Intensified treatment for schizophrenia, major depression, and bipolar depression after initial treatment failure

A Randomised, Controlled Trial to Investigate the Effect of an Intensified Pharmacological Treatment for Schizophrenia, Major Depressive Disorder and Bipolar Depression in Subjects Who Had a First-time Treatment Failure on Their First-line Treatment.

This study is testing if stronger medications can help people with schizophrenia, major depression, and bipolar depression who didn’t get better with their first treatments.

Quick facts

• Phase: PHASE3
• Study type: Interventional
• Enrollment: 1254 (estimated)
• Ages: 18 Years to 70 Years
• Sex: All
• Sponsor: UMC Utrecht (other)
• Locations: 1 site (Ramat Gan)
• Trial ID: NCT05603104 on ClinicalTrials.gov

What this trial studies

This clinical trial investigates whether early-intensified pharmacological treatments are more effective than standard second-line treatments for patients with schizophrenia, major depressive disorder, and bipolar depression who have not responded to first-line therapies. The study aims to compare the efficacy of third-line treatments, such as clozapine and esketamine, against conventional second-line options. By focusing on patients who have experienced treatment failure, the trial seeks to provide clearer evidence for optimizing treatment algorithms and potentially reduce unnecessary healthcare costs. The findings could lead to significant changes in clinical guidelines for managing these mental health disorders.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 to 70 with a primary diagnosis of schizophrenia, major depressive disorder, or bipolar depression who have not responded to first-line treatments.

Not a fit: Patients who have not yet undergone first-line treatment or those with other psychiatric disorders may not benefit from this study.

Why it matters

Potential benefit: If successful, this trial could lead to more effective treatment options for patients who do not respond to initial therapies, improving their overall mental health outcomes.

How similar studies have performed: Previous studies have indicated that third-line treatments can be effective, but this specific comparison of treatment algorithms is novel.

Eligibility criteria

Inclusion Criteria:

1\. In- or out patients, at least 18 years of age up until 70 (SZ study sample), 65 years (MDD study sample) and no limit for the BD study..

Being willing and able to provide written informed consent. Having a legal guardian to cosign is allowed. Informed consent will be signed at visit 1, before any study procedure.

3\. Female subjects of child bearing potential must be willing to ensure that they use effective contraception during the trial and as per the requirements in the protocol (section 8.2.1).Male subjects that will use valproate acid during the trial must use effective contraceptive measures during the trial.

4\. Meeting diagnostic criteria for a primary diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, major depressive disorder (without psychotic features) or bipolar depression (bipolar disorder type I and II currently in a depressive episode), according to DSM-5. The primary diagnosis will be confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2).

5\. Subject experiences a treatment failure due to lack of efficacy in the current episode, as confirmed by a CGI-I ≥3; preferably this treatment is a first-line pharmacotherapeutic agent for the primary DSM-5 diagnosis, and was prescribed for at least 4 weeks within an effective dose range as specified in the Summary of Product Characteristics (SmPCs). However, other lines of treatment are accepted as well.

6\. Subject and clinician intend to change pharmacotherapeutic treatment. 7. A minimum symptom severity threshold needs to be present (moderate level; see below) and subject needs to experience functional impairment.

* The minimum symptom severity threshold for SZ subjects is at least 2 PANSS positive or negative items with a score of 4, or at least one PANSS positive or negative item with a score of 5.
* The minimum symptom severity threshold for MDD is a score of ≥ 20 on the Montgomery Åsberg Depression Rating Scale (MADRS)
* The minimum symptom severity threshold for BD is a score of ≥20 on the Montgomery Åsberg Depression Rating Scale (MADRS)
* For all study samples: Functional impairment is defined as a score of 5 or higher on any of the three scales of the Sheehan Disability Scale (SDS).

Exclusion criteria:

1. Being pregnant or breastfeeding.
2. Subject has failed previously on the EIPT study medication (i.e. SZ: clozapine; MDD: esketamine intranasal/(es)ketamine IV) Treatment duration as ≥ 4 weeks within an efficacious dose range according to the SmPC.
3. Subject has a known intolerance to clozapine (SZ only), esketamine intranasal/ (es)ketamine IV (MDD only) or quetiapine (BD only) or to all medication options for a study sample (related to the TAU treatment arms) or all EIPT medications (BD study sample).
4. Meeting any of the contraindications of clozapine (SZ only), esketamine intranasal/ (es)ketamine IV (MDD only) or quetiapine (BD only), or to all medication options for a study sample (related to the TAU treatment arms), or all EIPT medications (BD study sample), as specified within the applicable SmPC.
5. Subject has participated in another clinical trial in which the subject received an experimental or investigational drug or agent within 30 days before visit 1.
6. Subject experiences any other significant disease or disorder which, in the opinion of the investigator, may either put the subjects at risk because of participation in the trial, or may influence the result of the trial, or the subject's ability to participate in the trial.
7. 7\. Subjects with active suicidal ideation with some intent to act, without specific plan ("Yes" to question 4 of the Columbia-Suicide Severity Rating Scale (C-SSRS)) or active suicidal ideation with specific plan and intent ("Yes" to question 5 of the C-SSRS), followed by an assessment by the treating clinician who determines it is not safe for the subject to participate in the study
8. Subject meets criteria for current substance use disorder, as confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2). Nicotine dependency is allowed, as well as mild and moderate alcohol and/or cannabis use disorder (as defined by MINI v7.0.2). Severe alcohol and/or cannabis use disorder are not allowed.
9. Subjects have not been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
10. Subjects dependent on the sponsor, investigator or trial site must be excluded from participation in advance.
11. For the SZ sample only: schizophrenia subjects cannot meet the modified Andreasen criteria for remission.
12. For the SZ sample only: Subjects that have any clinically significant abnormal values on the local laboratory test (especially ANC/WBC and liver values), electrocardiogram (ECG) or physician examinations.
13. For the BD sample only: a score of 12 or higher on the Young Mania Rating Scale (YMRS) in order to exclude subjects with predominant manic symptoms or mixed symptoms.
14. For the BD study sample only: Subjects with a history of antidepressant-induced mania or hypomania or recent rapid cycling (based on the medical file of the potential participant or the clinical judgment of the clinician).
15. For the BD study sample only: Subjects with pre-existing severe liver damage (as tested within the local laboratory test at visit 1).

Where this trial is running

Ramat Gan

• Sheba Medical Center — Ramat Gan, Israel (RECRUITING)

Study contacts

• Study coordinator: Inge Winter, Dr.

Conditions: Schizophrenia and Related Disorders, Major Depressive Disorder, Bipolar Depression