Persistence of suicidal ideation within acute phase treatment of major depressive disorder: analysis of clinical predictors

Suicidal ideation (SI) is common in major depressive disorder (MDD), and it is a risk factor for suicidal behaviour. Antidepressants are effective in reducing SI, but in some subjects, SI may persist for weeks. This study aimed to disentangle the contribution of baseline clinical characteristics in SI nonremission at week 6. Research involved 198 outpatients with MDD and SI collected within the Combining Medications to Enhance Depression Outcomes trial and treated with different antidepressant combinations. Although SI decreased from baseline to week 6 (P < 0.0001), 78 patients (39%) failed to achieve SI remission. Insomnia [OR, 0.72; 95% confidence interval (CI), 0.52–0.99], reduced need for sleep (OR, 0.75; 95% CI, 0.58–0.99), self-confidence (OR, 0.52; 95% CI, 0.32–0.82), cheerfulness (OR, 0.57; 95% CI, 0.33–0.98), and comorbid panic disorder (OR, 0.93; 95% CI, 0.87–0.99) at baseline were associated with lack of SI remission after controlling for baseline depression and SI scores. The combination of baseline SI and insomnia was moderately effective in predicting the lack of SI remission, with a specificity of 80% (95% CI, 72–87%) and an NPV of 68% (95% CI, 63–72%). In individuals with MDD and SI, the presence of insomnia and bipolar features should prompt a search for more effective treatment solutions in order to favour SI remission and prevent suicidal behaviour.


Introduction
Suicide is a global phenomenon that accounts for 1.4% of premature deaths worldwide (Bachmann, 2018). In mood disorders lifetime risk for suicide is estimated to range from 2 to 8% (Blair-West et al., 1999;Bostwick and Pankratz, 2000;Nordentoft et al., 2011) and mortality from suicide is more than 20 times higher than in the general population (Osby et al., 2001). Among depressive symptoms, suicidal ideation (SI), which has been reported in up to 60% of depressive outpatients (Sokero et al., 2003;Trivedi et al., 2013), is known to substantially increase suicidal risk: a meta-analysis has estimated that suicide was 2.3 times more likely in mood disorder patients who had previously expressed SI than in their counterpart who had not (Hubers et al., 2018). Based on this evidence, treating SI becomes a priority. Although antidepressant medications (ADs) have been debated about self-harm and SI in children and adolescent (Scahill et al., 2005;Hammad et al., 2006;Högberg et al., 2015), in adults they have univocally shown superiority to placebo in reducing SI (Gibbons et al., 2012;Näslund et al., 2018). Despite this, at least one in five patients who take ADs are not likely to obtain a complete SI remission (Zisook et al., 2011). We argue that, if these subjects could be identified as earlier as possible and their treatments enhanced or modified to improve their effectiveness, this strategy would allow to minimise suicidal risk. Prior research indicates several factors that are associated with the occurrence of SI in depressive episodes such as depression severity, age at onset and course of depressive disorder (Zisook et al., 2011), abuse and violence in childhood (Chou, 2012;Zisook et al., 2022) and mental disorder comorbidities (Hardt et al., 2015;Wiebenga et al., 2021). Moreover, SI has been related to depression psychopathology, in particular hopelessness (Wolfe et al., 2017;Ribeiro et al., 2018;Wiebenga et al., 2021) and self-blame (Olgiati et al., 2006), irritability (Jha et al., 2019), insomnia (Pigeon et al., 2012;Wang et al., 2019) and bipolar features (Akiskal et al., 2005;Weinstock et al., 2016;Rihmer and Rihmer, 2019). Little is known about the role of these clinical variables in predicting SI response during antidepressant treatment. To address this question, we analysed data from the Combining Medications to Enhance Depression Outcome (CO-MED) study  in order to ascertain which characteristics of major depressive disorder (MDD) assessed at baseline were associated with a lack of SI remission after six treatment weeks.

Subjects
In CO-MED trial, eligible subjects were aged 18-75 years, with a primary DSM-IV diagnosis of nonpsychotic MDD This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. and a HAM-D 17 score of at least 16 . To be included in the current analysis, two additional criteria were required: (a) to endorse SI at baseline and (b) to have no missing visit during follow-up period until week 6.

Treatment and data collection
The CO-MED trial was characterised by a single-blind placebo-controlled design and three treatment arms: (a) escitalopram plus placebo; (b) bupropion SR plus escitalopram; (c) venlafaxine XR plus mirtazapine. The trial included a short-term (12 weeks) treatment followed by a continuation phase (weeks 12-28) .
Research data were collected by a variety of assessment tools as reported in our previous publications Serretti et al., 2021): (a) a socio-demographic form including age, sex, ethnic group, education and monthly income; (b) the Mini International Neuropsychiatric Interview (M.I.N.I) (Sheehan et al., 1998) for retrospective evaluation of depressive disorder (chronic or recurrent course of depression; number of depressive episodes and age at onset of first episode) and to ascertain the lifetime occurrence of subthreshold hypomanic episodes (see below); (c) a battery of scales for cross-sectional clinical assessment including the 30-item Inventory of Depressive Symptomatology-Clinician Rating (IDS-C 30 ) (Corruble et al., 1999) and the 16-item Quick Inventory of Depressive Symptomatology (Rush et al., 2003), the Concise Associated Symptoms Tracking (CAST) (Trivedi et al., 2011b) for irritability, the Altman Self-Rating Mania Scale (ASRM) (Altman, 1998) and the Work and Social Adjustment Scale (WSAS) (Mundt et al., 2002) to ascertain functional impairment; (d) the Psychiatric Diagnostic Screening Questionnaire (Zimmerman and Mattia, 1999) to investigate comorbid mental disorders including panic disorder, generalised anxiety, obsessive-compulsive disorder, social phobia, posttraumatic stress disorder, and alcohol and substance use disorders; and (e) two questionnaires that were specifically developed for CO-MED project to investigate lifetime suicidal behaviour and experiences of neglect and abuse during childhood (Serretti et al., 2021;.

Suicidal ideation
SI was assessed by means of the Concise Health Risk Tracking-Self Report (CHRT) (Trivedi et al., 2011a). This version was composed of 12 items (overall score: 0-48), of which nine explored a generic suicidal propensity. Our analysis was based on the last three, which specifically investigated SI and plans over the last 24 h: scoring more than 1 at baseline was used as an inclusion criterion (see paragraph 'subjects') whereas a threshold less than 2 was selected to define SI remission at week 6.

Clinical variables
A number of clinical variables were compared between patients with and without SI remission: (a) chronic depression: depressive episode lasting for at least 6 months; (b) baseline depression severity (IDS-C 30 total score) and symptom profile including negative self-outlook, negative outlook of future, loss of pleasure, irritability (CAST), anxious mood, interpersonal sensitivity; poor concentration, difficulty in falling asleep, middle nocturnal insomnia and early awakening. Subsequently, we achieved a combined variable by pooling baseline scores of SI and middle nocturnal insomnia together: subjects scoring more than 8 were classified as 'SI plus insomnia' group and compared with the rest of the sample (see below); (c) bipolar spectrum variables, including: (i) age of onset (Benazzi, 2009); (ii) mood disorder recurrence (number of episodes/illness years) (Mazzarini et al., 2018); (iii) hypomanic symptoms occurring within major depressive episode (ASRM items): cheerfulness; self-confidence; reduced need for sleep; talkativeness; and goal-oriented hyperactivity; (iv) mixed depression, defined as a major depressive episode with three or more concurrent hypomanic symptoms (Akiskal et al., 2005); (v) lifetime subthreshold hypomania: a period of elated or irritable mood with at least two concurrent hypomanic symptoms (MINI interview), which did not fulfil DSM criteria for hypomanic/manic episode (Angst et al., 2003;Serretti et al., 2021); (d) lifetime most severe suicidal behaviour, rated via a 0 (no suicidal tendency) to 7 (suicide attempt with definite intent to die) scale; (e) comorbid mental disorders; and (f) experiences of neglect and abuse during childhood.

Statistical analyses
A preliminary power analysis was conducted to estimate minimum detectable differences between SI remitter and nonremitter groups, considering a type I error (alpha level) of 0.05 and a type II error (1-power) of 0.20. Univariate analyses were performed using Student's t-test and Chi-square test for continuous and categorical variables respectively. Significance threshold was set at alpha = 0.05, without a formal correction for multiple testing given the exploratory nature of our analysis (Amrhein et al., 2019). Multiple logistic regression analysis was used to test the association of each factor with SI remission by controlling for confounding variables (see Tables 1-3 for details). Statistical software was OpenStat version 8 December 2014 (https://openstat.info/OpenStatMain. htm). Power analysis was carried out via G*Power 3 program that was developed by a Düsseldorf University team (Germany) (Faul et al., 2007). Finally, to analyse the performance of 'SI plus insomnia' variable in predicting the lack of SI remission, a diagnostic test evaluation was conducted by means of Med-Calc free statistical calculator (https://www.medcalc.org/).

Results
Out of 665 participants in the CO-MED trial, our analysis involved 198 outpatients who endorsed SI and attended all scheduled visits until week 6. Their mean age was 44.19 + 11.53 years; 61 patients (31%) were male and 140 (71%) were of Caucasian origin. Overall depression score (IDS-C 30 ) was 40.45 + 9.13 at baseline and 22.65 + 12.14 after 6 weeks of AD use (t = 18.72; P < 0.0001). SI score (CHRT items 10-12), which was equal to 4.10 + 2.34 at baseline, decreased to 1.78 + 2.25 at week 6 (t = 10.05; P < 0.0001), although 78 patients (39%) failed to achieve SI remission. Power analysis suggested that this sample might have an adequate power (0.8) to detect a small-medium effect size (d = 0.45) or differences of at least 10.5% between comparison groups.

Role of demographic characteristics and depression severity
Patients in whom SI remitted were similar to their counterparts without remission as regard demographic features. Conversely, at clinical level, no remission group was characterised by higher baseline scores of SI (t = 3.34; P = 0.0010) and middle nocturnal insomnia (t = 2.55; P = 0.0114). These inverse correlations with SI remission were confirmed by multivariate analysis [SI: odds ratio (OR), 0.82; 95% CI, 0.71-0.96; middle nocturnal insomnia: OR, 0.71; 95% CI, 0.53-0.95] along with a direct correlation between lack of SI remission and lower levels of negative self-outlook (OR, 1.56; 95% CI, 1.07-2.27) after controlling for overall depression score (Table 1).

Bipolar spectrum variables
The distributions of hypomanic symptoms and bipolar spectrum markers are displayed in Table 3. Patients who failed to achieve SI remission endorsed higher levels of self-confidence (t = 2.528; P = 0.0123) and reduced need for sleep (t = 2.430; P = 0.0165) during depressive episode in comparison with remission group. The negative association between hypomanic symptoms and SI remission was confirmed after controlling for confounding effects exerted by depression severity and baseline SI (self-confidence: OR, 0.52; 95% CI, 0.32-0.82; reduced need for sleep: OR, 0.75; 95% CI, 0.58-0.99; cheerfulness: OR, 0.57; 95% CI, 0.33-0.98).

Suicidal ideation plus insomnia
Fifty-six patients (28%) had baseline SI plus insomnia; in comparison with the rest of the sample, this group was younger at illness onset (P = 0.0069) and associated with higher levels of overall depression (P = 0.0007), comorbid generalised anxiety (P = 0.0079) and post traumatic stress disorder (P = 0.0006), traumatic experiences during childhood (P = 0.0009) and worse suicidal behaviours (0.0004). In addition, these patients were less likely to experience SI remission at week 6 (P = 0.0014) ( Table 4). The combination of baseline SI and insomnia predicted the lack of SI remission with a specificity of 80% (95% CI, 72-87%) and a negative predictive value of 68% (95% CI, 63-72%).

Discussion
CO-MED data had already been used to analyse the prevalence and clinical correlates of SI (Zisook et al., 2011;Jha et al., 2020) as well as its prognostic impact along with other markers of depression severity (Zisook et al., 2011;Sung et al., 2013). Here, we focussed on baseline variables that could predict the persistence of SI during acute phase treatment. The severity of SI within the baseline assessment was strongly related to its lack of remission after 6 weeks. This was consistent with a large amount of literature displaying a negative correlation between the initial severity of depressive symptoms and the likelihood of remitting during treatment (Riedel et al., 2011;Zisook et al., 2019). Hence, it is arguable that depressed patients who report severe SI at baseline, similarly to those with higher levels of overall depression, may need augmentation or combination strategies to enhance antidepressant treatment response (Henssler et al., 2022). A somehow unexpected result of our study was to find a positive correlation between higher levels of negative self-outlook and SI remission after controlling for depression severity. At first glance, this finding seems to be in contrast with the large body of evidence supporting the connection between negative self-appraisal and suicidality (Madsen and Harris, 2021). Nonetheless, it becomes less difficult to understand thanks to the knowledge that some ADs (e.g. escitalopram and agomelatine) can quickly normalise self-referential processing in depressed patients, an effect which is thought to play an important role in their therapeutical activity (Delaveau et al., 2016;Komulainen et al., 2018). Thus, basically, we suggest that patients who exhibited higher levels of negative self-outlook might be more impaired in self-referential processing and, as such, more sensitive to antidepressant treatment. The most clear-cut result of our analysis was the association between insomnia and SI response. The combination of insomnia and severe SI before starting treatment, which involved more than one-quarter of our sample, had the strongest connection with SI persistence. As a predicting test, it was characterised by a good level of specificity and a small number (24/198) of false-positive results, at the expense of a lower sensitivity, and it was correlated with lifetime suicidal behaviour. The relationship between insomnia and suicidality has become a matter of extensive research in recent years (Pigeon et al., 2012;Wang et al., 2019). Despite considerable differences in study designs, samples and assessment techniques, there is converging evidence for insomnia as an empirical risk factor for suicidal behaviour Lau et al., 2020;Simmons et al., 2021). On the other hand, it is possible to reduce SI by targeting insomnia with both pharmacological treatment (McCall et al., 2019) as well as cognitive behavioural therapy (Jernelöv et al., 2021). Although the association between insomnia and suicidality can be independent of depression (Simmons et al., 2020), it appears to be stronger in depressed patients, among whom a direct correlation has been reported between higher levels of insomnia and the intensity of suicidal thinking (McCall et al., 2010;Bryan et al., 2015). This connection might not be limited to a short time horizon as in our study; in a longitudinal analysis of the NESDA study, for example, insomnia was associated with SI persistence for 6-9 years (Kivela et al., 2019). Exact pathophysiological mechanisms are not known yet; it has been hypothesised that sleep loss could increase susceptibility to suicidal thoughts and behaviours via its association with executive function deficits (Fernandes et al., 2021) and cognitive hyperarousal (Fernandes et al., 2021;Grove et al., 2021). The negative role of panic disorder during SI treatment was also consistent with available literature. In fact, among depressed patients, comorbid panic disorder has emerged as a risk factor for suicidality (Katz et al., 2011;Scheer et al., 2020;Zhang et al., 2022) as well as a poor prognostic factor (Buckman et al., 2021). The contribution of bipolar symptoms to convey an additional risk for suicidal behaviours during depressive episode is yet unclear, with studies yielding mixed results. For example, two prospective analyses of the Finnish Jorvi Bipolar Study have shown higher estimates of suicide attempts with mixed symptoms relative to depressive ones (Valtonen et al., 2008;Holma et al., 2014). Conversely, in a series of works based on the National Network of Depression Centres Mood Outcomes Program, mixed depressive and manic symptoms were associated with no excess risk for SI or behaviour (Fiedorowicz et al., 2021;Persons et al., 2022). Notably, prior studies analysed patients with bipolar depression (Valtonen et al., 2008;Persons et al., 2022) or mixed bipolar and unipolar samples (Holma et al., 2014;Fiedorowicz et al., 2021), whereas we only included subjects with MDD.
The CO-MED trial was characterised by a well-implemented design and a thorough clinical assessment. Despite this, we must acknowledge some limitations of our post hoc analysis. First, the group of patients without SI remission was relatively small and, therefore, underpowered to detect less clearcut differences from remitting subjects which, however, should be included in reliable prediction models (Abraham and Russell, 2008). A set of caveats involved the assessment of suicidality. In fact, no information was available about the characteristics of suicide attempts (impulsive or based on plans; use of potentially lethal methods; presence of intent to die, etc.) and symptomatology before their occurrence (SI; hypomanic symptoms, etc.). Moreover, no scales were administered to explore psychological correlates of suicidal behaviour such as hopelessness (Sokero et al., 2006;Ribeiro et al., 2018), thwarted belongingness and burdensomeness (Chu et al., 2017). As for bipolar markers, the ASRM scale does not assess hypomanic manifestations such as racing thoughts, distractibility, and excessive involvement in risky activities and behaviours, which are often observed in mixed depression (Perugi et al., 2015;Brancati et al., 2019). In addition, family history of bipolar illness, one of the most useful variables to distinguish bipolar II depression from MDD (Zimmerman et al., 2013), was not available for our sample. Such a missing information could have hindered the identification of bipolar spectrum cases and the assessment of their impact on suicidality. A recent analysis based on the Sequenced Treatment Alternatives to Relieve Depression study has supported the prognostic role of anhedonia and anxiety, which were associated with negative and positive SI trajectories respectively (Bloomfield-Clagett et al., 2022). These findings were not replicated in the current study but further research is warranted using larger samples and specific tools for the assessment of anhedonia and anxiety/related manifestations. Similarly, the lack of formal correction for multiple testing prompts for replication of the observed findings.
In conclusion, to investigate variables that can affect the course of SI during antidepressant treatment is a clinical need to stop its possible progression to attempted suicide. In this context, our analysis has emphasised the role of sleep disorders and bipolar features as outcome predictors, which might require more effective drug combinations without increasing risk for hypomanic switch or rapid cycling. The assessment of these clinical manifestations could help in planning the pharmacological treatment of SI and suicide prevention. Baseline SI + middle nocturnal insomnia scores ≥8. CI, confidence interval; PTSD, post traumatic stress disorder; SH, suicidal ideation. *P < 0.05.