Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multicenter, Double-Blind, Randomized, Parallel-Group, Placebo- Controlled Phase III Study of the Efficacy and Safety of Quetiapine Fumarate Sustained Release (Seroquel SRTM) in Combination With an Antidepressant in the Treatment of Patients With Major Depressive Disorder With Inadequate Response to an Antidepressant Treatment (PEARL STUDY)
Brief Summary: The purpose of this study is to evaluate the efficacy of quetiapine SR in combination with an antidepressant versus an antidepressant alone in patients with MDD with inadequate response to an antidepressant treatment.

PLEASE NOTE: Seroquel SR and Seroquel XR refer to the same formulation. The SR designation was changed to XR after consultation with FDA.


Options:
A: Inclusion Criteria:

1. Under the care of a GP and/or adult mental health services
2. Current episode of depression meeting DSM-5 criteria for major depressive disorder (MDD) - single or recurrent episode 3.17-item HAM-D score ≥ 14 - this cut-off reflects a pragmatic minimum severity of depression as also chosen in comparable studies such as STAR\*D (Rush et al 2006, Trivedi et al 2006)

4.Any gender and aged 18 years or over 5.Meet criteria for treatment resistant depression (Fekadu et al., 2009a; Cleare et al., 2015): current episode has not responded to at least two antidepressants given for at least 6 weeks at minimum therapeutic dose defined as fluoxetine ≥20mg/day, paroxetine ≥20mg/day, sertraline ≥50mg/day, citalopram ≥20mg/day, escitalopram ≥10mg/day, venlafaxine ≥75mg/day, duloxetine ≥60 mg/day, mirtazapine ≥15mg/day, tricyclic antidepressant ≥125mg/day, and dosage as guided by the national Maudsley Prescribing Guidelines or BNF for any other antidepressant. Please note, relapse whilst on an antidepressant also counts as a failed treatment trial 6.Current antidepressant treatment has remained unchanged and at, or above, a therapeutic dose for ≥6 weeks 7.Provision of written, informed consent.

Exclusion Criteria:

1. Diagnosis of bipolar disorder (defined as meeting DSM-5 criteria for bipolar 1 or bipolar 2) on the MINI 7.0 (as recommended treatments are different for bipolar depression)
2. Diagnosis of current psychosis (as recommended treatments are different for current psychosis - antidepressants plus antipsychotics is the first-line treatment recommendation (NiCE, 2009; Cleare et al., 2015)
3. Adequate use of lithium or quetiapine during the current episode. An adequate dose of lithium is defined as the patient taking lithium for at least 4 weeks at an adequate dose (leading to a documented plasma concentration of \>0.4mmol/L) and for quetiapine, prescription in the range of 150-300mg/d for 4 weeks or longer. Or, if the patient has taken an inadequate dose of lithium or quetiapine in the current episode, the patient and clinician are not willing to re-prescribe/take the medication.
4. Ongoing use of another atypical antipsychotic (discontinuation will be required before study entry i.e. any time prior to randomisation)
5. Known contraindication to use of either lithium or quetiapine: known hypersensitivity of lithium or quetiapine or any of their excipients; severe renal insufficiency / impairment; untreated hypothyroidism; severe cardiac disease / insufficiency; low sodium levels e.g. dehydrated patients or those on low sodium diets; Addison's disease; Brugada syndrome or family history of Brugada syndrome; the rare hereditary inborn errors of metabolism galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption; concomitant administration of cytochrome P450 3A4 inhibitors; or congenital QT prolongation.
6. We will not recruit any individual who is currently participating in a clinical trial of an investigational medical product (CTIMP).
7. Insufficient degree of comprehension or attention to be able to engage in trial procedures.
8. We will exclude women who are pregnant, actively trying for pregnancy, or currently breastfeeding. This will be based on verbal report of the subject. Otherwise the management will be as appropriate according to standard clinical practice within the context of a pragmatic, open trial, for example adequate contraceptive precautions decided on the clinical judgement of the prescriber.
B: Inclusion Criteria:

Male or female patients of ≥ 18 years of age that meet criteria for severe Major Depressive Disorder, without psychotic features (according to Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, \[DSM-IV\] and confirmed by Mini International Neuropsychiatric Interview \[MINI\]).

* With a total score Montgomery-Asberg Depression Rating Scale (MADRS) ≥ 30 and 6-item Hamilton Depression Rating Scale (HAMD-6) ≥ 12 and Clinical Global Impression of Severity (CGI-Severity) ≥ 4 at both screening and baseline.
* Requirement of hospitalization (not for social or other non-medical reasons) at screening visit and at least up to Visit 4.
* Patients willing and able to comply with the requirement for hospitalization and with all scheduled visits, tests and procedures required by the protocol.
* Informed consent document must be signed at screening visit, in accordance with Good Clinical Practice (GCP) and local regulatory requirements, prior to any study procedure.

Exclusion Criteria:

* More than two previous episodes of major depression that did not respond (according to investigator's opinion) to adequate doses and duration of two different antidepressant therapies.
* Lack of response to at least two antidepressant therapies given at adequate doses for at least 6 weeks for the current depressive episode.
* Concurrent presence of symptoms fulfilling criteria for any Axis I disorder other than anxiety disorders (with exception of the Obsessive-Compulsive Disorder (OCD)) or Major Depressive Disorder, in the investigator's judgment.
* Any previous diagnosis of a bipolar disorder, schizophrenia or OCD.
* Depression with catatonic features (according to DSM-IV), depression with post-partum onset, or organic mental disorders.
* The presence of an Axis II disorder
C: Inclusion Criteria:

* Patient is able to provide written informed consent before beginning any study related procedures
* Patient has a documented clinical diagnosis of major depressive disorder
* Patient is able to understand and comply with the requirements of the study, as judged by a study investigator

Exclusion Criteria:

* Patients with a history of non-compliance as judged by the study investigator
* Patients with a known lack of response to previous treatment with quetiapine
* Patients who have participated in a clinical trial within 4 weeks of randomization
D: Inclusion Criteria:

* Written informed consent.
* Men or women, 18-65 years of age.
* MDD, current, according to DSM-IV criteria and as diagnosed by the SCID- I/P during the screen and baseline visit of phase 1.
* A HAM-D-17 score \> 14 during the screen and baseline visit of phase 1.

Exclusion Criteria:

* Pregnant women or women of child bearing potential who are not using a medically accepted means of contraception (oral contraceptive or implant, condom, diaphragm, spermicide, intrauterine
* Device, tubal ligation, or partner with vasectomy).
* Serious suicide or homicide risk, as assessed by evaluating clinician.
* Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease or uncontrolled seizure disorder.
* History of multiple adverse drug reactions or allergy to the study drug.
* The following DSM-IV diagnoses: substance use disorders active within the last six months, any bipolar disorder (current or past), any psychotic disorder (current or past).
* Patients requiring excluded medications (see appendix 1 for details).
* Psychotic features in the current episode or a history of psychotic features.
* Prior course of ziprasidone, or intolerance to ziprasidone at any dose.
* Any investigational psychotropic drug within the last 3 months.
* Have failed more than 3 adequate antidepressant trials during the current MDE. Some examples of adequate dosage of an antidepressant trial include either \> 150 mg of imipramine (or its tricyclic equivalent), \> 60 mg of phenelzine (or its monoamine oxidase inhibitor equivalent), \> 20 mg of fluoxetine (or its SSRI-equivalent), \> 150mg of bupropion, \> 300mg of trazodone (or nefazodone), \>75 mg of venlafaxine, \>60mg of duloxetine, or \> 15mg of mirtazapine. A trial of adequate duration was defined as one during which the patient was on any given antidepressant at an adequate dose for a minimum of 6 weeks.

Answer: C