Cognition, inflammation and related risk factors in suicide attempts

DOCTORAL THESIS COGNITION, INFLAMMATION AND RELATED RISK FACTORS IN SUICIDE ATTEMPTS JESSICA FERNÁNDEZ SEVILLANO SUPERVISOR: ANA MARÍA GONZÁLEZ-PINTO ARRILLAGA VITORIA-GASTEIZ, 2022 (cc)2022 JESSICA FERNÁNDEZ SEVILLANO (cc by-nc 4.0) A ti, mamá, que luchaste heroicamente contra el COVID-19 para vivir y celebrar mis logros. Durante tu batalla eché de menos contarte los avances de este trabajo, pero ahora puedes ver el resultado de mi esfuerzo. Ese que tú me enseñaste. Gracias. AGRADECIMIENTOS Con estas líneas quiero expresar mi reconocimiento a mi directora de tesis, Ana GonzálezPinto, por las oportunidades de aprendizaje que me ha ofrecido durante estos años como investigadora en salud mental. Gracias a todas aquellas compañeras del equipo de investigación que han compartido en algún momento mis inquietudes y me han dado fuerzas y a todos los profesionales del servicio de Psiquiatría del Hospital Universitario Araba. Además, quiero agradecer a todos los co-autores que han colaborado con sus aportaciones, trabajo y dedicación para que este trabajo sea posible. Y por supuesto, a todos los voluntarios participantes cuya aportación ha sido indispensable para realizar esta tesis y que tanto me han enseñado no sólo como científica, sino a nivel humano. Mi especial agradecimiento a mi familia y pareja. A mis padres, Carlos y Azucena, porque cualquier logro de mi vida es y será siempre de ellos también. Gracias a los dos por estar a mi lado y apoyarme en mi proyecto de vida personal y profesional. Sois incondicionales. A mi abuelo Antonio, por decirme que me quiere siempre que tiene ocasión y a mi abuela Mariluz por estar orgullosa de mí simplemente por ser quien soy. Y a Igor, por su sentido del humor que me ayuda a tomarme las cosas menos en serio y por compartir el camino con serenidad haciendo más ligeras mis preocupaciones. También, a Diego, mi compañero de dramas y anécdotas a través del tiempo y la distancia. Por último, una breve mención cariñosa a las mascotas que han contribuido a mi salud mental en los momentos de trabajo más intenso: Kokito, Krypto y Andy. A todas las personas, las que están y las que estuvieron, que de alguna manera han sido parte de esta meta que ya es una realidad. FINANCIAL SUPPORT The author of this thesis has been a beneficiary of the Predoctoral Fellowship Programme of the Basque Government and has received financial support for an international stage from the Mental Health Networking Biomedical Research Centre (CIBERSAM) of the Institute of Health Carlos III (ISCIII). This work has derived from research projects supported by the Institute of Health Carlos III [grant number PI15/00789 (co-financed by the European Regional Development Fund (ERDF) / European Social Fund ‘Investing in your future’], the Basque Government [grant number 2017111104] and the University of the Basque Country [grant number 321218ELCY]. ACKNOWLEDGMENTS The author wants to acknowledge the Mental Health Networking Biomedical Research Centre (CIBERSAM), the Institute of Health Carlos III, the Basque Government, the University of the Basque Country (UPV/EHU) and Bioaraba Research Institute. ABBREVIATIONS 3. MANUSCRIPTS: OBJECTIVES, MATERIALS AND METHODS, RESULTS _________________________________________________________ 65 3.1. MANUSCRIPT 1: SUICIDAL BEHAVIOUR AND COGNITION: A SYSTEMATIC REVIEW WITH SPECIAL FOCUS ON PREFRONTAL DEFICITS_ ____________________________________________________________ 67 3.2. MANUSCRIPT 2: COGNITION IN RECENT SUICIDE ATTEMPTS: ALTERED EXECUTIVE FUNCTION __________________________________ 82 3.3. MANUSCRIPT 3: INFLAMMATION BIOMARKERS IN SUICIDE ATTEMPTS AND THEIR RELATION TO ABUSE, GLOBAL FUNCTIONING AND COGNITION _________________________________________________ 90 4. DISCUSSION ________________________________________________ 97 5. CONCLUSIONS ____________________________________________ 107 6. CURRENT AND FUTURE PRODUCTION DERIVED FROM THIS THESIS __________________________________________________________ 111 6.1. VITAMIN D AS A PREDICTOR OF SUICIDE ATTEMPTS AND GLOBAL FUNCTIONING ___________________________________________________ 113 6.2. C-REACTIVE PROTEIN (CRP) IN SUICIDAL BEHAVIOUR AND THE LINK TO COGNITIVE PERFORMANCE ______________________________ 117 6.3. TELEMEDICINE-BASED SUICIDE PREVENTION _______________ 120 7. REFERENCES _____________________________________________ 123 8. ANNEX 1: MANUSCRIPTS ___________________________________ 159 FIGURES AND TABLES FIGURES Figure 1. Age-standardized suicide rates (per 100.000 population) in 2019. ___________ 25 Figure 2. Age-standardized suicide rates in the world by sex in 2019. _______________ 26 Figure 3. Global suicides by age and country income level, 2019. __________________ 26 Figure 4. Suicide data in Spain in 2020. ______________________________________ 27 Figure 5. Number of suicides in Spain by territory in 2020. ______________________ 28 Figure 6. Distribution of suicide by sex and territory in Euskadi, 2020.______________ 28 Figure 7. The hematopoietic cell differentiation. _______________________________ 47 Figure 8. Distribution of major lymphoid tissues of the lymphatic system. ___________ 48 Figure 9. The three lines of defence of the immune system. ______________________ 48 Figure 10. Structure of the WAIS: indexes and subtests. _________________________ 69 Figure 11. PRISMA Flow chart. ___________________________________________ 72 Figure 12. Mean (SD) IL-6 plasma concentrations in each group. __________________ 96 TABLES Table 1. Summary of main suicide risk factors. ________________________________ 29 Table 2. Early theories of suicidal behaviour. _________________________________ 38 Table 3. Main studies of cytokines in suicide attempts. __________________________ 56 Table 4. Main characteristics and results of articles included in the review. ___________ 74 Table 5. Performance on each neuropsychological domain classified by diagnosis. _____ 76 Table 6. Sample distribution according to diagnosis, time of the attempt and symptoms. 81 Table 7. Cognitive domains and neuropsychological tests employed. _______________ 84 Table 8. Demographic and clinical variables.__________________________________ 87 Table 9. Performance on each cognitive domain by groupa. ______________________ 88 Table 10. Multiple regression of neuropsychological performancea._________________ 88 Table 11. Effect sizes of being female on executive functiona. _____________________ 89 Table 12. Demographic, clinical and cognitive variables. _________________________ 94 Table 13. Inflammation parameters across groups. _____________________________ 96 Table 14. Reference levels of 25-hydroxy vitamin D ___________________________ 115 Table 15. Main studies of CRP in suicide attempts. ____________________________ 119 1. INTRODUCTION 21 1.1. SUICIDE: EVOLUTION OF ITS CONCEPTUALIZATION. The etymology of the term suicide comes from the Latin suicidium; sui, in reference to self and -cidium, concerning the verb caedere or to kill. First records of the term, which was coined by Pierre François Guyot Desfontaines, date back to the mid-XVII century (Bertolote & Wasserman, 2021; Mesones, 2014) but nuances and connotations regarding the concept have evolved within the historical, sociological and cultural context as it is briefly detailed below: The first manuscript alluding to suicide is an Ancient Egyptian poem approximately dated in 2200 B.C. named The dispute between a man and his Ba (soul), a dialogue between a man who wishes to be dead and his soul which convinces him to remain alive (Moleón & Moleón, 2022). At that time suicide was considered a convenient solution to avoid excessive pain or disgrace (Mesones, 2014). Deliberate death starts to be rejected in the Ancient Greece except for some authorized suicides meant to preserve honour or avoid humiliation. Philosophers questioned the freedom behind suicide from different points of view: for Stoics, Epicureans and Cynics suicide was a free appropriate choice, in contrast to other great thinkers’, like Plato and Aristoteles, ideas. Similarly, despite being a condemnable act in Rome, suicide could be allowed for those with a mental disorder —insanus et uriosus in the Roman Law— and for upper-class citizens when honour, patriotism, disease or dignity were the cause of suicide (Mesones, 2014; Moleón & Moleón, 2022). It was not until the Ancient Age that suicide was extremely vilified and stigmatized. Although the Bible — with 9 references in the Old Testament and 1 in the New Testament— does not condemn suicide, Christians regarded it as an unforgivable sin and horrific crime that caused ex-communication from the church and brutal punishments to attempters (Andrés, 2015; Mesones, 2014; Moleón & Moleón, 2022; Picazo, 2017). In addition to this religious outlook, demonological concepts prevailed during the Middle Age. Suicide was an unmentionable sin product of the devil and, for this reason, euphemisms were often employed to refer to this behaviour. Those who died by suicide were buried in non-consecrated ground with a stake in the chest to prevent their soul from resuscitating (Mesones, 2014; Moleón & Moleón, 2022). 22 Suicide was gradually decriminalized in the Modern Age (XV-XVIII) thanks to some philosophers, such as David Hume, and the scientific knowledge. Suicide was understood as a frequent attempt to soothe the extreme suffering of the melancholic as Robert Burton described it in The Anatomy of Melancoly (1621) (Andrés, 2015; Moleón & Moleón, 2022). In this century, although suicide was no longer a punishable crime, the stigma was linked to madness and mental disorders remaining negative connotations (Picazo, 2017). In the XIX century, while Romanticism exalted the psychological pain and suicide as the self-expression of freedom, the concept of madness in suicide continued to be discussed. Philippe Pinel in his Traité medico-philosophique sur l’aliénation mentale (1801) posed that suicide is generally caused by melancholia but also by adversity or physical pain (Moleón & Moleón, 2022). Later, Jean-Étienne Esquirol in Maladies mentales (1838) argued that suicide is always a symptom, not an illness itself, of a mental disorder which could also be provoked by passions and tedium (Picazo, 2017). The stigma of the attempter and their families were no longer related to the evil but connected to a mental disorder instead. It is noteworthy that in this century Johann W. Goethe published The Sorrows of Young Werther (1774) causing the Werther Effect, that is, the massive imitation of the suicide following the method described in the novel (Mesones, 2014). In the XX century suicide was no longer a criminal action but the conflict remained; thinkers like Albert Camus and Jean-Paul Sartre opposed to suicide but others like Karl Jaspers, philosopher and psychiatrist, considered suicide as the only possible outcome of an unbearable situation that would otherwise tarnish the individual (Moleón & Moleón, 2022). In this century, suicide was first studied from a Social Sciences perspective. Émile Durkheim, convinced that social and not individual factors trigger suicide, developed a sociological approach to suicide in his work Le Suicide: Étude de Sociologie (1897). According to this author, suicide could be altruistic (sacrifice for the common good), egoistic (individualist act without the consideration of the impact on the society), fatalist (inadaptation and suffering caused by the society) and anomic (during social crisis most vulnerable individuals are affected by the context) depending on the grade of social integration of the individual and social rules (Giner et al., 2016; Mesones, 2014; Moleón & Moleón, 2022). Another relevant author of this period was Edwin Shneidman known as the father of Suicidology, a term he coined. He claimed to psychology the study and prevention of suicide as he found psychological pain or psychache was at the core of this behaviour. He was the founder of the Suicide Prevention Centre in 23 Los Angeles with the first telephone helpline for suicide prevention, the American Association of Suicidology and the Suicide, the Life-Threatening Behaviour Journal. He also created the psychological autopsy in 1962 to analyse Marilyn Monroe’s death (Mesones, 2014). Contemporarily, Freud studied suicide and he first regarded it as a self-directed aggression that avoids aggression toward others (Moleón & Moleón, 2022). Later, in Beyond the Pleasure Principle (1922) he posed that suicide was an expression of the death drive (Thanatos) that coexists in continuous conflict with the life drive (Eros) in every individual (Mesones, 2014), being the first author to describe the ambivalence behind suicide (Giner et al., 2016). Karl Menninger, extended the ideas of Freud categorizing suicide into three basic for : wish to kill (being unable to kill the object of rage, he kills himself), wish to be killed (due to guilt and shame) and wish to be dead (as a need for escaping from suffering) (Moleón & Moleón, 2022). First endeavours to operationally define and categorize suicide were made in this period. The Centre for Disease control proposed suicide as death as a result of an intentional, self-inflicted harm and the World Health Organization (WHO) defined a suicide attempt as the act with a nonfatal outcome which the deceased, knowing or expecting a fatal outcome, had initiated and carried out with the purpose of provoking the changes he desired (Giner et al., 2016). Classifications of suicidal behaviour arose in this century, being the most outstanding the one of Maris et al (1992) who categorized it into three axes: Axis I – behaviour (ideation, attempt or suicide), Axis II – (lethality, intentionality, circumstances, method, sex, age, race, marital status and occupation) and Axis III – (substance abuse, previous self-mutilation or eating disorders); the classification of Diekstra (1992) composed with three categories: suicide, suicide attempts or parasuicide and the classification of O’Carroll (1996) —suicidal ideation, behaviour related to suicide, completed suicide, self-inflicted wounds and behaviours with the intention of dying— which was later used to elaborate the Columbia Classification Algorithm for Suicide Assessment (C-CASA) (Giner et al., 2016). 24 Nowadays, according to Giner (2016) suicidal behaviour is understood as a spectrum of actions and thought processes. The current definition of the term according to the 5th version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (American Psychiatric Association, 2013) is the act of intentionally causing one’s own death, including a reference to the intention that was lacking in its etymology and which broadens the concept to a psychological dimension. The WHO now integrates into the concept a range of behaviours that include thinking about suicide (or ideation), planning for suicide, attempting suicide and suicide itself (World Health Organization [WHO], 2014). Suicidal ideation is defined in the DSM-5 as thoughts about selfharm, with deliberate consideration or planning of possible techniques of causing one’s own death which may result in a suicide attempt, a self-initiated sequence of behaviours by an individual who, at the time of the initiation, expected that the set of actions would lead to his or her own death (American Psychiatric Association, 2013). According to DSM-5 (American Psychiatric Association, 2013), a suicide attempt could be classified by its violence —overdoses are considered non-violent whereas jumping, gunshot, wounds and hanging are violent— by its lethality with high-lethality attempts requiring medical hospitalization and by the degree of planning versus impulsiveness. It is noteworthy that according to Oquendo et al. (2003) a suicide attempt is considered as such regardless of the actual harm or method; however, it would not be considered a suicide attempt if the individual is dissuaded by another or changes his or her mind before initiating the behaviour (American Psychiatric Association, 2013). In chapter 23 of the current classification of the International Classification of Diseases, ICD-11 (World Health Organization, 2019) —officially in effect since January 2022 there is a categorization based on the anatomical region injured or the external agent employed; for example: injuries to the neck, injuries to wrist or hand or harmful effects of substances. Each diagnosis is subdivided according to the intentionality and to who inflicted the injury; in the case of suicide, it would be categorized as self-harm specified by the method employed: for example, by fall or jump, by exposure to an object, by immersion or falling into the water, by a threat to breathing, by exposure or harmful effects of substances. However, this classification system is based on the most obvious physical feature to the detriment of the psychological aspects that underlie suicidal behaviour (Bertolote & Wasserman, 2021). In chapter 21 of ICD-11 (World Health Organization, 2019) suicide ideation, suicide attempt and suicidal behaviour can also be classified into the ambiguous category of abnormal symptoms, signs or clinical outcomes unclassifiable elsewhere (Anseán, 2021). 25 1.2. EPIDEMIOLOGY OF SUICIDE Nowadays, suicidal behaviour is a major health concern worldwide that represents a leading factor of mortality associated with disability and functional impairment and which causes approximately 800.000 casualties per year in the world (resulting in one death every 30 seconds with more than 20 suicide attempts behind every suicide (WHO, 2021). According to the WHO (2021), suicide is the cause of death of one in every 100 deaths (1.3%) with higher mortality than the Human Immunodeficiency Virus (HIV), malaria, breast cancer, war and homicide. The most frequent methods worldwide include handing, pesticide selfpoisoning and firearms; generally, women opt for self-poisoning and males firearms and hanging (Anseán, 2014). In comparison to the global average (9.0 per 100.000), Africa (11.2 per 100.000), Europe (10.5 per 100.000) and South-East Asia (10.2 per 100.000) had higher rates of suicide (WHO, 2021) (Figure 1). Globally suicide rates (Figure 2) are higher, more than twice, in males than in females —12.6 per 100.000 males; 5.4 per 100.000 females— but women have 3 times more attempts (Anseán, 2021; Moleón & Moleón, 2022; WHO, 2021). Low-and middleincome countries shared over 77% of the global suicides in 2019, but better suicide surveillance and data gathering are needed in those regions in order to comprehend the scope of the problem (WHO, 2021). Figure 1. Age-standardized suicide rates (per 100.000 population) in 2019. Retrieved from WHO, 2022. 32 1.2.2. CLINICAL FACTORS ▪ Prior Suicide Attempt: The strongest risk factor for suicide is having a prior autolytic attempt (Bostwick et al., 2016) which implies 25-40 times more risk of suicide (WHO, 2022), particularly 6 months after the attempt (Vuagnat et al., 2019) but also 32 years later (Probert-Lindström et al., 2020). ▪ Psychopathology: Approximately, 80-98% of suicide attempters had a mental disorder, as well as the 90% of suicide casualties, as revealed by psychological autopsies (Moleón & Moleón, 2022). The most common comorbid diagnosis —one out of two suicide attempters— is major depression disorder (MDD) (Navío & Villoria, 2014), which entails 20 times more risk of suicide (Ge et al., 2020). MDD diagnosis criteria according to DSM-5 (American Psychiatric Association, 2013) are summarized below: A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning: at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Note: Do not include symptoms that are clearly attributable to another medical condition. 1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, hopeless) or observation made by others (e.g., appears tearful). (Note: In children and adolescents, can be irritable mood). 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation). 3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (Note: In children, consider failure to make expected weight gain.). 4. Insomnia or hypersomnia nearly every day. 5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). 6. Fatigue or loss of energy nearly every day. 33 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick). 8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others). 9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide. B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. The episode is not attributable to the physiological effects of a substance or to another medical condition. Note: Criteria A-C constitute a major depressive episode. Major depressive episodes are common in bipolar disorder but are not required for the diagnosis of bipolar disorder. D. The occurrence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders. E. There has never been a manic episode or a hypomanic episode. MDD can be classified as a single/recurrent episode and according to its severity: mild, moderate, severe, with psychotic features, in partial remission and in full remission. It can be specified as follows: with anxious distress, with mixed features, with melancholic features, with mood-congruent psychotic features, with moodincongruent psychotic features and with catatonia. MDD can onset at any age, but particularly at puberty with a peak in the 20s. Its course is variable: some individuals rarely experience remission while others experience many years with few or no symptoms. Episode duration, psychotic features, prominent anxiety, personality disorders and symptom severity predict lower recovery rates. Episodes are more recurrent in those patients with prior severe episodes, history of multiple episodes and younger individuals. 34 Many bipolar patients debut with one or more depressive episodes and a large proportion of patients who initially appear to have MDD will prove, in time, to instead have a bipolar disorder. Both bipolar and unipolar depressions are a high-risk factors for suicide as 80% of depressive patients have autolytic ideation while 1450% will attempt suicide (Navío & Villoria, 2014). ▪ Drug abuse: Approximately 35% of attempters have a previous alcohol intake before attempting suicide (Borges et al., 2017). Besides, prior substance use disorders linked to smoking, alcohol, cannabis, cocaine, amphetamine and polysubstance abuse were associated to suicide risk (Amiri & Behnezhad, 2020; Armoon et al., 2021). ▪ Somatic illness, pain and functional impairment: Chronic diseases, functional impairment and pain are associated with elevated suicidal risk. Some illnesses such as neurological illness (Costanza et al., 2020), cancer (Calati et al., 2021), multiple sclerosis (Lewis et al., 2017) and fibromyalgia (Levine & Horesh, 2020) have been related to a higher suicide. Likewise, functional impairment (Fässberg et al., 2016; Lutz & Fiske, 2018) and chronic pain (Racine, 2018) have been related to suicidality. ▪ Sleep disorders: According to the metanalysis of Harris et al. (2020) sleep disorders —mainly insomnia and nightmares— without a psychopathological context involve a slightly higher risk of suicide ideation and attempts. 35 1.2.3. PSYCHOLOGICAL FACTORS ▪ Personality traits: Impulsivity, especially in men (Cross et al., 2011; Grissom & Reyes, 2019), hostility-aggression and anxiety-neuroticism are the main traits that have been associated with suicidal behaviour (Bi et al., 2017; Turecki et al., 2019). Concerning hostility-aggression trait, lifetime aggressive behaviour has also been linked to suicide (Buitron et al., 2018; Hartley et al., 2018). ▪ Self-esteem: Low self-esteem (Macalli et al., 2021; Nguyen et al., 2019) and selfcriticism (O’Neill et al., 2021) have been correlated with suicidal behaviour. Particularly, lower scores on social and familiar dimensions of self-esteem are associated with suicide (Perrot et al., 2018). ▪ Social support: At any age of the lifespan social isolation and seclusion are associated with suicide (Calati et al., 2019). Besides, suicides are more frequent in those without offspring (Qin & Mortensen, 2003). ▪ Hopelessness and Reasons for Living: Hopelessness is vastly described as a risk factor for suicide ideation, attempts and death ( Ribeiro et al., 2018). Individuals with few reasons for living are at increased risk of developing suicidal thoughts and attempting suicide (Brüdern et al., 2018). ▪ Stressful life events: accidents, diagnosis or worsening of a severe illness, bereavement, judicial processes, unwanted abrupt vital changes, unwanted pregnancy or abortion, amongst other stressful relevant events, increase the probability of suicide, especially in the shorter term (Howarth et al., 2020). ▪ Childhood / Adult abuse: Childhood and adult abuse —physical, sexual, emotional and negligence— including school (Zaborskis et al., 2019) and workplace bullying (Leach et al., 2020), have been widely reported as high-risk factors for suicidal behaviour (Ásgeirsdóttir et al., 2018; Björkenstam et al., 2017; Thompson et al., 2019). ▪ Attachment styles: Insecure attachment is a risk factor for suicidal ideation and behaviour (Green et al., 2020) in youngsters (Yang et al., 2021), adults (Zortea et al., 2021) and the elderly (Oon-Arom et al., 2019). 36 ▪ Coping skills: Coping is the way a person faces and overcomes stressors. There are two types of coping skills: 1) problem-based skills (search help, self-instruction, positive re-evaluation, search for alternative actions), which are oriented to finding a solution, and 2) emotional-based skills (evasive distraction, avoidance, preparing for the worst, emotional discharge, resigned acceptance) focusing in the person’s feelings without addressing the problem (Bazrafshan et al., 2014). Emotional-based coping skills are associated with suicidal behaviour while positive problem-based coping skills have a protective role against suicide (Horwitz et al., 2018; Lew et al., 2019). ▪ Neuropsychological performance: Performance on several neurocognitive domains has been associated with suicidal behaviour. As this is a core aspect of this thesis, this factor will be explained in detail in further sections of this document. 37 1.2.4. BIOLOGICAL FACTORS ▪ Genetics and epigenetics: Observation of familial aggregation of suicide has been described in large cohorts (Tidemalm et al., 2011). Twin and adoption studies support 30-50% of heritability; 17-36% when corrected by the transmission of psychiatric disorders (Lutz et al., 2017). Genetic studies have found more than 200 genes associated with suicide (Sokolowski et al., 2015) with inconsistent results. Genome-wideassociation studies (GWAS), which involve scanning complete sets of Deoxyribonucleic Acid (DNA) —genome— to find possible variations —single nucleotide polymorphisms (SNPs, also called snips) — have been conducted in relation to suicide pointing to a number of significant polymorphisms. Although results on the study of genetics in suicide are promising, they are likely to account only for a very small proportion of vulnerability (Sokolowski et al., 2015). Genes can be influenced by epigenetic processes, that is, the timing and expression of genes adjust to the social, physical and biological context. As many of these factors directly or indirectly affect suicidal behaviour, epigenetic regulation is likely a key contributor to suicidality mainly through DNA methylation and histone modifications (Labonté et al., 2013; Schneider et al., 2015; Turecki, 2014). ▪ Neurotransmitters: The function of serotonin, noradrenaline, dopamine, glutamate and gamma-aminobutyric acid (GABA) neurotransmitter systems has been found to be disrupted in suicide, including abnormalities in their receptors, transporters and synthesis pathways (Furczyk et al., 2013; Oquendo et al., 2014; Sudol & Mann, 2017; Wisłowska-Stanek et al., 2021). ▪ Inflammation and stress response The inflammatory and the tightly related stress responses are altered in suicide. As the link between inflammation and suicide is a core aspect of this thesis, a description of the mechanisms involved and evidence on the matter will be provided in detail in further sections of this document. 38 1.4. THEORETICAL MODELS OF SUICIDAL BEHAVIOUR Suicide is a highly complex and multifaceted phenomenon that results from the interplay of many contributing and facilitating variables mentioned in the previous section of this document, that is, the interaction between biological, sociodemographic, sociocultural, clinical and psychological factors. Although many suicide risk factors have been identified, how or why some of them interplay is not clear yet (O’Connor & Nock, 2014). Many theoretical models have been proposed to explain suicidal behaviour by attending to some or several of these factors. Earlier theories of suicidal behaviour (Table 2) focused on individual psychological factors but did not account for why most people with these features do not attempt suicide (O’Connor & Portzky, 2018). Table 2. Early theories of suicidal behaviour. Model Authors Basic premise of suicide risk Cubic model of suicide Shneidman (1985) Unbearable psychological pain Suicide as escape from self Baumeister (1990) Frustrated goals with profound self-blame and the need to escape from internal negative affect. Dialectical behaviour therapy Linehan (1993) Emotion dysregulation under psychological pain. Influence of biological and social factors. Cognitive behavioural model of suicidality Beck et al. (1990) The interpretation and perception of stressors are central to understand emotional impact. Emphasis on cognitive aspects: hopelessness. Adapted from (O’Connor & Nock, 2014). 39 Afterwards, plenty of models have tried to face this limitation, being the stress-diathesis model one of the most outstanding nowadays which poses that suicide depends on the interaction between vulnerability factors and stressors. The first stress-diathesis model in suicide was proposed by Schotte and Clum (1987). According to the authors, impaired social problem-solving acts as a diathesis or a vulnerability factor elevating suicide risk in the presence of stress. Afterwards, the clinical diathesis-stress model was developed by Mann et al. (1999), which postulated that psychological crisis or psychiatric disorders in combination with impulsive and aggressive traits as vulnerability factors will result in suicidal behaviour. The contemporary stress-diathesis model integrates the biopsychosocial approach resulting in a much broad perspective in which the interplay of biological (genetics, neurobiology, mental disorder), psychological and social vulnerability factors increase suicide risk under stress (Navío & Villoria, 2014; O’Connor & Nock, 2014). Taking into consideration this integrative perspective, in this thesis we explore the role of some psychological (neuropsychological performance, childhood trauma, aggressive behaviour) and biological (inflammation) diathesis or vulnerability factors that increase the risk of suicide attempts. 40 1.5. NEUROPSYCHOLOGICAL PERFORMANCE IN SUICIDE Neuropsychology is the branch of science concerned with the study of the psychological processes of the nervous system related to behaviour, emotion and cognition both under pathological and normal conditions (American Psychiatric Association, 2022). Cognitive function is a broad term that refers to the mental processes involved in the acquisition of knowledge, manipulation of information and reasoning and can be classified into major cognitive domains— perception, motor skills and construction, attention, memory, language and executive function— and subdomains depending on their function (Harvey, 2019). Neuropsychological evaluation measures and assess the individual performance on these cognitive domains and other related cognitive abilities using standardized psychometric instruments that can be domain-specific or generalized including several domains (Kiely, 2014). However, there are some difficulties and limitations in the classification domains and subdomains: 1) a large number of different theoretical models cause 2) inconsistencies and variations in classifications as 3) some processes may belong to different domains or even 4) processes are named and defined differently by each author resulting in a 5) convergence and overlap of constructs in neuropsychological tests (Harvey, 2019). As suicide —both ideation and attempts— implies behaviour, emotion and cognition, knowledge from psychology and neuropsychology can offer relevant insights to the understanding of this multifactorial complex phenomenon. Due to the fact that psychology is specialized in explaining human behaviour —understood as both observable (behaviour display) and unobservable (thoughts, emotions)— and neuropsychology seeks to unveil the cognitive processes behind it, an interesting approach gathering this knowledge opens to the field of suicidology: the study of the link between suicide and cognition. 41 1.2.5. RELEVANT NEUROPSYCHOLOGICAL DOMAINS IN SUICIDE Since this doctoral thesis focuses on the neuropsychological performance in suicidal attempts, an observable behaviour, the following paragraphs introduce relevant cognitive domains related to behaviour planning, organisation and display that have been selected to be assessed in the manuscripts of this thesis: executive function, attention, working memory and praxis. 1.2.5.1. EXECUTIVE FUNCTION Executive function is a set of complex higher-order cognitive processes that vary in their definition, and classification between the plethora of theoretical models that have been proposed throughout the history of neuropsychology. Luria was the first author to describe a proposal of the cognitive processes involved in this domain but it was not until 1982 that Lezak coined the term executive function (Trápaga et al., 2018). Until today, the complex conceptualization of executive function remains controversial and there is no agreement between authors about a unique definition and classification of the processes involved. Despite the lack of consensus, is widely accepted that executive function —mostly associated with the frontal lobe functions of the brain (Blázquez-Alisente et al., 2012)— is the cognitive domain responsible for the planning, implementation, organization, coordination, monitoring and directing thought and behaviour allowing the individual to adapt and respond to the environment (Kiely, 2014; Trápaga et al., 2018), including both external (e.g., situational demands, stimuli) and internal information (e.g., thoughts, memories) of the individual (Portellano, 2018). Executive function is necessary to set a goal, choose between available alternatives, estimate and predict possible outcomes and select, organize, initiate and modify the plan/course of action (Portellano, 2018). 48 Figure 8. Distribution of major lymphoid tissues of the lymphatic system. Retrieved from Delves et al., 2017. The defensive reaction of the immune system is termed the inflammatory or immune response which can be differentiated into (1) innate, natural or nonspecific and (2) adaptative, acquired or specific (Figure 9). Figure 9. The three lines of defence of the immune system. The immune system is composed of three levels of defence: 1) physical barriers of skin and mucosa, 2) the innate and 3) the adaptative immune responses. Retrieved from Delves et al., 2017. 49 The innate response is the most primitive and the first line of defence in the organism. It is a rapid response that does not need prior experience to work and that will react alike on future occasions (Abbas et al., 2022). Cells involved in this response destroying pathogens (Delves et al., 2017) are: ▪ Neutrophils ▪ Eosinophils ▪ Monocytes: macrophages. ▪ Natural killer ▪ Mastocytes ▪ Basophils ▪ Platelets In order to respond against a threat, the innate response cells need a pathogen identification mechanism. For this purpose, these cells have Pattern Recognition Receptors (PRR) that can recognize Pathogen-Associated Molecular Patterns (PAMPs), in other words, receptors that can identify molecules of pathogens. PRR also recognize Damage-Associated Molecular Patterns (DAMPs) which indicate the tissular damage in the affected location of the body (Abbas et al., 2022; Delves et al., 2017). Once PAMPs and DAMPs are detected, the inflammatory response avoids the proliferation of the pathogen and stimulates damaged tissue repair: 1) vasodilation and edema in the affected location to attract innate immune cells, 2) blood coagulation to impede pathogen dissemination, 3) pathogen delivery through the lymphatic system to the ganglia where adaptative response starts (Parham, 2021). The adaptative response is the second line of defence in the organism; slower but specific and with immunological memory which confers enhanced resistance against repeated infections. This response can be classified as cellular or humoral mediated by T lymphocytes or B lymphocytes, respectively. In the adaptative response, the harmful element is identified by the recognition of the antigens of pathogens, molecules located in the pathogen cell surface and which activate the specific immune response (Abbas et al., 2022; Fainboim & Geffner, 2013). 50 However, T and B lymphocytes differ in how they recognize antigens. First, T Cell Receptors in the T lymphocytes and B Cell Receptors in the B lymphocytes cell membranes interact with a small region of the antigen named epitope or the antigenic determinant. In the case of T lymphocyte response, this interaction is not enough to recognize the antigen. Epitopes are presented to the Antigen-Presenting Cells (ACPs) where they bind to the Major Histocompatibility Complex (MHC), a complex formed by proteins that are present on the surface of all cells characterizing them as belonging to the organism to avoid the immune system attack. When the antigenic determinant binds to the MHC in the ACP the latter is identified as an outsider by the T lymphocyte through its receptor. Once the threat is properly identified, cytotoxic CD8+ killer and CD4+ helper T cells carry out the immune response (Abbas et al., 2022; Fainboim & Geffner, 2013) In the humoral response, contrary to cellular response, B lymphocytes are able to directly recognize the antigenic determinant through B Cell Receptors initiating the synthesis of specific antibodies that will bind to the antigen forming the antigen-antibody complex (AgAb) whose function is to neutralize the toxicity of antigens and activate the response of other immune cells response. Once the pathogen is eliminated, the immunity response develops long-term protection against the same threat thanks to T and B memory lymphocytes that remain alert and in case of future infections of the same pathogen, they will be tackled faster and more effectively (Abbas et al., 2022; Fainboim & Geffner, 2013; Parham, 2021). 1.2.7.1. CYTOKINES Cytokines are small proteins secreted by cells of both innate and adaptative response — mainly macrophages and helper T cells— which are responsible for the regulation of diverse biological functions in the immune response: they control the growth and activity of other immune cells, their signals allow the cell communication in the inflammatory response and coordinate the transition from innate to adaptative response (Kany et al., 2019). Cytokines are pleiotropic (the same cytokine has many different effects or functions), redundant (multiple cytokines have the same effect), antagonistic (some cytokines are inhibited by others) and can be inducted in cascade (amplified production of a cytokine). These properties allow an entire network of immune cells to work with a relatively small number of cytokines (Soria et al., 2018). Cytokines may act in the site where they are located (autocrine action), in nearby cells (paracrine action) or in distant cells (endocrine action). 51 Cytokines can be vastly classified as chemokines, interleukins (IL), lymphokines, interferons (IFN), and tumour necrosis factor (TNF) (Soria et al., 2018): ▪ Chemokines are a type of cytokines in charge of the chemotaxis, cell movement promoted by chemical messages, of certain immune that must travel to the affected site. Up to date, about 50 chemokines have been identified. ▪ Interleukins (IL) are produced mainly by leucocytes and play an important role in the proliferation, migration, maturation, activation and differentiation of immune cells. Currently, over 43 members of this superfamily have been identified (IL-1 to IL-43). ▪ Interferons (IFN) antiviral agent which activates natural killer, macrophages and T lymphocytes. ▪ Tumour Necrosis Factors (TNF) are a group of proteins that kill or inhibit tumour cells and they are involved in several physiological and pathological processes. Most sounding examples are TNF-α and TNF-β which are potent mediators in the inflammatory response. Cytokines can also be classified by their inflammatory role as pro-inflammatory (IL-1α/β, TNF-α/β, IL-2, IL-6, IL-11, IL-18, IFN-γ) or anti-inflammatory (IL-4, IL-10) (Achtyes et al., 2020; Himmerich et al., 2019; Kany et al., 2019; Serafini et al., 2020). Nevertheless, this classification is not clear as pathway interactions and cytokine combinations can contribute to various and different physiological effects. Besides, some cytokine can change their inflammatory response by being pro-inflammatory or anti-inflammatory depending on the situation of the organism. Since cytokines have such potent effects, their action must be limited to avoid the pathogenic effects of a cytokine overdose, that is, the activation of cytokines has to be regulated to avoid inappropriate responses that would be detrimental to health. Dysregulation of cytokine secretion and their consequent signalizing network is an important component of pathological diseases like rheumatoid arthritis or systemic lupus erythematosus (Moulton & Tsokos, 2016). 52 1.2.7.2. IMMUNE SYSTEM – CENTRAL NERVOUS SYSTEM INTERACTION Despite being traditionally regarded as independent systems, both the immune system and the Central Nervous System (CNS) are interrelated which implies that psychological and behavioural factors can influence the immune system and vice versa (Soria et al., 2018). Classical studies on psychoneuroimmunology like Ader y Cohen’s (1975) showed that the immune response could be conditioned to certain stimuli, including stressors, and therefore it was proven its connection to the CNS processes. The immune system interacts bidirectionally with the CNS through the same molecular language shaped by neurotransmitters, neuropeptides, hormones and cytokines, in addition to the interaction with the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the upregulation and/or downregulation of the immune response. 1.2.7.2.1. THE STRESS RESPONSE AND HPA AXIS Under a physical and/or psychological stressor, the initial urgent response of the organism is immediately mediated by the sympathetic-adrenal-medullary system (SAM) which facilitates the state of alertness in the body by the release of adrenaline and noradrenaline from the adrenal medulla. As a result, body changes like pupilar and bronchial dilatation and heart rate increase allow a fast fight or flight response. Immediately after, the HPA axis activates and releases the corticotropin-releasing hormone (CRH) into the bloodstream. This hormone stimulates the liberation of the adrenocorticotropic hormone (ACTH) by the pituitary gland. ACTH then travels to the adrenal cortex leading to the release of glucocorticoids like cortisol that foster the aforementioned fight or flight response by increasing blood pressure and glucose availability to provide skeletal muscles with more energy and downregulating non-essential functions such as reproduction or sleep (Abbas et al., 2022). If maintained over time, these physiological changes meant to enhance survival can be extremely harmful to the organism. For this reason, through a negative feedback glucocorticoids themselves act as a control mechanism that ensures the HPA axis is restrained causing a reduction of the ACTH release. During chronic stress, this control system fails and cortisol is overproduced. Over time, immune cells express fewer receptors to cortisol and desensitize to its anti-inflammatory effects causing chronic inflammation (Gjerstad et al., 2018). 53 1.2.7.2.2. NEUROINFLAMMATION: THE INFLAMED MIND Microglia are brain cells that regulate brain development, maintenance of neuronal networks and neuroplasticity and repair. Furthermore, they are the innate immune response of the brain. Under stress and harmful stimuli, these cells suffer functional and morphological changes which trigger an inflammatory cascade fostered by cytokines, chemokines, secondary messengers and reactive oxygen species in the brain. This central inflammation is amplified resulting in the attraction of peripheric inflammatory mediators into the brain (DiSabato et al., 2016). Under normal conditions, the products of the immune system do not physically penetrate into the brain thanks to the protection of the blood-brain barrier (BBB). However, under a neuroinflammatory state the permeability of this barrier can be compromised and peripheric inflammatory products can enter the CNS enhancing neuroinflammation (DiSabato et al., 2016). Neuroinflammation causes neurotoxicity, synaptic dysfunction and has been implicated in neurodegenerative diseases like Alzheimer’s disease (Kwon & Koh, 2020), Parkinson’s disease (Kouli et al., 2020), Multiple Sclerosis (Vavasour et al., 2022), and ischemic stroke (Lian et al., 2020). 54 1.2.8. INFLAMMATION HYPOTHESIS IN SUICIDE Vulnerability factors such as genetic predisposition, prenatal and childhood experiences and stressful life events, amongst others, can result in a dysregulated immune response with an unbalance between pro-inflammatory and anti-inflammatory cytokines, blunted HPA axis activity and neuroinflammation. As the immune system communicates with the CNS and even its inflammatory products can trespass a compromised BBB, inflammation can have detrimental effects on the brain functions including the synthesis, release and reuptake of neurotransmitters —serotonin, glutamate and GABA— ultimately affecting neurocircuits that regulate emotion and behaviour which contributes to the etiopathogenesis of psychiatric disorders and suicide (Miller, 2020). The following paragraphs contain an explanation of some relevant inflammation biomarkers in the literature concerning suicide. 1.2.8.1. CYTOKINES IN SUICIDAL BEHAVIOUR The pathophysiology of suicidal behaviour has been linked to a disbalance between IL-2, IL6, TNF-α and IL-4 (Table 3), causing brain function alterations with implications for emotion, motivation and behaviour which may increase suicide risk (Brundin et al., 2017; Courtet et al., 2016; Vasupanrajit et al., 2021). According to several systematic reviews and meta-analyses (Black & Miller, 2015; Ducasse et al., 2015; Ganança et al., 2016; Serafini et al., 2020), IL-6 is the cytokine most consistently associated with suicidal behaviour. Out of the 17 main studies in the literature (Table 3), 8 describe elevated levels of IL-6 in cerebrospinal fluid (Bay-Richter et al., 2013; Lindqvist et al., 2009, 2011), plasma (Janelidze et al., 2011) and serum (Priya et al., 2016) of non-fatal attempters and post-mortem tissue of fatal suicide attempters (Hoyo-Becerra et al., 2013; Pandey et al., 2012, 2018). In addition, IL-6 might play a role in suicide risk as some studies report higher levels of these cytokines in patients with suicidal ideation (Achtyes et al., 2020; Dolsen et al., 2020; Karlović et al., 2012; Keaton et al., 2019; Martinez et al., 2012; O’Donovan et al., 2013). Although many studies show elevated IL-6 in suicide (González-Castro et al., 2021), some findings do not support this relationship (Coryell et al., 2018, 2020; Dolsen et al., 2020; Eidan et al., 2019; Gabbay et al., 2009; Isung et al., 2012; Jha et al., 2020; Tonelli et al., 2008; Vargas et al., 2013) or found lowered concentrations in suicide attempters (Kim et al., 2008). 55 The role of TNF-α in suicide has also been researched. Out of the 13 main studies that measure this cytokine in suicide (Table 3), 4 find higher plasma concentrations of non-fatal attempters (Janelidze et al., 2011) and in the post-mortem brain tissue of suicide casualties (Pandey et al., 2012, 2018). Similarly to IL-6, there are some studies (Coryell et al., 2018, 2020; Dolsen et al., 2020; Hoyo-Becerra et al., 2013; Huang & Lee, 2007; Jha et al., 2020; Lindqvist et al., 2009; Tonelli et al., 2008; Vargas et al., 2013) that do not find differences on TNF-α levels or describe an opposite relationship with lower concentrations in suicide attempters (Gabbay et al., 2009). Regarding IL-2, some studies (Nässberger & Träskman-Bendz, 1993) report increased levels in suicide attempters in opposition to other authors (Janelidze et al., 2011; Kim et al., 2008) that describe decreased levels in suicide and to the study of Rothenhäusler et al. (2006) with no differences between groups. Concerning IL-4, Tonelli et al. (2008) report elevated IL-4 levels in the post-mortem prefrontal cortex of suicide victims. Contrary to these authors, Kim et al. (2008) and Jha et al. (2020) find lower IL-4 plasma levels in suicide attempters and Gabbay et al. (2009) do not find any differences between groups. Although there is compelling evidence suggesting a connection between suicide and cytokines, there are contradictory results that indicate that the inflammation mechanisms involved in this complex behaviour are yet to be explored. Besides, the implication of cytokines in the pathophysiology and symptom severity of MDD without suicide has also been reported (Dowlati et al., 2010; Enache et al., 2019; Felger & Lotrich, 2013; Himmerich et al., 2019; Köhler et al., 2017; Lopresti et al., 2014; Miller, 2020; Raison et al., 2006; Ting et al., 2020; Valkanova et al., 2013; Young et al., 2014) making it necessary to explore the specific alterations related to suicide to be eligible as a biomarker. Therefore, comparisons of the cytokine profile between depressed suicide attempters, depressed non-attempters and healthy controls may shed light on the understanding of the specific inflammation profile exclusively implicated in suicidal behaviour. As only 5 (Eidan et al., 2019; Gabbay et al., 2009; Huang & Lee, 2007; Janelidze et al., 2011; Kim et al., 2008) out of the 20 main studies analysed in this section (Table 3) employ this thorough methodological design, there is ample room for future studies that delve into the topic following this strategy. 56 Table 3. Main studies of cytokines in suicide attempts. AUTHORS SUBJECTS SAMPLE IL-2 / IL2-R IL-4 IL-6 NASSBERGER AND TRASKMAN-BENDZ, 1993 SA HC Plasma IL-2R SA>HC* - - - ROTHENHÄUSLER ET AL., 2006 MDD SA HC Plasma IL-2R SA=HC - - - HUANG & LEE, 2007 MDD SA MDD NSA HC Plasma - - - SA=NSA=HC KIM ET AL., 2008 MDD SA MDD NSA HC Plasma SA<NSA* SA<HC* NSA<HC* SA=NSA SA<NSA* - TONELLI ET AL., 2008 SC HC Post-mortem tissue - SC> HC* SC=HC SC=HC GABBAY ET AL., 2009 MDD SA MDD NSA HC Plasma - SA=NSA=HC SA=NSA=HC SA<NSA* LINDQVIST ET AL., 2009 SA HC CSF - - SA>HC* SA=HC JANELIDZE ET AL., 2011 MDD SA MDD NSA HC Plasma SA<NSA* SA<HC* - SA>NSA* SA>HC* SA>NSA* SA>HC* ISUNG ET AL., 2012 SA HC CSF - - SA=HC - PANDEY ET AL., 2012 SC HC Post-mortem tissue - - SC>HC* SC>HC* HOYO-BECERRA ET AL., 2013 SC HC Post-mortem tissue - - SC>HC* SC=HC VARGAS ET AL., 2013 SA HC Plasma - - SA=NSA SA=NSA TNF-α 57 Composed from Black & Miller, 2015; Ducasse et al., 2015; Ganança et al., 2016; Miná et al., 2015; Serafini et al., 2020. SA: Suicide attempters SC: Suicide completers NSA: Non-suicide attempters with a psychiatric disorder SI: Suicidal Ideation HC: Healthy controls MDD: Major depression disorder CSF: Cerebrospinal Fluid * significant differences BAY-RICHTER ET AL., 2015 SA HC CSF - - SA>HC* SA=HC PRIYA ET AL., 2016 SA HC Serum - - SA>HC* - CORYELL ET AL., 2018 MDD SA MDD NSA Plasma - - SA=HC SA=HC PANDEY ET AL., 2018 SC HC Post-mortem tissue - - SA>HC* SA>HC* EIDAN ET AL., 2019 MDD SA MDD NSA HC Plasma - - SA=NSA - CORYELL ET AL., 2020 MDD SA MDD NSA Plasma - - SA=NSA SA=NSA DOLSEN ET AL., 2020 MDD / Anxiety SA MDD /Anxiety NSA Plasma - - SA=NSA SA=NSA JHA ET AL., 2020 MDD SA+SI MDDrisk NSA HC Plasma SA+SI= MDD-risk NSA=HC SA+SI < NSA* SA+SI < HC* SA+SI= MDD-risk NSA=HC SA+SI= MDD-risk NSA=HC 64 • To compare childhood trauma and recent stressful life events of MDD patients with a recent suicide attempt, MDD patients with history of suicide attempt, MDD nonattempters and healthy controls (Manuscript 2). ▪ To analyse the cytokine profile in recent and distant suicide MDD attempters in comparison to MDD non-attempters and healthy controls (Manuscript 3). ▪ To explore the relationship between cytokines and child/adult abuse, lifetime aggressive behaviour, global functioning and cognition (attention) (Manuscript 3). 3. MANUSCRIPTS: OBJECTIVES, MATERIALS AND METHODS, RESULTS 67 3.1. MANUSCRIPT 1: SUICIDAL BEHAVIOUR AND COGNITION: A SYSTEMATIC REVIEW WITH SPECIAL FOCUS ON PREFRONTAL DEFICITS (Fernández-Sevillano et al., 2021a) (Annex 1). 3.1.1. OBJECTIVES • To gather updated and homogenized evidence on neuropsychological prefrontal deficits related to behaviour organization and display in suicide attempts by comparing psychiatric patients with a suicide attempt with non-attempters that share the same diagnosis. • To analyse which cognitive alteration is more linked to suicide attempts in each mental disorder. • To compare the neuropsychological performance of attempters and non-attempters focusing on current psychiatric symptoms and the time of the attempt (recent/distant). 3.1.2. MATERIALS AND METHODS A systematic literature search, from 2000 to 2020 was performed on March 30th 2020 using Medline (Pubmed), Web of Science, SciELO Citation Index, PyscInfo, PsycArticles and Cochrane Library databases. Medical subject heading (MESH) terms and free-terms suicide, suicidal behavior and suicidal behaviour were combined with the terms executive function, working memory, prefrontal dysfunction, cognitive control, executive performance and the following terms related to specific neuropsychological tests: Iowa Gambling Test, IGT, Wisconsin Card Sorting Test, WCST, Controlled Oral Word Association Test, COWAT, Weschler Adult Intelligence Test, WAIS, Stroop Colour-Word Test, SCWT, Continuous Performance Test, CPT, Trail Making Test and TMT. The tests included were selected for being classical measures used in neuropsychological assessment which can provide evidence on the functioning of cognitive domains related to behaviour planning, organization and display: 68 ▪ Iowa Gambling Test, IGT (Bechara et al., 1994). The IGT measures decision-making by using 100 cards divided into four card decks (A, B, C, D that the participant has to choose from with the consequence of winning or losing money with each card. Participants start the game with $2000 and have to make the most profit possible without previously knowing that risk decks (A/B) bring higher benefits but also higher losses and, inversely, low-risk decks (C/D) derive lower profits but also lower penalties. ▪ Wisconsin Card Sorting Test, WCST (Heaton, 1981). The WSCT measures executive function with two mazes of 64 cards each. Each card has three types of attributes: shape (triangle, star, cross, circle), colour (red, blue, green and yellow) and number (one, two, three or four elements). The task consists of categorizing the cards following one of the three possible attributes. However, only the evaluator knows which attribute should be followed and gives constant feedback (wrong /correct) to the participant after each response. When 10 correct responses are accumulated the reference attribute changes without any warning to the participant. ▪ Controlled Oral Word Association Test, COWAT (Benton et al., 1994; Buriel et al., 2004). The COWAT, also known as FAS depending on the version, measures verbal fluency by giving 1 minute to the participant to name as many words as possible beginning with a given letter (usually C, F, L or also F, A, S; depending the version used). Successful retrieval requires executive function components to work, such as set-shifting and selfmonitoring. ▪ Stroop Colour Word Test, SCWT (Stroop, 1935). The SCWT consists of three tasks in which subjects are required to read three different tables as fast as possible. The first two tasks are the congruous condition: in the first condition the participant has to read a list of colour names printed in black ink and in the second, the participants have to say the name of the colour of the ink used to print each element on a list of unreadable characters (XXX). In the third task, also referred to as the colour-word condition, the names of colours are printed with an inconsistently congruent and incongruent colour ink and participants are required to name the colour 69 of the ink while avoiding naming the words written. SCWT may be used to measure multiple cognitive functions ranging from cognitive inhibition to attention, processing speed, cognitive flexibility and working memory (Scarpina & Tagini, 2017). ▪ Continuous Performance Test, CPT (Conners, 1994). The CPT assesses sustained attention and visual vigilance in scanning and concentrating on some stimulus. During 14 minutes and 360-trial administration, participants are required to push the spacebar when any letter appears, except the letter X. ▪ Trail Making Test, TMT (Brown & Partington, 2012). The TMT can be used to measure several cognitive abilities ranging from visual attention to task shifting, cognitive flexibility and processing speed. It consists of two parts (A and B) that should be performed in the shortest time possible: in the first part, participants are asked to connect consecutively 25 dots attending to the number written inside them; in the second part, participants are instructed to connect the dots in order alternating letter and numbers as in 1-A-2-B-3-C. ▪ Weschler Adult Intelligence Scale, WAIS (Wechsler, 1955, 2008, 2012). Originally published in 1955 (Wechsler, 1955), the WAIS has been revised until the fourth version in 2008 (Wechsler, 2008) to measure intelligence by using 15 subtests (Figure 10) that assess different cognitive domains and that categorized into four indexes: verbal comprehension, perceptual reasoning, working memory and processing speed. Figure 10. Structure of the WAIS: indexes and subtests. Retrieved from Drozdick et al., 2013. 70 Eligibility criteria After screening, records that met the following inclusion criteria were included in this review: 1) Published in English or Spanish language. 2) Performed at least one of the following neuropsychological tests: Iowa Gambling Test, Wisconsin Card Sorting Test, Controlled Oral Word Association Test, Weschler Adult Intelligence Test (any of the subtests), Stroop Colour-Word Test, Cognitive Performance Test and Trail Making Test. 3) Compared suicide attempters versus non-attempters. 4) Involved patients over 18 years old to discard neurodevelopment effects of cognitive functioning. 5) Involved patients in both groups diagnosed with the same mental disorder according to the Diagnostic and Statistical Manual of Mental Disorders or/and the International Classification of Diseases in their different versions depending on the date of publication of the records. 6) Conference and meeting abstracts, reviews, meta-analyses and pilot studies were excluded. Data collection and extraction PRISMA-P (Moher et al., 2015) checklist and flow-chart were used to ensure the quality of this systematic review. The quality of the studies included was assessed independently by 4 reviewers using the online Critical Appraisal Tools of the Basque Office for Health Technology Assessment (López de Argumedo et al., 2017). This tool allows researchers to collect and extract summarized data of each of the studies (Data extracted: Authors, year of publication, diagnosis, current symptomatology, time of attempt, neuropsychological test used and results) and rates the quality of papers as poor, medium or high according to a comprehensive checklist about the objective of the study, research question, methodological aspects (estimation of sample size, diagnostic criteria, inclusion/exclusion criteria of participants, reliable instruments for measurement, control of confounding factors, 71 minimization of possible bias), results, conclusions, external validity and conflict of interest statement. In this review, only medium and high-quality papers were included. Any disagreement between reviewers was solved by discussion. 3.1.3. RESULTS Of the 1153 papers identified (Figure 11), 17 studies met the inclusion criteria and were selected for this review. A total of 63 full-text articles were excluded: 13 for not having a control group (patients with the same diagnosis but no suicidal behaviour), 10 for using different neuropsychological tests from those established as eligibility criteria, 4 did not provide any data on diagnosis, 8 included patients less than 18 years old, 23 were excluded for record type (conference abstract, meeting abstract, revision, pilot study), 4 were excluded for the language of publication and 1 was excluded for scoring low quality according to the online Critical Appraisal Tools of the Basque Office for Health Technology Assessment. According to this criteria, 14 studies included were of high-quality and 3 of medium quality. 72 Figure 11. PRISMA Flow chart. 1.885 patients diagnosed with a mental illness comprise the total sample of this review, of whom 840 had attempted suicide and 1.045 had never attempted suicide. Out of the 17 studies in this review, 11 found neuropsychological deficits in a sample of 685 attempters compared to 814 non-attempters (n = 1499). Other 6 studies, comprising 155 attempters and 231 non-attempters (n = 386), did not find these differences. 73 Regarding the clinical profile, out of the 17 records selected, 4 (Adan et al., 2017; Kocatürk et al., 2015; Nangle et al., 2006; Verma et al., 2016) assessed 373 patients that had been diagnosed with schizophrenia or schizoaffective disorder. The rest 13 studies (Deisenhammer et al., 2018; Gilbert et al., 2011; Gorlyn et al., 2013; Ho et al., 2018; Jollant et al., 2013; Keilp et al., 2008, 2013, 2014; King et al., 2000; Malloy-Diniz et al., 2009; McGirr et al., 2012; Olié et al., 2015; Richard-Devantoy et al., 2012) assessed the neuropsychological functioning of 1512 patients with an affective disorder. Concerning the time of the suicide attempt, only 3 studies (Deisenhammer et al., 2018; King et al., 2000; Richard-Devantoy et al., 2012) are based on recent suicide attempts, whereas the rest 14 studies focused on lifetime history of previous suicide behaviour. Table 4 provides the main characteristics and results of the studies included in the review. For practical reasons, the results obtained were classified into five neuropsychological domains as follows: Executive function, decision-making, attention, constructional praxis and working memory. As some of the tests included measure different cognitive processes and could be classified into different domains, the criteria used for the categorization of results was made according to the most common objective of the authors using those measures and in a way that enabled results comparison. Specifically, executive function was measured with the WSCT (Heaton, 1981). Decision-making was considered an independent dimension of executive function as the studies included in this review assessed separately with the IGT (Bechara et al., 1994). Attention was measured with the TMT (Brown & Partington, 2012), SCWT (Stroop, 1935) and CPT (Conners, 1994) scores. Although Stroop Interference and TMTpart B scores could be also classified into the executive function domain this was not the objective of the majority of the studies. Constructional praxis and working memory were measured using the WAIS Block Design subtest and Digit subtest respectively (Wechsler, 1955, 2008, 2012) (Table 5). 80 found more errors in SCWT (U = 118.5; p = 0.03) and TMT-B (U = 98; p = 0.005) in recent suicide attempters (n = 20) than non-attempter patients (n = 20). In accordance with these results, Verma et al. (2016) assessed attention in 175 patients diagnosed with schizophrenia or schizoaffective disorder using TMT. Results indicate that patients with lifetime suicide intent had a poorer performance in TMT-A (t = 1.965, p = 0.026) and TMT-B (X2173=2.282, p = 0.012) when compared to non-attempters, who took more time to complete both tasks. Interestingly, Nangle et al. (2006) reported a significantly better ability to control and shift attention in schizophrenic patients with a previous history of suicidal behaviour (n = 28) measured with TMT Part-B compared to non-attempters (n = 50) with the same diagnosis (t = 2.06; p < 0.05). Constructional praxis and working memory Weschler Adult Intelligence Test (WAIS) Block Design subtest was used by Adan et al. (2017), Nangle et al. (2006) and King et al. (2000) to assess constructional praxis but there was no difference between groups. The same happened with the WAIS Digit subtest for measuring working memory in the studies conducted by Adan et al. (2017), Gilbert et al. (2011) and Keilp et al. (2013). Therefore, results indicate that these two domains may not be altered in patients who have attempted suicide. Diagnosis, current psychiatric symptoms and time of the attempt Schizophrenia Patients diagnosed with schizophrenia and previous history of suicidal behaviour showed a poorer performance in executive function (Adan et al., 2017; Kocatürk et al., 2015) compared to patients with schizophrenia who had never attempted suicide. Contradictory and insufficient results were found regarding attention as attempters outperformed nonattempters in one study (Nangle et al., 2006) and vice versa in another (Verma et al., 2016) (Table 6). 81 Table 6. Sample distribution according to diagnosis, time of the attempt and symptoms. Affective disorders n = 1512 Recent attempt 59 symptomatic Distant attempt 313 euthymic 350 symptomatic Never attempted 345 euthymic 445 symptomatic Schizophrenia n = 373 Distant attempt 118 symptomatic Never attempted 255 symptomatic Affective disorders In 7 studies (Jollant et al., 2013; Keilp et al., 2008, 2013, 2014; McGirr et al., 2012; Olié et al., 2015; Richard-Devantoy et al., 2012) cognitive performance was reported to be poorer in affective patients with suicide compared to clinically-similar patients without suicidal behaviour, while 5 studies (Deisenhammer et al., 2018; Gilbert et al., 2011; Gorlyn et al., 2013; Ho et al., 2018; King et al., 2000) did not find differences between groups. According to Richard-Devantoy et al. (2012), currently symptomatic patients who had recently attempted suicide had a poorer performance in attention compared to nonattempters. However, other authors found no differences in attention (King et al., 2000), executive function (King et al., 2000) and decision-making (Deisenhammer et al., 2018) in currently depressed attempters compared to clinically-matched non-attempters. Furthermore, currently symptomatic patients with a history of suicide attempt had poorer outcomes in attention (Keilp et al., 2008, 2013) and executive function (McGirr et al., 2012) but exhibited similar decision-making performance (Gorlyn et al., 2013; Ho et al., 2018) when compared to patients with affective symptoms without a history of suicide attempt. Finally, euthymic patients with history of suicidal behaviour had worse decision-making (Jollant et al., 2013), attention (Keilp et al., 2014; Olié et al., 2015) and executive function (Keilp et al., 2014) compared to euthymic non-attempters. Nonetheless, the study by Gilbert et al. (2011) conducted with a similar sample reported no differences on the cognitive performance between groups (Table 5). 82 3.2. MANUSCRIPT 2: COGNITION IN RECENT SUICIDE ATTEMPTS: ALTERED EXECUTIVE FUNCTION (Fernández-Sevillano et al., 2021b) (Annex 1). 3.2.1. OBJECTIVES • To compare the neuropsychological performance of MDD patients with a recent suicide attempt, MDD patients with history of suicide attempt, MDD non-attempters and healthy controls on the following cognitive domains: working memory, processing speed, decision-making, executive function, and attention. • To compare childhood trauma and recent stressful life events of MDD patients with a recent suicide attempt, MDD patients with history of suicide attempt, MDD nonattempters and healthy controls 3.2.2. MATERIALS AND METHODS Participants 96 participants were recruited from the Psychiatry Department of the Araba University Hospital—Santiago. All patients were diagnosed with MDD according to DSM-5 (American Psychiatric Association, 2013) criteria and were receiving psychopharmacological treatment for their condition. The sample was categorized into the following groups: 20 depressed patients who were hospitalized after a recent suicide attempt (≤ 30 days), 33 patients with a past suicide attempt during their lifetime and hospitalized for MDD episodes, 23 patients without history of suicidal attempts and hospitalized for MDD episodes and 20 healthy controls with no personal or family history of mental illness matched by age and sex with the reference group, that is, the recent suicide attempt group. Suicide attempt was defined as a self-initiated sequence of behaviours by an individual who, at the time of the initiation, expected that the set of actions would lead to his or her own death (DSM-5; American Psychiatric Association, 2013). The exclusion criteria for the three groups including patients were: presence of psychotic symptoms and other comorbid psychiatric disorders with the exception of tobacco use 83 disorder, acute infections, neurological illness, intellectual disability, dementia, organic diseases that compromise cognitive functioning, and cognitive syndromes. In addition to this, the exclusion criteria for healthy controls included either personal or a family history of major psychiatric disorders. All participants were between 18 and 65 years old and had signed an informed consent. This study was approved by the Euskadi Ethics Committee and was conducted according to the Declaration of Helsinki (World Medical Association, 2013). Procedure and Measures After recruitment and signature of the informed consent, each participant had an interview with a psychologist for sociodemographic data collection and clinical assessment. Sociodemographic variables included sex, age, education level, marital status and economic status. Clinical assessment included the number of previous attempts, age of index attempt for suicide attempter group, the number of previous depressive episodes and psychiatric medication for all patient groups. For all participants the assessment included a drug intake registry categorizing the consumption of each drug as use / abuse / dependence. Besides, depressive symptom severity was assessed using the 17-item Spanish version of the Hamilton Depression Rating Scale (HDRS) (Bobes et al., 2003; Hamilton, 1967), a structured instrument widely used in the psychiatric field (Failde et al., 2013; González-Ortega et al., 2015; Health Quality Ontario, 2017) that offers a quantitative measure of the severity of depressive symptoms in a clinical population according to the criteria of the evaluator who conducts the clinical interview. Each item has between three and five possible responses with 0–2 or 0–4 scores, respectively, and the total score ranges from 0 to 52. The 17-item Spanish version has good reliability, with a Cronbach's α of 0.72, and validity with a correlation with other scales for depressive symptoms (Montgomery–Asberg and Beck's Depression Inventory) ranging from 0.8 to 0.9. Recent (6 months) stressful events were measured in all participants using the Spanish version of the List of Threatening Experiences (LTE) (Brugha & Cragg, 1990; Motrico et al., 2013), a 12-item brief questionnaire with yes/no responses regarding personal, relational, financial, and health problems. This questionnaire has a high test–retest reliability (κ = 0.61– 0.87) and is a valid and reliable measure of stressful events in mental health, specifically in depression (OR = 1.64–2.57) (Motrico et al., 2013), which has been previously used in studies 84 with psychiatric populations (Casey et al., 2006; Cervilla et al., 2007; Dalgard et al., 2006; Powers et al., 2013). Childhood abuse and neglect of participants were assessed with the Spanish version of the Childhood Trauma Questionnaire—Short Form (CTQ-SF) (Bernstein & Fink, 1998; Hernandez et al., 2013), a self-administered 28-item questionnaire with five Likert responses (never, rarely, sometimes, often, and always) that has been extensively used (Brustenghi et al., 2019; Devi et al., 2019; Gutiérrez et al., 2015; Lee et al., 2015; Li et al., 2014; Xie et al., 2018) to evaluate the maltreatment dimensions that were detected in the original factorial analysis for construct validity (Bernstein & Fink, 1998): emotional (Cronbach's α = 0.87): physical (Cronbach's α = 0.89) and sexual (Cronbach's α = 0.94) abuse and physical (Cronbach's α = 0.66) and emotional (Cronbach's α = 0.83) neglect (Hernandez et al., 2013). Besides, the participants underwent a neuropsychological assessment using standardized instruments that evaluate the following cognitive domains: working memory, processing speed, decision-making, executive function, and attention. The test and measures used in each domain (Table 7) were adapted from previous existing literature on cognitive assessment in mental disorders (Bernardo et al., 2013; Cuesta et al., 2015). A description of each instrument can be found in the methods section of Manuscript 1 above. Table 7. Cognitive domains and neuropsychological tests employed. Working memory WAIS-IV Arithmetic: total score WAIS-IV Digit total score (Wechsler, 2008, 2012) Processing speed WAIS-IV Symbol Search: total score WAIS-IV Coding total score (Wechsler, 2008, 2012) Decision-making IGT: total money score (Bechara et al., 1994) Executive function WSCT: categories, errors, perseverative errors (Heaton, 1981) SCWT: interference score (Golden, 2001; Stroop, 1935) FAS Test: total correct answers (Benton et al., 1994; Buriel et al., 2004) Attention SCWT: Colour Word score (Golden, 2001) 85 Statistical Analyses Statistical analyses were performed using IBM SPSS Statistics v25 and R 2.5.1. with the help of an expert biomedical statistician. Data were checked for Gaussian distribution. Comparisons between groups regarding the sociodemographic and clinical variables were performed with ANOVA followed by Bonferroni post-hoc testing for continuous variables and chi-square for categorical variables. For the analyses of cognitive performance, measures selected from each test (Table 7) were gathered into the corresponding cognitive domain that is evaluated and the obtained scores were transformed into average z-scores. Backward multiple regressions were performed adjusting for the following confounding variables: age, sex, economic status, education, marital status, drug consumption (tobacco, cannabis, and alcohol), and severity of depressive symptoms according to the HDRS. In each model, only significant confounders (p<0.05) were included. 3.2.3. RESULTS Sociodemographic and clinical variables There were no significant differences between groups regarding sociodemographic variables (Table 8). In the recent attempt group, 35% of patients were recruited after an index attempt, 40% of patients reattempted for the second time, and 60% of patients had more than two reattempts. In the lifetime attempt group, 6.3% of patients had attempted suicide once, 34.4% twice, and 59.3% more than twice. Regarding psychiatric medication, the majority had similar psychopharmacological treatment as 94% were under polytherapy consisting of antidepressants and benzodiazepines, whereas 6% of patients were under monotherapy of either of those medications. In addition to having similar medication profiles, the severity of depressive symptoms was equally distributed across patient groups. Bonferroni post-hoc analyses revealed that all patient groups had significantly higher scores for depressive symptoms measured by the HDRS than healthy controls (p < 0.01 in each comparison), but with no difference between patient groups. Besides, healthy controls had fewer stressful events in the last 6 months than each of the patient groups (p < 0.05 in each comparison), with no difference between patient group. Also, post-hoc analyses of the CTQ-SF scores indicate greater general trauma (p = 86 0.003), emotional abuse (p = 0.003), emotional negligence (p = 0.006), and physical negligence (p = 0.009) in patients with a history of suicide attempts in comparison to healthy controls. Besides, patients with recent suicide attempts reported higher scores of childhood sexual abuse (p = 0.038) than healthy controls. There were no other significant differences between groups regarding trauma and abuse. 87 Table 8. Demographic and clinical variables. Recent attempters (n=20) Lifetime attempters (n=33) Depressed non-attempters (n=23) Healthy controls (n=20) Statistical contrast (p) Sex, n(%) Female Male 13 (65%) 7 (35%) 26 (78.8%) 7 (21.2%) 18 (78.3%) 5 (21.7%) 14 (70%) 6 (30%) X2 =1.617; p=0.656 Age, mean (SD) 44.70 (8.785) 44.45 (12.765) 50.57 (9.926) 44.58 (9.221) F(3,91) = 1.842; p=0.145 Education level, n(%) Primary Secondary Preparatory University 2 (10%) 7 (35%) 5 (25%) 6 (30%) 6 (18.2%) 11 (33.3%) 9 (27.3%) 7 (21.2%) 5 (21.7%) 7 (30.4%) 6 (26.1%) 5 (21.7%) 0 (0%) 6 (30%) 4 (20%) 10 (50%) X2 =9.886; p=0.360 Economic status, n(%) Low Medium High 7 (38.9%) 9 (50%) 2 (11.1%) 10 (37%) 11 (40.7%) 6 (22.3%) 10 (50%) 10 (50%) 0 6 (33.3%) 9 (50%) 3 (16.7%) X2 =5.61; p=0.468 Previous suicide attempts, mean (SD) 1.47 (1.87) 2.34 (2.04) - - t=-1.52; p=0.1 Age of index attempt, mean (SD) 33.55 (11.91) 31.83 (15.35) - - t=0.42; p=0.67 Previous depressive episodes, mean (SD) 2.60 (2.90) 7.50 (9.81) 2.38 (1.59) - F(2,47) =2.16; p>0.05 Depression severity (HDRS), mean (SD) 15.50 (7.23) 17.87 (6.54) 14.36 (8.93) 1.60 (2.09) F(3,89) = 25.741; p<0.01 Recent stressful events (LTE), mean (SD) 2.80 (1.70) 2.53 (2.11) 2.56 (1.90) 0.5 (1.15) F(3,91) = 7,281; p<0.01 CTQ total, mean (SD) 57 (25.63) 64.1 (21.66) 52.57 (23.06) 38.15 (7.12) F(3,80) = 4.54; p<0.05 CTQ emotional abuse, mean (SD) 11.15 (6.63) 13.19 (6.16) 10.38 (6.08) 7.57 (2.90) F(3,82) =3.112; p<0.05 CTQ physical abuse, mean (SD) 8.80 (4.93) 8.13 (5.02) 8.10 (5.73) 6.21 (2.36) F(3,82) =0.813; p=0.49 CTQ sexual abuse, mean (SD) 10 (7.48) 8.81 (5.58) 6.14 (2.15) 5.07 (0.27) F(3,82) =3.789; p<0.05 CTQ emotional negligence, mean (SD) 10.2 (5.02) 14.13 (6.07) 10.67 (5.94) 8.08 (1.85) F(3,80) =4.736; p<0.05 CTQ physical negligence, mean (SD) 11.55 (2.58) 13.06 (3.18) 11.68 (3.48) 9.93 (1.90) F(3,83) =3.770; p<0.05 HDRS: Hamilton Depression Rating Scale. LTE: List of Threatening Experiences. CTQ: Childhood Trauma Questionnaire. 88 Performance on Cognition The scores on the five domains included in this study are presented in Table 9. Table 9. Performance on each cognitive domain by groupa. aData are presented as means and standard deviations. All values are z-scores. For comparisons, backward stepwise multiple regressions were performed adjusted by significant confounders (age, sex, economic status, education level, marital status, depression severity and substance consumption) with healthy controls as the reference group. Healthy controls performed significantly better in processing speed, decision-making and attention than all patient groups, with no differences between them (Table 10). Table 10. Multiple regression of neuropsychological performancea. aData are presented as adjusted B coefficients assuming healthy controls as the reference group. * p<0.05; ** p<0.001 Recent attempters (n=20) Lifetime attempters (n=33) Depressed non-attempters (n=23) Healthy controls (n=20) Working memory -0.577 (0.822) -0.825 (0.867) -0.798 (0.845) 0 (0.784) Processing speed -1.002 (0.821) -1.403 (1.444) -1.306 (1.411) 0 (0.944) Decision making -0.772 (1.089) -0.726 (1.053) -0.873 (0.889) 0 (1.000) Executive function -0.191 (0.256) 0.066 (0.484) 0.070 (0.530) 0.021 (0.313) Attention -0.910 (0.770) -1.025 (0.667) -0.913 (0.646) 0.046 (0.781) Verbal memory Working memory Processing speed Decision making Executive function Attention Recent Attempters -0.176 -0.113 -1.065* -0.829* -0.229 -0.604* Lifetime Attempters -0.292 -0.221 -1.416** -0.664* 0.068 -0.577* Depressed Non-Attempters -0.174 -0.313 -1.050* -0.782* 0.072 -0.567* 89 As the main objective of this study was to determine the cognitive differences between recent suicide attempters and current non-suicidal depressed patients, the reference group for adjusted regressions was afterwards changed to recent attempters. The results yielded significant differences in the executive function domain. Both lifetime attempters and depressed non-attempters had significantly higher scores in this domain in comparison to recent attempters (B = 0.296, p = 0.019, and B= 0.301, p = 0.028, respectively); that is, recent suicide attempters had poorer performance on executive function. However, there were no significant differences between groups in the rest of the cognitive domains. Further analyses showed that there was an interaction between group (depressed recent attempters, depressed (Table 11) lifetime attempters, and depressed non-attempters) and sex on executive performance. According to these results, women with recent attempts had slightly better scores on executive function than males. However, in the rest of the groups, men outperformed women, especially in depressed non-attempter patients, with a large effect size indicating a strong interaction between sex and group. Table 11. Effect sizes of being female on executive functiona. a Adjusted for potential confounders b Effect size is interpreted as mean (standard deviation) differences between females and males on the executive function. Femaleb Recent Attempters 0.088 (-0.301, 0.478) Lifetime Attempters -0.239 (-0.624, 0.146) Depressed Non-Attempter -0.663 (-1.134, -0.192) Healthy Controls -0.189 (-2.058, 1.680) 96 Table 13. Inflammation parameters across groups. Recent attempters (01) (n=20) (mean;SD) Distant attempters (02) (n=33) (mean;SD) Depressed nonattempters (03) (n=23) (mean;SD) Healthy controls (04) (n=20) (mean;SD) Statistical contrast (p) Effect Size Bonferroni Post Hoc Test IL-2 77.66 (70.72) 59.89 (54.46) 52.64 (35.15) 70.52 (48.68) F(3,89)=0.91;p=0.44 0.03 01=02=03=04 IL-2R 124.11 (30.29) 141.29 (32.32) 136.43 (55.00) 135.00 (40.31) F(3,89)=0.71;p=0.55 0.02 01=02=03=04 IL-4 1.84 (1.47) 3.73 (7.22) 1.60 (0.68) 2.29 (0.50) F(3,89)=1,32;p=0.27 0.04 01=02=03=04 IL-6 5.94 (3.49) 5.90 (2.72) 5.41 (2.42) 3.60 (1.64) F(3,89)=3.69;p=0.01 0.11 01>04 02>04 TNF-α 43.74 (14.41) 45.74 (20.96) 44.41 (13.09) 39.21 (11.55) F(3,89)=0.67; p=0.57 0.00 01=02=03=04 Figure 12. Mean (SD) IL-6 plasma concentrations in each group. *p < 0.05 significant differences in comparison to controls. 5.94 (3.49)* 5.90 (2.72)* 5.41 (2.42) 3.6 (1.64) 0 1 2 3 4 5 6 7 RE CENT AT T E MPTERS LIFETIME AT T E MPTERS DEPRESSED NON - AT T E MPTERS HEALT HY CONTROLS IL-6 (PG/ML PLASMA) 4. DISCUSSION The first main finding in this thesis is that individuals who have attempted suicide have some neuropsychological alterations that are specific to suicide and not attributable to an underlying psychiatric disorder (Manuscript 1 and Manuscript 2). Previous studies (Keilp et al., 2001; Marzuk et al., 2005; McGirr et al., 2012; Westheide et al., 2008) and several systematic reviews and meta-analyses report neuropsychological alterations in suicide attempters (Huber et al., 2019; Jollant et al., 2011; Richard-Devantoy et al., 2012, 2014, 2016) but cognitive functioning is also impaired in a high proportion of patients with a mental disorder without suicidal behaviour (Allott et al., 2016; Baune et al., 2014; Chakrabarty et al., 2016; Grützner et al., 2019; MacQueen & Memedovich, 2017; Nakagome, 2017; Solé et al., 2017; Sommerfeldt et al., 2016; Zhou et al., 2017). Since cognitive deficits are present both in suicidal behaviour and mental illness, this raises the question whether the cognitive performance in suicide attempters is diagnosis-dependent or if there may be some alterations specifically related to the attempt. In order to address this inquiry, throughout this thesis the methodology employed was designed to control the possible effect of a psychiatric disorder by comparing clinically similar suicide attempters and suicide non-attempters. Therefore, the differences observed in cognitive performance are more attributable to suicidal behaviour than to the mental disorder itself. Regarding the altered cognitive domains in the Manuscript 1 patients with schizophrenia or an affective disorder that have attempted suicide (recent or distant) have worse attention performance than non-attempter patients with the same diagnosis and similar psychiatric symptoms. Besides, executive function is altered in currently symptomatic attempters diagnosed with schizophrenia (Adan et al., 2017; Kocatürk et al., 2015) and possibly in currently symptomatic attempters diagnosed with an affective disorder (McGirr et al., 2012). In contrast, inconclusive data has been found regarding decision-making and no differences are found in constructional praxis and working memory. Most of the studies in this review include distant suicide attempts; therefore, differences between groups suggest that cognitive alterations are present long after the attempt which might be a risk factor for re-attempts; however, these alterations have not necessarily been present in the period of time when the attempt occurred. In this sense, studies involving recent attempts could help to analyse the cognitive performance closely related to a suicide attempt. 99 In relation to this, Manuscript 2 gives evidence that recent suicide attempts are linked to alterations on the executive function. In this study, depressed patients with a suicide attempt in the last 30 days have significantly poorer performance on executive function than distant depressed attempters and depressed non-attempters. Alterations on this cognitive domain have already been described in patients with a history of suicide attempt (Adan et al., 2017; Keilp et al., 2001, 2008, 2013, 2014; McGirr et al., 2012; Richard-Devantoy et al., 2012) and in depressed patients without suicidal behaviour (Keilp et al., 2013; Sommerfeldt et al., 2016), especially in those with poor treatment response (Castellano et al., 2020), but to the best of our knowledge, this is the first study that compares recent, distant and never attempters diagnosed with MDD and healthy controls. Besides, our results show that sex has an influence on the executive function of recent suicidal attempters. The slightly better performance of women in recent attempt group might be linked to higher impulsivity scores found in men in previous studies (Cross et al., 2011; Grissom & Reyes, 2019) which would imply a higher tendency to think and behave without less planning, error detection, cognitive flexibility and inhibitory control (Jiménez et al., 2016), that is, a poorer performance in cognitive processes that are under executive function control. According to this, men would be more prone to make unadaptative impulsive choices under demanding or stressful events which could increase the risk of high lethality or fatal suicide attempts. Nonetheless, it is remarkable that depressed non-attempter men have a significantly better executive function performance. This may be due to the fact that cognitive symptoms related to depression, such as rumination and hypochondria, are more severe in women (Marcus et al., 2005) with a greater impact on their functionality (RiecherRössler, 2010). Apart from psychological factors, there are also biological differences such as, sex hormones (Giltay et al., 2012; Kumsar et al., 2014), dysregulation of the HPA axis (Zagni et al., 2016) and inflammatory parameters (Labaka et al., 2018) that make depression more adverse for women. 100 Additionally, neuropsychological assessment results reveal that all depressed patients with similar depression severity perform significantly worse than healthy controls in processing speed, decision making and attention but with no difference between groups. Consistent with previous literature (Alexopoulos et al., 2015; Chakrabarty et al., 2016; Cotrena et al., 2016; Keilp et al., 2008), this finding suggests that these alterations are associated with MDD being different from those specifically associated with recent suicide attempts and therefore each condition would be related to a different cognitive profile. According to our results, attention and executive function might be altered in suicide attempts. Attentional dysfunction interferes with the ability to process and interpret information to respond to situational demands. Executive function encompasses multiple cognitive processes that orchestrate thought and behaviour (Gläscher et al., 2012; Miller & Cohen, 2001) including response inhibition, task-shifting and the constant update of the working memory as stated in the comprehensive model proposed by Miyake et al. (2000). Other authors also incorporate planning, decision making, working memory and error detection among its functions (Gläscher et al., 2012; Miller & Cohen, 2001). The performance on both cognitive domains is subjected to the influence of individual factors, such as emotional regulation, personality traits and even traumatic events (Grissom & Reyes, 2019; Lerner et al., 2015; Phelps et al., 2014) . Deficits on these processes can lead to dysregulation of emotion, thoughts and actions (Bredemeier & Miller, 2015) which might contribute to considering suicide as a solution under critical circumstances (RichardDevantoy et al., 2014). In addition, these alterations may also increase interpersonal difficulties increasing the risk for attempted suicide (Jollant et al., 2007). Another relevant finding in this research is that individuals that have attempted suicide have inflammation alterations (Manuscript 3). Our results in Manuscript 3 suggest that suicide is accompanied by a systemic inflammatory response as IL-6 cytokine plasma concentration is elevated in both recent (last 30 days) and distant depressed suicide attempters. This is in accordance with several studies that find elevated IL-6 in cerebrospinal fluid (Bay-Richter et al., 2015; Lindqvist et al., 2011), plasma (Amitai et al., 2020; Isung et al., 2014; Janelidze et al., 2011; Keaton et al., 2019; Priya et al., 2016) and gene and protein expression related to IL-6 in post-mortem tissue of suicide attempters (Hoyo-Becerra et al., 2013; Pandey et al., 2012). 101 It is noteworthy that in our study this cytokine progressively decreases from its highest levels in recent suicide attempters to distant attempters, non-attempters and healthy controls, respectively suggesting a dose-effect role of IL-6 in suicidal behaviour. Although not statistically significant, IL-6 concentrations of depressed non-attempters show a tendency to be higher than healthy controls, in consonance with previous studies that observe more inflammation in depressive patients (Colasanto et al., 2020; Liu et al., 2017; Ting et al., 2020). However, as this study stratifies depressive patients according to their suicidal profile into separate groups, possible differences between non-suicidal depressive patients and healthy subjects might be more subtle than those observed in studies that include depressive patients into the same group regardless of their suicidal history. Despite IL-6 being one of the cytokines most frequently associated with suicide (Black & Miller, 2015; Ducasse et al., 2015; Ganança et al., 2016; Serafini et al., 2020), other studies describe no differences with non-attempters (Coryell et al., 2018, 2020; Dolsen et al., 2020; Eidan et al., 2019; Gabbay et al., 2009; Isung et al., 2012; Jha et al., 2020; Tonelli et al., 2008; Vargas et al., 2013), thus, its role in suicidal behaviour is yet to be elucidated. The mechanisms by which cytokines influence suicide risk are not clear but there is evidence of their immunomodulating role in the CNS (Borsini et al., 2015; Courtet et al., 2016; Dunn, 2006) affecting emotion, cognition and behaviour. In fact, areas of the brain that orchestrate and regulate these three psychological processes, such as hypothalamus, hippocampus, locus coeruleus and prefrontal cortex, are densely populated with cytokine receptors (Jeon et al., 2019). Hence, dysregulated continual synthesis of IL-6 has a pathological effect which may result in the development of psychiatric conditions (Tanaka et al., 2014) and increased suicide risk (Brundin et al., 2017). According to the prospective study of Batty et al. (2016) patients with higher levels of inflammation have a three-fold elevated risk of future suicide death, suggesting that inflammation is preceded and implicated in suicide attempts. Comparisons between groups on IL-2, IL2-R, IL-4 and TNF-α do not yield significant results and literature on these parameters remains contradictory. Regarding IL-2 and IL2-R, Janelidze et al. (2011) and Kim et al. (2008) describe lower IL-2 concentrations in suicide attempters in comparison to patients without a suicide attempt and healthy controls while Nässberger & Träskman-Bendz (1993) report increased IL-2 soluble receptor (IL-2R) plasma concentrations in suicide attempters, although Rothenhäusler et al. (2006) do not find these differences. Concerning IL-4 levels, there are studies that describe an increase in suicide 102 attempts (Tonelli et al., 2008), others a decrease (Jha et al., 2020; Kim et al., 2008) and the one of Gabbay et al. (2009) with no differences between groups. Regarding TNF-α, in the study of Janelidze et al. (2011) depressed suicide attempters have higher plasma levels than depressed non-attempters and healthy controls. Similarly, Pandey et al. (2012, 2018) find more concentration of TNF-α in the brain of adolescents who died by suicide. However, there are studies describing an opposite relationship (Gabbay et al., 2009) and others that do not support any connection (Coryell et al., 2018, 2020; Dolsen et al., 2020; Hoyo-Becerra et al., 2013; Huang & Lee, 2007; Jha et al., 2020; Lindqvist et al., 2009; Tonelli et al., 2008; Vargas et al., 2013). The last important finding in this investigation is that these inflammatory and cognitive alterations are interrelated and associated to other psychological risk factors in recent suicide attempts (Manuscript 2 and Manuscript 3). Inflammation and cognition are linked according to the results in the Manuscript 3 in which higher IL-6 levels are associated to lower scores on attention, the most clearly altered cognitive domain in suicide attempts according to the systematic review in the Manuscript 1. As previously mentioned in this document, cytokines can mediate cognition due to their effect on the CNS mechanisms and areas related to cognition (Jeon et al., 2019; Wilson et al., 2002) causing cognitive alterations that interfere with information processing, interpretation and behavioural response increasing suicide risk (Lara et al., 2015; Szanto, 2017). Regarding psychological risk factors, in Manuscript 2 recent suicide attempters report more child sexual abuse than the rest of the groups. Distant suicide attempters report more general trauma, emotional abuse and negligence and, in general, all patients had more recent stressful events than healthy controls. The accumulating effect of recent stressful events (Howarth et al., 2020) and previous history of childhood maltreatment elevates the risk for suicide in adult life (Bahk et al., 2017; Jiménez-Treviño et al., 2019; Zelazny et al., 2019). In Manuscript 3 results give evidence of the link between inflammation and trauma in recent suicide attempt. Higher IL-6 concentrations were independently linked to adult physical abuse and lower global functioning scores. In addition, higher levels of IL-4 were associated to history of child physical abuse and history of child aggressive behaviour. Numerous studies have linked suicide with childhood and adult abuse (Caravaca-Sánchez et al., 2019; 103 Coryell et al., 2020; Hartley et al., 2018; Salokangas et al., 2019; Thompson et al., 2019). Interestingly, a recent study relates suicide risk to IL-6 phenotypes and childhood adversity (Schiweck et al., 2020). Furthermore, these adverse experiences can have detrimental effects on cognition as described by several authors. In the study of Zelazny et al. (2019) higher scores on executive function protect from suicide in individuals with childhood maltreatment. Carvalho et al. (2020) find a poorer performance on the executive function of maltreated children in comparison to non-maltreated children and according to the study of Dannehl et al. (2017) these differences are also present in adults with history of childhood adversity, especially in those with physical abuse and neglect. All in all, adverse life events, even long time after, can dysregulate the immune system as a response to a stressful traumatic stimulus resulting in higher levels of inflammatory parameters (Brundin et al., 2017; Lippard & Nemeroff, 2020) which can affect cognitive performance (Jeon et al., 2019; Wilson et al., 2002) increasing suicide risk. In conclusion, our results give evidence on the specific cognitive and inflammation alternations in suicide attempts and their mutual interplay and association with other vulnerability factors that increase the suicidal risk. As cognitive performance can be trained and improved (Salagre et al., 2017), cognitive screening and stimulation may be proposed as a strategy for suicide prevention in at risk patients. Future studies are needed to identify possible differences between sex in each cognitive domain for a more personalized approach and for a better understanding of early detection vulnerability factors that may enable us to prevent suicide in at risk patients. Furthermore, the inflammation mechanisms involved in this complex behaviour are yet to be explored. Understanding the role of inflammation in suicide and identifying potential biomarkers for this multifactorial phenomenon remains a challenge for psychiatry. Although there is growing evidence for the neuroinflammation hypothesis of suicide, more research is needed to clarify inconsistent data found in literature. Future studies involving inflammation and suicide may focus on measuring the effect of psychological protective factors and continue the research on the biological mechanisms involving the immune response. Finally, deeper knowledge on the interplay of biological and clinical aspects in MDD patients with suicide attempts would enable novel and personalized treatment options and the development of more effective preventive interventions. 104 Limitations The research conducted on this thesis has the following limitations that should be mentioned: - In the Manuscript 1 only studies published in English or Spanish between the years 2000 and 2020 were included in the systematic review and grey literature was excluded. In addition, due to the scarcity of studies that involve non-attempter clinically-matched control group, the number of articles and sample of patients in this systematic review was limited. Thus, further studies are needed to clarify the cognitive domains that are altered in subjects with suicidal behaviour. Regarding executive function results were contradictory, therefore it is necessary to confirm these findings in future investigations as we endeavour in Manuscript 2. Another limitation of this review is the neuropsychological battery defined as eligibility criteria, which had to be reduced to widely-used instruments but, as a result, we discarded heterogeneous data from other tests and cognitive domains. - In the Manuscript 2 there are a number of limitations. Recent and past trauma events were assessed using self-administered and self-reported scales in MDD patients who can be biased when reporting this information. As more women recently attempted suicide than men, sex-related differences on executive function found in recent attempters must be interpreted with caution and further confirmatory studies are advisable. Moreover, some factors that have been described in the literature as potentially influencing suicidal behaviour in major depression, such as anxiety (Miret et al., 2013) or mixed symptoms (Popovic et al., 2015), were not assessed. - In the Manuscript 3 although general sample was not small, each group sample size was not large for cluster comparisons. However, this thorough methodological design composed by four groups that differentiates recent and distant suicide attempters was crucial to obtain specific outcomes of clinically different groups. Recent and distant trauma events were assessed using a standardized protocol but information could be biased when reporting this information. Patients with other psychiatric conditions and substance use disorder were excluded from the study in order to control significant interactions with inflammation, which may result in a less 105 representative population of at-risk patients. Due to their health status, patients with suicidal attempts involving extremely severe injuries were not recruited during the first month after the attempt. Thus, the sample of recent attempters is less representative regarding this method. Some factors that could potentially influence our results, such as the presence of anxiety, mixed symptoms, BMI and psychopharmacological treatment were not assessed. Individual biomarkers of inflammation were measured instead of full pathway involving receptors and transduction mechanisms. 113 This thesis is a final product gathering the efforts of the last years, but it is not the end of our interest on suicidal behaviour. As research is an alive path, these findings and the challenges faced on the clinical practice lead to further questions and inquiries that encourage us to continue researching into this topic. In this section, preliminary results of current and future production that has derived from this thesis are briefly presented. 6.1. VITAMIN D AS A PREDICTOR OF SUICIDE ATTEMPTS AND GLOBAL FUNCTIONING 6.1.1. BACKGROUND Another promising biomarker for suicide attempts is vitamin D, an indirect measure of the inflammatory state of the organism. Amongst other significant functions in the organism, vitamin D has immunomodulating properties by regulating the production, differentiation and function of cytokines (Borges et al., 2011; Guillot et al., 2010; Yin & Agrawal, 2014). In fact, it has been described an inverse association between vitamin D and IL-6 levels (Liu et al., 2011) and low levels of vitamin D have been associated with chronic inflammatory diseases such as multiple sclerosis, asthma, inflammatory bowel disease and autoimmune rheumatic diseases (Piędel et al., 2021; Yin & Agrawal, 2014; Zheng et al., 2016). Therefore, vitamin D can be an indirect measure of the inflammatory state of the organism. Many studies give evidence of the link between suicide and vitamin D (Grudet et al., 2014; Tariq et al., 2011; Umhau et al., 2013; Fond et al., 2018; Gokalp, 2020; Kim et al., 2020; Postolache et al., 2020; Wei et al., 2021; Yagci & Avci, 2021) and MDD (Anglin et al., 2013; Ju et al., 2013; Köhnke et al., 2020; Manzanos et al., 2020; Ronaldson et al., 2020; Sherchand et al., 2018; Spedding, 2014). In order to be eligible as a suicide biomarker, vitamin D levels should be specifically different in depressed patients with a suicide attempt than in depressed non-attempters. For this reason, comparing depressed suicide attempters, depressed nonattempters and healthy controls could shed light on the role of this vitamin in relation to suicide. 114 6.1.2. METHOD Participants 110 participants were recruited from the Psychiatry Department of the Araba University Hospital – Santiago from the year 2018 to 2020. The sample (n=110) was composed of 52 depressed patients that had recently attempted suicide (<30 days), 23 depressed patients without a lifetime history of suicide attempts and 35 healthy volunteers that were invited to participate through a public advertisement in the hospital. All patients had been diagnosed with MDD according to DSM-5 (American Psychiatric Association, 2013) before the study and were under psychopharmacological treatment for their condition. Suicide attempts were defined as self-initiated sequence of behaviours by an individual who, at the time of the initiation, expected that the set of actions would lead to his or her own death (DSM-5; American Psychiatric Association, 2013). Patients with a diagnosis of a psychotic disorder were not eligible for this study. Exclusion criteria for all participants included substance use disorder except tobacco, neurological or/and neurodegenerative illness, severe organic disease, systemic autoimmune disease, acute infections, being under recent (last week) anti-inflammatory treatment and vitamin D supplementation (last year). Besides, healthy controls with personal or family history of severe psychiatric disorders and/or suicide attempts were not included in the study. Procedure and Measures All patients were interviewed for sociodemographic and clinical data gathering by an experienced psychologist. Clinical variables included psychopharmacological treatment, depression severity and global functioning. The severity of depressive symptoms was assessed by the Spanish version of the Hamilton Depression Rating Scale (HDRS) (Bobes et al., 2003; Hamilton, 1967) and the Global Assessment of Functioning scale (GAF) was used to measure global functioning (American Psychiatric Association, 2013). Healthy volunteers were only interviewed for sociodemographic data gathering. Besides, all participants had a 10mL venous blood extraction for serum 25-hydroxy vitamin D analysis. Seasonality data was gathered to register the season of the year when the blood extraction was conducted on each participant. At the hospital laboratory Alinity i 25-OH Vitamin D Reagent Kit (08P45) was employed to quantify serum 25-OH vitamin D levels and reference levels were categorized as in Table 14. 115 Table 14. Reference levels of 25-hydroxy vitamin D Deficient < 10 ng/mL Suboptimal 10 - 30 ng/mL Optimal 30 -100 ng/mL Toxic >100 ng/mL 6.1.3. PRELIMINARY RESULTS The sample was composed of 102 participants, 46 depressed patients who had recently attempted suicide (<30days), 22 non-attempter depressed patients and 34 healthy controls. There were no differences regarding sex (X2(2,102)=0.12; p=0.94) and age (F(2,99)=2.35; p=0.10) between groups and depression severity (t(63)=0.98; p=0.33) between patient groups. Patients with a suicide attempt (M=53.88, SD=11.11) had significantly lower global functioning scores (t=-3.75; p=0.001) than depressed non-attempter patients (M=69.33, SD=15.84). Although the majority of participants had 25-hydroxy-vitamin D under optimal concentration (30ng/mL), deficient levels (<10ng/mL) were only registered in the suicidal attempter group with a 91.3% of patients under the optimal concentration. One-way ANOVA revealed significant differences (F(2,99)=11.39; p<0.001) between groups regarding 25-hydroxy-vitamin D levels. Specifically, according to Bonferroni Post Hoc test, depressed recent suicide attempters had significantly lower levels of vitamin D in comparison to non-attempter depressed patients (p<0.001, 95% C.I.= -21.32, -6.41) and healthy controls (p=0.03, 95% C.I.= -14.73, -1.72), whereas there were no differences between non-attempter depressed patients and healthy controls (p=0.11). These differences remained significant after ANCOVA comparisons controlling for stationality (F(2,99)=9.86; p<0.001) in all groups and for psychopharmacological treatment (F(68)=21.54; p<0.001) in patient groups whose participants were mostly prescribed a combination of SSRI/SNRI antidepressant and benzodiazepines (45.6%). The odds of attempting suicide in the whole sample (both groups of patients with depressive episodes and healthy controls) were approximately 7 times higher with suboptimal vitamin D levels (<30 ng/mL), OR=6.79 (95% CI: 2.14, 21.62) and increased to almost 9 times considering only patients (attempters and depressed non-attempters) in the sample, OR=8.75 (95% CI: 2.33, 32.93). 116 In patients, Vitamin D levels did not correlate with depression severity (r=-0.18; p=0.16) but correlated positively with global functioning scores (r=0.30, p=0.02). Furthermore, backward multiple regression revealed that vitamin D levels were a predictor of global functionality scores (B=0.03; p=0.02) without any significant influence of other possible covariables (i.e, sex, age, depression severity) included in the first step of the model but removed afterwards for not being subsequently significant. 6.1.4. CONCLUSIONS In this study, patients with a recent depressed suicide attempt have lower levels of vitamin D than depressed non-attempters and healthy controls. As the severity of depression is similar in both patient groups, the differences observed on vitamin D levels between these groups could not be attributed to the mental disorder. In addition, in this study vitamin D predicts suicide risk as the odds for attempting suicide in the whole sample are approximately 7 times higher with suboptimal (30ng/mL) vitamin D levels and for the depressed sample exclusively the odds for attempting suicide are almost 9 times higher with suboptimal vitamin D levels. In line with our results, other studies have also found that low vitamin D levels increase the risk for suicide but they either lack a patient control group to control the possible effect of the diagnosis (Gokalp, 2020; Wei et al., 2021; Yagci & Avci, 2021) or include different diagnosis in the attempter group (Gokalp, 2020; Grudet et al., 2014; Umhau et al., 2013; Yagci & Avci, 2021). A possible explanation for the link between the risk of an attempt and vitamin D may be due to its immunomodulating effects on the inflammatory response which, in turn, has been widely described to be associated to suicide (Batty et al., 2016; Bokor et al., 2021; Brundin et al., 2015; Ducasse et al., 2015; Ganança et al., 2016; Keaton et al., 2019). Vitamin D can also predict the global functioning of depressive patients. This finding suggests that the neuromodulating functions of vitamin D in the brain (Anjum et al., 2018; Lee et al., 2021; Morello et al., 2020) might have a wider role in behavior and emotion, affecting the global performance in daily life areas such as employment, social life, self-care and leisure. As disability (Marlow et al., 2021) has been associated with suicide risk, global functioning scores might be an indirect measure that could help clinicians to estimate the risk of a suicide attempt and the burden of disease caused by a mental disorder. 117 These results highlight the potential predictive value of vitamin D in relation to suicide, a cost-effective objective biomarker that could warn clinicians when handling an hypovitaminosis D, specially, in MDD patients. Thus, it could be beneficial to include vitamin D in the blood-test protocol of psychiatric care units, reinforcing its use with patients at-risk for suicide and considering its supplementation in those patients under optimal levels. 6.2. C-REACTIVE PROTEIN (CRP) IN SUICIDAL BEHAVIOUR AND THE LINK TO COGNITIVE PERFORMANCE 6.2.1. BACKGROUND CRP is a protein found in the blood that serves as a marker of inflammation. Circulating CRP levels increase during acute inflammation (the first 4-24 hours) as its synthesis is triggered mostly by the release of IL-6 in response to a pathogen (El Ayadi et al., 2018). Thus, CRP is an inflammation biomarker which is far easier to obtain than cytokine concentration and already available in clinical practice. For this reason, many studies have explored the link between CRP and suicidal behaviour giving evidence of elevated levels in suicide attempts (Table 15) (Aguglia et al., 2019, 2020; Cáceda et al., 2018; Courtet et al., 2015; Ekinci & Ekinci, 2017; Gambi et al., 2005; Gibbs et al., 2016; Loas et al., 2016; Oh et al., 2019; Priya et al., 2016) and suicidal ideation (Chang et al., 2017; De Berardis et al., 2013; Karlović et al., 2012; O’Donovan et al., 2013; Park & Kim, 2017). However, some contradictory results also emerge from studies focusing on CRP and suicidal behaviour finding no association between them (da Graça Cantarelli et al., 2015; Dolsen et al., 2020; Ducasse et al., 2015; Kim et al., 2019; Peng et al., 2018; Vargas et al., 2013; Ventorp et al., 2015); thus, further studies are needed to clarify the association of CRP and suicidal behaviour. 118 6.2.2. METHOD 1102 patients treated for a major depressive episode in the Urgence et Post-Urgence Psychiatrique Unit at the Montpellier University Hospital conformed this sample. 678 had attempted suicide and 424 were non-attempter patients. Exclusion criteria were any inflammatory disorder, current treatment with antibiotics or anti-inflammatory medications, incapable or refusal to participate in the study. Clinical experts (psychiatrists and psychologists) conducted sociodemographic, clinical (CTQ) and cognitive (D2 Test, National Adult Reading Test-NART) data gathering. Blood extractions were conducted for CPR measurement. 6.2.1. PRELIMINARY RESULTS Non-adjusted differences between groups revealed that patients with a suicidal attempt have more emotional (t=3.702; p=0.000), physical (t=3.076; p=0.002) and sexual (t=2.837; p=0.005) abuse. Besides, they had a poorer performance on the following attention scores: D2 Processed Items score (t=-3.234; p=0.001), D2 error percentage (t=2.203; p=0.028) D2 processed-errors (t=-3.502; p=0.000) and differences remained significant after controlling for age and intelligence (IQ). Regarding inflammation, these patients had significantly higher CPR levels that depressed non-attempters (t=-3.519; p=0.000). Backward multiple regressions revealed that a suicide attempt was less probable with a better attention performance (B=-0.003; p=0.001) controlled for sex in the model. Besides, the odds of attempting suicide were 1.16 higher when CRP increased one unit (Exp(B)=1.16; C.I.=1.067-1.261). Furthermore, a better performance on attention (D2 Processed score) was predicted by lower CRP levels (B=5.270; p=0.000) adjusted for age, suicide ideation and IQ. 6.2.1. CONCLUSIONS The CRP could be a potential cost-effective biomarker for suicide that is an indirect measure of the inflammatory state in the organism. According to these results, CRP is elevated in suicide attempters and relates to their cognitive performance on attention domain. As CRP can be easily obtained in a blood test, future studies are needed to consider its implementation in the current Treatment as Usual in psychiatric care units. 119 Table 15. Main studies of CRP in suicide attempts. AUTHOR SUBJECTS SAMPLE CRP GAMBI ET AL.,2005 MDD SA MDD NSA Serum SA>NSA* VARGAS ET AL., 2013 SA HC Plasma SA=HC COURTET ET AL., 2015 MDD SA MDD NSA Serum SA>NSA* DA GRAÇA CANTARELLI ET AL., 2015 Mood Disorders SA Mood Disorders NSA Serum SA=NSA DUCASSE ET AL., 2015 BD SA BD NSA Serum SA=NSA VENTORP ET AL., 2015 MDD SA MDD NSA HC Plasma SA=NSA=HC GIBBS ET AL., 2016 SA SI NSA Serum SA>SI>NSA LOAS ET AL., 2016 Mood Disorder / Anxiety SA Mood Disorder / Anxiety NSA Serum SA>NSA* PRIYA ET AL., 2016 SA HC Serum SA>HC* EKINCI ET AL., 2017 MDD SA MDD NSA HC Serum SA>NSA* SA>HC* CÁCEDA ET AL., 2018 MDD ND Positive correlation with the number of SAs PENG ET AL., 2018 MDD SA MDD NSA Serum SA=NSA AGUGLIA ET AL., 2019 SA NSA Serum SA>NSA* KIM ET AL., 2019 MDD SA MDD SI Plasma SA=SI OH ET AL., 2019 MDD SA MDD NSA ND SA>NSA* AGUGLIA ET AL., 2020 SA SA re-attempt Serum SA re-attempt > SA* DOLSEN ET AL., 2020 MDD/Anxiety SA MDD/Anxiety NSA Plasma SA=NSA Composed from Chen et al., 2020; Miola et al., 2021. SA: Suicide attempters NSA: Non suicide attempters with a psychiatric disorder SI: Suicidal Ideation HC: Healthy controls MDD: Major depression disorder BD: Bipolar disorder ND: No data * significant differences 120 6.3. TELEMEDICINE-BASED SUICIDE PREVENTION 6.3.1. BACKGROUND One of the main risk factors for completed suicide is previous history of suicide attempts (Bostwick et al., 2016) with 25-40 times more risk of suicide (WHO, 2022). Telemedicine can offer continuous support to at-risk patients which might reduce the rate of reattempts (Cebrià et al., 2013; Exbrayat et al., 2017; Miller et al., 2017) but further research is needed to assess its efficacy. Suicide prevention remains a challenge and should be targeted to at-risk population such as patients with a previous attempt. Hospital context provides a great opportunity to implement preventive interventions for reducing suicide risk as many patients arrive at Emergency Services when attempts occur and can enrol in post-discharged followup programmes. The objective of this study is to assess the efficacy of a 5 (Week 1, Month 1, Month 3, Month 6, Month 12) telephone calls follow-up intervention on the delay of suicide re-attempts in a group of patients with a recent suicide attempt (last month) in comparison to a group of patients with a recent suicide attempt without a telephone followup. 6.3.2. METHOD 140 patients were recruited from the Psychiatry Department of the Araba University Hospital – Santiago shortly after (less than a month) visiting the emergency service due to a suicide attempt. 70 patients, in addition to the Treatment as Usual (TAU) received, agreed to roll-up in a 5 (Week 1, Month 1, Month 3, Month 6, Month 12) telephone calls follow-up intervention targeted to reduce suicide risk and conducted by a trained nurse. Another 70 patients only received TAU as control group. All patients were interviewed for sociodemographic and clinical data gathering by an experienced psychologist. 6.3.3. PRELIMINARY RESULTS The sample was composed by 89 women (63.3%) and 51 men (36.4%) with a mean age of 46.37 (SD=12.69). The most frequent method for attempting suicide was drug poisoning (89.3%) followed by defenestration (5.7%), cuts (3.6%), hanging (0.7%) and fireguns (0.7%). Adherence to the telemedicine programme in the intervention group was mostly excellent with a 51.5% of patients completing 4-5 of the 5 phone calls programmed, 26.5% completed 2-3 phone calls and 22.1% had a low adherence with only completing one phone call. The intensity of suicide ideation measured by Columbia-Suicide Severity Rating Scale decreased 121 significantly from the first phone call to the last (t=2.46; p=0.02). Regarding the main objective, the telemedicine intervention showed significant efficacy on relapse delay (t=2.204; p=0.03). Besides, after 12 months of follow-up patients on the telemedicine programme (X=0.37; SD=0.81) had significantly less relapses (t=-1.978; p=0.05) than patients with TAU (X=0.67; SD=0.99). 6.3.4. CONCLUSIONS The telemedicine-based suicide prevention programme has been effective in delaying and reducing suicide attempts. Besides, it has reduced the suicide ideation intensity and has achieved an excellent adherence in most of the patients. 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