Intensified Pharmacological Treatment for Schizophrenia, Major Depressive Disorder and Bipolar Depression After a First-time Treatment Failure (INTENSIFY)
Schizophrenia and Related Disorders, Major Depressive Disorder, Bipolar Depression
About this trial
This is an interventional treatment trial for Schizophrenia and Related Disorders
Eligibility Criteria
Inclusion Criteria: In- or out patients, at least 18 years of age up until 70. Being willing and able to provide written informed consent. If unable, having a legal guardian to provide written informed consent is allowed (subject's opinion will also be considered in these cases). 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). 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 currently experiences his/her first treatment failure due to lack of efficacy; this treatment is a first-line pharmacotherapeutic agent for the primary DSM-5 diagnosis, and was prescribed for at least 4 weeks within the dose range as specified in the Summary of Product Characteristics (SmPCs). Subject has failed on current psychopharmacological treatment of current episode of SZ/MDD/BD, as confirmed by a CGI-I ≥3. Subject and clinician intend to change pharmacotherapeutic treatment. 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: Being pregnant or breastfeeding. Subject has failed previously on the EIPT study medication (i.e. SZ: clozapine; MDD: esketamine intranasal/(es)ketamine IV) or the TAU treatment for BD (quetiapine) due to inefficacy. 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). 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)., 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 currently uses more than the allowed psychotropic concomitant medication and needs to stay on this medication during the study. 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. Current active suicidal ideation within the last 2 weeks, defined as a score of 1 or higher on CDSS question 8, followed by an assessment by the treating clinician who determines it is not safe for the subject to participate in the study. For MDD/BD study samples: Subject meets criteria for current alcohol and/or drugs substance use disorderdependency, as confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2). For all study samples: Nnicotine dependency is allowed, as well as mild alcohol and/or cannabis use disorder (as defined by MINI v7.0.2). Moderate and severe alcohol and/or cannabis use disorder are not allowed. Subjects who are admitted in the (psychiatric) clinic due to a court or administrative order are not allowed to participate in the study. For the SZ sample only: schizophrenia subjects cannot meet the modified Andreasen criteria for remission. For the BD sample only: a score of 8 or higher on the Young Mania Rating Scale (YMRS) in order to exclude subjects with predominant manic symptoms or mixed symptoms.
Sites / Locations
- Sheba Medical Center
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Experimental
Active Comparator
Experimental
Active Comparator
Experimental
Active Comparator
Schizophrenia EIPT: Switch to clozapine
Schizophrenia TAU: second-line antispychotic
Major Depressive Disorder EIPT: second-line antidepressant + esketamine nasal spray
Major Depressive Disorder TAU: second-line antidepressant
Bipolar Depression EIPT: Switch to one of the following combinations:
Bipolar Depression TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine
Schizophrenia randomized to EIPT: Switch to clozapine. Brand, dosage, frequency and duration up to the investigator's discretion
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)
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).
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).
Bipolar Depression randomized to EIPT: Switch to 1. one of the following: escitalopram, sertraline, duloxetine or venlafaxine plus 2. two of the following: lithium, lamotrigine, valproate acid or quetiapine
Bipolar Depression randomized to TAU: Switch to quetiapine plus lithium or valproate acid or lamotrigine Compound, brand, dosage, frequency and duration up to the investigator's discretion (in accordance with SmPC).