Sustaining Remission of Psychotic Depression

The original STOP-PD study established that the combination of olanzapine and sertraline was
significantly better than olanzapine alone in achieving remission of psychotic depression.
This STOP-PD-II Sustaining Remission study aims to assess the long-term tolerability of
taking this combination of medications and their efficacy at preventing a relapse of the
symptoms. The acute phase of the study will monitor the efficacy and tolerability of the
olanzapine and sertraline combination, including investigation of weight and metabolic
variables, age effects on treatment response and tolerability, and the association of genetic
polymorphisms to response or relapse. When subjects are stabilized on these medications for a
period of 8 weeks they will be invited to participate in the randomized phase of the
research: the olanzapine will be placebo-controlled, meaning half of the subjects will
continue to take the olanzapine/sertraline combination and half will take a
sertraline/placebo combination, for a period of 36 weeks. Symptoms and side effects will be
monitored regularly throughout this phase. Randomization will be stratified on a 1:1 basis by
age 60 and above.

Inclusion Criteria:

1. Aged 18-85 years, inclusive

2. Diagnosis: Diagnostic Statistical Manual-IV Trade Revision (DSM IV-TR) non-bipolar
major depression with psychotic features established by both clinical interview with
research psychiatrist and administration of SCID-IV.

3. Score >2 on Schedule for Affective Disorders (SADS) delusion severity item

4. Score >1 on any of the three conviction items of the Delusion Assessment Scale (DAS)
(does not alter belief in response to reality testing)

5. 17-item HAM-D score of >20

Exclusion Criteria:

1. Current or lifetime DSM-IV-TR history of schizophrenia or other psychotic disorders or
meeting current criteria for brief psychotic disorder, body dysmorphic disorder or
obsessive-compulsive disorder

2. Current or lifetime DSM-IV-TR bipolar affective disorder

3. History of DSM-IV-TR defined alcohol or substance abuse or dependence within the past
three months

4. Dementia or clinically significant cognitive impairment prior to index episode of
depression, and/or a mean score >3 on 26-item caregiver assessment

5. Type 1 diabetes mellitus (defined as insulin-dependent diabetes mellitus with onset
before age 35, and/or diabetes mellitus complicated by prior documented episode of
ketoacidosis

6. Acute or unstable medical illness within the past 3 months; current abnormal serum
free T4; current abnormally low vitamin B4 or folic acid level; medical conditions
and/or medications for which psychotic or depressive symptoms can be a direct
manifestation; neurological disease associated with extrapyramidal signs and symptoms;
epilepsy, if the person has had one or more grand mal seizures within the past 12
months.

7. The need for treatment with any psychotropic medication other than sertraline,
olanzapine or lorazepam; or with an anticonvulsant medication with mood-stabilizing
properties.

8. Current pregnancy or plan to become pregnant during the course of the study; breast
feeding in women with infants.

9. A documented history of being unable to tolerate olanzapine or sertraline including
significant bradycardia (heart rate of <50 bpm), and serum sodium level of 129mmol/L
or below.

10. History of non-response of the index episode of psychotic depression to at least a
6-week trial of at least 150mg/day sertraline combined with 15mg/day olanzapine

11. Patients showing ongoing improvement in current episode of psychotic depression with
treatment other than sertraline or olanzapine

12. Patients who are in immediate need of electroconvulsive therapy (ECT) (imminent risk
of suicide, refusing to eat, catatonic)