Major Depression and the Degree of Suicidality: Results of the European Group for the Study of Resistant Depression (GSRD)

Major Depression and the Degree of Suicidality: Results of the European Group for the Study of... Background: This European multicenter study aimed to elucidate suicidality in major depressive disorder. Previous surveys suggest a prevalence of suicidality in major depressive disorder of ≥50%, but little is known about the association of different degrees of suicidality with socio-demographic, psychosocial, and clinical characteristics. Methods: We stratified 1410 major depressive disorder patients into 3 categories of suicidality based on the Hamilton Rating Scale for Depression item 3 (suicidality) ratings (0 = no suicidality; 1–2= mild/moderate suicidality; 3–4 = severe suicidality). Chi-squared tests, analyses of covariance, and Spearman correlation analyses were applied for the data analyses. Results: The prevalence rate of suicidality in major depressive disorder amounted to  46.67% (Hamilton Rating Scale for Depression item 3 score ≥1). 53.33% were allocated into the no, 38.44% into the mild/moderate, and 8.23% into the severe suicidality patient group. Due to the stratification of our major depressive disorder patient sample according to different levels of suicidality, we identified some socio-demographic, psychosocial, and clinical variables differentiating from the patient group without suicidality already in presence of mild/moderate suicidality (depressive symptom severity, treatment resistance, psychotic features, add-on medications in general), whereas others separated only when severe suicidality was manifest (inpatient treatment, augmentation with antipsychotics and benzodiazepines, melancholic features, somatic comorbidities). Received: December 10, 2017; Revised: January 14, 2018; Accepted: February 22, 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is 539 properly cited. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 540 | International Journal of Neuropsychopharmacology, 2018 Significance Statement Suicidality represents a meaningful clinical challenge in the treatment of patients suffering from unipolar depression. In our European multicenter study, we examined socio-demographic, psychosocial, and clinical features in different degrees of sui- cidality (no, mild/moderate, and severe suicidality). For some variables (depressive symptom severity, treatment resistance, psychotic features, add-on medications in general), we found significant differences already between patients exhibiting mild/ moderate severity and those without suicidality. For other investigated variables, however, significant differences compared with the absence of suicidality could be determined only in case of the presence of severe suicidality. This applies to the variables inpatient treatment, augmentation with antipsychotics and benzodiazepines, melancholic features, and somatic comorbidities. Conclusions: As even mild/moderate suicidality is associated with a failure of achieving treatment response, adequate recognition of this condition should be ensured in the clinical practice. Keywords: augmentation/combination treatment, major depressive disorder, suicidality, treatment response Introduction Major depressive disorder (MDD) represents one of the most 3)” of the Group for the Study of Resistant Depression (GSRD). common medical illnesses worldwide with a median 12-month Altogether, 10 centers in 8 European countries were involved in prevalence rate of 6.9% (Wittchen et  al., 2011) and a lifetime this study, which was approved by the ethics committees of all prevalence rate varying between 11.2% and 16% (Bauer et  al., participating centers. Each participant had to provide written 2013; Dold and Kasper, 2017). In European countries, more informed consent prior to study entry. than approximately 30 million people are affected by uni- polar depressive disorders (Wittchen et  al., 2011), which cause Patients diminished quality of life, functional impairment, and con- Study participants were men and women, aged 18  years and siderable economic burden (Bandelow et  al., 2008W ; ittchen older, who met the DSM-IV-TR criteria for MDD. The diagnosis et  al., 2011; Bauer et  al., 2013). It is estimated that up to 10% had to be established by the Mini-International Neuropsychiatric of all MDD patients attempt suicide (Holma et  al., 2014), and Interview (Sheehan et  al., 1998). A  further inclusion criterion population-based surveys suggest for inpatients with MDD a was at least one adequate previous treatment with antidepres- 20-fold increased risk of completed suicide compared with the sant drugs (≥4 weeks in sufficient dose; supplementary Table 1). general population (Høyer et  al., 2000Osb ; y et  al., 2001). The Patients were excluded from this study if they presented any vast  majority of subjects attempting suicide exhibited before- current primary psychiatric disorder other than MDD, any sub- hand a manifestation of suicidality that can be regarded as a stance disorder (except nicotine and caffeine) within the previ- strong antecedent for later suicide attempts (Kessler et al., 1999; ous 6 months, or any severe personality disorder. Brown et  al., 2000; Sokero et  al., 2003; Vuorilehto et  al., 2014). However, inversely only a small proportion of the patients dis- Data Collection playing suicidality ultimately attempt suicide (Kessler et  al., 1999). Depending on the applied definitions, the prevalence of The patients’ socio-demographic, psychosocial, and clinical suicidality amounts to more than 55% in patients with predom- information were gathered within a detailed clinical inter - inant MDD (Asnis et al., 1993; Schaffer et al., 2000; Sokero et al., view conducted by specifically trained psychiatrists and spe- 2003; Zisook et  al., 2009). Despite its clinical significance, little cific questionnaires (cross-sectional data collection process). is known regarding the various degrees of suicidality, as most Lifetime and current diagnoses, course of illness, comorbidi- of the trials investigating this condition in MDD stratified their ties, and psychopathological features were evaluated on the participants into patient groups with vs without suicidality in a basis of the MINI modified for the GSRD. The degree of suicidal- dichotomous manner. However, to the best of our knowledge we ity was determined by the item 3 (suicidality) of the Hamilton are not aware of surveys itemizing their study sample according Rating Scale for Depression (HAM-D) (Hamilton, 1960). Severity to different categories of suicidality as realized in the present of depression was assessed using the Montgomery and Åsberg European multicenter research project. In this study, we sought Depression Rating Scale (MADRS) (Montgomery and Asberg, (1) to examine the prevalence of different levels of suicidality 1979) and the 17- and 21-item HAM-D. Additionally, the symp- in a large naturalistic MDD sample (n = 1410), (2) to investigate tom severity at the onset of the present MDD episode was socio-demographic, psychosocial, and clinical features associ- evaluated by retrospective MADRS scores. These scores were ated with suicidality, and (3) to explore the differences of these estimated according to the patient’s statements and informa- variables between the various degrees of suicidality. tion obtained from medical records. Hence, symptom changes during the current depressive episode could be operationalized by calculating MADRS total score changes (retrospective MADRS Methods score - present MADRS score). Treatment nonresponse was defined by a MADRS total cut-off score of ≥22 and <50% MADRS Study Design total score improvement after at least one adequate antidepres- From 2011 to 2016, all participants were recruited in the con- sant trial (≥4 weeks duration in adequate dose; see supplemen- text of the European multicenter project “Clinical and Biological tary Table 1). Treatment resistance was defined as the failure to Correlates of Resistant Depression and Related Phenotypes (TRD respond to ≥2 consecutive adequate antidepressant trials. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Dold et al. | 541 percentage of patients without occupation (67.83%) compared Statistical Analyses with the no suicidality group (49.60%, P < .0001). Recurrent MDD All participants were stratified into 3 categories of suicidality was more likely in subjects with mild/moderate (95.02%) than based on the HAM-D item 3 (suicidality) ratings: patients with without suicidality (88.03%, < P .0001). Psychotic symptoms an item-score of 0 (absent) represent the no suicidality study emerged less frequently in the no suicidality group (6.78%) group, participants with item-scores of 1 (feels life is not worth compared with the mild/moderate (14.94%, < P .0001) and severe living) or 2 (wishes he were dead or any thoughts of possible (18.97%, P < .0001) suicidality groups. Melancholic features were death to self) were grouped together in the mild/moderate suici- more often present in MDD patients characterized by severe dality group, and patients with item-scores of 3 (suicide ideas or (81.90%) than mild/moderate (59.23%, P < .0001) and no suicidal- gesture) or 4 (suicide attempts) represent the severe suicidality ity (58.51%, P < .0001). Inpatient treatment was more frequently patient group. Descriptive statistics (means, SD, and/or percent- applied in MDD patients exhibiting severe (69.83%) compared ages) were used to present the characteristics of the 3 patient with mild/moderate (35.79%, P< .0001) and no suicidality groups. To identify statistical significance of categorical vari- (28.32%, P < .0001). ables between the 3 levels of suicidality, chi-squared tests were performed. ANCOVA with the suicidality groups (fixed effect) Comorbidities and recruitment sites (random factor) as variables were used for analyzing continuous characteristics. Posthoc analyses were We found a significantly higher proportion of comorbid diabetes accomplished to compare the 3 suicidality groups with each and heart disease in patients with severe suicidality (15.52% other in pairs. Statistical significance was conservatively set at and 12.93%, respectively) than mild/moderate (5.72% and 3.51%, a P value of ≤.0011, corresponding to the Bonferroni correction respectively) and no suicidality (4.65% and 5.05%, respectively), for multiple comparisons (45 variables). Furthermore, we per - whereas no significant differences emerged in the comparison formed Spearman correlation analyses to examine the associ- of mild/moderate to no suicidality. ation between the HAM-D item 3 subscores and the investigated continuous variables. The data were analyzed using SPSS soft- Depressive Symptom Severity and Treatment ware, version 24.0. Response With respect to the depressive symptom severity measured by Results mean 17-item and 21-item HAM-D scores as well as present and retrospective MADRS scores, we found significantly higher Study Sample mean scores for patients suffering from severe and mild/mod- A total of 1410 MDD patients could be included in this study. erate suicidality compared with no suicidality and from severe Socio-demographic, psychosocial, and clinical features of the compared with mild/moderate suicidality. When analyzing patient sample are shown in Table 1. Of our participants, 33.12% MADRS total change, we determined a higher reduction in the were male, 96.17% were Caucasians, and the mean age was no suicidality group than in the severe (mean difference: 5.56 50.28 ± 14.11  years. 90.99% exhibited recurrent MDD, 10.92% points) and mild/moderate (mean difference: 5.93 points) sui- psychotic features, 60.71% melancholic features, and 2.34% cidality groups, whereas there was no significant difference atypical features.  46.31% suffered from at least one somatic between mild/moderate and severe suicidality. Accordingly, the comorbidity and the most often identified psychiatric comor - response rates were higher in the no suicidality group (38.16%) bidity was an anxiety disorder (20.85%). 34.61% of the partici- compared with the mild/moderate (8.49%, P < .0001) and severe pants were treated in an inpatient setting. The mean MADRS suicidality groups (11.21%,P < .0001) (Figure  2). Inversely, treat- total score was 24.61 ± 11.29 and the 21-item HAM-D amounted ment resistance rates were lower in patients without (29.52%) to 19.78± 9.05 points. Benzodiazepines (BZD)/BZD-like drugs than with mild/moderate (53.32%, < P .0001) and severe suicidal- (33.05%), antidepressants (29.50%), and antipsychotics (25.67%) ity (52.59%, P< .0001). No significant differences in response and were the most frequently prescribed compounds for augmenta- resistance rates were identified when comparing severe to mild/ tion/combination medications. moderate suicidality. Prevalence of Suicidality Itemized by Severity Psychopharmacotherapy Overall, 658 of 1410 (46.67%) MDD patients showed suicidality Augmentation/combination treatment strategies in general evidenced by a HAM-D item 3 score ≥1. 27.45% met the criteria were more frequently established the higher the degree of for HAM-D item 3 score 1, 10.99% for score 2, 5.53% for score 3, suicidality was: 88.79% of the patients with severe suicidal- and 2.70% for score 4 (Figure 1). Hence, the no suicidality patient ity received augmentation/combination medications and the group comprised 752 (53.33%) MDD patients, the mild/moderate mean number of concurrently prescribed psychiatric drugs suicidality group 542 (38.44%) participants, and the severe suici- amounted  to 2.92± 1.13. For mild/moderate and no suicidality, dality group 116 (8.23%) patients. the polypharmacy rates were 63.65% and 54.12% and the mean numbers of psychiatric drugs were 2.27 ± 1.24 and 2.01 ± 1.17, respectively. We determined statistical significances between Socio-Demographic, Psychosocial, and Clinical all 3 categories of suicidality for both, the polypharmacy rates Variables and the mean number of drugs (P< .0001 for all comparisons). Among the investigated socio-demographic, psychosocial, and With respect to the individual augmentation/combination strat- clinical features, we found the following significant differences egies, we found a significantly higher proportion of patients between the 3 suicidality groups (severe, mild/moderate, and no receiving antidepressant combination treatment, augmenta- suicidality) (Tables 1 and ; 2supplementary Tables 2–4). In the tion with antipsychotic drugs, add-on treatment with BZD/ patient group with severe suicidality, we determined a higher BZD-like agents, and adjunctive medication with low-potency Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 542 | International Journal of Neuropsychopharmacology, 2018 Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Table 1. Patients’ Demographic, Clinical, and Treatment Characteristics for the Comparison of MDD Patients with No vs Mild/Moderate vs Severe Suicidality MDD Sample No Suicidality group Mild/Moderate Suicidality Severe Suicidality P Value 2 2 Characteristics total (n = 1410) score 0 (n = 752) group (n = 542) group (n = 116) x /F (ANCOVA/x ) Gender, n (%) Male 467 (33.12) 236 (31.38) 186 (34.32) 45 (38.79) 3.06 .2165 Female 943 (66.88) 516 (68.62) 356 (65.68) 71 (61.21) Age, mean (SD), y 50.28 (14.11) 50.79 (14.39) 48.15 (13.35) 55.46 (14.35) 2.13 .13 Marital status, n (%) Married / live with 703 (49.86) 405 (53.86) 247 (45.57) 51 (43.97) 10.40 .0056 Single/divorced/separated/widowed 707 (50.14) 347 (46.14) 295 (54.43) 65 (56.03) Ethnic origin, n (%) Caucasian 1356 (96.17) 721 (95.88) 520 (95.94) 115 (99.14) 3.03 .2903 Weight, mean (SD), kg 73.23 (16.80) 72.58 (16.69) 73.31 (16.26) 77.09 (19.46) 1.04 .36 Highest level of education and/or degree, n (%) (n = 1395) University education/non-university high education/high level general 755 (54.12) 426 (57.41) 281 (52.04) 48 (42.48) 10.35 .0057 education General secondary / technical education/ elementary school/ none 640 (45.88) 316 (42.59) 259 (47.96) 65 (57.52) Occupational status, n (%) (n = 1408) Employed 659 (46.80) 379 (50.40) 243 (44.92) 37 (32.17) 14.56 .0007 Without occupation 749 (53.20) 373 (49.60) 298 (55.08) 78 (67.83) Depressive episode, n (%) Single 127 (9.01) 90 (11.97) 27 (4.98) 10 (8.62) 18.78 <.0001 Recurrent 1283 (90.99) 662 (88.03) 515 (95.02) 106 (91.38) With psychotic features 154 (10.92) 51 (6.78) 81 (14.94) 22 (18.97) 29.98 <.0001 With melancholic features 856 (60.71) 440 (58.51) 321 (59.23) 95 (81.90) 23.86 <.0001 With atypical features 33 (2.34) 20 (2.66) 8 (1.48) 5 (4.31) 4.08 .1303 Setting, n (%) Inpatient 488 (34.61) 213 (28.32) 194 (35.79) 81 (69.83) 77.04 <.0001 Outpatient 922 (65.39) 539 (71.68) 348 (64.21) 35 (30.17) Psychiatric comorbidities, n (%) Any anxiety disorder 294 (20.85) 150 (19.95) 122 (22.51) 22 (18.97) 1.53 .4664 Generalized anxiety disorder 151 (10.71) 73 (9.71) 71 (13.10) 7 (6.03) 6.68 .0355 Panic disorder 114 (8.09) 63 (8.38) 40 (7.38) 11 (9.48) 0.75 .6859 Agoraphobia 113 (8.01) 57 (7.58) 46 (8.49) 10 (8.62) 0.42 .8127 Social phobia 45 (3.19) 18 (2.39) 24 (4.43) 3 (2.59) 4.37 .1125 Obsessive-compulsive disorder 22 (1.56) 10 (1.33) 9 (1.66) 3 (2.59) 1.10 .5765 Posttraumatic stress disorder 20 (1.42) 9 (1.20) 8 (1.48) 3 (2.59) 1.40 .4945 Anorexia nervosa 1 (0.07) 0 (0.00) 1 (0.18) 0 (0.00) 1.60 .4488 Bulimia nervosa 8 (0.57) 2 (0.27) 6 (1.11) 0 (0.00) 4.67 .0968 Somatic comorbidities, n (%) Any somatic comorbidity 653 (46.31) 341 (45.35) 242 (44.65) 70 (60.34) 10.07 .0065 Hypertension 267 (18.94) 146 (19.41) 88 (16.24) 33 (28.45) 9.52 .0086 Thyroid disease 204 (14.47) 114 (15.16) 70 (12.92) 20 (17.24) 2.07 .3556 Migraine 156 (11.06) 72 (9.57) 71 (13.10) 13 (11.21) 3.98 .1367 Diabetes 84 (5.96) 35 (4.65) 31 (5.72) 18 (15.52) 21.26 <.0001 Dold et al. | 543 Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Table 1. Continued MDD Sample No Suicidality group Mild/Moderate Suicidality Severe Suicidality P Value 2 2 Characteristics total (n = 1410) score 0 (n = 752) group (n = 542) group (n = 116) x /F (ANCOVA/x ) Heart disease 72 (5.11) 38 (5.05) 19 (3.51) 15 (12.93) 17.53 .0002 Arthritis 65 (4.61) 24 (3.19) 32 (5.90) 9 (7.76) 8.12 .0172 Asthma 48 (3.40) 22 (2.93) 19 (3.51) 7 (6.03) 2.98 .2252 HAM-D total 21-item, mean (SD) 19.78 (9.05) 16.37 (8.71) 22.94 (7.21) 27.08 (9.32) 48.33 <.0001* *Post-hoc (Bonferoni, LSD, Tukey-HSD): significant differences between all 3 study groups HAM-D total 17-item, mean (SD) 18.76 (8.74) 15.46 (8.42) 21.89 (7.06) 25.47 (8.68) 52.99 <.0001* *Post-hoc (Bonferoni, LSD, Tukey-HSD): significant differences between all 3 study groups MADRS total, mean (SD) 24.61 (11.29) 19.66 (10.93) 29.50 (8.01) 33.79 (10.95) 66.75 <.0001* *Post-hoc (Bonferoni, LSD, Tukey-HSD): significant differences between all 3 study groups MADRS total at onset of current MDD episode, mean (SD) 34.06 (7.70) 31.87 (7.36) 35.75 (6.79) 40.36 (8.39) 13.33 <.0001* *Post-hoc (Bonferoni, LSD, Tukey-HSD): significant differences between all 3 study groups MADRS total change (present MADRS - retrospective MADRS), mean (SD) -9.36 (10.80) -12.10 (11.75) -6.17 (8.10) -6.54 (10.79) 22.08 <.0001* *Post-hoc (Bonferoni, LSD, Tukey-HSD): significant differences between all 3 study groups with the exception of the comparison mild/moderate vs severe suicidality Treatment response, n (%) Response 346 (24.54) 287 (38.16) 46 (8.49) 13 (11.21) 173.87 <.0001 Nonresponse 492 (34.89) 243 (32.31) 207 (38.19) 42 (36.21) Resistance 572 (40.57) 222 (29.52) 289 (53.32) 61 (52.59) Psychopharmacotherapy Number of psychiatric drugs, mean (SD) 2.18 (1.22) 2.01 (1.17) 2.27 (1.24) 2.92 (1.13) 9.51 <.0001* *Post-hoc (Bonferoni, LSD, Tukey-HSD): significant differences between all 3 study groups Polypsychopharmacy, n (%) 855 (60.64) 407 (54.12) 345 (63.65) 103 (88.79) 53.97 <.0001 Monotherapy, n (%) 555 (39.36) 345 (45.88) 197 (36.35) 13 (11.21) Administered first-line antidepressant (in the current MDD episode), n (%) Selective serotonin reuptake inhibitors 734 (52.06) 433 (57.58) 257 (47.42) 44 (37.93) 49.05 .0003 Serotonin-norepinephrine reuptake inhibitors 336 (23.83) 150 (19.95) 147 (27.12) 39 (33.62) Noradrenergic and specific serotonergic antidepressants 121 (8.58) 67 (8.91) 40 (7.38) 14 (12.07) Tricyclic antidepressants 74 (5.25) 35 (4.65) 29 (5.35) 10 (8.62) Agomelatine 69 (4.89) 13 (1.73) 15 (2.77) 4 (3.45) Noradrenaline-dopamine reuptake inhibitors 32 (2.27) 32 (4.26) 36 (6.64) 1 (0.86) Serotonin antagonist and reuptake inhibitors 28 (1.99) 14 (1.86) 12 (2.21) 2 (1.72) Vortioxetine 6 (0.43) 2 (0.27) 1 (0.18) 0 (0.00) Monoamine oxidase inhibitors 5 (0.35) 1 (0.13) 2 (0.37) 2 (1.72) Noradrenaline reuptake inhibitors 3 (0.21) 3 (0.40) 3 (0.55) 0 (0.00) Tianeptine 2 (0.14) 2 (0.27) 0 (0.00) 0 (0.00) Fluoxetine equivalents, mean (SD), mg/d 39.86 (20.78) 37.53 (21.17) 42.12 (19.64) 45.06 (21.47) 7.90 .0008* 544 | International Journal of Neuropsychopharmacology, 2018 antipsychotics (comprising the so-called low-potency first-gen- eration antipsychotics and the SGA quetiapine <100 mg/d) in the severe compared with the no suicidality group. In addition, the differences were significant between severe and mild/moder- ate suicidality for augmentation treatment with antipsychotics, BZD/BZD-like drugs, and low-potency antipsychotics, but not for antidepressant combination medications. Furthermore, no significant difference for any individual augmentation/combin- ation strategy could be identified for the comparison mild/mod- erate vs no suicidality. In terms of the established first-line antidepressant treatment, we could see that selective serotonin reuptake inhibitors (SSRIs) were more likely administered in patients without (57.58%) than with severe suicidality (37.93%, < P .0001). Inversely, serotonin-norepinephrine reuptake inhibitors (SNRIs) were more frequently prescribed when severe suici- dality was present (33.62%) in comparison to the absence of suicidality (19.95%, P < .0001). Moreover, we found higher pre- scription rates of the noradrenergic and specific serotonergic antidepressants (NaSSAs) and tricyclic antidepressants in the severe compared with the no suicidality group (12.07% vs 8.91% and 8.62% vs 4.65%, respectively, P < .0001 for all com- parisons). The dosing of the administered antidepressants expressed in fluoxetine equivalents was significantly higher in the severe suicidality group (45.06 ± 21.47 mg/d) than in the mild/moderate (42.12± 19.64  mg/d) and no suicidality group (37.53 ± 21.17 mg/d). Correlation Analyses Applying Spearman correlation analyses (Table),   w 3 e found a positive correlation between the HAM-D item 3 subscores and the variables 17-item HAM-D total score (r = .41, P < .0001), 21-item HAM-D total score (r = .42, P < .0001), current MADRS total score (r = .51,P < .0001), retrospective MADRS total score (r = .35, P < .0001), MADRS total score change (r = .24, P < .0001), mean number of simultaneously dispensed psychiatric drugs (r = .20, P < .0001), and antidepressant dosing expressed by fluox- etine equivalents (r = .15,P < .0001). Discussion A major finding of this European multicenter, cross-sectional study comprising 1410 MDD patients represents the observa- tion that the higher the degree of suicidality was, the higher was the depressive symptom severity measured by various rating scales (current and retrospective MADRS, HAM-D). With regard to treatment response patterns (MADRS change, response sta- tus measurement), we found that mild/moderate and severe suicidality differentiated both significantly from the absence of suicidality. Concerning the realization of inpatient treatment, antipsychotic augmentation treatment, add-on medication with BZD/BZD-like drugs, the occurrence of melancholic fea- tures, and the presence of comorbid diabetes and heart disease however, we could determine that severe suicidality separated significantly from mild/moderate and no suicidality without identifying significant differences between no and mild/mod- erate suicidality. Prevalence of Suicidality in MDD A total 46.67% of the 1410 MDD patients participating in our research project exhibited suicidality measured by the HAM-D item 3 (suicidality) score. This observed prevalence rate can be Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Table 1. Continued MDD Sample No Suicidality group Mild/Moderate Suicidality Severe Suicidality P Value 2 2 Characteristics total (n = 1410) score 0 (n = 752) group (n = 542) group (n = 116) x /F (ANCOVA/x ) *Post-hoc (Bonferoni, LSD, Tukey-HSD): significant differences between all 3 study groups with the exception of the comparison mild/moderate vs severe suicidality Applied psychopharmacological combination and augmentation strategies (in addition to the ongoing antidepressant treatment), n (%) Combination with at least 1 additional antidepressant 416 (29.50) 190 (25.27) 175 (32.29) 51 (43.97) 19.94 <.0001 Augmentation with at least 1 antipsychotic drug 362 (25.67) 161 (21.41) 146 (26.94) 55 (47.41) 34.18 <.0001 Augmentation with at least 1 mood stabilizer 159 (11.28) 74 (9.84) 65 (11.99) 20 (17.24) 5.85 .0536 Augmentation with at least 1 BZD/BZD-like drug 466 (33.05) 208 (27.66) 192 (35.42) 66 (56.90) 38.99 <.0001 Augmentation with at least 1 low-potency antipsychotic 91 (6.45) 42 (5.59) 32 (5.90) 17 (14.66) 14.14 .0009 Augmentation with pregabalin 102 (7.23) 48 (6.38) 44 (8.12) 10 (8.62) 1.78 .4116 Abbreviations: BZD ,benzodiazepines; HAM-D, Hamilton Rating Scale for Depression; MADRS Montgomer , y Åsberg Depression Rating Scale; MDD major de , pressive disorder. The no suicidality group comprised MDD patients with a HAM-D item 3 score of 0 (absent), the mild/moderate suicidality study group incorporated participants with HAM-D item 3 scores of 1 (feels life is not worth living) or 2 (wishes he were dead or any thoughts of possible death to self), and patients with HAM-D item 3 scores of 3 (suicide ideas or gesture) or 4 (suicide attempts) represented the severe suicidality patient group. The P values indicated in bold were significant after Bonferroni correction. Comprising the so-called low-potency first-generation antipsychotics and the SGA quetiapine <100 mg/d. Dold et al. | 545 Figure 1. Hamilton Rating Scale for Depression (HAM-D) item 3 (suicidality) ratings. The numbers and percentages of the patients refer to the whole analyzed study sample comprising 1410 patients with major depressive disorder. Figure 2. Treatment response, nonresponse, and resistance rates in the no, mild/moderate, and severe suicidality patient groups. regarded as in agreement with other trial results although some of the HAM-D, which could be shown to be a valid approach to studies revealed slightly higher rates (Asnis et al., 1993 Sc; haffer adequately assess suicidality (Desseilles et al., 2012). et  al., 2000; Sokero et  al., 2003; Zisook et  al., 2009). However, The use of the HAM-D item 3 (suicidality) score for the evalu- most of these surveys assessed suicidality before implement- ation of suicidality was also applied in a large number of clinical ing adequate antidepressant treatment (Zisook et  al., 2009, trials and meta-analyses investigating the suicide risk of vari- 2011; Morris et  al., 2010), whereas our patient sample already ous antidepressant drugs (Beasley et al., 1991 Letizia et  ; al., 1996; received a course of antidepressants before the cross-sectional Acharya et  al., 2006). However, the criticism of the FDA on the data collection process and subsequently comprised also treat- HAM-D item 3 assessment should be considered in this regard, ment responders. This methodological difference might account as it led subsequently to the development of a further rating to the slightly lower prevalence of suicidality in our investiga- instrument for the appraisal of suicidal ideation and behavior tion. Another meaningful variation from previous trials on this in clinical and research settings, the Columbia–Suicide Severity research question represents the allocation to the examined Rating Scale (Posner et al., 2011). patients groups. While the vast majority of previous studies In our trial, 38.44% of all participants fulfilled the predefined compared patients with suicidality with those without suicidal- criteria for mild/moderate suicidality (HAM-D item 3 score 1 or ity in a dichotomous manner, we expanded this approach and 2) and 8.23% for severe suicidality (HAM-D item 3 score ≥3). In this stratified our MDD participants according to different degrees of context, it should be taken into account that we allocated already suicidality (no, mild/moderate, and severe suicidality). The study patients with a HAM-D item 3 score 1 to the mild/moderate suici- group assignment was based on the item 3 subscore (suicidality) dality group, whereas some other studies (Vuorilehto et al., 2014) Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 546 | International Journal of Neuropsychopharmacology, 2018 Table  2. Overview Regarding the Statistically Significant Between-Group Differences (No vs Mild/Moderate vs Severe Suicidality) and the Accompanying Posthoc Tests (No vs Mild/Moderate Suicidality, No vs Severe Suicidality, Mild/Moderate vs Severe Suicidality) No vs Mild/Moderate vs No vs Mild/Moderate No vs Severe Mild/Moderate vs Severe Characteristics Severe Suicidality Suicidality Suicidality Suicidality Occupational status, n (%) X X Single vs recurrent episodes, n (%) X X Presence of psychotic features, n (%) X X X Presence of melancholic features, n (%) X X X Inpatient vs outpatient treatment, n (%) X X X Comorbid diabetes, n (%) X X X Comorbid heart disease, n (%) X X X HAM-D total 21-item, mean (SD) X X X X HAM-D total 17-item, mean (SD) X X X X MADRS total, mean (SD) X X X X MADRS total at onset of current MDD X X X X episode, mean (SD) MADRS total change (present MADRS - X X X retrospective MADRS), mean (SD) Treatment response (response vs X X X nonresponse vs resistance), n (%) Number of psychiatric drugs, mean (SD) X X X X Poly- vs monopsychopharmacy, n (%) X X X X Administered first-line antidepressant X X (in the current MDD episode), n (%) Fluoxetine equivalents, mean (SD), mg/d X X X Combination with at least 1 additional X X antidepressant, n (%) Augmentation with at least 1 antipsychotic X X X drug, n (%) Augmentation with at least 1 BZD/BZD-like X X X drug, n (%) Augmentation with at least 1 low-potency X X X antipsychotic, n (%) Abbreviations: BZD ,benzodiazepines; HAM-D, Hamilton Rating Scale for Depression; MADRS Montgomer , y Åsberg Depression Rating Scale; MDD major de , pressive disorder. This overview table summarizes the statistically significant differences between the 3 analyzed patient groups (no vs mild/moderate vs severe suicidality) and the accompanying posthoc tests (no vs mild/moderate suicidality, no vs severe suicidality, mild/moderate vs severe suicidality) determined in the chi-squared tests (cat- egorical variables) and ANCOVA (continuous variables). An “X” indicates the presence of a significant between-group difference, whereas an empty square represents the absence of a significant difference for the relevant comparison. T able 1 and Supplementary online tables 2–4 provide the corresponding numerical results of the statistical data analyses. Comprising the so-called low-potency first-generation antipsychotics and the SGA quetiapine <100 mg/d. Table  3. Spearman Correlation Analyses Investigating the defined the cut-off score on 2 or even higher. Using such a high Association between the Hamilton Rating Scale for Depression (HAM- cut-off score would cause an exclusion of patients with mild sui- D) Item 3 (Suicidality) Subscores and the Continuous Demographic cidality from the suicidality study groups, and the relevant patient and Clinical Variables data were subsequently analyzed in the control group without suicidality. This is why we a priori decided to itemize our MDD Characteristics r P Value patient sample according to different categories of suicidality. Age, mean (SD), y .0154 .5648 Due to this methodological measure, we could uncover that some Weight, mean (SD), kg .0048 .0736 socio-demographic and clinical variables differentiated from the HAM-D total 17-item, mean (SD) .4147 <.0001 patient group without suicidality already when mild/moderate HAM-D total 21-item, mean (SD) .4174 <.0001 suicidality symptoms were present (depressive symptom severity, MADRS total, mean (SD) .5075 <.0001 treatment resistance), whereas others only separated just in cases MADRS total at onset of current MDD .3452 <.0001 of severe suicidality (occupational status, inpatient treatment, add- episode, mean (SD) on pharmacotherapy with antipsychotics and BZD/BZD-like drugs, MADRS total change (present MADRS - .2413 <.0001 comorbid diabetes and heart disease, melancholic features). retrospective MADRS), mean (SD) The present study aimed to investigate the characteristics Number of psychiatric drugs, mean (SD) .1987 <.0001 of different degrees of suicidality in MDD based on the HAM-D Fluoxetine equivalents, mean (SD), mg/d .1451 <.0001 item 3 subscores. However, the presence of suicidality does not necessarily lead to later suicide attempts. Therefore, it should Abbreviations: HAM-D ,Hamilton Rating Scale for Depression; be critically considered that suicidality cannot be equated with MADRS, Montgomery Åsberg Depression Rating Scale; MDD major de , pressive disorder. suicide risk in our study, which did not seek to examine suicide The P values indicated in bold were significant after Bonferroni correction. attempts even if the subscore 4 of the HAM-D item 3 represents manifest suicide behavior. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Dold et al. | 547 Gunnell et  al., 2005; Juurlink et  al., 2006; Möller, 2006, 2008; Suicidality and Depressive Symptom Severity Barbui et al., 2009; Seemüller et al., 2009T ; ermorshuizen et al., Regarding the depressive symptomatology, we could determine 2015; Baldessarini et al., 2017). Even if our study did not primarily an association between increased suicidality and high amount aim to elucidate the impact of antidepressant pharmacotherapy of depressive symptom severity in both the descriptive statistics on the levels of suicidality, we could determine in a naturalistic and the correlation analyses. These observations are concordant way that the presence of suicidality led to a shift from SSRIs with those of a number of previously conducted studies (Pages prescriptions to an increased administration of SNRIs. While et al., 1997; Sokero et al., 2003; Zisook et al., 2011; Vuorilehto et al., 58% of the MDD patients without suicidality received SSRIs as 2014). The findings for other variables can be interpreted in a first-line antidepressants, just 20% were treated with SNRIs. The similar way. For instance, we explored an association between higher the degree of suicidality was, the more narrow the pre- severe suicidality and (1) a higher proportion of MDD patients scription rates of both substance classes (38% for SSRIs and 34% receiving inpatient treatment, (2) a larger use of augmentation/ for SNRIs in severe suicidality). The observed higher prescrip- combination treatment strategies, (3) a higher proportion of tion rates of NaSSAs and tricyclic antidepressants in the severe psychotic and melancholic features, and (4) a higher amount of suicidality patient group correspond to meta-analytic findings subjects without occupation. All these variables can be regarded suggesting efficacy of frequently used agents of each substance as parameters for severe symptom burden due to MDD. The class, mirtazapine and amitriptyline, in subsamples represent- observed association between suicidality and symptom sev-er ing severely depressed patients (Kasper et  al., 1997). Moreover, ity is particularly remarkable against the backdrop that the the NaSSA mirtazapine was associated with significantly lower HAM-D and MADRS total scores, which served as indicators for suicide risk in a pooled data analysis of 15 placebo-controlled the depressive symptom severity in our study, comprise already RCTs (Kasper et al., 2010). the relevant subscores measuring suicidal ideation and behavior. Beyond this influence of the different categories of suicidal- Hence, our findings suggest that suicidality represents a common ity on the prescription practice of the first-line antidepressants, and sensitive measure of the severity of depressive conditions. we could see an association between the levels of suicidality and the administration of augmentation/combination strategies when analyzing the mean number of simultaneously prescribed Suicidality and Treatment Response Pattern psychiatric drugs (ANCOVA, correlation analysis). Moreover, the One meaningful finding of this study represents the observa- dichotomous rates of patients receiving augmentation/combin- tion that already mild/moderate suicidality was associated with ation treatment rose from 54% (absence of suicidality) to 89% treatment nonresponse and resistance. The difference between in case of severe suicidality, whereas inversely the number of mild/moderate and high suicidality on the other hand was not monotherapy-treated patients decreased from 46% (no suicidal- significant. As clinical consequence of these results, adequate ity) to 11% (severe suicidality). With respect to the individual dis- recognition of even mild/moderate suicidality in MDD should be pensed augmentation/combination strategies, add-on treatment ensured in the psychiatric routine care as this condition is asso- with antidepressants, antipsychotics, benzodiazepines, and ciated with a failure of achieving treatment response. However, low-potency antipsychotic drugs were significantly associated when interpreting our statistical findings of an association with the presence of severe suicidality. It should be mentioned between suicidality and failed treatment response, it should be in this regard that growing evidence suggests potent antisui- critically considered that it cannot be concluded that the direc- cidal properties of the N-methyl-D-aspartate receptor antagonist tion of causality goes from suicidality to treatment nonresponse ketamine, which is increasingly used to manage acute suicidal and resistance. It appears, however, more likely that the failure crises in MDD (Niciu et al., 2014; Xu et al., 2016; Kraus et al., 2017). of achieving treatment response leads to suicidality or that, at However, there is a need for further clinical studies to substanti- least, the relationship can be regarded as bidirectional. ate its effectiveness in everyday clinical practice. The inverse findings, however, could be determined with respect to the presence of comorbid diabetes and heart disease. Study Limitations For these somatic comorbidities, we could evidence significant between-group differences only for severe (vs no and mild/mod- The naturalistic cross-sectional design of our study should be erate suicidality), but not for mild/moderate suicidality in com- taken into account as potential limitation. With this approach, parison to the absence of suicidality. Interestingly, we found no we aimed to recruit a real-world MDD patient sample. In con- significant between-group differences with regard to the psy- trast, patients exhibiting HAM-D item 3 scores of 3 or 4 are com- chiatric comorbidities. These results vary from those of another monly excluded from participation in randomized controlled study in which concurrent social phobia and bulimia nervosa clinical trials due to ethical reasons. Therefore, clinical studies could be identified as potential risk factors for suicidality in usually examine a MDD population with low degrees of suici- MDD patients (Morris et  al., 2010). Reasons for these different dality. On the contrary, the present naturalistic survey did not findings may be attributable to differences in the investigated exclude those patients to improve the generalizability of the MDD study sample as Morris et al. (2010) analyzed data of exclu- study findings. However, our participants were enrolled exclu- sively nonpsychotic outpatients prior to the implementation of sively from tertiary care settings (European university/academic psychopharmacotherapy. psychiatric treatment centers). Therefore, our study sample could be not completely representative. Furthermore, we cannot definitely rule out that in some participants, the enrollment pro- Suicidality and Psychopharmacotherapy cess might be biased by the requirement of ≥4-week antidepres- Some data suggest that antidepressant drugs may potentially sant drug treatment as precondition for study entry. With regard be associated with increased suicide risk and suicidal behavior to the MADRS score estimation, a potential bias due to a lack in some MDD patients, particularly in adolescents and younger of the calculation of inter-rater reliability should be considered. adults. However, recent clinical trial findings were inconsistent However, all specialists participating in the data collection pro- in this regard (Montgomery et  al., 1995F; ergusson et  al., 2005; cess received special training in performing the MADRS ratings. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 548 | International Journal of Neuropsychopharmacology, 2018 A  further limitation concerning the data analyses represents Baldessarini RJ, Lau WK, Sim J, Sum MY, Sim K (2017) Suicidal risks a lack of information in terms of previous suicide attempts. in reports of long-term controlled trials of antidepressants Moreover, possible cross-site differences should be taken into for major depressive disorder II. Int J Neuropsychopharmacol account although we considered this issue within the statistical 20:281–284. analyses (center was random factor in the ANCOVA). Bandelow B, Zohar J, Hollander E, Kasper S, Moller HJ, WFSBP Task Force on Treatment Guidelines for Anxiety, Obsessive- Compulsive and Post-Traumatic Stress Disorders (2008) Acknowledgments World federation of societies of biological psychiatry (WFSBP) The European Group for the Study of Resistant Depression guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders - (GSRD) received an unrestricted grant sponsored by Lundbeck A/S. The sponsor had no influence on designing the study, data first revision. World J Biol Psychiatry 9:248–312. Barbui C, Esposito E, Cipriani A (2009) Selective serotonin collection, data analyses, interpretation of data, writing of the report, and on the decision to submit the study for publication. reuptake inhibitors and risk of suicide: a systematic review of observational studies. CMAJ 180:291–297. Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Möller HJ, Statement of Interest World Federation of Societies of Biological Psychiatry. Task Force on Unipolar Depressive Disorders (2013) World feder - Dr. Dold has received a travel grant from Janssen-Cilag. Dr. Souery ation of societies of biological psychiatry (WFSBP) guidelines has received grant/research support from GlaxoSmithKline and for biological treatment of unipolar depressive disorders, Lundbeck and he has served as a consultant or on advisory part 1: update 2013 on the acute and continuation treatment boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, of unipolar depressive disorders. World J Biol Psychiatry and Lundbeck. Dr. Mendlewicz is a member of the faculty of 14:334–385. the Lundbeck International Neuroscience Foundation and of Beasley CM Jr, Dornseif BE, Bosomworth JC, Sayler ME, Rampey the advisory board of Servier. 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J Clin Psychiatry with adolescents and adults. Am J Psychiatry 168:1266–1277. 72:1322–1332. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Neuropsychopharmacology Oxford University Press
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Abstract

Background: This European multicenter study aimed to elucidate suicidality in major depressive disorder. Previous surveys suggest a prevalence of suicidality in major depressive disorder of ≥50%, but little is known about the association of different degrees of suicidality with socio-demographic, psychosocial, and clinical characteristics. Methods: We stratified 1410 major depressive disorder patients into 3 categories of suicidality based on the Hamilton Rating Scale for Depression item 3 (suicidality) ratings (0 = no suicidality; 1–2= mild/moderate suicidality; 3–4 = severe suicidality). Chi-squared tests, analyses of covariance, and Spearman correlation analyses were applied for the data analyses. Results: The prevalence rate of suicidality in major depressive disorder amounted to  46.67% (Hamilton Rating Scale for Depression item 3 score ≥1). 53.33% were allocated into the no, 38.44% into the mild/moderate, and 8.23% into the severe suicidality patient group. Due to the stratification of our major depressive disorder patient sample according to different levels of suicidality, we identified some socio-demographic, psychosocial, and clinical variables differentiating from the patient group without suicidality already in presence of mild/moderate suicidality (depressive symptom severity, treatment resistance, psychotic features, add-on medications in general), whereas others separated only when severe suicidality was manifest (inpatient treatment, augmentation with antipsychotics and benzodiazepines, melancholic features, somatic comorbidities). Received: December 10, 2017; Revised: January 14, 2018; Accepted: February 22, 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is 539 properly cited. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 540 | International Journal of Neuropsychopharmacology, 2018 Significance Statement Suicidality represents a meaningful clinical challenge in the treatment of patients suffering from unipolar depression. In our European multicenter study, we examined socio-demographic, psychosocial, and clinical features in different degrees of sui- cidality (no, mild/moderate, and severe suicidality). For some variables (depressive symptom severity, treatment resistance, psychotic features, add-on medications in general), we found significant differences already between patients exhibiting mild/ moderate severity and those without suicidality. For other investigated variables, however, significant differences compared with the absence of suicidality could be determined only in case of the presence of severe suicidality. This applies to the variables inpatient treatment, augmentation with antipsychotics and benzodiazepines, melancholic features, and somatic comorbidities. Conclusions: As even mild/moderate suicidality is associated with a failure of achieving treatment response, adequate recognition of this condition should be ensured in the clinical practice. Keywords: augmentation/combination treatment, major depressive disorder, suicidality, treatment response Introduction Major depressive disorder (MDD) represents one of the most 3)” of the Group for the Study of Resistant Depression (GSRD). common medical illnesses worldwide with a median 12-month Altogether, 10 centers in 8 European countries were involved in prevalence rate of 6.9% (Wittchen et  al., 2011) and a lifetime this study, which was approved by the ethics committees of all prevalence rate varying between 11.2% and 16% (Bauer et  al., participating centers. Each participant had to provide written 2013; Dold and Kasper, 2017). In European countries, more informed consent prior to study entry. than approximately 30 million people are affected by uni- polar depressive disorders (Wittchen et  al., 2011), which cause Patients diminished quality of life, functional impairment, and con- Study participants were men and women, aged 18  years and siderable economic burden (Bandelow et  al., 2008W ; ittchen older, who met the DSM-IV-TR criteria for MDD. The diagnosis et  al., 2011; Bauer et  al., 2013). It is estimated that up to 10% had to be established by the Mini-International Neuropsychiatric of all MDD patients attempt suicide (Holma et  al., 2014), and Interview (Sheehan et  al., 1998). A  further inclusion criterion population-based surveys suggest for inpatients with MDD a was at least one adequate previous treatment with antidepres- 20-fold increased risk of completed suicide compared with the sant drugs (≥4 weeks in sufficient dose; supplementary Table 1). general population (Høyer et  al., 2000Osb ; y et  al., 2001). The Patients were excluded from this study if they presented any vast  majority of subjects attempting suicide exhibited before- current primary psychiatric disorder other than MDD, any sub- hand a manifestation of suicidality that can be regarded as a stance disorder (except nicotine and caffeine) within the previ- strong antecedent for later suicide attempts (Kessler et al., 1999; ous 6 months, or any severe personality disorder. Brown et  al., 2000; Sokero et  al., 2003; Vuorilehto et  al., 2014). However, inversely only a small proportion of the patients dis- Data Collection playing suicidality ultimately attempt suicide (Kessler et  al., 1999). Depending on the applied definitions, the prevalence of The patients’ socio-demographic, psychosocial, and clinical suicidality amounts to more than 55% in patients with predom- information were gathered within a detailed clinical inter - inant MDD (Asnis et al., 1993; Schaffer et al., 2000; Sokero et al., view conducted by specifically trained psychiatrists and spe- 2003; Zisook et  al., 2009). Despite its clinical significance, little cific questionnaires (cross-sectional data collection process). is known regarding the various degrees of suicidality, as most Lifetime and current diagnoses, course of illness, comorbidi- of the trials investigating this condition in MDD stratified their ties, and psychopathological features were evaluated on the participants into patient groups with vs without suicidality in a basis of the MINI modified for the GSRD. The degree of suicidal- dichotomous manner. However, to the best of our knowledge we ity was determined by the item 3 (suicidality) of the Hamilton are not aware of surveys itemizing their study sample according Rating Scale for Depression (HAM-D) (Hamilton, 1960). Severity to different categories of suicidality as realized in the present of depression was assessed using the Montgomery and Åsberg European multicenter research project. In this study, we sought Depression Rating Scale (MADRS) (Montgomery and Asberg, (1) to examine the prevalence of different levels of suicidality 1979) and the 17- and 21-item HAM-D. Additionally, the symp- in a large naturalistic MDD sample (n = 1410), (2) to investigate tom severity at the onset of the present MDD episode was socio-demographic, psychosocial, and clinical features associ- evaluated by retrospective MADRS scores. These scores were ated with suicidality, and (3) to explore the differences of these estimated according to the patient’s statements and informa- variables between the various degrees of suicidality. tion obtained from medical records. Hence, symptom changes during the current depressive episode could be operationalized by calculating MADRS total score changes (retrospective MADRS Methods score - present MADRS score). Treatment nonresponse was defined by a MADRS total cut-off score of ≥22 and <50% MADRS Study Design total score improvement after at least one adequate antidepres- From 2011 to 2016, all participants were recruited in the con- sant trial (≥4 weeks duration in adequate dose; see supplemen- text of the European multicenter project “Clinical and Biological tary Table 1). Treatment resistance was defined as the failure to Correlates of Resistant Depression and Related Phenotypes (TRD respond to ≥2 consecutive adequate antidepressant trials. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Dold et al. | 541 percentage of patients without occupation (67.83%) compared Statistical Analyses with the no suicidality group (49.60%, P < .0001). Recurrent MDD All participants were stratified into 3 categories of suicidality was more likely in subjects with mild/moderate (95.02%) than based on the HAM-D item 3 (suicidality) ratings: patients with without suicidality (88.03%, < P .0001). Psychotic symptoms an item-score of 0 (absent) represent the no suicidality study emerged less frequently in the no suicidality group (6.78%) group, participants with item-scores of 1 (feels life is not worth compared with the mild/moderate (14.94%, < P .0001) and severe living) or 2 (wishes he were dead or any thoughts of possible (18.97%, P < .0001) suicidality groups. Melancholic features were death to self) were grouped together in the mild/moderate suici- more often present in MDD patients characterized by severe dality group, and patients with item-scores of 3 (suicide ideas or (81.90%) than mild/moderate (59.23%, P < .0001) and no suicidal- gesture) or 4 (suicide attempts) represent the severe suicidality ity (58.51%, P < .0001). Inpatient treatment was more frequently patient group. Descriptive statistics (means, SD, and/or percent- applied in MDD patients exhibiting severe (69.83%) compared ages) were used to present the characteristics of the 3 patient with mild/moderate (35.79%, P< .0001) and no suicidality groups. To identify statistical significance of categorical vari- (28.32%, P < .0001). ables between the 3 levels of suicidality, chi-squared tests were performed. ANCOVA with the suicidality groups (fixed effect) Comorbidities and recruitment sites (random factor) as variables were used for analyzing continuous characteristics. Posthoc analyses were We found a significantly higher proportion of comorbid diabetes accomplished to compare the 3 suicidality groups with each and heart disease in patients with severe suicidality (15.52% other in pairs. Statistical significance was conservatively set at and 12.93%, respectively) than mild/moderate (5.72% and 3.51%, a P value of ≤.0011, corresponding to the Bonferroni correction respectively) and no suicidality (4.65% and 5.05%, respectively), for multiple comparisons (45 variables). Furthermore, we per - whereas no significant differences emerged in the comparison formed Spearman correlation analyses to examine the associ- of mild/moderate to no suicidality. ation between the HAM-D item 3 subscores and the investigated continuous variables. The data were analyzed using SPSS soft- Depressive Symptom Severity and Treatment ware, version 24.0. Response With respect to the depressive symptom severity measured by Results mean 17-item and 21-item HAM-D scores as well as present and retrospective MADRS scores, we found significantly higher Study Sample mean scores for patients suffering from severe and mild/mod- A total of 1410 MDD patients could be included in this study. erate suicidality compared with no suicidality and from severe Socio-demographic, psychosocial, and clinical features of the compared with mild/moderate suicidality. When analyzing patient sample are shown in Table 1. Of our participants, 33.12% MADRS total change, we determined a higher reduction in the were male, 96.17% were Caucasians, and the mean age was no suicidality group than in the severe (mean difference: 5.56 50.28 ± 14.11  years. 90.99% exhibited recurrent MDD, 10.92% points) and mild/moderate (mean difference: 5.93 points) sui- psychotic features, 60.71% melancholic features, and 2.34% cidality groups, whereas there was no significant difference atypical features.  46.31% suffered from at least one somatic between mild/moderate and severe suicidality. Accordingly, the comorbidity and the most often identified psychiatric comor - response rates were higher in the no suicidality group (38.16%) bidity was an anxiety disorder (20.85%). 34.61% of the partici- compared with the mild/moderate (8.49%, P < .0001) and severe pants were treated in an inpatient setting. The mean MADRS suicidality groups (11.21%,P < .0001) (Figure  2). Inversely, treat- total score was 24.61 ± 11.29 and the 21-item HAM-D amounted ment resistance rates were lower in patients without (29.52%) to 19.78± 9.05 points. Benzodiazepines (BZD)/BZD-like drugs than with mild/moderate (53.32%, < P .0001) and severe suicidal- (33.05%), antidepressants (29.50%), and antipsychotics (25.67%) ity (52.59%, P< .0001). No significant differences in response and were the most frequently prescribed compounds for augmenta- resistance rates were identified when comparing severe to mild/ tion/combination medications. moderate suicidality. Prevalence of Suicidality Itemized by Severity Psychopharmacotherapy Overall, 658 of 1410 (46.67%) MDD patients showed suicidality Augmentation/combination treatment strategies in general evidenced by a HAM-D item 3 score ≥1. 27.45% met the criteria were more frequently established the higher the degree of for HAM-D item 3 score 1, 10.99% for score 2, 5.53% for score 3, suicidality was: 88.79% of the patients with severe suicidal- and 2.70% for score 4 (Figure 1). Hence, the no suicidality patient ity received augmentation/combination medications and the group comprised 752 (53.33%) MDD patients, the mild/moderate mean number of concurrently prescribed psychiatric drugs suicidality group 542 (38.44%) participants, and the severe suici- amounted  to 2.92± 1.13. For mild/moderate and no suicidality, dality group 116 (8.23%) patients. the polypharmacy rates were 63.65% and 54.12% and the mean numbers of psychiatric drugs were 2.27 ± 1.24 and 2.01 ± 1.17, respectively. We determined statistical significances between Socio-Demographic, Psychosocial, and Clinical all 3 categories of suicidality for both, the polypharmacy rates Variables and the mean number of drugs (P< .0001 for all comparisons). Among the investigated socio-demographic, psychosocial, and With respect to the individual augmentation/combination strat- clinical features, we found the following significant differences egies, we found a significantly higher proportion of patients between the 3 suicidality groups (severe, mild/moderate, and no receiving antidepressant combination treatment, augmenta- suicidality) (Tables 1 and ; 2supplementary Tables 2–4). In the tion with antipsychotic drugs, add-on treatment with BZD/ patient group with severe suicidality, we determined a higher BZD-like agents, and adjunctive medication with low-potency Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 542 | International Journal of Neuropsychopharmacology, 2018 Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Table 1. Patients’ Demographic, Clinical, and Treatment Characteristics for the Comparison of MDD Patients with No vs Mild/Moderate vs Severe Suicidality MDD Sample No Suicidality group Mild/Moderate Suicidality Severe Suicidality P Value 2 2 Characteristics total (n = 1410) score 0 (n = 752) group (n = 542) group (n = 116) x /F (ANCOVA/x ) Gender, n (%) Male 467 (33.12) 236 (31.38) 186 (34.32) 45 (38.79) 3.06 .2165 Female 943 (66.88) 516 (68.62) 356 (65.68) 71 (61.21) Age, mean (SD), y 50.28 (14.11) 50.79 (14.39) 48.15 (13.35) 55.46 (14.35) 2.13 .13 Marital status, n (%) Married / live with 703 (49.86) 405 (53.86) 247 (45.57) 51 (43.97) 10.40 .0056 Single/divorced/separated/widowed 707 (50.14) 347 (46.14) 295 (54.43) 65 (56.03) Ethnic origin, n (%) Caucasian 1356 (96.17) 721 (95.88) 520 (95.94) 115 (99.14) 3.03 .2903 Weight, mean (SD), kg 73.23 (16.80) 72.58 (16.69) 73.31 (16.26) 77.09 (19.46) 1.04 .36 Highest level of education and/or degree, n (%) (n = 1395) University education/non-university high education/high level general 755 (54.12) 426 (57.41) 281 (52.04) 48 (42.48) 10.35 .0057 education General secondary / technical education/ elementary school/ none 640 (45.88) 316 (42.59) 259 (47.96) 65 (57.52) Occupational status, n (%) (n = 1408) Employed 659 (46.80) 379 (50.40) 243 (44.92) 37 (32.17) 14.56 .0007 Without occupation 749 (53.20) 373 (49.60) 298 (55.08) 78 (67.83) Depressive episode, n (%) Single 127 (9.01) 90 (11.97) 27 (4.98) 10 (8.62) 18.78 <.0001 Recurrent 1283 (90.99) 662 (88.03) 515 (95.02) 106 (91.38) With psychotic features 154 (10.92) 51 (6.78) 81 (14.94) 22 (18.97) 29.98 <.0001 With melancholic features 856 (60.71) 440 (58.51) 321 (59.23) 95 (81.90) 23.86 <.0001 With atypical features 33 (2.34) 20 (2.66) 8 (1.48) 5 (4.31) 4.08 .1303 Setting, n (%) Inpatient 488 (34.61) 213 (28.32) 194 (35.79) 81 (69.83) 77.04 <.0001 Outpatient 922 (65.39) 539 (71.68) 348 (64.21) 35 (30.17) Psychiatric comorbidities, n (%) Any anxiety disorder 294 (20.85) 150 (19.95) 122 (22.51) 22 (18.97) 1.53 .4664 Generalized anxiety disorder 151 (10.71) 73 (9.71) 71 (13.10) 7 (6.03) 6.68 .0355 Panic disorder 114 (8.09) 63 (8.38) 40 (7.38) 11 (9.48) 0.75 .6859 Agoraphobia 113 (8.01) 57 (7.58) 46 (8.49) 10 (8.62) 0.42 .8127 Social phobia 45 (3.19) 18 (2.39) 24 (4.43) 3 (2.59) 4.37 .1125 Obsessive-compulsive disorder 22 (1.56) 10 (1.33) 9 (1.66) 3 (2.59) 1.10 .5765 Posttraumatic stress disorder 20 (1.42) 9 (1.20) 8 (1.48) 3 (2.59) 1.40 .4945 Anorexia nervosa 1 (0.07) 0 (0.00) 1 (0.18) 0 (0.00) 1.60 .4488 Bulimia nervosa 8 (0.57) 2 (0.27) 6 (1.11) 0 (0.00) 4.67 .0968 Somatic comorbidities, n (%) Any somatic comorbidity 653 (46.31) 341 (45.35) 242 (44.65) 70 (60.34) 10.07 .0065 Hypertension 267 (18.94) 146 (19.41) 88 (16.24) 33 (28.45) 9.52 .0086 Thyroid disease 204 (14.47) 114 (15.16) 70 (12.92) 20 (17.24) 2.07 .3556 Migraine 156 (11.06) 72 (9.57) 71 (13.10) 13 (11.21) 3.98 .1367 Diabetes 84 (5.96) 35 (4.65) 31 (5.72) 18 (15.52) 21.26 <.0001 Dold et al. | 543 Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Table 1. Continued MDD Sample No Suicidality group Mild/Moderate Suicidality Severe Suicidality P Value 2 2 Characteristics total (n = 1410) score 0 (n = 752) group (n = 542) group (n = 116) x /F (ANCOVA/x ) Heart disease 72 (5.11) 38 (5.05) 19 (3.51) 15 (12.93) 17.53 .0002 Arthritis 65 (4.61) 24 (3.19) 32 (5.90) 9 (7.76) 8.12 .0172 Asthma 48 (3.40) 22 (2.93) 19 (3.51) 7 (6.03) 2.98 .2252 HAM-D total 21-item, mean (SD) 19.78 (9.05) 16.37 (8.71) 22.94 (7.21) 27.08 (9.32) 48.33 <.0001* *Post-hoc (Bonferoni, LSD, Tukey-HSD): significant differences between all 3 study groups HAM-D total 17-item, mean (SD) 18.76 (8.74) 15.46 (8.42) 21.89 (7.06) 25.47 (8.68) 52.99 <.0001* *Post-hoc (Bonferoni, LSD, Tukey-HSD): significant differences between all 3 study groups MADRS total, mean (SD) 24.61 (11.29) 19.66 (10.93) 29.50 (8.01) 33.79 (10.95) 66.75 <.0001* *Post-hoc (Bonferoni, LSD, Tukey-HSD): significant differences between all 3 study groups MADRS total at onset of current MDD episode, mean (SD) 34.06 (7.70) 31.87 (7.36) 35.75 (6.79) 40.36 (8.39) 13.33 <.0001* *Post-hoc (Bonferoni, LSD, Tukey-HSD): significant differences between all 3 study groups MADRS total change (present MADRS - retrospective MADRS), mean (SD) -9.36 (10.80) -12.10 (11.75) -6.17 (8.10) -6.54 (10.79) 22.08 <.0001* *Post-hoc (Bonferoni, LSD, Tukey-HSD): significant differences between all 3 study groups with the exception of the comparison mild/moderate vs severe suicidality Treatment response, n (%) Response 346 (24.54) 287 (38.16) 46 (8.49) 13 (11.21) 173.87 <.0001 Nonresponse 492 (34.89) 243 (32.31) 207 (38.19) 42 (36.21) Resistance 572 (40.57) 222 (29.52) 289 (53.32) 61 (52.59) Psychopharmacotherapy Number of psychiatric drugs, mean (SD) 2.18 (1.22) 2.01 (1.17) 2.27 (1.24) 2.92 (1.13) 9.51 <.0001* *Post-hoc (Bonferoni, LSD, Tukey-HSD): significant differences between all 3 study groups Polypsychopharmacy, n (%) 855 (60.64) 407 (54.12) 345 (63.65) 103 (88.79) 53.97 <.0001 Monotherapy, n (%) 555 (39.36) 345 (45.88) 197 (36.35) 13 (11.21) Administered first-line antidepressant (in the current MDD episode), n (%) Selective serotonin reuptake inhibitors 734 (52.06) 433 (57.58) 257 (47.42) 44 (37.93) 49.05 .0003 Serotonin-norepinephrine reuptake inhibitors 336 (23.83) 150 (19.95) 147 (27.12) 39 (33.62) Noradrenergic and specific serotonergic antidepressants 121 (8.58) 67 (8.91) 40 (7.38) 14 (12.07) Tricyclic antidepressants 74 (5.25) 35 (4.65) 29 (5.35) 10 (8.62) Agomelatine 69 (4.89) 13 (1.73) 15 (2.77) 4 (3.45) Noradrenaline-dopamine reuptake inhibitors 32 (2.27) 32 (4.26) 36 (6.64) 1 (0.86) Serotonin antagonist and reuptake inhibitors 28 (1.99) 14 (1.86) 12 (2.21) 2 (1.72) Vortioxetine 6 (0.43) 2 (0.27) 1 (0.18) 0 (0.00) Monoamine oxidase inhibitors 5 (0.35) 1 (0.13) 2 (0.37) 2 (1.72) Noradrenaline reuptake inhibitors 3 (0.21) 3 (0.40) 3 (0.55) 0 (0.00) Tianeptine 2 (0.14) 2 (0.27) 0 (0.00) 0 (0.00) Fluoxetine equivalents, mean (SD), mg/d 39.86 (20.78) 37.53 (21.17) 42.12 (19.64) 45.06 (21.47) 7.90 .0008* 544 | International Journal of Neuropsychopharmacology, 2018 antipsychotics (comprising the so-called low-potency first-gen- eration antipsychotics and the SGA quetiapine <100 mg/d) in the severe compared with the no suicidality group. In addition, the differences were significant between severe and mild/moder- ate suicidality for augmentation treatment with antipsychotics, BZD/BZD-like drugs, and low-potency antipsychotics, but not for antidepressant combination medications. Furthermore, no significant difference for any individual augmentation/combin- ation strategy could be identified for the comparison mild/mod- erate vs no suicidality. In terms of the established first-line antidepressant treatment, we could see that selective serotonin reuptake inhibitors (SSRIs) were more likely administered in patients without (57.58%) than with severe suicidality (37.93%, < P .0001). Inversely, serotonin-norepinephrine reuptake inhibitors (SNRIs) were more frequently prescribed when severe suici- dality was present (33.62%) in comparison to the absence of suicidality (19.95%, P < .0001). Moreover, we found higher pre- scription rates of the noradrenergic and specific serotonergic antidepressants (NaSSAs) and tricyclic antidepressants in the severe compared with the no suicidality group (12.07% vs 8.91% and 8.62% vs 4.65%, respectively, P < .0001 for all com- parisons). The dosing of the administered antidepressants expressed in fluoxetine equivalents was significantly higher in the severe suicidality group (45.06 ± 21.47 mg/d) than in the mild/moderate (42.12± 19.64  mg/d) and no suicidality group (37.53 ± 21.17 mg/d). Correlation Analyses Applying Spearman correlation analyses (Table),   w 3 e found a positive correlation between the HAM-D item 3 subscores and the variables 17-item HAM-D total score (r = .41, P < .0001), 21-item HAM-D total score (r = .42, P < .0001), current MADRS total score (r = .51,P < .0001), retrospective MADRS total score (r = .35, P < .0001), MADRS total score change (r = .24, P < .0001), mean number of simultaneously dispensed psychiatric drugs (r = .20, P < .0001), and antidepressant dosing expressed by fluox- etine equivalents (r = .15,P < .0001). Discussion A major finding of this European multicenter, cross-sectional study comprising 1410 MDD patients represents the observa- tion that the higher the degree of suicidality was, the higher was the depressive symptom severity measured by various rating scales (current and retrospective MADRS, HAM-D). With regard to treatment response patterns (MADRS change, response sta- tus measurement), we found that mild/moderate and severe suicidality differentiated both significantly from the absence of suicidality. Concerning the realization of inpatient treatment, antipsychotic augmentation treatment, add-on medication with BZD/BZD-like drugs, the occurrence of melancholic fea- tures, and the presence of comorbid diabetes and heart disease however, we could determine that severe suicidality separated significantly from mild/moderate and no suicidality without identifying significant differences between no and mild/mod- erate suicidality. Prevalence of Suicidality in MDD A total 46.67% of the 1410 MDD patients participating in our research project exhibited suicidality measured by the HAM-D item 3 (suicidality) score. This observed prevalence rate can be Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Table 1. Continued MDD Sample No Suicidality group Mild/Moderate Suicidality Severe Suicidality P Value 2 2 Characteristics total (n = 1410) score 0 (n = 752) group (n = 542) group (n = 116) x /F (ANCOVA/x ) *Post-hoc (Bonferoni, LSD, Tukey-HSD): significant differences between all 3 study groups with the exception of the comparison mild/moderate vs severe suicidality Applied psychopharmacological combination and augmentation strategies (in addition to the ongoing antidepressant treatment), n (%) Combination with at least 1 additional antidepressant 416 (29.50) 190 (25.27) 175 (32.29) 51 (43.97) 19.94 <.0001 Augmentation with at least 1 antipsychotic drug 362 (25.67) 161 (21.41) 146 (26.94) 55 (47.41) 34.18 <.0001 Augmentation with at least 1 mood stabilizer 159 (11.28) 74 (9.84) 65 (11.99) 20 (17.24) 5.85 .0536 Augmentation with at least 1 BZD/BZD-like drug 466 (33.05) 208 (27.66) 192 (35.42) 66 (56.90) 38.99 <.0001 Augmentation with at least 1 low-potency antipsychotic 91 (6.45) 42 (5.59) 32 (5.90) 17 (14.66) 14.14 .0009 Augmentation with pregabalin 102 (7.23) 48 (6.38) 44 (8.12) 10 (8.62) 1.78 .4116 Abbreviations: BZD ,benzodiazepines; HAM-D, Hamilton Rating Scale for Depression; MADRS Montgomer , y Åsberg Depression Rating Scale; MDD major de , pressive disorder. The no suicidality group comprised MDD patients with a HAM-D item 3 score of 0 (absent), the mild/moderate suicidality study group incorporated participants with HAM-D item 3 scores of 1 (feels life is not worth living) or 2 (wishes he were dead or any thoughts of possible death to self), and patients with HAM-D item 3 scores of 3 (suicide ideas or gesture) or 4 (suicide attempts) represented the severe suicidality patient group. The P values indicated in bold were significant after Bonferroni correction. Comprising the so-called low-potency first-generation antipsychotics and the SGA quetiapine <100 mg/d. Dold et al. | 545 Figure 1. Hamilton Rating Scale for Depression (HAM-D) item 3 (suicidality) ratings. The numbers and percentages of the patients refer to the whole analyzed study sample comprising 1410 patients with major depressive disorder. Figure 2. Treatment response, nonresponse, and resistance rates in the no, mild/moderate, and severe suicidality patient groups. regarded as in agreement with other trial results although some of the HAM-D, which could be shown to be a valid approach to studies revealed slightly higher rates (Asnis et al., 1993 Sc; haffer adequately assess suicidality (Desseilles et al., 2012). et  al., 2000; Sokero et  al., 2003; Zisook et  al., 2009). However, The use of the HAM-D item 3 (suicidality) score for the evalu- most of these surveys assessed suicidality before implement- ation of suicidality was also applied in a large number of clinical ing adequate antidepressant treatment (Zisook et  al., 2009, trials and meta-analyses investigating the suicide risk of vari- 2011; Morris et  al., 2010), whereas our patient sample already ous antidepressant drugs (Beasley et al., 1991 Letizia et  ; al., 1996; received a course of antidepressants before the cross-sectional Acharya et  al., 2006). However, the criticism of the FDA on the data collection process and subsequently comprised also treat- HAM-D item 3 assessment should be considered in this regard, ment responders. This methodological difference might account as it led subsequently to the development of a further rating to the slightly lower prevalence of suicidality in our investiga- instrument for the appraisal of suicidal ideation and behavior tion. Another meaningful variation from previous trials on this in clinical and research settings, the Columbia–Suicide Severity research question represents the allocation to the examined Rating Scale (Posner et al., 2011). patients groups. While the vast majority of previous studies In our trial, 38.44% of all participants fulfilled the predefined compared patients with suicidality with those without suicidal- criteria for mild/moderate suicidality (HAM-D item 3 score 1 or ity in a dichotomous manner, we expanded this approach and 2) and 8.23% for severe suicidality (HAM-D item 3 score ≥3). In this stratified our MDD participants according to different degrees of context, it should be taken into account that we allocated already suicidality (no, mild/moderate, and severe suicidality). The study patients with a HAM-D item 3 score 1 to the mild/moderate suici- group assignment was based on the item 3 subscore (suicidality) dality group, whereas some other studies (Vuorilehto et al., 2014) Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 546 | International Journal of Neuropsychopharmacology, 2018 Table  2. Overview Regarding the Statistically Significant Between-Group Differences (No vs Mild/Moderate vs Severe Suicidality) and the Accompanying Posthoc Tests (No vs Mild/Moderate Suicidality, No vs Severe Suicidality, Mild/Moderate vs Severe Suicidality) No vs Mild/Moderate vs No vs Mild/Moderate No vs Severe Mild/Moderate vs Severe Characteristics Severe Suicidality Suicidality Suicidality Suicidality Occupational status, n (%) X X Single vs recurrent episodes, n (%) X X Presence of psychotic features, n (%) X X X Presence of melancholic features, n (%) X X X Inpatient vs outpatient treatment, n (%) X X X Comorbid diabetes, n (%) X X X Comorbid heart disease, n (%) X X X HAM-D total 21-item, mean (SD) X X X X HAM-D total 17-item, mean (SD) X X X X MADRS total, mean (SD) X X X X MADRS total at onset of current MDD X X X X episode, mean (SD) MADRS total change (present MADRS - X X X retrospective MADRS), mean (SD) Treatment response (response vs X X X nonresponse vs resistance), n (%) Number of psychiatric drugs, mean (SD) X X X X Poly- vs monopsychopharmacy, n (%) X X X X Administered first-line antidepressant X X (in the current MDD episode), n (%) Fluoxetine equivalents, mean (SD), mg/d X X X Combination with at least 1 additional X X antidepressant, n (%) Augmentation with at least 1 antipsychotic X X X drug, n (%) Augmentation with at least 1 BZD/BZD-like X X X drug, n (%) Augmentation with at least 1 low-potency X X X antipsychotic, n (%) Abbreviations: BZD ,benzodiazepines; HAM-D, Hamilton Rating Scale for Depression; MADRS Montgomer , y Åsberg Depression Rating Scale; MDD major de , pressive disorder. This overview table summarizes the statistically significant differences between the 3 analyzed patient groups (no vs mild/moderate vs severe suicidality) and the accompanying posthoc tests (no vs mild/moderate suicidality, no vs severe suicidality, mild/moderate vs severe suicidality) determined in the chi-squared tests (cat- egorical variables) and ANCOVA (continuous variables). An “X” indicates the presence of a significant between-group difference, whereas an empty square represents the absence of a significant difference for the relevant comparison. T able 1 and Supplementary online tables 2–4 provide the corresponding numerical results of the statistical data analyses. Comprising the so-called low-potency first-generation antipsychotics and the SGA quetiapine <100 mg/d. Table  3. Spearman Correlation Analyses Investigating the defined the cut-off score on 2 or even higher. Using such a high Association between the Hamilton Rating Scale for Depression (HAM- cut-off score would cause an exclusion of patients with mild sui- D) Item 3 (Suicidality) Subscores and the Continuous Demographic cidality from the suicidality study groups, and the relevant patient and Clinical Variables data were subsequently analyzed in the control group without suicidality. This is why we a priori decided to itemize our MDD Characteristics r P Value patient sample according to different categories of suicidality. Age, mean (SD), y .0154 .5648 Due to this methodological measure, we could uncover that some Weight, mean (SD), kg .0048 .0736 socio-demographic and clinical variables differentiated from the HAM-D total 17-item, mean (SD) .4147 <.0001 patient group without suicidality already when mild/moderate HAM-D total 21-item, mean (SD) .4174 <.0001 suicidality symptoms were present (depressive symptom severity, MADRS total, mean (SD) .5075 <.0001 treatment resistance), whereas others only separated just in cases MADRS total at onset of current MDD .3452 <.0001 of severe suicidality (occupational status, inpatient treatment, add- episode, mean (SD) on pharmacotherapy with antipsychotics and BZD/BZD-like drugs, MADRS total change (present MADRS - .2413 <.0001 comorbid diabetes and heart disease, melancholic features). retrospective MADRS), mean (SD) The present study aimed to investigate the characteristics Number of psychiatric drugs, mean (SD) .1987 <.0001 of different degrees of suicidality in MDD based on the HAM-D Fluoxetine equivalents, mean (SD), mg/d .1451 <.0001 item 3 subscores. However, the presence of suicidality does not necessarily lead to later suicide attempts. Therefore, it should Abbreviations: HAM-D ,Hamilton Rating Scale for Depression; be critically considered that suicidality cannot be equated with MADRS, Montgomery Åsberg Depression Rating Scale; MDD major de , pressive disorder. suicide risk in our study, which did not seek to examine suicide The P values indicated in bold were significant after Bonferroni correction. attempts even if the subscore 4 of the HAM-D item 3 represents manifest suicide behavior. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Dold et al. | 547 Gunnell et  al., 2005; Juurlink et  al., 2006; Möller, 2006, 2008; Suicidality and Depressive Symptom Severity Barbui et al., 2009; Seemüller et al., 2009T ; ermorshuizen et al., Regarding the depressive symptomatology, we could determine 2015; Baldessarini et al., 2017). Even if our study did not primarily an association between increased suicidality and high amount aim to elucidate the impact of antidepressant pharmacotherapy of depressive symptom severity in both the descriptive statistics on the levels of suicidality, we could determine in a naturalistic and the correlation analyses. These observations are concordant way that the presence of suicidality led to a shift from SSRIs with those of a number of previously conducted studies (Pages prescriptions to an increased administration of SNRIs. While et al., 1997; Sokero et al., 2003; Zisook et al., 2011; Vuorilehto et al., 58% of the MDD patients without suicidality received SSRIs as 2014). The findings for other variables can be interpreted in a first-line antidepressants, just 20% were treated with SNRIs. The similar way. For instance, we explored an association between higher the degree of suicidality was, the more narrow the pre- severe suicidality and (1) a higher proportion of MDD patients scription rates of both substance classes (38% for SSRIs and 34% receiving inpatient treatment, (2) a larger use of augmentation/ for SNRIs in severe suicidality). The observed higher prescrip- combination treatment strategies, (3) a higher proportion of tion rates of NaSSAs and tricyclic antidepressants in the severe psychotic and melancholic features, and (4) a higher amount of suicidality patient group correspond to meta-analytic findings subjects without occupation. All these variables can be regarded suggesting efficacy of frequently used agents of each substance as parameters for severe symptom burden due to MDD. The class, mirtazapine and amitriptyline, in subsamples represent- observed association between suicidality and symptom sev-er ing severely depressed patients (Kasper et  al., 1997). Moreover, ity is particularly remarkable against the backdrop that the the NaSSA mirtazapine was associated with significantly lower HAM-D and MADRS total scores, which served as indicators for suicide risk in a pooled data analysis of 15 placebo-controlled the depressive symptom severity in our study, comprise already RCTs (Kasper et al., 2010). the relevant subscores measuring suicidal ideation and behavior. Beyond this influence of the different categories of suicidal- Hence, our findings suggest that suicidality represents a common ity on the prescription practice of the first-line antidepressants, and sensitive measure of the severity of depressive conditions. we could see an association between the levels of suicidality and the administration of augmentation/combination strategies when analyzing the mean number of simultaneously prescribed Suicidality and Treatment Response Pattern psychiatric drugs (ANCOVA, correlation analysis). Moreover, the One meaningful finding of this study represents the observa- dichotomous rates of patients receiving augmentation/combin- tion that already mild/moderate suicidality was associated with ation treatment rose from 54% (absence of suicidality) to 89% treatment nonresponse and resistance. The difference between in case of severe suicidality, whereas inversely the number of mild/moderate and high suicidality on the other hand was not monotherapy-treated patients decreased from 46% (no suicidal- significant. As clinical consequence of these results, adequate ity) to 11% (severe suicidality). With respect to the individual dis- recognition of even mild/moderate suicidality in MDD should be pensed augmentation/combination strategies, add-on treatment ensured in the psychiatric routine care as this condition is asso- with antidepressants, antipsychotics, benzodiazepines, and ciated with a failure of achieving treatment response. However, low-potency antipsychotic drugs were significantly associated when interpreting our statistical findings of an association with the presence of severe suicidality. It should be mentioned between suicidality and failed treatment response, it should be in this regard that growing evidence suggests potent antisui- critically considered that it cannot be concluded that the direc- cidal properties of the N-methyl-D-aspartate receptor antagonist tion of causality goes from suicidality to treatment nonresponse ketamine, which is increasingly used to manage acute suicidal and resistance. It appears, however, more likely that the failure crises in MDD (Niciu et al., 2014; Xu et al., 2016; Kraus et al., 2017). of achieving treatment response leads to suicidality or that, at However, there is a need for further clinical studies to substanti- least, the relationship can be regarded as bidirectional. ate its effectiveness in everyday clinical practice. The inverse findings, however, could be determined with respect to the presence of comorbid diabetes and heart disease. Study Limitations For these somatic comorbidities, we could evidence significant between-group differences only for severe (vs no and mild/mod- The naturalistic cross-sectional design of our study should be erate suicidality), but not for mild/moderate suicidality in com- taken into account as potential limitation. With this approach, parison to the absence of suicidality. Interestingly, we found no we aimed to recruit a real-world MDD patient sample. In con- significant between-group differences with regard to the psy- trast, patients exhibiting HAM-D item 3 scores of 3 or 4 are com- chiatric comorbidities. These results vary from those of another monly excluded from participation in randomized controlled study in which concurrent social phobia and bulimia nervosa clinical trials due to ethical reasons. Therefore, clinical studies could be identified as potential risk factors for suicidality in usually examine a MDD population with low degrees of suici- MDD patients (Morris et  al., 2010). Reasons for these different dality. On the contrary, the present naturalistic survey did not findings may be attributable to differences in the investigated exclude those patients to improve the generalizability of the MDD study sample as Morris et al. (2010) analyzed data of exclu- study findings. However, our participants were enrolled exclu- sively nonpsychotic outpatients prior to the implementation of sively from tertiary care settings (European university/academic psychopharmacotherapy. psychiatric treatment centers). Therefore, our study sample could be not completely representative. Furthermore, we cannot definitely rule out that in some participants, the enrollment pro- Suicidality and Psychopharmacotherapy cess might be biased by the requirement of ≥4-week antidepres- Some data suggest that antidepressant drugs may potentially sant drug treatment as precondition for study entry. With regard be associated with increased suicide risk and suicidal behavior to the MADRS score estimation, a potential bias due to a lack in some MDD patients, particularly in adolescents and younger of the calculation of inter-rater reliability should be considered. adults. However, recent clinical trial findings were inconsistent However, all specialists participating in the data collection pro- in this regard (Montgomery et  al., 1995F; ergusson et  al., 2005; cess received special training in performing the MADRS ratings. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/539/4904544 by Ed 'DeepDyve' Gillespie user on 21 June 2018 548 | International Journal of Neuropsychopharmacology, 2018 A  further limitation concerning the data analyses represents Baldessarini RJ, Lau WK, Sim J, Sum MY, Sim K (2017) Suicidal risks a lack of information in terms of previous suicide attempts. in reports of long-term controlled trials of antidepressants Moreover, possible cross-site differences should be taken into for major depressive disorder II. Int J Neuropsychopharmacol account although we considered this issue within the statistical 20:281–284. analyses (center was random factor in the ANCOVA). Bandelow B, Zohar J, Hollander E, Kasper S, Moller HJ, WFSBP Task Force on Treatment Guidelines for Anxiety, Obsessive- Compulsive and Post-Traumatic Stress Disorders (2008) Acknowledgments World federation of societies of biological psychiatry (WFSBP) The European Group for the Study of Resistant Depression guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders - (GSRD) received an unrestricted grant sponsored by Lundbeck A/S. The sponsor had no influence on designing the study, data first revision. World J Biol Psychiatry 9:248–312. Barbui C, Esposito E, Cipriani A (2009) Selective serotonin collection, data analyses, interpretation of data, writing of the report, and on the decision to submit the study for publication. reuptake inhibitors and risk of suicide: a systematic review of observational studies. CMAJ 180:291–297. Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Möller HJ, Statement of Interest World Federation of Societies of Biological Psychiatry. Task Force on Unipolar Depressive Disorders (2013) World feder - Dr. Dold has received a travel grant from Janssen-Cilag. Dr. Souery ation of societies of biological psychiatry (WFSBP) guidelines has received grant/research support from GlaxoSmithKline and for biological treatment of unipolar depressive disorders, Lundbeck and he has served as a consultant or on advisory part 1: update 2013 on the acute and continuation treatment boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, of unipolar depressive disorders. World J Biol Psychiatry and Lundbeck. Dr. Mendlewicz is a member of the faculty of 14:334–385. the Lundbeck International Neuroscience Foundation and of Beasley CM Jr, Dornseif BE, Bosomworth JC, Sayler ME, Rampey the advisory board of Servier. 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International Journal of NeuropsychopharmacologyOxford University Press

Published: Feb 23, 2018

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