Schizophrenia (SZ) affects approximately 4.5 million people across the European Union (EU) and is associated with annual healthcare and societal costs of 29 billion Euros. The impact on the daily life of patients is huge, ranging from frequent relapses and hospitalisations, the inability to maintain a job or continue scholing, to a low quality of life, impaired cognitive functioning, suicidal ideation and an increase morbidity rate, next to the large burden for carers 1. When diagnosed with schizophrenia or related disorder, patients are commonly prescribed antipsychotics. One-third of the schizophrenia patients are regarded treatment-resistant (TR), meaning that at least two antipsychotic trials have failed. Typically, clozapine is prescribed for TR patients, which is effective for approximately 40% of patients. Clozapine is among the most effective treatments, with the lowest all-cause mortality. Although it is among the most effective antipsychotics, it is generally not used earlier in the illness course due to a small risk of severe neutropenia/agranulocytosis, which is why patients treated with clozapine are intensely monitored. However, this small risk outweighs the burden of not receiving an effective treatment.
Since clozapine is among the most effective treatments, this leads to the research question whether earlier initiation of third-line treatment ('early intensified' pharmacological treatment; EIPT) would be more beneficial than the current second-line treatments (treatment as usual; TAU). If this is indeed the case, this could lead to the prevention of unnecessary trials of ineffective treatments, hospitalisations, and recommendations for adaptations of worldwide guidelines as well as a reduction of healthcare and societal costs The INTENSIFY-Schizophrenia trial is part of the larger Horizon 2021 project Psych-STRATA, with the central goal of paving the way for a shift towards a treatment decision-making process tailored for the individual at risk for treatment resistance. To that end, the inestigators aim to establish evidence-based criteria to make decisions of early intense treatment in individuals at risk for treatment resistance across the major psychiatric disorders of schizophrenia, bipolar disorder and major depression. The current protocol focuses on the sample of schizophrenia patients.
In- or out patients, at least 18 years of age up until 70.
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 use effective contraception during the trial as per the requirements of the applicable SmPCs and should have a negative pregnancy test at visit 1 or 2 (before randomisation; section 8.2).
Meeting diagnostic criteria for a primary diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder, according to DSM-5. The primary diagnosis will be confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2).
Being pregnant or breastfeeding.
Subject has used clozapine in the past.
Subject has a known intolerance to clozapine or to all TAU medication options.
Meeting any of the contraindications of clozapine or to all TAU medication options, as specified within the applicable SmPC.
Parallel
Clozapine
DrugParticipants are randomized to clozapine or second-line antipsychotics. When randomised to clozapine, they will receive clozapine for six weeks.
Second-line Antipsychotics (treatment as usual)
DrugParticipants are randomized to clozapine or second-line antipsychotics. When randomized to second-line antipsychotics, this means participants will receive treatment as usual. The physician has the choice to administer any second-line antipsychotic. More specification is not possible, as this is a choice the physician makes with the participant based on the characteristic and preference of the participant (in line with standard clinical practice).
Change in symptom severity on Positive and Negative Syndrome Scale
Change in symptom severity (EIPT vs. TAU) total score from baseline (visit 2) to end of treatment (visit 4). This is measured using the Positive And Negative Syndrome Scale. Minimum score is 30, maimum score 210. A bigger mean change means a better outcome.
Compare symptomatic remission.
Comparison of the proportion of participants (EIPT vs. TAU) that is in symptomatic remission at visit 4. Remission is defined as meeting all the Positive and Negative Syndrome Scale modified Andreasen criteria (Low scores (≤3) P1. Delusions; P3. Hallucinatory behavior; P2. Conceptual disorganization; N1. Blunted affect; N4. Passive/apathetic social withdrawal; N6. Lack of spontaneity and flow of conversation; G5. Mannerisms/posturing; G9. Unusual thought content. There is no minimum or maximum score; either a participants meets the criteria or not (dichotomous outcome).
To compare changes in PANSS subscale scores (positive, negative and general) between the two treatment arms.
To compare changes in Positive and Negative Syndrome Scale subscale scores (positive (mimumum score 7, maximum score 49), negative (minimum score 7, maximum score 49) and general( (minimum score 16, maximum score 112)) between the two treatment arms over the six-week treatment period (visit 2 versus visit 4). Lower scores mean better outcomes.
Compare changes in the levels of depression and anxiety
To compare changes in the levels of depression and anxiety as assessed with the Hospital Anxiety and Depression Scale between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4). Lower scores mean less depression and anxiety.
To compare changes in cognitive performance as measured through the Trail Making Test
To compare changes in cognitive performance as measured through the Trail Making Test between the two treatment arms over the six weeks treatment period (visit 2 versus visit 4). A lower time to complete the test means better cognitive performance.
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