Treatment of Adolescents with Depression (TRACED): A pilot study on predictors for treatment response

The intervention that will be applied in this trial is known as Acute Tryptophan Depletion (ATD). ATD is a dietary method that diminishes brain serotonin (5-HT) synthesis for a short period of 5 to 7 hours. This study will consist of a randomised double-blind within subject repeated measures design of ATD or a balanced control condition (BAL) prior to pharmacological treatment as usual (TAS) with fluoxetine in adolescent patients with Major Depressive Disorder (MDD). Prior to study participation, participants will be provided with an information sheet and consent form. Informed consent will be obtained from both the subjects and their parents/guardians. This study will consist of two phases, Phase A and Phase B. Phase A will be conducted over two study days, spaced one week apart. On each study day, participants will either participate in the ATD or the BAL condition. The ATD challenge procedure is as follows: The Moja-De ATD protocol employs amino acid administration within an aqueous suspension, in which the relevant amino acid quantities are linked to the participants’ body weights. The amino acid quantities ATD Moja-De are (dosage per 10 kg of body weight): L-phenylalanine (PHE 1.32 g), L-leucine (LEU 1.32 g), L-isoleucine (ILE 0.84 g), L-methionine (MET 0.5 g), L-valine (VAL 0.96 g), L-threonine (THR 0.6 g), and L-lysine (LYS 0.96 g). The BAL beverage contains the same amino acid quantities with an additional 0.7 g of L-tryptophan (TRP) per 10 kg of body weight. Research has shown that ATD is a safe and effective serotonergic challenge procedure, and that it can be safely used in minors (Moja-De ATD-test protocol). The amino acid mixtures will be prepared by an approved manufacturing facility. The ATD amino acid beverage is made up of the 7 dry amino acid as per the above calculations / 100 kg subject dissolved in 200mL with SyrSpend SF (Purified Water, Modified Food Starch, Sodium Citrate, Citric Acid, Malic Acid, Sodium Benzoate, Sucralose, Simethicone and Cherry Flavour). Each subject receives a proportional amount of ATD amino acids within an aqueous suspension according to the individual body weight. For example, a 50 kg subject will receive 100 mL SyrSpend SF with the respective amino acids related to the individual body weight. The BAL beverage is made up of the same 7 dry amino acids in the ATD with the addition of tryptophan (a total of 8 amino acids) in the same way as the ATD beverage. Each subject receives a proportional amount of BAL amino acids within an aqueous suspension according to the individual body weight. Following the administration of both ATD / BAL beverages, Apple juice will be offered following the mixture to wash out the taste. Tryptophan free breakfast and lunch will be provided to participants on both study days. After the intake of the challenge procedures (ATD or BAL), behavioural experiments will be conducted, including an attention testing battery, an emotional face recognition task, and a reversal-learning task. The randomisation procedure will be managed by Princess Margaret Hospital Clinical Trials Pharmacy. In Phase A 8 blood samples (3 mls each; 24 mls total) will be taken from each subject on each of the study days. 3 mls will be taken at baseline followed by 3mls every hour over 7 hours. An IV cannula will be placed by an experienced medical doctor which will remain in place so that regular blood samples can be obtained. The baseline blood sample will be taken after the IV cannula is inserted. The IV cannula will then be flushed with 3 – 4 mls of normal saline to maintain patency. For each subsequent blood sample that is taken, 2 – 3 mls of blood will be drawn and discarded before a definitive blood sample is collected. The IV cannula will then be flushed with 3-4 mls of normal saline. Phase B will take place over a period of 12 weeks, where participants will be reviewed by a Consultant Psychiatrist once per week. During these 12 weeks, participants will be prescribed and administered a dose of fluoxetine of 20mg per day after an introduction period of 7 days with 10mg. The mode of administration of fluoxetine will be an oral tablet. This medication regime is in line with the NICE guidelines. Adherence to fluoxetine will be monitored through the return of an empty drug packet. In Phase B, further blood samples for each subject will be taken on a weekly basis over the 12 week phase. During Phase A and Phase B, participants’ mood will be monitored using the Beck Depression Inventory, the Hamilton Depression Rating Scale, and the Revised Children’s Depression Rating Scale.