This study will evaluate the safety, tolerability and efficacy of RO4917523, in comparison to placebo, in patients with treatment-resistant depression. Following a washout period from existing anti-depressant medication, cohorts of patients will be randomized to receive daily oral RO4917523 at up to five different doses (according to the safety and tolerability observed at the lower doses during the study), or placebo. The anticipated time on study treatment is 10 days (in an inpatient unit), and the target sample size is <100 individuals.

Inclusion Criteria:

• adult patients, 18-65 years of age;
• recurrent major depressive disorder, without psychotic features;
• at least 3 lifetime treatment failures, at least 2 of which must have occurred within the current depressive episode;
• baseline minimal severity defined by a HAM-D score of 18 or above;
• willing to be hospitalized for at least 16 consecutive days.

Exclusion Criteria:

• history of bipolar disorder, schizoaffective disorder or schizophrenia;
• history of psychosis, including psychotic depression;
• significant past or present neurological disorder, including seizures, stroke and/or head trauma.