Balancing the beautiful and the good in pursuit of biomarkers for depression.

265 nia, and antipsychotic medications used to treat or prevent recurrence of mania/hy pomania impact dopamine transmission. More over, the prefrontal corticalstriatal reward neural network, which has been implicat ed in bipolar disorder and predisposition to mania/hypomania, has extensive dopa mine projections: midbrain ventral teg men tal area to ventral striatum (mesolimbic), midbrain substantia nigra pars compacta to dorsal striatum (nigro striatal), and ventral tegmental area to prefrontal cortex (mesocortical) pathways. Furthermore, amphetamineinduced ventral striatal dopamine release was positively associated with increase in mania/ hypomania in adults with bipolar disorder vs. non-psychiatric control participants; and a large rodent literature associates elevated reward network ventral tegmental area dopamine transmission with rewarddriven impulsive behavior, as well as other features of mania/hypomania, such as reduced sleep and increased energy. Together, these findings indicate that the combination of specific reward expectan cy paradigms and multimodal imaging ap p roaches examining reward expectancyrelated neural network activity and underlying dopaminergic modulation is a promising way to identify biomarkers reflecting neurobiological mechanisms predisposing to mania/hypomania. Bipolar disorder has also been conceptualized as a disorder of energy regulation, involving high levels of mitochondrial dysfunction and oxidative stress that might result from elevated dopamine transmission. Elegant translational work in mice and hu mans has shown that sustained elevated do pamine synthesis results in ele vated cy tosolic dopamine, which in turn leads to increased metabolism of dopamine by mon oamine oxidase. In this pro cess, mon oamine oxidase anchors to the outer mito chondrial membrane and transfers ele ctrons generated by dopamine deamination into the mitochondri al intermembrane space, increasing electron transport chain activity and supporting elevated dopamine synthesis and release. Increased metabolic demand can, however, ultimately lead to impaired mitochondrial function and a toxic cascade in which elevated oxidative stressinduced mitochondrial dysfunction results in cytosolic dopamine oxidation, with elevat ed cytosolic dopamine further contributing to mitochondrial oxidative stress. Thus, elevated dopamine transmis sion and asso ciated mitochondrial dysfunction is a putative mechanism underlying the energy regulation dysfunction characterizing mania/ hypo mania in bipolar disorder. These examples provide possible app roaches that can be adopted by future studies aiming to identify biomarkers reflecting core neurobiological mechanisms underlying key features characterizing and predis pos ing to mania/hypomania. An im portant point to note, however, is that these features, especially rewarddriven impulsive decisionmaking and behavior, are associated, at least in part, with other disorders, such as substance use disorders. Thus, these approaches will likely yield biomark ers that are not necessarily specific to a given psychiatric disorder as currently defined by the DSM5, but instead reflect neurobiological mechanisms underlying constructs that cut across different diagnostic categories. This transdiagnostic approach accords with the Research Domain Criteria model, where the two reward expectancy contexts described above link with two subconstructs of the Reward Valuation construct of Positive Valence Systems. As AbiDargham et al highlight in their paper, a given DSM5defined disorder may be associated with several different biomarkers, each reflecting a neurobiological mechanism related to a transdiagnostic construct, which may promote a move toward biologically-based classification systems in psychiatry. Clearly, there is a need for extensive work replicating findings in independent samples to ultimately provide robust and reliable biomarkers of any given disorder. Yet, I remain hopeful that with increasingly sophisticated neuroimaging methodologies (e.g., higher field strength magnetic resonance imaging), alongside better animal and cellular models, there is now an opportunity to elucidate neurobio logi cal mechanisms of key transdiagnostic constructs and provide robust biomarkers to help shape new classification systems. This will yield targets to aid risk identification and help develop new interventions. As AbiDargham et al note, this is not only a major scientific goal in our field, but is also a critical clinical mission to improve the health and wellbeing of all of those suffering from these debilitating and yet common illnesses.