Animal models of suicide-trait-related behaviors
Oz Malkesman1,3, Daniel S. Pine2,3, Tyson Tragon1,3, Daniel R. Austin1,3, Ioline D. Henter3, Guang Chen1,3 and Husseini K. Manji1,3

Laboratory of Molecular Pathophysiology, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA 2 Section on Development and Affective Neuroscience, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA 3 Mood and Anxiety Disorders Research Program, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA

Although antidepressants are moderately effective in treating major depressive disorder (MDD), concerns have arisen that selective serotonin-reuptake inhibitors (SSRIs) are associated with suicidal thinking and behavior, especially in children, adolescents and young adults. Almost no experimental research in model systems has considered the mechanisms by which SSRIs might be associated with this potential side effect in some susceptible individuals. Suicide is a complex behavior and impossible to fully reproduce in an animal model. However, by investigating traits that show strong cross-species parallels in addition to associations with suicide in humans, animal models might elucidate the mechanisms by which SSRIs are associated with suicidal thinking and behavior. Traits linked with suicide in humans that can be successfully modeled in rodents include aggression, impulsivity, irritability and hopelessness/helplessness. Modeling these relevant traits in animals can help to clarify the impact of SSRIs on these traits, suggesting avenues for reducing suicide risk in this vulnerable population. Introduction In 2005, suicide was the eleventh leading cause of death in the United States [1]. For individuals aged 5 to 14, however, suicide was the fourth, and for those aged 15 to 24 it was the third leading cause of death. Suicide in young people is a global concern, and youth suicide prevention is an important priority in most countries [2]. The risk of suicide during antidepressant drug treatment (specifically during treatment with selective serotonin-reuptake inhibitors [SSRIs]) has been debated for >40 years. Although some studies have supported this association [3], others have noted methodological limitations that preclude firm conclusions [4,5]. Considerable controversy surrounds the specific relationship between antidepressants and suicide in the young. Major depressive disorder (MDD) is the most frequent diagnosis among youths committing suicide [6], and antidepressant medications are at least moderately effective in treating MDD in the young [7]. However, concerns have arisen that
Corresponding author: Manji, H.K. (manji@nih.gov).

antidepressants in general, and SSRIs in particular, might actually increase risk for suicidal thoughts and behavior in this population [5]. Based on data supporting this concern, in October 2004 the U.S. Food and Drug Administration (FDA) ordered pharmaceutical companies to add a black box warning (the FDA’s most serious drug warning label) regarding the possible link between antidepressant treatment and suicide in children and adolescents [8]. This warning was expanded in May 2007 to encompass increased risk of suicidal symptoms in young adults 18 to 24 years of age, based on new data indicating that this group was also at risk [9]. The new warning also stated that there was no evidence of increased risk for adults older than age 24. Although the FDA panel endorsed the risk of antidepressant-related suicidality, the precise nature of this relationship is poorly understood owing to two limitations. First, researchers conducting clinical trials of antidepressant efficacy collected only a few details for some patients regarding the nature of the particular events involving suicidal thoughts or behavior, which might have compromised the degree of accuracy in classifying each event as a ‘true’ instance of suicidal behavior. Moreover, no instances of completed suicide were observed in any trial, nor did the available data precisely elucidate the specific behaviors altered by antidepressants. Although suicidal thoughts and behaviors represent reasonable predictors of risk for completed suicide, the overwhelming majority of individuals exhibiting these features will not commit suicide. Second, considerable heterogeneity was present across randomized control trials in terms of the antidepressant studied, patient characteristics, number of sites and datacollection procedures. Furthermore, certain studies found no significant correlation between SSRI treatment and suicide in children and/or adolescents [10]. Notably, a US study of children and adolescents aged 10 to 19 years found a significant inverse relationship for changes in regional rates of antidepressant medication treatment and changes in regional suicide rates [11]. For each 1% increase in the use of SSRIs among adolescents, there was a decrease of 0.23 suicides per 100 000 adolescents per year. This finding is consistent with other studies showing a decline in US youth suicide rates after the introduction of SSRIs [12].

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Several studies also reported an increased number of postsynaptic 5HT2 receptors in the brains of depressed patients and suicide victims. although it is likely that altered monoamine levels alone cannot explain this disorder. it is important to note that. genetic and antidepressant studies. and many studies support the idea that disrupted production or release of serotonin and other neurotransmitters contributes to the neurobiological basis of this disorder. SSRIs are associated with a remission rate of 30–40%. and numerous studies have identified personality traits that are risk factors for suicidal behavior [16. SSRIs and depressive symptoms Selective serotonin reuptake inhibitors (SSRIs) encompass a large class of antidepressant drugs available to treat depression. Modeling suicide-trait-related behaviors in animals Animal models are essential for translational research. particularly SSRIs. and that an increase in the 5-HT2C receptor gene (Cys23Ser) allele was associated with MDD. In addition. specific traits associated with suicide in humans can be successfully modeled in animals. it is important to note that most of the relevant . Chronic antidepressants usually reduce serotonin turnover in patients. regardless of whether they were diagnosed with MDD or bipolar disorder. Suicide is a complex behavior. the limbic system and cortex). Here. that the 5HT2A gene allelic association was found with the 102 T/C polymorphic variant and MDD. increase serotonin levels in the synapse by preventing presynaptic reuptake of this neurotransmitter. Furthermore. The aforementioned evidence highlights the need to identify the mechanisms by which SSRIs might be associated with the potential side effect of suicide in some susceptible individuals [3]. Chronic treatment with SSRIs reduces cell body 5-HT1A density. With regard to suicide. indeed. Postmortem findings also support SSRI-mediated increases in CREB activity. many fundamental physiological and behavioral responses have been evolutionarily conserved between species. In the context of this article. Thus. The potential use of animal models to elucidate this issue is the focus of this article.g. Animal studies have revealed that chronic antidepressant treatment alters crucial regulators of neuroplastic function. depressed patients were found to have significantly lower maximal velocity of serotonin uptake in the CSF compared with matched controls. CSF studies have noted reduced CSF 5-hydroxyindoleacetic acid (5-HIAA). Specifically.4 was blunted in depressed patients. Studying the results from various paradigms that model these traits in animals can provide a starting point for examining the mechanisms through which SSRIs might act to increase or decrease suicide risk. Work is currently underway to further examine how SSRIs alter synaptic and network function via intracellular cascades and how these changes relate to monoamine synthesis. serotonergic dysfunction is also implicated in the development of unipolar depression. intravenous infusion of tryptophan increased prolactin plasma levels. suicide attempts and suicide completion. impulsivity. the most obvious limitation of the animal model strategy is the vastly different behavior of humans compared with any other animal. this is particularly notable because serotonin is synthesized from tryptophan. including those implicated in mood disorders (e. this does not correlate well with changes in mood. For instance. An animal model is defined as any experimental paradigm developed in an animal for the express purpose of studying a human condition. irritability and hopelessness/helplessness (Table 1 and Figures 1–4 summarize the most often used and best known of these paradigms). Evidence from challenge. Thus. data from a variety of studies indicate that abnormalities of the serotonergic system are present in MDD. a serotonin metabolite. Recent investigations have examined the molecular basis of chronic SSRI treatment. no perfect animal model exists for any aspect of any psychiatric disorder. Although acute treatment with SSRIs can elicit a rapid change in serotonin levels. In challenge studies. These four traits are known to correlate with suicidal ideation. although some evidence exists of deliberate self-endangering behavior 166 among animal species [15]. Although limitations in animal models have been duly noted [13]. mood improves after chronic treatment (14–30 days). we focus on modeling four major risk factors associated with suicidal behavior in humans: aggression. thereby increasing serotonergic neuron firing. even agents whose primary biochemical target is not the serotonergic system. limiting their long-term efficacy in the general population. release and reuptake at the synapse. brain-derived neurotrophic factor. providing new insight into their mechanism of action and helping to better understand the role of serotonin in depression. furthermore. Similarly. The usefulness of SSRIs in treating depression has long indicated that serotonin is crucial to the etiology or pathophysiology of depression. through different mechanisms. can reliably induce these behaviors in animal models [3]. see Ref. which seems to be less abundantly expressed in the temporal cortex of severely depressed individuals [78]. Other studies have revealed that individuals with MDD have a blunted physiological response to serotonin receptor 5-HT1A agonists in vivo and abnormal 5-HT1A receptor binding postmortem. although this release Trends in Pharmacological Sciences Vol. in healthy subjects. vascular endothelial growth factor and cAMP response binding element (CREB) (for review. animal models might prove very useful in the investigation of these effects in patients who are prescribed SSRIs. however.30 No. or for self-aggression. In the context of this article. recent positron emission tomography studies have yielded in vivo evidence of reduced preand postsynaptic 5-HT1A receptor binding in individuals with MDD.17]. including the mitogen-activated protein kinase pathway. the involvement of personality traits in susceptibility to suicidality has been the subject of research since the 1950 s. the acute changes in monoamine levels produced by SSRIs do not seem to be intrinsically beneficial but might instead activate intracellular cascades that lead to prolonged changes in neuroplasticity [76].Opinion Box 1. although it is obviously not possible to develop an animal model of suicide that has face validity for that behavior. The serotonin network itself originates in the brain stem but projects to most brain regions. antidepressants. In addition. typically. a tryptophan depletion diet induced a rapid depressive relapse in SSRI-treated patients. all support the involvement of the serotonergic system in the pathophysiology of depression (summarized in Ref. Genetic studies have also noted that the 5-HTTLPR (serotonintransporter-linked polymorphic region) short variant is associated with poor response to fluoxetine in individuals with MDD. [77]). in addition to studies of serotonin metabolism in cerebrospinal fluid (CSF) and investigations of serotonin receptors. Antidepressant studies have also noted the antidepressant efficacy of agents that increase intrasynptic serotonin. and all can be successfully modeled and manipulated in animals [16]. and there are no existing animal models for suicide per se. in both suicidal and impulsive-aggressive patients. so that life-saving medications are not withheld from those not at risk (see Box 1 for further discussion of SSRIs and the role of serotonin in depressive disorders). [76]). antidepressants usually decrease 5-HT2 density in the rat prefrontal cortex. In addition. Thus. and these responses can elucidate phenotypes relevant to human emotional behaviors [14]. All SSRIs.

Renaud and colleagues [20] found that high levels of aggression were associated with the risk of suicide in children and adolescents. even after controlling for differences in psychopathology between suicides and controls. prospective and family studies have identified a strong link between aggression and suicide [18]. It consists of several shock trials from which the animal can escape. Avoidance test: several days after screening. data on latency to escape are used to measure recovery.30 No. Chasing behavior: rapid pursuit of the intruder by the test male. The paradigm is conducted over a time period ranging from (Figure 4) a few days to two weeks. the shock is associated with a conditioned stimulus (light or auditory cue). and the associated panel pressing delivers food into the chamber. the FDA analysis demonstrated that antidepressant treat167 . in most cases. an uncomfortable stimulus is given (e. As the session proceeds. it is considered to be ‘helpless’. ‘helpless’ animals are given an active avoidance test (Figure 4). weight. Various behavioral Various behavioral paradigms attempt to monitor irritability in mice. clinical. with or without physical contact. This paradigm is based on the principle (Figure 2) task that a selection of smaller immediate gains is an ‘impulsive’ choice. Wrestling: vigorous shoving and sparring when both animals take on an upright posture. retrospective. but the operant delayed Impulsivity reinforcement reinforcement task is the most frequently used. Studies of adolescent inpatients indicate that youths with a history of frequent violent behavior more frequently have a history of suicide attempts than non-violent inpatients [18]. In these paradigms. it is considered to have ‘learned helplessness’. Responsiveness to uncomfortable stimuli: these paradigms measure irritability as the responsiveness of an animal to a uniformly uncomfortable situation. exhibiting ‘despair-like’ behavior. In the test. to differentiate these behavioral differences across the life span. Tail rattling: rapid lateral quivering of the tail. This paradigm is based on the assumption that animals will normally try to escape an aversive Hopelessness/ Learned stimulus (i. but the resident intruder is the most frequently used. Selected paradigms for assessing suicide-trait-related behaviors in animals Trait Aggression (Figure 1) Trends in Pharmacological Sciences Vol. this measure can also be used to assess impulsivity. In animals that exhibit aggression. The test consists of several escapable shock trials. foot shock). Thus. a white bottle brush moving against the animal or a puff of air blown sharply through a straw onto the back of the animal’s neck) and the animal’s response is quantified. these results are also consistent with those obtained by Shaffer and colleagues [6]. screening and avoidance test. any animal model attempting to thoroughly assess the impact of SSRIs on suicidality in the young would need to investigate this paradigm in prepubertal and juvenile rodents. Notably. it is considered to have ‘recovered’. Screening: screening usually occurs the day after induction. and is divided into three phases: induction. Two of the most Irritability paradigms frequently used are described here: (Figure 3) Resistance to capture or attempts to struggle while being restrained: many of the tests used to measure irritability involve assessing rodent struggling behavior in response to human handling. As a response to moderate restraint applied by the handler. Brent and colleagues [19] found that a lifetime history of aggression differentiated adolescent suicide victims from matched controls. a mouse will either exhibit a passive or irritated response (Figure 3). the association between aggression and suicide attempts in community and inpatient samples persists when mood and disruptive behavior problems are controlled [21]. and the following behaviors are measured for a period of ten minutes: Attack bites: biting of the intruder mouse (Figure 1b).g. If an animal fails to escape a certain number of trials. mice are trained to choose between two visual stimuli (a light cue presented on either the left or right side). usually performed by both animals simultaneously (Figure 1d). a delay is introduced into the response (nose-poke) associated with the large reward. If an animal manages to escape a set number of trials. one of which results in a small quantity of reinforcer (food) and the other resulting in a large quantity of reinforcer. Animals that exhibit enhanced reactivity to the stimuli are considered to display irritable behavior. The number of trials and intensity of the shock varies. Mice are first trained over several sessions to respond to a visual stimulus (light cue) with a nose-poke. Aggression Multiple epidemiologic. just before or after attacking (Figure 1c). The extent and duration of struggling behavior is used to measure irritability. if it does not escape. In addition to number of escape failures. Attack latency: latency time to the first attack (in seconds) from the introduction of the intruder mouse. the nature of the choice is between a small but immediate quantity of reinforcer versus a larger but delayed quantity of reinforcer (Figure 2). Refs [72] [73] [74] [75] animal studies conducted to date have focused on adult rodents.e.Opinion Table 1. The duration between each shock trial is randomized and. whereas the opposite bias is an index of ‘self control’. A naı ¨ve. Operant delayed Various behavioral paradigms attempt to assess impulsivity in mice.and age-matched mouse (‘intruder’) is placed into a cage that the experimental mouse has been housed in for an extended period of time (the ‘home-cage’). otherwise it is deemed to be ‘non-helpless’. although shock intensity and time window allotted for escape can vary. however.4 Relevant paradigm Description Resident intruder Various behavioral paradigms attempt to assess aggression in mice. Induction: after a habituation period. the animal is given several foot shock trials from which it cannot escape. Duration between shock trials is again randomized. Moreover. but when the stimulus is inescapable they will eventually stop trying to helplessness helplessness paradigm escape.

The degree and duration of the struggling response can be quantified and is used as a measurement of irritability (Table 1). Figure 1 adapted. from Lafayette Instruments website: ‘Product 9-Hole Box for Rat and Mouse’ (www. with permission. Table 1 contains a description of the task.com). and the following behaviors are measured for a period of ten minutes: attack bites (b).c adapted.30 No. with permission. the animal is being tested for positional passivity (a). [73]. In this image. weight. a naı ¨ve. from Ref. Figure 1b adapted.4 Figure 1. Figure 2. chasing behavior and attack latency (Table 1). wrestling (d). [74]. Figure 3. [72]. Schematic displaying the 9-hole nose-poke operant delayed reinforcement chamber (a) accompanied by a diagram displaying the delayed reward task (b). from Ref. Figure 1b.Opinion Trends in Pharmacological Sciences Vol. positional struggle (b) and struggle during supine restraint (c). with permission.and age-matched mouse is placed into the home cage (a cage that the experimental mouse has been housed in for an extended period of time) of the test mouse (a). tail rattling (c). Photograph for Figure 1a taken. 168 . from Ref. When the animal is moderately restrained by the handler it will exhibit either a passive response or attempt to escape. with permission. In the resident-intruder paradigm.lafayetteneuroscience.

Various preclinical models have greatly contributed to our understanding of the neural correlates of impulsivity in rodents [31]. Therefore. but the resident-intruder paradigm is the most frequently used (Table 1. the ability to reduce aggressive behavior in resident rodents in this paradigm is an ability shared by acute treatment with all the pharmacologically disparate antidepressant compounds tested. Although the findings are not consistent. and only seven percent thought for >24 hours [35]. chronic treatment with these disparate compounds increases aggressive behavior in rats [26]. ment was associated with symptoms of treatment-emergent hostility or agitation [22]. monoamine oxidase inhibitors (MAOIs). tricyclic antidepressants (TCAs) and atypical antidepressants such as mianserin and iprindole. and most notably younger ones. some children might experience an ‘activation syndrome’ characterized by signs of hyperarousal and impulsivity [36]. social circumstances that are conducive to the development of aggressive behaviors are positively correlated with a marker of central serotonergic activity [28]. indicating prenatal sensitization [30]. 24% took <10 min. especially because the influence of age is independent from the influence of gender or diagnosis [33]. Other reports also support the notion that younger suicides are more likely to be the result of an impulsive act. Evidence also indicates that suicide completers. Conwell and colleagues [34] found that older age was significantly associated with more predetermined and planned self-destructive acts. see Ref. of those who attempted suicide. rather than antidepressant. Interestingly. However. non-narcotic analgesics) and cut themselves more frequently than adults when attempting suicide. This species difference in response to antidepressant and anxiolytic drugs is most likely to be due to the functional differences in aggressive behavior between rats and mice. mice with selected genetic targeting of the serotonergic system exhibit severe to mild behavioral alterations. mice and hamsters. Adolescents use more nonspecific medications (e. Many tests can be used to model aggression (for a thorough review of this topic. resource competition) [24]. lack of reflection regarding the consequences of one’s behavior and inability to postpone reward (delay aversion) [31].g. many studies support the role of impulsivity in suicidal behavior. Impulsivity The behavioral expressions of impulsivity include disturbed inhibition of behavior. 75% took <1 hour to make the decision. mice will violently defend their territory. in young boys. During the course of SSRI treatment. Notably. Pet-1 E26 transcription-specific factor is a precise marker of developing and adult serotonergic neurons and is expressed shortly before serotonin appears in the hindbrain. In addition. from Refs [73. additional work to explore the mechanism(s) by which SSRIs might enhance impulsivity and/or aggression during specific developmental phases is clearly necessary. Figure 1a adapted. [25]). Laboratory research has produced detailed descriptions of aggression and defense patterns in rats. Different aspects of impulsivity can be studied with operant-behavior paradigms in laboratory settings (Table 1. showing strong similarities (but also some differences) across species [23]. For instance. less violent methods and fewer warnings of suicidal intent. A diagram depicting the learned helplessness screening or avoidance test is displayed (a). a series of studies of suicide completers found that high levels of impulsivity correlated strongly and significantly with high levels of aggressive behavior or hostility.4 Figure 4. Pet-1 (plasmacytoma-expressed transcript 1) knockout mice showed increased aggression [29]. One avenue of research that merits further study is the role of the serotonergic system in mediating the behavioral effects of SSRIs on aggression. the aggressive behavior of male mice in the resident-intruder studies is particularly sensitive to anxiolytic. Figure 2) that typically assess impulsiv169 . research with a focus on the stimulus antecedents of aggression. In addition. with permission. In addition. Figure 1). its response characteristics and its outcomes indicates several detailed correspondences between offensive aggression in laboratory rodents and human aggression (e. and in contrast to the rat studies.Opinion Trends in Pharmacological Sciences Vol. whereas rats live in social colonies where excessively violent behavior is detrimental to the social group [27]. aggression was found to be elevated in MAO-A-inhibited mice only after acute pharmacologic challenge. have higher levels of impulsivity than controls [32]. One study found that. along with a sample timeline for the learned helplessness procedure (b) (Table 1).30 No. Furthermore.g. serotonin-norepinephrine reuptake inhibitors. By contrast. various forms of aggressive behavior have been found to be significantly associated with increased sensation seeking and impulsivity [37].75]. drug activity [27]. Several studies found that. the authors also found an important age effect [32]. some researchers have suggested that the treatment of impulsive aggression or the provision of violence prevention interventions might reduce suicide risk [38]. including SSRIs. 25% took <5 min. which might reflect increased impulsivity in this age group. Interestingly.

Indeed. they develop more complex and subtle feelings and behaviors [63]. as opposed to aggression and impulsivity. whereas chronic irritability shows a quadratic variation with a peak in mid-adolescence [44]. fda. It has been described when the animal becomes wild and/or restless in response to a tactile or auditory stimulus [47]. irritable adolescent males seem to be more likely to contemplate suicidal behavior than those who do not display irritability [41]. These results support the FDA’s suggested correlates of suicidality. Hopelessness/helplessness One of the most prominent correlates of suicidal ideation is hopelessness. and it has more recently been defined as an extreme reaction to relatively minute stimuli [48]. Figure 4).32 times greater odds of also having irritability than those without suicidal ideation. therefore. Hopelessness has been defined 170 Trends in Pharmacological Sciences Vol. In addition. however. the most often used proxy for assessing hopelessness is the learned helplessness paradigm [59] (Table 1. Opiate withdrawal is relatively simple to induce and. affecting children and adolescents. very few studies discuss the effects of different medications (especially antidepressants) on these behaviors as a function of age.30 No. hopelessness differentiated between attempts and completions [57]. hopelessness involves the assessment of some level of subjective state changes [56]. It has been found to significantly predict suicidal ideation [55]. these models of impulsivity are sensitive to both pharmacological manipulations and selective brain lesions in animals [39]. 128) [40]. The concept of behavior is in itself complicated by the fact that the intrinsic arousability of underlying brain systems might change in many ways as organisms age [63]. is not purely ‘behaviorally’ defined but involves some level of subjective state changes. irritable behavior in rodents seems to occur most robustly and frequently during periods of psychoactive drug withdrawal. Figure 3). As with irritability. the FDA black box warning regarding the link between suicide and SSRIs is age dependent. can be easily used as part of a test battery. Some of the specific behaviors discussed earlier do indeed show developmental patterns that imply specific changes in brain systems as the organism ages. defined as ‘. although its importance might vary across age groups [17]. irritability. . for instance. although the patterns of development of this transmission might vary between species [65]. In addition. Most studies have also found that hopelessness is an important risk factor for suicide completion [17]. Several studies have found a specific association between chronic irritability and MDD. studies have shown that symptoms of low self-esteem and hopelessness in teenage boys lead to thoughts of self-harm [56]. In animal models. levels of hopelessness were greater in completers in several long-term prospective studies involving hospitalized suicidal ideators and psychiatric outpatients [58]. at least in humans. Other research has shown that adult rats exhibit different levels of impulsivity and responsiveness . and a variety of drugs can induce irritability in rodents including parachlorophenylalanine [50]. Akiskal and Benazzi [42] found that patients with suicidal ideation had 1. Notably.45]. although the mood may be present without observed manifestation’ (pp. However. antidepressants have been shown to increase irritability in several open clinical case series [46]. Although some studies exist regarding age-related changes in rodents for the behaviors described in the preceding sections. One study showed that female mice treated neonatally with an SSRI exhibited increased helplessness that was reversed by chronic antidepressant treatment [62]. Age as a variable in the research of behaviors related to suicide traits One issue of particular relevance to this discussion is that of age. In addition. Methods also exist to evaluate withdrawal without drugs. This is a crucial point that needs careful investigation. Irritability Another major risk factor for suicidality is irritability [17]. For instance. subsyndromal symptoms such as irritability predict the later onset of MDD [43. enabling young animals to cope with emergency situations that could compromise their survival. behaviors related to fear.org/cder/drug/antidepressants/MG_template. which has been conducted successfully in several species including rats and mice [60]. the modeling of irritability in rodents is particularly complicated. Irritability has been studied in rodents for many years. is marked by a transition from play fighting to adult aggression in most mammalian species [64]. even in children [49]. TCAs. all prevent and reverse learned helplessness in animals [61].4 in the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) [54] as a pervasive pessimism about the future. especially for opiate drugs [52. anger and separation distress emerge at early developmental stages.a feeling state characterized by reduced control over temper which usually results in irascible verbal or behavioural outbursts. MAOIs and atypical antidepressants. However. The learned helplessness paradigm is used in preclinical pharmacological studies to assess the antidepressant effect of new compounds. As organisms age. As noted in the introduction. therefore. Though limited. one of the most common symptoms reported by children with a range of psychiatric conditions is irritability [43]. midazole [51]. Episodic irritability shows a linear variation with age.Opinion ity based on choices that the animal makes. In a longitudinal study of patients with affective disorders. aggression behaviors undergo substantial transitions during different phases of development in the life span of rodents [65].53]. . Several paradigms are used to measure irritability in laboratory animals (Table 1. thereby establishing an environmental and behavioral avenue to induce irritability [52]. Several studies found that irritability is strongly associated with suicidal ideation and suicide attempts [41].pdf). which state that parents of depressed children receiving antidepressants should watch for new or worse levels of irritability in their children (www. and so on. in which chronic. Puberty. which make modeling hopelessness in rodents very complicated. including SSRIs. In addition. trimethyltin [51].

Pediatrics 119. (2007) Annual summary of vital statistics: 2005. (2006) Personality traits as correlates of suicide attempts and suicidal ideation in young adults. basal dopamine levels in rodents are age dependent [68]. 191–202 18 Grosz. concerns that SSRIs were potentially associated with suicidal thinking and behavior in a small subset of children. 356. Although the data on how developmental behavioral patterns correlate with changes in brain systems during the life span are sparse. several main risk factors for suicidal behavior can be modeled and manipulated in animals. impulsivity. notably. Animal models are widely used in translational medical research. ‘adolescent’ refers to PND 36–59. et al. 915–918 11 Olfson. D. D. Compr. Disclosure statement We would like to acknowledge the support of the Intramural Research Program of the National Institute of Mental Health. (1994) Correlates of violence risk in hospitalized adolescents. 243–265 3 Goodman. M. Psychiatry 60. (2007) Risk of adverse behavioral effects with pediatric use of antidepressants. and Marttunen. R. and might prove useful in revealing the true risks of antidepressant use in the young. (2003) Association between antidepressant prescribing and suicide in Australia. et al. J.fda. et al. DC. and approaches to prevention.E. especially from changes seen in young animals. A. Gen. J. antidepressants. Am. Psychiatr. 332–339 6 Shaffer. However. 467–477 17 Brezo. risk factors. especially in the young. Psychol. Arch. (2001) The neurobiology and genetics of suicide and attempted suicide: a focus on the serotonergic system. J. et al. Acknowledgements This work was supported by the Intramural Research Program (IRP) at the National Institute of Mental Health (NIMH-NIH. BMJ 326. 36. 2004. impulsivity. 87–96 4 Gibbons. considerable data show that the common antidepressants are effective in treating MDD for a large proportion of afflicted patients. M. Am. and youth suicide in New York City: 1993 through 1998. 978–982 12 Hall.K. et al.A. J. and Leon. Conclusions and summary MDD is the second most common psychiatric disorder in the US [71]. (1985) Animal models of self-destructive behavior and suicide. Aug 16. Med. Engl. J. A promising direction for identifying the mechanisms by which SSRIs might be associated with these deleterious effects. Neuropsychopharmacology 24. although the need to develop new antidepressant treatments persists. J.K. (2003) Relationship between antidepressant medication treatment and suicide in adolescents. Paediatr. adolescents and young adults led the FDA to issue a black box warning for those medications [4. but to date no animal models of suicide have been developed. Arch. and the risk of suicide. 8. Clin. J. et al. 326–357 15 Crawley. Food and Drug Administration. et al. H. and that adolescent males are more vulnerable to the loss of control that leads to hopelessness [67]. W. These are urgently needed to determine the precise effects of SSRIs on suicidal ideation and suicide attempts. J. T.F. 299–310 16 Mann.N. Psychiatry 63. et al.J. (2006) Suicidality in pediatric patients treated with antidepressant drugs.gov). 339–348 7 Bridge.A. and it is known that both juvenile and adolescent rats can display helplessness in the learned helplessness paradigm [70].M is now with Johnson and Johnson Pharmaceutical Research and Development. (2007) Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. We declare that. R. Clin. will help researchers to assess the extent to which the FDA black box decision is justified. Psychopharmacology (Berl. and Mombereau.C.30 No. is the use of animal models. Future studies can help us to understand the underlying mechanisms of antidepressants on these behaviors and on suicide risk and. 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This work was undertaken under the auspices of the NIMH IRP. a good animal model for these purposes should determine changes in those behaviors in response to different antidepressants in at least three different age groups (‘childhood’. Mol. Psychiatry 9. except for income received from our primary employer. Presently. et al. Trends in Pharmacological Sciences Vol. Gen.nih. C. Psychiatry 35. and. 296–300 171 .A. no financial support or compensation has been received from any individual or corporate entity over the past three years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.8].(www. Arch.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-10TAB08-Hammads-Review. In addition. 1683–1696 8 Hamaad. 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