Disentangling Pharmacological and Expectation Effects in Antidepressant Discontinuation

The Discontinuation Related Signs and Symptoms Scale is a self-report questionnaire to assess discontinuation symptoms, incorporating 43 discontinuation symptoms of antidepressants with intensity ratings ranging from 0 (not present) - 3 (severe) each. Total sum score ranges from 0-129 with higher scores indicating more pronounced discontinuation symptoms.

The Posner Task manipulates attentional resources, provokes emotional responses and robustly activates limbic, prefrontal, and visuo-spatial brain circuits. In short, participants respond as fast as possible to a dot target by button pressing while neutral, happy, sad or fearful face distractors are presented. Targets are preceded by either spatially-directing cues leading to covert shifts in the attentional focus (i.e., low attentional resources to process distractors) or non-spatial cues leaving the attentional focus on the distractors. Reaction times will be measured in milliseconds (ms) for each condition, difference scores will be calculated under high attention to faces for happy and neutral faces, sad and neutral faces, as well as fearful and neutral faces.

The Discontinuation Related Signs and Symptoms Scale is a self-report questionnaire to assess discontinuation symptoms, incorporating 43 discontinuation symptoms of antidepressants with intensity ratings ranging from 0 (not present) - 3 (severe) each. Total sum score ranges from 0-129 with higher scores indicating more pronounced discontinuation symptoms.

Appearance of a new, depressive episode after full remission of depressive symptoms and a period of recovery. Potential recurrence will be monitored weekly during run-in and (dis-) continuation phase, biweekly during monitoring phase, and 6, 9 and 12 months post-baseline based on BDI-II and MADRS scores. If recurrence is suspected (as indicated by BDI-II scores >19 OR MADRS scores >21 over two weeks/study visits), corresponding SCID-5-CV sections will be conducted to (dis-)confirm recurrence.

Self-reported measure of subjective stress, including 10 items with 5 rating categories (0-4), total scores range between 0-40 with higher scores indicating more pronounced stress.

Self-report questionnaire as indicator of state and trait anxiety and depression, divided in 2 sections (state vs. trait) consisting of 20 statements with 4 response options (1-4), respectively. Total scores per scale range between 20 and 80 with higher sum scores indicating higher state/trait anxiety or depression.

Self-reported measure to assess patients' treatment expectations, consisting of 15 items with 11 response options (0-10), total scores range from 0-150 with higher scores indicating more positive treatment expectations.

The Generic rating scale for treatment expectations is one of three subscales of the 'Generic rating scale for previous treatment experiences, treatment expectations, and treatment effects' (GEEE). The subscale Generic rating scale for treatment expectations consists of three items that assess expectations towards treatment on a numeric rating scale with eleven response options (0-10); total scores of all three subscales combined range from 0-30 with higher scores indicating higher treatment expectations.

Self-report measure to assess side effects of antidepressant medication, including 36 items (symptom descriptions) with 4 response options (0-3). Items are additionally evaluated on their relation to antidepressant medication (Yes/ No questions). Total scores range from 0-108 with higher scores indicating stronger experiences of side effects.

The Generic rating scale for previous treatment experiences is one of three subscales of the 'Generic rating scale for previous treatment experiences, treatment expectations, and treatment effects' (GEEE). It is a self-reported assessment of previous experiences with treatment, i.e., antidepressant discontinuation. If experience with antidepressant discontinuation is indicated, the subsequent 3 items rate the experiences on a numeric analogue scale each (ranging from 0-10), total score range from 0-30; higher scores indicate more pre-experiences with antidepressant discontinuation.

Assessed via blood analysis.

Salivary Alpha-Amylase and cortisol levels assessed via saliva sampling.

10-item scale measuring the personality traits Extraversion, Agreeableness, Conscientiousness, Emotional Stability, and Openness to assess the influence of personality traits on treatment outcome at baseline. The items are rated on a five-step scale from 1 "disagree strongly" to 5 "agree strongly". The scale consists of 2 BFI items for each Big Five Dimension.

Self-report questionnaire to assess sensitivity to approach or avoidance goals; 24 items; each item is rated on a 4-point scale from 1 (not at all true for me) to 4 (very true for me).

Self-report questionnaire to assess amount of somatosensory amplification tendencies; 10 items; items are rated on a 5-point scale from 1 (not at all true) - 5 (extremely true); total scores range from 10-50 with higher scores indicating more somatosensory amplification.

Expert-rated semi-structured interview to assess DSM-5 diagnoses.

Self-report questionnaire to assess mental well-being by 7 statements about thoughts and feelings using 5 response options, total scores range from 7-35 with higher scores reflecting a higher level of mental well-being.

Self-report measure comprising 4 items that assess core symptoms/signs of depression and anxiety. Two items assess depression; two items assess anxiety, all by means of a four level Likert scale (0-3), so that total scores for each subscale range from 0-6. A score of 3 or greater on the depression subscale indicates a higher probability of symptoms of depression; a score of 3 or greater on the anxiety subscale indicates a higher probability of symptoms of anxiety.

Self-report questionnaire to assess illness burden; 7 items; each item rated on a 0 (no disability)-10(maximum disability) standardized numerical analogue scale; total scores range from 0-70 with higher scores indicating more pronounced disability.

Assesses the consumption (volume and frequency) of nicotine, caffeine, alcohol, pain medication, tranquilizers, or recreational drugs.

Perceived warmth and competence from both the assessor's perspective (11 items, 0 (not at all) to 5 (very much)) and participants' perspectives (12 items, 0 (not at all) to 5 (very much)) will be assessed. Higher scores indicate higher ratings of warmth and competence.

Interview-based measure assessing adverse events, followed by an expert-rating of the intensity and description of the adverse events (1-5) and causal relation to treatment (1-6). Higher scores indicate more and/or a higher intensity of adverse events.

Single item that asks participants to indicate whether they believe they discontinued or remained on their initial medication. Optional item of the 'Generic rating scale for previous treatment experiences, treatment expectations, and treatment effects' (GEEE).

Single item that asks participants to rate whether they perceive their depressive disorder as a biologically or a psychologically caused illness on a single item ranging from 0 (biologically caused) to 10 (psychologically caused).

The Generic rating scale for treatment effects is one of three subscales of the 'Generic rating scale for previous treatment experiences, treatment expectations, and treatment effects' (GEEE). The subscale 'Generic rating scale for treatment effects' consists of three items that assess current treatment effects, i.e., effects of antidepressant discontinuation or continuation, on a numeric rating scale with eleven response options (0-10) each; total scores range from 0-30 with higher scores indicating more pronounced effects of antidepressant discontinuation.

Self-report measure to assess depressive symptoms, including 21 items with 4 response options (0-3), total scores range from 0-63 with higher scores indicating more pronounced depressive symptoms).

Expert-rated interview to assess the severity of depression by 10 items with up to 7 rating categories (0-6) for each item, total scores range between 0-60 with higher scores indicating more pronounced depressive symptoms.

Treatment adherence assessed by a single item in the clinical interview about adherence to intake of study medication during the experimental phase and remaining on or off antidepressant medication during the clinical observation phase, respectively. Further details will be published elsewhere, a link to the registration of the overarching project Z03 will be added as soon as available.

Functional and structural imaging data will be acquired using a 3T MR system (Trio, Siemens Healthcare, Erlangen, Germany at the Institute of Systems Neuroscience, director C. Büchel) with a 64-channel head/neck coil. All structural and functional images will be acquired using standardized MR protocols as described in, provided by and analyzed in the CRC-overarching central project Z03 to later allow for pooled analysis of harmonized multi-center data ('Mega-analysis'). These include (i) resting state functional MRI (rsfMRI), (ii) 3D-MPRage T1-weighted sequence, and (iii) Diffusion Tensor Imaging (DTI). Further details will be published in the registration of the CRC-overarching central project Z03, a link will be added as soon as available.

Self-reported measure of subjective stress, including 10 items with 5 rating categories (0-4), total scores range between 0-40 with higher scores indicating more pronounced stress.

Self-report questionnaire as indicator of state and trait anxiety and depression, divided in 2 sections (state vs. trait) consisting of 20 statements with 4 response options (1-4), respectively. Total scores per scale range between 20 and 80 with higher sum scores indicating higher state/trait anxiety or depression. Trait scale measured at baseline only.

The Discontinuation Related Signs and Symptoms Scale is a self-report questionnaire to assess discontinuation symptoms, incorporating 43 discontinuation symptoms of antidepressants with intensity ratings ranging from 0 (not present) - 3 (severe) each. Total sum score ranges from 0-129 with higher scores indicating more pronounced discontinuation symptoms.