Depression is one of the most common and serious disorders treated by mental health practitioners. While there are many pharmacologic, psychotherapeutic, and combination treatment options available to clinicians, many patients with depression do not respond optimally to the initial treatment offered. When initial treatment is limited to antidepressant medications, approximately 20-35% of patients do not respond. Even after multiple, sequential interventions only about 50% of patients achieve complete remission. Because of the substantial mortality and morbidity associated with inadequate treatment, treatment-resistant depression is a major public health problem. The scope of this problem is vast both in terms of the numbers of affected individuals and the resultant societal and economic burdens. Despite the enormous public health significance of this problem, systematic research on treatment-resistant depression has yielded only limited success. In particular, the timely and accurate identification of treatment-resistant patients has been problematic. It is generally accepted that there is a biologically-determined latency period that delays the onset of response to antidepressant treatment. This lag is believed to reflect the time required to reach therapeutic drug levels or to achieve adequate intensity of psychotherapy coupled with the time needed for the requisite biochemical and electrophysiological adaptations to occur. Over the last decade, a series of studies has demonstrated the ability of novel approaches ? including ketamine and sleep deprivation therapy ? to provide significant amelioration of symptoms within a few hours. However, symptoms typically return within a period of days after discontinuation of the acute intervention. The exact mechanism(s) of action of these modalities is not clear. The pharmacologic effect of ketamine appears to involve blockade of glutamatergic NMDA receptors and facilitation of AMPA receptors. One research question concerns whether variations in dose levels might produce longer-lasting effects without a significant increase in adverse events (which, to date, have been minimal). Finally, while a recent study has shown that repeated administration of ketamine over several days is well tolerated, symptoms nevertheless returned within days of drug discontinuation for almost all patients. While recent research has increased understanding of the mechanism of circadian rhythms and the sleep-wake cycle, the rationale for an association between sleep deprivation and symptom relief also remains unclear. The promising results of these Proof of Concept trials suggest that a more ambitious program of research might accelerate development of rapid-onset antidepressant treatment. This initiative aims to test new compounds (e.g. NMDA antagonists (other than Ketamine Hydrochloride), allosteric modulators of AMPA receptors, 5HT4 receptor compounds, Thyrotropin-Releasing Hormone (TRH)) or non-pharmacologic interventions other than sleep deprivation (e.g., TMS, ECT, MST). As NIMH?s current portfolio includes research on both ketamine and sleep deprivation, proposals to study these interventions are not solicited. The proposed initiative is envisioned to include the unique resources and expertise of NIMH?s Intramural Research Program (IRP). The outcome of this initiative could be expected to lead to an enhanced understanding of underlying mechanisms and development of innovative, rapidly-acting treatment approaches for treatment-resistant depression. The general approach required for this initiative will be to first establish a small team of clinical trial sites and subsequently to test identified interventions (pharmacologic and/or non-pharmacologic) in adequately powered Proof of Concept trials in humans. Trials will be initiated after promising interventions are identified by members of the team (including the NIMH Intramural Research Program), and approved by the RAPID steering committee and the NIMH Contracting Officer?s Technical Representative (COTR) (sometimes also referred to as the Government Program Officer (GPO)). If any compound/intervention identified under this contract or in the field proves to be promising, the Government may choose to conduct a larger efficacy trial with that compound/intervention in lieu of other smaller Proof of Concept trials (see Tasks 4 and 5). All efforts within each task area outlined below will be controlled by task order procedures outlined in more detail in the contract. These procedures require the issuance of a task order request by NIMH, the Contractor?s response/proposal to a request (including a technical approach and budget), and final NIMH approval to begin the task order. Costs shall not be incurred or reimbursed until a task order has been approved. The approved total cost is a ceiling that cannot be exceeded without further authorization. The emphasis and objective in this contract is to identify and test the most promising interventions for treatment resistant depression (either pharmacologic or nonpharmacologic).