Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomised Pragmatic Trial Comparing the Clinical and Cost Effectiveness of Lithium and Quetiapine Augmentation in Treatment Resistant Depression
Brief Summary: LQD is a multicentre randomised clinical trial comparing the clinical and cost effectiveness of lithium versus quetiapine when used as add-on therapies to antidepressant medication for patients with treatment resistant depression. The Lithium versus Quetiapine in Depression (LQD) study will assess patients over 12 months to establish which (if any) treatment is more likely to improve TRD over a long duration of time. Professor Anthony Cleare is the Chief Investigator and recruitment began in November 2016.


Options:
A: Inclusion Criteria:

1. Male or female subjects, age 18-65
2. A current primary diagnosis of unipolar major depression based on certain criteria
3. Have a score of \> 18 on the 17-item Hamilton Depression scale
4. A history of prior failure of at least one adequate trial of an FDA-approved antidepressant. The antidepressant failure must have occurred within the current episode of major depression
5. Females of childbearing potential will be allowed as long as they are taking adequate contraceptive precautions

Exclusion Criteria:

1. A primary Axis I diagnosis other than primary unipolar major depression
2. A history suggestive of hypomania or mania during the current episode or during the person's lifetime
3. A history of psychosis, dementia, organic affective disorders or alcohol and/or substance abuse in the previous six months

   * Individuals with a current or past diagnosis of schizoid, schizotypal, borderline or antisocial or any other current or past severe personality disorder
   * Individuals with a current or past diagnosis of schizophrenia or schizoaffective disorder
4. A history of failure to respond to electroconvulsive therapy during the current or any prior lifetime episode of major depression
5. A history of failure of a prior adequate trial of paroxetine or paroxetine-CR for the treatment of Major Depression
6. Significant, coexisting medical conditions that might make it unsafe to take either of the study medications, or in which any average reasonable clinician would assume that the medical condition may, in fact, be exacerbating the current episode of depression or impede the person's ability to recover fully from their depressive illness
7. Presence of significant medical abnormalities on baseline laboratory values or physical examination, including vital signs

   * Individuals with any significant abnormalities of thyroid function
   * Subjects on thyroid supplementation must have been on a stable dose for six months prior to the screening visit
8. Individuals who will require concomitant psychotropic medications, including benzodiazepines

   * Subjects with severe insomnia will be allowed to take a maximum of 10 mg of zolpidem on two nights weekly at the investigator's discretion.
   * Zolpidem may not be taken on the night before the study visit.
   * Each dose of zolpidem should be listed on the concurrent medication case report form
9. Medications likely to cause significant effects on mood and anxiety are also excluded
10. Individuals with a positive urine drug screen for drugs of abuse at the screening visit
11. Use during the time of the study of any medications known to affect the metabolism of lamotrigine

    * Individuals on valproate and carbamazepine will be specifically excluded
    * Investigators should be aware that oral contraceptives have been reported to lower the levels of lamotrigine, but any change in dosing is left to the judgment of the investigator
12. Subjects who have taken other psychoactive drugs within certain time frames of the screening visit
13. The presence of significant risk of suicide
14. Pregnant females or those who are breastfeeding infants
15. A history of hypersensitivity or intolerance to either of the study medications, lamotrigine or paroxetine or paroxetine-CR
16. Subjects initiating or terminating psychotherapy within 12 weeks of the screening visit
17. Individuals who are currently on disability for a psychiatric disorder, or who are in any other way likely to experience considerable secondary gain from the persistence of their psychiatric illness, such as pending legal litigation of any type
18. Individuals who in the opinion of the investigator would not be able to understand or comply with the study requirements
B: Inclusion Criteria:

* Diagnosis of major depression (clinical diagnosis, guided by DSM-IV criteria).
* History of attempted suicide or deliberate self-harm in the previous 12 months.
* Inadequate response to at least two antidepressants given sequentially at an adequate dose for an adequate time for the current depressive episode.
* Uncertainty about which treatment arm would be best for participant.
* Age 18 or above.
* Agreement between investigator and patient to enter the study.

Exclusion Criteria:

* In addition to major depression, a primary diagnosis of any concurrent Axis I disorder (according to DSM-IV criteria) will constitute an exclusion criterion; by contrast, any concurrent Axis II disorder (according to DSM-IV criteria) will not constitute an exclusion criterion.
* Previous exposure to lithium was associated with lack of efficacy or unwanted adverse reactions.
* Clinical conditions contraindicate the experimental treatment arm (for example thyroid or kidney disease or abnormalities).
* Pregnant/lactating women.
* Women of childbearing potential not practicing a reliable method of contraception.
C: 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.
D: Inclusion Criteria:

1. Patients who are either inpatients or outpatients
2. Patients who have the ability to understand and to provide informed consent to the examination, observation, and evaluation processes specified in this protocol, and have signed the informed consent form based on a full understanding of the trial
3. Patients diagnosed as having either "296.2x Major Depressive Disorder, Single Episode" or "296.3x Major Depressive Disorder, Recurrent" according to DSM-IV-TR, and for whom the current episode of major depressive disorder has been ongoing for more than 8 weeks
4. Patients with a HAM-D17 total score of 18 or more

Exclusion Criteria:

1. Female patients of child bearing potential who wish to become pregnant during the treatment period, or within 4 weeks after study completion/discontinuation
2. Female patients who are pregnant, possibly pregnant, or breast feeding
3. Patients judged to be unable to tolerate any type of antidpressant treatment (including drugs not being used in the current episode of major depressive disorder), based on treatment history to date
4. Patients who have previously received electro-convulsive therapy
5. Patients who have participated in clinical studies on medical devices or other drugs within the past month
6. Patients at risk of having serious adverse events or developing symptoms that could interfere with safety and efficacy evaluations (such as symptoms of fibromyalgia syndrome overlapping with symptoms of depression), based on previous medical history
7. Patients with a history or a complication of diabetes
8. Patients with thyroid disease (excluding patients who are stabilized on drug therapy for at least 3 months)
9. Patients with a history of serotonin syndrome or psychotropic neuroleptic malignant syndrome
10. Patients with a history of seizure disorder (epilepsy etc.)

Answer: C