Positron Emission Tomography Assessment of Ketamine Binding of the Serotonin Transporter

Study Overview
=================
Brief Summary
-----------------
The study at hand is the first to investigate ketamine's SERT binding in humans, by utilizing the highly selective SERT radioligand [11C]DASB and positron emission tomography.

Detailed Description
-----------------
Intravenous application of ketamine is currently dramatically gaining in significance as a rapid and highly effective antidepressant treatment option. Ketamine modulates various neurotransmitter systems, though the mechanisms responsible for its antidepressant effects remain unkownn. However, the serotonin transporter (SERT) presents a target of high interest due to the SERT's fundamental role in depression's pathophysiology as well as in antidepressant response. The study at hand is the first to investigate ketamine's SERT binding in humans, by utilizing the highly selective SERT radioligand [11C]DASB and positron emission tomography. Further, investigation of severely depressed patients provides the unique opportunity to establish the relationship between ketamine's SERT binding and its antidepressant efficacy.

Official Title
-----------------
Positron Emission Tomography Assessment of Ketamine Binding of the Serotonin Transporter and Its Relevance for Rapid Antidepressant Response

Conditions
-----------------
Depression, Ketamine

Intervention / Treatment
-----------------
* Drug: (S)-ketamine (Main study)
* Drug: (S)-ketamine (Pilot II)
* Drug: (R,S)-ketamine (Pilot II)
* Drug: Placebo
* Other: PILOT Study II: PET1
* Other: PILOT Study II: PET2
* Other: Main Study: PET1
* Other: Main Study: PET2
* Other: PILOT Study I: PET1
* Other: PILOT Study I: PET2
* Drug: (R,S)-ketamine (Pilot I)
* Drug: (R,S)-ketamine (Pilot III)
* Other: PILOT Study III: PET1
* Other: PILOT Study III: PET2


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 18-55 years somatic health severe unipolar depression according to DSM-IV (SCID) und HAM-D (for patients) capable of giving informed consent negative pregnancy test (females) Exclusion Criteria: severe somatic illness psychiatric disorder (for healthy controls) an axis I comorbidity other than MDD , other than anxiety symptoms (for patients) clinically relevant alterations in blood draw, ecg, and somatic testing substance dependency disorder intake of psychopharmacological medication in last 6 months first degree relative with Axis 1 disorder (for Pilot I study)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Pilot I and Pilot III not randomised
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: (S)-ketamine<br>Ketanest® S (Esketaminhydrochlorid) 5mg/ml and 25mg/ml ampoules; Actavis Italy S.P.A./Pfizer Corporation Austria GmbH Dosis: 0.25mg/kg bodyweight i.v. over 40 Minutes (ending 10 minutes before PET measurement) all patients and 10 HC (randomized, double blind) Interventions: Drug: (S)-ketamine (Main study) Other: Main study: PET1 Other: Main study: PET2 | Drug: (S)-ketamine (Main study)<br>* Ketanest® S (Esketaminhydrochlorid) 5mg/ml and 25mg/ml ampoules; Actavis Italy S.P.A./Pfizer Corporation Austria GmbH Dosis: 0.25mg/kg bodyweight i.v. over 40 Minutes (ending 10 minutes before PET measurement)<br>* Other names: Esketaminhydrochlorid;Other: Main Study: PET1<br>* [11C]DASB PET<br>Other: Main Study: PET2<br>* [11C]DASB PET<br>|
| Placebo Comparator: Placebo<br>0.9% saline solution i.v. over 40 Minutes (ending 10 minutes before PET measurement) 10 HC (randomized, double blind) Interventions: Drug: Placebo Other: Main study: PET1 Other: Main study: PET2 | Drug: Placebo<br>* 0.9% saline solution i.v. over 40 Minutes (ending 10 minutes before PET measurement)<br>Other: Main Study: PET1<br>* [11C]DASB PET<br>Other: Main Study: PET2<br>* [11C]DASB PET<br>|
| Experimental: (S)-ketamine (Pilot Study II, 5 subj.)<br>Ketanest® S (Esketaminhydrochlorid) 5mg/ml and 25mg/ml ampoules; Actavis Italy S.P.A./Pfizer Corporation Austria GmbH Dosis: 0.10mg/kg bodyweight bolus applied over 5 minutes (starting 15 minutes before PET measurement) and continuous infusion of 0.30mg/kg bodyweight applied over the course of 130 minutes. Pilot-study II is cross-over design! Interventions: Drug: (S)-ketamine (Pilot II) Other: PILOT Study II: PET1 Other: PILOT Study II: PET2 | Drug: (S)-ketamine (Pilot II)<br>* Ketanest® S (Esketaminhydrochlorid) 5mg/ml and 25mg/ml ampoules; Actavis Italy S.P.A./Pfizer Corporation Austria GmbH Dosis: 0.10mg/kg bodyweight i.v. bolus applied over 5 minutes (starting 15 minutes before PET measurement) and continuous infusion of 0.30mg/kg bodyweight i.v. applied over the course of 130 minutes.<br>* Other names: Esketaminhydrochlorid;Other: PILOT Study II: PET1<br>* [11C]DASB PET<br>Other: PILOT Study II: PET2<br>* [11C]DASB PET<br>|
| Experimental: (R,S)-ketamine (Pilot Study II, 5 subj.)<br>Ketamin-hameln (Ketaminhydrochlorid) 50mg/ml Ampullen; Hameln Pharma Plus GmbH; Sanova Pharma Dosis: 0.20mg/kg bodyweight bolus applied over 5 minutes (starting 15 minutes before PET measurement) and continuous infusion of 0.60mg/kg bodyweight applied over the course of 130 minutes. Pilot-study II is cross-over design! Interventions: Drug: (R,S)-ketamine (Pilot II) Other: PILOT Study II: PET1 Other: PILOT Study II: PET2 | Drug: (R,S)-ketamine (Pilot II)<br>* Ketamin-hameln (Ketaminhydrochlorid) 50mg/ml Ampullen; Hameln Pharma Plus GmbH; Sanova Pharma Dosis: 0.20mg/kg bodyweight i.v. bolus applied over 5 minutes (starting 15 minutes before PET measurement) and continuous infusion of 0.60mg/kg bodyweight applied i.v. over the course of 130 minutes.<br>* Other names: Ketaminhydrochlorid;Other: PILOT Study II: PET1<br>* [11C]DASB PET<br>Other: PILOT Study II: PET2<br>* [11C]DASB PET<br>|
| Experimental: (R,S)-ketamine (Pilot Study I, 12 subj.)<br>Ketamin-hameln (Ketaminhydrochlorid) 50mg/ml Ampullen; Hameln Pharma Plus GmbH; Sanova Pharma Dosis: 0.50mg/kg bodyweight i.v. over 40 Minutes (ending 5 minutes before PET measurement) Interventions: Drug: (R,S)-ketamine (Pilot I) Other: PILOT Study I: PET1 Other: PILOT Study I: PET2 | Other: PILOT Study I: PET1<br>* [11C]DASB PET<br>Other: PILOT Study I: PET2<br>* [11C]DASB PET<br>Drug: (R,S)-ketamine (Pilot I)<br>* Ketamin-hameln (Ketaminhydrochlorid) 50mg/ml Ampullen; Hameln Pharma Plus GmbH; Sanova Pharma Dosis: 0.50mg/kg bodyweight i.v. over 40 Minutes (ending 10 minutes before PET measurement)<br>* Other names: Ketaminhydrochlorid;|
| Experimental: (R,S)-ketamine (Pilot Study III, 12 subj.)<br>Ketamin-hameln (Ketaminhydrochlorid) 50mg/ml Ampullen; Hameln Pharma Plus GmbH; Sanova Pharma Dosis: 0.80mg/kg bodyweight i.v. over 50 Minutes Interventions: Drug: (R,S)-ketamine (Pilot III) Other: PILOT Study III: PET1 Other: PILOT Study III: PET2 | Drug: (R,S)-ketamine (Pilot III)<br>* Ketamin-hameln (Ketaminhydrochlorid) 50mg/ml Ampullen; Hameln Pharma Plus GmbH; Sanova Pharma Dosis: 0.80mg/kg bodyweight i.v. over 50<br>* Other names: Ketaminhydrochlorid;Other: PILOT Study III: PET1<br>* [11C]DASB PET<br>Other: PILOT Study III: PET2<br>* [11C]DASB PET<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pilot Study II: (S)-ketamine SERT occupancy assessed with DASB binding potential (BP) | Occupancy assessed using kinetic modeling | during PET/during 135 minutes of infusion | 
| Pilot Study II: (R,S)-ketamine SERT occupancy assessed with DASB binding potential (BP) | Occupancy assessed using kinetic modeling | during PET/during 135 minutes of infusion | 
| Main Study: (S)-ketamine SERT occupancy assessed with DASB binding potential (BP) | Occupancy (%)=(1-BPND PET 2 (treatment) / BPND PET 1 (baseline)) x100 | during PET/starting 10 minutes afer 40 minutes of infusion | 
| Pilot Study I: (R,S)-ketamine SERT occupancy assessed with DASB binding potential (BP) | Occupancy (%)=(1-BPND PET 2 (treatment) / BPND PET 1 (baseline)) x100 | during PET/starting 10 minutes afer 40 minutes of infusion | 
| Pilot Study III: (R,S)-ketamine SERT occupancy assessed with DASB binding potential (BP) | Occupancy (%)=(1-BPND PET 2 (treatment) / BPND PET 1 (baseline)) x100 | during PET | 
| Pilot Study III: resting state MRI | changes to rsFC and rsfMRI after (R,S)-ketamine | after PET 2 | 
| Pilot Study III: MRS | changes to Glutamate, GABA, and metabolites after (R,S)-ketami | after PET 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hamilton Depression Rating Scale Points |  | 2 hours after infusion to baseline | 
| Change in Hamilton Depression Rating Scale Points |  | 1 day after infusion to baseline |