Arguments for the specificity of the antisuicidal effect of lithium

Affective disorders are characterized by first a high recurrence risk, second a 30-50 times increased suicide risk and third a 2- to 3 times increased overall mortality. In contrast to a populistic belief no scientific evidence exists that antidepressant treatment, particularly long-term treatment, could reduce the the risk of suicidal acts in depressive patients with a history of suicide attempts. Data, however, coming from international, systematic, retrospective analyses of well-documented long-term courses of illness in reliably diagnosed patients, and from a large national, prospective long-term trial on the prophylactic efficacy of lithium versus carbamazepine and amitriptyline has accumulated in the last 10-15 years strongly supporting a (possibly specific) antisuicidal effect of lithium. The large collaborative IGSLI study (International Group for the Study of Lithium-treated Patients) covering 5,616 patient years clearly showed that adequate long-term lithium treatment significantly reduces and even normalizes the excess mortality of patients with affective disorders. A metaanalysis on 17,000 patients pooled from 28 studies demonstrated that the rate of suicidal acts is 8.6 fold higher in patients without lithium as compared to those with regular lithium treatment. A post-hoc analysis of a large multicenter, controlled long-term trial found no suicidal acts in 146 patients randomized to lithium compared to 9 suicidal acts in 139 patients randomized to carbamazepine. Reanalysis of the data from the IGSLI study supports the concept of the specificity of lithium, i.e., evidence could be provided that lithium also reduces suicidal behavior in patients who do not benefit from the lithium treatment in terms of episode reduction. CONCLUSION: Lithium has to be considered as a first line mood stabilizer in affective disorders, particularly in patients with a history of suicide attempts. Extreme caution is required when lithium is discontinued or a patient is switched to another mood stabilizer, because such a patient might have been protected against suicidal impulses in spite of an incomplete response as to the number and quality of depressive/manic episodes.     

Suicidal Behavior in Mood Disorders: Response to Pharmacological Treatment

Suicidal behavior is strongly associated with depression, especially if accompanied by behavioral activation, dysphoria, or agitation. It may respond to some treatments, but the design of scientifically sound, ethical trials to test for therapeutic effects on suicidal behavior is highly challenging. In bipolar disorder, and possibly also unipolar major depression, an underprescribed medical intervention with substantial evidence of preventive effects on suicidal behavior is long-term treatment with lithium. It is unclear whether this effect is specifically antisuicidal or reflects beneficial effects of lithium on depression, mood instability, and perhaps aggression and impulsivity. Antisuicidal effects of anticonvulsant mood stabilizers (carbamazepine, lamotrigine, valproate) appear to be less than with lithium. Further evaluation is needed for potential antisuicidal effects of atypical antipsychotics with growing evidence of efficacy in depression, particularly acute bipolar depression, while generally lacking risk of inducing agitation, mania, or mood instability. Short-term and long-term value and safety of antidepressants are relatively secure for unipolar depression but uncertain and poorly tested for bipolar depression; their effects on suicidal risk in unipolar depression may be age-dependent. Sedative anxiolytics are virtually unstudied as regards suicidal risks. Adequate management of suicidal risks in mood disorder patients requires comprehensive, clinically skillful monitoring and timely interventions.     

Antidepressants and suicidal behavior in bipolar disorder

Patients with bipolar disorder are at very high risk for suicidal ideation, non-fatal suicidal behaviors and suicide and are frequently treated with antidepressants. However, no prospective, randomized, controlled study specifically evaluating an antidepressant on suicidality in bipolar disorder has yet been completed. Indeed, antidepressants have not yet been shown to reduce suicide attempts or suicide in depressive disorders and may increase suicidal behavior in pediatric, and possibly adult, major depressive disorder. Available data on the effects of antidepressants on suicidality in bipolar disorder are mixed. Considerable research indicates that mixed states are associated with suicidality and that antidepressants, especially when administered as monotherapy, are associated with both suicidality and manic conversion. In contrast, growing research suggests that antidepressants administered in combination with mood stabilizers may reduce depressive symptoms in patients with bipolar depression. Further, the only prospective, long-term study evaluating antidepressant treatment and mortality in bipolar disorder, although open-label, found antidepressants and/or antipsychotics in combination with lithium, but not lithium alone, reduced suicide in bipolar and unipolar patients (Angst F, et al. J Affect Disord 2002: 68: 167–181). We conclude that antidepressants may induce suicidality in a subset of persons with depressive (and probably anxious) presentations; that this induction may represent a form of manic conversion, and hence a bipolar phenotype, and that lithium's therapeutic properties may include the ability to prevent antidepressant-induced suicidality.     

Psychopharmacologic strategies for the prevention of suicidal behavior in bipolar patients

Current pharmacological strategies for the prevention of the suicide behavior in bipolar patients are reviewed. Additionally, these studies are discussed in the context of a stress–diathesis model, to explore whether this model explains the empirical fact that some drugs appear to have antisuicidal properties while others do not. A review of the relevant literature suggests that lithium and serotonin enhancing antidepressants reduce suicidal behavior in bipolar patients. A stress–diathesis model explains the differential effect of such medications compared to other antidepressants or mood stabilizers by proposing additional effects of these medications on the diathesis for suicidal behavior. This effect may be mediated by augmentation of serotonergic function, which is linked to suicidal behavior. Serotonergic enhancing drugs therefore can potentially reduce suicidal behavior.     

Newer Prophylactic Agents for Bipolar Disorder and Their Influence on Suicidality

ABSTRACT

Different from lithium, there is little known so far on the effect of (newer) anticonvulsants on suicidality in bipolar patients. We evaluated data of 128 patients with bipolar disorders for suicidal ideation. These patients were treated with various mood-stabilizing medications for at least 3 months. No suicide attempt or completed suicide occurred in this cohort during prospective follow up for an average of 13.3 ± 12.1 years. Compared to lithium, the relative risk of suicidal ideation was numerically slightly higher for valproate, carbamazepine and a small group treated with either levetiracetam, oxcarbazepine or topiramate, but lower in patients treated with lamotrigine, without reaching statistical significance. Confounding variables in more intensive care of these patients participating in a naturalistic study may blur small differences and contribute to a generally favorable outcome.     

Newer prophylactic agents for bipolar disorder and their influence on suicidality.

Different from lithium, there is little known so far on the effect of (newer) anticonvulsants on suicidality in bipolar patients. We evaluated data of 128 patients with bipolar disorders for suicidal ideation. These patients were treated with various mood-stabilizing medications for at least 3 months. No suicide attempt or completed suicide occurred in this cohort during prospective follow up for an average of 13.3 +/- 12.1 years. Compared to lithium, the relative risk of suicidal ideation was numerically slightly higher for valproate, carbamazepine and a small group treated with either levetiracetam, oxcarbazepine or topiramate, but lower in patients treated with lamotrigine, without reaching statistical significance. Confounding variables in more intensive care of these patients participating in a naturalistic study may blur small differences and contribute to a generally favorable outcome.     

Profil toxique du lithium : revue exhaustive de la littérature avec méta-analyse des résultats

Objectives

Lithium is a widely used and effective treatment for mood disorders. There has been concern about the safety of lithium but no adequate recent synthesis of the evidence on adverse effects was published in French language. The objective of this study was to produce a clinically informative, systematic toxicity profile of lithium.

Materials and methods

We up-to-dated the systematic review and meta-analysis of randomized controlled trials and observational studies investigating the association between lithium and all reported major adverse effects that we previously published. We searched electronic databases specialist journals, reference lists, textbooks and conference abstracts. We used a hierarchy of evidence which considered RCTs, cohorts, case-control studies and case reports including patients with mood disorders treated with lithium. Outcome measures were renal, thyroid and parathyroid function; weight change, skin disorders, hair disorders and teratogenicity.

Results

Five thousand nine hundred and eighty-eight abstracts were screened for eligibility and 390 studies included in the analysis. On average, glomerular filtration rate was reduced by –9.30 mls/min [95 % CI –12.15 to –6.44, P < 0.001] and urinary concentrating ability was reduced by 15 % of normal maximum. Lithium use may increase rates of renal failure but absolute risk appears to be of the order of 0.3 %. The prevalence of clinical hypothyroidism was increased in patients taking lithium [OR 5.78, 95 % CI 2.00 to 16.67, P = 0.001], whilst thyroid stimulating hormone was increased on average by 4.00 iU/mL [95 % CI 3.90 to 4.10, P =  < 0.001]. Lithium treatment was associated with increased blood calcium [+0.09 mmol/L, 95 % CI 0.02 to 0.09; P = 0.009], and parathyroid hormone [+7.32 pg/mL, 95 % CI 3.42 to 11.23; P < 0.001]. Lithium was associated with more weight gain than placebo [OR 1.89 (1.27 to 2.82) P = 0.002], but not olanzapine [OR 0.32 (0.21 to 0.49) P ≤ 0.001]. There was no statistically significant increased risk of congenital malformations, alopecia, or skin disorders despite many suggesting such associations.

Conclusions

Lithium is associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism and weight gain. There is little evidence for a clinically significant reduction in renal function in the majority of patients and the risk of end-stage renal failure is low. The risk of congenital malformations is uncertain; the balance of risks should be considered before lithium is withdrawn during pregnancy. The consistent finding of a high prevalence of hyperparathyroidism means calcium levels should be checked before and during treatment.     

Methylation and QTDT analysis of the 5-HT2A receptor 102C allele: analysis of suicidality in major psychosis

Suicide is an act deliberately initiated and performed by a person with full knowledge that a fatal outcome is probable. The serotonin 2A (5-HT2A) receptor gene has been implicated in the pathogenesis of suicidal behaviour by a genetic association between the 5-HT2A T102C silent polymorphism and suicidality in patients with mood disorders and schizophrenia. However, a recent meta-analysis failed to confirm this association. We developed an improved quantitative assay for the measurement of allele-specific methylation of the 5-HT2A gene, and found that the methylation of the C allele in the pre-frontal cortex of heterozygous suicide victims (n = 10) was not significantly different in comparison with the non-suicide group (n = 10) (p = 0.084). We also analyzed methylation of the C allele in white blood cell DNA from bipolar and schizophrenic attempters and found a significant difference in the schizophrenic attempters (p = 0.00013) but not in the bipolar attempters (p = 0.616).Because the 5-HT2A gene is subject to imprinting, the parent-of-origin may affect inheritance of suicidal behaviour. Thus, we examined the parental origin of specific alleles for genetic association in a genetic family-based sample of major psychoses in which information on suicidal behaviour was available. This result suggests that methylation of the 102C allele does not influence completed suicide.     

Suicide risk in mood disorders

PURPOSE OF REVIEW: The aim of this review is to highlight the traditional and newly recognized suicide risk factors in patients with mood disorders. RECENT FINDINGS: Current research findings clearly suggest that suicidal behaviour in patients with mood disorder is a 'state-dependent' phenomenon. Recently, there is, however, a growing body of evidence that besides the well accepted clinically explorable suicide risk factors in mood disorders (e.g., severe depression, prior suicide attempt, comorbid anxiety, substance use, personality disorders and so on), mixed state of depression could also be an important precursor of suicidal behaviour. This might be particularly true in unrecognized cases of bipolar depressives, when antidepressant monotherapy (unprotected by mood stabilizers or atypical antipsychotics) can worsen the clinical picture and rarely induce an aggressive or self-destructive behaviour. SUMMARY: In the majority of patients with mood disorders, suicidal behaviour is predictable and preventable, with a good chance. A careful and systematic exploration of suicide risk factors in patients with mood disorder helps clinicians to identify patients at high suicide risk. A successful, acute and long-term treatment of these patients substantially reduces the suicidal behaviour even in this high-risk population.     

Les idéations suicidaires chez les nouveaux arrivants en maison d’arrêt

Suicide in prison is in increase for several years and participates in a major problem of public health. The number of suicide in prison arises mainly during first moment of incarceration, in particular under fifteen days. Eighty percent of the subjects who attempt to commit suicide or commit suicide express such ideas months before. So the expression of suicidal ideations is a risk factor of suicide and their detection is crucial. This study has investigated suicidal risks in prisoners with the assessment of the rate of suicidal ideation as well as their link with risk factors such as depressive disorders, individual factors or life's event's life, etc. Participants were recruited from all-male adults, who just arrived in prison since one week in prison of Hauts-de-Seine, Nanterre, France. One hundred prisoners able to read and fill in the scales in autonomy way were evaluated from March to June 2007 using a structured interview, Beck Depression inventory (BDI), Scale of suicidal ideation by Beck (SSI) and a short version of Mini International Neuropsychiatric Interview (MINI). The SSI assesses precisely the presence of suicidal ideations and suicidal risk as well as its severity and the score gives some information on the severity of the suicidal risk. The BDI assesses the presence of depressive symptoms as well as the severity of depression according to a classification: Light, medium or severe depression. Eleven out of 100 prisoners have suicidal ideations in SSI. They are not connected significantly to the incarceration (χ² = 3.52, P = 0.05). The scores go from 3 to 27 (the maximum score for this scale is 36) and the medium score is 8.81: four people have scores around the medium score, four people have a score smaller than 5, three people have a score higher than 9. The group of prisoners who have suicidal ideations (n = 11) was compared with the group of prisoners without suicidal ideations (n = 89). Suicidal ideations are in link with the severity of depression in BDI (χ² = 12.53, P < 0.001) but not with its presence only: Prisoners who have suicidal ideations have a medium score of depression higher than prisoners who have not suicidal ideations (16.45 against 6.01, the maximum score for this scale is 39). Ninety-one percent of prisoners who have suicidal ideations suffer from medium or severe depression against 35 % of prisoners without suicidal ideations. Nevertheless, the difference is not significant if we compare the two groups with all types of depression-light, medium or severe (χ² = 2.74, P < 0.05). Moreover anxious and psychotics symptoms, in particular hallucinations in MINI are linked significantly with suicidal ideation (anxiety: χ² = 22.62, P = 0.00001; psychosis: χ² = 6.639, P = 0.01; hallucinations: χ² = 12.8, P = 0.001). Significant risk factors for suicidal ideation in prisoners are life's event such as personal suicidal attempt (χ² = 25.58, P < 0.000001) and substance use history (χ² = 7.76, P < 0.01) and the lack of family support (χ² = 8.7, P < 0.01). It is not the case for suicidal attempt in family (χ² = 1.663, P < 0.05) and a recent death (χ² = 1.24, P < 0.015). Prisoners, who are more than 35 years old, are married, have children and are in prison for murder(s) or rape(s) have significantly more suicidal ideations. Some prisoners who have not suicidal ideation in the SSI have a suicidal risk in the MINI. So we can think these ideas are under-expressed in the SSI because prisoners can feel uncomfortable to express such ideas. Moreover there is more than the half of prisoners who present some signs of depression in BDI for less than one third of prisoners in MINI: Depression can be over-expressed in BDI, what explain it is the severity of depression which is in link with suicidal ideations and no only its presence because a lot of prisoners (with or without suicidal ideations) seem to have a depression with the assessment of BDI. The results must be used with care because the population of the study is quite small, in particular for prisoners who have suicidal ideations. Furthermore it is very heterogeneous and judging origins of the link between suicidal ideations and risk factors is very difficult. In conclusion, these results cannot be generalised to the whole prison; they are specifics to this place of research. Symptoms of depression, anxiety and psychosis as well as personal history of suicidal attempt, substance use and a lack of family support are risk factors for suicidal ideations in prisoners. The precocious detection of suicidal ideation and risk factors would prevent from suicide and reduce the risks.     

Atypical antipsychotics and suicide in mood and anxiety disorders

Abstract:  Globally, a million people commit suicide every year, and 10–20 million attempt it. Mood disorders, especially major depressive disorder (MDD) and bipolar disorder, are the most common psychiatric conditions associated with suicide. Primary (psychiatric and physical illness), secondary (psychosocial), and tertiary (demographic) risk factors for suicide have been identified. Comorbid psychiatric illness, particularly anxiety symptoms or disorders, significantly increase the risk of suicidal behavior. Current standard risk assessments and precautions may be of limited value, while assessing the severity of anxiety and agitation may be more effective in identifying patients at risk. Lithium is the medication that has most consistently demonstrated an antisuicidal effect. The effects of antidepressants and conventional antipsychotics on suicide risk are uncertain, but atypical antipsychotics appear promising. Atypical antipsychotics have beneficial effects on depressed mood both in patients with MDD and in patients with bipolar disorder. In addition, data in patients with schizophrenia have demonstrated a significant improvement in the incidence of suicidal behavior with clozapine compared with olanzapine. Electroconvulsive therapy appears to have an acute benefit on suicidality.     

Bipolar disorders and suicidal behaviour

Rihmer Z, Kiss K. Bipolar disorders and suicidal behaviour. Bipolar Disord 2002: 4(Suppl. 1): 21–25. © Blackwell Munksgaard, 2002
Major depressive disorder is the leading cause of suicide, particularly in the absence of adequate treatment. The aim of this paper is to analyse the relationship between different forms of major mood disorders and suicidal behaviour. Population-based epidemiological surveys as well as clinical studies on the clinically explorable suicide risk factors in bipolar and unipolar depressive disorders are reviewed. The present literature shows that patients with bipolar disorders are at higher risk of attempted and completed suicide than that of patients with unipolar major depression. Contrasting only bipolar I and bipolar II patients, current findings indicate that the rate of prior suicide attempt is higher in bipolar II patients, and bipolar II disorder is overrepresented in depressed suicide victims. Among patients with different clinical manifestations of major mood disorders (unipolar major depression, bipolar I and bipolar II disorder), bipolar patients in general, and bipolar II subjects in particular carry the highest risk of suicide.     

Tentative de suicide médicamenteuse : la quadrature du cercle des poètes non disparus

In November 2008, the suicidal gestures met in a general hospital in Lyon were within 79.9% of cases of acute drug overdoses (n = 174). These behaviors have a function that cannot be summarized in one simple search of death. The overdose is designed to immobilize a suffering process. In this, it can be compared to the writing process. The commentary on Plato's Phaedrus by J. Derrida, shows a Pharmakon (medication/poison) function of writing. By analogy, it is informative on the choice of using drug for suicide attempters. Writing and suicide are seen by the subject who commits them, as remedies for memory. But they are also its poison. The reversibility of the drug powers hints the fact that suicide attempt obeys a rollover process. The psychiatrist's role may be to subvert this process by causing the patient to rebel against the role of scapegoat (Pharmakos) of his own suffering. The choice to take refuge in the medication is an evidence of the transfer from the patient to the doctor (Pharmakeus). If we want to catch to the original principle of reversibility that we see at work in the drug committed suicide, we must consider the question of time. The overdose would represent the quest of a safe place away from time. The issue of suicidal psychiatric care then becomes the creation of spaces where reversibility is negotiable, sometimes manageable. Of places such as speech, movement which is to balance a network of ambiguities.     

Parent of origin effect and allelic expression imbalance of the serotonin transporter in bipolar disorder and suicidal behaviour

Suicide and suicidal behaviour are a major health concern worldwide particularly in patients with mood disorders. Family, adoption and twin studies show that genetics influences suicidal behaviour. The serotonin transporter (5HTT) plays an important role in the pathophysiology of mood disorders and may also be involved in suicidal behaviour since 5HTT binding is decreased in the brain of suicide completers. Because the effect of genomic imprinting in the 5HTT gene on suicidal behaviour has not been investigated, we analysed the parent-of-origin effect (POE) of four 5HTT markers and the differential expression of the 5HTT G2651T (rs1042173) alleles in suicide attempters affected by bipolar disorder. We performed a family based association study and ETDT/QTDT analyses of the rs25531, HTTLPR, VNTR-2 and G2651T polymorphisms in 312 nuclear families with at least one subject affected by bipolar disorder. The main outcomes investigated in this study are bipolar disorder diagnosis, suicide attempts, suicidal behaviour severity and age at onset of bipolar disorder. We also compared the allele-specific mRNA levels in lymphoblastoid cells from 13 bipolar suicide attempters and 8 bipolar non-suicide attempters. Allele 2651T was transmitted significantly more often to bipolar patients (P = 0.042). There was no significant difference between maternal and paternal transmission ratios. Furthermore, there was no significant difference in the ratio of T/G-specific mRNA expression between bipolar attempters and non-attempters. These data do not support a role for differential allelic expression of 5HTT for suicidal behaviour in bipolar disorder. Small sample size and the fact that RNA was obtained from lymphoblastoid cell lines were some of the limitations of this study.     

Lithium in drinking water and suicide rates across the East of England

Lithium can be found naturally in drinking water. In clinical practice, it is widely used in pharmacological doses for the treatment of bipolar disorder; and may also prevent suicidal behaviour in people with mood disorders. In two studies, lithium levels in tap water have been significantly and negatively correlated with suicide. We measured lithium levels in tap water in the 47 subdivisions of the East of England and correlated these with the respective suicide standardised mortality ratio in each subdivision. We found no association between lithium in drinking water and suicide rates across the East of England from 2006 to 2008.     

Le modèle du tempérament et du caractère de Cloninger appliqué dans le trouble bipolaire de l’adulte : recension de la littérature d’une approche tempéramentale

Context

Although psychiatric research uses clear diagnostic criteria to describe bipolar disorders, therapists in clinical practice are often confronted with patients presenting a number of symptoms with different degrees of intensity and belonging to more than one diagnostic category. With respect to this actual clinical complexity, there is an increasing interest in a dimensional approach of psychopathological traits to gain better understanding of mental disorders. In the 1980s, Robert Cloninger elaborated on a psychobiological model to explain personality in clinical groups as well as in general population. His model was then operationalised with a questionnaire evaluating temperament (harm avoidance, novelty seeking, reward dependence and persistence) and character (self-directeness, cooperativeness, self-transcendence): the Temperament and Character Inventory (TCI).

Objective

To review all studies conducted in adult bipolar samples on temperament and character according to Cloninger's psychobiological model.

Materials and methods

A search was conducted on MedLine and PsycInfo for all articles written in English or French, between 1986 and September 2008, on temperament and character in bipolar disorder. The words bipolar disorder or mania had to be associated with the following keywords temperament, TCI, Cloninger, TPQ, harm avoidance, novelty seeking, reward dependence.

Results

Across studies, compared to the general population, bipolar subjects have significantly higher harm avoidance, higher novelty seeking and lower self-directness. Some studies have investigated differences between bipolar disorders and other psychopathologies like depression, and borderline personality disorder. Among studies on depression and bipolar disorder, there is no consensus on the findings. Compared to borderline personality disorder patients, bipolar disorder subjects have lower harm avoidance and higher self-directness and cooperativeness. This finding is consistent with Cloninger's hypothesis that all personality disorders have lower self-directness than any axis I disorder. With respect to other temperament and character traits, studies yielded results either contradictory or non-significant. No difference was found when the bipolar group was subdivided according to the clinical presentation (type I vs II) and the suicidal risk, apart from harm avoidance. Bipolar subjects with substance related disorders displayed higher novelty seeking and lower persistence, which might be explained by a low dopaminergic activity that had to be compensated with drug intake. Low persistence causes greater difficulties to overcome substance dependence. However, it is not possible to determine whether these temperament characteristics are specifically linked to bipolar disorder, substance related disorders, or both. Similar limitations apply to bipolar patients with comorbid anxiety disorders, who presented higher harm avoidance and lower self-directness.

Conclusions

Across studies, there are limitations which impede the generalization of the findings to other clinical populations. Age, gender, cultural characteristics, mood status during evaluation, group size, versions of the TCI questionnaire, suicidal risk, clinical type (BP I vs II) and comorbidity differ from one study to another. These methodological variables should be controlled in future studies. Nevertheless, adult bipolar patients appear to present a different temperamental profile than other clinical groups and general population. Therefore, Cloninger's psychobiological model of temperament remains an interesting avenue for future researches in bipolar disorder.