The INTENSIFY Trial: The Effect of a Six-Week Intensified Pharmacological Treatment (Third-Line Medication) for Bipolar Disorder Compared to Treatment as Usual (Second-Line Medication) in Participants Who Did Not Respond to a First-Line Medication Treatment.

This is a phase III multicentre controlled, randomised open label trial for bipolar disorder, subjects are randomised to a 6 week pharmacological treatment as usual (second-line treatment) or to the early-intensified pharmacological treatment (third-line treatment). 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 1.one of the following: escitalopram, sertraline, duloxetine, bupropion or venlafaxine plus 2.two of the following: lithium, valproate acid or quetiapine Frequency and Duration of Medication Escitalopram: The recommended dose is 10 mg orally (one 10 mg tablet) once daily. Depending on individual participant response, the dose may be increased to a maximum of 20 mg (one 20 mg tablet) daily. Usually, 2-4 weeks are necessary for antidepressant response, although the onset of therapeutic effect may be seen earlier. Sertraline: Sertraline treatment should be initiated with a dose of 50 mg orally once daily. The usual therapeutic dose for depression is 50 mg/day. Participants not responding to a dose of 50 mg/day may benefit from dose increases. Due to the elimination half-life of sertraline, dose changes should be made in steps of 50 mg at intervals of at least 1 week up to a maximum of 200 mg/day. The onset of therapeutic effect may be seen within 7 days; however, for full activity, 2 to 4 weeks are usually necessary for depression. Bupropion: Bupropion is produced as immediate-release, sustained-release, and extended-release tablets. Immediate-release tablets: initial dose: 100 mg orally twice a day, increase if necessary after 3 days to 100 mg orally three times a day. Maintenance dose: 100 mg orally three times a day. Maximum dose: 450 mg/day in up to 4 divided doses; single doses should not exceed 150 mg. Sustained-release tablets: initial dose: 150 mg orally once a day in the morning, increase if necessary, after 3 days to 150 mg orally twice a day. Maintenance dose: 150 mg orally twice a day. Maximum dose: 400 mg/day; maximum single dose should not exceed 200 mg. Extended-release tablets: initial dose: 150 mg orally once a day in the morning, increase if necessary, after 4 days to 300 mg orally once a day. Maintenance dose: 300 mg orally once a day. Maximum dose: 450 mg/day Venlafaxine: The recommended initial dose is 75 mg taken once daily orally. Participants not responding to the initial 75 mg/day dose may benefit from dose increases up to a maximum dose of 375 mg/day. Dosage increases can be made at intervals of 2 weeks or more. If clinically warranted due to symptom severity, dose increases can be made at more frequent intervals, but not less than 4 days. Lithium: Dosage should be adjusted to maintain a serum lithium concentration 0.6 to 0.8 mmol/L. Dosage will vary from one individual to another, but usually 900mg to 1200mg per day in divided doses will maintain this concentration. Serum lithium concentration should be assessed frequently during the acute phase, and in uncomplicated cases/during maintenance, every 2 months. Recommended start-dose is 450-500 mg/day orally, depending on the formulation used (450mg tablet or 2x250mg tablet). As specified in the PI, (excluding rapid dosing) the lithium blood levels should be determined to inform further dosing 4-5 days after each dose change and this task will remain with the regular treating doctor. For treatment of depressive symptoms, plasma levels between 0.4-0.8 mmol/l are recommended. Valproate acid: Initially dosage should start with 500 mg daily increasing by 500 mg/day at three-day intervals until symptom control is achieved. This is generally within the range 1,000 to 2,000 mg/day, (i.e. 20 to 30 mg/kg/day). Where adequate control is not achieved within this range the dose may be further increased to 2,500 mg/day Valproate acid: Initially dosage should start with 500 mg daily increasing by 500 mg/day at three-day intervals until symptom control is achieved. This is generally within the range 1,000 to 2,000 mg/day, (i.e. 20 to 30 mg/kg/day). Where adequate control is not achieved within this range the dose may be further increased to 2,500 mg/day Quetiapine: When treating depressive episodes in bipolar disorder, treatment should be initiated either by the treating psychiatrist or by the general practitioner after consultation with the psychiatrist. Tablets should be administered once daily at bedtime with titration as follows: 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4). The dose may be adjusted up to 600 mg/day in increments of 100 mg/day depending on the clinical response and tolerability of the individual patient. 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 as part of this study are widely used (alone or in combination) in clinical practice and carry well-known safety profiles. The study has a naturalistic design, meaning that the medication is used commercially, as in daily clinical practice. Therefore, the minimum effective dose, target dose, the dose ranges and dose titrations as described in the latest applicable Product Information sheets available on the Australian Government Therapeutic Goods Administration websites are to be followed. Medication doses may be modified at any time during the treatment phase as per the treating doctor’s discretion. Current clinical practice treatment guidelines are quite heterogeneous on the order and combination of treatments, as the disease is heterogeneous and needs to be tailored to the patient. In clinical practice, all psychopharmacological treatments that are selected for this study sample are used in different orders in patients in different phases of their disease; therefore, there is no expected difference from TAU regarding adverse effects. 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 The first two weeks of the chosen medication will be supplied by the study team for participant convenience, but all ongoing prescriptions must be from their regular treating doctor. It is not expected nor required that participants return their used and unused medication. Compliance will be monitored using standardised self-report, two questions are asked to rate medication adherence: “In the past week, how difficult was it to take your medication as how they were prescribed to you?” and “In the past week, how many days have you taken your medication the way they are prescribed to you?” Both questions are answered on a 7-point Likert scale.