OSU6162 as add-on in SSRI/SNRI-resistant Depression

This is a randomised, placebo-controlled, parallel-group trial comparing OSU6162 at flexible dosage with placebo as add-on to treatment with an SSRI/SNRI in patients with depression that have not responded to treatment with an SSRI/SNRI per se for at least 6 weeks. The study will last for 6 weeks, after which those not having responded will leave the trial and those having responded will be offered to continue treatment without unblinding for another 4 weeks. Optional Substudy 1 and 2: Baseline and treatment-associated change in reward-related striatal activity per fMRI-assessment. (Substudy 1).

Brain signal variability per fMRI-assessment. (Substudy 1). Probabilistic Reward Task (PRT). (Substudy 2).

While assessment of the efficacy and safety of OSU6162 is the main objective of this study, possible differences between the two treatment groups with respect to a number of biomarkers in serum will also be explored.

Multicenter trial: Multiple sites four Gothenburg, Lund, Stockholm and Uppsala.

The treatment period will be 6 weeks during which all subjects will make 7 study visits and be in contact with study nurse or physician by phone at 4 occasions. The first visit is a screening visit followed by a baseline visit for inclusion and start of treatment with OSU6162 or placebo.

Optional for the subjects Substudy 1 and 2: Baseline and treatment-associated change in reward-related striatal activity per fMRI-assessment. (Substudy 1).

Brain signal variability per fMRI-assessment. (Substudy 1). Probabilistic Reward Task (PRT). (Substudy 2).

Those responding to treatment will be offered to participate in the extension phase of the study for an additional 4 weeks during which the subjects will make 3 study visits and take 3 telephone interviews.

Before inclusion in the study, all subjects will be informed both verbally and in writing about its purpose, its procedures, and possible risks associated with participation. Before any study-specific procedures take place, written informed consent will be obtained.

Multicenter trial. Multiple sites 4: Sahlgrenska University Hospital Gothenburg, Skåne University Hospital Psychiatry Lund, North Stockholm psychiatry Stockholm region and Uppsala University Hospital Department of neuroscience Uppsala.

For participation in the extension phase, four factors must be fulfilled: 1. The subject must regard himself/herself as clearly improved and be willing to continue. 2. The investigator must assess the subject as clearly improved. 3. The subject must display at least 50% reduction on HDRS6 as compared to baseline. 4. The subject must have signed a new informed consent.

While assessment of the efficacy and safety of OSU6162 is the main objective of this study, possible differences between the two treatment groups with respect to a number of biomarkers in serum will also be explored.

The primary evaluation of efficacy will be undertaken at the endpoint of the 6-week trial. All analyses will however be repeated also at the endpoint of the 4-week extension phase for subjects participating in this part of the study.

Data will be analysed using mixed models for repeated measurement which means that the model includes data from all depression ratings from baseline to endpoint; this method, which is usually recommended to be used in depression trials by the authorities, is considered to handle data loss due to patients leaving a study prematurely in a better way than imputation methods such as the last observation carried forward (LOCF) technique.

Eligibility Criteria:
Inclusion Criteria

In order to be included in the study, subjects must meet the following criteria:

1. Signed informed consent.
2. Age: 25-65 on the day of screening.
3. Meeting DSM-5 criteria for major depressive disorder as confirmed by the Mini International Neuropsychiatric Interview (MINI).
4. A symptom-free period preceding the current episode within the past two years confirmed at interview.
5. Not significantly improved, as judged by both doctor and patient, after having been treated with one of the following SSRIs/SNRIs: citalopram, escitalopram, paroxetine, sertraline, fluoxetine, duloxetine, or venlafaxine for at least 6 weeks.
6. Displaying a sum score of MADRS ≥22.
7. In women of childbearing potential (WOCBP): negative result of a pregnancy test and a method of contraception with a failure rate of less than 1 %. Contraception must be used during the treatment and follow-up period. Acceptable forms of contraception are:

   1. Use of combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation

      * oral
      * intravaginal
      * transdermal
   2. progestogen-only hormonal contraception associated with inhibition of ovulation:

      * oral
      * injectable
      * implantable
   3. Placement of intrauterine device (IUD) or intrauterine hormone releasing system (IUS)
   4. Bilateral tubal occlusion or ligation
   5. Vasectomised partner (with appropriate post-vasectomy documentation of the absence of sperm in the ejaculate and provided that male partner is the sole sexual partner of the WOCBP trial participant).
   6. Sexual abstinence.
8. Male patients must agree to use condoms during the study and for 2 weeks after the end of the study/last dose of IMP, unless their partner is using a highly efficient method of contraception, as described above.

Exclusion criteria

Subjects must not be included in the study if any of the following criteria are met:

1. Meeting MINI criteria at interview for suicidality, manic episode, hypomanic episode, bipolar I, bipolar II, bipolar unspecified, bipolar I with psychotic symptoms, panic disorder (current), agoraphobia, posttraumatic stress disorder, alcohol dependency, alcohol abuse, substance dependency (non-alcoholic), substance abuse (non-alcoholic), psychotic disorders, mood disorders with psychotic features, anorexia nervosa, bulimia nervosa, anorexia nervosa binge eating / purging type, or antisocial personality disorder.

   Meeting MINI criteria at interview for generalised anxiety disorder, obsessive compulsive disorder or social anxiety (social phobia), unless the present symptoms can predominantly be attributed to a diagnosis of major depressive disorder.
2. A history of substance/alcohol abuse within 2 years prior to screening.
3. A previous diagnosis of a personality disorder, autism spectrum disorder, attention-deficit/hyperactivity disorder, or intellectual disability.
4. Any other previously diagnosed or suspected CNS disorder that according to the investigator renders the patient unsuitable for participation in the trial.
5. Any factor that according to the investigator renders it unlikely that the patient will comply with the instructions regarding treatment, visits etc.
6. Any somatic illness that according to the investigator renders the patient unsuitable for participation in the trial.
7. Any signs or symptoms of somatic illness resulting from assessment of vital signs, physical examination, clinical laboratory tests, and 12-lead ECG that according to the investigator renders the patient unsuitable for participation for safety reasons, including a QTc-time on ECG exceeding 450 ms in men and 460 ms in women.
8. Any change in dosage of said SSRI/SNRI within 4 weeks prior to screening or at any time during the course of the trial.
9. Treatment with any other psychoactive drug than said SSRI/SNRI with the exception of using mirtazapine up to 15 mg for sleep, occasional use of benzodiazepines and benzodiazepine-like anxiolytics or hypnotics and occasional use of antihistaminergic sedatives (without anti-dopaminergic effects) within 4 weeks prior to screening and at any time during the course of the trial.
10. Patients who are receiving concomitant therapy with potent cytochrome P450 enzyme inhibitors (e.g., bupropion, fluvoxamin, ketoconazole, itraconazole, telithromycin, clarithromycin, protease inhibitors, quinidine, and terbinafine).
11. Ongoing treatment with drugs with a narrow therapeutic window where either lower or higher serum levels are potentially harmful (including but not limited to warfarin along with other anticoagulants, digoxin along with other antiarrythmics, anticonvulsants prescribed for treatment of epilepsy, cyclosporine, immunosuppressants, and lithium).
12. Current treatment with any prescribed or OTC drug that according to the investigator renders the subject unsuitable for participation in the trial.
13. Previous intake of OSU6162.
14. Current participation in another clinical trial.
15. Nursing women.