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(PSYCHIATRIC TIMES) - Although several antimanic agents are available to treat individuals with bipolar disorder (BD), many patients have a less than satisfactory response or experience adverse effects.1 With the exception of lithium, all of the current antimanic agents are either anticonvulsant or antipsychotic drugs. It is remarkable that no drug has been developed specifically for BD, especially because this illness was conceptualized more than a century ago. The lack of available therapeutics with a novel mechanism of action results in large part from our modest understanding of the relevant molecular and cellular substrates of this complex emotional, behavioral, and activity disorder.

Different strategies have been proposed for the development of better compounds for patients with psychiatric disorders. It has been argued that the ultimate goal of drug development should be to reduce the prevalence of psychiatric disorders through cure therapeutics and strategic preventive measures. Insel and Scolnick2 have suggested that drug development for mental disorders over the past 50 years has been significantly stalled compared with other areas of medicine and that drastically different approaches are in order.

It is our firm opinion that we are entering an era in which we will be able to develop markedly improved treatments for severe mood disorders. A growing body of data suggests that mood disorders arise from abnormalities in synaptic and neuronal plasticity cascades, leading to aberrant information processing in critical synapses and circuits.

Thus, these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters. In this article, we discuss current approaches to drug development in mood disorders at the Mood and Anxiety Disorders Program of the Intramural Research Program at the National Institute of Mental Health and provide an example of one such approach.

Drug development models
At the Mood and Anxiety Disorders Program, the model of drug development that we are pursuing is based on 2 highly integrated preclinical-clinical pathways:

1. Understanding the long-term, therapeutically relevant targets of the medications currently in use. For example, in the case of SSRIs, instead of studying the initial increases in intrasynaptic serotonin, the goal would be to study the long-term changes in synaptic and neural plasticity that likely underlie their delayed therapeutic effects. Such knowledge can then be used to design new drugs directed at the target(s).

2. Understanding the pathophysiology of the illness and using that knowledge to design therapeutics to attenuate or prevent pathological processes. These may be envisioned as true disease-modifying strategies rather than simply as symptom control.

Because of space limitations, this article focuses on the first approach. For there to be substantial progress in generating novel compounds, susceptibility genes involved in illness need to be identified. However, this alone is insufficient to provide the knowledge necessary to expand our current therapeutic armamentarium. Fundamentally, we need information about the intracellular signaling cascades that are disrupted within the complex set of interacting neuronal networks and the specific changes that occur within these systems as a result of the effective treatments administered in a therapeutically relevant paradigm and in a time sensitive manner.

For example, much could be learned by gathering information at the precise point when there is a change in mood episode poles (switch from depression to mania) in BD or when an effective treatment intervention takes place. The advent of methodologies such as subtractive hybridization, messenger RNA differential display, and microarrays has illustrated the importance of hypothesis-generating by mimicking the conditions of illness or examining when effective treatments act (eg, in an animal model of mania and lithium treatment); this is particularly true when dealing with disorders whose pathophysiology remains elusive.3

Thus, it may be very useful to develop drugs that are based on pertinent intracellular signaling molecular targets of current mood stabilizers; these later could be adapted to optimize efficacy, specificity, and/or adverse-effect profiles. In addition, all current medications have a considerable onset lag before their full therapeutic properties are activated (implying changes in gene expression, protein function, and—more generally—plasticity). Thus, identification of targets after prolonged treatments in cell- and animal-based models may be a useful approach in the development of novel therapeutics.

This approach may increase the likelihood of identifying relevant downstream targets with potentially more potent and rapid actions. Ultimately, novel agents identified in this manner also may benefit patients who are treatment-resistant, because alterations in the intracellular pathways (ie, defects) could simply be bypassed to the end-stage molecular targets that are ultimately relevant to the therapeutic effects. The use of this strategy could provide clues on how to bypass the defect in a number of ways. There is no shortage of targets, and the task of determining the ones that are most therapeutically relevant is challenging.

Our work attempts to focus on those target proteins and pathways with the most evidence for involvement in mood disorders, the greatest relevance to current disease models, or where other medications with the same or similar actions have been developed and could be used for proof-of-concept trials.

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