Hemofagocitoza limfohistiocitară iatrogenă indusă de medicamente

Introduction

Suicide has a global mortality rate of 1.4% of all deaths, representing a serious public health problem. Every year, 800,000 people commit suicide (World Health Organization, 2019)⁽¹⁾, 90% of whom had a mental illness. Among these, affective disorders account for 43.2%, with 30-40% major depressive disorder and 50% bipolar disorder, and substance use disorders were present in 25.7%⁽²⁾.

The components of suicidality are multiple: cognitive, psychological, social, environmental and physiological, which interact, showing the multidimensional nature of suicidality, that must be reflected in the heterogeneous strategies through which it is managed⁽³⁾. The treatment should be based on addressing the etiological factors in these dimensions. Thus, pharmacotherapy reduces the neurobiological dysfunctions, and the cognitive dysfunctions arising from adverse life events are addressed through psychotherapy. These refer to a multidimensional model that provides the clinician with holistic information about the circumstances in which the psychiatric condition arose, that can be integrated into development strategies to manage it⁽³⁾.

The severity of psychiatric disorders is not directly correlated with suicide, and growing evidence supports the view that suicidal behavior is a specific entity⁽⁴⁾. Suicidal behavior is not explained solely by the presence of a psychiatric illness, but this is one of the most important risk factors involved in the suicidal process⁽¹⁾.

Risk factors and protective factors need to be better understood for adequate suicide prevention, such as the role of personal decision-making capacity, social support, spiritual and religious interventions, and reducing treatment differences in mental healthcare⁽¹⁾. There is extensive variation in suicidality among individuals, even though there are patterns in risk factors and predisposing factors. This variation is due to individual life experiences such as culture, customs, personal values, norms, social circumstances and personality traits⁽³⁾.

An increased risk of suicide has been found in several categories of psychiatric disorders, including psychotic disorders and bipolar disorder⁽¹⁾.

It is necessary for the clinician to remain flexible and in contact with the patient in order to provide safety during transitions in care and to incorporate nonpharmacological treatment to increase coping strategies, prevent future suicide attempts, manage associated conditions and involve families⁽⁵⁾, using the suicide predictors cited below.

Suicide risk in psychotic disorders

Early-onset psychotic disorders affect the 15-35 years old age group, in which suicide is the second leading cause of death, after road accidents⁽⁶⁾.

Psychotic disorders have a prevalence of 3%, and schizophrenia of 0.7%, involving impaired contact with reality and disorganization which lead to decreased functioning in social, professional and family domains, and also to suicide⁽⁷⁾. The life expectancy of patients with schizophrenia is reduced by 13-15 years due to cardiovascular disease or suicide, which is the most important cause of early mortality in these patients⁽⁶⁾.

People with schizophrenia and other primary psychotic disorders have a suicide rate of 5-14%, with a sharp increase in the first years after the contact with mental health services. In the first year of treatment, 10% attempt suicide, and the risk of suicide is critical in the first month after the first episode of psychosis⁽⁶⁾. People who experience their first episode of psychosis at an early age have higher suicide rates compared to people who experience their first episode in adulthood⁽⁷⁾.

Studies have shown that a large proportion of people who die by suicide have been in contact with mental health services in the 12 months prior to their death – 25%⁽⁷⁾. A diagnosis of schizophrenia was present in 16% of all those who died by suicide, and the onset of the illness was recent in 10% (less than 12 months prior to death)⁽⁶⁾, often having been recently discharged from hospital and under the care of mental health services, which supports an acute and severe diagnosis⁽⁷⁾.

In schizophrenia, suicide, with a rate of 10%, occurs more frequently in the early stages of the disease, with an annual incidence 12 times higher than in the general population. In the first year, there is a 60% increase in the risk of suicide compared to other stages of the disease⁽⁶⁾.

The presence of suicidal risk factors (unemployment, social isolation, alcohol and substance abuse) in patients with recent-onset schizophrenia is less common than in patients with a longer duration of illness, and represents, together with comorbid affective disorders, a sudden and recent disturbance due to severe mental illness⁽⁷⁾. Other risk factors in the first psychotic episode are history of suicidal ideation and depressive symptoms, and the prolonged duration of the degree of disruption at the onset of schizophrenia is reflected in the patient’s social circumstances, work and relationships, which may already be fractured during the prodromal period, as well as in the presence of affective disorders⁽⁷⁾. Clinicians should take these into account during care, discharge planning and post-discharge follow-up.

It has been observed that, in the first psychotic episode of schizophrenia spectrum disorders, there are three trajectories of suicide risk that help to make predictions for suicide, supporting early clinical intervention⁽⁸⁾. In the first trajectory, the patient in the first psychotic episode enters treatment with low suicide risk, which remains low under treatment. In the second trajectory, the patient enters treatment with a mild to moderate suicide risk, which decreases under treatment (improvement). In the third trajectory, the patient enters treatment with low suicide risk, which worsens under treatment⁽⁸⁾. The low-risk and improvement trajectories are characterized by improvements in depression, positive symptoms, quality of life and recovery over time. The trajectory of deterioration shows improvements in positive symptoms and quality of life, but not in depression and recovery. Focusing on positive symptoms and quality of life in therapy during the first episode of psychosis masks the symptoms of depression, worsening the suicide risk, leading to a higher risk of suicide attempts and death by suicide during treatment⁽⁸⁾. Older age, longer duration of untreated psychosis, sleep difficulties, substance use (cocaine, alcohol), no change in depressive symptoms and recovery, with greater depressive symptoms, greater positive symptoms, lower recovery scores, no difference in baseline improvement class, suicidal ideation and previous suicide attempts characterize the increased suicide risk⁽⁸⁾.

More than positive symptoms, recovery and quality of life in psychosis are new clinical predictors of suicide risk trajectories, because patients want to live a meaningful and fulfilling life, and this could be the goal of clinical intervention. An increased risk of suicide occurs when depressive symptoms persist and the levels of recovery are low. An improvement in suicide risk occurs with improvement in depression and recovery⁽⁸⁾.

The study of Wastler et al. (2024) shows that, in the first psychotic episode, 80% of patients are at a low risk of suicide, 15% are at an increased risk of suicide, and 5% are at a worsened risk of suicide under treatment. In people with multiple episodes of psychosis and affective disorders with psychotic features, these results cannot be generalized⁽⁸⁾.

Other predictors of suicidal behavior in the first psychotic episode are those related to cognition, whose impairment has been described in psychotic disorders⁽⁹⁾. Cognition refers to neurocognition, social cognition and metacognition⁽⁷⁾. Approximately 70% of patients with psychotic disorders show neurocognitive impairment, with lower IQ and alterations in specific neurocognitive domains⁽⁹⁾. The domains of social cognition are: attribution style, emotion recognition, social perception and knowledge, theory of mind, which are affected in psychosis. Metacognition is the ability to form representations about one’s own and others’ mental states, and these representations allow the formation, challenging and revision of ideas about what is believed, felt, dreamed or feared in various contexts⁽⁹⁾. Insight has two constructs: clinical insight and cognitive insight, which is the metacognitive ability to reevaluate thoughts and beliefs in order to draw relevant conclusions. The results of the study on cognition in recently onset psychotic disorders and previous suicidal behavior refer to:

neurocognitive function was not linked to a history of suicidal behavior;

greater cognitive insight;

social cognition and metacognition – extremely low externalization of bias, better theory of mind, presence of jumping to biased conclusions, which is the therapeutic target for increasing insight in psychotic disorders;

some authors say that poorer cognitive functioning and depressive symptoms are predictors of suicidal behavior;

theory of mind deficits are a predictor of suicidal behavior;

clinical and cognitive insight is deficient in psychotic disorders;

depression and history of suicide attempts are mediating factors between clinical insight and suicidality;

cognitive insight is not related to suicide attempts, but to a history of suicidal ideation⁽⁹⁾.

A one-third reduction in suicide deaths and a one-third reduction in suicide attempts were observed when early intervention was provided for early-onset psychotic disorders through pharmacotherapy, psychotherapy, case management, related services and psychosocial therapy⁽⁶⁾. Education about psychosis was also considered a form of early intervention, because educated people are more likely to seek treatment when the psychotic symptoms appear, which leads to a decrease in morbidity and mortality⁽⁷⁾. It has been observed that those who are less symptomatic and have a better quality of life are less likely to be victims of suicidal behavior⁽⁶⁾.

Suicidal behavior has significant repercussions in terms of loss of life, premature death by homicide, accidental death, cardiovascular disease, respiratory disease and socio-professional consequences, with lower employment rates and repercussions on family, friends and society⁽⁶⁾.

Early interventions have also included individual or group family support to reduce the consequences of their relative’s suicide⁽⁶⁾.

Suicide risk in bipolar disorder

Bipolar disorder (BD) is a chronic illness marked by hypomanic, manic and depressive episodes, mixed states and subsyndromal symptoms of impaired functioning. BD is associated with many psychiatric (e.g., anxiety disorders and substance use disorders) and somatic comorbidities. The heritability of bipolar disorder is substantial, and the age of onset is young. The 12-month prevalence of bipolar disorder is 1.5%, with equal prevalence in women and men⁽¹⁰⁾. The lifetime prevalence of BD worldwide is 2.4%⁽¹²⁾.

Life expectancy in bipolar disorder is reduced by 12.9 years due to:

Natural causes, such as cardiovascular disease, stroke, metabolic syndrome due to anxiety disorders and substance use disorders, which are common comorbidities of BD⁽¹¹⁾. Bipolar disorder is known to be an independent risk factor for major adverse cardiac events even after the cardiovascular disease is taken into account⁽¹⁰⁾.

Unnatural causes – accidents, traffic injuries, accidental poisoning and suicide⁽¹⁰⁾.

People with bipolar disorder have a suicide rate 24 times higher than the general population, accounting for 4-14% of all suicides⁽¹⁰⁾. Bipolar disorder has the highest risk of suicide of all psychiatric disorders⁽⁹⁾, having a suicide rate of 5-20%, with no difference between type I bipolar disorder and type II bipolar disorder, afflicting 40 million people worldwide, causing increased psychosocial, financial and medical burden, as well as increased mortality from suicide and other causes⁽⁸⁾. In low- and middle-income countries, access to care is low due to poverty, low education and poor care, leading to poor adherence, with increased treatment discontinuation rates and worsened outcomes⁽¹⁰⁾.

Suicide attempt is an important predictor of completed suicide; the lifetime prevalence of suicide attempt is 33.9%, higher than in schizophrenia (14.6%) and major depression (31%)⁽¹²⁾. The combination of bipolar disorder and a history of suicide attempt is the strongest predictor of completed suicide. In women, the prevalence of suicide attempt is higher than in men, because they more frequently experience depressive episodes, rapid cycling and a history of physical and sexual abuse in childhood. Also, more lethal methods of suicide are present in men⁽¹²⁾. People with bipolar disorder who associate personality disorders, a history of suicidal behavior, a family history of suicide attempt or suicide, poor QoL, poor relationships or social support and abuse or neglect in childhood are more likely to experience suicide attempt or suicide⁽³⁾.

More than half of completed suicides in the BD population were committed by individuals with a history of suicide attempt. The risk of suicide increases 37-fold when there is a history of suicide attempt, because this can increase the threshold and tolerance for pain or the capacity for suicide. After multiple suicide attempts, when suicidal ideation occurs, fewer precipitating stimuli are needed to activate the next suicide attempt⁽³⁾.

Comparison between suicides in BD and non-BD:

The bipolar disorder group had the following characteristics:

younger;

fewer psychosocial stressors;

previous suicide attempts and contact with acute health services at a higher rate;

bipolar disorder has a greater impact on women, as demonstrated by the low male-to-female ratio for suicide⁽¹¹⁾;

BD individuals use more lethal methods than the general population⁽¹²⁾.

Individuals with bipolar disorder have prominent risk factors for suicide: male gender, white, single, divorced, childless, young age at onset of illness, younger than 35 or older than 75, unemployed, suicidal ideation, history of suicide attempt, family history of suicide attempt or death by suicide, mixed or depressive mood, predominantly depressive polarity, rapid cycling pattern^(2,10). Rapid cycling is associated with female gender, mixed features, exposure to antidepressants, maltreatment in childhood, metabolic disturbances and hypothyroidism⁽¹⁰⁾. Frequent hospitalizations for depression, bipolar disorder type I, substance abuse and comorbidities with other psychiatric disorders are also cited⁽¹²⁾.

The pathophysiology of bipolar disorder is represented by genetic, inflammatory, mitochondrial and neurostructural alterations⁽¹⁰⁾:

Heredity in bipolar disorder is 60-80%, being determined by 298 risk genome sequences for BD. The environmental factors (adversities in childhood, cardiometabolic disorders and lifestyle factors) overlap with this heredity and interact with genetic risk to shape clinical manifestations.

Mitochondrial dysfunction is uncertain, and consists of atypical brain energy metabolism.

Circadian rhythm dysregulation has genetic causes in bipolar disorder.

The inflammatory mechanisms in BD have genetic causes, disruption of the HPA axis and infections with cytomegalovirus and herpes simplex type 2, which cause chronic inflammation that activates microglia, excitotoxicity, oxidative stress and disrupts cognitive circuits and mood regulation.

Cardiometabolic comorbidities are present in bipolar disorder, which increase the inflammatory processes.

Neurostructural alterations of the brain also occur in BD, represented by frontotemporoparietal cortical atrophy, which worsens with manic episodes, disturbances of white matter in the corpus callosum and cingulum. Functional MRI has shown disruption of the fronto-limbic network and consequent dysregulation of emotions, global cognition and behavior, as well as disruption of the cognitive network and those related to dopamine and serotonin⁽¹⁰⁾.

Alternating periods of elevation and depression characterize the spectrum of BD disorders, which are accompanied by changes in neural activity, cognition, behavior and personality⁽³⁾.

Suicide prevention in bipolar disorder

Pharmacotherapy using algorithms;

First-line treatment – mood stabilizers and atypical antipsychotics, which reduce suicidal behavior and the number of deaths by suicide;

Lithium, which has an anti-suicidal effect^(11);

Psychosocial interventions⁽¹²⁾;

Psychotherapy for bipolar disorder⁽¹¹⁾.

Of particular note here is the psychotherapy for suicidality, represented by cognitive behavioral therapy (CBD), dialectical behavioral therapy (DBT) and acceptance and commitment therapy (ACT)⁽²⁾. Acceptance and commitment therapy belongs to the third wave of behavioral therapy, reducing suicidal ideation and impulsive behaviors. It is widely used in mental disorders with an increased risk of suicide. It encourages patients not to suppress or change painful feelings, but to accept them, develop psychological flexibility, accept their experiences, and engage in behaviors that correspond to their own ideals based on personal values⁽²⁾.

Bipolar disorder triggers suicide through interaction with other factors: severity of illness, impulsivity, hopelessness, hostility, aggressiveness. In BD, impulsivity can be a constant feature in the progression of the illness or a state-dependent feature that fluctuates with the severity of the illness. It occurs predominantly in remitted bipolar disorder. Impulsivity, more than suicide planning, has been shown to predict suicide attempt. It transfers from suicidal ideation to suicide attempt⁽²⁾. Impulsivity leads to adverse health outcomes, such as increased global functional impairment, a higher number of early-onset episodes, a higher number of previous suicide attempt, substance abuse, increased hospitalization rates and a higher risk of suicide⁽²⁾.

Suicidal tendencies in bipolar disorder are the result of the interaction of causal factors: cognitive-affective, neurophysiological (genetic and aggravated by symptomatic depressive or manic periods), environmental, or social. The biological component in bipolar disorder is more pronounced than in other psychiatric contexts, and there is a need to take into account the physiological aspects of its etiology along with its psychosocial counterparts. Genetic factors and symptomatic periods partly lead to suicidality in bipolar disorder⁽³⁾.

Symptomatic periods and their effects on physiology and experience in BD represent a predisposition (diathesis), because they can increase vulnerability to suicidality through difficult regulation of affect, restricted thinking, causing psychological pain, increased impulsivity and aggression, decreased stress resilience and frequent exposure⁽³⁾.

Psychological factors of suicide in bipolar disorder

Depression typically leads to suicidality, but not exclusively, through low mood, hopelessness, rumination, mental pain and low stress sensitivity, which interact with:

stressful social and environmental circumstances;

physiological states;

other cognitions related to taking one’s own life;

cognitive interpretation of events as devastating, justifying suicide;

negative interpretation of social or environmental circumstances as inescapable and hopeless, with a diminished ability to see other solutions to perceived problems.

Thus, in depression, the person contemplates suicide, seeing death as the only solution or escape⁽³⁾.

Suicidal ideation frequently occurs in bipolar disorder as a result of increased exposure to cognitive or psychological states. When death is seen as an end to one’s problems and pain, this tendency is further exacerbated⁽³⁾.

Depressive periods are not the only ones that lead to suicidality in BD:

periods of high risk of suicidality also include mixed states with a significant depressive component (mixed depression);

when recovering from depression, as energy and motivation increase, individuals may be strong enough to complete suicide;

mania – individuals act on suicidal ideation when they transition from mania to depression or a mixed state;

increased suicidality is also determined by the use of antidepressants, and the onset of suicidal ideation during this treatment is genetically determined;

rapid cycling BD has a higher rate of suicide attempt than non-rapid cycling BD, because it leads to exposure to stressors associated with symptomatic periods, which can exacerbate the existing suicidal tendencies⁽³⁾.

Genetic factors in bipolar disorder

Suicidal tendencies in bipolar disorder run in families, which is thought to be due to a mix of genetically inherited responses to stress, having a mental health condition, copying behavior and thought patterns, and being exposed to similar environments and stressors⁽³⁾.

Improving suicidal behavior prediction is an urgent need in the context of psychiatric disorders that are highly associated with suicide risk, such as bipolar disorder⁽⁴⁾.

The study of Auxilia et al. (2025)⁽⁴⁾ is the first to explore the staging of suicide based on a wide set of variables, finding risk factors and protective factors associated with the stages: gender, duration of BD, duration of untreated illness, type II bipolar disorder, number of depressive episodes, onset of depression, lithium treatment, comorbidities with alcohol use, substance use and anxiety. The cohort participants were classified into five stages, based on suicidal behavior:

Stage 0 – no suicidal ideation.

Stage 1 – suicidal ideation without suicide attempt.

Stage 2a – non-violent/severe suicide attempt.

Stage 2b – violent/severe suicide attempt.

Stage 3 – multiple suicide attempts⁽⁴⁾.

Results

Stage 1:

long duration of untreated illness;

increased emotional lability;

lower functioning than in stage 0 is a risk factor for suicidal ideation, not for suicide attempt;

female gender;

an onset of elevated mood (hypomaniacal, maniacal and mixed) is less likely to lead to suicidal ideation;

increased scores of affective lability as a risk factor for suicidal ideation⁽⁴⁾.

Stage 2a:

long duration of untreated illness;

female gender;

risk factor – substance use disorder;

increased anxiety;

protective factors – male gender, lithium treatment;

the onset of depression is associated with a higher rate of suicide attempt, because the manic episode is promptly treated to avoid more severe consequences, or because in mania there is grandiose optimism or less hopelessness; this also involves the extent of insight, with contrasting implications – lack of insight in mania leads to an increase in the number of relapses and suicide attempt by decreasing adherence to treatment, but greater insight also implies greater awareness of the illness, with a consequent increase in suicidal ideation;

history of childhood trauma, which causes suicide attempts in women and increased irritability in men⁽⁴⁾.

Stage 2b:

short duration of untreated illness;

male gender;

alcohol use disorder (risk factor);

childhood trauma leads to a reduced ability to regulate emotions and impulsivity, leading to suicidality;

type I bipolar disorder;

a protective factor is the increased anxiety against violent suicide attempt.

However, people with anxiety are treated with benzodiazepines, which are risk factors for suicide attempt and suicide. Lithium treatment is a protective factor⁽⁴⁾.

Stage 3:

long duration of untreated illness;

type IIbipolar disorder, many depressive episodes; the explanation is that three-quarters of the time spent ill is represented by depressive episodes, which expose individuals to a prolonged and sustained risk of suicide; in addition, mixed episodes may occur due to treatment with antidepressants;

alcohol use disorder is a risk factor because it involves impulsivity, which is linked to suicide attempt, alcohol causing neurocognitive alterations, with a risk of suicidal behavior;

low anxiety – if anxiety disorders occur, there is a lower probability of repeating the suicide attempt;

longer duration of illness; individuals with a duration of illness longer than two years have suicide attempts more frequently than those with a shorter duration of illness – the explanation is that those who engage in suicide attempt access medical care more promptly⁽⁴⁾.

Other parameters of staging

Biological parameters⁽⁴⁾:

Reduced bilirubin in advanced stages, in those with a history of one or more suicide attempts (stages 2-3). Being an endogenous antioxidant, its decrease indicates an alteration in the defense against oxidative stress.

Uric acid. There is an inverse correlation with the severity of suicidal ideation in patients with major depression or BD, due to its association with purinergic transmission and antioxidant action.

Hemoglobin is low in advanced stages of bipolar disorder due to its association with an inflammatory state, as many systemic cytokines are known to inhibit erythropoiesis.

Inflammation is widespread in BD and less pronounced in euthymic phases. CRP is thus considered a marker of recent suicidal behavior.

Cognitive variables⁽⁴⁾:

Poorer verbal memory performance has been associated with violent suicide attempt.

Impairment of working memory and inhibitory control occurs in patients with bipolar disorder and a history of suicidal behavior.

Benefits of the suicidality staging

1. Staging suicidality in bipolar disorder allows the identification of different phenotypes, with distinct risk factors for progression to more severe stages.

2. This can improve the care of individuals with BD who are at risk for suicidal behavior.

3. Proactive treatment plans can be adapted to different stages of risk.

4. Risk stages can be addressed preventively through psychoeducation, substance abuse prevention, addressing affective lability, addressing anxiety disorders, assessing childhood trauma, while in advanced stages, pharmacotherapy and safety planning are necessary.

5. Mental health resources can be allocated more efficiently⁽⁴⁾.    n