Antidepressiv användning och spottkortisol vid depression och ångest Författarlänkar öppen överlagspanel Leonie Manthey en 1 Frans G. aCaroline Leeds a 1 Visa mer https://doi.org/10.1016/j.euroneuro.2011.03.002 Få rättigheter och innehåll Open Access finansierad av holländska universitet Under en Elsevier användarlicensfri tillgång Abstrakt Antidepressiva medel är en effektiv behandling för depression och ångest. Dessa störningar följs ofta av förhöjda kortisolnivåer . Antidepressiva läkemedel kan påverka hypotalamus-hypofys-adrenalaxeln , vars förändring kan vara delvis ansvarig för behandlingseffekten. Sambandet mellan antidepressiva medel och kortisol undersöktes i 1526 personer av den nederländska studien av depression och ångest som gruppades till "SSRI-användare" ( = 309), "tricykliska antidepressiva (TCA) användare" (n = 49) ), "andra antidepressiva användare" (n = 100) och "icke-användare" (n = nio688) serotoninåterupptagshämmare (n 1068). Alla ämnen hade en aktuell eller tidigare diagnos av ångest och / eller depression. Ämnen gavs 7 salivprover från vilka 3 kortisolindikatorer beräknades: kortisoluppvakningsrespons(CAR), kortisol och kortisolundertryck efter intag av 0,5 mg dexametason . I jämförelse med icke-användare hade TCA-användare en platta CAR (effektstorlek: Cohens 0,34); SSRI- användare hade högre kortisolnivåer på kvällen ( 0,03). Dessa fynd tyder på att antidepressiva subtyper är associerade med tydliga förändringar av HPA-axeln . TCA-användare, som visade en platta CAR, uppvisade de starkaste förändringarna av spyttkortisol. d = d = 0,04); och SSRI-användare visade minskad kortisolundertryck efter intag av dexametason ( d = Föregående artikelNästa artikel Nyckelord antidepressiva medel;Kortisol;TCA;SSRI;Hypotalamus-hypofys-binjuraxeln 1 . Introduktion En hyperaktiv hypotalamus-hypofys-adrenal (HPA) -axel, som indikeras av ökade kortisolnivåer ( Bhagwagar et al., 2005 ) har ofta hittats hos personer med depression och ångest . Antidepressiva medel som används för att behandla depression och ångest ( Rose, 2007 ) kan påverka HPA-axelaktiviteten genom förändringar i glukokortikoid (GRs) och mineralokortikoidreceptorer (MRs) ( Bjartmar et al., 2000 ). Dessa förändringar kan delvis vara ansvariga för behandlingseffektivitet ( Pariante, 2009 ). Vidare har ökade kortisolnivåer visat sig vara associerade med ett antal fysiska sjukdomar (t.ex.diabetes , osteoporos) ( Bruehl et al., 2007; Nieman, 2007 ) som ofta förekommer med depression och / eller ångest ( Nouwen et al., 2010 ). Det är oklart om antidepressiv behandling påverkar fysiska sjukdomar hos ängsliga och deprimerade patienter genom modifierade kortisolnivåer. Av dessa skäl är studier av effekterna av antidepressiva medel på HPA-axeln kliniskt viktiga. Forskningen om kortisolhalten hos antidepressiva användare har dock givit resultat som skiljer sig från antidepressiva typer och kortisolåtgärder. Studier var vanligtvis begränsade till ett litet antal personer med diagnos av depression och den genomsnittliga interventionstiden var fem eller sex veckor ( Deuschle et al., 2003 ). I dessa studier resulterade TCA-behandling vanligtvis ( Deuschle et al., 1997 ), men inte alltid ( Dam, 1988 ), till ökad kortisolundertryckning i dexametason-undertryckningstestet (DST) som mäter HPA-axelns svar på administrering av en syntetisk analog av kortisol. TCA-respondenterna hade starkare undertryckta kortisolnivåer vid morgon, eftermiddag och kvällstidpunkter ( Deuschle et al., 2003 ) än SSRI- respondenter. Långsiktig SSRI-användning minskade kortisol och normaliserad kortisolundertryckning i en studie (Aihara et al., 2007 ) men inte i en annan ( Vythilingam et al., 2004 ). I en tredje studie minskade SSRI-behandling inte spottkortisol oavsett efterlämnad eller ej eftergiven status ( Weber-Hamann et al., 2007 ). I motsats till de förmodade HPA-axel-dämpningseffekterna som härrör från långtidsanvändning befanns kortvarig TCA- och SSRI-användning aktivera HPA-axeln ( Holsboer och Barden, 1996 ). Forskning om föreningarna av icke-TCA / icke-SSRI-antidepressiva läkemedel och HPA-axelfunktionen var begränsad till en studie där tetracykliska antidepressiva medel och selektiva serotoninåterupptagningsförstärkare reducerade tidigare ökad kortikosteronutsöndring i stressade råttor ( Szymanska et al., 2009 ). Forskning på antidepressiva medel och kortisol hos ängsna patienter var ännu mindre. Ökad kortisolnivå har förknippats med vissa typer av ångest, både i vår egen arbetsgrupp ( Vreeburg et al., 2010 ) och i andra studier ( Mantella et al., 2008 ), även om dessa resultat har varit inkonsekventa. Antidepressiva medel, såsom SSRI och TCA, har varit effektiva behandlingar för ångestsjukdomar ( Baldwin et al., 2005 ) och kan sänka kortisolhalterna hos ängslösa patienter som det har visat sig göra hos deprimerade patienter ( Deuschle et al., 1997 ). Även om kronisk antidepressiv användning är vanlig, är de långsiktiga effekterna (≥ 12 månader) har inte studerats väl. Ännu viktigare var vi inte medvetna om studier som jämförde effekterna av olika grupper av antidepressiva medel på kortisolindikatorer. En fullständigare förståelse av den biologiska mekanismen som ligger till grund för effekterna av antidepressiva medel kan resultera i förbättrade behandlingsalternativ för ängsliga och deprimerade patienter. Vi presenterar en tvärsnittsstudie som jämför cortisolnivåerna i salivarkortisol i TCA, SSRI, andra antidepressiva och icke-användare med en livstidsdiagnos av en depressiv och / eller en ångestsyndrom som deltar i den nederländska studien av depression och ångest (NESDA). Baserat på litteraturen väntade vi att hitta förändrade kortisolindikatorer (minskad bil, lägre basal kvällsnivåer och ökad undertryck i DST) hos antidepressiva användare jämfört med icke-användare. 2 . Experimentella procedurer 2.1. Subjects Subjects participated in the Netherlands Study of Depression and Anxiety (NESDA), a longitudinal cohort study consisting of 2981 respondents recruited from the community, general practices, and specialized mental health care institutions. Objectives and methods of the NESDA project have been described in an earlier publication (Penninx et al., 2008). Subjects completed a baseline measurement consisting of a medical exam, an in-person interview, collection of saliva samples, and questionnaires. The study protocol was approved by the Ethical Review Board of each participating center and all subjects signed an informed consent form before participation. Att utvärdera föreningarna mellan antidepressiva medel use and salivary cortisol, only subjects reporting a current or past diagnosis of a depressive and/or anxiety disorder (referred to as a lifetime disorder) were included. The presence of a depressive disorder (Major Depressive Disorder [MDD] or dysthymia) or anxiety disorder (generalized anxiety disorder, social phobia, or panic disorder) was assessed by the DSM-IV Composite Interview Diagnostic Instrument (WHO version 2.1). As previous research in our study group showed that remitted depressed and anxious subjects had a marginally heightened CAR (Vreeburg et al., 2009a; Vreeburg et al., 2010), indicating an increased biological vulnerability, those with a past diagnosis of either disorder were also included. In addition to subjects without lifetime disorders (n = 687), subjects who lacked cortisol data (n = 636), used corticosteroids (n = 105), were pregnant or breastfeeding (n = 10), or reported irregular antidepressant use (n = 17) were excluded (Vreeburg et al., 2009a). The remaining subjects (n = 1526) were available for analysis. All subjects who had used any antidepressant medication in the month prior to the baseline interview (n = 458) were defined as antidepressant users and further subdivided into SSRI users, TCA users, and other antidepressant users. Subjects who had not used antidepressants in the month prior to baseline interview were defined as non-users (n = 1068). Of the non-users, 15% reported some antidepressant use in the past 3 years. The following groups resulted: 309 SSRI users, 49 TCA users, 100 other antidepressant users, and 1068 non-users. 2.2. Measures of antidepressant use Medication use during the month prior to the baseline assessment was assessed via medication containers brought to the interview (80.7%) and subject self-report. Antidepressant users provided information on the daily dose, frequency of use, duration of treatment, and type of antidepressant used. Antidepressiva medel klassificerades som SSRI (ATC koder N06AB02-N06AB10), TCA (ATC koder N06AA01-N06AA23) och andra antidepressiva medel (ATC-koder N06AX05, n06aX11, N06AX16, och N06AX21, inklusive tetracykliska antidepressiva [n = 25], serotonin–norepinephrine reuptake inhibitors [n = 82], and trazodone [n = 1]), indicating that 8 subjects took more than one 'other' antidepressant. Due to small group sizes, the other AD user group was not further subdivided. For those reporting the use of multiple antidepressants, we assigned subjects to one of the three user groups based on relative strengths of the prescribed medications. SSRIs are usually prescribed as first-choice treatment for MDD as they have a milder side effect profile than TCAs but similar efficacy in moderately depressed patients. In severely depressed patients, or in those who do not tolerate the adverse effects of SSRIs or do not improve with SSRI treatment, TCAs are recommended (Peretti et al., 2000). Using this information, subjects taking both a TCA and another type of antidepressant (n = 5) remained in the TCA user group as TCAs are believed to have stronger effects than other antidepressant types. Subjects taking an SSRI and another non-TCA antidepressant (n = 10) were classified as SSRI users. In order to compare dosages of different antidepressants, the Mean Daily Dose for each user was calculated by dividing the milligrams of antidepressant used daily by the Defined Daily Dose as defined by the World Health Organization for each antidepressant. 2.3. Cortisol measures A detailed description of cortisol measures can be found elsewhere (Vreeburg et al., 2009b). To summarize, respondents collected saliva samples at home on a regular, preferably working, day shortly after the baseline interview was conducted. Subjects were instructed to refrain from eating, smoking, drinking tea or coffee, or brushing teeth 15 min prior to sampling and no dental work was allowed in the 24 h preceding sample collection. Seven saliva samples were collected over a two-day period using Salivettes© (Sarstedt, Germany). On day 1, samples were taken at awakening (T1) and at 30 min (T2), 45 min (T3), and 60 min (T4) post-awakening. Two samples were taken in the evening at 22:00 h (T5) and 23:00 h (T6). Subjects ingested 0.5 mg of dexamethasone immediately after T6 and one salivary sample was taken at awakening on day 2 (T7). Samples were refrigerated after collection and returned by mail. In the laboratory, Salivettes were centrifuged at 2000 g for 10 min, aliquoted, and stored at − 80 °C and cortisol analysis was carried out using competitive electrochemiluminescence immunoassay (Roche, Switzerland). The functional detection limit was 2.0 nmol/l and the intra- and interassay variability coefficients in the measuring range were less than 10%. The following three cortisol indicators were calculated from the seven cortisol samples. Cortisol awakening response (CAR): The CAR was calculated by analysis of T1 to T4 with linear mixed models (LMM) and two aggregate indicators: the area under the curve with respect to the ground (AUCG) and the area under the curve with respect to the increase (AUCI) (Pruessner et al., 2003). The AUCG is an estimate of the total cortisol secretion during the first hour after awakening. The AUCI is a measure of the dynamic of the cortisol awakening response, related to the sensitivity of the system, emphasizing changes over time. Evening cortisol: The basal cortisol level was defined as the average of the two evening cortisol values (T5 and T6). For subjects with a single missing evening value, the remaining cortisol value was used. Dexamethasone suppression test (DST): In addition to the cortisol level at awakening after dexamethasone ingestion (T7), a cortisol suppression ratio was calculated by dividing the cortisol level at awakening on day 1 (T1) by the post-dexamethasone cortisol level at awakening on day 2 (T7). Higher DST ratios indicated a larger difference between T1 and T7 and, accordingly, a greater cortisol-suppressing effect of dexamethasone. 2.4. Covariates The four categories of confounding variables were: sociodemographic indicators, psychiatric indicators, health indicators, and sampling factors. These variables altered cortisol levels in previous analyses of the NESDA data (Vreeburg et al., 2009b). A detailed description is located in additional publications (Penninx et al., 2008; Vreeburg et al., 2009a). Sociodemographic indicators included age, sex, and level of education. Psychiatric indicators consisted of a lifetime diagnosis of comorbid anxiety and depression as subjects with comorbid disorder were found to have a higher CAR in previous research in this study group (Vreeburg et al., 2009a). The Inventory of Depressive Symptomatology Self-Report (IDS-SR), a rating scale for depression severity, was not associated with cortisol levels in NESDA (Vreeburg et al., 2009b). However, as the sample used in our analyses was slightly different to the one defined previously, the IDS-SR was included as a covariate in a sensitivity analysis. In order to account for possible associations between cortisol and anxiety severity, we also included the Beck Anxiety Questionnaire as covariate in a separate sensitivity analysis. Health indicators included tobacco use and the current level of physical activity. Tobacco use was grouped into current smokers, former smokers, and non-smokers. Additionally, the number of smoked cigarettes per day was counted in order to exclude the heavy smokers (defined as smoking > 25 cigarettes/day) in a sensitivity analysis. Physical activity was measured using the International Physical Activity Questionnaire and expressed in 1000 MET-minutes per week. Sampling factors included seasonal light, weekday or weekend status, work status, awakening time, and hours of sleep per night. Seasonal light was evaluated by defining the month of sampling as either a dark month (October through March) or a light month (April through September). Average sleep duration during the four weeks prior to sampling was categorized as ≤ 6 or > 6 h per night. 2.5. Statistical analyses Characteristics of study groups were expressed by frequencies or means and compared using χ2 statistics (categorical variables) or analysis of variance (continuous variables). Positively skewed cortisol indicators (T1–T4, AUCG, evening cortisol, T7 and DST) were naturally log-transformed for subsequent analyses. Back-transformed values are given in Table 2. Post-hoc tests on individual group differences were performed using the Fisher Least Significant Difference test. Differences in AUCG, AUCI, evening cortisol, T7, and DST across groups were analyzed using analysis of covariance (ANCOVA), adjusting for covariates. Cohen's d (the difference in marginal estimated means, divided by their pooled standard deviation) was calculated as a measure of effect size. Further analysis of the CAR was carried out with random coefficient analysis of the four morning cortisol data points using Linear Mixed Models (LMM). LMM retains original values on all data points while accommodating for missing data and taking into account correlations between repeated measurements within subjects. Linear regression analyses on dosage of antidepressant (Mean Daily Dose) and duration of use (months) were conducted on the SSRI and TCA user groups. Other AD users were excluded from these analyses due to the multiple antidepressants types included in this group. Analyses were adjusted for the described covariates. To determine the stability of our results, all analyses were also corrected for severity of depression and anxiety in sensitivity analyses. Additionally, heavy smokers (defined as smoking > 25 cigarettes/day), users of multiple antidepressants, and lithium users were excluded in different sensitivity analyses in order to investigate the robustness of our results. Statistical significance was set at p < 0.05. SPSS 16.0 software was used for all analyses (SPSS Inc, Chicago, Ill.). 3. Results Characteristics of the study groups are shown in Table 1. TCA users were older than SSRI users, other users, and non-users. Non-users were more likely to have sampled during a light month and on a working day. Antidepressant users more often had comorbid anxiety and depression than non-users. TCA users used smaller antidepressant doses than the other groups. Results of analyses of covariance are shown in Table 2. Table 1. Characteristics of study groups (n = 1526). N SSRI users (n = 309) TCA users (n = 49) Other AD users (n = 100) Non-users (n = 1068) P-value Sociodemographics 1529 Age 1529 42.8 (41.5–44.1)a 48.9 (46.3–51.4)a,b,c 43.8 (41.8–45.9)b 43.1 (42.3–43.9)c 0.01 % Male 1529 33.7 26.5 40.0 32.3 0.33 Years of education 1529 11.6 (11.2–12.0) 11.4 (10.5–12.3) 11.9 (11.2–12.6) 11.9 (11.7–12.1) 0.68 Sampling factors 1529 % Sampled during light months 1529 53.7 49.0 48.0 59.0 0.05 % Sampled on weekday 1529 90.0 89.8 90.0 92.4 0.47 % sampled on work day 1529 52.1 51.0 55.0 63.0 0.002 Awakening time 1529 7 h 36 min (7 h 28 min–7 h 45 min) 7 h 30 min (7 h 12 min–7 h 48 min) 7 h 31 min (7 h 17 min–7 h 45 min) 7 h 27 min (7 h 23 min–7 h 32 min) 0.35 % > 6 h per night 1529 72.8 69.4 71.0 69.4 0.71 Health indicators 1529 Tobacco use 1529 0.11 % Former smoker 1529 32.4 38.8 29.0 38.4 % Current smoker 1529 39.8 44.9 40.0 34.4 Level of physical activity1 (in MET-minutes) 1529 22.6 (19.9–25.5)a 22.1 (16.7–29.0) 20.0 (16.1–24.8)b 27.2 (25.7–28.7)a,b 0.001 Psychiatric indicators 1529 Lifetime diagnosis 1529 < 0.001 % Depressive disorder only 1529 22.3 12.2 22.0 33.2 % Anxiety disorder only 7.4 12.2 5.0 18.2 % Comorbid anxiety/depressive disorder 1529 70.2 75.5 73.0 48.6 Severity of psychopathology IDS-SR Mood/Cognition Subscale 1526 8.3 (7.81–8.87)a 7.6 (6.21–8.93)b 8.6 (7.7–9.5)c 6.3 (6.0–6.5)a,b,c < 0.001 IDS-SR Anxiety/Arousal Subscale 1526 5.8 (5.5–6.1)a 6.1 (5.4–6.9)b 4.9 (4.7–5.1)c 4.9 (4.7–5.1)a,b,c < 0.001 Beck Anxiety Questionnaire 1520 13.1 (12.0–14.3)a 14.0 (11.4–17.1)b 12.9 (10.8–15.3)c 9.0 (8.6–9.5)a,b,c < 0.001 Antidepressant use Duration of use (mean in months, 95% C.I.) 455 14.4 (12.3–16.9) 19.0 (12.1–29.3)a 11.7 (9.2–14.7)a – 0.12 Daily dosage level2 (mean, 95% C.I.) 455 1.2 (1.2–1.2)a,b 1.0 (0.9–1.1)a,c 1.1 (1.1–1.2)b,c – < 0.001 IDS-SR indicates Inventory of Depressive Symptomatology Self-Report. P-value was calculated by analysis of variance (ANOVA) or the χ2 test. Significance is inferred at P < 0.05. Numbers in bold indicate a significant P value. Matching superscript letters are given for values that differ significantly within a row (post-hoc test, P < 0.05). CI = confidence interval, SSRI = selective serotonin reuptake inhibitor, TCA = tricyclic antidepressant, and AD = antidepressant. For duration of use, dosage and physical activity back-transformed means (95%C.I.s) are presented, based on estimated marginal means. 1MET-minute = (Metabolic Equivalent minute), multiple of the resting metabolic rate. 2A comparative daily dosage level (stated as Mean Daily Dose) was calculated by dividing the milligrams of antidepressant used daily by the defined daily dosage (DDD) for the specific antidepressant. Table 2. Associations between antidepressant use and salivary cortisol indicators (n = 1526). Cortisol characteristics N SSRI users (n = 309) SSRI users vs. non-users TCA users (n = 49) TCA users vs. non-users Other AD users (n = 100) Other AD users vs. non-users Non-users (n = 1068) Mean (C.I. 95%) P-value Mean (C.I. 95%) P-value Mean (C.I. 95%) P-value Mean (C.I. 95%) Unadjusted values Cortisol awakening response (CAR) Cortisol T1 (awakening, nmol/l) 1512 15.8 (15.1–16.5) 0.84 18.3 (16.4–20.5) 0.009 15.6 (14.4–16.9) 0.92 15.7 (15.3–16.1) Cortisol T2 (+ 30 min, nmol/l) 1495 19.8 (18.9–20.9) 0.48 18.1 (15.9–20.4) 0.25 19.0 (17.4–20.7) 0.57 19.5 (19.0–20.0) Cortisol T3 (+ 45 min, nmol/l) 1481 18.6 (17.6–19.6) 0.23 18.4 (16.4–20.6) 0.54 18.7 (17.0–20.5) 0.40 17.9 (17.4–18.4) Cortisol T4 (+ 60 min, nmol/l) 1491 16.0 (15.1–16.8) 0.56 16.9 (14.7–19.3) 0.31 16.0 (14.5–17.6) 0.67 15.7 (15.2–16.1) AUCG (nmol/l/h) 1464 18.5 (17.7–19.3) 0.32 18.9 (17.0–21.0) 0.42 18.0 (16.7–19.4) 0.99 18.0 (17.6–18.5) AUCI (nmol/l/h) 1464 2.7 (2.0–3.4) 0.56 0.09 (− 1.7–1.9) 0.01 2.3 (1.0–3.5) 0.78 2.5 (2.1–2.8) Evening cortisol (nmol/l/h)a 1520 5.3 (5.0–5.6) 0.007 5.8 (5.0–6.7) 0.02 5.3 (4.8–5.9) 0.09 4.8 (4.7–5.0) Dexamethasone suppression test (DST) Cortisol T7 (awakening day 2, nmol/l) 1470 7.3 (6.9–7.7) 0.001 8.5 (7.4–9.7) < 0.001 7.3 (6.7–8.1) 0.03 6.5 (6.4–6.7) Cortisol suppression ratio (nmol/l)b 1457 2.3 (2.2–2.5) 0.001 2.4 (2.0–2.8) 0.29 2.3 (2.0–2.5) 0.02 2.6 (2.5–2.7) Adjusted valuesc AUCG (nmol/l/h) 1464 18.5 (17.8–19.3) 0.33 18.4 (16.5–20.4) 0.72 17.9 (16.6–19.3) 0.81 18.0 (17.6–18.5) AUCI (nmol/l/h) 1464 2.8 (2.1–3.5) 0.41 0.2 (− 1.6–2.1) 0.03 2.4 (1.1–3.7) 0.88 2.4 (2.0–2.8) Evening cortisol (nmol/l) 1520 5.3 (5.0–5.6) 0.02 5.6 (4.9–6.5) 0.05 5.3 (4.8–5.8) 0.18 4.9 (4.7–5.0) Cortisol T7 (awakening day 2, nmol/l) 1470 7.2 (6.9–7.7) 0.003 8.2 (7.1–9.3) 0.002 7.2 (6.6–7.9) 0.08 6.6 (6.4–6.8) Cortisol suppression ratio (nmol/l) 1457 2.3 (2.2–2.5) 0.002 2.4 (2.1–2.8) 0.37 2.3 (2.1–2.5) 0.05 2.6 (2.5–2.7) SSRI = selective serotonin reuptake inhibitor, TCA = tricyclic antidepressant, AD = antidepressant, AUCG = area under the morning curve with respect to the ground, AUCI = area under the morning curve with respect to the increase, T = time point, and CI = confidence interval. For all cortisol indicators except for AUCI backtransformed means (95%C.I.s) are presented, based on estimated marginal means, calculated by analysis of covariance (ANCOVA). For AUCI estimated marginal means (95%C.I.s) are presented. P-values are calculated by ANCOVA comparing two groups at a time. Significance is inferred at P < 0.05. Numbers in bold indicate a significant P value. a The evening cortisol level is the average of T5 and T6 (taken at 22:00 h and 23:00 h). b The cortisol suppression ratio is the ratio of salivary cortisol at T1 to salivary cortisol at T7 after 0.5 mg dexamethasone. c Adjusted for sociodemographic variables (sex, age, education), psychiatric indicators (comorbidity), health indicators (smoking and physical activity), and sampling factors (seasonal light, work status, weekday/weekend, awakening time, sleep). 3.1. Cortisol awakening response A large percentage of the TCA users (42.9%) did not show the characteristic increase in cortisol in the first hour of awakening as compared to only 26.2% of SSRI users, 33.0% other AD users, and 28.1% non-users. Adjusted CAR results showed that TCA, SSRI, and other AD users did not differ from non-users on overall cortisol levels, reflected by analysis of AUCG and a non significant group effect in LMM analysis (F (3,1500) = 0.14, p = 0.94). The time course of the awakening response of TCA users differed from that of non-users as well as of SSRI users and other AD users, reflected by analysis of AUCI (effect size [Cohen's d] = 0.34, p = 0.03, TCA users vs. non-users, see Table 2) and a significant group * time interaction in the LMM analysis (F (3,3268) = 4.53, p = 0.004; TCA users vs. non-users, data not shown). As can be seen in Fig. 1, TCA users had a considerably flattened CAR compared to all other groups. None of the other antidepressant user groups differed from the non-user group on the AUCI. Download high-res image (189KB)Download full-size image Figure 1. Mean salivary cortisol levels of the CAR, evening cortisol and cortisol after dexamethasone administration adjusted for sociodemographic variables, psychiatric indicators, health indicators, and sampling factors. Numerical values for cortisol indicators are shown. 3.2. Evening cortisol Unadjusted and adjusted evening cortisol levels were significantly higher for SSRI users (d = 0.04, p = 0.02) and marginally significant for TCA users (effect size = 0.17, p = 0.05) as compared to non-users. Other AD users did not differ from non-users. 3.3. Dexamethasone suppression test After adjustment for covariates, T7 cortisol levels in SSRI and TCA users were higher (SSRI vs. non-users: d = 0.19, p = 0.003; TCA vs. non-users: d = 0.46, p = 0.002) but other AD users differed only marginally from non-users at T7. Unadjusted and adjusted cortisol suppression ratios were lower in SSRI users (d = 0. 03, p = 0.002) and marginally significant in other AD users (d = 0.22, p = 0.05) as compared to non-users, indicating a smaller cortisol suppressing effect of dexamethasone. Consistent results were found for SSRI users (vs. non-users), who had both higher T7 values and the expected lower cortisol suppression ratio. For the TCA users, results of the DST and T7 were incongruous. TCA users had higher T7 values, but a non-statistically significant lower cortisol suppression ratio. As the number of subjects using TCAs was much smaller than in the SSRI group, type II errors could have occurred for the latter contrasts. Due to these discrepancies between T7 and the DST in the TCA group, no conclusions could be drawn on basis of these findings and only the suppression findings of the SSRI group (which were consistent across cortisol indicators) were considered in the discussion. Additional adjustment for severity with the IDS-SR and BAI as well as the exclusion of multiple antidepressant users, lithium users, and heavy smokers did not significantly alter the results in any of the conducted analyses (data not shown). 3.4. Antidepressant dose and duration In the linear regression analyses, performed in SSRI and TCA users separately (n = 358), dosage level or duration of use was not associated with cortisol indicators (data not shown). 4. Discussion In this study, the relationship between antidepressant use and multiple salivary cortisol measures was investigated in 1526 NESDA participants with a lifetime diagnosis of depression and/or anxiety. As compared to non-users, TCA users had a flattened CAR, SSRI users had higher evening cortisol levels, and SSRI users displayed a lower suppressing effect of dexamethasone. Though previous studies have linked lower morning cortisol levels at a single time point with TCA use (Deuschle et al., 2003), the association between TCA use and the CAR has not previously been studied. However, the atypical AUCI pattern seen in the majority of TCA users in our study is unlikely to indicate that TCAs are clinically effective by producing a flattened CAR. As the CAR is commonly viewed as a healthy reaction to awakening, with awakening representing a natural stressor (Kuehner et al., 2007), the atypical curve most probably reflects an impaired ability to react to the stress of awakening in more severely depressed and difficult-to-treat subjects for whom TCAs are prescribed. A biological explanation for the atypical curve may lie in the effects of antidepressants on the two main corticosteroid receptors, GR and MR (Bjartmar et al., 2000). GRs are assumed to restore corticosteroid homeostasis after circadian peaks. Consequently, increased expression of GR may increase suppression of cortisol levels (Eiring and Sulser, 1997). Most animal studies (Johansson et al., 1998), but not all of them (Pariante et al., 2003), found that chronic TCA administration resulted in upregulation of GRs, which might contribute to the observed flattened CAR. Additionally, the MR was recently identified as a modulator of the CAR (De Rijk et al., 2006) and found to be upregulated after chronic TCA administration in many (Bjartmar et al., 2000), but not all (Przegalinski and Budziszewska, 1993), animal studies. Thus the MR may also contribute to the flattened CAR. However, the total cortisol secretion during the first hour after awakening (i.e., AUCG) was not reduced in TCA users as compared to non-users. Therefore, an increased sensitivity to corticosteroids in response to TCAs is unlikely to be the sole biological explanation for our findings. We observed higher basal cortisol levels and decreased cortisol suppression in SSRI users. Previous studies reported lower (Vythilingam et al., 2004) or unchanged (Deuschle et al., 2003; Juruena et al., 2010) basal levels and variously altered (decreased, increased and unchanged) cortisol suppression in users (Aihara et al., 2007; Deuschle et al., 2003; Vythilingam et al., 2004; Watson et al., 2006). There are several possible explanations for these discrepancies. Associations of reduced cortisol levels with a positive treatment response (Deuschle et al., 2003) indicated that normalized cortisol levels may not reflect antidepressant use alone. On the other hand, in NESDA (Vreeburg et al., 2009a) and other studies, (Bhagwagar et al., 2003) elevated cortisol levels were found in both current and remitted depressed subjects and an intervention reported no association between suppression after prednisolone administration and treatment response (Juruena et al., 2010). Altered HPA axis activity may reflect a biological vulnerability (Juruena et al., 2010), independent of treatment success (Vreeburg et al., 2009a). However, an intervention study found that impaired response to the prednisolone suppression test was associated with treatment resistance (Juruena et al., 2009). Therefore, additional randomized intervention studies are needed in order to investigate the relationship between the different cortisol indicators and treatment response. Alternatively, the cortisol-reducing effects of antidepressants in intervention studies may be temporary, implying that conflicting findings were due to inter-study differences in treatment duration. Indeed, an animal study showed the up-regulating effect of antidepressants on MR and GR receptor levels to be transient in nature (Reul et al., 1993). In contrast to the five or six weeks of treatment in intervention studies (Deuschle, 2003), 88.5% of NESDA users reported at least two months of antidepressant use and 47.1% of users reported chronic use (≥ 12 months). However, as we found an altered CAR in TCA users, the majority of whom were chronic users, altered stress responses might persist in TCA users. Furthermore, dampening of the HPA axis has been hypothesized to be related to therapeutic efficacy of antidepressants (Pariante, 2009) and antidepressants have been shown to be an effective long-term treatment. The long-term effects of antidepressants on cortisol need further investigation in prospective studies before firm conclusions can be drawn. Alternatively, the discrepancies of our results with previous findings could be due to the inclusion of subjects with lifetime diagnoses, leading to a broader range of illness severity. As subjects in need of antidepressant treatment are usually more severely ill than non-users, this may confound the association between antidepressants and cortisol. However, although antidepressant users scored higher than non-users on the IDS-SR in the present study, severity did not confound the associations found. Our study had several limitations. We performed a cross-sectional analysis, which precluded causal inferences. Since our study categorized length of use in number of months and the majority of users reported at least two months of use, it was not possible to evaluate cortisol levels after five or six weeks to directly compare our results with those found in short-term intervention studies. In addition, the ambulatory setting and the consequent possibility of non-compliance with instructions on saliva collection may have resulted in measurement error. Despite these limitations, our study had many valuable features. Our large sample size and multiple cortisol measurements allowed us to compare sizable groups of users of different antidepressant types on several cortisol measures indicative of different aspects of HPA axis activity, while adjusting for many potential confounders. In conclusion, we found an atypical cortisol awakening response in TCA users as well as higher basal cortisol levels and decreased cortisol suppression for SSRI users as compared to non-users within a sample of 1526 NESDA participants with a lifetime disorder of depression and/or anxiety. These findings suggest that antidepressant subtypes may be associated with distinct alterations of the HPA axis. Possible antidepressant-induced alterations of the HPA axis might also affect comorbid physical diseases for which altered cortisol levels are an underlying cause or contributor, such as diabetes, cardiovascular disease and osteoporosis, in subjects with anxiety and depression (Bruehl et al., 2007; Nieman, 2007). Further research on these effects in randomized trials and prospective cohort studies may lead to a better understanding of the varied efficacies of antidepressants and more effective drug treatments for anxious and depressed patients. Role of the funding source The funding sources mentioned in the Acknowledgments had no further role in the study design, the collection, analysis and interpretation of data, the writing of the report and the decision to submit the paper for publication. Contributors Ms. Manthey and Ms. Leeds searched for literature, analyzed the data, and wrote the article. Ms. Leeds wrote the first draft under the supervision of Ms. Manthey, who later completed the final version. Ms. Manthey was also involved in data gathering (interviews with participants). Dr. Giltay and Ms. van Veen are the supervisors of Ms. Manthey and provided regular feedback on the written material and helped with the statistical analysis. Ms. Vreeburg was responsible for the data cleaning of the salivary cortisol data, contributed to the Experimental procedures section on salivary cortisol, and supplied input on cortisol related content. Prof. Penninx and Prof. Zitman are the promoters of Ms. Manthey, reading the article approximately once every two months and providing feedback. Conflict of interest All authors declare that they have no conflicts of interest. Acknowledgments The infrastructure for the NESDA study (http://www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMw, grant number 10-000-1002) and is supported by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Scientific Institute for Quality of Health Care (IQ Healthcare), Netherlands Institute for Health Services Research (NIVEL) and Netherlands Institute of Mental Health and Addiction (Trimbos)). References Aihara et al., 2007 M. Aihara, I. Ida, N. Yuuki, A. Oshima, H. Kurnano, K. Takahashi, M. Fukuda, N. Oriuchi, K. Endo, H. Matsuda, M. 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Abstrakt
Antidepressiva medel är en effektiv behandling för depression och ångest. Dessa störningar följs ofta av förhöjda kortisolnivåer. Antidepressiva läkemedel kan påverka hypotalamus-hypofys-adrenalaxeln, vars förändring kan vara delvis ansvarig för behandlingseffekten. Föreningen mellan antidepressiva medel och kortisol undersöktes i 1526 patienter av den nederländska studien av depression och ångest som grupperade till SSRI-användare (n = 309), "tricykliska antidepressiva (TCA) användare" (n = 49) ), "andra antidepressiva användare" (n = 100) och "icke-användare" (n = 1068). Alla ämnen hade en aktuell eller tidigare diagnos av ångest och / eller depression. Ämnen gavs 7 salivprover från vilka 3 kortisolindikatorer beräknades: kortisoluppvakningsrespons (CAR), kvällskortisol och kortisolundertryck efter intag av 0,5 mg dexametason. I jämförelse med icke-användare hade TCA-användare en platta CAR (effektstorlek: Cohen's d = 0,34); SSRI-användare hade högre kortisolnivåer på kvällen (d = 0,04); och SSRI-användare visade minskad kortisolundertryck efter intag av dexametason (d = 0,03). Dessa fynd tyder på att antidepressiva subtyper är associerade med tydliga förändringar av HPA-axeln. TCA-användare, som visade en platta CAR, uppvisade de starkaste förändringarna av spyttkortisol. Dessa fynd tyder på att antidepressiva subtyper är associerade med tydliga förändringar av HPA-axeln. TCA-användare, som visade en platta CAR, uppvisade de starkaste förändringarna av spyttkortisol. Dessa fynd tyder på att antidepressiva subtyper är associerade med tydliga förändringar av HPA-axeln. TCA-användare, som visade en platta CAR, uppvisade de starkaste förändringarna av spyttkortisol.
PMID
21458959 [Indexed for MEDLINE] KÄLLA:https://www.ncbi.nlm.nih.gov/m/pubmed/21458959/STUDIEN
Diskussion
I denna studie var sambandet mellan antidepressiva användning och flera salivkortisol åtgärder undersöktes i 1526 NESDA deltagare med en livslängd diagnosen depression och / eller ångest. Jämfört med icke-användare, TCA-användare hade tillplattad CAR, SSRI-användare hade högre kväll kortisolnivåer och SSRI-användare visas en lägre hämmande effekten av dexametason.
Även tidigare studier har kopplat lägre kortisolnivåer på morgonen vid en enda tidpunkt med TCA-användning ( Deuschle et al., 2003 ), har sambandet mellan TCA-användning och CAR inte tidigare studerats. Det atypiska AUC I- mönstret som ses hos majoriteten av TCA-användare i vår studie är dock osannolikt att indikera att TCAs är kliniskt effektiva genom att producera en platta CAR. Eftersom bilen normalt ses som en hälsosam reaktion på uppvaknande, med uppvaknande som representerar en naturlig stressor ( Kuehner et al., 2007 ), återspeglar den atypiska kurvan förmodligen en nedsatt förmåga att reagera på stressen av uppvaknande i svårare deprimerade och svåra -till-behandla ämnen för vilka TCA-preparat är föreskrivna.
En biologisk förklaring till den atypiska kurvan kan ligga i effekterna av antidepressiva medel på de två huvudsakliga kortikosteroidreceptorerna, GR och MR ( Bjartmar et al., 2000 ). GRs antas återställa kortikosteroidhomeostas efter cirkadiska toppar. Följaktligen kan ökat uttryck av GR öka ökning av kortisolnivåer ( Eiring och Sulser, 1997 ). De flesta djurstudierna ( Johansson et al., 1998 ), men inte alla av dem ( Pariante et al., 2003 ), fann att kronisk TCA-administration resulterade i uppreglering av GRs, vilket kan bidra till den observerade planerade CAR. Dessutom identifierades MR nyligen som en modulator av CAR ( De Rijk et al., 2006) och befanns vara uppreglerade efter kronisk TCA-administrering hos många ( Bjartmar et al., 2000 ), men inte alla ( Przegalinski och Budziszewska, 1993 ), djurstudier. Således kan MR också bidra till den planade CAR. Den totala kortisolsekretionen under den första timmen efter uppvaknandet (dvs. AUC G ) reducerades emellertid inte i TCA-användare jämfört med icke-användare. Därför är det osannolikt att en ökad känslighet för kortikosteroider som svar på TCAs är den enda biologiska förklaringen av våra resultat.
Vi observerade högre basala kortisolnivåer och minskad kortisolundertryck hos SSRI-användare. Tidigare studier rapporterade lägre ( Vythilingam et al., 2004 ) eller oförändrad ( Deuschle et al., 2003 , Juruena et al., 2010 ) basala nivåer och olika förändrade (minskad, ökad och oförändrad) kortisolundertryckning hos användare ( Aihara et al. , 2007 , Deuschle et al., 2003 , Vythilingam et al., 2004 , Watson et al., 2006 ). Det finns flera möjliga förklaringar för dessa skillnader. Föreningar av reducerade kortisolnivåer med positivt behandlingssvar ( Deuschle et al., 2003) indikerade att normaliserade kortisolhalter inte kan återspegla antidepressiv användning ensam. Å andra sidan hittades i NESDA ( Vreeburg et al., 2009a ) och andra studier, ( Bhagwagar et al., 2003 ) förhöjda kortisolnivåer i både nuvarande och återgivna deprimerade patienter och en intervention rapporterade ingen samband mellan undertryck efter prednisolonadministration och behandlingssvar ( Juruena et al., 2010 ). Ändrad HPA-axelaktivitet kan spegla en biologisk sårbarhet ( Juruena et al., 2010 ), oberoende av behandlingssucces ( Vreeburg et al., 2009a ). En interventionsstudie fann emellertid att nedsatt respons på prednisolonundertrycknings testet associerades med behandlingsresistens (Juruena et al., 2009 ). Därför behövs ytterligare randomiserade interventionsstudier för att undersöka förhållandet mellan de olika kortisolindikatorerna och behandlingssvaret.
Alternativt kan de kortisolreducerande effekterna av antidepressiva medel i interventionsstudier vara tillfälliga, vilket innebär att motstridiga resultat berodde på inter-studie skillnader i behandlingsvaraktighet. Faktum är att en djurstudie visade den uppreglerande effekten av antidepressiva medel på MR- och GR-receptornivåer att vara övergående i naturen ( Reul et al., 1993 ). I motsats till de fem eller sex veckors behandling i interventionsstudier ( Deuschle, 2003 ) rapporterade 88,5% av NESDA-användarna minst två månader av antidepressiv användning och 47,1% av användarna rapporterade kronisk användning (≥12 månader). Emellertid, som vi hittade en förändrad CAR i TCA-användare, varav majoriteten var kroniska användare, kan förändrade spänningsresponser kvarstå hos TCA-användare. Vidare har dämpning av HPA-axeln antagits för att vara relaterad till terapeutisk effekt av antidepressiva medel ( Pariante, 2009 ) och antidepressiva medel har visat sig vara en effektiv långsiktig behandling. De långsiktiga effekterna av antidepressiva medel på kortisol behöver ytterligare undersökning i prospektiva studier innan slutsatser kan dras.
Alternativt kan skillnaderna i våra resultat med tidigare resultat bero på att ämnen med livstidsdiagnoser inkluderas, vilket leder till ett större antal sjukdomar. Eftersom ämnen som behöver behandling med antidepressiva medel vanligen är svårare än andra användare, kan detta förknippa sambandet mellan antidepressiva medel och kortisol. Emellertid, även om antidepressiva användare gjorde högre resultat än icke-användare på IDS-SR i den föreliggande studien, störde svårighetsgraden inte de föreningar som hittades.
Vår studie hade flera begränsningar. Vi utförde en tvärsnittsanalys, som utesluter orsakssamband. Eftersom vår studie kategoriserad användbarhet under antal månader och majoriteten av användarna rapporterade minst två månaders användning, var det inte möjligt att utvärdera kortisolhalterna efter fem eller sex veckor för att direkt jämföra våra resultat med de som hittades vid kortvarig intervention studier. Dessutom kan den ambulatoriska inställningen och den därmed följande risken för bristande överensstämmelse med instruktioner om salivinsamling ha resulterat i mätfel. Trots dessa begränsningar hade vår studie många värdefulla funktioner. Vår stora provstorlek och flera kortisolmätningar gjorde det möjligt för oss att jämföra betydande grupper av användare av olika antidepressiva typer på flera kortisolåtgärder som indikerar olika aspekter av HPA-axelaktivitet,
Sammanfattningsvis fann vi ett atypiskt kortisoluppvakningsrespons hos TCA-användare samt högre basala kortisolnivåer och minskad kortisolundertryckning för SSRI-användare jämfört med icke-användare inom ett prov av 1526 NESDA-deltagare med en livstids störning av depression och / eller ångest . Dessa fynd tyder på att antidepressiva subtyper kan associeras med tydliga förändringar av HPA-axeln. Eventuella antidepressiva inducerade förändringar av HPA-axeln kan också påverka comorbida fysiska sjukdomar för vilka förändrade kortisolnivåer är en bakomliggande orsak eller bidragsgivare, såsom diabetes, hjärt-kärlsjukdom och osteoporos hos personer med ångest och depression ( Bruehl et al., 2007 , Nieman, 2007 ).
Ytterligare forskning om dessa effekter i slumpmässiga studier och prospektiva kohortstudier kan leda till en bättre förståelse av de olika effekterna av antidepressiva medel och effektivare läkemedelsbehandlingar för ängsliga och deprimerade patienter.
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Om någon känner sig felaktigt behandlad i denna blogg. Lämna meddelande på sidan så kommer felaktigheter att behandlas. Ni andra, lämna gärna förslag på ämnen ni vill veta mer om.