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.
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).
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.
Parallel
Clozapine
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Esketamine Nasal Product
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Escitalopram
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Sertraline
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Venlafaxine
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Lithium
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Valproate acid
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Quetiapine
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Second-line Antidepressants
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Second-line Antipsychotics
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Ketamine Hydrochloride
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Esketamine hydrochloride
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Bupropion
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Treatment groupsSee each treatment group below.
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.
All study samples: to compare changes in the severity and improvement
All study samples: to compare changes in the severity and improvement sub-scores of the Clinical Global Impression Scale between the two treatment arms over the six weeks treatment period (visit 2 versus visit 4).
All study samples: to compare changes in the levels of depression and anxiety
All study samples: to compare changes in the levels of depression and anxiety as assessed with the Hospital Anxiety and Depression Scale bbetween the two treatment arms over the six weeks treatment period (visit 2 versus visit 4).
All study samples: to compare changes in cognitive performance #1
All study samples: 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).
All study samples: to compare changes in cognitive performance #2
All study samples: to compare changes in cognitive performance as measured through the Digit Symbol Substitution Test between the two treatment arms over four weeks (Major Depressive Disorder Group)/six weeks (Schizophrenia/Bipolar Depression groups) treatment period (visit 2 versus visit 4).
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