- Email: [email protected]
Understanding suicide: Focusing on its mechanisms through a lithium lens
Accepted Manuscript
Understanding suicide: Focusing on its mechanisms through a lithium lens Gin S Malhi , Pritha Das , Tim Outhred , Lauren Irwin , Grace Morris , Amber Hamilton , Katie Lynch , Zola Mannie PII: DOI: Reference:
S0165-0327(18)31354-5 https://doi.org/10.1016/j.jad.2018.08.036 JAD 10033
To appear in:
Journal of Affective Disorders
Received date: Revised date: Accepted date:
25 June 2018 8 August 2018 9 August 2018
Please cite this article as: Gin S Malhi , Pritha Das , Tim Outhred , Lauren Irwin , Grace Morris , Amber Hamilton , Katie Lynch , Zola Mannie , Understanding suicide: Focusing on its mechanisms through a lithium lens , Journal of Affective Disorders (2018), doi: https://doi.org/10.1016/j.jad.2018.08.036
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Highlights:
AC
CE
PT
ED
M
AN US
The need for novel potential treatment targets to be identified by understanding the mechanisms of suicide is discussed How a deeper understanding of suicide can be achieved by examining lithium’s antisuicidal properties is illustrated An integrated neurocognitive and neurobiological model of suicide is proposed to provide a framework for future research Practical recommendations for the assessment of suicidal thinking and behaviour alongside its neural underpinnings are outlined
CR IP T
1
ACCEPTED MANUSCRIPT
Understanding suicide: Focusing on its mechanisms through a lithium lens
CR IP T
Author Statement
Contributors: Gin S Malhi 1,2,3,*, Pritha Das 1,2,3, Tim Outhred 1,2,3, Lauren Irwin 1,2,3, Grace Morris 1,2,3,
AN US
Amber Hamilton 1,2,3, Katie Lynch5, Zola Mannie 1,2,3,
1
Academic Department of Psychiatry, Northern Sydney Local Health District, St Leonards, NSW Australia
2
Sydney Medical School Northern, University of Sydney, NSW Australia
3
M
CADE Clinic, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW Australia 4
5
ED
NSW Health and Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW Australia Center for Neural Science, New York University, New York, NY 10003, USA
AC
CE
PT
* Corresponding Author: Gin S Malhi Discipline of Psychiatry, Sydney Medical School, University of Sydney, Sydney, NSW, 2065, Australia. Email: [email protected]
Abstract
Background: Current intervention strategies have been slow in reducing suicide rates, particularly in mood disorders. Thus, for intervention and prevention, a new approach is necessary. Investigating the effects of a medication known for its anti-suicidal properties on neurobiological and neurocognitive substrates of suicidal thinking may provide a deeper and more meaningful understanding of suicide. 2
ACCEPTED MANUSCRIPT
Method: A literature search of recognised databases was conducted to examine the intersection of suicide, mood disorders, and the mechanisms of lithium.
CR IP T
Results: This review synthesises the extant evidence of putative suicide biomarkers and endophenotypes and melds these with known actions of lithium to provide a comprehensive picture of processes underlying suicide. Specifically, the central importance of glycogen synthase kinase-3β (GSK3β) is discussed in detail because it modulates multiple systems that have been repeatedly implicated in suicide, and which lithium also exerts effects on. Limitations:
AN US
Suicide also occurs outside of mood disorders but we limited our discussion to mood because of our focus on lithium and extending our existing model of suicidal thinking and behaviour that is contextualised within mood disorders. Conclusions: Focusing on the neurobiological mechanisms underpinning suicidal thinking and
M
behaviours through a lithium lens identifies important targets for assessment and intervention. The use of objective measures is critical and using these within a framework that integrates
ED
findings from different perspectives and domains of research is likely to yield replicable and validated markers that can be employed both clinically and for further investigation of this
AC
CE
PT
complex phenomenon.
3
ACCEPTED MANUSCRIPT
Keywords: Suicide prevention, biomarkers, endophenotypes, pharmacological
CR IP T
treatment, lithium, GSK3β.
Introduction
A global target of 10% reduction in suicide by 2020 and 50% by 2023 has been set by the World Health Organisation (WHO; World Health Organization, 2014) because, despite
AN US
concerted, multifaceted efforts, the rate of reduction in suicide has been dishearteningly slow. Part of the reason for this is the complexity of suicide and its multifactorial aetiology. Hence, a deeper understanding of its underlying mechanisms and the processes that drive suicidal
M
behaviour is crucial for the development of effective preventative strategies.
ED
Suicide occurs in many situations but is most common in mood disorders. Indeed, the risk of suicide in mood disorders is 30 times greater than in the general population and 72-87%
PT
of completed suicides involve patients with either major depression or bipolar disorder (Arsenault-Lapierre et al., 2004). Therefore, it is necessary to examine suicide in the context of
CE
mood disorders and identify potential targets for better treatment and prevention. But in order
AC
to achieve this, a suitably sophisticated model is needed – one which bridges the gap between molecular mechanisms and clinical effects. A recent neurocognitive model of suicide in the context of bipolar disorder provides a useful developmental framework for the psychological processes that culminate in suicide (Malhi et al., 2018). This model brings together the neurobiological antecedents and the many environmental and psychosocial contributing factors 4
ACCEPTED MANUSCRIPT
that result in the emergence of suicidal thinking. Therefore, after briefly reviewing this model, this paper specifically examines the underlying neurobiology of suicide, and uses our knowledge of lithium in this context to focus on the inception of suicidal thinking.
CR IP T
Method A literature search of articles was conducted to examine the intersection of suicide, mood disorders and mechanisms and the role of lithium. Recognized databases such as Scopus,
AN US
PubMed, and PsycINFO using the keywords “suicide”, “suicide in mood disorders”, “suicide treatment”, “suicide prevention”, “suicide endophenotypes “,“neurocognitive model”, “suicide biomarkers”, “lithium treatment”, “lithium targets”, “anti-suicidal effects”, “GSK3β”, “treatment response”, “lithium response”, “treatment outcomes”. Bibliographies of identified
M
articles were further scrutinized for papers and book chapters of relevance, that is, those with
ED
partial key words, in addition to drawing on literature known to the authors. These were deemed to be relevant if they addressed any of the keywords.
PT
A Neurocognitive Model of Suicide in the Context of Mood Disorders
CE
The distinguishing feature of our recently proposed model of suicide (Malhi et al., 2018) is that, while it briefly alludes to the underlying mechanisms implicated in the process of
AC
suicidal thinking, it also draws attention to factors involved in the generation of suicidal thinking or ideation and eventual enactment of suicide. And though it is tailored to bipolar disorders (BD), it can be applied more generally to mood disorders as a whole, in particular major depressive disorder (MDD). This is because, even in BD, suicidal behaviours occur predominantly during depressive and depressive-mixed mood states, as opposed to when 5
ACCEPTED MANUSCRIPT
experiencing symptoms of mania (Schaffer et al., 2015). Depression therefore provides continuity between bipolar and unipolar disorders and allows the model to meaningfully reflect suicidal processes across the spectrum of mood disorders. Specifically, suicide follows from the engagement of negative and maladaptive cognitive appraisal processes that take hold during
CR IP T
depression. Indeed, negative cognitive appraisals have strong associations with depressive symptoms while hyper/mania is characterised by both positive and negative appraisals and positive appraisals, although maladaptive in this context, are however, incompatible with
AN US
suicidal thinking (Kelly et al., 2012), explaining in part the higher prevalence of suicide during depressive episodes.
The factors impacting the appraisal system are myriad and include the consequences of
M
perturbations in neurobiological systems and neurocognitive processes, all of which occur in the context of mood disorders and inter-current interpersonal difficulties. Therefore, targeting
ED
related biomarkers, neuropsychological vulnerabilities, and endophenotypes may provide a
PT
means of modulating appraisal processes so as to prevent the emergence of suicidal ideation. Traditionally, once suicidal ideation manifests, the focus of clinical management shifts to the
CE
prevention of engagement in suicidal acts (i.e. acting on suicidal thoughts). However, the Neurocognitive Model of Suicide (see Figure 1; Malhi et al., 2018) outlines the factors that
AC
escalate progression of suicidal thinking from ideation to attempt through intent, which also involves planning and in particular, the development and implementation of a suicide strategy. This then provides further opportunities to intervene and halt the process. Briefly, the emergence of suicidal thinking/ideation, if untreated, leads to engagement in suicidal acts, and it is the degree in the intensity of one’s motivation to act on such thinking and the volition to do 6
ACCEPTED MANUSCRIPT
so that explain the differences in suicide related expression between the mood disorders rather than the emergence of suicidal thinking. For instance, lethality risk is significantly higher in BD than MDD (Raja and Azzoni, 2004; Zalsman et al., 2006). The model reveals that prevailing maladaptive cognitions increase motivation and volition to act on suicidal ideation and that, as
CR IP T
the severity and intensity of suicidal ideation and intent increases, the likelihood of suicidal attempts is also increased. But importantly, driving these motivations and volitions are underlying neurobiological and neurocognitive abnormalities, appraisal processes, and
AN US
prevailing maladaptive cognitions that intensify in the context of interpersonal difficulties. The model therefore illustrates how neurobiological and neurocognitive factors can impinge upon, and ultimately drive a dysregulated stress response, and in so doing impair the appraisal system, which is fundamental to the inception of suicidal thinking. It therefore facilitates and
M
encourages the identification of neurobiological and neurocognitive markers of suicide that
ED
may serve as targets of psychopharmacological treatments, while at the same time drawing attention to prevailing cognitions and interpersonal difficulties that can be targeted by
PT
psychosocial interventions.
CE
This paper builds on this model by exploring the deep underlying processes that commence with changes at the cellular level culminating in suicidal thinking. To aid this
AC
exploration, a zoom lens approach is used that considers a common element, namely lithium, which is known to operate at multiple levels and reliably link changes across different domains as having sufficient stepping stones to bridge the gap between the clinical phenomenology of suicidal thinking or ideation and its cellular substrates. In this approach, we briefly examine
7
ACCEPTED MANUSCRIPT
biomarkers, endophenotypes, and neuropsychological vulnerabilities, which in unison create a useful framework for understanding suicide in mood disorders. [Insert Figure 1 here]
CR IP T
Biomarkers
Investigation and identification of biomarkers is a useful strategy to employ in gaining understanding of underlying processes or changes involved in suicide. Biomarkers is a term that
AN US
refers to objectively measured and evaluated characteristics that give indication to normal and pathological processes as well as therapeutic responses (Atkinson Jr et al., 2001; Quevedo and Yatham, 2018), and in psychopathology, biomarkers are state-dependent, that is, they are present during the illness and subside with treatment response(Ref). However, in suicide, some
M
of these biomarkers may be considered as candidate or potential endophenotypes in their own
PT
(see Section below).
ED
right while others may have strong associations with well-established suicide endophenotypes
Research linking biomarkers to suicide is limited and fragmented. A number of
CE
candidate biomarkers have been identified, but few have been corroborated sufficiently to be regarded as either specific or robust. Over the years, investigators have examined the
AC
neuroendocrine stress axis and related systems including inflammatory processes and regulatory neurobiology. For example, dysregulation of the HPA axis has long been known to occur in mood disorders, and, in suicide research, HPA axis dysfunction has been demonstrated in suicide attempters by non-suppression of cortisol during the dexamethasone suppression test (DST) (Courtet et al., 2011b; Mann et al., 2009). Similarly, proinflammatory cytokines, 8
ACCEPTED MANUSCRIPT
known to play a role in mood disorders, may also serve as potential suicide biomarkers because of their involvement in suicidal behaviours (Chang et al., 2017; O'Donovan et al., 2013). In a similar vein, reductions in brain derived neurotrophic factor (BDNF), leading to
CR IP T
compromised neuroplasticity and impaired neurogenesis, have also been linked to suicide (Ambrus et al., 2016; Braquehais et al., 2012; Jokinen et al., 2007; Jokinen and Nordström, 2009). Importantly, and completing the loop to some extent, BDNF, as a major mediator of neuroplasticity, has been found to be under the regulation of both proinflammatory cytokines
AN US
(Calabrese et al., 2014) and the HPA axis (Ambrus et al., 2016; Kunugi et al., 2010). Oxidative stress is also implicated in suicidal behaviours (Vargas et al., 2013).
Other potential biomarkers linked to suicide include circadian rhythm disruption,
M
possibly through the Circadian Locomotor Output Cycles Kaput (CLOCK) gene expression as
ED
seen in suicidal bipolar patients (Bellivier et al., 2015; Pawlak et al., 2015). Accordingly, sleep disruption significantly potentiates suicide risk among bipolar patients with a past history of
PT
suicide attempts (Stange et al., 2016) and ‘next-day’ suicidal ideation in mood disordered patients (Ballard et al., 2016), and is increasingly considered a significant suicide risk factor
CE
(Ballard et al., 2016; Bernert et al., 2015).
AC
Potential biomarkers of significance also include metabolic and receptor alterations in neurotransmission. For instance, the serotonergic system, extending from genes (e.g. serotonin transporter (5HTT), Tryptophan Hydroxylase 1 and 2 (TPH1 and TPH2)) to receptors (e.g. upregulation of whole serotonin 1A receptor (5HT1A )and serotonin 2A receptor (5HT2A) postsynaptic receptors in the PFC) and even its metabolites (e.g. reductions in the cerebrospinal 9
ACCEPTED MANUSCRIPT
fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA)), is implicated in suicidal behaviours (BlascoFontecilla and Oquendo, 2016; Courtet et al., 2011b; Mann et al., 2009; Samuelsson et al., 2006; Turecki, 2016). Additionally, 5HT receptor binding is also implicated in suicide phenotypes (individual characteristics closely associated with suicide, such as hopelessness). For example,
CR IP T
inverse correlations have been found between orbitofrontal cortex (OFC) 5HT1A binding and aggression and between hopelessness and 5HT2A receptor binding. Other important
neurotransmitters implicated in suicide and its endophenotypes include dopamine (DA),
AN US
acetylcholine (Ach), glutamate (Glu) and γ-Aminobutyric acid (GABA). However, a detailed discussion of their involvement is beyond the scope of this paper. Endophenotypes
M
Given the complexity of suicide, one potentially fruitful strategy that could shed light on
ED
its inner mechanisms is to identify accessible endophenotypes. Once characterised, these endophenotypes can serve as building blocks which, in conjunction with evidence from
PT
translational studies, can be used to map pathways and processes that together form a framework that links suicidal behaviours to its substrates - at each level of brain function.
CE
Pursuing this approach may also facilitate the development of suitable animal models that in
AC
turn enable the experimental manipulation of the underlying neurobiology of suicide and its endophenotypes, and perhaps even allow the exploration of treatment effects (Gould et al., 2017).
Although all endophenotypes are biomarkers, not all biomarkers are endophenotypes as they do not fulfil the stringent criteria of an endophenotype, particularly the state 10
ACCEPTED MANUSCRIPT
independence criteria (Beauchaine, 2009; Beauchaine and Constantino, 2017; Lenzenweger, 2013). As such, endophenotypes are 1) characteristics associated with an illness or risk of illness in the general population, 2) heritable, 3) are primarily state independent, 4) co-segregate with the illness within families, thus linking the trait to gene variants, 5) are present in non-affected
CR IP T
family members more so than in the general population, suggestive of a genetic basis, and 6) can be reliably measured and specific to the disorder or illness of interest (Beauchaine, 2009; Courtet et al., 2011b; Gottesman and Gould, 2003), although it has been recently suggested
AN US
that this specificity may be relaxed to allow for transdiagnostic vulnerabilities and complexities (Beauchaine and Constantino, 2017). Therefore, endophenotypes are enduring genetically influenced traits. Identification and understanding of suicide endophenotypes will help to identify the neurobiological and neurocognitive basis of suicide in mood disorders. Therefore,
M
characterizing endophenotypes that can be systematically measured will allow for testing of
ED
putative mechanisms. This is particularly important for the development of targeted interventions and for objectively evaluating efficacy of new treatments (Blasco-Fontecilla and
PT
Oquendo, 2016; Courtet et al., 2011b; Kovacsics et al., 2009).
CE
At the neurocognitive level, the endophenotypes of suicide in mood disorders that are most promising are aggressive and impulsive personality traits and disadvantageous decision-
AC
making (Courtet et al., 2011b; Hoehne et al., 2015; Kovacsics et al., 2009; Mathews et al., 2013; Richard-Devantoy et al., 2015). Interestingly, the emerging neural substrates of these cognitive processes, as revealed by functional neuroimaging, encompass brain regions strongly implicated in mood disorders, for example the OFC, dorsolateral and ventrolateral cortices (DLPFC and VLPFC), anterior cingulate cortex (ACC) and their subcortical connections (Broche11
ACCEPTED MANUSCRIPT
Perez et al., 2016; Coutlee and Huettel, 2012; Rudebeck et al., 2017). In practice, aggressive and impulsive personality traits and the propensity to make poor decisions may adversely influence the cognitive appraisal of social and environmental factors such that decisions and actions with clearly destructive outcomes – in particular for one’s self – can seem reasonable (Anderson and
CR IP T
Bushman, 2002; Bortolato et al., 2013; Rogers, 2011). Indeed, the General Aggression Model (GAM; Anderson and Bushman, 2002) suggests that impulsive responses are elicited from
immediate appraisals of self, situation and environment that are governed by internal states,
AN US
and are either automatic, or based on rudimentary decision-making processes. As such they do not require extensive thought, and therefore little or no reappraisal is engaged. Aggregation of the consequences of such impulsive and poor decision-making can eventualise in sustained feelings of defeat and entrapment, generating and exacerbating suicidal ideation. Interestingly,
M
twin studies and family studies have shown have shown heritability and genetic transmission of
ED
aggressive and impulsive traits (Anokhin et al., 2015; Mann et al., 2009), that interact with environmental factors – suggesting that expression of aggressive-impulsivity is context
PT
dependent. This means that the heritable genetic predisposition may then be moderated by
CE
environmental factors such as exposure to violent behaviours of any kind, including suicidal attempts and various forms of childhood abuse (Turecki, 2005), to perhaps produce aggressive-
AC
impulsivity schema that influence decision-making (Fontaine and Dodge, 2006), and subsequent adoption of maladaptive appraisal systems and coping strategies. Additionally, through the use of the delay discount task, a measure of both impulsivity and decision-making in a twin study, this genetic transmission endorsed heritability of impulsivity traits and potentially decisionmaking (Anokhin et al., 2015). 12
ACCEPTED MANUSCRIPT
In addition to aggressive-impulsivity and disadvantageous decision-making, other biomarkers with potential for endophenotypic categorisation include autonomic dysregulation with altered skin conductance as demonstrated by electrodermal hypo responsivity (Chistiakov et al., 2012; Courtet et al., 2011b), 5HT dysfunction as shown by low levels of CSF 5-HIAA
CR IP T
(Jimenez-Trevino et al., 2011; Mann et al., 2009), prolactin response to fenfluramine (Chistiakov et al., 2012; Courtet et al., 2011b) and, based on functional and pharmacological neuroimaging, altered serotonergic metabolism in the amygdala and PFC and altered serotonergic modulation
AN US
of the PFC (Courtet et al., 2011a), early onset major depression and cortisol response to
psychosocial stress (Mann et al., 2009) and interestingly, alterations in markers of second messenger function such as GSK-3 (Mann et al., 2009) and lithium response (Chistiakov et al., 2012). However, in this review, to demonstrate the potential of endophenotypes as
M
pharmacological targets, specifically, lithium, we will focus on the two well-established
ED
endophenotypes, namely aggressive impulsivity and impaired decision-making.
PT
Additionally, numerous biomarkers have strong associations with aggressive impulsivity and impaired decision making, strengthening the role of these biomarkers in potentiating suicidal
CE
behaviours (See Figure 4). For instance, proinflammatory cytokines and oxidative stress are
AC
associated with aggressive impulsivity (See Figure 4; Beurel and Jope, 2014; Gill et al., 2010), while circadian clocks are implicated in the regulation of aggression (Hood and Amir, 2018) and decision-making (Ingram et al., 2016). Specifically, the Hood & Amir (2018) review discusses evidence from human and non-human species, and what we can extrapolate from this review is that circadian clock genes alter neurotransmitter metabolism in emotion evoking brain
13
ACCEPTED MANUSCRIPT
networks e.g. amygdala and this activation or disinhibition increases the risk of impulsivity, and expression of aggressive behaviours. Additionally, with regards to human decision-making, an experimental paradigm of ethical and risky decision-making revealed that RNA-based chronotypes are significantly pronounced than questionnaire based chronotypes, and this
or phase of oscillating clock genes (Ingram et al., 2016).
CR IP T
suggests that individual decision-making may be influenced by the timing of the circadian drive
Serotonergic dysfunction as evidenced by a reduced prolactin response to fenfluramine
AN US
(a 5HT agonist) is also associated with aggressive impulsivity and impaired decision-making in suicidal patients (Courtet et al., 2011b; Mann, 2013; Mann et al., 2001). Indeed, the neurobiological basis of aggressive impulsivity implicating the various neurotransmitters has
M
been subject to an extensive review which highlights the fact that they can serve as potential targets for psychopharmacological treatments (Comai et al., 2012). Potentially, any intervention
ED
that produces changes in these two endophenotypes may do so via direct and/or indirect but
PT
variable effects on these biomarkers.
CE
Interestingly, a mechanistic pathway from stress, via inflammation and oxidative stress to aggressive impulsivity and ultimately suicidal behaviours, is thought to involve the pivotal
AC
protein, glycogen synthase kinase 3 beta (GSK3β; see later) through which lithium exerts effects (Beurel and Jope, 2014; Coccaro et al., 2016; Luca et al., 2016). Linking biomarkers and endophenotypes to suicide via lithium therapy To clarify the series of events that commence at the cellular level and build successively to create suicidal thinking or ideation, a common element is needed – one which is known to 14
ACCEPTED MANUSCRIPT
operate at each level and thereby reliably links observed changes across different domains. Lithium is one such candidate, although other compounds (see (Tondo and Baldessarini, 2016) for a review) and ketamine (Price et al., 2014) may also be considered in this context, although their scope of operation needs further determination. Clinically, lithium is known to be anti-
CR IP T
suicidal, and many of its cellular and intracellular actions are also well known. In addition, its effects on neurocognition, neural networks, and neurotransmission are measurable and are increasingly being investigated and understood (Malhi and Outhred, 2016). Thus, by tracing the
AN US
effects of lithium and using its properties as a lens to focus on various levels, a mechanistic framework can be developed that may provide a deeper understanding of suicide processes
M
and also point to potential targets for therapeutic and preventative interventions.
ED
[Insert Figure 2 here]
PT
Lithium therapy
CE
Developmental Perspective: Although lithium is considered the ‘gold standard’ for the treatment of bipolar disorders in adults, it has also been approved by the Food and Drug
AC
Administration (FDA) for the treatment of paediatric bipolar disorders in children and adolescents aged 12 years and above (Grant and Salpekar, 2018; Stepanova and Findling, 2017). However, in an open-label long-term treatment it was shown to be effective in the treatment of multiple phases of the illness in children and adolescents (from ages of 7 to 17 years old) although this effect is dependent on initial treatment response, that is, only those who initially 15
ACCEPTED MANUSCRIPT
responded well continued to do so during continuation treatment (Findling et al., 2013). As with adults, the dosing schedule requires titration depending on point of entry weight (< 30 kgs >) but electrocardiogram(ECG) monitoring does not seem to be a specific recommendation for its use by the American Academy of Child and Adolescent Psychiatry (AACAP) in this population
CR IP T
group (Grant and Salpekar, 2018). With newer dosing paradigms, it is also well tolerated and safe to prescribe and administer (Findling et al., 2011; Findling et al., 2015), but, similar to
adults, therapeutic drug monitoring is still necessary (Landersdorfer et al., 2017). Potential side
AN US
effects include dermatologic, endocrine, gastro-intestinal, haematological, neurological and renal complications but these may be mitigated by the adoption of countering strategies, e.g. reducing salt and caffeine intake, increasing or maintaining adequate hydration, ingestion of lithium with food. For those experiencing extrapyramidal symptoms or metabolic effects from
M
second generation antipsychotics, lithium may be preferred. Despite the promising evidence for
PT
(Duffy and Grof, 2018).
ED
lithium therapy in children and adolescents, the full range of benefits remains little understood
Suicidal thinking and behaviours: Lithium is primarily known as a mood stabilising agent
CE
and is used mainly in the management of BD. However, it is increasingly apparent that, in addition to its profound mood stabilising effects, lithium has distinct independent anti-suicidal
AC
properties (Ahrens and Müller-Oerlinghausen, 2001; Ernst and Goldberg, 2004; Khan et al., 2011; Lewitzka et al., 2015b; Smith and Cipriani, 2017), that appear to be specific to lithium, as compared to other medications (Bellivier and Guillaume, 2016). In support of this view, a most recent meta-analytic review reveals increasing evidence of long-term lithium treatment antisuicidal effects in patients with both BD and major depressive disorder (MDD), particularly 16
ACCEPTED MANUSCRIPT
during depressive phase of BD (Tondo and Baldessarini, 2018). Generally, most other treatments (e.g. interpersonal therapy (IPT) and antidepressants) reduce suicidal behaviours by ameliorating depressive symptoms (Weitz et al., 2014; Zisook et al., 2011), suggesting that improvements in mood are a pre-requisite for these treatments to have any impact on suicidal
CR IP T
thinking and behaviours. In contrast, lithium appears to achieve the same without necessarily improving mood (Jones et al., 2017), and possibly does so because it exerts effects on multiple levels. Notably, this anti-suicidal effect is also superior to that effected by other treatments,
AN US
such as valproic acid and antidepressants (Toffol et al., 2015).
This evidence is primarily based on adult investigations as no such evidence exists in children and adolescents due to paucity of such investigations (see review(Cipriani et al.,
M
2013).Indeed, although there is evidence of lithium effects on aggressive behaviour in children
ED
and adolescents with explosive aggression and conduct disorders (Masi et al., 2009). Lithium is thought to be most beneficial in preventing suicidal behaviours in the long-
PT
term, (Baldessarini et al., 2006; Tondo and Baldessarini, 2016, 2018). Its acute efficacy in this regard is largely unknown, but this will be illuminated when findings are reported from at least
CE
one randomized, placebo controlled multicentre trial of lithium and treatment as usual (TAU)
AC
assessing potential acute effects on suicidal ideation and behaviour in mood disordered patients during depressive episodes that is currently underway (Lewitzka et al., 2015a). Promising preliminary evidence from an exploratory proof of concept randomized double-blind parallel group study seems to suggest that therapeutic levels can be achieved within 4 weeks of treatment, and this short-term lithium treatment is beneficial in reducing suicidal behaviours.
17
ACCEPTED MANUSCRIPT
Neurocognition: The direct and indirect impact of lithium and its mechanisms of action on suicide endophenotypes in humans is yet to be thoroughly investigated, but there is already emerging evidence from animal studies of its effects on some endophenotypes such as aggressive impulsivity. For example, animal evidence reveals that lithium specifically reduces
CR IP T
impulsivity in mice, as measured by the delay discounting task (a test of decision making, where the steep rate of discounting measures impulsive decisions; see Homberg, 2012) whereas valproate has no effect (Halcomb et al., 2013) and likewise, in rats, where lithium but not
AN US
valproic acid or carbamazepine reduced premature responses in a three-choice serial reaction time task (3-CSRTT), that were independent of its motivation for food effects (Ohmura et al., 2012).
M
Also, anti-aggressive effects of lithium in humans have been historically reported since John Cade’s 1949 publication and subsequent open-label studies of psychiatric patients and
ED
single- and double-blind studies of prison inmates (Jones et al., 2011; Muller-Oerlinghausen and
PT
Lewitzka, 2010; Sheard, 1971; Sheard et al., 1976) but no recent investigations have been published in adults, although there is evidence of lithium effects on aggressive behaviour in
CE
children and adolescents with explosive aggression and conduct disorders (Masi et al., 2009). No such studies have been conducted in mood disordered patients with suicidal behaviours.
AC
Indeed, although there is evidence of lithium effects on aggressive behaviour in children and adolescents with explosive aggression and conduct disorders (Masi et al., 2009),. However, based on the evidence of anti-aggressive effects, there is potential for lithium to also reduce suicide risk in this population, perhaps via its effects on the endophenotype of aggression.
18
ACCEPTED MANUSCRIPT
To date, and to our knowledge, only one study has investigated the effects of lithium specifically on decision-making in humans, and none in animal models. In this study, the Iowa Gambling Task (IGT) was used, and revealed a possible normalisation effect of lithium on decision-making, such that those taking lithium selected safer (less risky) options (Adida et al.,
CR IP T
2015). Given the paucity of evidence of the direct or indirect effects of lithium on
endophenotypes thus far, an alternative approach that may prove useful is to examine the effects of lithium on neurobiological markers linked to identified suicide endophenotypes (See
AN US
Figure 2). Lithium effects on decision-making have not been investigated in this population, but lithium seemingly interacts with psychotic symptoms to produce a less favourable outcome in executive control (Lera-Miguel et al., 2015). As suicidal thinking often presents during depressive and mixed states rather than a psychotic presentation, this may not be a significant
M
issue.
ED
Neurocircuitry: Brain regions where lithium exerts its effects, and which are also the
PT
most robustly implicated in suicide, are the PFC, hippocampus and ACC. For instance, lithium has been shown to reverse grey matter volume changes in brain regions typically characterized
CE
by reductions in suicidal bipolar patients e.g. OFC, DLPFC, anterior cingulate cortex (ACC) and superior temporal cortex (STC) (Benedetti et al., 2011; Malhi et al., 2013; Toffol et al., 2015). In
AC
some instances, this ‘recovery’ occurs to the extent that volumes are greater than in health (Hallahan et al., 2011). This evidence stems from multiple sources, including animal studies, post mortem (both animal and human) and in vivo techniques and may be a specific effect of lithium. For instance, lithium treated rodents attain selective increases in cortical whole brain (WBV) and grey matter (GMV) volumes, with no effects on striatal regions, whereas haloperidol 19
ACCEPTED MANUSCRIPT
decreases these volumes (Vernon et al., 2012). Importantly, these lithium induced increases appear to be sustained, as demonstrated by post mortem animal evidence (Vernon et al., 2012). Increases in cortical GMV and white matter (WM) tract integrity have also been observed in lithium treated bipolar patients compared to lithium-free patients (Benedetti et al.,
CR IP T
2013; Benedetti et al., 2015; Benedetti et al., 2011), and, even in healthy individuals, lithium produces increases in ACC and PFC GMV (Monkul et al., 2007). Such effects have also been noted in bipolar patients with psychotic depression, involving in particular, the hippocampus
AN US
(Giakoumatos et al., 2015). This is noteworthy because, in rodents, lithium has been shown to increase cell numbers in the hippocampus (Rajkowska et al., 2016), as well as increase PFC and hippocampal oscillatory activity (Nguyen et al., 2017). These increases in structure and activity perhaps reflect lithium’s role in cell proliferation and regeneration as well as axonal repair –
M
thus restoring structural connectivity. Such changes possibly underpin suicide-related
ED
neurocognitive dysfunction and its modification by lithium therapy.
PT
Neurobiology: Despite the clinical complexity of lithium therapy, its effects at the neurobiological level are clear and demonstrable. The variety of neurobiological processes
CE
associated with the clinical effects of lithium can be broadly conceptualised as intracellular (neuroprotection via neurotrophic factors & anti-apoptosis via anti-inflammatory and anti-
AC
oxidative properties and circadian CLOCK gene expression) and extracellular mechanisms (neurotransmission and hypothalamic-pituitary-adrenal (HPA) axis activity) (Figure 3)(Benedetti et al., 2007; Geoffroy and Etain, 2017; Malhi and Outhred, 2016; Malhi et al., 2017). Intriguingly, although at a clinical level lithium has seeming specificity, at cellular and molecular levels, it engages with a multitude of targets and appears non-specific in its actions. However, it 20
ACCEPTED MANUSCRIPT
is this broad range of actions that is perhaps key to its ability to stabilise complex systems and achieve both its effects on mood and separately on suicide. For instance, it may be because of its simultaneous actions on multiple targets that lithium is able to establish homeostasis by preventing and circumventing actions of other compensatory systems, which would normally
specificity is best exemplified by its actions on GSK3β.
CR IP T
limit and/or reverse the effects of any agent. This multi-pronged diversity of action with clinical
GSK3β: In the adult brain, GSK3β is a widely distributed serine/threonine protein kinase
AN US
that is concentrated in particular in the PFC (Pandey et al., 2009) - a brain region strongly implicated directly and as part of various neurocircuits in suicide-related neurocognition, especially disadvantageous decision-making.
M
It is through its direct and indirect inhibition of the GSK3β pathway that lithium effects
ED
changes in inflammation, circadian rhythm CLOCK gene expression, monoaminergic neurotransmission, oxidative stress, neuroplasticity, physiological stress response and
PT
neurocognition (Geoffroy and Etain, 2017; Malhi and Outhred, 2016) (See Figure 3 and a summary schematic in Figure 4). The indirect pathways include the inositol monophosphate 1-
CE
phosphatase (ImPase1), myoInositol (mI), myristoylated alanine-rich c kinase substrate
AC
(MARCKS) and cyclic adenosine monophosphate (cAMP) pathways, but it is beyond the scope of this review to give a detailed examination of these. However, regardless of pathway, lithium, via its effects on GSK3β ultimately exerts effects on the neurobiological targets as above. And via GSK3β induced changes, lithium is ultimately able to alter suicidal thinking and behaviours.
21
ACCEPTED MANUSCRIPT
However, to better understand how lithium achieves this, it is important to examine the links between GSK3β, lithium, and suicide-related biomarkers and neurocognition. [Insert Figure 3 here]
CR IP T
Cellular Mechanisms: As discussed earlier, GSK3β has many functions that are mediated via multiple signalling pathways. Its functions involve neurotransmission, neuroplasticity,
neuronal growth and metabolism (Can et al., 2014) (See Figure 3 & 5). (Rowe et al., 2007). At
AN US
the extracellular level, there are bidirectional effects between GSK3β and HPA axis activity as well as neurotransmission (see Figure 3) (See (Malhi and Outhred, 2016) for detailed discussion of this bi-directionality. Psychological stress, which is important in suicidal thinking and behaviours, especially in the context of mood disorders, induces GSK3β activation via HPA
M
dysregulation, and this subsequently increases proinflammatory cytokines e.g. interleukin-6 (IL-
ED
6) and tumour necrosis factor-alpha (TNF-α). Of note, both of these have been shown to be associated with the aforementioned suicide-related aggressive impulsivity endophenotype
PT
(Bellivier and Guillaume, 2016). Evidence from animal studies suggests that GSK3β plays a key role in the control of oxidative stress resistance in hippocampal neuronal cells, the region of the
CE
brain most pivotal to memory processes, especially in mood disorders (Schafer et al., 2004), and
AC
that GSK3β activation specifically impairs learning and inhibits hippocampal-dependent long term potentiation (LTP) (Jope et al., 2017). Furthermore, GSK3β activation is itself modulated by BDNF, indicating that it is involved in the regulation of synaptic strength and plasticity, and that it achieves these changes either independently or through the tyrosine receptor kinase B (TrkB) pathway (Can et al., 2014; Gupta et al., 2014).
22
ACCEPTED MANUSCRIPT
Finally, activated GSK3β is also involved in the regulation of circadian rhythms (Bellivier et al., 2015), which have been strongly implicated in suicide and mood disorders through associative circadian rhythm CLOCK genes (Pawlak et al., 2015). Indeed, a mouse model of circadian rhythmicity has revealed that rhythms in the suprachiasmatic nucleus (SCN) of the
CR IP T
hypothalamus, hippocampal CLOCK genes and synaptic plasticity are directly regulated by
GSK3β (Besing et al., 2015; Besing et al., 2017). In humans, evidence of GSK3β regulation of circadian rhythms in suicide is sparse, but in mood disorders it has been found that BD lithium
AN US
treatment non-responders significantly increased expression of GSK3β while decreasing
expression of circadian clock genes in (Geoffroy et al., 2017), suggestive of an dysregulated association between GSK3β activity and circadian clock genes, an effect that was not seen in
M
treatment responders.
In sum, the actions of GSK3β, which are modulated directly by lithium, ultimately impact
ED
a number of key systems – all linked or strongly associated with suicidal thinking and
PT
behaviours and mood disorders.
Neurotransmission: Alterations in monoaminergic systems, involving serotonin in
CE
particular, have long been implicated in suicidal behaviours. For example, reductions in the
AC
concentration of serotonin metabolites such as 5-Hydroxyindoleacetic acid (5-HIAA), reflecting reduced serotonergic activity, have been thought of as potential biomarkers of suicide in psychiatric patients (Chatzittofis et al., 2013; Mann and Currier, 2007). Similarly diminished midbrain serotonin transporter binding in depressed suicide attempters (Miller et al., 2013) is also thought to reflect serotonergic neurotransmission compromise.
23
ACCEPTED MANUSCRIPT
Further bolstering the role of 5HT in suicide, links have been drawn between serotoninrelated genes and cognitive suicide endophenotypes. For example, the genes of tryptophan hydroxylase 1 (TPH1), a rate-limiting enzyme of serotonergic synthesis, and the 5hydroxytryptamine receptor 2A (HTR2A) have been associated with aggressive impulsivity
CR IP T
(Antypa et al., 2013; Bortolato et al., 2013). Similarly, the suicide endophenotype of
disadvantageous decision-making has been shown to be modulated by polymorphisms in
serotonergic genes, the serotonin transporter gene, SLC6A4, TPH1, MAOA and TPH2 (Jollant et
AN US
al., 2007). Thus, it would appear that the neural substrates of aggressive impulsivity and
disadvantageous decision-making involve changes in serotonergic neurotransmission at several levels.
M
Interestingly, GSK3β appears to be heavily involved in serotonergic neurotransmission. For example, animal evidence indicates that phosphorylation of GSK3β in the mouse brain is
ED
regulated by serotonergic activity, with 5-hydroxytryptamine receptor 1A (HTR1A) mediating
PT
increases while 5-hydroxytryptamine 2 (5HT2) receptors mediate decreases (Li et al., 2004). Furthermore, in Tryptophan hydroxylase 2 (TPH2) Knockin mice it was shown that the TPH gene
CE
produced serotonin (5-HT) synthesis deficiency that lead to activation in cortical GSK3 and associated behavioural abnormalities in a test that models endophenotypes of mood regulation
AC
(Beaulieu et al., 2008). The TPH2 gene induced GSK3β activation is further evidence of 5-HT involvement in GSK3β activity albeit in mood regulation. Therefore, serotonin is potentially an important target for the activity of GSK3β in the context of suicide.
24
ACCEPTED MANUSCRIPT
In sum, the intricate link between GSK3β activity and identified biomarkers implicated in suicide (see Figure 3) that are also associated with suicide endophenotypes, gives sufficient impetus to target and inhibit GSK3β in order to reduce suicide risk. The fact that lithium is an
CR IP T
effective inhibitor of GSK3β is therefore of considerable clinical significance. Limitations
There are methodological barriers that arose as a result of the complexity of both
AN US
suicide and lithium mechanisms of action. The expansive results returned by the search terms used precluded an extensive review of all relevant aspects of lithium’s anti-suicidal actions. Additionally, the present discussion was limited to suicide in the context of mood disorders, given the focus on lithium’s actions within the framework of the Neurocognitive Model of
M
Suicide that concentrates on suicidal thinking and behaviours within mood disorders.
ED
Furthermore, epigenetic mechanisms and potential role for lithium to reverse these epigenetic changes could not be addressed in this review.
PT
[Insert Figure 4 here]
CE
Conclusions and Future directions
AC
Suicide is a process. Tracking precisely where and when pharmacological interventions effect changes in that process is of clinical significance. But to achieve this, future research needs to adopt a longitudinal and prospective design so as to tap into the antecedents of suicide. This paper provides a novel perspective on the evaluation of suicide intervention strategies, by which treatments other than lithium may be considered. Figure 4 illustrates in
25
ACCEPTED MANUSCRIPT
summary form the mechanisms by which lithium perhaps effects its protective actions against suicidal thinking and behaviours. It provides an exemplar of the multi-level approach that can be used in the development of pharmacological agents for suicide prevention. An examination of the mechanisms of suicide – viewed through the lens of lithium’s actions - provides an
CR IP T
important neurobiological perspective that adds depth to the Neurocognitive Model of Suicide. This then provides a framework for enriching our understanding of suicide and improving
clinical practice, and within which targeted interventions can be developed. By combining
AN US
probes from different domains, for example blood and saliva biomarkers, brain neuroimaging techniques, parameters of neurocognitive function, and actigraphy monitoring, with the current approach of subjective self-reports, the responsiveness of individuals with suicidal thinking to therapeutic interventions such as lithium can be tracked and dissected in detail (see
[Insert Table 1 here]
ED
M
Table 1).
PT
Importantly, this broad set of assessments may be applicable in suicide assessment more generally – such that objective measurements of suicide can be made, and reliance on
CE
subjective self-reports can be minimised. It is therefore of great benefit to conduct further
AC
research in this area so as to identify and validate robust measures for use in clinical practice. Measuring changes at each of these levels of suicidal thinking and in each of these systems should provide a more comprehensive and meaningful picture of the neural brain of suicide insights which in themselves are likely to provide new opportunities for intervention and prevention.
26
ACCEPTED MANUSCRIPT
Role of funding source: The research conducted is supported by Australian Rotary Health Fund, NHMRC Program Grants (APP1073041; APP1050848 and APP1121510), the Ramsay Health Research and Teaching Fund, NSW Agency for Clinical Innovation and NSW Ministry of Health, Lundbeck and grants
CR IP T
(PRG-0-090-14; SRG-0-089-16) awarded to GSM from the American Foundation for Suicide Prevention. The content is solely the responsibility of the authors and does not necessarily represent the official views of the American Foundation for Suicide Prevention nor any of the sponsors.
AN US
Acknowledgements: GM conceived the idea, approach and structure of review and in consensus with ZM, PD and TO as to the best approach to take. GM subsequently conducted multiple edits keeping an overview of the scope of the review within the commissioned parameters. ZM performed primary literature searches with secondary searches conducted by LI and KL. ZM also synthesised evidence to
M
produce the initial drafts, and GM, LI, PD and KL edited multiple drafts as often as necessary. The final
ED
drafts were produced with all named authors having viewed the manuscript and making
CE
PT
recommendations to improve the quality and coherence of the paper.
References
AC
Adida, M., Jollant, F., Clark, L., Guillaume, S., Goodwin, G.M., Azorin, J.M., Courtet, P., 2015. Lithium might be associated with better decision-making performance in euthymic bipolar patients. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 25, 788797. Ahrens, B., Müller-Oerlinghausen, B., 2001. Does lithium exert an independent antisuicidal effect? Pharmacopsychiatry, 34 132-136. Ambrus, L., Lindqvist, D., Träskman-Bendz, L., Westrin, Å., 2016. Hypothalamic–pituitary–adrenal axis hyperactivity is associated with decreased brain-derived neurotrophic factor in female suicide attempters Nord J Psychiatry 70 575-581.
27
ACCEPTED MANUSCRIPT
Anderson, C.A., Bushman, B.J., 2002. Human aggression. Annual review of psychology 53, 27-51. Anokhin, A.P., Grant, J.D., Mulligan, R.C., Heath, A.C., 2015. The genetics of impulsivity: evidence for the heritability of delay discounting. Biol Psychiatry 77, 887-894. Antypa, N., Serretti, A., Rujescu, D., 2013. Serotonergic genes and suicide: a systematic review. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 23, 1125-1142.
CR IP T
Arsenault-Lapierre, G., Kim, C., Turecki, G., 2004. Psychiatric diagnoses in 3275 suicides: a meta-analysis. BMC psychiatry 4, 37. Atkinson Jr, A.J., Colburn, W.A., DeGruttola, V.G., DeMets, D.L., Downing, G.J., &, Spilker, B.A., 2001. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clinical pharmacology and therapeutics 69, 89-95. Baldessarini, R.J., Tondo, L., Davis, P., Pompili, M., Goodwin, F.K., Hennen, J., 2006. Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord 8, 625639.
AN US
Ballard, E.D., Vande Voort, J.L., Bernert, R.A., Luckenbaugh, D.A., Richards, E.M., Niciu, M.J., Furey, M.L., Duncan, W.C., Jr., Zarate, C.A., Jr., 2016. Nocturnal Wakefulness Is Associated With Next-Day Suicidal Ideation in Major Depressive Disorder and Bipolar Disorder. J Clin Psychiatry 77, 825-831. Beauchaine, T.P., 2009. The Role of Biomarkers and Endophenotypes in Prevention and Treatment of Psychopathological Disorders. Biomarkers in medicine 3, 1-3.
M
Beauchaine, T.P., Constantino, J.N., 2017. Redefining the endophenotype concept to accommodate transdiagnostic vulnerabilities and etiological complexity. Biomarkers in medicine.
ED
Beaulieu, J.M., Zhang, X., Rodriguiz, R.M., Sotnikova, T.D., Cools, M.J., Wetsel, W.C., Gainetdinov, R.R., Caron, M.G., 2008. Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proceedings of the National Academy of Sciences of the United States of America 105, 1333-1338. Bellivier, F., Geoffroy, P.A., Etain, B., Scott, J., 2015. Sleep- and circadian rhythm-associated pathways as therapeutic targets in bipolar disorder. Expert opinion on therapeutic targets 19, 747-763.
PT
Bellivier, F., Guillaume, S., 2016. Lithium: The Key Antisuicide Agent In: Courtet, P. (Ed.), Understanding Suicide. Springer, Cham, Switzerland, pp. 303-311.
CE
Benedetti, F., Bollettini, I., Barberi, I., Radaelli, D., Poletti, S., Locatelli, C., Pirovano, A., Lorenzi, C., Falini, A., Colombo, C., Smeraldi, E., 2013. Lithium and GSK3-beta promoter gene variants influence white matter microstructure in bipolar disorder. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 38, 313-327.
AC
Benedetti, F., Dallaspezia, S., Fulgosi, M.C., Lorenzi, C., Serretti, A., Barbini, B., Colombo, C., Smeraldi, E., 2007. Actimetric evidence that CLOCK 3111 T/C SNP influences sleep and activity patterns in patients affected by bipolar depression. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 144b, 631-635. Benedetti, F., Poletti, S., Radaelli, D., Locatelli, C., Pirovano, A., Lorenzi, C., Vai, B., Bollettini, I., Falini, A., Smeraldi, E., Colombo, C., 2015. Lithium and GSK-3beta promoter gene variants influence cortical gray matter volumes in bipolar disorder. Psychopharmacology (Berl) 232, 1325-1336.
28
ACCEPTED MANUSCRIPT
Benedetti, F., Radaelli, D., Poletti, S., Locatelli, C., Falini, A., Colombo, C., Smeraldi, E., 2011. Opposite effects of suicidality and lithium on gray matter volumes in bipolar depression J. Affect. Disord 135, 139147. Bernert, R.A., Kim, J.S., Iwata, N.G., Perlis, M.L., 2015. Sleep disturbances as an evidence-based suicide risk factor. Curr Psychiatry Rep 17, 554.
CR IP T
Besing, R.C., Paul, J.R., Hablitz, L.M., Rogers, C.O., Johnson, R.L., Young, M.E., Gamble, K.L., 2015. Circadian rhythmicity of active GSK3 isoforms modulates molecular clock gene rhythms in the suprachiasmatic nucleus. Journal of biological rhythms 30, 155-160. Besing, R.C., Rogers, C.O., Paul, J.R., Hablitz, L.M., Johnson, R.L., McMahon, L.L., Gamble, K.L., 2017. GSK3 activity regulates rhythms in hippocampal clock gene expression and synaptic plasticity. Hippocampus 27, 890-898. Beurel, E., Jope, R.S., 2014. Inflammation and lithium: clues to mechanisms contributing to suicidelinked traits. Transl Psychiatry 4, e488.
AN US
Blasco-Fontecilla, H., Oquendo, M.A., 2016. Biomarkers of Suicide: Predicting the Predictable?, In: Courtet, P. (Ed.), Understanding Suicide. Springer, pp. 77-83.
Bortolato, M., Pivac, N., Muck Seler, D., Nikolac Perkovic, M., Pessia, M., Di Giovanni, G., 2013. The role of the serotonergic system at the interface of aggression and suicide. Neuroscience 236, 160-185. Braquehais, M.D., Picouto, M.D., Casas, M., Sher, L., 2012. Hypothalamic-pituitary-adrenal axis dysfunction as a neurobiological correlate of emotion dysregulation in adolescent suicide World Journal of Pediatrics 8 197-206.
M
Broche-Perez, Y., Herrera Jimenez, L.F., Omar-Martinez, E., 2016. Neural substrates of decision-making. Neurologia (Barcelona, Spain) 31, 319-325.
ED
Calabrese, F., Rossetti, A.C., Racagni, G., Gass, P., Riva, M.A., Molteni, R., 2014. Brain-derived neurotrophic factor: a bridge between inflammation and neuroplasticity. Frontiers in cellular neuroscience 8, 430.
PT
Can, A., Schulze, T.G., Gould, T.D., 2014. Molecular actions and clinical pharmacogenetics of lithium therapy. Pharmacology, biochemistry, and behavior 123, 3-16.
CE
Chang, C.C., Tzeng, N.S., Kao, Y.C., Yeh, C.B., Chang, H.A., 2017. The relationships of current suicidal ideation with inflammatory markers and heart rate variability in unmedicated patients with major depressive disorder. Psychiatry Res 258, 449-456.
AC
Chatzittofis, A., Nordstrom, P., Hellstrom, C., Arver, S., Asberg, M., Jokinen, J., 2013. CSF 5-HIAA, cortisol and DHEAS levels in suicide attempters. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 23, 1280-1287. Chistiakov, D.A., Kekelidze, Z.I., Chekhonin, V.P., 2012. Endophenotypes as a measure of suicidality. Journal of applied genetics 53, 389-413. Cipriani, A., Hawton, K., Stockton, S., Geddes, J.R., 2013. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. . British Medical Journal 346, , f3646. Coccaro, E.F., Lee, R., Gozal, D., 2016. Elevated Plasma Oxidative Stress Markers in Individuals With Intermittent Explosive Disorder and Correlation With Aggression in Humans. Biol Psychiatry 79, 127-135.
29
ACCEPTED MANUSCRIPT
Comai, S., Tau, M., Gobbi, G., 2012. The psychopharmacology of aggressive behavior: a translational approach: part 1: neurobiology. Journal of clinical psychopharmacology 32, 83-94. Courtet, P., Gottesman, II, Jollant, F., Gould, T.D., 2011a. The neuroscience of suicidal behaviors: what can we expect from endophenotype strategies? Transl Psychiatry 1. Courtet, P., Gottesman, I.I., Jollant, F., Gould, T.D., 2011b. The neuroscience of suicidal behaviors: what can we expect from endophenotype strategies? . Translational Psychiatry 1, e7.
CR IP T
Coutlee, C.G., Huettel, S.A., 2012. The functional neuroanatomy of decision making: prefrontal control of thought and action. Brain research 1428, 3-12. Duffy, A., Grof, P., 2018. Lithium Treatment in Children and Adolescents. Pharmacopsychiatry.
Ernst, C.L., Goldberg, J.F., 2004. Antisuicide properties of psychotropic drugs: a critical review. Harvard review of psychiatry 12, 14-41.
AN US
Findling, R.L., Kafantaris, V., Pavuluri, M., McNamara, N.K., Frazier, J.A., Sikich, L., Kowatch, R., Rowles, B.M., Clemons, T.E., Taylor-Zapata, P., 2013. Post-acute effectiveness of lithium in pediatric bipolar I disorder. Journal of child and adolescent psychopharmacology 23, 80-90. Findling, R.L., Kafantaris, V., Pavuluri, M., McNamara, N.K., McClellan, J., Frazier, J.A., Sikich, L., Kowatch, R., Lingler, J., Faber, J., Rowles, B.M., Clemons, T.E., Taylor-Zapata, P., 2011. Dosing strategies for lithium monotherapy in children and adolescents with bipolar I disorder. Journal of child and adolescent psychopharmacology 21, 195-205.
M
Findling, R.L., Robb, A., McNamara, N.K., Pavuluri, M.N., Kafantaris, V., Scheffer, R., Frazier, J.A., Rynn, M., DelBello, M., Kowatch, R.A., Rowles, B.M., Lingler, J., Martz, K., Anand, R., Clemons, T.E., TaylorZapata, P., 2015. Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, PlaceboControlled Study. Pediatrics 136, 885-894.
ED
Fontaine, R.G., Dodge, K.A., 2006. Real-Time Decision Making and Aggressive Behavior in Youth: A Heuristic Model of Response Evaluation and Decision (RED). Aggressive behavior 32, 604-624.
PT
Geoffroy, P.A., Curis, E., Courtin, C., Moreira, J., Morvillers, T., Etain, B., Laplanche, J.L., Bellivier, F., Marie-Claire, C., 2017. Lithium response in bipolar disorders and core clock genes expression. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry, 1-14. Geoffroy, P.A., Etain, B., 2017. Lithium and Circadian Rhythms. Springer, Switzerland.
CE
Giakoumatos, C.I., Nanda, P., Mathew, I.T., Tandon, N., Shah, J., Bishop, J.R., Clementz, B.A., Pearlson, G.D., Sweeney, J.A., Tamminga, C.A., Keshavan, M.S., 2015. Effects of lithium on cortical thickness and hippocampal subfield volumes in psychotic bipolar disorder. J Psychiatr Res 61, 180-187.
AC
Gill, R., Tsung, A., Billiar, T., 2010. Linking oxidative stress to inflammation: Toll-like receptors. Free radical biology & medicine 48, 1121-1132. Gottesman, I.I., Gould, T.D., 2003. The endophenotype concept in psychiatry: etymology and strategic intentions The American journal of psychiatry 160, 636-645. Gould, T.D., Georgiou, P., Brenner, L.A., Brundin, L., Can, A., Courtet, P., Donaldson, Z.R., Dwivedi, Y., Guillaume, S., Gottesman, II, Kanekar, S., Lowry, C.A., Renshaw, P.F., Rujescu, D., Smith, E.G., Turecki, G., Zanos, P., Zarate, C.A., Jr., Zunszain, P.A., Postolache, T.T., 2017. Animal models to improve our understanding and treatment of suicidal behavior. Transl Psychiatry 7, e1092.
30
ACCEPTED MANUSCRIPT
Grant, B., Salpekar, J.A., 2018. Using Lithium in Children and Adolescents with Bipolar Disorder: Efficacy, Tolerability, and Practical Considerations. Paediatric drugs. Gupta, V., Chitranshi, N., You, Y., Klistorner, A., Graham, S., 2014. Brain derived neurotrophic factor is involved in the regulation of glycogen synthase kinase 3beta (GSK3beta) signalling. Biochemical and biophysical research communications 454, 381-386.
CR IP T
Halcomb, M.E., Gould, T.D., Grahame, N.J., 2013. Lithium, but not valproate, reduces impulsive choice in the delay-discounting task in mice. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 38, 1937-1944. Hallahan, B., Newell, J., Soares, J.C., Brambilla, P., Strakowski, S.M., Fleck, D.E., Kieseppä, T., Altshuler, L.L., Fornito, A., Malhi, G.S., 2011. Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient data. Biol Psychiatry 69, 326-335. Hoehne, A., Richard-Devantoy, S., Ding, Y., Turecki, G., Jollant, F., 2015. First-degree relatives of suicide completers may have impaired decision-making but functional cognitive control. J Psychiatr Res 68, 192197.
AN US
Homberg, J.R., 2012. Serotonin and decision making processes. Neuroscience and biobehavioral reviews 36, 218-236. Hood, S., Amir, S., 2018. Biological Clocks and Rhythms of Anger and Aggression. Frontiers in behavioral neuroscience 12, 4.
M
Ingram, K.K., Ay, A., Kwon, S.B., Woods, K., Escobar, S., Gordon, M., Smith, I.H., Bearden, N., Filipowicz, A., Jain, K., 2016. Molecular insights into chronotype and time-of-day effects on decision-making. Sci Rep 6, 29392. Jimenez-Trevino, L., Blasco-Fontecilla, H., Braquehais, M.D., Ceverino-Dominguez, A., Baca-Garcia, E., 2011. Endophenotypes and suicide behaviour. Actas espanolas de psiquiatria 39, 61-69.
ED
Jokinen, J., Carlborg, A., Mårtensson, B., Forslund, K., Nordström, A.L., Nordström, P., 2007. DST nonsuppression predicts suicide after attempted suicide. Psychiatry Research 150, 297-303.
PT
Jokinen, J., Nordström, P., 2009. HPA axis hyperactivity and attempted suicide in young adult mood disorder inpatients Journal of Affective Disorders 116 117-120.
CE
Jollant, F., Buresi, C., Guillaume, S., Jaussent, I., Bellivier, F., Leboyer, M., Castelnau, D., Malafosse, A., Courtet, P., 2007. The influence of four serotonin-related genes on decision-making in suicide attempters. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 144B, 615-624.
AC
Jones, H., Geddes, J., Cipriani, A., 2017. Lithium and suicide prevention, The Science and Practice of Lithium Therapy. Springer, pp. 223-240. Jones, R.M., Arlidge, J., Gillham, R., Reagu, S., van den Bree, M., Taylor, P.J., 2011. Efficacy of mood stabilisers in the treatment of impulsive or repetitive aggression: systematic review and meta-analysis. The British journal of psychiatry : the journal of mental science 198, 93-98. Jope, R.S., Cheng, Y., Lowell, J.A., Worthen, R.J., Sitbon, Y.H., Beurel, E., 2017. Stressed and Inflamed, Can GSK3 Be Blamed? Trends in biochemical sciences 42, 180-192. Kelly, R.E., Mansell, W., Sadhnani, V., Wood, A.M., 2012. Positive and negative appraisals of the consequences of activated states uniquely relate to symptoms of hypomania and depression. . Cogn Emot 26, 899-906.
31
ACCEPTED MANUSCRIPT
Khan, A., Khan, S.R., Hobus, J., Faucett, J., Mehra, V., Giller, E.L., Rudolph, R.L., 2011. Differential pattern of response in mood symptoms and suicide risk measures in severely ill depressed patients assigned to citalopram with placebo or citalopram combined with lithium: role of lithium levels. J Psychiatr Res 45, 1489-1496. Kovacsics, C.E., Gottesman, I.I., Gould, T.D., 2009. Lithium's antisuicidal efficacy: elucidation of neurobiological targets using endophenotype strategies Annu Rev Pharmacol Toxicol. 49 175-198.
CR IP T
Kunugi, H., Hori, H., Adachi, N., Numakawa, T., 2010. Interface between hypothalamic-pituitary-adrenal axis and brain-derived neurotrophic factor in depression. Psychiatry and clinical neurosciences 64, 447459. Landersdorfer, C.B., Findling, R.L., Frazier, J.A., Kafantaris, V., Kirkpatrick, C.M., 2017. Lithium in Paediatric Patients with Bipolar Disorder: Implications for Selection of Dosage Regimens via Population Pharmacokinetics/Pharmacodynamics. Clinical pharmacokinetics 56, 77-90.
AN US
Lenzenweger, M.F., 2013. Thinking clearly about the endophenotype-intermediate phenotypebiomarker distinctions in developmental psychopathology research. Development and psychopathology 25, 1347-1357. Lera-Miguel, S., Andres-Perpina, S., Fatjo-Vilas, M., Fananas, L., Lazaro, L., 2015. Two-year follow-up of treated adolescents with early-onset bipolar disorder: Changes in neurocognition. J Affect Disord 172, 48-54.
M
Lewitzka, U., Jabs, B., Fulle, M., Holthoff, V., Juckel, G., Uhl, I., Kittel-Schneider, S., Reif, A., ReifLeonhard, C., Gruber, O., Djawid, B., Goodday, S., Haussmann, R., Pfennig, A., Ritter, P., Conell, J., Severus, E., Bauer, M., 2015a. Does lithium reduce acute suicidal ideation and behavior? A protocol for a randomized, placebo-controlled multicenter trial of lithium plus Treatment As Usual (TAU) in patients with suicidal major depressive episode. BMC psychiatry 15, 117.
ED
Lewitzka, U., Severus, E., Bauer, R., Ritter, P., Muller-Oerlinghausen, B., Bauer, M., 2015b. The suicide prevention effect of lithium: more than 20 years of evidence-a narrative review. International journal of bipolar disorders 3, 32.
PT
Li, X., Zhu, W., Roh, M.S., Friedman, A.B., Rosborough, K., Jope, R.S., 2004. In vivo regulation of glycogen synthase kinase-3beta (GSK3beta) by serotonergic activity in mouse brain. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 29, 1426-1431.
CE
Luca, A., Calandra, C., Luca, M., 2016. Gsk3 Signalling and Redox Status in Bipolar Disorder: Evidence from Lithium Efficacy. Oxidative medicine and cellular longevity 2016, 3030547. Malhi, G.S., Outhred, T., 2016. Therapeutic mechanisms of lithium in bipolar disorder: recent advances and current understanding. . CNS drugs, 30 931-949.
AC
Malhi, G.S., Outhred, T., Das, P., 2017. Lithium: neurotransmission and cellular mechanism pathways underlying neuroprogression in bipolar disorder. , In: Malhi, G.S., Masson, M.C., Bellivier, F. (Eds.), The Science and Practice of Lithium Therapy Springer, Cham., Switzerland, pp. 55-75. Malhi, G.S., Outhred, T., Das, P., Morris, G., Hamilton, A., Mannie, Z., 2018. Modelling Suicide in Bipolar Disorders. Bipolar Disord. Malhi, G.S., Tanious, M., Das, P., Coulston, C.M., Berk, M., 2013. Potential mechanisms of action of lithium in bipolar disorder CNS drugs 27 135-153.
32
ACCEPTED MANUSCRIPT
Mann, J.J., 2013. The serotonergic system in mood disorders and suicidal behaviour. . Philos Trans R Soc Lond B Biol Sci. 368 20120537. Mann, J.J., Arango, V.A., Avenevoli, S., Brent, D.A., Champagne, F.A., Clayton, P.J., &, Kleinman, J., 2009. Candidate endophenotypes for genetic studies of suicidal behavior Biol. Psychiatry 65, 556-563. Mann, J.J., Brent, D.A., Arango, V., 2001. The neurobiology and genetics of suicide and attempted suicide: a focus on the serotonergic system. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 24, 467-477.
CR IP T
Mann, J.J., Currier, ., 2 . A review of prospective studies of biologic predictors of suicidal behavior in mood disorders Arch. Suicide Res 11 3-16. Masi, G., Milone, A., Manfredi, A., Pari, C., Paziente, A., Millepiedi, S., 2009. Effectiveness of lithium in children and adolescents with conduct disorder: a retrospective naturalistic study. CNS Drugs 23, 59-69. Mathews, D., Richards, E., Niciu, M., Ionescu, D., Rasimas, J., Zarate, C., 2013. Neurobiological aspects of suicide and suicide attempts in bipolar disorder J Transl Neurosci. 4 203-216.
AN US
Miller, J.M., Hesselgrave, N., Ogden, R.T., Sullivan, G.M., Oquendo, M.A., Mann, J.J., Parsey, R.V., 2013. Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder. Biol Psychiatry 74, 287-295. Monkul, E.S., Matsuo, K., Nicoletti, M.A., Dierschke, N., Hatch, J.P., Dalwani, M., Brambilla, P., Caetano, S., Sassi, R.B., Mallinger, A.G., Soares, J.C., 2007. Prefrontal gray matter increases in healthy individuals after lithium treatment: a voxel-based morphometry study. Neuroscience letters 429, 7-11.
M
Muller-Oerlinghausen, B., Lewitzka, U., 2010. Lithium reduces pathological aggression and suicidality: a mini-review. Neuropsychobiology 62, 43-49.
ED
Nguyen, T., Fan, T., George, S.R., Perreault, M.L., 2017. Disparate Effects of Lithium and a GSK-3 Inhibitor on Neuronal Oscillatory Activity in Prefrontal Cortex and Hippocampus. Frontiers in aging neuroscience 9, 434.
PT
O'Donovan, A., Rush, G., Hoatam, G., Hughes, B.M., McCrohan, A., Kelleher, C., O'Farrelly, C., Malone, K.M., 2013. Suicidal ideation is associated with elevated inflammation in patients with major depressive disorder. Depression and anxiety 30, 307-314.
CE
Ohmura, Y., Tsutsui-Kimura, I., Kumamoto, H., Minami, M., Izumi, T., Yamaguchi, T., Yoshida, T., Yoshioka, M., 2012. Lithium, but not valproic acid or carbamazepine, suppresses impulsive-like action in rats. Psychopharmacology (Berl) 219, 421-432.
AC
Pawlak, J., Dmitrzak-Weglarz, M., Maciukiewicz, M., Wilkosc, M., Leszczynska-Rodziewicz, A., Zaremba, D., &, Hauser, J., 2015. Suicidal behavior in the context of disrupted rhythmicity in bipolar disorder— Data from an association study of suicide attempts with clock genes Psychiatry Res 226 517-520. Price, R.B., Iosifescu, D.V., Murrough, J.W., Chang, L.C., Al Jurdi, R.K., Iqbal, S.Z., Soleimani, L., Charney, D.S., Foulkes, A.L., Mathew, S.J., 2014. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depression and anxiety 31, 335-343. Quevedo, J., Yatham, L.N., 2018. Biomarkers in mood disorders: Are we there yet? J Affect Disord 233, 12. Raja, M., Azzoni, A., 2004. Suicide attempts: differences between unipolar and bipolar patients and among groups with different lethality risk. J Affect Disord 82, 437-442.
33
ACCEPTED MANUSCRIPT
Rajkowska, G., Clarke, G., Mahajan, G., Licht, C.M., van de Werd, H.J., Yuan, P., Stockmeier, C.A., Manji, H.K., Uylings, H.B., 2016. Differential effect of lithium on cell number in the hippocampus and prefrontal cortex in adult mice: a stereological study. Bipolar Disord 18, 41-51. Richard-Devantoy, S., Berlim, M.T., Jollant, F., 2015. Suicidal behaviour and memory: A systematic review and meta-analysis. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 16, 544-566.
CR IP T
Rogers, R.D., 2011. The roles of dopamine and serotonin in decision making: evidence from pharmacological experiments in humans. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 36, 114-132.
Rowe, M.K., Wiest, C., Chuang, D.M., 2007. GSK-3 is a viable potential target for therapeutic intervention in bipolar disorder. Neuroscience and biobehavioral reviews 31, 920-931. Rudebeck, P.H., Saunders, R.C., Lundgren, D.A., Murray, E.A., 2017. Specialized Representations of Value in the Orbital and Ventrolateral Prefrontal Cortex: Desirability versus Availability of Outcomes. Neuron 95, 1208-1220 e1205.
AN US
Samuelsson, M., Jokinen, J., Nordström, A.L., Nordström, P., 2006. CSF 5-HIAA, suicide intent and hopelessness in the prediction of early suicide in male high‐risk suicide attempters Acta Psychiatr. Scand. 113, 44-47. Schafer, M., Goodenough, S., Moosmann, B., Behl, C., 2004. Inhibition of glycogen synthase kinase 3 beta is involved in the resistance to oxidative stress in neuronal HT22 cells. Brain research 1005, 84-89.
M
Schaffer, A., Isometsä, E.T., Azorin, J.M., Cassidy, F., Goldstein, T., Rihmer, Z., &, Reis, C., 2015. A review of factors associated with greater likelihood of suicide attempts and suicide deaths in bipolar disorder: Part II of a report of the International Society for Bipolar Disorders Task Force on Suicide in Bipolar Disorder Aust N Z J Psychiatry 49 1006-1020.
ED
Sheard, M., 1971. Effect of lithium on human aggression. Nature 230, 113-114. Sheard, M.H., Marini, J.L., Bridges, C.I., Wagner, E., 1976. The effect of lithium on impulsive aggressive behavior in man. The American journal of psychiatry 133, 1409-1413.
PT
Smith, K.A., Cipriani, A., 2017. Lithium and suicide in mood disorders: Updated meta-review of the scientific literature. . Bipolar Disord 00, 1-12.
CE
Stange, J.P., Kleiman, E.M., Sylvia, L.G., Magalhaes, P.V., Berk, M., Nierenberg, A.A., Deckersbach, T., 2016. Specific mood symptoms confer risk for subsequent suicidal ideation in Bipolar Disorder with and without suicide attempt history: Multi-wave data from STEP-BD. Depression and anxiety 33, 464-472.
AC
Stepanova, E., Findling, R.L., 2017. Psychopharmacology of Bipolar Disorders in Children and Adolescents. Pediatric clinics of North America 64, 1209-1222. Toffol, E., Hatonen, T., Tanskanen, A., Lonnqvist, J., Wahlbeck, K., Joffe, G., Tiihonen, J., Haukka, J., Partonen, T., 2015. Lithium is associated with decrease in all-cause and suicide mortality in high-risk bipolar patients: A nationwide registry-based prospective cohort study. J Affect Disord 183, 159-165. Tondo, L., Baldessarini, R.J., 2016. Suicidal Behavior in Mood Disorders: Response to Pharmacological Treatment. Curr Psychiatry Rep 18, 88. Tondo, L., Baldessarini, R.J., 2018. Antisuicidal Effects in Mood Disorders: Are They Unique to Lithium? Pharmacopsychiatry.
34
ACCEPTED MANUSCRIPT
Turecki, G., 2005. Dissecting the suicide phenotype: the role of impulsive-aggressive behaviours. Journal of psychiatry & neuroscience : JPN 30, 398-408. Turecki, G., 2016. Epigenetics, in: Courtet, P. (Ed.), Understanding Suicide. Springer, pp. 97-110. Vargas, H.O., Nunes, S.O., Pizzo de Castro, M., Bortolasci, C.C., Sabbatini Barbosa, D., Kaminami Morimoto, H., Venugopal, K., Dodd, S., Maes, M., Berk, M., 2013. Oxidative stress and lowered total antioxidant status are associated with a history of suicide attempts. J Affect Disord 150, 923-930.
CR IP T
Vernon, A.C., Natesan, S., Crum, W.R., Cooper, J.D., Modo, M., Williams, S.C., Kapur, S., 2012. Contrasting effects of haloperidol and lithium on rodent brain structure: a magnetic resonance imaging study with postmortem confirmation. Biol Psychiatry 71, 855-863. Weitz, E., Hollon, S.D., Kerkhof, A., Cuijpers, P., 2014. Do depression treatments reduce suicidal ideation? The effects of CBT, IPT, pharmacotherapy, and placebo on suicidality. J Affect Disord 167, 98103. World Health Organization, 2014. Preventing suicide: a global imperative World Health Organization.
AN US
Zalsman, G., Braun, M., Arendt, M., Grunebaum, M.F., Sher, L., Burke, A.K., &, Oquendo, M.A., 2006. A comparison of the medical lethality of suicide attempts in bipolar and major depressive disorders. . Bipolar Disorders, 8, 558-565.
M
Zisook, S., Lesser, I.M., Lebowitz, B., Rush, A.J., Kallenberg, G., Wisniewski, S.R., Nierenberg, A.A., Fava, M., Luther, J.F., Morris, D.W., Trivedi, M.H., 2011. Effect of antidepressant medication treatment on suicidal ideation and behavior in a randomized trial: an exploratory report from the Combining Medications to Enhance Depression Outcomes Study. J Clin Psychiatry 72, 1322-1332.
ED
Figure Captions – Understanding suicide: focusing on its mechanisms through a lithium lens
PT
(Malhi et al., 2018)
CE
Figure 1. The Neurocognitive Model of Suicide in the context of Mood Disorders (adapted from Malhi et al, 2018), depicts the levels at which abnormalities are present in suicidal
AC
individuals alongside its neural substrates. This multi-factorial model accommodates neurobiological factors, including cellular mechanisms and neurotransmission, and the neurocircuitry that underpins neurocognitive processes. Together, changes at these levels contribute to the clinical presentation of suicidal thinking and behaviours. Approaching suicide from this perspective enables a deep understanding of the mechanisms underlying suicide. The 35
ACCEPTED MANUSCRIPT
model illustrates how psychopharmacological treatments can target suicidal thinking at multiple levels, by modifying cellular and molecular mechanisms, neurotransmission,
CR IP T
neurocircuitry and neurocognition.
Figure 2. The actions of lithium bridge suicidal thinking and its underlying neurobiology. A schematic bridging the underlying neurobiological mechanisms of the clinical anti-suicidal
AN US
effects of lithium (black arrows) to suicidal thinking and behaviours, via endophenotypes and cognitive appraisal. Suicide endophenotypes are well established, but underlying neurobiological mechanisms remain a grey area (indicated by grey shading). Although direct evidence for lithium’s effects on suicide endophenotypes and cognitive appraisals is limited
M
(grey, dashed arrows), lithium’s neurobiological mechanisms are well understood and evidence
ED
of its anti-suicidal effects continues to grow. These mechanisms can be linked to suicidal thinking and behaviours via suicide endophenotypes, connections which may be bidirectional.
PT
Therefore, by looking through the lens of lithium, we may be able to examine the
CE
neurobiological processes that are abnormal in suicidal individuals.
AC
Figure 3. Schematic depicting the potential biomarkers affected by lithium and therefore implicated in suicide in mood disorders. By inhibiting GSK3β activity lithium targets a number of anti-suicidal biomarkers. Intracellularly, lithium inhibits GSK3β directly and thereby reduces oxidative stress and inflammation. Inhibition of GSK3β by lithium also enhances neuroplasticity and serves to regulate circadian CLOCK gene expression. Extracellularly, lithium has 36
ACCEPTED MANUSCRIPT
bidirectional effects on GSK3β that result in modulation of the HPA axis and regulation of neurotransmission – involving serotonin (5HT) in particular.
CR IP T
Figure 4. A schematic summary of the pathways through which lithium prevents suicide.
Importantly, this gives a framework by which to approach evaluation of novel agents for suicide intervention. Assessment of suicide can be conducted at each node of the pathway, broadening
AN US
the methods by which suicidal thinking and behaviour can be identified clinically.
M
Table 1. Potential tools for suicide assessment.
Empirical Assessments
Emerging Assessments
Clinical presentation
Sheehan Suicidality Tracking Scale (S-STS)
Interpersonal Needs Questionnaire (INQ) (Van
(Coric et al., 2009)
Orden et al., 2012)
Columbia Suicide Severity Rating Scale (C-SSRS)
Acquired Capability for Suicide Scale (ACSS)
(Posner et al., 2011)
(Van Orden et al., 2008)
Buss-Perry Aggression Questionnaire – Short
Point Subtraction Aggression Paradigm (PSAP)
Form (BPAQ-SF) (Bryant and Smith, 2001)
(Bridge et al., 2015) (Geniole et al., 2017)
AC
CE
PT
ED
Assessment Level
Neurocognition
Barratt Impulsiveness Scale (BIS) (Fossati et al., 2002, Bridge et al., 2015)
(Skibsted et al., 2017). Cambridge Gambling Task (CGT) (Masaki et al.,
37
ACCEPTED MANUSCRIPT
Overt Aggression Scale (OAS) (Malone et al., 1994, Rifkin et al., 1997).
2016) (Halcomb et al., 2013) Information Sampling Test (IST) (Bersani et al.,
Iowa Gambling Task (IGT)
2016).
Delay Discounting Task (DDT)
Resilience Appraisal Scale (RAS) (Johnson et al.,
CR IP T
2010) Implicit Association Test of Risk Propensity Self-Concept (IAT-RPSC) (Horcajo et al., 2014),
Functional and resting state MRI (fMRI and
Pharmaco-Magnetoencelography (pMEG)
rsMRI)
(Muthukumaraswamy, 2014)
Diffusion tensor imaging (DTI)
AN US
Neurocircuitry
Magnetic resonance spectroscopy (MRS) (Szulc
M
et al., 2018)
Dexamethasone suppression test (DST)*
Actigraphy of sleep parameters** (Geoffroy et
and neurotransmission
(Mann et al., 2006, Jokinen et al., 2007)
al., 2014, Morgenthaler et al., 2007).
Dexamethasone/corticotrophin-releasing
Biological Rhythms Interview for Assessment in
hormone suppression test (Dex/CRH)* (Bschor
Neuropsychiatry** (BRIAN; Giglio et al., 2009)
PT
ED
Cellular mechanisms
et al., 2011).
CE
F2-isoprostanes* (Milne et al., 2005)
Melatonin* (Pacchierotti et al., 2001, Pfeffer et
AC
al., 2018). Pittsburgh Sleep Quality Index (PSQI; Buysse et al., 1989) Cerebrospinal fluid 5-HIAA (CSF 5-HIAA)* Interleukin-6 (IL-6)*
38
Malondialdehyde (MDA)* (Vargas et al., 2013)
ACCEPTED MANUSCRIPT
Tumor necrosis factor α (TNFα)* Brain-derived neurotrophic factor (BDNF)* GSK3β*
CR IP T
* measured from blood or saliva
** These measures are included as assessments of cellular mechanisms because of their
association with circadian rhythm dysregulation and CLOCK genes, such that they can be
AC
CE
PT
ED
M
AN US
considered behavioural manifestations of molecular clock gene alterations or mutations.
39
Understanding suicide: Focusing on its mechanisms through a lithium lens Gin S Malhi , Pritha Das , Tim Outhred , Lauren Irwin , Grace Morris , Amber Hamilton , Katie Lynch , Zola Mannie PII: DOI: Reference:
S0165-0327(18)31354-5 https://doi.org/10.1016/j.jad.2018.08.036 JAD 10033
To appear in:
Journal of Affective Disorders
Received date: Revised date: Accepted date:
25 June 2018 8 August 2018 9 August 2018
Please cite this article as: Gin S Malhi , Pritha Das , Tim Outhred , Lauren Irwin , Grace Morris , Amber Hamilton , Katie Lynch , Zola Mannie , Understanding suicide: Focusing on its mechanisms through a lithium lens , Journal of Affective Disorders (2018), doi: https://doi.org/10.1016/j.jad.2018.08.036
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Highlights:
AC
CE
PT
ED
M
AN US
The need for novel potential treatment targets to be identified by understanding the mechanisms of suicide is discussed How a deeper understanding of suicide can be achieved by examining lithium’s antisuicidal properties is illustrated An integrated neurocognitive and neurobiological model of suicide is proposed to provide a framework for future research Practical recommendations for the assessment of suicidal thinking and behaviour alongside its neural underpinnings are outlined
CR IP T
1
ACCEPTED MANUSCRIPT
Understanding suicide: Focusing on its mechanisms through a lithium lens
CR IP T
Author Statement
Contributors: Gin S Malhi 1,2,3,*, Pritha Das 1,2,3, Tim Outhred 1,2,3, Lauren Irwin 1,2,3, Grace Morris 1,2,3,
AN US
Amber Hamilton 1,2,3, Katie Lynch5, Zola Mannie 1,2,3,
1
Academic Department of Psychiatry, Northern Sydney Local Health District, St Leonards, NSW Australia
2
Sydney Medical School Northern, University of Sydney, NSW Australia
3
M
CADE Clinic, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW Australia 4
5
ED
NSW Health and Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW Australia Center for Neural Science, New York University, New York, NY 10003, USA
AC
CE
PT
* Corresponding Author: Gin S Malhi Discipline of Psychiatry, Sydney Medical School, University of Sydney, Sydney, NSW, 2065, Australia. Email: [email protected]
Abstract
Background: Current intervention strategies have been slow in reducing suicide rates, particularly in mood disorders. Thus, for intervention and prevention, a new approach is necessary. Investigating the effects of a medication known for its anti-suicidal properties on neurobiological and neurocognitive substrates of suicidal thinking may provide a deeper and more meaningful understanding of suicide. 2
ACCEPTED MANUSCRIPT
Method: A literature search of recognised databases was conducted to examine the intersection of suicide, mood disorders, and the mechanisms of lithium.
CR IP T
Results: This review synthesises the extant evidence of putative suicide biomarkers and endophenotypes and melds these with known actions of lithium to provide a comprehensive picture of processes underlying suicide. Specifically, the central importance of glycogen synthase kinase-3β (GSK3β) is discussed in detail because it modulates multiple systems that have been repeatedly implicated in suicide, and which lithium also exerts effects on. Limitations:
AN US
Suicide also occurs outside of mood disorders but we limited our discussion to mood because of our focus on lithium and extending our existing model of suicidal thinking and behaviour that is contextualised within mood disorders. Conclusions: Focusing on the neurobiological mechanisms underpinning suicidal thinking and
M
behaviours through a lithium lens identifies important targets for assessment and intervention. The use of objective measures is critical and using these within a framework that integrates
ED
findings from different perspectives and domains of research is likely to yield replicable and validated markers that can be employed both clinically and for further investigation of this
AC
CE
PT
complex phenomenon.
3
ACCEPTED MANUSCRIPT
Keywords: Suicide prevention, biomarkers, endophenotypes, pharmacological
CR IP T
treatment, lithium, GSK3β.
Introduction
A global target of 10% reduction in suicide by 2020 and 50% by 2023 has been set by the World Health Organisation (WHO; World Health Organization, 2014) because, despite
AN US
concerted, multifaceted efforts, the rate of reduction in suicide has been dishearteningly slow. Part of the reason for this is the complexity of suicide and its multifactorial aetiology. Hence, a deeper understanding of its underlying mechanisms and the processes that drive suicidal
M
behaviour is crucial for the development of effective preventative strategies.
ED
Suicide occurs in many situations but is most common in mood disorders. Indeed, the risk of suicide in mood disorders is 30 times greater than in the general population and 72-87%
PT
of completed suicides involve patients with either major depression or bipolar disorder (Arsenault-Lapierre et al., 2004). Therefore, it is necessary to examine suicide in the context of
CE
mood disorders and identify potential targets for better treatment and prevention. But in order
AC
to achieve this, a suitably sophisticated model is needed – one which bridges the gap between molecular mechanisms and clinical effects. A recent neurocognitive model of suicide in the context of bipolar disorder provides a useful developmental framework for the psychological processes that culminate in suicide (Malhi et al., 2018). This model brings together the neurobiological antecedents and the many environmental and psychosocial contributing factors 4
ACCEPTED MANUSCRIPT
that result in the emergence of suicidal thinking. Therefore, after briefly reviewing this model, this paper specifically examines the underlying neurobiology of suicide, and uses our knowledge of lithium in this context to focus on the inception of suicidal thinking.
CR IP T
Method A literature search of articles was conducted to examine the intersection of suicide, mood disorders and mechanisms and the role of lithium. Recognized databases such as Scopus,
AN US
PubMed, and PsycINFO using the keywords “suicide”, “suicide in mood disorders”, “suicide treatment”, “suicide prevention”, “suicide endophenotypes “,“neurocognitive model”, “suicide biomarkers”, “lithium treatment”, “lithium targets”, “anti-suicidal effects”, “GSK3β”, “treatment response”, “lithium response”, “treatment outcomes”. Bibliographies of identified
M
articles were further scrutinized for papers and book chapters of relevance, that is, those with
ED
partial key words, in addition to drawing on literature known to the authors. These were deemed to be relevant if they addressed any of the keywords.
PT
A Neurocognitive Model of Suicide in the Context of Mood Disorders
CE
The distinguishing feature of our recently proposed model of suicide (Malhi et al., 2018) is that, while it briefly alludes to the underlying mechanisms implicated in the process of
AC
suicidal thinking, it also draws attention to factors involved in the generation of suicidal thinking or ideation and eventual enactment of suicide. And though it is tailored to bipolar disorders (BD), it can be applied more generally to mood disorders as a whole, in particular major depressive disorder (MDD). This is because, even in BD, suicidal behaviours occur predominantly during depressive and depressive-mixed mood states, as opposed to when 5
ACCEPTED MANUSCRIPT
experiencing symptoms of mania (Schaffer et al., 2015). Depression therefore provides continuity between bipolar and unipolar disorders and allows the model to meaningfully reflect suicidal processes across the spectrum of mood disorders. Specifically, suicide follows from the engagement of negative and maladaptive cognitive appraisal processes that take hold during
CR IP T
depression. Indeed, negative cognitive appraisals have strong associations with depressive symptoms while hyper/mania is characterised by both positive and negative appraisals and positive appraisals, although maladaptive in this context, are however, incompatible with
AN US
suicidal thinking (Kelly et al., 2012), explaining in part the higher prevalence of suicide during depressive episodes.
The factors impacting the appraisal system are myriad and include the consequences of
M
perturbations in neurobiological systems and neurocognitive processes, all of which occur in the context of mood disorders and inter-current interpersonal difficulties. Therefore, targeting
ED
related biomarkers, neuropsychological vulnerabilities, and endophenotypes may provide a
PT
means of modulating appraisal processes so as to prevent the emergence of suicidal ideation. Traditionally, once suicidal ideation manifests, the focus of clinical management shifts to the
CE
prevention of engagement in suicidal acts (i.e. acting on suicidal thoughts). However, the Neurocognitive Model of Suicide (see Figure 1; Malhi et al., 2018) outlines the factors that
AC
escalate progression of suicidal thinking from ideation to attempt through intent, which also involves planning and in particular, the development and implementation of a suicide strategy. This then provides further opportunities to intervene and halt the process. Briefly, the emergence of suicidal thinking/ideation, if untreated, leads to engagement in suicidal acts, and it is the degree in the intensity of one’s motivation to act on such thinking and the volition to do 6
ACCEPTED MANUSCRIPT
so that explain the differences in suicide related expression between the mood disorders rather than the emergence of suicidal thinking. For instance, lethality risk is significantly higher in BD than MDD (Raja and Azzoni, 2004; Zalsman et al., 2006). The model reveals that prevailing maladaptive cognitions increase motivation and volition to act on suicidal ideation and that, as
CR IP T
the severity and intensity of suicidal ideation and intent increases, the likelihood of suicidal attempts is also increased. But importantly, driving these motivations and volitions are underlying neurobiological and neurocognitive abnormalities, appraisal processes, and
AN US
prevailing maladaptive cognitions that intensify in the context of interpersonal difficulties. The model therefore illustrates how neurobiological and neurocognitive factors can impinge upon, and ultimately drive a dysregulated stress response, and in so doing impair the appraisal system, which is fundamental to the inception of suicidal thinking. It therefore facilitates and
M
encourages the identification of neurobiological and neurocognitive markers of suicide that
ED
may serve as targets of psychopharmacological treatments, while at the same time drawing attention to prevailing cognitions and interpersonal difficulties that can be targeted by
PT
psychosocial interventions.
CE
This paper builds on this model by exploring the deep underlying processes that commence with changes at the cellular level culminating in suicidal thinking. To aid this
AC
exploration, a zoom lens approach is used that considers a common element, namely lithium, which is known to operate at multiple levels and reliably link changes across different domains as having sufficient stepping stones to bridge the gap between the clinical phenomenology of suicidal thinking or ideation and its cellular substrates. In this approach, we briefly examine
7
ACCEPTED MANUSCRIPT
biomarkers, endophenotypes, and neuropsychological vulnerabilities, which in unison create a useful framework for understanding suicide in mood disorders. [Insert Figure 1 here]
CR IP T
Biomarkers
Investigation and identification of biomarkers is a useful strategy to employ in gaining understanding of underlying processes or changes involved in suicide. Biomarkers is a term that
AN US
refers to objectively measured and evaluated characteristics that give indication to normal and pathological processes as well as therapeutic responses (Atkinson Jr et al., 2001; Quevedo and Yatham, 2018), and in psychopathology, biomarkers are state-dependent, that is, they are present during the illness and subside with treatment response(Ref). However, in suicide, some
M
of these biomarkers may be considered as candidate or potential endophenotypes in their own
PT
(see Section below).
ED
right while others may have strong associations with well-established suicide endophenotypes
Research linking biomarkers to suicide is limited and fragmented. A number of
CE
candidate biomarkers have been identified, but few have been corroborated sufficiently to be regarded as either specific or robust. Over the years, investigators have examined the
AC
neuroendocrine stress axis and related systems including inflammatory processes and regulatory neurobiology. For example, dysregulation of the HPA axis has long been known to occur in mood disorders, and, in suicide research, HPA axis dysfunction has been demonstrated in suicide attempters by non-suppression of cortisol during the dexamethasone suppression test (DST) (Courtet et al., 2011b; Mann et al., 2009). Similarly, proinflammatory cytokines, 8
ACCEPTED MANUSCRIPT
known to play a role in mood disorders, may also serve as potential suicide biomarkers because of their involvement in suicidal behaviours (Chang et al., 2017; O'Donovan et al., 2013). In a similar vein, reductions in brain derived neurotrophic factor (BDNF), leading to
CR IP T
compromised neuroplasticity and impaired neurogenesis, have also been linked to suicide (Ambrus et al., 2016; Braquehais et al., 2012; Jokinen et al., 2007; Jokinen and Nordström, 2009). Importantly, and completing the loop to some extent, BDNF, as a major mediator of neuroplasticity, has been found to be under the regulation of both proinflammatory cytokines
AN US
(Calabrese et al., 2014) and the HPA axis (Ambrus et al., 2016; Kunugi et al., 2010). Oxidative stress is also implicated in suicidal behaviours (Vargas et al., 2013).
Other potential biomarkers linked to suicide include circadian rhythm disruption,
M
possibly through the Circadian Locomotor Output Cycles Kaput (CLOCK) gene expression as
ED
seen in suicidal bipolar patients (Bellivier et al., 2015; Pawlak et al., 2015). Accordingly, sleep disruption significantly potentiates suicide risk among bipolar patients with a past history of
PT
suicide attempts (Stange et al., 2016) and ‘next-day’ suicidal ideation in mood disordered patients (Ballard et al., 2016), and is increasingly considered a significant suicide risk factor
CE
(Ballard et al., 2016; Bernert et al., 2015).
AC
Potential biomarkers of significance also include metabolic and receptor alterations in neurotransmission. For instance, the serotonergic system, extending from genes (e.g. serotonin transporter (5HTT), Tryptophan Hydroxylase 1 and 2 (TPH1 and TPH2)) to receptors (e.g. upregulation of whole serotonin 1A receptor (5HT1A )and serotonin 2A receptor (5HT2A) postsynaptic receptors in the PFC) and even its metabolites (e.g. reductions in the cerebrospinal 9
ACCEPTED MANUSCRIPT
fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA)), is implicated in suicidal behaviours (BlascoFontecilla and Oquendo, 2016; Courtet et al., 2011b; Mann et al., 2009; Samuelsson et al., 2006; Turecki, 2016). Additionally, 5HT receptor binding is also implicated in suicide phenotypes (individual characteristics closely associated with suicide, such as hopelessness). For example,
CR IP T
inverse correlations have been found between orbitofrontal cortex (OFC) 5HT1A binding and aggression and between hopelessness and 5HT2A receptor binding. Other important
neurotransmitters implicated in suicide and its endophenotypes include dopamine (DA),
AN US
acetylcholine (Ach), glutamate (Glu) and γ-Aminobutyric acid (GABA). However, a detailed discussion of their involvement is beyond the scope of this paper. Endophenotypes
M
Given the complexity of suicide, one potentially fruitful strategy that could shed light on
ED
its inner mechanisms is to identify accessible endophenotypes. Once characterised, these endophenotypes can serve as building blocks which, in conjunction with evidence from
PT
translational studies, can be used to map pathways and processes that together form a framework that links suicidal behaviours to its substrates - at each level of brain function.
CE
Pursuing this approach may also facilitate the development of suitable animal models that in
AC
turn enable the experimental manipulation of the underlying neurobiology of suicide and its endophenotypes, and perhaps even allow the exploration of treatment effects (Gould et al., 2017).
Although all endophenotypes are biomarkers, not all biomarkers are endophenotypes as they do not fulfil the stringent criteria of an endophenotype, particularly the state 10
ACCEPTED MANUSCRIPT
independence criteria (Beauchaine, 2009; Beauchaine and Constantino, 2017; Lenzenweger, 2013). As such, endophenotypes are 1) characteristics associated with an illness or risk of illness in the general population, 2) heritable, 3) are primarily state independent, 4) co-segregate with the illness within families, thus linking the trait to gene variants, 5) are present in non-affected
CR IP T
family members more so than in the general population, suggestive of a genetic basis, and 6) can be reliably measured and specific to the disorder or illness of interest (Beauchaine, 2009; Courtet et al., 2011b; Gottesman and Gould, 2003), although it has been recently suggested
AN US
that this specificity may be relaxed to allow for transdiagnostic vulnerabilities and complexities (Beauchaine and Constantino, 2017). Therefore, endophenotypes are enduring genetically influenced traits. Identification and understanding of suicide endophenotypes will help to identify the neurobiological and neurocognitive basis of suicide in mood disorders. Therefore,
M
characterizing endophenotypes that can be systematically measured will allow for testing of
ED
putative mechanisms. This is particularly important for the development of targeted interventions and for objectively evaluating efficacy of new treatments (Blasco-Fontecilla and
PT
Oquendo, 2016; Courtet et al., 2011b; Kovacsics et al., 2009).
CE
At the neurocognitive level, the endophenotypes of suicide in mood disorders that are most promising are aggressive and impulsive personality traits and disadvantageous decision-
AC
making (Courtet et al., 2011b; Hoehne et al., 2015; Kovacsics et al., 2009; Mathews et al., 2013; Richard-Devantoy et al., 2015). Interestingly, the emerging neural substrates of these cognitive processes, as revealed by functional neuroimaging, encompass brain regions strongly implicated in mood disorders, for example the OFC, dorsolateral and ventrolateral cortices (DLPFC and VLPFC), anterior cingulate cortex (ACC) and their subcortical connections (Broche11
ACCEPTED MANUSCRIPT
Perez et al., 2016; Coutlee and Huettel, 2012; Rudebeck et al., 2017). In practice, aggressive and impulsive personality traits and the propensity to make poor decisions may adversely influence the cognitive appraisal of social and environmental factors such that decisions and actions with clearly destructive outcomes – in particular for one’s self – can seem reasonable (Anderson and
CR IP T
Bushman, 2002; Bortolato et al., 2013; Rogers, 2011). Indeed, the General Aggression Model (GAM; Anderson and Bushman, 2002) suggests that impulsive responses are elicited from
immediate appraisals of self, situation and environment that are governed by internal states,
AN US
and are either automatic, or based on rudimentary decision-making processes. As such they do not require extensive thought, and therefore little or no reappraisal is engaged. Aggregation of the consequences of such impulsive and poor decision-making can eventualise in sustained feelings of defeat and entrapment, generating and exacerbating suicidal ideation. Interestingly,
M
twin studies and family studies have shown have shown heritability and genetic transmission of
ED
aggressive and impulsive traits (Anokhin et al., 2015; Mann et al., 2009), that interact with environmental factors – suggesting that expression of aggressive-impulsivity is context
PT
dependent. This means that the heritable genetic predisposition may then be moderated by
CE
environmental factors such as exposure to violent behaviours of any kind, including suicidal attempts and various forms of childhood abuse (Turecki, 2005), to perhaps produce aggressive-
AC
impulsivity schema that influence decision-making (Fontaine and Dodge, 2006), and subsequent adoption of maladaptive appraisal systems and coping strategies. Additionally, through the use of the delay discount task, a measure of both impulsivity and decision-making in a twin study, this genetic transmission endorsed heritability of impulsivity traits and potentially decisionmaking (Anokhin et al., 2015). 12
ACCEPTED MANUSCRIPT
In addition to aggressive-impulsivity and disadvantageous decision-making, other biomarkers with potential for endophenotypic categorisation include autonomic dysregulation with altered skin conductance as demonstrated by electrodermal hypo responsivity (Chistiakov et al., 2012; Courtet et al., 2011b), 5HT dysfunction as shown by low levels of CSF 5-HIAA
CR IP T
(Jimenez-Trevino et al., 2011; Mann et al., 2009), prolactin response to fenfluramine (Chistiakov et al., 2012; Courtet et al., 2011b) and, based on functional and pharmacological neuroimaging, altered serotonergic metabolism in the amygdala and PFC and altered serotonergic modulation
AN US
of the PFC (Courtet et al., 2011a), early onset major depression and cortisol response to
psychosocial stress (Mann et al., 2009) and interestingly, alterations in markers of second messenger function such as GSK-3 (Mann et al., 2009) and lithium response (Chistiakov et al., 2012). However, in this review, to demonstrate the potential of endophenotypes as
M
pharmacological targets, specifically, lithium, we will focus on the two well-established
ED
endophenotypes, namely aggressive impulsivity and impaired decision-making.
PT
Additionally, numerous biomarkers have strong associations with aggressive impulsivity and impaired decision making, strengthening the role of these biomarkers in potentiating suicidal
CE
behaviours (See Figure 4). For instance, proinflammatory cytokines and oxidative stress are
AC
associated with aggressive impulsivity (See Figure 4; Beurel and Jope, 2014; Gill et al., 2010), while circadian clocks are implicated in the regulation of aggression (Hood and Amir, 2018) and decision-making (Ingram et al., 2016). Specifically, the Hood & Amir (2018) review discusses evidence from human and non-human species, and what we can extrapolate from this review is that circadian clock genes alter neurotransmitter metabolism in emotion evoking brain
13
ACCEPTED MANUSCRIPT
networks e.g. amygdala and this activation or disinhibition increases the risk of impulsivity, and expression of aggressive behaviours. Additionally, with regards to human decision-making, an experimental paradigm of ethical and risky decision-making revealed that RNA-based chronotypes are significantly pronounced than questionnaire based chronotypes, and this
or phase of oscillating clock genes (Ingram et al., 2016).
CR IP T
suggests that individual decision-making may be influenced by the timing of the circadian drive
Serotonergic dysfunction as evidenced by a reduced prolactin response to fenfluramine
AN US
(a 5HT agonist) is also associated with aggressive impulsivity and impaired decision-making in suicidal patients (Courtet et al., 2011b; Mann, 2013; Mann et al., 2001). Indeed, the neurobiological basis of aggressive impulsivity implicating the various neurotransmitters has
M
been subject to an extensive review which highlights the fact that they can serve as potential targets for psychopharmacological treatments (Comai et al., 2012). Potentially, any intervention
ED
that produces changes in these two endophenotypes may do so via direct and/or indirect but
PT
variable effects on these biomarkers.
CE
Interestingly, a mechanistic pathway from stress, via inflammation and oxidative stress to aggressive impulsivity and ultimately suicidal behaviours, is thought to involve the pivotal
AC
protein, glycogen synthase kinase 3 beta (GSK3β; see later) through which lithium exerts effects (Beurel and Jope, 2014; Coccaro et al., 2016; Luca et al., 2016). Linking biomarkers and endophenotypes to suicide via lithium therapy To clarify the series of events that commence at the cellular level and build successively to create suicidal thinking or ideation, a common element is needed – one which is known to 14
ACCEPTED MANUSCRIPT
operate at each level and thereby reliably links observed changes across different domains. Lithium is one such candidate, although other compounds (see (Tondo and Baldessarini, 2016) for a review) and ketamine (Price et al., 2014) may also be considered in this context, although their scope of operation needs further determination. Clinically, lithium is known to be anti-
CR IP T
suicidal, and many of its cellular and intracellular actions are also well known. In addition, its effects on neurocognition, neural networks, and neurotransmission are measurable and are increasingly being investigated and understood (Malhi and Outhred, 2016). Thus, by tracing the
AN US
effects of lithium and using its properties as a lens to focus on various levels, a mechanistic framework can be developed that may provide a deeper understanding of suicide processes
M
and also point to potential targets for therapeutic and preventative interventions.
ED
[Insert Figure 2 here]
PT
Lithium therapy
CE
Developmental Perspective: Although lithium is considered the ‘gold standard’ for the treatment of bipolar disorders in adults, it has also been approved by the Food and Drug
AC
Administration (FDA) for the treatment of paediatric bipolar disorders in children and adolescents aged 12 years and above (Grant and Salpekar, 2018; Stepanova and Findling, 2017). However, in an open-label long-term treatment it was shown to be effective in the treatment of multiple phases of the illness in children and adolescents (from ages of 7 to 17 years old) although this effect is dependent on initial treatment response, that is, only those who initially 15
ACCEPTED MANUSCRIPT
responded well continued to do so during continuation treatment (Findling et al., 2013). As with adults, the dosing schedule requires titration depending on point of entry weight (< 30 kgs >) but electrocardiogram(ECG) monitoring does not seem to be a specific recommendation for its use by the American Academy of Child and Adolescent Psychiatry (AACAP) in this population
CR IP T
group (Grant and Salpekar, 2018). With newer dosing paradigms, it is also well tolerated and safe to prescribe and administer (Findling et al., 2011; Findling et al., 2015), but, similar to
adults, therapeutic drug monitoring is still necessary (Landersdorfer et al., 2017). Potential side
AN US
effects include dermatologic, endocrine, gastro-intestinal, haematological, neurological and renal complications but these may be mitigated by the adoption of countering strategies, e.g. reducing salt and caffeine intake, increasing or maintaining adequate hydration, ingestion of lithium with food. For those experiencing extrapyramidal symptoms or metabolic effects from
M
second generation antipsychotics, lithium may be preferred. Despite the promising evidence for
PT
(Duffy and Grof, 2018).
ED
lithium therapy in children and adolescents, the full range of benefits remains little understood
Suicidal thinking and behaviours: Lithium is primarily known as a mood stabilising agent
CE
and is used mainly in the management of BD. However, it is increasingly apparent that, in addition to its profound mood stabilising effects, lithium has distinct independent anti-suicidal
AC
properties (Ahrens and Müller-Oerlinghausen, 2001; Ernst and Goldberg, 2004; Khan et al., 2011; Lewitzka et al., 2015b; Smith and Cipriani, 2017), that appear to be specific to lithium, as compared to other medications (Bellivier and Guillaume, 2016). In support of this view, a most recent meta-analytic review reveals increasing evidence of long-term lithium treatment antisuicidal effects in patients with both BD and major depressive disorder (MDD), particularly 16
ACCEPTED MANUSCRIPT
during depressive phase of BD (Tondo and Baldessarini, 2018). Generally, most other treatments (e.g. interpersonal therapy (IPT) and antidepressants) reduce suicidal behaviours by ameliorating depressive symptoms (Weitz et al., 2014; Zisook et al., 2011), suggesting that improvements in mood are a pre-requisite for these treatments to have any impact on suicidal
CR IP T
thinking and behaviours. In contrast, lithium appears to achieve the same without necessarily improving mood (Jones et al., 2017), and possibly does so because it exerts effects on multiple levels. Notably, this anti-suicidal effect is also superior to that effected by other treatments,
AN US
such as valproic acid and antidepressants (Toffol et al., 2015).
This evidence is primarily based on adult investigations as no such evidence exists in children and adolescents due to paucity of such investigations (see review(Cipriani et al.,
M
2013).Indeed, although there is evidence of lithium effects on aggressive behaviour in children
ED
and adolescents with explosive aggression and conduct disorders (Masi et al., 2009). Lithium is thought to be most beneficial in preventing suicidal behaviours in the long-
PT
term, (Baldessarini et al., 2006; Tondo and Baldessarini, 2016, 2018). Its acute efficacy in this regard is largely unknown, but this will be illuminated when findings are reported from at least
CE
one randomized, placebo controlled multicentre trial of lithium and treatment as usual (TAU)
AC
assessing potential acute effects on suicidal ideation and behaviour in mood disordered patients during depressive episodes that is currently underway (Lewitzka et al., 2015a). Promising preliminary evidence from an exploratory proof of concept randomized double-blind parallel group study seems to suggest that therapeutic levels can be achieved within 4 weeks of treatment, and this short-term lithium treatment is beneficial in reducing suicidal behaviours.
17
ACCEPTED MANUSCRIPT
Neurocognition: The direct and indirect impact of lithium and its mechanisms of action on suicide endophenotypes in humans is yet to be thoroughly investigated, but there is already emerging evidence from animal studies of its effects on some endophenotypes such as aggressive impulsivity. For example, animal evidence reveals that lithium specifically reduces
CR IP T
impulsivity in mice, as measured by the delay discounting task (a test of decision making, where the steep rate of discounting measures impulsive decisions; see Homberg, 2012) whereas valproate has no effect (Halcomb et al., 2013) and likewise, in rats, where lithium but not
AN US
valproic acid or carbamazepine reduced premature responses in a three-choice serial reaction time task (3-CSRTT), that were independent of its motivation for food effects (Ohmura et al., 2012).
M
Also, anti-aggressive effects of lithium in humans have been historically reported since John Cade’s 1949 publication and subsequent open-label studies of psychiatric patients and
ED
single- and double-blind studies of prison inmates (Jones et al., 2011; Muller-Oerlinghausen and
PT
Lewitzka, 2010; Sheard, 1971; Sheard et al., 1976) but no recent investigations have been published in adults, although there is evidence of lithium effects on aggressive behaviour in
CE
children and adolescents with explosive aggression and conduct disorders (Masi et al., 2009). No such studies have been conducted in mood disordered patients with suicidal behaviours.
AC
Indeed, although there is evidence of lithium effects on aggressive behaviour in children and adolescents with explosive aggression and conduct disorders (Masi et al., 2009),. However, based on the evidence of anti-aggressive effects, there is potential for lithium to also reduce suicide risk in this population, perhaps via its effects on the endophenotype of aggression.
18
ACCEPTED MANUSCRIPT
To date, and to our knowledge, only one study has investigated the effects of lithium specifically on decision-making in humans, and none in animal models. In this study, the Iowa Gambling Task (IGT) was used, and revealed a possible normalisation effect of lithium on decision-making, such that those taking lithium selected safer (less risky) options (Adida et al.,
CR IP T
2015). Given the paucity of evidence of the direct or indirect effects of lithium on
endophenotypes thus far, an alternative approach that may prove useful is to examine the effects of lithium on neurobiological markers linked to identified suicide endophenotypes (See
AN US
Figure 2). Lithium effects on decision-making have not been investigated in this population, but lithium seemingly interacts with psychotic symptoms to produce a less favourable outcome in executive control (Lera-Miguel et al., 2015). As suicidal thinking often presents during depressive and mixed states rather than a psychotic presentation, this may not be a significant
M
issue.
ED
Neurocircuitry: Brain regions where lithium exerts its effects, and which are also the
PT
most robustly implicated in suicide, are the PFC, hippocampus and ACC. For instance, lithium has been shown to reverse grey matter volume changes in brain regions typically characterized
CE
by reductions in suicidal bipolar patients e.g. OFC, DLPFC, anterior cingulate cortex (ACC) and superior temporal cortex (STC) (Benedetti et al., 2011; Malhi et al., 2013; Toffol et al., 2015). In
AC
some instances, this ‘recovery’ occurs to the extent that volumes are greater than in health (Hallahan et al., 2011). This evidence stems from multiple sources, including animal studies, post mortem (both animal and human) and in vivo techniques and may be a specific effect of lithium. For instance, lithium treated rodents attain selective increases in cortical whole brain (WBV) and grey matter (GMV) volumes, with no effects on striatal regions, whereas haloperidol 19
ACCEPTED MANUSCRIPT
decreases these volumes (Vernon et al., 2012). Importantly, these lithium induced increases appear to be sustained, as demonstrated by post mortem animal evidence (Vernon et al., 2012). Increases in cortical GMV and white matter (WM) tract integrity have also been observed in lithium treated bipolar patients compared to lithium-free patients (Benedetti et al.,
CR IP T
2013; Benedetti et al., 2015; Benedetti et al., 2011), and, even in healthy individuals, lithium produces increases in ACC and PFC GMV (Monkul et al., 2007). Such effects have also been noted in bipolar patients with psychotic depression, involving in particular, the hippocampus
AN US
(Giakoumatos et al., 2015). This is noteworthy because, in rodents, lithium has been shown to increase cell numbers in the hippocampus (Rajkowska et al., 2016), as well as increase PFC and hippocampal oscillatory activity (Nguyen et al., 2017). These increases in structure and activity perhaps reflect lithium’s role in cell proliferation and regeneration as well as axonal repair –
M
thus restoring structural connectivity. Such changes possibly underpin suicide-related
ED
neurocognitive dysfunction and its modification by lithium therapy.
PT
Neurobiology: Despite the clinical complexity of lithium therapy, its effects at the neurobiological level are clear and demonstrable. The variety of neurobiological processes
CE
associated with the clinical effects of lithium can be broadly conceptualised as intracellular (neuroprotection via neurotrophic factors & anti-apoptosis via anti-inflammatory and anti-
AC
oxidative properties and circadian CLOCK gene expression) and extracellular mechanisms (neurotransmission and hypothalamic-pituitary-adrenal (HPA) axis activity) (Figure 3)(Benedetti et al., 2007; Geoffroy and Etain, 2017; Malhi and Outhred, 2016; Malhi et al., 2017). Intriguingly, although at a clinical level lithium has seeming specificity, at cellular and molecular levels, it engages with a multitude of targets and appears non-specific in its actions. However, it 20
ACCEPTED MANUSCRIPT
is this broad range of actions that is perhaps key to its ability to stabilise complex systems and achieve both its effects on mood and separately on suicide. For instance, it may be because of its simultaneous actions on multiple targets that lithium is able to establish homeostasis by preventing and circumventing actions of other compensatory systems, which would normally
specificity is best exemplified by its actions on GSK3β.
CR IP T
limit and/or reverse the effects of any agent. This multi-pronged diversity of action with clinical
GSK3β: In the adult brain, GSK3β is a widely distributed serine/threonine protein kinase
AN US
that is concentrated in particular in the PFC (Pandey et al., 2009) - a brain region strongly implicated directly and as part of various neurocircuits in suicide-related neurocognition, especially disadvantageous decision-making.
M
It is through its direct and indirect inhibition of the GSK3β pathway that lithium effects
ED
changes in inflammation, circadian rhythm CLOCK gene expression, monoaminergic neurotransmission, oxidative stress, neuroplasticity, physiological stress response and
PT
neurocognition (Geoffroy and Etain, 2017; Malhi and Outhred, 2016) (See Figure 3 and a summary schematic in Figure 4). The indirect pathways include the inositol monophosphate 1-
CE
phosphatase (ImPase1), myoInositol (mI), myristoylated alanine-rich c kinase substrate
AC
(MARCKS) and cyclic adenosine monophosphate (cAMP) pathways, but it is beyond the scope of this review to give a detailed examination of these. However, regardless of pathway, lithium, via its effects on GSK3β ultimately exerts effects on the neurobiological targets as above. And via GSK3β induced changes, lithium is ultimately able to alter suicidal thinking and behaviours.
21
ACCEPTED MANUSCRIPT
However, to better understand how lithium achieves this, it is important to examine the links between GSK3β, lithium, and suicide-related biomarkers and neurocognition. [Insert Figure 3 here]
CR IP T
Cellular Mechanisms: As discussed earlier, GSK3β has many functions that are mediated via multiple signalling pathways. Its functions involve neurotransmission, neuroplasticity,
neuronal growth and metabolism (Can et al., 2014) (See Figure 3 & 5). (Rowe et al., 2007). At
AN US
the extracellular level, there are bidirectional effects between GSK3β and HPA axis activity as well as neurotransmission (see Figure 3) (See (Malhi and Outhred, 2016) for detailed discussion of this bi-directionality. Psychological stress, which is important in suicidal thinking and behaviours, especially in the context of mood disorders, induces GSK3β activation via HPA
M
dysregulation, and this subsequently increases proinflammatory cytokines e.g. interleukin-6 (IL-
ED
6) and tumour necrosis factor-alpha (TNF-α). Of note, both of these have been shown to be associated with the aforementioned suicide-related aggressive impulsivity endophenotype
PT
(Bellivier and Guillaume, 2016). Evidence from animal studies suggests that GSK3β plays a key role in the control of oxidative stress resistance in hippocampal neuronal cells, the region of the
CE
brain most pivotal to memory processes, especially in mood disorders (Schafer et al., 2004), and
AC
that GSK3β activation specifically impairs learning and inhibits hippocampal-dependent long term potentiation (LTP) (Jope et al., 2017). Furthermore, GSK3β activation is itself modulated by BDNF, indicating that it is involved in the regulation of synaptic strength and plasticity, and that it achieves these changes either independently or through the tyrosine receptor kinase B (TrkB) pathway (Can et al., 2014; Gupta et al., 2014).
22
ACCEPTED MANUSCRIPT
Finally, activated GSK3β is also involved in the regulation of circadian rhythms (Bellivier et al., 2015), which have been strongly implicated in suicide and mood disorders through associative circadian rhythm CLOCK genes (Pawlak et al., 2015). Indeed, a mouse model of circadian rhythmicity has revealed that rhythms in the suprachiasmatic nucleus (SCN) of the
CR IP T
hypothalamus, hippocampal CLOCK genes and synaptic plasticity are directly regulated by
GSK3β (Besing et al., 2015; Besing et al., 2017). In humans, evidence of GSK3β regulation of circadian rhythms in suicide is sparse, but in mood disorders it has been found that BD lithium
AN US
treatment non-responders significantly increased expression of GSK3β while decreasing
expression of circadian clock genes in (Geoffroy et al., 2017), suggestive of an dysregulated association between GSK3β activity and circadian clock genes, an effect that was not seen in
M
treatment responders.
In sum, the actions of GSK3β, which are modulated directly by lithium, ultimately impact
ED
a number of key systems – all linked or strongly associated with suicidal thinking and
PT
behaviours and mood disorders.
Neurotransmission: Alterations in monoaminergic systems, involving serotonin in
CE
particular, have long been implicated in suicidal behaviours. For example, reductions in the
AC
concentration of serotonin metabolites such as 5-Hydroxyindoleacetic acid (5-HIAA), reflecting reduced serotonergic activity, have been thought of as potential biomarkers of suicide in psychiatric patients (Chatzittofis et al., 2013; Mann and Currier, 2007). Similarly diminished midbrain serotonin transporter binding in depressed suicide attempters (Miller et al., 2013) is also thought to reflect serotonergic neurotransmission compromise.
23
ACCEPTED MANUSCRIPT
Further bolstering the role of 5HT in suicide, links have been drawn between serotoninrelated genes and cognitive suicide endophenotypes. For example, the genes of tryptophan hydroxylase 1 (TPH1), a rate-limiting enzyme of serotonergic synthesis, and the 5hydroxytryptamine receptor 2A (HTR2A) have been associated with aggressive impulsivity
CR IP T
(Antypa et al., 2013; Bortolato et al., 2013). Similarly, the suicide endophenotype of
disadvantageous decision-making has been shown to be modulated by polymorphisms in
serotonergic genes, the serotonin transporter gene, SLC6A4, TPH1, MAOA and TPH2 (Jollant et
AN US
al., 2007). Thus, it would appear that the neural substrates of aggressive impulsivity and
disadvantageous decision-making involve changes in serotonergic neurotransmission at several levels.
M
Interestingly, GSK3β appears to be heavily involved in serotonergic neurotransmission. For example, animal evidence indicates that phosphorylation of GSK3β in the mouse brain is
ED
regulated by serotonergic activity, with 5-hydroxytryptamine receptor 1A (HTR1A) mediating
PT
increases while 5-hydroxytryptamine 2 (5HT2) receptors mediate decreases (Li et al., 2004). Furthermore, in Tryptophan hydroxylase 2 (TPH2) Knockin mice it was shown that the TPH gene
CE
produced serotonin (5-HT) synthesis deficiency that lead to activation in cortical GSK3 and associated behavioural abnormalities in a test that models endophenotypes of mood regulation
AC
(Beaulieu et al., 2008). The TPH2 gene induced GSK3β activation is further evidence of 5-HT involvement in GSK3β activity albeit in mood regulation. Therefore, serotonin is potentially an important target for the activity of GSK3β in the context of suicide.
24
ACCEPTED MANUSCRIPT
In sum, the intricate link between GSK3β activity and identified biomarkers implicated in suicide (see Figure 3) that are also associated with suicide endophenotypes, gives sufficient impetus to target and inhibit GSK3β in order to reduce suicide risk. The fact that lithium is an
CR IP T
effective inhibitor of GSK3β is therefore of considerable clinical significance. Limitations
There are methodological barriers that arose as a result of the complexity of both
AN US
suicide and lithium mechanisms of action. The expansive results returned by the search terms used precluded an extensive review of all relevant aspects of lithium’s anti-suicidal actions. Additionally, the present discussion was limited to suicide in the context of mood disorders, given the focus on lithium’s actions within the framework of the Neurocognitive Model of
M
Suicide that concentrates on suicidal thinking and behaviours within mood disorders.
ED
Furthermore, epigenetic mechanisms and potential role for lithium to reverse these epigenetic changes could not be addressed in this review.
PT
[Insert Figure 4 here]
CE
Conclusions and Future directions
AC
Suicide is a process. Tracking precisely where and when pharmacological interventions effect changes in that process is of clinical significance. But to achieve this, future research needs to adopt a longitudinal and prospective design so as to tap into the antecedents of suicide. This paper provides a novel perspective on the evaluation of suicide intervention strategies, by which treatments other than lithium may be considered. Figure 4 illustrates in
25
ACCEPTED MANUSCRIPT
summary form the mechanisms by which lithium perhaps effects its protective actions against suicidal thinking and behaviours. It provides an exemplar of the multi-level approach that can be used in the development of pharmacological agents for suicide prevention. An examination of the mechanisms of suicide – viewed through the lens of lithium’s actions - provides an
CR IP T
important neurobiological perspective that adds depth to the Neurocognitive Model of Suicide. This then provides a framework for enriching our understanding of suicide and improving
clinical practice, and within which targeted interventions can be developed. By combining
AN US
probes from different domains, for example blood and saliva biomarkers, brain neuroimaging techniques, parameters of neurocognitive function, and actigraphy monitoring, with the current approach of subjective self-reports, the responsiveness of individuals with suicidal thinking to therapeutic interventions such as lithium can be tracked and dissected in detail (see
[Insert Table 1 here]
ED
M
Table 1).
PT
Importantly, this broad set of assessments may be applicable in suicide assessment more generally – such that objective measurements of suicide can be made, and reliance on
CE
subjective self-reports can be minimised. It is therefore of great benefit to conduct further
AC
research in this area so as to identify and validate robust measures for use in clinical practice. Measuring changes at each of these levels of suicidal thinking and in each of these systems should provide a more comprehensive and meaningful picture of the neural brain of suicide insights which in themselves are likely to provide new opportunities for intervention and prevention.
26
ACCEPTED MANUSCRIPT
Role of funding source: The research conducted is supported by Australian Rotary Health Fund, NHMRC Program Grants (APP1073041; APP1050848 and APP1121510), the Ramsay Health Research and Teaching Fund, NSW Agency for Clinical Innovation and NSW Ministry of Health, Lundbeck and grants
CR IP T
(PRG-0-090-14; SRG-0-089-16) awarded to GSM from the American Foundation for Suicide Prevention. The content is solely the responsibility of the authors and does not necessarily represent the official views of the American Foundation for Suicide Prevention nor any of the sponsors.
AN US
Acknowledgements: GM conceived the idea, approach and structure of review and in consensus with ZM, PD and TO as to the best approach to take. GM subsequently conducted multiple edits keeping an overview of the scope of the review within the commissioned parameters. ZM performed primary literature searches with secondary searches conducted by LI and KL. ZM also synthesised evidence to
M
produce the initial drafts, and GM, LI, PD and KL edited multiple drafts as often as necessary. The final
ED
drafts were produced with all named authors having viewed the manuscript and making
CE
PT
recommendations to improve the quality and coherence of the paper.
References
AC
Adida, M., Jollant, F., Clark, L., Guillaume, S., Goodwin, G.M., Azorin, J.M., Courtet, P., 2015. Lithium might be associated with better decision-making performance in euthymic bipolar patients. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 25, 788797. Ahrens, B., Müller-Oerlinghausen, B., 2001. Does lithium exert an independent antisuicidal effect? Pharmacopsychiatry, 34 132-136. Ambrus, L., Lindqvist, D., Träskman-Bendz, L., Westrin, Å., 2016. Hypothalamic–pituitary–adrenal axis hyperactivity is associated with decreased brain-derived neurotrophic factor in female suicide attempters Nord J Psychiatry 70 575-581.
27
ACCEPTED MANUSCRIPT
Anderson, C.A., Bushman, B.J., 2002. Human aggression. Annual review of psychology 53, 27-51. Anokhin, A.P., Grant, J.D., Mulligan, R.C., Heath, A.C., 2015. The genetics of impulsivity: evidence for the heritability of delay discounting. Biol Psychiatry 77, 887-894. Antypa, N., Serretti, A., Rujescu, D., 2013. Serotonergic genes and suicide: a systematic review. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 23, 1125-1142.
CR IP T
Arsenault-Lapierre, G., Kim, C., Turecki, G., 2004. Psychiatric diagnoses in 3275 suicides: a meta-analysis. BMC psychiatry 4, 37. Atkinson Jr, A.J., Colburn, W.A., DeGruttola, V.G., DeMets, D.L., Downing, G.J., &, Spilker, B.A., 2001. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clinical pharmacology and therapeutics 69, 89-95. Baldessarini, R.J., Tondo, L., Davis, P., Pompili, M., Goodwin, F.K., Hennen, J., 2006. Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord 8, 625639.
AN US
Ballard, E.D., Vande Voort, J.L., Bernert, R.A., Luckenbaugh, D.A., Richards, E.M., Niciu, M.J., Furey, M.L., Duncan, W.C., Jr., Zarate, C.A., Jr., 2016. Nocturnal Wakefulness Is Associated With Next-Day Suicidal Ideation in Major Depressive Disorder and Bipolar Disorder. J Clin Psychiatry 77, 825-831. Beauchaine, T.P., 2009. The Role of Biomarkers and Endophenotypes in Prevention and Treatment of Psychopathological Disorders. Biomarkers in medicine 3, 1-3.
M
Beauchaine, T.P., Constantino, J.N., 2017. Redefining the endophenotype concept to accommodate transdiagnostic vulnerabilities and etiological complexity. Biomarkers in medicine.
ED
Beaulieu, J.M., Zhang, X., Rodriguiz, R.M., Sotnikova, T.D., Cools, M.J., Wetsel, W.C., Gainetdinov, R.R., Caron, M.G., 2008. Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proceedings of the National Academy of Sciences of the United States of America 105, 1333-1338. Bellivier, F., Geoffroy, P.A., Etain, B., Scott, J., 2015. Sleep- and circadian rhythm-associated pathways as therapeutic targets in bipolar disorder. Expert opinion on therapeutic targets 19, 747-763.
PT
Bellivier, F., Guillaume, S., 2016. Lithium: The Key Antisuicide Agent In: Courtet, P. (Ed.), Understanding Suicide. Springer, Cham, Switzerland, pp. 303-311.
CE
Benedetti, F., Bollettini, I., Barberi, I., Radaelli, D., Poletti, S., Locatelli, C., Pirovano, A., Lorenzi, C., Falini, A., Colombo, C., Smeraldi, E., 2013. Lithium and GSK3-beta promoter gene variants influence white matter microstructure in bipolar disorder. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 38, 313-327.
AC
Benedetti, F., Dallaspezia, S., Fulgosi, M.C., Lorenzi, C., Serretti, A., Barbini, B., Colombo, C., Smeraldi, E., 2007. Actimetric evidence that CLOCK 3111 T/C SNP influences sleep and activity patterns in patients affected by bipolar depression. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 144b, 631-635. Benedetti, F., Poletti, S., Radaelli, D., Locatelli, C., Pirovano, A., Lorenzi, C., Vai, B., Bollettini, I., Falini, A., Smeraldi, E., Colombo, C., 2015. Lithium and GSK-3beta promoter gene variants influence cortical gray matter volumes in bipolar disorder. Psychopharmacology (Berl) 232, 1325-1336.
28
ACCEPTED MANUSCRIPT
Benedetti, F., Radaelli, D., Poletti, S., Locatelli, C., Falini, A., Colombo, C., Smeraldi, E., 2011. Opposite effects of suicidality and lithium on gray matter volumes in bipolar depression J. Affect. Disord 135, 139147. Bernert, R.A., Kim, J.S., Iwata, N.G., Perlis, M.L., 2015. Sleep disturbances as an evidence-based suicide risk factor. Curr Psychiatry Rep 17, 554.
CR IP T
Besing, R.C., Paul, J.R., Hablitz, L.M., Rogers, C.O., Johnson, R.L., Young, M.E., Gamble, K.L., 2015. Circadian rhythmicity of active GSK3 isoforms modulates molecular clock gene rhythms in the suprachiasmatic nucleus. Journal of biological rhythms 30, 155-160. Besing, R.C., Rogers, C.O., Paul, J.R., Hablitz, L.M., Johnson, R.L., McMahon, L.L., Gamble, K.L., 2017. GSK3 activity regulates rhythms in hippocampal clock gene expression and synaptic plasticity. Hippocampus 27, 890-898. Beurel, E., Jope, R.S., 2014. Inflammation and lithium: clues to mechanisms contributing to suicidelinked traits. Transl Psychiatry 4, e488.
AN US
Blasco-Fontecilla, H., Oquendo, M.A., 2016. Biomarkers of Suicide: Predicting the Predictable?, In: Courtet, P. (Ed.), Understanding Suicide. Springer, pp. 77-83.
Bortolato, M., Pivac, N., Muck Seler, D., Nikolac Perkovic, M., Pessia, M., Di Giovanni, G., 2013. The role of the serotonergic system at the interface of aggression and suicide. Neuroscience 236, 160-185. Braquehais, M.D., Picouto, M.D., Casas, M., Sher, L., 2012. Hypothalamic-pituitary-adrenal axis dysfunction as a neurobiological correlate of emotion dysregulation in adolescent suicide World Journal of Pediatrics 8 197-206.
M
Broche-Perez, Y., Herrera Jimenez, L.F., Omar-Martinez, E., 2016. Neural substrates of decision-making. Neurologia (Barcelona, Spain) 31, 319-325.
ED
Calabrese, F., Rossetti, A.C., Racagni, G., Gass, P., Riva, M.A., Molteni, R., 2014. Brain-derived neurotrophic factor: a bridge between inflammation and neuroplasticity. Frontiers in cellular neuroscience 8, 430.
PT
Can, A., Schulze, T.G., Gould, T.D., 2014. Molecular actions and clinical pharmacogenetics of lithium therapy. Pharmacology, biochemistry, and behavior 123, 3-16.
CE
Chang, C.C., Tzeng, N.S., Kao, Y.C., Yeh, C.B., Chang, H.A., 2017. The relationships of current suicidal ideation with inflammatory markers and heart rate variability in unmedicated patients with major depressive disorder. Psychiatry Res 258, 449-456.
AC
Chatzittofis, A., Nordstrom, P., Hellstrom, C., Arver, S., Asberg, M., Jokinen, J., 2013. CSF 5-HIAA, cortisol and DHEAS levels in suicide attempters. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 23, 1280-1287. Chistiakov, D.A., Kekelidze, Z.I., Chekhonin, V.P., 2012. Endophenotypes as a measure of suicidality. Journal of applied genetics 53, 389-413. Cipriani, A., Hawton, K., Stockton, S., Geddes, J.R., 2013. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. . British Medical Journal 346, , f3646. Coccaro, E.F., Lee, R., Gozal, D., 2016. Elevated Plasma Oxidative Stress Markers in Individuals With Intermittent Explosive Disorder and Correlation With Aggression in Humans. Biol Psychiatry 79, 127-135.
29
ACCEPTED MANUSCRIPT
Comai, S., Tau, M., Gobbi, G., 2012. The psychopharmacology of aggressive behavior: a translational approach: part 1: neurobiology. Journal of clinical psychopharmacology 32, 83-94. Courtet, P., Gottesman, II, Jollant, F., Gould, T.D., 2011a. The neuroscience of suicidal behaviors: what can we expect from endophenotype strategies? Transl Psychiatry 1. Courtet, P., Gottesman, I.I., Jollant, F., Gould, T.D., 2011b. The neuroscience of suicidal behaviors: what can we expect from endophenotype strategies? . Translational Psychiatry 1, e7.
CR IP T
Coutlee, C.G., Huettel, S.A., 2012. The functional neuroanatomy of decision making: prefrontal control of thought and action. Brain research 1428, 3-12. Duffy, A., Grof, P., 2018. Lithium Treatment in Children and Adolescents. Pharmacopsychiatry.
Ernst, C.L., Goldberg, J.F., 2004. Antisuicide properties of psychotropic drugs: a critical review. Harvard review of psychiatry 12, 14-41.
AN US
Findling, R.L., Kafantaris, V., Pavuluri, M., McNamara, N.K., Frazier, J.A., Sikich, L., Kowatch, R., Rowles, B.M., Clemons, T.E., Taylor-Zapata, P., 2013. Post-acute effectiveness of lithium in pediatric bipolar I disorder. Journal of child and adolescent psychopharmacology 23, 80-90. Findling, R.L., Kafantaris, V., Pavuluri, M., McNamara, N.K., McClellan, J., Frazier, J.A., Sikich, L., Kowatch, R., Lingler, J., Faber, J., Rowles, B.M., Clemons, T.E., Taylor-Zapata, P., 2011. Dosing strategies for lithium monotherapy in children and adolescents with bipolar I disorder. Journal of child and adolescent psychopharmacology 21, 195-205.
M
Findling, R.L., Robb, A., McNamara, N.K., Pavuluri, M.N., Kafantaris, V., Scheffer, R., Frazier, J.A., Rynn, M., DelBello, M., Kowatch, R.A., Rowles, B.M., Lingler, J., Martz, K., Anand, R., Clemons, T.E., TaylorZapata, P., 2015. Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, PlaceboControlled Study. Pediatrics 136, 885-894.
ED
Fontaine, R.G., Dodge, K.A., 2006. Real-Time Decision Making and Aggressive Behavior in Youth: A Heuristic Model of Response Evaluation and Decision (RED). Aggressive behavior 32, 604-624.
PT
Geoffroy, P.A., Curis, E., Courtin, C., Moreira, J., Morvillers, T., Etain, B., Laplanche, J.L., Bellivier, F., Marie-Claire, C., 2017. Lithium response in bipolar disorders and core clock genes expression. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry, 1-14. Geoffroy, P.A., Etain, B., 2017. Lithium and Circadian Rhythms. Springer, Switzerland.
CE
Giakoumatos, C.I., Nanda, P., Mathew, I.T., Tandon, N., Shah, J., Bishop, J.R., Clementz, B.A., Pearlson, G.D., Sweeney, J.A., Tamminga, C.A., Keshavan, M.S., 2015. Effects of lithium on cortical thickness and hippocampal subfield volumes in psychotic bipolar disorder. J Psychiatr Res 61, 180-187.
AC
Gill, R., Tsung, A., Billiar, T., 2010. Linking oxidative stress to inflammation: Toll-like receptors. Free radical biology & medicine 48, 1121-1132. Gottesman, I.I., Gould, T.D., 2003. The endophenotype concept in psychiatry: etymology and strategic intentions The American journal of psychiatry 160, 636-645. Gould, T.D., Georgiou, P., Brenner, L.A., Brundin, L., Can, A., Courtet, P., Donaldson, Z.R., Dwivedi, Y., Guillaume, S., Gottesman, II, Kanekar, S., Lowry, C.A., Renshaw, P.F., Rujescu, D., Smith, E.G., Turecki, G., Zanos, P., Zarate, C.A., Jr., Zunszain, P.A., Postolache, T.T., 2017. Animal models to improve our understanding and treatment of suicidal behavior. Transl Psychiatry 7, e1092.
30
ACCEPTED MANUSCRIPT
Grant, B., Salpekar, J.A., 2018. Using Lithium in Children and Adolescents with Bipolar Disorder: Efficacy, Tolerability, and Practical Considerations. Paediatric drugs. Gupta, V., Chitranshi, N., You, Y., Klistorner, A., Graham, S., 2014. Brain derived neurotrophic factor is involved in the regulation of glycogen synthase kinase 3beta (GSK3beta) signalling. Biochemical and biophysical research communications 454, 381-386.
CR IP T
Halcomb, M.E., Gould, T.D., Grahame, N.J., 2013. Lithium, but not valproate, reduces impulsive choice in the delay-discounting task in mice. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 38, 1937-1944. Hallahan, B., Newell, J., Soares, J.C., Brambilla, P., Strakowski, S.M., Fleck, D.E., Kieseppä, T., Altshuler, L.L., Fornito, A., Malhi, G.S., 2011. Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient data. Biol Psychiatry 69, 326-335. Hoehne, A., Richard-Devantoy, S., Ding, Y., Turecki, G., Jollant, F., 2015. First-degree relatives of suicide completers may have impaired decision-making but functional cognitive control. J Psychiatr Res 68, 192197.
AN US
Homberg, J.R., 2012. Serotonin and decision making processes. Neuroscience and biobehavioral reviews 36, 218-236. Hood, S., Amir, S., 2018. Biological Clocks and Rhythms of Anger and Aggression. Frontiers in behavioral neuroscience 12, 4.
M
Ingram, K.K., Ay, A., Kwon, S.B., Woods, K., Escobar, S., Gordon, M., Smith, I.H., Bearden, N., Filipowicz, A., Jain, K., 2016. Molecular insights into chronotype and time-of-day effects on decision-making. Sci Rep 6, 29392. Jimenez-Trevino, L., Blasco-Fontecilla, H., Braquehais, M.D., Ceverino-Dominguez, A., Baca-Garcia, E., 2011. Endophenotypes and suicide behaviour. Actas espanolas de psiquiatria 39, 61-69.
ED
Jokinen, J., Carlborg, A., Mårtensson, B., Forslund, K., Nordström, A.L., Nordström, P., 2007. DST nonsuppression predicts suicide after attempted suicide. Psychiatry Research 150, 297-303.
PT
Jokinen, J., Nordström, P., 2009. HPA axis hyperactivity and attempted suicide in young adult mood disorder inpatients Journal of Affective Disorders 116 117-120.
CE
Jollant, F., Buresi, C., Guillaume, S., Jaussent, I., Bellivier, F., Leboyer, M., Castelnau, D., Malafosse, A., Courtet, P., 2007. The influence of four serotonin-related genes on decision-making in suicide attempters. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 144B, 615-624.
AC
Jones, H., Geddes, J., Cipriani, A., 2017. Lithium and suicide prevention, The Science and Practice of Lithium Therapy. Springer, pp. 223-240. Jones, R.M., Arlidge, J., Gillham, R., Reagu, S., van den Bree, M., Taylor, P.J., 2011. Efficacy of mood stabilisers in the treatment of impulsive or repetitive aggression: systematic review and meta-analysis. The British journal of psychiatry : the journal of mental science 198, 93-98. Jope, R.S., Cheng, Y., Lowell, J.A., Worthen, R.J., Sitbon, Y.H., Beurel, E., 2017. Stressed and Inflamed, Can GSK3 Be Blamed? Trends in biochemical sciences 42, 180-192. Kelly, R.E., Mansell, W., Sadhnani, V., Wood, A.M., 2012. Positive and negative appraisals of the consequences of activated states uniquely relate to symptoms of hypomania and depression. . Cogn Emot 26, 899-906.
31
ACCEPTED MANUSCRIPT
Khan, A., Khan, S.R., Hobus, J., Faucett, J., Mehra, V., Giller, E.L., Rudolph, R.L., 2011. Differential pattern of response in mood symptoms and suicide risk measures in severely ill depressed patients assigned to citalopram with placebo or citalopram combined with lithium: role of lithium levels. J Psychiatr Res 45, 1489-1496. Kovacsics, C.E., Gottesman, I.I., Gould, T.D., 2009. Lithium's antisuicidal efficacy: elucidation of neurobiological targets using endophenotype strategies Annu Rev Pharmacol Toxicol. 49 175-198.
CR IP T
Kunugi, H., Hori, H., Adachi, N., Numakawa, T., 2010. Interface between hypothalamic-pituitary-adrenal axis and brain-derived neurotrophic factor in depression. Psychiatry and clinical neurosciences 64, 447459. Landersdorfer, C.B., Findling, R.L., Frazier, J.A., Kafantaris, V., Kirkpatrick, C.M., 2017. Lithium in Paediatric Patients with Bipolar Disorder: Implications for Selection of Dosage Regimens via Population Pharmacokinetics/Pharmacodynamics. Clinical pharmacokinetics 56, 77-90.
AN US
Lenzenweger, M.F., 2013. Thinking clearly about the endophenotype-intermediate phenotypebiomarker distinctions in developmental psychopathology research. Development and psychopathology 25, 1347-1357. Lera-Miguel, S., Andres-Perpina, S., Fatjo-Vilas, M., Fananas, L., Lazaro, L., 2015. Two-year follow-up of treated adolescents with early-onset bipolar disorder: Changes in neurocognition. J Affect Disord 172, 48-54.
M
Lewitzka, U., Jabs, B., Fulle, M., Holthoff, V., Juckel, G., Uhl, I., Kittel-Schneider, S., Reif, A., ReifLeonhard, C., Gruber, O., Djawid, B., Goodday, S., Haussmann, R., Pfennig, A., Ritter, P., Conell, J., Severus, E., Bauer, M., 2015a. Does lithium reduce acute suicidal ideation and behavior? A protocol for a randomized, placebo-controlled multicenter trial of lithium plus Treatment As Usual (TAU) in patients with suicidal major depressive episode. BMC psychiatry 15, 117.
ED
Lewitzka, U., Severus, E., Bauer, R., Ritter, P., Muller-Oerlinghausen, B., Bauer, M., 2015b. The suicide prevention effect of lithium: more than 20 years of evidence-a narrative review. International journal of bipolar disorders 3, 32.
PT
Li, X., Zhu, W., Roh, M.S., Friedman, A.B., Rosborough, K., Jope, R.S., 2004. In vivo regulation of glycogen synthase kinase-3beta (GSK3beta) by serotonergic activity in mouse brain. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 29, 1426-1431.
CE
Luca, A., Calandra, C., Luca, M., 2016. Gsk3 Signalling and Redox Status in Bipolar Disorder: Evidence from Lithium Efficacy. Oxidative medicine and cellular longevity 2016, 3030547. Malhi, G.S., Outhred, T., 2016. Therapeutic mechanisms of lithium in bipolar disorder: recent advances and current understanding. . CNS drugs, 30 931-949.
AC
Malhi, G.S., Outhred, T., Das, P., 2017. Lithium: neurotransmission and cellular mechanism pathways underlying neuroprogression in bipolar disorder. , In: Malhi, G.S., Masson, M.C., Bellivier, F. (Eds.), The Science and Practice of Lithium Therapy Springer, Cham., Switzerland, pp. 55-75. Malhi, G.S., Outhred, T., Das, P., Morris, G., Hamilton, A., Mannie, Z., 2018. Modelling Suicide in Bipolar Disorders. Bipolar Disord. Malhi, G.S., Tanious, M., Das, P., Coulston, C.M., Berk, M., 2013. Potential mechanisms of action of lithium in bipolar disorder CNS drugs 27 135-153.
32
ACCEPTED MANUSCRIPT
Mann, J.J., 2013. The serotonergic system in mood disorders and suicidal behaviour. . Philos Trans R Soc Lond B Biol Sci. 368 20120537. Mann, J.J., Arango, V.A., Avenevoli, S., Brent, D.A., Champagne, F.A., Clayton, P.J., &, Kleinman, J., 2009. Candidate endophenotypes for genetic studies of suicidal behavior Biol. Psychiatry 65, 556-563. Mann, J.J., Brent, D.A., Arango, V., 2001. The neurobiology and genetics of suicide and attempted suicide: a focus on the serotonergic system. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 24, 467-477.
CR IP T
Mann, J.J., Currier, ., 2 . A review of prospective studies of biologic predictors of suicidal behavior in mood disorders Arch. Suicide Res 11 3-16. Masi, G., Milone, A., Manfredi, A., Pari, C., Paziente, A., Millepiedi, S., 2009. Effectiveness of lithium in children and adolescents with conduct disorder: a retrospective naturalistic study. CNS Drugs 23, 59-69. Mathews, D., Richards, E., Niciu, M., Ionescu, D., Rasimas, J., Zarate, C., 2013. Neurobiological aspects of suicide and suicide attempts in bipolar disorder J Transl Neurosci. 4 203-216.
AN US
Miller, J.M., Hesselgrave, N., Ogden, R.T., Sullivan, G.M., Oquendo, M.A., Mann, J.J., Parsey, R.V., 2013. Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder. Biol Psychiatry 74, 287-295. Monkul, E.S., Matsuo, K., Nicoletti, M.A., Dierschke, N., Hatch, J.P., Dalwani, M., Brambilla, P., Caetano, S., Sassi, R.B., Mallinger, A.G., Soares, J.C., 2007. Prefrontal gray matter increases in healthy individuals after lithium treatment: a voxel-based morphometry study. Neuroscience letters 429, 7-11.
M
Muller-Oerlinghausen, B., Lewitzka, U., 2010. Lithium reduces pathological aggression and suicidality: a mini-review. Neuropsychobiology 62, 43-49.
ED
Nguyen, T., Fan, T., George, S.R., Perreault, M.L., 2017. Disparate Effects of Lithium and a GSK-3 Inhibitor on Neuronal Oscillatory Activity in Prefrontal Cortex and Hippocampus. Frontiers in aging neuroscience 9, 434.
PT
O'Donovan, A., Rush, G., Hoatam, G., Hughes, B.M., McCrohan, A., Kelleher, C., O'Farrelly, C., Malone, K.M., 2013. Suicidal ideation is associated with elevated inflammation in patients with major depressive disorder. Depression and anxiety 30, 307-314.
CE
Ohmura, Y., Tsutsui-Kimura, I., Kumamoto, H., Minami, M., Izumi, T., Yamaguchi, T., Yoshida, T., Yoshioka, M., 2012. Lithium, but not valproic acid or carbamazepine, suppresses impulsive-like action in rats. Psychopharmacology (Berl) 219, 421-432.
AC
Pawlak, J., Dmitrzak-Weglarz, M., Maciukiewicz, M., Wilkosc, M., Leszczynska-Rodziewicz, A., Zaremba, D., &, Hauser, J., 2015. Suicidal behavior in the context of disrupted rhythmicity in bipolar disorder— Data from an association study of suicide attempts with clock genes Psychiatry Res 226 517-520. Price, R.B., Iosifescu, D.V., Murrough, J.W., Chang, L.C., Al Jurdi, R.K., Iqbal, S.Z., Soleimani, L., Charney, D.S., Foulkes, A.L., Mathew, S.J., 2014. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depression and anxiety 31, 335-343. Quevedo, J., Yatham, L.N., 2018. Biomarkers in mood disorders: Are we there yet? J Affect Disord 233, 12. Raja, M., Azzoni, A., 2004. Suicide attempts: differences between unipolar and bipolar patients and among groups with different lethality risk. J Affect Disord 82, 437-442.
33
ACCEPTED MANUSCRIPT
Rajkowska, G., Clarke, G., Mahajan, G., Licht, C.M., van de Werd, H.J., Yuan, P., Stockmeier, C.A., Manji, H.K., Uylings, H.B., 2016. Differential effect of lithium on cell number in the hippocampus and prefrontal cortex in adult mice: a stereological study. Bipolar Disord 18, 41-51. Richard-Devantoy, S., Berlim, M.T., Jollant, F., 2015. Suicidal behaviour and memory: A systematic review and meta-analysis. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 16, 544-566.
CR IP T
Rogers, R.D., 2011. The roles of dopamine and serotonin in decision making: evidence from pharmacological experiments in humans. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 36, 114-132.
Rowe, M.K., Wiest, C., Chuang, D.M., 2007. GSK-3 is a viable potential target for therapeutic intervention in bipolar disorder. Neuroscience and biobehavioral reviews 31, 920-931. Rudebeck, P.H., Saunders, R.C., Lundgren, D.A., Murray, E.A., 2017. Specialized Representations of Value in the Orbital and Ventrolateral Prefrontal Cortex: Desirability versus Availability of Outcomes. Neuron 95, 1208-1220 e1205.
AN US
Samuelsson, M., Jokinen, J., Nordström, A.L., Nordström, P., 2006. CSF 5-HIAA, suicide intent and hopelessness in the prediction of early suicide in male high‐risk suicide attempters Acta Psychiatr. Scand. 113, 44-47. Schafer, M., Goodenough, S., Moosmann, B., Behl, C., 2004. Inhibition of glycogen synthase kinase 3 beta is involved in the resistance to oxidative stress in neuronal HT22 cells. Brain research 1005, 84-89.
M
Schaffer, A., Isometsä, E.T., Azorin, J.M., Cassidy, F., Goldstein, T., Rihmer, Z., &, Reis, C., 2015. A review of factors associated with greater likelihood of suicide attempts and suicide deaths in bipolar disorder: Part II of a report of the International Society for Bipolar Disorders Task Force on Suicide in Bipolar Disorder Aust N Z J Psychiatry 49 1006-1020.
ED
Sheard, M., 1971. Effect of lithium on human aggression. Nature 230, 113-114. Sheard, M.H., Marini, J.L., Bridges, C.I., Wagner, E., 1976. The effect of lithium on impulsive aggressive behavior in man. The American journal of psychiatry 133, 1409-1413.
PT
Smith, K.A., Cipriani, A., 2017. Lithium and suicide in mood disorders: Updated meta-review of the scientific literature. . Bipolar Disord 00, 1-12.
CE
Stange, J.P., Kleiman, E.M., Sylvia, L.G., Magalhaes, P.V., Berk, M., Nierenberg, A.A., Deckersbach, T., 2016. Specific mood symptoms confer risk for subsequent suicidal ideation in Bipolar Disorder with and without suicide attempt history: Multi-wave data from STEP-BD. Depression and anxiety 33, 464-472.
AC
Stepanova, E., Findling, R.L., 2017. Psychopharmacology of Bipolar Disorders in Children and Adolescents. Pediatric clinics of North America 64, 1209-1222. Toffol, E., Hatonen, T., Tanskanen, A., Lonnqvist, J., Wahlbeck, K., Joffe, G., Tiihonen, J., Haukka, J., Partonen, T., 2015. Lithium is associated with decrease in all-cause and suicide mortality in high-risk bipolar patients: A nationwide registry-based prospective cohort study. J Affect Disord 183, 159-165. Tondo, L., Baldessarini, R.J., 2016. Suicidal Behavior in Mood Disorders: Response to Pharmacological Treatment. Curr Psychiatry Rep 18, 88. Tondo, L., Baldessarini, R.J., 2018. Antisuicidal Effects in Mood Disorders: Are They Unique to Lithium? Pharmacopsychiatry.
34
ACCEPTED MANUSCRIPT
Turecki, G., 2005. Dissecting the suicide phenotype: the role of impulsive-aggressive behaviours. Journal of psychiatry & neuroscience : JPN 30, 398-408. Turecki, G., 2016. Epigenetics, in: Courtet, P. (Ed.), Understanding Suicide. Springer, pp. 97-110. Vargas, H.O., Nunes, S.O., Pizzo de Castro, M., Bortolasci, C.C., Sabbatini Barbosa, D., Kaminami Morimoto, H., Venugopal, K., Dodd, S., Maes, M., Berk, M., 2013. Oxidative stress and lowered total antioxidant status are associated with a history of suicide attempts. J Affect Disord 150, 923-930.
CR IP T
Vernon, A.C., Natesan, S., Crum, W.R., Cooper, J.D., Modo, M., Williams, S.C., Kapur, S., 2012. Contrasting effects of haloperidol and lithium on rodent brain structure: a magnetic resonance imaging study with postmortem confirmation. Biol Psychiatry 71, 855-863. Weitz, E., Hollon, S.D., Kerkhof, A., Cuijpers, P., 2014. Do depression treatments reduce suicidal ideation? The effects of CBT, IPT, pharmacotherapy, and placebo on suicidality. J Affect Disord 167, 98103. World Health Organization, 2014. Preventing suicide: a global imperative World Health Organization.
AN US
Zalsman, G., Braun, M., Arendt, M., Grunebaum, M.F., Sher, L., Burke, A.K., &, Oquendo, M.A., 2006. A comparison of the medical lethality of suicide attempts in bipolar and major depressive disorders. . Bipolar Disorders, 8, 558-565.
M
Zisook, S., Lesser, I.M., Lebowitz, B., Rush, A.J., Kallenberg, G., Wisniewski, S.R., Nierenberg, A.A., Fava, M., Luther, J.F., Morris, D.W., Trivedi, M.H., 2011. Effect of antidepressant medication treatment on suicidal ideation and behavior in a randomized trial: an exploratory report from the Combining Medications to Enhance Depression Outcomes Study. J Clin Psychiatry 72, 1322-1332.
ED
Figure Captions – Understanding suicide: focusing on its mechanisms through a lithium lens
PT
(Malhi et al., 2018)
CE
Figure 1. The Neurocognitive Model of Suicide in the context of Mood Disorders (adapted from Malhi et al, 2018), depicts the levels at which abnormalities are present in suicidal
AC
individuals alongside its neural substrates. This multi-factorial model accommodates neurobiological factors, including cellular mechanisms and neurotransmission, and the neurocircuitry that underpins neurocognitive processes. Together, changes at these levels contribute to the clinical presentation of suicidal thinking and behaviours. Approaching suicide from this perspective enables a deep understanding of the mechanisms underlying suicide. The 35
ACCEPTED MANUSCRIPT
model illustrates how psychopharmacological treatments can target suicidal thinking at multiple levels, by modifying cellular and molecular mechanisms, neurotransmission,
CR IP T
neurocircuitry and neurocognition.
Figure 2. The actions of lithium bridge suicidal thinking and its underlying neurobiology. A schematic bridging the underlying neurobiological mechanisms of the clinical anti-suicidal
AN US
effects of lithium (black arrows) to suicidal thinking and behaviours, via endophenotypes and cognitive appraisal. Suicide endophenotypes are well established, but underlying neurobiological mechanisms remain a grey area (indicated by grey shading). Although direct evidence for lithium’s effects on suicide endophenotypes and cognitive appraisals is limited
M
(grey, dashed arrows), lithium’s neurobiological mechanisms are well understood and evidence
ED
of its anti-suicidal effects continues to grow. These mechanisms can be linked to suicidal thinking and behaviours via suicide endophenotypes, connections which may be bidirectional.
PT
Therefore, by looking through the lens of lithium, we may be able to examine the
CE
neurobiological processes that are abnormal in suicidal individuals.
AC
Figure 3. Schematic depicting the potential biomarkers affected by lithium and therefore implicated in suicide in mood disorders. By inhibiting GSK3β activity lithium targets a number of anti-suicidal biomarkers. Intracellularly, lithium inhibits GSK3β directly and thereby reduces oxidative stress and inflammation. Inhibition of GSK3β by lithium also enhances neuroplasticity and serves to regulate circadian CLOCK gene expression. Extracellularly, lithium has 36
ACCEPTED MANUSCRIPT
bidirectional effects on GSK3β that result in modulation of the HPA axis and regulation of neurotransmission – involving serotonin (5HT) in particular.
CR IP T
Figure 4. A schematic summary of the pathways through which lithium prevents suicide.
Importantly, this gives a framework by which to approach evaluation of novel agents for suicide intervention. Assessment of suicide can be conducted at each node of the pathway, broadening
AN US
the methods by which suicidal thinking and behaviour can be identified clinically.
M
Table 1. Potential tools for suicide assessment.
Empirical Assessments
Emerging Assessments
Clinical presentation
Sheehan Suicidality Tracking Scale (S-STS)
Interpersonal Needs Questionnaire (INQ) (Van
(Coric et al., 2009)
Orden et al., 2012)
Columbia Suicide Severity Rating Scale (C-SSRS)
Acquired Capability for Suicide Scale (ACSS)
(Posner et al., 2011)
(Van Orden et al., 2008)
Buss-Perry Aggression Questionnaire – Short
Point Subtraction Aggression Paradigm (PSAP)
Form (BPAQ-SF) (Bryant and Smith, 2001)
(Bridge et al., 2015) (Geniole et al., 2017)
AC
CE
PT
ED
Assessment Level
Neurocognition
Barratt Impulsiveness Scale (BIS) (Fossati et al., 2002, Bridge et al., 2015)
(Skibsted et al., 2017). Cambridge Gambling Task (CGT) (Masaki et al.,
37
ACCEPTED MANUSCRIPT
Overt Aggression Scale (OAS) (Malone et al., 1994, Rifkin et al., 1997).
2016) (Halcomb et al., 2013) Information Sampling Test (IST) (Bersani et al.,
Iowa Gambling Task (IGT)
2016).
Delay Discounting Task (DDT)
Resilience Appraisal Scale (RAS) (Johnson et al.,
CR IP T
2010) Implicit Association Test of Risk Propensity Self-Concept (IAT-RPSC) (Horcajo et al., 2014),
Functional and resting state MRI (fMRI and
Pharmaco-Magnetoencelography (pMEG)
rsMRI)
(Muthukumaraswamy, 2014)
Diffusion tensor imaging (DTI)
AN US
Neurocircuitry
Magnetic resonance spectroscopy (MRS) (Szulc
M
et al., 2018)
Dexamethasone suppression test (DST)*
Actigraphy of sleep parameters** (Geoffroy et
and neurotransmission
(Mann et al., 2006, Jokinen et al., 2007)
al., 2014, Morgenthaler et al., 2007).
Dexamethasone/corticotrophin-releasing
Biological Rhythms Interview for Assessment in
hormone suppression test (Dex/CRH)* (Bschor
Neuropsychiatry** (BRIAN; Giglio et al., 2009)
PT
ED
Cellular mechanisms
et al., 2011).
CE
F2-isoprostanes* (Milne et al., 2005)
Melatonin* (Pacchierotti et al., 2001, Pfeffer et
AC
al., 2018). Pittsburgh Sleep Quality Index (PSQI; Buysse et al., 1989) Cerebrospinal fluid 5-HIAA (CSF 5-HIAA)* Interleukin-6 (IL-6)*
38
Malondialdehyde (MDA)* (Vargas et al., 2013)
ACCEPTED MANUSCRIPT
Tumor necrosis factor α (TNFα)* Brain-derived neurotrophic factor (BDNF)* GSK3β*
CR IP T
* measured from blood or saliva
** These measures are included as assessments of cellular mechanisms because of their
association with circadian rhythm dysregulation and CLOCK genes, such that they can be
AC
CE
PT
ED
M
AN US
considered behavioural manifestations of molecular clock gene alterations or mutations.
39