Predictive animal models of mania: hits, misses and future directions

Abstract

Mania has long been recognized as aberrant behaviour indicative of mental illness. Manic states include a variety of complex and multifaceted symptoms that challenge clear clinical distinctions. Symptoms include over-activity, hypersexuality, irritability and reduced need for sleep, with cognitive deficits recently linked to functional outcome. Current treatments have arisen through serendipity or from other disorders. Hence, treatments are not efficacious for all patients, and there is an urgent need to develop targeted therapeutics. Part of the drug discovery process is the assessment of therapeutics in animal models. Here we review pharmacological, environmental and genetic manipulations developed to test the efficacy of therapeutics in animal models of mania. The merits of these models are discussed in terms of the manipulation used and the facet of mania measured. Moreover, the predictive validity of these models is discussed in the context of differentiating drugs that succeed or fail to meet criteria as approved mania treatments. The multifaceted symptomatology of mania has not been reflected in the majority of animal models, where locomotor activity remains the primary measure. This approach has resulted in numerous false positives for putative treatments. Recent work highlights the need to utilize multivariate strategies to enable comprehensive assessment of affective and cognitive dysfunction. Advances in therapeutic treatment may depend on novel models developed with an integrated approach that includes: (i) a comprehensive battery of tests for different aspects of mania, (ii) utilization of genetic information to establish aetiological validity and (iii) objective quantification of patient behaviour with translational cross-species paradigms.

Figure 1

Symptoms and assays of mania. The symptoms of bipolar mania as described by DSM-IV rating scales (green circle). Also the neurocognitive symptoms associated with bipolar mania (yellow circle). The putative measurements of these symptoms (green and yellow rectangles respectively) are also provided. BPM = Behavioural Pattern Monitor, 5C-CPT = 5-choice continuous performance test, PPI = prepulse inhibition, IGT = Iowa gambling task, ASST = attentional set-shifting task, DD task = delayed discounting task.

Figure 2

Hypothetical results of a putative treatment study in a pharmacological animal model of mania. The dependent measure of mania-like activity is on the y-axis and the seven treatment group by two pre-treatment groups are depicted on the x-axis. Veh = vehicle, Lam = lamotrigine (used here as a negative control), Li = lithium, Val = valproate (both used here as positive controls), Ds1 = dose 1, Ds2 = dose 2, Ds3 = dose 3 of the drug studied. Each of the treatment groups in the vehicle pretreatment arm would not affect ‘mania’-like behaviour. The ‘mania’-inducing pretreatment would increase the ‘mania’ symptoms of each treatment group in comparison with the corresponding treatment group in the vehicle pretreatment arm. Given that lamotrigine does not treat bipolar mania while lithium and valproate do, one would expect no improvement in mania with lamotrigine, but improvements are observed for lithium and valproate in the mania model. For the test therapeutic, a dose–response effect would be observed. Ideally, treatment effects would be assessed after a chronic 4 week plus treatment duration.

Figure 3

Hypothetical results of a putative treatment study in a mutant animal model of mania. The dependent measure of mania-like activity is on the y-axis, and the treatment groups are depicted on the x-axis. WT = wild-type littermate mice, Mt = genetically modified mouse model of mania. Veh = vehicle, Lam = lamotrigine (used here as a negative control), Li = lithium, Val = valproate (both used here as positive controls), Ds1 = dose 1, Ds2 = dose 2, Ds3 = dose 3 of the drug studied. The Mt mice would exhibit more ‘mania’ symptoms in comparison with WT mice. Given that lamotrigine does not treat Bipolar mania while lithium and valproate do, one would expect no improvement in mania with lamotrigine in either group, but improvements/normalization are observed for lithium and valproate treated mutant mice. For the test therapeutic, a dose–response effect would be observed in treating Mt mice. Ideally all treatments would be assessed using a chronic 4 week plus study.