A randomised, controlled trial to investigate the effect of a four/six week intensified pharmacological treatment for schizophrenia, major depressive disorder and bipolar depression compared to treatment as usual in subjects who had a first-time treatment failure on their first-line treatment.

The primary objective of this randomized, controlled trial is to evaluate the **treatment response** in subjects with schizophrenia, schizoaffective disorder, schizophreniform disorder, major depressive disorder, or bipolar disorder type I and II, who have experienced a first-time treatment failure on their first-line treatment. The study aims to compare the mean change in symptom severity between an early-intensified pharmacological treatment and treatment as usual. This comparison is crucial for determining the efficacy of intensified treatment strategies in improving patient outcomes across these psychiatric conditions.

Secondary objectives include:

• Comparing changes in the severity and improvement sub-scores of the Clinical Global Impression Scale between the two treatment arms over the treatment period.
• Assessing changes in depression and anxiety levels using the Hospital Anxiety and Depression Scale.
• Evaluating changes in cognitive performance through various cognitive tests.
• Comparing changes in quality of life and functioning measures.
• Assessing the presence of side effects as measured through GASE and reported spontaneously.
• Comparing the use of concomitant medication between the treatment arms.
• Evaluating premature discontinuation rates, including timing and reasons.
• Comparing long-term effects of the treatment between the study arms.
• For schizophrenia samples, comparing changes in Positive And Negative Syndrome Scale subscale scores.
• Comparing the proportion of participants in remission at visit 4, with specific criteria for schizophrenia and major depressive disorder/bipolar disorder.

The clinical trial involves a total of **309 participants** diagnosed with **schizophrenia**, schizoaffective disorder, schizophreniform disorder, major depressive disorder, or bipolar disorder type I and II, currently in a depressive episode. The study population includes both male and female subjects, aged between 18 and 70 years. Participants were selected based on their experience of a first-time treatment failure on their first-line treatment, with a confirmed primary diagnosis according to DSM-5 criteria. The trial includes both inpatients and outpatients, and subjects must be willing and able to provide written informed consent, or have a legal guardian do so if necessary. Female participants of childbearing potential are required to use effective contraception during the trial. The study population is characterized by a moderate level of symptom severity and functional impairment, and participants are required to have an intention to change their pharmacotherapeutic treatment. The trial includes a vulnerable population, reflecting the complex nature of the psychiatric conditions under investigation.

The clinical trial is designed as a **randomized, controlled** study to evaluate the efficacy of an intensified pharmacological treatment regimen for patients with **schizophrenia**, major depressive disorder, and bipolar depression who have experienced a first-time treatment failure on their initial therapy. The trial will compare the treatment response, measured as a change in symptom severity, between the intensified treatment and the standard treatment as usual. The study will involve participants aged 18 to 70 years who meet the diagnostic criteria for the specified conditions according to DSM-5 and have experienced a lack of efficacy with their current first-line treatment.

The trial will span an estimated duration from July 2023 to June 2026, with participant involvement lasting up to six weeks, depending on the specific condition being treated. The study will include several key visits: an initial **screening visit** to confirm eligibility, a baseline visit (Visit 2) to establish symptom severity, and subsequent follow-up visits at four weeks for major depressive disorder and six weeks for schizophrenia and bipolar depression (Visit 4). The primary endpoint will be the change in symptom severity from baseline to the end of the treatment period, assessed using the Positive and Negative Syndrome Scale for schizophrenia and the Montgomery-Asberg Depression Rating Scale for major depressive disorder and bipolar depression.

Participants will be required to attend all scheduled visits and adhere to the treatment protocol. The trial will be conducted under a double-blind design to ensure unbiased results. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or any adverse events that compromise participant safety. The trial aims to provide valuable insights into the effectiveness of early-intensified pharmacological interventions for these psychiatric conditions.

The clinical trial involves the administration of **Spravato** 28 mg nasal spray, solution, which contains the active substance **esketamine hydrochloride**. This medication is administered via **nasal spray** with a maximum daily dose of 84 mg and a total maximum dose of 672 mg over a treatment period of 4 weeks. The pharmaceutical form is a nasal spray solution, and it is not a paediatric formulation.

**Esketamine** is also used in the trial in a different form, administered via **infusion**. The maximum daily dose is 1.0 mg/kg, with a total maximum dose of 8 mg/kg over a 4-week period. This formulation is also not intended for paediatric use.

**Bupropion hydrochloride** is administered orally with a maximum daily dose of 450 mg and a total maximum dose of 18,900 mg over a 6-week period. The pharmaceutical form is not specified, and it is not a paediatric formulation.

**Quetiapine** is administered orally with a maximum daily dose of 600 mg and a total maximum dose of 25,200 mg over a 6-week period. The pharmaceutical form is not specified, and it is not a paediatric formulation.

**Sodium valproate**, also known as **valproic acid**, is administered orally with a maximum daily dose of 2000 mg and a total maximum dose of 84,000 mg over a 6-week period. The pharmaceutical form is not specified, and it is not a paediatric formulation.

**Venlafaxine** is administered orally with a maximum daily dose of 375 mg and a total maximum dose of 15,750 mg over a 6-week period. The pharmaceutical form is not specified, and it is not a paediatric formulation.

**Lamotrigine** is administered orally with a maximum daily dose of 200 mg and a total maximum dose of 8400 mg over a 6-week period. The pharmaceutical form is not specified, and it is not a paediatric formulation.

**Ketamine** is administered via **infusion** with a maximum daily dose of 1 mg/kg and a total maximum dose of 8 mg/kg over a 4-week period. The pharmaceutical form is not specified, and it is not a paediatric formulation.

**Sertraline** is administered orally with a maximum daily dose of 200 mg and a total maximum dose of 8400 mg over a 6-week period. The pharmaceutical form is not specified, and it is not a paediatric formulation.

**Duloxetine** is administered orally with a maximum daily dose of 120 mg and a total maximum dose of 5040 mg over a 6-week period. The pharmaceutical form is not specified, and it is not a paediatric formulation.

**Clozapine** is administered orally with a maximum daily dose of 900 mg and a total maximum dose of 37,800 mg over a 6-week period. The pharmaceutical form is not specified, and it is not a paediatric formulation.

**Escitalopram** is administered orally with a maximum daily dose of 20 mg and a total maximum dose of 840 mg over a 6-week period. The pharmaceutical form is not specified, and it is not a paediatric formulation.

**Lithium** is administered orally with a maximum daily dose of 800 mg and a total maximum dose of 33,600 mg over a 6-week period. The pharmaceutical form is not specified, and it is not a paediatric formulation.

Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to compare the efficacy of these treatments in subjects with schizophrenia, major depressive disorder, and bipolar depression who have experienced a first-time treatment failure on their first-line treatment.

Efficacy in this clinical trial will be assessed by evaluating the change in symptom severity from baseline to the end of the treatment period. The primary endpoint is the change in symptom severity total score from baseline (visit 2) to four weeks for major depressive disorder (MDD) and six weeks for schizophrenia (SZ) and bipolar depression (BD) (visit 4). For schizophrenia, the Positive and Negative Syndrome Scale (PANSS) will be utilized to measure symptom changes. For major depressive disorder and bipolar depression, the Montgomery-Åsberg Depression Rating Scale (MADRS) will be applied. These scales are validated tools commonly used in clinical settings to assess the severity of symptoms in these conditions.