IMPase in Treatment-resistant Depression

Ebselen, a potential new drug for treatment resistent depression (TRD).

Clinical depression is an important public health problem, associated with an even greater burden of illness than other common diseases such as angina, arthritis, asthma, and diabetes. The burden of illness is particularly high for depressed patients in specialist psychiatric care who often fare poorly with current treatments and who typically experience substantial functional disability with a significantly increased risk of suicide. A limiting factor in improving outcome for such patients is the lack of acceptable pharmacological approaches for so-called 'TRD'. In a recent large randomised trial, even specialist mood disorder services with access to expert psychological and pharmacological treatment, struggled to improve therapeutic response rates compared to 'treatment as usual'. This indicates that improving the management of TRD requires more than improved access to specialist clinics - new, more effective and better tolerated therapies are needed.

The principal aim of the current study is to examine the utility of a potential new lithium-mimetic drug, ebselen, in patients with TRD. Lithium itself is known to be efficacious in the management of TRD as an 'add-on' treatment to ineffective antidepressant medication. However, its poor tolerability and safety and the need for regular blood tests has resulted in it having a low acceptability for both patients and clinicians.

Lithium has many pharmacological targets but inhibition of an enzyme called inositol monophosphatase (IMPase) is an important candidate for its therapeutic effects in mood disorders. However, this potential mechanism has not been tested previously in depressed patients. Ebselen is an organoselenium compound, developed originally as an antioxidant for use in neuroprotection, post-stroke. Although clinical trials indicated that ebselen was safe and well-tolerated, its therapeutic activity in stroke patients was limited and its commercial development was halted. Subsequent work in the University of Oxford's Department of Pharmacology found that ebselen is a bioavailable and brain penetrant inhibitor of inositol monophosphatase (IMPase) (Ki ≈ 1 μM) (8). This finding provides an opportunity to use ebselen as a means of testing the role of IMPase inhibition in the therapeutic effect of lithium in TRD.

Recently, experimental medicine models developed in the University of Oxford's Department of Psychiatry have shown promise in describing early surrogate markers of patient responsiveness to antidepressants. Traditionally, the translation of novel potential antidepressant compounds from animal studies to humans has involved placebo-controlled clinical trials that are expensive and take many years. The newer, more experimental medicine studies exploiting the use of surrogate markers for depression and antidepressant drug action have the potential to transform this field and refine development decisions while minimising time and cost and burden on patients.

The surrogate markers of antidepressant efficacy that the investigators have developed for this process are based on cognitive theories of depression and antidepressant action. Cognitive theories of depression outline the role of negative emotional biases in information processing in the aetiology and maintenance of the disorder. For example, compared to controls, depressed patients are more likely to perceive ambiguous facial expressions as negative and to retrieve negative self-relevant information in both explicit and indirect memory paradigms. These cognitive biases are believed to play a key role in the persistence of the depressed state because increased accessibility of negative perceptions and memories maintains and exaggerates the depressed mood leading to a self-perpetuating cycle.

Importantly, cognitive biases shift early in antidepressant treatment, and positive changes in emotional processing can be demonstrated in relatively small groups of patients. Subsequent studies showed that early positive shifts in emotional processing predict eventual therapeutic outcome to antidepressant medication.

The investigators have previously used these experimental medicine approaches to assess the effects of ebselen in healthy volunteers. The investigators found that, given at a dose of 600 mg, as well as 1200 mg twice daily, ebselen produced a greater recognition of some positive emotions, an effect the investigators have noted with numerous typical and atypical antidepressants and a strong predictor of clinical antidepressant activity. The investigators also utilised magnetic resonance spectroscopy (MRS), and demonstrated a reduction in brain inositol after treatment with ebselen. This provides evidence for IMPase target engagement of ebselen at the dose proposed for this study. Therefore, the investigators now have substantial data that indicates that ebselen is a valid means of testing IMPase inhibition as a potential antidepressant mechanism in a clinical population of TRD patients, using an experimental medicine approach.