Clinical and Cost-Effectiveness of PSYCHOnlineTHERAPY: Study Protocol of a Multicenter Blended Outpatient Psychotherapy Cluster Randomized Controlled Trial for Patients With Depressive and Anxiety Disorders

Introduction: Internet- and mobile-based interventions (IMIs) and their integration into routine psychotherapy (i.e., blended therapy) can offer a means of complementing psychotherapy in a flexible and resource optimized way. Objective: The present study will evaluate the non-inferiority, cost-effectiveness, and safety of two versions of integrated blended psychotherapy for depression and anxiety compared to standard cognitive behavioral therapy (CBT). Methods: A three-armed multicenter cluster-randomized controlled non-inferiority trial will be conducted comparing two implementations of blended psychotherapy (PSYCHOnlineTHERAPYfix/flex) compared to CBT. Seventy-five outpatient psychotherapists with a CBT-license will be randomized in a 1:1:1 ratio. Each of them is asked to include 12 patients on average with depressive or anxiety disorders resulting in a total sample size of N = 900. All patients receive up to a maximum of 16 psychotherapy sessions, either as routine CBT or alternating with Online self-help sessions (fix: 8/8; flex: 0–16). Assessments will be conducted at patient study inclusion (pre-treatment) and 6, 12, 18, and 24 weeks and 12 months post-inclusion. The primary outcome is depression and anxiety severity at 18 weeks post-inclusion (post-treatment) using the Patient Health Questionnaire Anxiety and Depression Scale. Secondary outcomes are depression and anxiety remission, treatment response, health-related quality of life, patient satisfaction, working alliance, psychotherapy adherence, and patient safety. Additionally, several potential moderators and mediators including patient characteristics and attitudes toward the interventions will be examined, complemented by ecological day-to-day digital behavior variables via passive smartphone sensing as part of an integrated smart-sensing sub-study. Data-analysis will be performed on an intention-to-treat basis with additional per-protocol analyses. In addition, cost-effectiveness and cost-utility analyses will be conducted from a societal and a public health care perspective. Additionally, qualitative interviews on acceptance, feasibility, and optimization potential will be conducted and analyzed. Discussion: PSYCHOnlineTHERAPY will provide evidence on blended psychotherapy in one of the largest ever conducted psychotherapy trials. If shown to be non-inferior and cost-effective, PSYCHOnlineTHERAPY has the potential to innovate psychotherapy in the near future by extending the ways of conducting psychotherapy. The rigorous health care services approach will facilitate a timely implementation of blended psychotherapy into standard care

Experimental protocol and analysis procedure.

<p>(A) During rapid pH-cycling from pH 7.5 to 5.5 extracellular the fluorescence increases or decreases due to extracellular pH-change. These fluorescence-changes are superimposed by the exocytosis and endocytosis signal. (B) Magnification of the fluorescence trace in (A). For further analysis, images were divided into two series depending on the pH value. (C) Difference function (f′) of the respective fluorescence trace, where the minima and maxima (red triangles) serve as detection-markers for switching between the two different pH-phases. Values below a predefined threshold (red points) are analyzed as phase with pH 7.5 and as phase with pH 5.5, respectively. (D) Corresponding fluorescence traces of the signal at pH 7.5, which represents the kinetics of exocytosis and endocytosis, and at pH 5.5, which represents the kinetics of the alkaline vesicle population.</p

The time constant for reacidification increases with rising action potential frequency.

<p>The time constant for reacidification increases with rising action potential frequency.</p

Dynamic Properties of the Alkaline Vesicle Population at Hippocampal Synapses

<div><p>In compensatory endocytosis, scission of vesicles from the plasma membrane to the cytoplasm is a prerequisite for intravesicular reacidification and accumulation of neurotransmitter molecules. Here, we provide time-resolved measurements of the dynamics of the alkaline vesicle population which appears upon endocytic retrieval. Using fast perfusion pH-cycling in live-cell microscopy, synapto-pHluorin expressing rat hippocampal neurons were electrically stimulated. We found that the relative size of the alkaline vesicle population depended significantly on the electrical stimulus size: With increasing number of action potentials the relative size of the alkaline vesicle population expanded. In contrast to that, increasing the stimulus frequency reduced the relative size of the population of alkaline vesicles. Measurement of the time constant for reacification and calculation of the time constant for endocytosis revealed that both time constants were variable with regard to the stimulus condition. Furthermore, we show that the dynamics of the alkaline vesicle population can be predicted by a simple mathematical model. In conclusion, here a novel methodical approach to analyze dynamic properties of alkaline vesicles is presented and validated as a convenient method for the detection of intracellular events. Using this method we show that the population of alkaline vesicles is highly dynamic and depends both on stimulus strength and frequency. Our results implicate that determination of the alkaline vesicle population size may provide new insights into the kinetics of endocytic retrieval.</p></div

The time constant for endocytosis derived by deconvolution shows no clear dependency on the stimulus frequency.

<p>The time constant for endocytosis derived by deconvolution shows no clear dependency on the stimulus frequency.</p

The time constant for endocytosis calculated by the decay of the surface pool shows no clear dependency on the stimulus frequency.

<p>The time constant for endocytosis calculated by the decay of the surface pool shows no clear dependency on the stimulus frequency.</p

Variation of the relative size of the alkaline vesicle population can be predicted by modeling.

<p>For simulation, the time constants for endocytosis and for reacidification were modeled to be variable to the stimulus condition. (A) Relative size of the alkaline vesicle population depending on the action potential number according to the “ideal” model. Endocytosis time constants were derived by deconvolution. The relative alkaline vesicle population size decreased with rising number of action potentials. The stimulus 50ap20Hz was omitted, as it was not possible to calculate an endocytosis time constant by deconvolution due to low signal-to-noise ratio. (B) Relative size of the alkaline vesicle population depending on the action potential frequency according to the “ideal” model. Endocytosis time constants were derived by deconvolution. The relative alkaline vesicle population size increased with rising number of action potential frequency. (C) Relative size of the alkaline vesicle population depending on the action potential number according to the “ideal” model. Endocytosis time constants were derived by monoexponential curve fitting from the decaying surface pool time course. The calculated relative alkaline vesicle population size reflects the experimentally defined alkaline vesicle population dynamics (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102723#pone-0102723-g003" target="_blank">Figure 3</a>) except for stimulation with 50ap20Hz. (D) Relative size of the alkaline vesicle population depending on the action potential frequency according to the “ideal” model. Endocytosis time constants were derived by monoexponential curve fitting from the decaying surface pool time course. The calculated relative alkaline vesicle population size reflects the experimentally defined alkaline vesicle population dynamics (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102723#pone-0102723-g004" target="_blank">Figure 4</a>) except for stimulation with 200ap80Hz.</p

The time constant for endocytosis calculated by the decay of the surface pool shows no clear dependency on the action potential number.

<p>The time constant for endocytosis calculated by the decay of the surface pool shows no clear dependency on the action potential number.</p

Two different approaches for the calculation of the endocytosis time constant.

<p>(A) Deconvolution of the reacidification time course from the alkaline vesicle population dynamics and estimated endocytosis time course. For analysis, experimental data from the action potential number series was used (stimulation paradigms: 200 pulses at 20 Hz). Stimulus begin was at 40 seconds. (B) Calculation of the time course of the surface pool, which is determined by the alkaline vesicle population (fluorescence time course at pH 5.5) subtracted from the total pHluorin (fluorescence time course at pH 7.5). The endocytosis time constants were calculated by monoexponential curve fitting. Stimulus begin was at 40 seconds.</p

Determination of the alkaline vesicle population of synaptic vesicles with synapto-pHluorin and VGLUT1-pHluorin.

<p>(A) Mean time courses of normalized fluorescence of VGLUT1-pHluorin (VGLUT1pH) and synapto-pHluorin (spH) (N = 5). Bottom: Magnification of the red rectangle marked in (A). To determine the size of the alkaline vesicle population, difference of fluorescence was measured between end of surface fluorescence quenching and the end of reacidification when a stable baseline of fluorescence was reached. (B) 1. Difference image at pH 7.5 before and after stimulation of neurons transfected with VGLUT1-pHluorin. 2. Representative image of the alkaline vesicle population of neurons transfected with VGLUT1-pHluorin taken at pH 5.5 directly after stimulation. (C) Correlation between normalized fluorescence of the difference image before and after stimulation and normalized fluorescence of the alkaline vesicle population of neurons transfected with VGLUT1-pHluorin. (D) Representative images of neurons transfected with VGLUT1-pHluorin and incubated with αSyt1-cypHer. 1. One-color image (αSyt1-cypHer). 2. Dual-color-image (VGLUT1-pHluorin and αSyt1-cypHer) (Overlay). (E) 1. Difference image at pH 7.5 before and after stimulation of neurons transfected with synapto-pHluorin. 2. Representative image of alkaline vesicle population of neurons transfected with synapto-pHluorin taken at pH 5.5 directly after stimulation. (F) Fraction of the alkaline vesicle population depending on the fluorescent probe. There was no significant difference between the two fluorescent probes (VGLUT1-pHluorin: 39.38%, synapto-pHluorin: 37.69%, p>0.05, N = 5 each).</p