A Phase 3 interventional study of Escitalopram and Sertraline in Bipolar Depression, sponsored by Dr. Inge Winter. Recruiting at 13 sites in 6 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-09-26.
Sponsored by Dr. Inge Winter · Phase 3, Interventional, and Treatment
Bipolar disorders affect approximately 4.5 million people across the European Union (EU) and are associated with high annual healthcare and societal costs. Bipolar disorder I and II represent disorders that cause extreme fluctuation in a person's mood, energy, and ability to function, in which symptoms of (hypo)mania and depression alternate. The depressive episodes of bipolar disorders are often referred to as bipolar depression (BD). In other words: it is a phase/state of the disorder. For many patients with BD, the depressive polarity is often more pervasive and more debilitating than manic states, with estimates that depressed mood accounts for up to two-thirds of the time spent unwell, even with treatment. The burden of not received an effective treatment for BD is high: more severe psychopathology, higher rates of unemployment, more hospitalisations, lower quality of life, lower cognitive functioning, risk of suicide, comorbidities and poorer social and occupational functioning and thus more carer burden. For BD, the treatment guidelines are very heterogeneous, amongst other reasons because the disease is heterogeneous and treatments should be tailored to the patients. There is no clear treatment algorithm and it cannot yet be predicted which treatment will be effective. Especially the place of adjunctive antidepressants is under debate. Usually, for psychiatric disorders (including bipolar disorder), a patient is considered to be treatment-resistant is two medicinal treatments have been tried (in sufficient duration and dosage) without sufficient success. For BD, there is no consensus on when to consider a patient as treatment-resistant, but the most common definition is after one prior treatment failure. This raises the research question whether adjunctive antidepressants to treat BD should be introduced earlier in the treatment. Additionally, The INTENSIFY trial is part of the larger Horizon 2021 project, 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, we 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.
Rationale Bipolar disorders affect approximately 4.5 million people across the European Union (EU) and are associated with high annual healthcare and societal costs. Bipolar disorder I and II represent disorders that cause extreme fluctuation in a person's mood, energy, and ability to function, in which symptoms of (hypo)mania and depression alternate. The depressive episodes of bipolar disorders are often referred to as bipolar depression (BD). In other words: it is a phase/state of the disorder. For many patients with BD, the depressive polarity is often more pervasive and more debilitating than manic states, with estimates that depressed mood accounts for up to two-thirds of the time spent unwell, even with treatment. The burden of not received an effective treatment for BD is high: more severe psychopathology, higher rates of unemployment, more hospitalisations, lower quality of life, lower cognitive functioning, risk of suicide, comorbidities and poorer social and occupational functioning and thus more carer burden. For BD, the treatment guidelines are very heterogeneous, amongst other reasons because the disease is heterogeneous and treatments should be tailored to the patients. There is no clear treatment algorithm and it cannot yet be predicted which treatment will be effective. Especially the place of adjunctive antidepressants is under debate. Usually, for psychiatric disorders (including bipolar disorder), a patient is considered to be treatment-resistant is two medicinal treatments have been tried (in sufficient duration and dosage) without sufficient success. For BD, there is no consensus on when to consider a patient as treatment-resistant, but the most common definition is after one prior treatment failure. This raises the research question whether adjunctive antidepressants to treat BD should be introduced earlier in the treatment. Additionally, The INTENSIFY trial is part of the larger Horizon 2021 project, 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, we 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.
Objective The primary objective is to compare the treatment response (baseline; visit 2 vs. end of treatment; visit 4), expressed as symptom severity at six weeks and changes in symptom severity from baseline, as measured through the Montgomery-Åsberg Depression Rating Scale (MADRS) under an early-intensified pharmacological treatment to that under treatment as usual, in subjects who had a first-time treatment failure on their first-line treatment.
Main trial endpoints Change in symptom severity total score from baseline (visit 2) to end of treatment (visit 4). This is measured using MADRS.
Secondary trial endpoints
Trial design The clinical study is an international, multicenter controlled, randomised, open label trial (with blinded raters), with a treatment duration of six weeks.
Trial population The aim is to recruit 418 subjects with bipolar disorder type I or II, currently in a depressive episode. Male and female subjects, in- and out-patients, with the age of at least 18 old are eligible for participation. The main exclusion criteria are defined to protect the wellbeing of subjects, e.g. being pregnant or breastfeeding, subjects with previous failure on quetiapine, meeting any contraindications, or participants with a known intolerance to quetiapine.
Interventions
Subjects are randomised to treatment as usual (second-line treatment) or to the early-intensified pharmacological treatment (third-line treatment). Treatment per can be found in the table below:
Table 1. Overview of treatment randomisation per study sample.
Treatment as Usual (TAU) Switch to quetiapine plus lithium or valproate acid Early-Intensified Pharmacological Treatment (EIPT) Switch to
Ethical considerations relating to the clinical trial including the expected benefit to the individual subject or group of subjects represented by the trial subjects as well as the nature and extent of burden and risks All medications studied in the current trial are widely used (alone or in combination) in clinical practice and the risks for side effects are well established. In the current study, clinical practice is mimicked as much as possible to maximize generalisability and for feasibility purposes. To this end, Summaries of Product Characteristics (SmPCs) are followed with regards to contraindications (implemented as exclusion criterion), safety measures and allowed combinations with other medications. Site visits and assessments are kept to a minimum to keep subject burden at an acceptable level, while meeting the objectives of the study. Blood samples for biomarker analyses are only collected when subjects provide consent; safety measures are performed as part of clinical routine.
Overall, the risks are similar to daily clinical practice; the only difference relative to clinical practice is the application of three pharmacological treatments (EIPT) versus two (TAU) earlier in the illness. Still, these additional treatment options are also commonly prescribed by clinicians. There are no indications in existing literature or clinical practice that the earlier introduction of these medications poses a safety risk when used in an earlier illness phase than indicated in the SmPC.
A benefit of the study is that if it indeed turns out that the early-intensified treatment is associated with more symptom improvement compared to treatment as usual, future patients have to go through less trial and error, which results in a reduced burden (higher quality of life, less unemployment, less hospitalisations) for patients and carers as well as lower societal and healthcare costs.
IMPORTANT: the study was submitted to the European authorities before (see NCT05603104) and they requested to split this study into 3 studies (1 for each diagnostic category). We have done this and created 3 new ClinicalTrials.gov studies as well, from which this is one for bipolar depression. The ClinicalTrials.gov numbers of the related trials are NCT05958875 for the INTENSIFY SZ trial and NCT05973851 for the INTENSIFY MDD trial. The site in the UK (London) followed the advice and will submit 3 separate protocols and are therefore included in the current record. However, Israel already submitted this as one protocol. Therefore, we keep the old clinicaltrials.gov number for Israel (NCT05603104).
1,601 studies on the registry are indexed under Bipolar Disorder; 254 are open to participants now.
This study's planned enrollment of 418 is above the median of 64 across 1,223 interventional studies indexed under Bipolar Disorder.
Browse Bipolar Disorder studies →Dr. Inge Winter is the lead sponsor of 4 studies on the registry; 4 are open to participants now.
Counted across the registry records on this site, refreshed daily.
A minimum symptom severity threshold needs to be present (moderate leve) and subject needs to experience functional impairment.
Exclusion criteria
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 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
See arm description
Also known as: ATC code: N06AB10
See arm description
Also known as: ATC code: N06AB06
See arm description
Also known as: ATC code: N06AX16
See arm description
Also known as: ATC code: N05AN01
See arm description
Also known as: ATC code: N03AG01
See arm description
Also known as: ATC code: N05AH04
See arm description
Also known as: ATC cose: N06AX12
Comparing the change in symptom severity on Montgomery Asberg Depression Rating Scale
Mean in symptom severity (EIPT vs. TAU) total score from baseline (visit 2) to end of treatment (visit 4). This is measured using the Montgomery Asberg Depression Rating Scale.Minimum score is 0, maximum score is 60. A bigger mean change means a better outcome
Time frame: 6 weeks
Compare proportion of participants that is in symptomatic remission
Comparison of the proportion of participants (EIPT vs. TAU) that is in symptomatic remission at visit 4. Remission is defined as a Montgomery Asberg Depression Rating scale score of ≤ 12.
Time frame: 6 weeks
Compare the change in the severity and improvement CGI-S sub-scores
To compare changes in the severity sub-score of the Clinical Global Impression Scale (CGI 2) between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4). Higher scores indicate higher illness severity. Minimum score: 1, maximum score: 7
Time frame: 6 weeks
Compare the change in the severity and improvement CGI-I sub-scores
To compare mean changes in the total improvement sub-score of the Clinical Global Impression (CGI 2) between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4). A higher score means lower treatment improvement. Minimum score: 1, maximum score: 7
Time frame: 6 weeks
Compare the 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 four week treatment period (visit 2 versus visit 4). Lower scores mean less depression and anxiety.
Time frame: 6 weeks
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 four weeks treatment period (visit 2 versus visit 4). A lower time to complete the test means better cognitive performance.
Time frame: 6 weeks
To compare the changes in cognitive performance as measured through the Rey Auditory Verbal Learning Test
To compare changes in cognitive performance as measured through the Rey Auditory Verbal Learning Test between the two treatment arms over the six weeks treatment period (visit 2 versus visit 4). A higher scores means better cognitive performance.
Time frame: 6 weeks
To compare the changes in subjective cognitive performance as measured through the Perceived Deficits Questionnaire
To compare changes in cognitive performance as measured through the Perceived Deficits Questionnaire between the two treatment arms over the six weeks treatment period (visit 2 versus visit 4). A higher scores means worse subjective cognitive performance.
Time frame: 6 weeks
To compare the changes in functioning on the Leuven Affective and Pleasure Scale
To compare changes in the functioning measure, Leuven Affective and Pleasure Scale, between the two treatment arms over the six weeks treatment period (visit 2 versus visit 4). A higher scores means worse functioning. Minimum score: 0, Maximum score: 160
Time frame: 6 weeks
To compare the changes in functioning on the Sheehan Disability Scale
To compare changes in the functioning measure,Sheehan Disability Scale, between the two treatment arms over the six weeks treatment period (visit 2 versus visit 4). A higher scores means worse functioning. Minimum score: 0, maximum score 30.
Time frame: 6 weeks
To compare the changes in quality of life measure, Quality of Life Enjoyment and Satisfaction Questionnaire Short Form
To compare changes in quality of life measure, Quality of Life Enjoyment and Satisfaction Questionnaire Short Form between the two treatment arms over the four weeks treatment period (visit 2 versus visit 4). A higher scores means better quality of life. Minimum score: 16, maximum score: 80.
Time frame: 6 weeks
To compare the changes in quality of life measure, Quality of Life Scale -100, subscale inner tension
To compare changes in quality of life measure, Quality of Life Scale -100, subscale inner tension between the two treatment arms over the four weeks treatment period (visit 2 versus visit 4). This is a dichotomous scale (unsatisfactory or satisfactory). More 'satisfactory' answers means higher quality of life.
Time frame: 6 weeks
To compare the frequency of occurence of side effects between the two treatment arms.
To compare presence of side effects as measured through General Assessment of Side Effects Scale and reported spontaneously between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4). Higher scores means more side effects. Minimum score: 0 side effects, maximum score: 38 side effects.
Time frame: 6 weeks
To compare the proportion of participants using concomitant medication between the two treatment arms.
To compare use of concomitant medication between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4) effects.
Time frame: 6 weeks
To compare the proportion of participants who prematurely discontinue between the two treatment arms.
To compare premature discontinuation between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4).
Time frame: 6 weeks
To compare the reason of participants that prematurely discontinue the study treatment between the two treatment arms.
To compare the difference in reasons for premature treatment discontinuation between the two treatment arms (EIPT/TAU) over the six week treatment period (visit 2 versus visit 4).
Time frame: 6 weeks
To compare changes in suicidal ideation between treatment arms.
Changes on the Columbia-Suicide Severity Rating Scale (C-SSRS) throughout the study; EIPT vs TAU. Higher score means higher suicidal ideation. Max score is 5.
Time frame: 6 weeks.
To compare occurrence of (hypo)manic episode during the study between the treatment arms
Occurrence of (hypo)manic episodes throughout the study (including V5); EIPT vs TAU. Scores of 12 or higher means that a participant is in a (hypo)manic episode of bipolar disorder.
Time frame: 6 weeks.
Plan to share: Yes
Supporting information: Study protocol, Csr
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Dr. Inge Winter