Rationale and design of a double-blinded, randomized placebo-controlled trial of 40 Hz light neurostimulation therapy for depression (FELIX)

Figures & data

Table 1. List of inclusion and exclusion criteria.

Inclusion

Exclusion

18–75 years Diagnosis of major depressive episode according to DSM-5 MDI score > 21 at screening Stable antidepressant medication and/or psychotherapy for at least two weeks before starting the trial. No planned change of antidepressant medication for the 8-weeks study period Willingness to comply with scheduled plan and using the device for 1 h per day for 42 days. Understanding the oral and written study information and willing to sign an informed consent.

History of photosensitive migraines and/or epileptic seizures Known eye disorders that might be sensitive to light treatment. Diagnosis of bipolar disorder according to DSM-5 criteria Suicidal ideation corresponding to a score of 2 or more on the HAM-D17 scale item 3 or if patient or investigator is uncertain of the degree of suicidal risk. Current psychotic symptoms. However, subjects with a prior psychotic depression or subjects with an actual psychotic depression episode that at time of informed consent no longer fulfils the psychosis criteria are allowed to participate. Current drug or alcohol dependence based on their medical records or the M.I.N.I. interview. Diagnosis of borderline personality disorder according to DSM-5 criteria Being enrolled in another investigational treatment study. Progressive neurodegenerative or neoplastic disease. Inability to understand the study procedures or handling of the NSS device. Pregnancy at time of inclusion or unsafe contraception in women of fertile age

Figure 1. Visual representation of study design and follow-up visits. HAM-D₁₇: Hamilton Depression Rating Scale 17 item version; MDI: Major Depression Inventory; WHO-5 World Health Organization Quality of Life Index; PSQI: Pittsburg Sleep Quality Index; SIDAS: Suicidal Ideation Assessment Scale; YMRS: Young Mania Rating Scale; UKU: The UKU Side Effect Rating Scale; SCIP: The Screen for Cognitive Impairment in Psychiatry. TMT-B: Trail Making Test Part B; FERT-Facial Emotion Recognition Task; ECMT: Emotional Categorization and Memory Test; SSVEPs: Steady State Visually Evoked Potentials.

Figure 2. Representation of light paradigms and the design of invisible spectral flicker. Set 1: Cyan and red, set 2: blue and yellow.

Table 2. Light matching in two different treatment conditions.

Group	CCT [K]	u’	v’	Radiant intensity [W/sr]	α-opic EDI metrics [lx]
					Melanopic	Cyanopic	Chloropic	Erythropic	Rhodopic
Active	3.186	0.2478	0.5061	0.3522	292	180	325	383	308
Placebo	3.197	0.2479	0.5046	0.3624	300	186	327	384	315

CCT: Correlated Color Temperature (Kelvin), u’ and v’ are chromaticity coordinates used to describe the color of light. EDI: Equivalent Daylight Illuminance. Field of view/angle of the measurement device is 2°. Measurements are made at 50 cm distance.

Table 3. Summary of study endpoints.

	Endpoints	Description
Primary	Hamilton Depression Rating Scale 6 (HAM-D6) Time points of measurement: baseline, day 7, day 21, day 42, and day 56. The primary endpoint is the mean difference in scores between treatments at baseline and day 42.	The scale is designed to rate the severity of depression in patients by a healthcare professional. The assessment scale contains 6 items pertaining to the symptoms of depression experienced over the last three days. The score ranges from 0 to 24 [0–4] = no depression [5–6] = subclinical depression [7–8] = mild depression [9–11] = moderate depression [12–22] = moderate-severe depression A 2–3-point change in score is considered a minimum clinically important difference (MID) [39,50].
Secondary	Major Depression Inventory (MDI) Time points of measurement: baseline, day 7, day 21, day 42, and day 56	MDI is a depression self-assessment questionnaire. It consists of the 10 ICD-10 symptoms of depression. The sum of 10 questions indicates the degree of depression. The score ranges from 0 to 50 <21 = normal [21 − 25] = mild depression [26–30] = moderate depression ≥ 31 = severe depression [41]
	Neurocognitive battery Time points of measurement: baseline, day 7, and day 42	Assessing attention and recognition of emotional facial expressions using Facial Expression Recognition Test (FERT) and self-referent memory for emotional words using the Emotional Categorization and Memory test (ECMT). Non-emotional cognition is investigated with the Screen for Cognitive Impairment in Psychiatry (SCIP) and the Trail Making Test B (TMT-B) [51,52].
	Sleep diary covering last 7 days. Time points of measurement: continuous, by subjects themselves	Average last 7 days’ sleep parameters: Duration, falling asleep and waking up times, sleep quality, daytime sleep.
	Pittsburg Sleep Quality Index (PSQI) Time points of measurement: Baseline, and day 42	Seven component scores are derived, each scored 0 (no difficulty) to 3 (severe difficulty). The component scores are summed to produce a global score (range 0–21). Higher scores indicate worse sleep quality [53].
	WHO quality of life index (WHO-5) Time points of measurement: Baseline and day 21, day 42, and day 56	The score ranges from 0 to 25, with 0 representing the worst possible and 25 representing the best possible quality of life. To obtain a percentage score ranging from 0 to 100, the raw score is multiplied by 4. A percentage score of 0 represents the worst possible, whereas 100 represents the best possible quality of life. A 10% difference indicates a significant change [54].
Safety	The UKU Side Effects Scale Adverse Event (AE) Report Form The safety endpoint is the presence or absence of any adverse events during the treatment period.	All device-related adverse events will be reported and analyzed throughout the treatment and follow-up periods [55].
	Suicidal Ideation Attributes Scale (SIDAS) Time points of measurement: baseline, day 7, day 21, day 42, and day 56	The scale consists of 5 items: frequency, controllability, closeness to attempt, level of distress, and impact on daily functioning. Items are measured on a 10-point scale. The total score ranges from 0 to 50 (50 = worst). A cut-off of 21 may indicate a high risk of suicidal behavior [56].
	Young Mania Rating Scale (YMRS) Time points of measurement: Baseline, day 7, day 21, day 42, and day 56	The Scale assesses the manic symptoms that the light therapy could induce. The scale has 11 items and is based on the patient’s subjective report on his/her clinical condition over the last 48 h. Core mania symptoms include elevated mood, increased motor activity, irritability, and aggressive behavior. The Young Mania Rating Scale total score ranges from 0 to 60, where higher scores indicate more severe mania [57].
Adherence	The eye-tracking function of the device	Average device usage in minutes per day will be calculated. High adherence is considered 70% of the recommended duration of 1-h treatment per day.

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Data availability statement

After publication of the results, anonymized data can be made available from the principal investigator (K.M.) upon reasonable request.