Intensified Pharmacological Treatment for Schizophrenia, Major Depressive Disorder and Bipolar Depression After a First-time Treatment Failure

NCT05603104 | Recruiting Phase 3 DMC

• 1 other identifier: 2022-502185-24-00 (EU CT #)
• Study Type: interventional
• Target: 1,254
• Locations: 1 country
• Sites: 1

Brief Summary

Schizophrenia, bipolar and major depressive disorders collectively affect over 10 million people across the EU and are associated with annual healthcare and societal costs in excess of 100 billion Euros. When diagnosed with one of these disorders, patients are prescribed psychotropic medication such as antidepressants, mood stabilisers or antipsychotics. It is unknown whether this first-line treatment will be successful. After this first-line treatment fails, usually a second-line treatment is initiated, and when this is not successful either a third-line treatment is initiated. Third-line treatments are quite successful, especially when compared to second-line treatments. The research question is whether the third-line treatments (early-intensified treatments) when used earlier in the disease course for schizophrenia, bipolar and major depressive disorders. If this is indeed the case, this could lead to the prevention of unnecessary trials of ineffective treatments and adaptations of worldwide guidelines as well as a reduction of healthcare and societal costs.

Conditions

Major Depressive Disorder; Bipolar Depression; Schizophrenia and Related Disorders

Outcome Measures

Primary Outcomes (1)

• Change in symptom severity

  Change in symptom severity total score from baseline (visit 2) to end of treatment (visit 4). For Schizophrenia, this is measured using the Positive And Negative Syndrome Scale. For Major Depressive Disorder and Bipolar Depression, Montgomery Åsberg Depression Rating Scale is applied.

  6 weeks

Secondary Outcomes (17)

• All study samples: to compare changes in the severity and improvement

  6 weeks

• All study samples: to compare changes in the levels of depression and anxiety

  6 weeks

• All study samples: to compare changes in cognitive performance #1

  6 weeks

• All study samples: to compare changes in cognitive performance #2

  6 weeks

• All study samples: to compare changes in cognitive performance #3

  6 weeks

Study Arms (6)

Schizophrenia EIPT: Switch to clozapine

EXPERIMENTAL

Schizophrenia randomized to EIPT: Switch to clozapine. Brand, dosage, frequency and duration up to the investigator's discretion

Drug: Clozapine

Schizophrenia TAU: second-line antispychotic

ACTIVE COMPARATOR

Schizophrenia randomized to TAU: switch to second-line antispychotic. Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC)

Drug: Second-line Antipsychotics

Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray

EXPERIMENTAL

Major depressive disorder randomized to EIPT: Switch to second-line antidepressant + esketamine nasal spray or (es)ketamine infusion. Antidepressant: Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC). Esketamine nasal spray: 2 times per week for 4 weeks. Initial dose 28 mg, after that increases can be made with 28 mg per increase (up to 84 mg per week). This decision is up to the investigator's discretion (in accordance with SmPC). (Es)ketamine infusion: performed twice weekly for 4 weeks. Compound, brand up to the investigator's discretion (in accordance with SmPC).

Drug: Esketamine Nasal Product; Drug: Second-line Antidepressants; Drug: Ketamine Hydrochloride; Drug: Esketamine hydrochloride

Major Depressive Disorder TAU: second-line antidepressant

ACTIVE COMPARATOR

Major depressive disorder randomized to TAU: Switch to second-line antidepressant + esketamine nasal spray or ketamine IV or esketamine IV . Antidepressant: Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC).

Drug: Second-line Antidepressants

Bipolar Depression EIPT: Switch to one of the following combinations:

EXPERIMENTAL

Bipolar Depression randomized to EIPT: Switch to 1. one of the following: escitalopram, sertraline, bupropion or venlafaxine plus 2. two of the following: lithium, valproate acid or quetiapine

Drug: Escitalopram; Drug: Sertraline; Drug: Venlafaxine; Drug: Lithium; Drug: Valproate acid; Drug: Quetiapine; Drug: Bupropion

Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine

ACTIVE COMPARATOR

Bipolar Depression randomized to TAU: Switch to quetiapine plus lithium or valproate acid Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC).

Drug: Lithium; Drug: Valproate acid; Drug: Quetiapine

Interventions

Clozapine DRUG

See arm description

Also known as: ATC code: N05AH02

Schizophrenia EIPT: Switch to clozapine

Esketamine Nasal Product DRUG

See arm description

Also known as: ATC code: N06AB10

Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray

Escitalopram DRUG

See arm description

Also known as: ATC code: N06AB10

Bipolar Depression EIPT: Switch to one of the following combinations:

Sertraline DRUG

See arm description

Also known as: ATC code: N06AB06

Bipolar Depression EIPT: Switch to one of the following combinations:

Venlafaxine DRUG

See arm description

Also known as: ATC code: N06AX16

Bipolar Depression EIPT: Switch to one of the following combinations:

Lithium DRUG

See arm description

Also known as: ATC code: N05AN01

Bipolar Depression EIPT: Switch to one of the following combinations:; Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine

Valproate acid DRUG

See arm description

Also known as: ATC code: N03AG01

Bipolar Depression EIPT: Switch to one of the following combinations:; Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine

Quetiapine DRUG

See arm description

Also known as: ATC code: N05AH04

Bipolar Depression EIPT: Switch to one of the following combinations:; Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine

Second-line Antidepressants DRUG

See arm description

Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray; Major Depressive Disorder TAU: second-line antidepressant

Second-line Antipsychotics DRUG

See arm description

Schizophrenia TAU: second-line antispychotic

Ketamine Hydrochloride DRUG

See arm description

Also known as: N01AX03

Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray

Esketamine hydrochloride DRUG

See arm description

Also known as: N015X14

Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray

Bupropion DRUG

See arm description

Also known as: ATC code: N06AX12

Bipolar Depression EIPT: Switch to one of the following combinations:

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. 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.
• \. 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.
• \. 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).
• \. 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.
• \. 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).

You may not qualify if:

• Being pregnant or breastfeeding.
• 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.
• 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).
• 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.
• 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.
• 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.
• \. 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
• 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.
• Subjects have not been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
• Subjects dependent on the sponsor, investigator or trial site must be excluded from participation in advance.
• For the SZ sample only: schizophrenia subjects cannot meet the modified Andreasen criteria for remission.
• 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.
• 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.
• 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).
• For the BD study sample only: Subjects with pre-existing severe liver damage (as tested within the local laboratory test at visit 1).

Sponsors & Collaborators

• Dr. Inge Winter: lead
• Universität Münster: collaborator

Study Sites (1)

Sheba Medical Center

Ramat Gan, Israel

RECRUITING

MeSH Terms

Conditions

Schizophrenia; Depressive Disorder, Major; Bipolar Disorder

Interventions

Clozapine; Escitalopram; Sertraline; Venlafaxine Hydrochloride; Lithium; Quetiapine Fumarate; Ketamine; Bupropion

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Depressive Disorder; Mood Disorders; Bipolar and Related Disorders

Intervention Hierarchy (Ancestors)

Dibenzazepines; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Propylamines; Amines; Organic Chemicals; Nitriles; Benzofurans; Heterocyclic Compounds, 2-Ring; 1-Naphthylamine; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Cyclohexanols; Hexanols; Fatty Alcohols; Alcohols; Phenethylamines; Ethylamines; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Lipids; Metals, Alkali; Elements; Inorganic Chemicals; Metals, Light; Metals; Dibenzothiazepines; Thiazepines; Thiepins; Sulfur Compounds; Propiophenones; Ketones

Central Study Contacts

Inge Winter, Dr.

CONTACT

+31875553227; i.winter@umcutrecht.nl

Cynthia Okhuijsen-Pfeifer, Dr.

CONTACT

+31875553227; c.pfeifer@umcutrecht.nl

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Open label, except for the assesseors of the primary outcome
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Workpackage leader

Model Details: Parallel randomization to the treatment as usual (TAU) or early-intensified pharmacological treatment (EIPT) group for each of the study groups (schizophrenia, major depressive disorder, bipolar depression) leading to 6 arms.

Study Record Dates

• First Submitted: October 13, 2022
• First Posted: November 2, 2022
• Study Start: April 27, 2025
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): June 30, 2028
• Last Updated: January 22, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, CSR

Locations

IL (1)