8.1. HTA report compared with other publications

A 2017 systematic review showed that phototherapy has a favourable effect on symptoms of depression and the circadian rhythm. The review included RCTs as well as observational studies and nonrandomized interventional studies [119]. Another systematic review which included only RCTs likewise concluded that phototherapy is effective for SAD treatment and can reduce the severity of depression symptoms when compared with placebo [29]. The effect sizes of phototherapy were similar to those of antidepressant therapy. The review did not survey AEs [29]. Yet another systematic review based on RCTs on morning phototherapy with white light showed a minor favourable effect resulting from the reduction of symptoms of depression. The authors critically noted, however, that the included studies were of poor quality [120]. The results of the other systematic reviews are consistent with the findings of the present benefit assessment. Based on studies with largely high risk of bias, the benefit assessment also revealed a minor favourable effect of light box therapy on depression-related outcomes.

The studies included in this HTA report observed few AEs in patients receiving phototherapy. According to a systematic review which investigated explicitly eye-specific AEs of phototherapy, between 0% and 45% of patients, depending on the study, had eye complaints due to phototherapy. However, there was no evidence of phototherapy causing eye injury. The authors see a need for further research on patients with existing eye disorders and patients taking photosensitizing medications [121].

A Cochrane Review compared phototherapy versus antidepressants (fluoxetine) in SAD treatment. The review identified the same RCTs which were included in the present HTA report. The studies were inconclusive as to whether phototherapy or antidepressant therapy works better against SAD [23].

The present HTA report did not find any studies on vitamin D therapy of SAD. A 2017 systematic review [122] reported on an RCT in which 8 SAD patients received 100 000 IU of vitamin D and 7 SAD patients received phototherapy [21]. After 1 week, the reduction of depressive symptoms was greater on vitamin D therapy than on phototherapy, but since the intervention period was shorter than 2 weeks, the study was excluded from this HTA report.

8.2. HTA report compared with guidelines

The AMWF National Disease Management Guideline for unipolar depression recommends phototherapy and antidepressants (SSRI) as first-line therapies for SAD [13]. For phototherapy, it recommends using patient-facing light boxes. The present HTA report revealed an indication of their benefit. While the guideline recommends using devices emitting fluorescent white light of at least 2500 lux in the mornings, the present HTA also included studies with phototherapy devices emitting lower lux levels (at least 300), different light colours, and therapy at different times of day. However, those studies were in the minority.

The National Disease Management Guideline [13] does not mention vitamin D as a treatment option and therefore does not take a stance in favour or against taking vitamin D – neither in the treatment of SAD nor in the treatment of nonseasonal depression. This is consistent with the evidence gap identified in this regard by this HTA report.

The British National Institute for Health and Care Excellence guideline recommends antidepressant and psychotherapy for the treatment of depression and recommends treating all types of depression in the same way. It explicitly states that SAD patients should be made aware of the uncertain evidence regarding the effectiveness of phototherapy due to the studies being mostly small and barely conclusive [123].

8.3. Critical reflection on the approach used

During the HTA process, necessary specifications were made regarding the intervention and comparator intervention; these specifications facilitate the HTA, but adversely impact its informative value. The term “vitamin therapies” was narrowed down to vitamin D therapy because vitamin D deficiency in the winter months is believed to be a potential cause of the development of SAD [12]. Other SAD-related vitamin therapies were disregarded. As comparator therapies, placebo, no therapy, and active interventions recommended for the treatment of SAD were included, namely second-generation antidepressants and psychotherapeutic measures recognized in Germany [13]. Other measures, such as a change in diet or outdoor exercise were not included as comparator interventions, and therefore, no conclusions can be drawn about them.

For phototherapy, an inclusive approach was taken. Since the HTA report focused on phototherapy in general, different forms and applications of phototherapy (lux level, device type, light colour, time and duration of phototherapy) were included. Nevertheless, a post-hoc subgroup analysis by type of phototherapy was conducted to permit more specific conclusions on its effectiveness. In general, thresholds had to be defined as to the conditions under which phototherapy was deemed an active intervention versus placebo. This report used the threshold of 400 lux, loosely following the definition in the systematic review by Golden 2005 [29]. Even if studies classified the use of a light box emitting less than 300 lux as an active intervention, it was considered a placebo for the purposes of this HTA since the lux level was below the defined threshold. On the other hand, any placebos defined as such by study authors were deemed placebos in this HTA, even if thresholds deviated; for instance, the placebo lamp emitted 500 lux in one study [72] and 400 lux in another [68]. Consequently, the lux levels in these interventions, which were classified as placebo, were higher or equal to the “active phototherapy” of another study, at 400 lux [51]. These types of interventions with 400 and 500 lux lamps can also be viewed as low-dose phototherapy. Using low-dose active therapy as the placebo leads to the effect of phototherapy being underestimated. Comparing low-dose active therapy with placebo likewise underestimates the effect of phototherapy. The fact that an indication of greater benefit of phototherapy was nevertheless found under these conditions underscores its effectiveness.

The patient interviews revealed that depression-related outcomes such as response or remission were relevant from the patient perspective. In the literature, response is often defined as a 50% reduction of the baseline depression score, while remission requires a 50% reduction as well as achievement of a score not to exceed a defined threshold. Studies have shown that this operationalization is valid for various scales [124,125].

As one of the inclusion criteria, an intervention period of at least 2 weeks was specified. This decision was made in consultation with the clinical expert Dr Maximilian Huhn and with the intention to ensure that any observed effects were actually due to the intervention – which would be unlikely in case of a shorter intervention period. This specification is the reason why studies of a shorter intervention period were disregarded in this HTA.