v1ou;ķo=|_ov;ƑƏ;u;bmu;lbvvbomŐ!" v1ou;o=ƽƐƏőĺ$_;u;-v-vb]mb=b1-m|1ouu;Ѵ-|bom0;|;;m|_;0-v;- line TNFα level at the first ECT session (prior to ECT series), the 2and 4hr TNFα levels, and the relative (%) symptom reduction -=|;u|_;$v;ub;v-vu;=Ѵ;1|;70|_;!"v1ou;ŐρƷƴĺƔѶѶķ p = .001; ρƷƴĺƔƕƓķ p = .001; ρƷƴĺѵƏƏķ p < .001, respectively) (Table 3). Low TNFα concentrations and symptom reduction accordbm] |o |_; !" v1ou; ;u; bm|;uu;Ѵ-|;7 Őb]u;Ƒőĺ$_;v; 1ourelations were inconsistent in subsequent ECT sessions (fifth and last). The TNFα level at both the first ECT session (baseline) and 4 hr ECT Measurement NMean Standard deviation Range First -v;Ѵbm; 30 1.65 0.56 2.42 2 hr 30 1.42 0.47 1.91 4 hr 30 1.34 0.43 1.88 Fifth -v;Ѵbm; 30 1.64 0.45 2.23 2 hr 30 1.41 0.39 1.76 4 hr 30 1.48 0.46 1.82 Last -v;Ѵbm; 25 1.59 0.43 1.70 2 hr 25 1.42 0.39 1.68 4 hr 25 1.39 0.43 2.00 $ƑՊMeans, standard deviations, and ranges of plasma TNFα levels during ECT series (pg/ml)
ՊՍՊ | ՊƔo=Ѷ SORRI ET AL. were lower in responders (50% symptom reduction) than in nonresponders (p = .035 and p = .006, respectively). The dichotomized response had a statistically significant or trend level (p < .1) correlation with smaller number of ECT treatments (ρƷƴĺƒƑķ p = .084) and with lower baseline TNFα levels (ρƷƴĺƒƖķp = .032). The best fitting logistic regression model for predicting the dichotomized response (p = ĺƏƒőbm1Ѵ7;7$-Ѵr_-0-v;Ѵbm;-Ѵ;Ő!ƷƏĺƑƏķƖƔѷ ƏĺƏƓŋƐĺƐƔķp = ĺƏƕő-m7ml0;uo=$|u;-|l;m|vŐ!ƷƏĺƕѵķ ƖƔѷƏĺƔƕŋƐĺƏƑķp = .07) as explanatory variables. This model explained 31.0% of the outcome variance (Nagelkerke R square); the sensitivity for response was 90.9% and specificity 50%. Gender and age had nonsignificant correlations with the dichotomized response. Neither gender nor age had any predictive effect on the response, and omitting these variables from the model did not change the predictive values. No correlations were found between clinical parameters (e.g., duration of convulsions, heart rate variability, or changes in blood pressure during ECT) and the TNFα level or clinical outcome. ƓՊ|Պ"&"" The most interesting finding in the present study was that a low TNFα level at the first ECT (0, 2, and 4 hr) appeared to predict a reduction in symptoms. No similar correlations were found during subsequent sessions. No findings suggesting associations between a low TNFα level and symptom reduction during ECT have been reported in previous studies (First et al., 1996; Fluitman et al., 2011; Hestad et al., 2003; !o||;u;|-ѴĺķƑƏƐƒĸ!v_;|-ѴĺķƑƏƐѵĸ,bm1bu;|-ѴĺķƑƏƐѵőĺ=u;rѴb1-|;7 in the future studies, this finding supports the role of TNFα in the r-|_o];m;vbvo=-m7bm|_;l;1_-mbvlo=-1|bomo=$ĸb|l- also guide the selection of treatment modalities for patients with se- ;u;ĺ$_;u;_-v0;;m-b7;-ub-|bombm$α levels in different studies. However, some of these have reported similar ranges of plasma TNFα levels in depressed patients compared to those in the ru;v;m|v|7Őol;;|-ѴĺķƑƏƏƖĸனomo-m;|-ѴĺķƑƏƐƒőĺ The decrease in the plasma TNFα level after each session was a consistent finding in the present study. This was observed in every studied session between the baseline measurement and both the 2and 4hr measurements. The effect of ECT on the TNFα level appears to be transitory because the TNFα level returned to the basic level &!ƐՊPlasma TNFα levels at first, fifth, and last ECT sessions in patients with $ƒՊCorrelations between plasma TNFα levels and relative Őѷővlr|olu;71|bombmr-|b;m|vb|_7ubm]$ ECT Measurement rho p First -v;Ѵbm; ƴĺƔƔѶ .001* 2 hr ƴĺƔƕƓ .001* 4 hr ƴĺѵƏƏ .001* Fifth -v;Ѵbm; ƴĺƑѶƒ .130 2 hr ƴĺƐƖƐ .312 4 hr ƴĺƑѶƓ .128 Last -v;Ѵbm; ƴĺƔƏƒ .10 2 hr ƴĺƒƖƏ .054 4 hr ƴĺƓƔƔ .022 *"b]mb=b1-m|-=|;uom=;uuombĽv1ouu;1|bomĺ &!ƑՊFirst ECT 4hr TNFα levels and relative symptom u;71|bombm!"ĺR2 linear = .21 R2 linear=0.21
ѵo=ѶՊ | ՊՊՍ SORRI ET AL. before next ECT session. This finding differs from some previous reports in which the TNFα level either increased, did not change, or decreased by ECT (First et al., 1996; Fluitman et al., 2011; Hestad et al., 2003; Rotter et al., 2013; Rush et al., 2016; Zincir et al., 2016). The design of the study by Hestad et al. (Fluitman et al., 2011) somewhat u;v;l0Ѵ;v|_;7;vb]mo=|_;ru;v;m|v|7ĺm|_;buv|7ķ|_;$α level was measured during the ECT series at baseline and 1 hr after the first, fourth, and last ECT session. They reported a decrease in the baseline TNFα level during the ECT series and 24 hr and 1 week after |_;Ѵ-v|$v;vvbomŐѴb|l-m;|-ѴĺķƑƏƐƐőĺ77b|bom-ѴѴķ-7;1u;-v;bm the TNFα level was observed in a study in which measurements were taken 1 day before the ECT series, at the time of the clinical response |o $ķ -m7 Ɛ7- -=|;u |_; v;ub;v Ő!v_ ;|-Ѵĺķ ƑƏƐѵőĺ m 1om|u-v|ķ Fluitman et al. (Rotter et al., 2013) reported an immediate increase in the TNFα level after every single session of ECT but found no constant change in the baseline TNFα level during the ECT series. The TNFα levels in these two latter studies were serum (not plasma) levels, making comparison with the present results difficult. Moreover, three studies found no change in the serum/plasma/plasma (respectively) TNFα level during and after the ECT series (First et al., 1996; Hestad et al., 2003; Zincir et al., 2016). However, in these studies, the timing of the blood samplings and procedures were somewhat different, hampering comparison with the present results (First et al., 1996; Hestad et al., 2003; Zincir et al., 2016). Unfortunately, the postECT TNFα levels (e.g., 1 week after the series) were not available in the present study. However, if we would have observed a persistent decrease in the TNFα level after the ECT series, we would have presumed that this decrease was already apparent in the baseline measurements in different sessions during the ECT series. ;1u;-v;vbm|_;$α level by anesthetics and muscle relaxant drugs (methohexital and succinylcholine) administered during ECT _-;0;;mu;rou|;7bmr-|b;m|vb|_Ő"|;Ѵ_-ll;u;|-ѴĺķƑƏƐƐőĺ Whether this decrease found in the present study in the TNFα level is related to the anesthetics used or the antiinflammatory mechanisms of ECT are inconclusive and require further research. llm;7vu;]Ѵ-|bom-m7-1|b-|bomo=|_;bm=Ѵ-ll-|ouu;vromv; vv|;l -u; bmoѴ;7b|_ ŐbѴѴ;u ;|-Ѵĺķ ƑƏƏƖőĺ ";;u-Ѵ v|7b;v have reported elevated TNFα levels in the blood and cerebrospinal =Ѵb7 bm r-|b;m|v b|_ ŐoѴ-|b ;|-Ѵĺķ ƑƏƐƏĸ oѴ7vlb|_ ;|-Ѵĺķ ƑƏƐѵĸ-m]ş;;ķƑƏƏƕĸb;|-ѴĺķƑƏƐƑĸ-u|bm;ķ-u-h-mbķ+;_7-ķ şoul-mķƑƏƐƑĸ"|;Ѵ_-ll;u;|-ѴĺķƑƏƐƐőķ0||_bv=bm7bm]-vt;v- |bom;7bm-u;1;m|l;|-Ŋ-m-ѴvbvŐmbvl-m;|-ѴĺķƐƖƖƖőĺo;;uķ-m elevated TNFα level has been somewhat associated with severe forms o=7;ru;vvbomŐmbvl-m;|-ѴĺķƐƖƖƖőĺmo|_;ul;|-Ŋ-m-Ѵvbvo=bm=Ѵ-ll-|ou0bol-uh;uvbmr-|b;m|vb|_m7;u]obm]-m|b7;ru;vv-m| treatment reported no decrease in the elevated baseline TNFα level. m|_-|u;rou|ķ_o;;uķ|_;u;-v-7;1u;-v;bm|_;$α level in revrom7;uv1olr-u;7b|_momu;vrom7;uvŐ_Ѵ;u;|-ѴĺķƑƏƐƕőĺ The main limitation of the present study is the relatively small samrѴ;vb;ĺ77b|bom-ѴѴķ|_;Ѵ-1ho=_;-Ѵ|_1om|uoѴv_-lr;u;7|_;bm|;upretation of the results. Circulating TNFα levels are affected by various l;|-0oѴb1-m7r-|_oѴo]b1-Ѵ1om7b|bomvbm-77b|bom|oŐ1u7Ѵ;ķ bm1-m;ķ omm-]_|omķ 1ouuoķ ş !o1_;ķ ƑƏƐƒĸ "bm_- ;| -Ѵĺķ 2013). Moreover, plasma TNFα levels may be affected by anesthesia 7ubm]$v;ub;vŐ"|;Ѵ_-ll;u;|-ѴĺķƑƏƐƐőĺ;m|_o]_|_;7b1_o|- omized response correlated significantly with lower baseline TNFα levels, these levels predicted the dichotomized response only at trend level in the logistic regression model. The association should therefore be confirmed in a larger sample. The baseline (before any treatment) TNFα levels used here, however, reflect only the influence of the disou7;uŐőķmo||_;;==;1|o=$ĺ$_;v|u;m]|_vo=|_bvv|7bm1Ѵ7; the standardized timing of repeated blood sampling during the individual ECT sessions and throughout the ECT series, which improves the u;Ѵb-0bѴb|o=|_;u;vѴ|vĺ$_vķ|_;;==;1|vo=0o|_|_;7bvou7;uŐő and the treatment (ECT) on TNFα levels have been considered. m1om1ѴvbomķѴo$α levels before and after the first ECT session predict symptom reduction after the ECT series. Every individual ECT session seemed to decrease the plasma TNFα level at 2 and 4 hr compared with baseline. This effect, however, was transitory because the baseline level did not change between the sessions. The predictive value of the first ECT session TNFα levels associated with final symptom reduction would be clinically interesting, if replicated in the further studies. )$" vĺ$;u_b"-Ѵom;mbv-ulѴ-1hmoѴ;7];7=ou_;u;1;ѴѴ;m||;1_mbcal assistance. This study was funded by grants from the Competitive Research Funding of Tampere University Hospital. CONFLICTS OF INTEREST None declared. ! Annamari Sorri http://orcid.org/0000-0002-3565-2805 REFERENCES 00-vbķ"ĺķovv;bmbķĺķo7-00;umb-ķĺķv_u-=bķĺķşh_om7-7;_ķ "ĺŐƑƏƐƑőĺ==;1|o=1;Ѵ;1ob0-77Ŋom|u;-|l;m|omvlr|olv-m7 v;ulŊѵ1om1;m|u-|bomvbmr-|b;m|vb|_l-fou7;ru;vvb;7bvouder: Randomized doubleblind placebocontrolled study. Journal of Affective Disorders, 141, 308–314. https://doi.org/10.1016/ j.jad.2012.03.033 h_om7-7;_ķ"ĺķ-=-ubķ"ĺķ!-bvbķĺķ-v;_bķĺĺķ_ou;bv_bķĺķ"-Ѵ;_bķĺķĻ -l-ѴbrouķĺŐƑƏƏƖőĺѴbmb1-Ѵ|ub-Ѵo=-7fm1|b;1;Ѵ;1ob0|u;-|l;m|bm r-|b;m|vb|_l-fou7;ru;vvbomĹ7o0Ѵ;0Ѵbm7-m7rѴ-1;0o1om|uoѴѴ;7 trial. 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