Second‐generation antidepressants for treatment of seasonal affective disorder

Abstract

Background

Seasonal affective disorder (SAD) is a seasonal pattern of recurrent depressive episodes that is often treated with second‐generation antidepressants (SGAs), light therapy, or psychotherapy.

Objectives

To assess the efficacy and safety of second‐generation antidepressants (SGAs) for the treatment of seasonal affective disorder (SAD) in adults in comparison with placebo, light therapy, other SGAs, or psychotherapy.

Search methods

This is an update of an earlier review first published in 2011. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 1) in the Cochrane Library (all years), Ovid MEDLINE, Embase, and PsycINFO (2011 to January 2020), together with the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (all available years), for reports of randomised controlled trials (RCTs). We hand searched the reference lists of all included studies and other systematic reviews. We searched ClinicalTrials.gov for unpublished/ongoing trials. We ran a separate update search for reports of adverse events in the Ovid databases. 

Selection criteria

For efficacy we included RCTs of SGAs compared with other SGAs, placebo, light therapy, or psychotherapy in adult participants with SAD. For adverse events we also included non‐randomised studies.

Data collection and analysis

Two review authors independently screened abstracts and full‐text publications against the inclusion criteria. Data extraction and 'Risk of bias' assessment were conducted individually. We pooled data for meta‐analysis where the participant groups were similar, and the studies assessed the same treatments with the same comparator and had similar definitions of outcome measures over a similar duration of treatment.

Main results

In this update we identified no new RCT on the effectiveness of SGAs in SAD patients. We included 2 additional single‐arm observational studies that reported on adverse events of SGAs. 

For efficacy we included three RCTs of between five and eight weeks' duration with a total of 204 participants. For adverse events we included two RCTs and five observational (non‐randomised) studies of five to eight weeks' duration with a total of 249 participants. All participants met the DSM (Diagnostic and Statistical Manual of Mental Disorders) criteria for SAD. The average age ranged from 34 to 42 years, and the majority of participants were female (66% to 100%).

Results from one trial with 68 participants showed that fluoxetine (20/36) was numerically superior to placebo (11/32) in achieving clinical response; however, the confidence interval (CI) included both a potential benefit as well as no benefit of fluoxetine (risk ratio (RR) 1.62, 95% CI 0.92 to 2.83, very low‐certainty evidence). The number of adverse events was similar in both groups (very low‐certainty evidence).

Two trials involving a total of 136 participants compared fluoxetine versus light therapy. Meta‐analysis showed fluoxetine and light therapy to be approximately equal in treating seasonal depression: RR of response 0.98 (95% CI 0.77 to 1.24, low‐certainty evidence), RR of remission 0.81 (95% CI 0.39 to 1.71, very low‐certainty evidence). The number of adverse events was similar in both groups (low‐certainty evidence).

We did not identify any eligible study comparing SGA with another SGA or with psychotherapy.

Two RCTs and five non‐randomised studies reported adverse event data on a total of 249 participants who received bupropion, fluoxetine, escitalopram, duloxetine, nefazodone, reboxetine, light therapy, or placebo. We were only able to obtain crude rates of adverse events, therefore caution is advised regarding interpretation of this information. Between 0% and 100% of participants who received an SGA suffered an adverse event, and between 0% and 25% of participants withdrew from the study due to adverse events.

Authors' conclusions

Evidence for the effectiveness of SGAs is limited to one small trial of fluoxetine compared with placebo showing a non‐significant effect in favour of fluoxetine, and two small trials comparing fluoxetine against light therapy suggesting equivalence between the two interventions. The lack of available evidence precluded us from drawing any overall conclusions on the use of SGAs for SAD. Further, larger RCTs are required to expand and strengthen the evidence base on this topic, and should also include comparisons with psychotherapy and other SGAs.

Data on adverse events were sparse, and a comparative analysis was not possible. The data we obtained on adverse events is therefore not robust, and our confidence in the data is limited. Overall, up to 25% of participants treated with SGAs for SAD withdrew from the study early due to adverse events.

Plain language summary

Second‐generation antidepressants for winter depression

Background

Seasonal affective disorder (winter depression) is a type of depression that recurs in the autumn and lasts until the spring. Its symptoms are similar to those of regular depression, except sufferers are usually very tired and have an increase in their appetite. It is more common in countries with few daylight hours in winter. One of the mainstays of treatment for all depression, including winter depression, is second‐generation antidepressants (SGAs), such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs). It is not clear how well these drugs work and how they compare to each other or to other types of therapy for winter depression, such as light therapy.

Results

We found three trials with a total of 204 participants that looked at one SGA (fluoxetine) compared with placebo (dummy pill) or light therapy. One trial (68 participants) compared fluoxetine with placebo, although participants receiving fluoxetine were more likely to respond to treatment, there wasn't enough data to be sure of any differences with placebo. Approximately the same number of participants in both groups experienced a side effect.

We found two trials with a total of 136 participants that compared fluoxetine with light therapy. When we combined the results of these two trials, we found that the two treatments were similar in their effects: approximately 66 out of 100 people improved in both the fluoxetine and light therapy groups. The number of participants with side effects was also about the same in the fluoxetine and light therapy groups.

We found five additional studies that provided information on the safety of SGAs for the treatment of winter depression. They reported side effects of the SGAs bupropion, fluoxetine, escitalopram, duloxetine, nefazodone, and reboxetine. We were unable to compare the drugs directly, but we can report that about 0% to 25% of people left the study early due to side effects, and the most common side effects were nausea, diarrhoea, disturbed sleep, decreased sex drive, dry mouth, and agitation. We could not compare the rates of side effects in people taking SGAs compared with placebo, which means that our confidence in the information on side effects is limited.

Certainty of the evidence

The certainty of evidence for the effectiveness and safety of fluoxetine compared to placebo was very low. The certainty of evidence for the effectiveness and safety of fluoxetine compared to light therapy was low.

Summary of findings

Summary of findings 1. Fluoxetine compared with placebo for seasonal affective disorder.

Fluoxetine compared with placebo for seasonal affective disorder
Patient or population: adults with seasonal affective disorder Settings: outpatients Intervention: fluoxetine Comparison: placebo
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Placebo	Fluoxetine
Response (> 50% improvement on 29‐item HAM‐D SIGH‐SAD) 5 weeks	34 per 100	56 per 100 (32 to 97)	RR 1.62 (0.92 to 2.83)	68 (1 study, Lam 1995)	⊕⊝⊝⊝ very low1
Clinical Global Impression – Improvement score	No evidence identified.
Quality of life	No evidence identified.
Remission	No evidence identified.
Speed of onset of response	No evidence identified.
Overall adverse events 5 weeks	91 per 100	97 per 100 (86 to 110)	RR 1.07 (0.95 to 1.21)	68 (1 study, Lam 1995)	⊕⊝⊝⊝ very low1
*The basis for the assumed risk (e.g. the median control group risk across studies) is the rate in the placebo group. The corresponding risk (and its 95% CI) is based on the assumed risk in the fluoxetine group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HAM‐D SIGH‐SAD: Structured Interview Guide for the Hamilton Depression Rating Scale ‐ Seasonal Affective Disorder Version; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

¹Downgraded by one level because the trial has an unclear risk of bias in all but one 'Risk of bias' domains, and two levels for serious imprecision due to the small number of participants in the trial and because the confidence interval includes both benefit and no effect.

Summary of findings 2. Fluoxetine compared with light therapy for seasonal affective disorder.

Fluoxetine compared with light therapy for seasonal affective disorder
Patient or population: adults with seasonal affective disorder Settings: outpatients Intervention: fluoxetine Comparison: light therapy
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Light therapy	Fluoxetine
Response (> 50% improvement on 24‐item HAM‐D SIGH‐SAD) 5 to 8 weeks	68 per 100	67 per 100 (52 to 87)	RR 0.98 (0.77 to 1.24)	136 (2 studies, Lam 2006, Ruhrmann 1998)	⊕⊕⊝⊝ low1
Clinical Global Impression – Improvement score	No evidence identified.
Quality of life (SF‐20 and Q‐LES‐Q) 8 weeks	SF‐20: The mean change from baseline was 7.82 Q‐LES‐Q:The mean change from baseline was 20.26	SF‐20: The mean change from baseline was 1.56 higher (4.2 lower to 7.32 higher) Q‐LES‐Q:The mean change from baseline was 1.21 higher (4.87 lower to 7.29 higher)	‐	96 (1 study, Lam 2006)	⊕⊕⊝⊝ low2	mean difference of change from baseline self calculated by review authors
Remission (response plus end score 8 or less) 5 to 8 weeks	68 per 100	55 per 100 (22 to 94)	RR 0.81 (0.39 to 1.71)	136 (2 studies, Lam 2006, Ruhrmann 1998)	⊕⊝⊝⊝ very low3
Time to onset of response	No evidence identified
Adverse events (at least 1 treatment‐emergent adverse event) 8 weeks	77 per 100	75 per 100 (60 to 94)	RR 0.97 (0.78 to 1.22)	96 (1 study, Lam 2006)	⊕⊕⊝⊝ low4
*The basis for the assumed risk (e.g. the median control group risk across studies) is the response rate in the light therapy groups in the 2 included trials. The corresponding risk (and its 95% CI) is based on the assumed risk in the fluoxetine group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HAM‐D SIGH‐SAD: Structured Interview Guide for the Hamilton Depression Rating Scale ‐ Seasonal Affective Disorder Version; NR: not reported; Q‐LES‐Q: Quality of Life Enjoyment and Satisfaction Questionnaire; RR: risk ratio; SF‐20: 20‐Item Short Form Health Survey
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

¹Downgraded by one level because the risk of bias was high in one study, and one level for imprecision because the optimal information size was not reached (too few participants).
²The data are from only one trial with a low risk of bias; however, we downgraded by two level for imprecision because the optimal information size was not reached (too few participants) and the confidence interval was broad including both a benefit for fluoxetin and for light therapy.
³Downgraded by one level for inconsistency, one level because the risk of bias was high in one study, and one level for imprecision because the optimal information size was not reached (too few participants).
⁴The data are from only one trial with a low risk of bias; however, we downgraded by one level for imprecision because the optimal information size was not reached (too few participants), and one level for indirectness because the outcome encompasses many adverse effects, allowing no direct conclusions.

Background

Description of the condition

Seasonal affective disorder (SAD) is a seasonal pattern of recurrent major depressive episodes that occur during autumn or winter and remit in spring or summer (Rosenthal 1984). In addition to the predictable seasonal pattern of depression, people suffering from SAD experience atypical symptoms including hypersomnia, carbohydrate craving with increased appetite and weight gain, and extreme fatigue (Sohn 2005). The prevalence of SAD ranges from 1.5% to 10%, with higher prevalence rates in more northern latitudes (Byrne 2008; Levitt 2000; Wirz‐Justice 2018).

SAD is a multifactorial condition. Chronobiological mechanisms related to circadian rhythms, melatonin, alterations of the serotonergic neurotransmitter system, and photoperiodism (length of dark hours relative to light hours in a 24‐hour period) are all thought to play a role in SAD (Ciarleglio 2011; Levitan 2007; Oldham 2014). Although it is commonly believed that a seasonal pattern of depression occurs almost exclusively in locations with very few hours of daylight in winter (Moscovitch 2004), a Canadian study on the prevalence of SAD over eight degrees of latitude did not support this theory (Levitt 2002). It is assumed that the major monoaminergic neurotransmitters serotonin, norepinephrine, and dopamine are fundamental to the pathology of SAD, and that the condition results from the interaction of genetic vulnerability and environmental factors (Gonda 2020; Levitan 2007).

Description of the intervention

Since their introduction to the market in the late 1980s, second‐generation antidepressants (SGAs) have established themselves as a dominant form of pharmacotherapy for depressive disorders (Gartlehner 2011, Gartlehner 2017).

In general, SGAs work through their effect on neurotransmitters in the central nervous system. SGAs can be classified into three groups: selective serotonin reuptake inhibitors (SSRIs); serotonin and norepinephrine reuptake inhibitors (SNRIs); and others. The SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) act by selectively inhibiting the reuptake of serotonin (5‐hydroxy‐tryptamine, 5‐HT) at the presynaptic neuronal membrane. The SNRIs (desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine) are potent inhibitors of serotonin and norepinephrine reuptake. Some SSRIs and SNRIs may also exert dopamine reuptake inhibition, but this is not essential to their categorisation. Other SGAs include mirtazapine, which is an antagonist at presynaptic alpha‐2 autoreceptors (which disinhibits norepinephrine release) and a 5‐HT2 receptor antagonist (Gartlehner 2008; Hansen 2009). Bupropion is an inhibitor of the neuronal uptake of norepinephrine and dopamine (Khan 2016). Reboxetine is a norepinephrine reuptake inhibitor that does not act on serotonin (Kent 2000). Similarly, agomelatine is a melatonin‐1 (MT1) and MT2 receptor agonist and 5‐HT2C receptor antagonist (Hickie 2011). Vortioxetine is a 5‐HT transporter inhibitor, an agonist at the 5‐HT1A receptor, a partial agonist at the 5‐HT1B receptor and an antagonist at the 5‐HT1D, 5‐HT3 and 5‐HT7 receptor. Vilazodon acts as an SSRI together with agonism at the 5‐HT1A receptor (Wagner 2018).

Clinical guidelines recommend SGAs for the treatment of SAD (DGPPN 2015; NICE 2009). The German depression guideline and the Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders recommend early‐morning bright‐light therapy for SAD (DGPPN 2015, Malhi 2021), whilst the National Institute for Health and Care Excellence (NICE) also recommends psychotherapy for the condition (NICE 2009). We therefore investigated the efficacy and adverse events of SGAs when used for the treatment of SAD and included other treatment alternatives like light therapy and psychotherapy as comparators.

How the intervention might work

Much research into the aetiology of SAD has focused on the role of circadian rhythms and melatonin (Lam 2006), and early‐morning bright‐light exposure is a common and effective treatment for SAD (Golden 2005; Pjrek 2020). On the neurochemical level, changes in both the serotonergic and catecholaminergic neurotransmitter systems seem to play a key role in the disorder (Neumeister 2001). Targeting these systems with serotonin or norepinephrine reuptake inhibition, or both, provides the biological plausibility for the mechanism of action of the SGAs. Indeed, the therapeutic action of SGAs in SAD is similar to that in non‐seasonal depression, even though the role of daylight and circadian rhythms in the pathogenesis of SAD might be different to non‐seasonal depression (Ciarleglio 2011; Pjrek 2005).

Why it is important to do this review

Bright‐light therapy is considered to be an effective treatment for seasonal affective disorder (Pjrek 2020), and is recommended in clinical guidelines (DGPPN 2015; Kennedy 2001). Indeed, one systematic review and meta‐analysis suggested that effect sizes for light therapy in SAD are comparable to those seen in trials of SGAs (Golden 2005). Also, the last version of this review found similar effects of light therapy and SGAs in SAD treatment (Thaler 2011). Unfortunately, light therapy is time intensive; typical regimens suggest at least 30 minutes of light exposure immediately after waking (Lam 2006), which may result in poor adherence to therapy (Michalak 2002; Nussbaumer‐Streit 2018). Hence, it was important to determine the efficacy of SGAs in treating SAD, in particular in comparison to light therapy. Furthermore, interest in the comparative efficacy of SGAs is still high, with many reviews seeking to provide guidance to physicians about the most appropriate SGA for depression (Cipriani 2018; Gartlehner 2011; Monden 2018; Wagner 2018). The original version of this review was published in 2011 and required an update (Thaler 2011).

Objectives

To assess the efficacy and safety of second‐generation antidepressants (SGAs) for the treatment of seasonal affective disorder (SAD) in adults in comparison with placebo, light therapy, other SGAs, or psychotherapy.

Methods

Criteria for considering studies for this review

Types of studies

Efficacy (beneficial effects)

We included randomised controlled trials (RCTs) of at least four weeks' duration. We included cluster‐RCTs, with data from cross‐over trials eligible up to the point of crossing over.

Adverse events

We included both experimental and observational (non‐randomised) studies (Barbui 2009; Higgins 2020):

• RCTs of SGAs for SAD, of at least four weeks' duration;

• controlled and uncontrolled non‐randomised studies of SGAs for SAD, of at least four weeks' duration.

Types of participants

We included studies involving adults (at least 18 years of age) with a DSM‐IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) (APA 2000), or equivalent diagnosis of SAD (major depressive disorder (MDD) with a seasonal pattern). Studies that enrolled SAD participants with bipolar depression were excluded; because patients with bipolar disorders are primarily treated with mood stabilisers, not with antidepressants, while SGAs are the first line treatment for patients with unipolar depression. Studies with participants with secondary co‐morbidities were considered for inclusion.

Types of interventions

Experimental interventions

We considered trials of the following SGAs:

• SSRIs: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline;

• SNRIs: desvenlafaxine, duloxetine, milnacipran, mirtazapine, venlafaxine;

• other: agomelatine, bupropion, nefazodone, reboxetine, trazodone, levomilnacipran, vilazodone, vortioxetine.

Comparison interventions

We compared any SGA with another SGA, placebo, light therapy, or psychotherapy as a comparator. Commonly used psychological therapy approaches include behavioural therapy, cognitive behavioural therapy, and psychodynamic therapy. Placebo could be pills that look like an SGA but have no therapeutic value (sugar pill), or light therapy devices that emit little lux and therefore have no therapeutic value.

Types of outcome measures

Primary outcomes

The primary outcome is the proportion of participants achieving a clinical response, calculated from the number of participants randomised (intention‐to‐treat analysis). Clinical response was defined by the trial authors and included:

1. the proportion of participants experiencing a greater than 50% improvement on the Hamilton Depression Scale (HAM‐D) (Hamilton 1980), combined with the eight‐item supplementary scale for seasonal affective disorder (Structured Interview Guide for the Hamilton Depression Rating Scale ‐ Seasonal Affective Disorder Version (SIGH‐SAD)) (Williams 1988);

2. the proportion of participants experiencing a greater than 50% improvement on the HAM‐D.

Secondary outcomes

1. Proportion of participants reporting a Clinical Global Impression – Improvement (CGI‐I) score of 1 or 2 (much improved or very much improved) (Guy 1970).

2. Improvement in quality of life (QOL), as measured by a validated QOL tool (e.g. 36‐item Short Form Health Survey (SF‐36)) (Ware 1992).

3. Remission, as defined by the study authors.

4. Speed of onset of response.

5. Occurrence of adverse events, such as suicidality (suicidal thinking or behaviour), sexual side effects, seizures, biochemical adverse events (e.g. hyponatraemia), weight change, and gastrointestinal symptoms, as well as withdrawals attributable to adverse events and serious adverse events.

Search methods for identification of studies

Electronic searches

An Information Specialist with the Cochrane Common Mental Disorders Group ran an updated search on the following databases to identify reports of RCTs (29 January 2020) (Appendix 1):

• Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 1) in the Cochrane Library (all years);

• Ovid MEDLINE (2011 to 29 January 2020);

• Ovid Embase (2011 to 29 January 2020);

• Ovid PsycINFO (2011 to 29 January 2020);

• Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (archived database) (2011 to June 2016 only).

International trial protocols registered on the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) were captured via CENTRAL on the Cochrane Library.

The Information Specialist also ran a separate search for adverse events (Ovid databases) (24 February 2020) (Appendix 2).

We applied no restrictions to language or publication status.

Searches for the earlier version of this review, published in 2011, are shown in Appendix 3.

Searching other resources

In addition, we handsearched the references of all included studies and pertinent review articles. We ran a separate search of the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov/) to detect ongoing or unpublished studies. Finally, we contacted experts in the field of SAD to ensure that we were aware of all published and unpublished trials.

Data collection and analysis

Selection of studies

Two review authors (BNS, KT, AC, TP, AS, or GG) independently reviewed the titles and abstracts of records identified by the search. We retrieved full‐text copies of all studies that potentially met the inclusion criteria based on abstract review, and two review authors (BNS, KT, AC, TP, AS, or GG) independently reviewed these to determine their eligibility. Any disagreements between review authors were discussed with and resolved by a third party (BNS or GG). We used Covidence software to facilitate title/abstract and full‐text screening (Covidence).

No studies published only as abstracts were considered for inclusion in the review, hence there was no need to contact trial authors for information required to permit an appraisal of trial quality.

Data extraction and management

Two review authors (BNS, KT) independently abstracted data from the included trials. A third review author (AC) checked the data for accuracy and completeness. Any discrepancies were resolved by consensus or by involving a third review author.

We extracted the following study characteristics.

• Methods: study design, duration of study, duration of treatment period, number of study centres, Country.

• Participants: number of participants, age (mean or range), proportion of women, diagnostic criteria, inclusion and exclusion criteria.

• Interventions: intervention, comparison.

• Outcomes: primary and secondary outcomes specified.

• Notes: funding for studies and conflicts of interest of authors.

All possible comparisons based on our inclusion criteria were as follows.

1. SGAs versus placebo

2. SGAs versus light therapy

3. SGAs versus other SGAs

4. SGAs versus psychotherapy

In the case of missing data, we would have contacted the study authors, but this was not necessary.

Assessment of risk of bias in included studies

We assessed the risk of bias of randomised trials using the Cochrane 'Risk of bias' tool, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). The tool includes assessment of: random sequence generation; allocation concealment; blinding of participants, personnel, and outcome assessors; incomplete outcome data; selective outcome reporting; and other potential threats to validity. Specifically, we assessed attrition (loss of participants during a study) in the trials and the reasons for it, particularly where the attrition rates between two groups in a trial were substantially different. In addition, we assessed whether all relevant outcomes for the trial were reported in the published articles. We assessed each domain as low, high, or unclear risk of bias.

For non‐randomised studies, we used criteria involving selection of cases or cohorts and controls, adjustment for confounders, methods of outcomes assessment, length of follow‐up, and statistical analysis (Deeks 2003). We entered our 'Risk of bias' assessment into the standard 'Risk of bias' tables (used to generate figures in the report), as well as in an Additional table (Table 3; Table 4; Table 5; Table 6; Table 7). Two review authors (BNS, KT) independently assessed the risk of bias. Any discrepancies were resolved by consensus or by involving a third review author.

1. 'Risk of bias' table (non‐randomised study), Dilsaver 1992.

Domain	Authors' judgement	Support for judgement
How did allocation occur? Was there concealment of allocation?	High risk	All participants received active therapy with bupropion. No concealment of allocation
Blinding? (participants)	High risk	Open‐label
Follow‐up equal and complete?	High risk	33% attrition
Baseline comparability of groups?	Unclear	Only 1 group
Intention‐to‐treat analysis	High risk	Intention‐to‐treat analysis not employed.
Intervention clearly specified?	Low risk	Intervention clearly described.
Outcomes clearly specified?	High risk	Outcome of interest (adverse events) not clearly specified.
Interpretation based on results?	Low risk	Yes

2. 'Risk of bias' table (non‐randomised study), Pjrek 2007.

Domain	Authors' judgement	Support for judgement
How did allocation occur? Was there concealment of allocation?	High risk	All participants received active therapy with escitalopram. No concealment of allocation
Blinding? (participants)	High risk	Open‐label
Follow‐up equal and complete?	Low risk	10% attrition
Baseline comparability of groups?	Unclear	Only 1 group
Intention‐to‐treat analysis	Low risk	Intention‐to‐treat analysis employed.
Intervention clearly specified?	Low risk	Intervention clearly described.
Outcomes clearly specified?	Low risk	Outcomes clearly specified, including prospective adverse events recording with Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale.
Interpretation based on results?	Low risk	Yes

3. 'Risk of bias' table (non‐randomised study), Pjrek 2008.

Domain	Authors' judgement	Support for judgement
How did allocation occur? Was there concealment of allocation?	High risk	All participants received active therapy with duloxetine. No concealment of allocation
Blinding? (participants)	High risk	Open‐label
Follow‐up equal and complete?	High risk	23% attrition
Baseline comparability of groups?	Unclear	Only 1 group
Intention‐to‐treat analysis	High risk	LOCF analysis employed.
Intervention clearly specified?	Low risk	Intervention clearly described.
Outcomes clearly specified?	Low risk	Outcomes clearly specified, including prospective adverse events recording with Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale.
Interpretation based on results?	High risk	No, due to high attrition and use of LOCF approach for missing data

LOCF: last observation carried forward

4. 'Risk of bias' table (non‐randomised study), Pjrek 2009.

Domain	Authors' judgement	Support for judgement
How did allocation occur? Was there concealment of allocation?	High risk	All participants received active therapy with reboxetine. No concealment of allocation
Blinding? (participants)	High risk	Open‐label
Follow‐up equal and complete?	High risk	27% attrition
Baseline comparability of groups?	Unclear	Only 1 group
Intention‐to‐treat analysis	High risk	LOCF analysis employed.
Intervention clearly specified?	Low risk	Intervention clearly described.
Outcomes clearly specified?	Low risk	Outcomes clearly specified, including prospective adverse events recording with Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale.
Interpretation based on results?	High risk	No, due to high attrition and use of LOCF approach for missing data

LOCF: last observation carried forward

5. 'Risk of bias' table (non‐randomised study), Shen 2005.

Domain	Authors' judgement	Support for judgement
How did allocation occur? Was there concealment of allocation?	High risk	All participants received active therapy with nefazodone. No concealment of allocation
Blinding? (participants)	High risk	Open‐label
Follow‐up equal and complete?	High risk	33% attrition
Baseline comparability of groups?	Unclear	Only 1 group
Intention‐to‐treat analysis	High risk	No intention‐to‐treat analysis employed.
Intervention clearly specified?	Low risk	Intervention clearly described.
Outcomes clearly specified?	High risk	For adverse events a questionnaire was used (no details about the questionnaire).
Interpretation based on results?	High risk	Adverse events are reported vaguely without presentation of absolute numbers.

Measures of treatment effect

We used the extracted data from the original studies to construct 2 x 2 tables (e.g. clinical response versus no response for antidepressant versus comparator). Where multiple studies allowed for pooling, we calculated the risk ratio (RR) with 95% confidence intervals (CI) for each outcome. We planned to calculate the number needed to treat for an additional beneficial outcome (NNTB) and risk difference (RD). In addition, we planned to pool continuous data using the mean difference (MD) or standardised mean difference (SMD).

Unit of analysis issues

For any included trials with multiple treatment groups (e.g. differing doses of one SGA versus placebo or multiple SGAs versus placebo), we would include the data for the treatment arms and halve the data from the placebo arm, or collapse the data for different doses into one group where this was considered to be clinically appropriate (Hansen 2009). We planned to include data from cluster‐randomised studies and from the first period of cross‐over studies.

Dealing with missing data

We used an intention‐to‐treat analysis where data were missing from participants who dropped out of trials before completion, assuming in such cases that participants did not achieve a clinical response or remission. We planned that where data regarding an assessed outcome were not reported, we would contact authors of publications or pharmaceutical companies to obtain the missing results, but this was not necessary. We have reported the proportion of participants for whom no outcome data were obtained (because of attrition) in the 'Risk of bias' assessment of each trial, and considered the potential impact of the missing data in our interpretation of the results.

Assessment of heterogeneity

We used the Cochran Chi² test (Q‐test) to assess heterogeneity, considering a P value less than 0.10 as statistically significant. We used the I² statistic to estimate the degree of heterogeneity, which describes the percentage of total variation across studies that results from heterogeneity rather than chance. We interpreted the importance of any heterogeneity in terms of its magnitude and the direction of effects. We did not consider thresholds, instead adopting the overlapping bands suggested in the Cochrane Handbook. For example, we considered an I² of:

• 0% to 40% as probably not important;

• 30% to 60% as representing moderate heterogeneity;

• 50% to 90% as substantial heterogeneity;

• 75% to 100% as considerable heterogeneity (Higgins 2020).

Assessment of reporting biases

Had we found more than 10 studies, we would have undertaken an analysis of a funnel plot, which is a graph used to detect publication bias. We wanted to know whether the largest studies were near the average with small studies spread on both sides of the average. Variations from this assumption can indicate the existence of publication bias, but asymmetry may not necessarily be caused by publication bias.

Data synthesis

We analysed data using Review Manager 5 (Review Manager 2020). We pooled data for meta‐analysis where the participant groups were similar, and the studies assessed the same treatments with the same comparator and had similar definitions of outcome measures over a similar duration of treatment. We used a fixed‐effect model because we expected studies to be very similar. Studies reporting dichotomous data were weighted using the Mantel‐Haenszel method. We rated the strength of the evidence based on the system developed by the GRADE Working Group (Guyatt 2011).

We performed a narrative analysis of data on adverse events comparing crude rates. We planned to conduct quantitative analysis of the rate of adverse events only if we located a sufficient number of prospective observational studies or randomised trials that contained data on adverse events suitable for pooling.

Subgroup analysis and investigation of heterogeneity

We planned to perform subgroup analyses of SSRIs and SNRIs, but this was not possible due to the limited number of identified studies.

Sensitivity analysis

We performed sensitivity analysis using a random‐effects model  to see if this would change the pooled results. We planned to conduct additional sensitivity analyses excluding small studies, studies with a high risk of bias, and studies published in abstract form; however, due to the limited number of trials available it was not possible to perform these analyses.

Summary of findings and assessment of the certainty of the evidence

Two review authors (BNS, KT) assessed the certainty of evidence using the GRADE approach, which considers risk of bias, inconsistency, indirectness, imprecision, and publication bias for each outcome. Evidence from RCTs starts at a level of high certainty. Concerns about any of the aforementioned domains would result in downgrading of the evidence by one or two levels; explanations for our decisions would be provided in the 'Summary of findings' tables. For example, we would downgrade one level for imprecision if the 95% CI included both a beneficial or non‐beneficial effect. We assessed the certainty of the evidence as high, moderate, low, or very low according to the GRADE approach (Guyatt 2011). We created two 'Summary of findings' tables, one for the comparison SGAs versus placebo (Table 1), and one for SGAs versus light therapy (Table 2).

Results

Description of studies

Results of the search

We conducted searches for efficacy and for adverse events separately. The 2020 update search retrieved 168 records for efficacy and 179 records for adverse events. After additional de‐duplication in Covidence, 295 records remained for screening. We considered 29 citations to be relevant after title and abstract screening. We obtained all 29 full‐text publications, of which 25 were excluded for the following reasons: ineligible study design (15 articles), ineligible population (5 articles), wrong intervention (1 article), wrong outcomes (1 article), and duplicates of records already included in the original version of this review (3 articles). For detailed information on the results of the search of the original review, see Thaler 2011. Finally, we included three RCTs (five publications) that had already been included in the original version of this review (Lam 1995; Lam 2006; Ruhrmann 1998), and five observational studies providing additional information on adverse events (eight publications) (Dilsaver 1992; Pjrek 2007; Pjrek 2008; Pjrek 2009; Shen 2005) (see Figure 1). Dilsaver 1992 and Shen 2005 were newly identified in this update. 

1.

Study flow diagram.

Included studies

Randomised controlled trials

We included three RCTs of an SGA versus placebo or light therapy for SAD (Lam 1995; Lam 2006; Ruhrmann 1998). The three trials included a total of 204 participants and provided evidence on two comparisons:

• fluoxetine versus placebo (68 participants) (Lam 1995);

• fluoxetine versus light therapy (136 participants) (Lam 2006; Ruhrmann 1998).

The trials had a treatment duration of five to eight weeks, and all trials incorporated an initial placebo wash‐out period. Two trials were sponsored by pharmaceutical companies (Lam 1995; Ruhrmann 1998), and one trial was funded by the Canadian Institute of Health Research (Lam 2006).

Trials were generally small (40 to 96 participants) and recruited participants in Canada and Germany. All participants met DSM‐III‐R (Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised) or DSM‐IV criteria for depression with a seasonal pattern. Trials typically had more females than males (66% to 78% females), and the average age ranged from 39 to 41 years.

All SGAs were prescribed orally and taken at recommended doses. Light therapy was at 3000 lux or 10,000 lux.

All trials provided data on the HAM‐D 17‐item or 21‐item, with the supplementary seven‐ or eight‐item subscale for SAD (SIGH‐SAD or SUPP). One trial provided quality of life data (Lam 2006).

Non‐randomised studies

We also included five prospective, single‐arm, open‐label observational studies of bupropion, escitalopram, duloxetine, nefazodone, and reboxetine for data on adverse events. These studies included between 9 and 26 participants and recruited participants with a DSM‐III‐R or DSM‐IV‐TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) diagnosis of SAD at the Medical University of Vienna, Austria, in the USA, and in Canada. The studies lasted five (Dilsaver 1992), six (Pjrek 2009), or eight weeks (Pjrek 2007; Pjrek 2008; Shen 2005). About 70% to 100% of participants were female, and the average age ranged from 34 to 42 years. Adverse events were recorded weekly or bi‐weekly using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale (Pjrek 2007; Pjrek 2008; Pjrek 2009), or collected with a self‐reported questionnaire (Shen 2005), or unsystematically assessed without specifying the exact method of assessment (Dilsaver 1992).

For further details on the included studies, see Characteristics of included studies.

Excluded studies

Overall, we excluded 33 studies on full‐text level in the original review, and 25 in this update. In the following section we provide detailed exclusion reasons only for those records that a reader might plausibly expect to see amongst the included studies.

We excluded three studies where participants were randomised to bupropion or placebo for the prevention of SAD because the population did not meet our inclusion criteria (GlaxoSmithKline 2003; GlaxoSmithKline 2003a; GlaxoSmithKline 2004), that is the participants did not have symptoms of SAD at the time of enrolment.

We excluded two studies because the population did not meet our inclusion criteria (Moscovitch 2004; Seo 2013). One study was reported in a journal article and two conference abstracts. The study was a multicentre, eight‐week, randomised trial of sertraline versus placebo in 187 participants with a DSM‐III‐R diagnosis of major depression or bipolar disorder with a seasonal pattern, which did not meet our inclusion criteria (Moscovitch 2004). The second trial assessed the effect of bupropion hydrochloride extended‐release in people with major depressive disorder with atypical features not specifically in people with SAD (Seo 2013).

Finally, a six‐week study of 183 participants with major depression randomised to 20 to 40 mg/day of fluoxetine or 300 to 450 mg/day of moclobemide presented separate results for the 34 SAD participants included in the trial (Partonen 1996). We excluded this study because the comparator was moclobemide (our eligibility criteria specified we would only include comparisons with other SGAs, light therapy, psychotherapy, or placebo).

For further information regarding the excluded studies, see Characteristics of excluded studies.

Ongoing studies

We did not identify any ongoing studies.

Risk of bias in included studies

Whilst one well‐conducted and well‐reported trial had an overall low risk of bias (Lam 2006), overall the risk of bias in the included RCTs was high. The major source of bias was incomplete outcome data (high overall or differential attrition). The risk of bias in the non‐randomised studies (assessed using the Cochrane 'Risk of bias' tool and the Deeks 2003 criteria) was high, primarily due to small sample size, lack of blinding, and high attrition. See Characteristics of included studies for further details on the risk of bias of the included studies, and Figure 2 and Figure 3 for an overview of the risk of bias.

2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

In the following section we describe the risk of bias for the three included RCTs. Details on risk of bias for the non‐randomised studies are provided in Other potential sources of bias.

Allocation

One trial described computer‐generated randomisation techniques and was assessed as at low risk of bias for random sequence generation (Lam 2006). Otherwise, the method of random sequence generation was not described. Similarly, an adequate method of allocation concealment (using opaque envelopes) was reported in only one trial (Lam 2006), which was assessed as at low risk of bias.

Blinding

All three trials were described as 'double‐blind'. In the two trials that compared an SGA with light therapy, the authors went to great lengths to maintain the blinding of participants in the placebo light‐therapy treatment by disguising the dim light control or by informing participants that the purpose of the trial was to determine the appropriate wavelength of light (Lam 2006; Ruhrmann 1998); furthermore, the blinding of raters (assessors) was clearly described. We assessed these two trials as at low risk of performance and detection bias.

Incomplete outcome data

In one trial of fluoxetine versus light therapy, there was a high rate of differential attrition: 20% in the bright‐light group compared with 5% in the fluoxetine group (Ruhrmann 1998). We assessed this trial as at high risk of attrition bias.

Selective reporting

None of the trials had a protocol available; however, all trials provided detailed reporting of the results as described in the respective methods sections.

Other potential sources of bias

All five observational studies were conducted prospectively (Dilsaver 1992; Pjrek 2007; Pjrek 2008; Pjrek 2009; Shen 2005). Nonetheless, the authors did not report how the allocation to the particular SGA was decided. All five studies were open‐label, and no attempt was made to blind participants, personnel, or outcome assessors. The interventions and outcomes were clearly described in all studies, and the evaluation in the published articles was based on the results, except for in two studies (Dilsaver 1992; Shen 2005): Dilsaver 1992 did not specify how adverse events were defined or assessed, and Shen 2005 did not report results on adverse events numerically. All five studies were small (12 to 26 participants), and four suffered high attrition: 23% (Pjrek 2008), 27% (Pjrek 2009), 33% (Shen 2005), and 33% (Dilsaver 1992). Overall, the high attrition and small study size resulted in a judgement of high risk of other bias for these studies. The analysis of the risk of bias of the non‐randomised studies is presented in tabular format in Table 3, Table 4, Table 5, Table 6, and Table 7.

Effects of interventions

See: Table 1; Table 2

In this section we present the efficacy and adverse event results for our two main comparisons: SGAs versus placebo and SGAs versus light therapy. We also present a narrative summary of adverse events data for SGAs.

Fluoxetine versus placebo

Primary outcome

1.1 Fifty per cent improvement on the Hamilton Depression Scale (HAM‐D) combined with the eight‐item supplementary scale for seasonal affective disorder (Structured Interview Guide for the Hamilton Depression Rating Scale ‐ Seasonal Affective Disorder Version (SIGH‐SAD))

One five‐week trial of 68 participants randomised participants to 20 mg/day of fluoxetine or placebo (Lam 1995). The risk ratio for clinical response was 1.62 (95% confidence interval (CI) 0.92 to 2.83) (Analysis 1.1). We rated the certainty of evidence as very low.

1.1. Analysis.

Comparison 1: Fluoxetine versus placebo, Outcome 1: Response (> 50% improvement on 29‐item HAM‐D SIGH‐SAD)

1.2 Fifty per cent improvement on the HAM‐D

No data available.

Secondary outcomes

1.3 Clinical Global Impression – Improvement (CGI‐I) score of 1 or 2 (much improved or very much improved)

No data available.

1.4 Improvement of quality of life (QOL) as measured by a validated QOL tool

No data available.

1.5 Remission, as defined by the study authors

No data available.

1.6 Speed of onset of response

No data available.

1.7 Occurrence of adverse events

Overall, 35 of 36 participants in the fluoxetine group suffered an adverse event, compared with 29 out of 32 in the placebo group. This corresponds to a risk ratio of 1.07 (95% CI 0.95 to 1.21) (Analysis 1.2). We rated the certainty of evidence as very low. The authors reported no statistically significant differences between groups for any specific adverse event such as headache, insomnia, and dyspepsia, but did not report the exact number of participants in each arm that experienced these adverse events. Adverse events are presented in Table 8.

1.2. Analysis.

Comparison 1: Fluoxetine versus placebo, Outcome 2: Harm: overall adverse events

6. Adverse events.

Study ID	Lam 2006		Lam 1995		Dilsaver 1992	Pjrek 2007	Pjrek 2008	Pjrek 2009	Shen 2005
Study design	RCT		RCT		Open‐label observational study	Open‐label observational study	Open‐label observational study	Open‐label observational study	Open‐label observational study
SGA	Fluoxetine	Light therapy	Fluoxetine	Placebo	Bupoprion	Escitalopram	Duloxetine	Reboxetine	Nefazodone
Number of participants (N)	N = 48	N = 48	N = 36	N = 32	N = 15	N = 20	N = 26	N = 15	N = 9
Overall AEs (%)	75	77	97	91	0	55		100
Withdrawal due to AEs (%)	25	23	6	3		0	15.4	13.3
Gastrointestinal
Abdominal pain (%)	8.3	6.3
Nausea (%)	10.4	4.2				40	53.8	20
Diarrhoea (%)	10.4	4.2				5	23.1	0.0
Constipation (%)	6.3	8.3				5	11.5	26.7
Decreased appetite (%)	14.6	14.6				5		6.7
Increased appetite (%)	14.6	8.3					3.8
Weight loss (%)	6.3	2.1					3.8
Central nervous system
Anxiety (%)	25.0	12.5
Nervousness (%)	10.4	12.5
Agitation (%)	12.5	0
Dizziness (%)						5		0.0
Tremor (%)	6.3	2.1					3.8	33.3
Irritability (%)	8.3	4.2
Sleepiness (%)	12.5	8.3					3.8	26.7
Increased sleep (%)	18.8	12.5						6.7
Decreased sleep (%)	20.8	22.9
Sleep disturbance (%)	29.2	2.1					7.7		44.4
Headache (%)	10.4	16.7				5	7.7	13.3	0
Paraesthesia (%)								20.0
Sexual dysfunction
Decreased sex drive (%)	16.7	14.6				20		0
Male erection problems (%)	6.3	4.7
Female delayed orgasm (%)	6.3	0
Other
Feeling faint (%)	0	6.3
Palpitations (%)	10.4	0					3.8	60.0
Sweating (%)	10.4	6.3					11.5	73.3
Flushing (%)	4.2	6.3
Muscle pain (%)	12.5	12.5
Weakness/fatigue (%)	16.7	16.5
Rash (%)	6.3	0
Dry mouth (%)	14.6	18.8					11.5	86.7	0
Hypersalivation (%)								6.7
Dry eyes (%)								6.7
Urinary retention (%)								6.7
Concentration problems (%)							3.8		0
Dilated pupils (%)							3.8
Emotional indifference (%)							3.8
Photosensitivity (%)							3.8
Vivid dreams (%)							3.8
Psychomotor agitation (%)								73.3
Orthostatic dysregulation (%)								60.0
Accomodative dysfunction (%)								26.7

AE: adverse event; RCT: randomised controlled trial; SGA: second‐generation antidepressant

Results for this comparison and the illustrative comparative risks are presented in Table 1.

Fluoxetine versus light therapy

Primary outcome

2.1 Fifty per cent improvement on the Hamilton Depression Scale (HAM‐D) combined with the eight‐item supplementary scale for seasonal affective disorder (Structured Interview Guide for the Hamilton Depression Rating Scale ‐ Seasonal Affective Disorder Version (SIGH‐SAD))

Meta‐analysis of two RCTs (136 participants) showed little to no differences in response and remission between fluoxetine and light therapy. Response was assessed after five, Ruhrmann 1998, or eight weeks, Lam 2006, based on a greater than 50% improvement in the 24‐item SIGH‐SAD tool. The pooled risk ratio of response was 0.98 (95% CI 0.77 to 1.24, low‐certainty evidence) (Analysis 2.1; Figure 4). This corresponds to a response rate of between 66% and 68% for both comparators. Heterogeneity for this result was low (I² = 0%). Using a random‐effects model (as sensitivity analysis) resulted in the same pooled effect.

2.1. Analysis.

Comparison 2: Fluoxetine versus light therapy, Outcome 1: Response (> 50% improvement on 24‐item HAM‐D SIGH‐SAD)

4.

Forest plot of comparison: Fluoxetine versus light therapy, outcome: 1.1 Response (> 50% improvement on 24‐item HAM‐D SIGH‐SAD).

2.2 Fifty per cent improvement on the HAM‐D

No data available.

Secondary outcomes

2.3 Clinical Global Impression – Improvement (CGI‐I) score of 1 or 2 (much improved or very much improved)

No data available.

1.4 Improvement of quality of life (QOL) as measured by a validated QOL tool

Data were available for health‐related quality of life from one trial with 96 participants (Lam 2006). The authors found little to no difference in improvement in quality of life between the fluoxetine and light therapy groups on two scales: the 20‐Item Short Form Health Survey (SF‐20) (fluoxetine group = mean change from baseline 9.38 (SD 14.39) versus light group = mean change from baseline 7.82 (standard deviation (SD) 15.49) ) the mean difference of mean changes from baseline was 1.56 (95% CI ‐4.42 to 7.54); and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q‐LES‐Q) (fluoxetine = mean change from baseline 21.77 (SD 17.04) versus light therapy = mean change from baseline 20.56 (SD 13.11)), mean difference of mean changes from baseline was 1.21 (‐4.87 to 7.29). We rated the certainty of evidence as low.

1.5 Remission, as defined by the study authors

Between 46% and 50% of participants in both study arms achieved remission (Ruhrmann 1998, Lam 2006). Heterogeneity for this outcome was high (I² = 61%), which may be attributed to greater difference in the rate of remission between the two groups in the smaller trial. Presumably this is a result of a very low number of participants in this trial (N = 40). The pooled risk ratio of remission is 0.91 (95% CI 0.64 to 1.30) (Analysis 2.2; Figure 5). We performed sensitivity analysis using a random‐effects model. The pooled result was similar: RR 0.81 (95% CI 0.39, 1.71). We rated the certainty of evidence as very low.

2.2. Analysis.

Comparison 2: Fluoxetine versus light therapy, Outcome 2: Remission (response plus end score 8 or less)

5.

Forest plot of comparison: Fluoxetine versus light therapy, outcome: 1.2 Remission (response plus end score 8 or less).

1.6 Speed of onset of response

No data available.

1.7 Occurrence of adverse events

Overall, similar numbers of participants in the fluoxetine and light therapy groups experienced an adverse event (75% in for fluoxetine versus 77% for light treatment, risk ratio 0.97, 95% CI 0.78 to 1.22, low‐certainty evidence; Lam 2006) (Analysis 2.3). The authors reported the number of cases of specific adverse events in each group, with differences between groups for only three adverse events (agitation, sleep disturbance, and palpitations, all worse with fluoxetine compared to placebo) (Analysis 2.4; Analysis 2.5; Analysis 2.6); however, the effect rate for all adverse events was low, and confidence intervals were very wide. Details on the number of adverse events in each group are provided in Table 8.

2.3. Analysis.

Comparison 2: Fluoxetine versus light therapy, Outcome 3: Harm: at least 1 treatment‐emergent adverse event

2.4. Analysis.

Comparison 2: Fluoxetine versus light therapy, Outcome 4: Harm: agitation

2.5. Analysis.

Comparison 2: Fluoxetine versus light therapy, Outcome 5: Harm: sleep disturbance

2.6. Analysis.

Comparison 2: Fluoxetine versus light therapy, Outcome 6: Harm: palpitations

Results for this comparison and the illustrative comparative risks are presented in Table 2.

3. SGAs versus other SGA

We did not find any eligible study for this comparison.

4. SGAs versus psychotherapy

We did not find any eligible study for this comparison.

Narrative summary of adverse events: bupropion, fluoxetine, escitalopram, duloxetine, nefazodone, reboxetine

We obtained controlled data on adverse events from two RCTs (Lam 1995; Lam 2006), and crude rates of specific adverse events from five observational studies (Dilsaver 1992; Pjrek 2007; Pjrek 2008; Pjrek 2009; Shen 2005), on fluoxetine (Lam 1995; Lam 2006), bupropion (Dilsaver 1992), escitalopram (Pjrek 2007), duloxetine (Pjrek 2008), nefazodone (Shen 2005), and reboxetine (Pjrek 2009). One RCT included for efficacy provided no evidence on adverse events (Ruhrmann 1998). The SGA arms of these studies involved a total of 169 participants; we obtained data regarding adverse events from 249 participants. Quantitative analysis of the comparative rates of adverse events between SGAs was not possible due to a lack of data, therefore a narrative overview of adverse events with crude rates for all of the included SGAs is presented here. It is important to note that the data presented here on adverse events are not robust, and any interpretation of the data needs to be undertaken with caution.

Overall, between 0% and 100% of participants in the SGA groups suffered an adverse event. Between 0% and 25% of participants withdrew from the study because of adverse events. An overview of all adverse events is provided in Table 8. The most common adverse events were: nausea (range 10% to 54%); diarrhoea (range 5% to 23%); sleep disturbance (range 8% to 44%); decreased sex drive (range 15% to 20%); dry mouth (range 11% to 86%); and psychomotor agitation (73% (data for reboxetine only)). Shen 2005 reported numerical results on sleep disturbance (insomnia), and reported generally that the most frequent adverse events at week 4 were headache, difficulty concentrating, dry mouth, and increased thirst without providing specific numbers, and that all had disappeared at eight weeks of study duration.

Discussion

Summary of main results

We aimed to assess the efficacy and safety of SGAs for the treatment of SAD in adults. In particular, we wanted to find and pool randomised trials of SGAs versus placebo to determine if SGAs are efficacious for SAD and to define the adverse events profile compared with placebo. Furthermore, we hoped to locate head‐to‐head studies of SGAs compared with other SGAs or with light therapy or psychotherapy to determine the comparative efficacy of SGAs.

We found evidence on only one SGA, fluoxetine. Based on the results of the single available RCT, it is not clear that fluoxetine is more efficacious than placebo for SAD. The risk ratio (RR) of depression response favours fluoxetine, but the confidence interval includes both a beneficial and no beneficial effect of fluoxetine (RR 1.62, 95% CI 0.92 to 2.83). We assessed the risk of bias for this trial as unclear in most domains, that is random sequence generation, allocation concealment, blinding, and attrition. The certainty of evidence for this effect is very low because the trial has an unclear risk of bias in most domains, and the effect is imprecise. There was an approximately equal occurrence of adverse events in the two groups; however, the reporting of adverse events in this study was poor (only an overall adverse event rate is reported). Future trials should seek to clarify the incidence of specific treatment‐emergent adverse events in participants with SAD receiving fluoxetine versus those receiving placebo. The results of this comparison are presented in Table 1.

Similarly, the pooled results from two RCTs of fluoxetine versus light therapy did not demonstrate superior response of either therapy (RR 0.98, 95% CI 0.77 to 1.24). We assessed the certainty of evidence as low, as risk of bias was high in one study, and imprecision was also high because the optimal information size was not achieved. Adverse events data were available from one of the trials, which showed generally similar proportions in both groups. The results of this comparison are presented in Table 2.

Overall, adverse events data were sparse, and no comparative analysis of the rates of adverse events between SGAs was possible (data on adverse events are presented in Table 8). Overall, 0 to 25% of participants treated with SGAs for SAD withdrew from the study early due to adverse events (across all studies 24 of 201). Because of the lack of evidence for the safety of SGAs when used for SAD, it may be reasonable to assume that SGAs have a similar adverse events profile when used in people with SAD and those suffering from major depressive disorder. One large systematic review of all SGAs for major depressive disorder provides evidence on the incidence of adverse events (Gartlehner 2008). Overall, 61% of participants in 80 trials reported at least one adverse event. The most common adverse events were constipation, diarrhoea, dizziness, insomnia, nausea, sexual adverse events, and somnolence.

Overall completeness and applicability of evidence

All three RCTs and the five non‐randomised studies included adult participants with moderate depression who met the DSM‐III or DSM‐IV criteria for SAD (depression with a seasonal pattern). The trials were conducted in North America (Canada and the USA) and Europe (Germany and Austria). Standard doses and method of administration of fluoxetine were used throughout. The studies varied between five and eight weeks in duration, which is an adequate time frame in which to see effects on response according to the German Depression Guideline (DGPPN 2015). In order to fully elucidate adverse events, a longer time period would probably have been necessary. The primary outcome of this review, response to treatment, was measured in all included RCTs. Overall, the available evidence is too weak to make robust conclusions. Furthermore, no head‐to‐head evidence on the comparative effectiveness of SGAs or a comparison with psychotherapy was available. Lastly, the data were too sparse to conduct any comparative quantitative analyses of adverse events.

Certainty of the evidence

For the comparison of fluoxetine with placebo, we graded the certainty of evidence for the outcomes treatment response and adverse events as very low. The certainty of the evidence was limited by the quality of the study because all domains but one were rated as unclear risk of bias). It was also limited by serious imprecision due to the small sample size and broad confidence intervals. No data were reported in the identified trial for our secondary outcomes (for details see Table 1).

For the second comparison, we included two RCTs of fluoxetine versus light therapy with a total of 136 participants. We rated the certainty of evidence as low for the outcome treatment response, due to a high risk of bias and imprecision (small sample size) in one study. For remission, we rated the certainty of evidence as very low. We rated down for inconsistency between the two pooled studies, imprecision, and because one study had a high risk of bias. For quality of life, we also assessed the certainty of evidence as very low. We rated down because of imprecision and indirectness and because no relative effect was calculated, so no direct comparison was possible. For adverse events, the certainty of the evidence was low because of very serious imprecision. No data were reported for our other secondary outcomes (for details see Table 2).

The non‐randomised studies included for the purpose of evaluating adverse event outcomes suffered high attrition and did not blind participants or outcome assessors. Our confidence in the results presented from these studies was very low because of their observational design, high risk of bias, and small study size (resulting in very serious imprecision).

Potential biases in the review process

We conducted extensive searches. Despite this, publication bias remains a threat for systematic reviews, and we cannot rule out the possibility that we may have missed some trials of SGAs conducted in participants with SAD.

We focused on SAD patients in the context of MDD and excluded studies with SAD patients with bipolar disorder. Therefore we also excluded the study by Moscovitch et al. (Moscovitch 2004) although the proportion of SAD patients with bipolar disorder was only 10%.  The results are in agreement with our results for the comparison of SGA vs. placebo. Moscovitch et al. compared sertraline with placebo and also  showed no statistical significant difference in response with 55.9% of participants achieving response in the sertraline group and 50% achieving response under placebo. A future update of this review might consider broadening the inclusion criteria to also include studies with a small proportion of bipolar SAD patients.

Agreements and disagreements with other studies or reviews

The first version of this review (Thaler 2011) came to the same conclusion as this update. A recent Health Technology Assessment also concluded that SGAs and light therapy show similar treatment effects (Nussbaumer‐Streit 2020). 

Authors' conclusions

Implications for practice.

Based on the results of the one available randomised controlled trial (RCT) for our first comparison, it is unclear whether fluoxetine is more efficacious than placebo for seasonal affective disorder (SAD). Clinicians should be aware that no RCT evidence supports the use of fluoxetine for SAD, and that further research is needed to establish the effects of fluoxetine for this disorder.

Similarly, the pooled results from two RCTs of fluoxetine versus light therapy did not demonstrate superiority of either therapy. Our findings show little difference in efficacy and safety between fluoxetine and light therapy. However, the currently available evidence is based on two small studies, which limits confidence in the findings.

In making treatment decisions, clinicians can discuss with patients what is known and not known about the risks and benefits of SGAs in treating SAD. Part of this discussion might include the information that SAD is seen as a subtype of MDD, where there is evidence of SGA efficacy (Gartlehner 2017).

Implications for research.

The current evidence base for the use of SGAs to treat SAD is very sparse. To demonstrate the efficacy and safety of fluoxetine and other SGAs compared with placebo, future trials should be sufficiently powered to detect true differences. Randomisation, allocation concealment, and attrition should be optimised and better reported. Well‐conducted, adequately powered, randomised, placebo‐controlled trials of other SGAs are also needed to demonstrate their efficacy for treating SAD, as none are currently available.

No randomised trial evidence supports the use of any SGA for SAD. Once the general efficacy of an SGA for SAD has been established, comparative (head‐to‐head) trials of the SGAs are needed to characterise the comparative efficacy between the SGAs and the comparison between SGAs and light therapy. Additional, much larger trials comparing fluoxetine and light therapy are required to clarify whether any clinically important differences exist between these two therapeutic approaches. New trials comparing SGAs and psychotherapy for SAD are also needed.

All future trials of SGAs for SAD should adequately and comprehensively capture the number and types of adverse events, ideally using a prespecified side‐effect rating scale. The allocation concealment in the trials included in this review was well‐conducted and could serve as a model for future researchers.

What's new

Date	Event	Description
26 February 2021	New search has been performed	We ran a new search on 29 January 2020 and added two additional non‐randomised controlled trials to the review.
26 February 2021	New citation required but conclusions have not changed	This update identified two additional non‐randomised controlled trials. No change in conclusions.

History

Protocol first published: Issue 7, 2010
Review first published: Issue 12, 2011

Appendices

Appendix 1. Efficacy ‐  search strategy

P11‐R11: Second‐generation antidepressants for seasonal affective disorder
Date of update search: 29 Jan 2020
Ovid MEDLINE (2011‐ onwards), n=61
Ovid Embase (2011 onwards), n=96
Ovid PsycINFO (2011 onwards), n=31
CCMDCTR (2011‐to June 2016), n=14
CENTRAL (not CCMDCTR) (Issue 1 of 12, 2020 (all years)), n=59
Total=261
Duplicates removed, n=93
To Screen, n=168
Database: Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations and Daily <1946 to January 28, 2020>
Search Strategy:
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
1 Seasonal Affective Disorder/ (1207)
2 (seasonal affective disorder* or seasonal depression or seasonal mood disorder* or winter depression or (season* adj5 (mood or depress* or affective disorder* or affective symptom*))).ti,ab,kf. (1962)
3 SIGH‐SAD.mp. (77)
4 or/1‐3 (2198)
5 exp Antidepressive Agents/ (146915)
6 exp Neurotransmitter Uptake Inhibitors/ (145052)
7 exp Monoamine Oxidase Inhibitors/ (21554)
8 (antidepress* or anti depress* or MAOI* or monoamine oxidase inhibit* or ((serotonin or norepinephrine or noradrenaline or nor epinephrine or nor adrenaline or neurotransmitt* or dopamine*) and (uptake or reuptake or re‐uptake)) or noradrenerg* or antiadrenergic or anti adrenergic or SSRI* or SNRI* or TCA* or tricyclic* or tetracyclic* or heterocyclic* or psychotropic* or second generation).ti,ab,kf. (194291)
9 (Agomelatine or Alaproclate or Amoxapine or Amineptine or Amitriptylin* or Amitriptylinoxide or Atomoxetine or Befloxatone or Benactyzine or Binospirone or Brofaromine or (Bupropion or Amfebutamone) or Butriptyline or Caroxazone or Cianopramine or Cilobamine or Cimoxatone or Citalopram or (Chlorimipramin* or Clomipramin* or Chlomipramin* or Clomipramine) or Clorgyline or Clovoxamine or (CX157 or Tyrima) or Demexiptiline or Deprenyl or (Desipramine* or Pertofrane) or Desvenlafaxine or Dibenzepin or Diclofensine or Dimetacrin* or Dosulepin or Dothiepin or Doxepin or Duloxetine or Desvenlafaxine or DVS‐233 or Escitalopram or Etoperidone or Femoxetine or Fluotracen or Fluoxetine or Fluvoxamine or (Hyperforin or Hypericum or St John*) or Imipramin* or Iprindole or Iproniazid* or Ipsapirone or Isocarboxazid* or Levomilnacipran or Lofepramine* or Lorpiprazole or (Lu AA21004 or Vortioxetine) or Lu AA24530 or (LY2216684 or Edivoxetine) or Maprotiline or Melitracen or Mepiprazole or Metapramine or Mianserin or Milnacipran or Minaprine or Mirtazapine or Moclobemide or Nefazodone or Nialamide or Nitroxazepine or Nomifensine or Norfenfluramine or Nortriptylin* or Noxiptilin* or Opipramol or Oxaflozane or Paroxetine or Phenelzine or Pheniprazine or Pipofezine or Pirlindole or Pivagabine or Pizotyline or Propizepine or Protriptylin* or Quinupramine or Reboxetine or Rolipram or Scopolamine or Selegiline or Sertraline or Setiptiline or Teciptiline or Thozalinone or Tianeptin* or Toloxatone or Tranylcypromin* or Trazodone or Trimipramine or (Tryptophan not depletion) or Venlafaxine or Viloxazine or Vilazodone or Vortioxetine or Viqualine or Zimelidine).mp. (160902)
10 or/5‐9 (422747)
11 4 and 10 (518)
12 controlled clinical trial.pt. (93545)
13 randomized controlled trial.pt. (499471)
14 clinical trials as topic/ (189963)
15 (randomi#ed or randomi#ation or randomi#ing).ti,ab,kf. (617786)
16 (RCT or "at random" or (random* adj3 (administ* or allocat* or assign* or class* or cluster or crossover or cross‐over or control* or determine* or divide* or division or distribut* or expose* or fashion or number* or place* or pragmatic or quasi or recruit* or split or subsitut* or treat*))).ti,ab,kf. (542215)
17 placebo.ab,ti,kf. (210513)
18 trial.ti. (212124)
19 (control* adj3 group*).ab. (521309)
20 (control* and (trial or study or group*) and (waitlist* or wait* list* or ((treatment or care) adj2 usual))).ti,ab,kf,hw. (24012)
21 ((single or double or triple or treble) adj2 (blind* or mask* or dummy)).ti,ab,kf. (170271)
22 double‐blind method/ or random allocation/ or single‐blind method/ (274817)
23 or/12‐22 (1682420)
24 exp animals/ not humans.sh. (4668261)
25 23 not 24 (1455867)
26 11 and 25 (177)
27 (2 or 3) and (8 or 9) (438)
28 (2011* or 2012* or 2013* or 2014* or 2015* or 2016* or 2017* or 2018* or 2019*).yr,dp,dt,ep,ez. (10253097)
29 26 and 28 (44)
30 (2 or 3) and (8 or 9) (438)
31 (SIGH‐SAD or seasonal affective disorder* or seasonal depression or seasonal mood disorder* or winter depression or (season* adj5 (mood or depress* or affective disorder* or affective symptom*))).ti. (1111)
32 30 or 31 (1329)
33 limit 32 to ("in data review" or in process or publisher) (21)
34 29 or 33 (61)
***************************
Database: Embase <1974 to 2020 Week 04>
Search Strategy:
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
1 seasonal affective disorder/ (1336)
2 (seasonal affective disorder* or seasonal depression or seasonal mood disorder* or winter depression or (season* adj5 (mood? or depress* or affective disorder* or affective symptom*))).ti,ab,kw. (2486)
3 SIGH‐SAD.mp. (94)
4 or/1‐3 (2925)
5 exp Antidepressant Agent/ (418012)
6 Serotonin Receptor Affecting Agent/ or Serotonin Uptake Inhibitor/ or Serotonin Noradrenalin Reuptake Inhibitor/ or Triple Reuptake inhibitor/ (49166)
7 Dopamine Receptor Affecting Agent/ or Dopamine Uptake Inhibitor/ (1584)
8 Adrenergic Receptor Affecting Agent/ or Noradrenalin Uptake Inhibitor/ (3756)
9 Neurotransmitter Uptake Inhibitors/ (165)
10 exp Monoamine Oxidase Inhibitor/ (43998)
11 (antidepress* or anti depress* or MAOI* or monoamine oxidase inhibit* or ((serotonin or norepinephrine or noradrenaline or nor epinephrine or nor adrenaline or neurotransmitt* or dopamine*) and (uptake or reuptake or re‐uptake)) or noradrenerg* or antiadrenergic or anti adrenergic or SSRI* or SNRI* or TCA* or tricyclic* or tetracyclic* or heterocyclic* or psychotropic* or second generation).ti,ab,kw. (262574)
12 (Agomelatine or Alaproclate or Amoxapine or Amineptine or Amitriptylin* or Amitriptylinoxide or Atomoxetine or Befloxatone or Benactyzine or Binospirone or Brofaromine or (Bupropion or Amfebutamone) or Butriptyline or Caroxazone or Cianopramine or Cilobamine or Cimoxatone or Citalopram or (Chlorimipramin* or Clomipramin* or Chlomipramin* or Clomipramine) or Clorgyline or Clovoxamine or (CX157 or Tyrima) or Demexiptiline or Deprenyl or (Desipramine* or Pertofrane) or Desvenlafaxine or Dibenzepin or Diclofensine or Dimetacrin* or Dosulepin or Dothiepin or Doxepin or Duloxetine or Desvenlafaxine or DVS‐233 or Escitalopram or Etoperidone or Femoxetine or Fluotracen or Fluoxetine or Fluvoxamine or (Hyperforin or Hypericum or St John*) or Imipramin* or Iprindole or Iproniazid* or Ipsapirone or Isocarboxazid* or Levomilnacipran or Lofepramine* or Lorpiprazole or (Lu AA21004 or Vortioxetine) or Lu AA24530 or (LY2216684 or Edivoxetine) or Maprotiline or Melitracen or Mepiprazole or Metapramine or Mianserin or Milnacipran or Minaprine or Mirtazapine or Moclobemide or Nefazodone or Nialamide or Nitroxazepine or Nomifensine or Norfenfluramine or Nortriptylin* or Noxiptilin* or Opipramol or Oxaflozane or Paroxetine or Phenelzine or Pheniprazine or Pipofezine or Pirlindole or Pivagabine or Pizotyline or Propizepine or Protriptylin* or Quinupramine or Reboxetine or Rolipram or Scopolamine or Selegiline or Sertraline or Setiptiline or Teciptiline or Thozalinone or Tianeptin* or Toloxatone or Tranylcypromin* or Trazodone or Trimipramine or (Tryptophan not depletion) or Venlafaxine or Viloxazine or Vilazodone or Vortioxetine or Viqualine or Zimelidine).mp. (302825)
13 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 (654477)
14 randomized controlled trial/ (588097)
15 randomization.de. (85764)
16 controlled clinical trial/ and (Disease Management or Drug Therapy or Prevention or Rehabilitation or Therapy).fs. (253732)
17 *clinical trial/ (17572)
18 placebo.de. (346438)
19 placebo.ti,ab. (300490)
20 trial.ti. (290116)
21 (randomi#ed or randomi#ation or randomi#ing).ti,ab,kw. (887867)
22 (RCT or "at random" or (random* adj3 (administ* or allocat* or assign* or class* or cluster or control* or crossover or cross‐over or determine* or divide* or division or distribut* or expose* or fashion or number* or place* or pragmatic or quasi or recruit* or split or subsitut* or treat*))).ti,ab,kw. (743549)
23 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$ or dummy)).mp. (302372)
24 (control* and (study or group?) and (waitlist* or wait* list* or ((treatment or care) adj2 usual))).ti,ab,kw,hw. (37575)
25 or/14‐24 (1687835)
26 ((animal or nonhuman) not (human and (animal or nonhuman))).de. (5594099)
27 25 not 26 (1534906)
28 4 and 13 and 27 (259)
29 (2011* or 2012* or 2013* or 2014* or 2015* or 2016* or 2017* or 2018* or 2019* or 2020*).yr,dp,dc. (14007681)
30 28 and 29 (96)
***************************
Database: PsycINFO <1806 to January Week 3 2020>
Search Strategy:
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
1 seasonal affective disorder/ (1059)
2 (seasonal affective disorder* or seasonal depression or seasonal mood disorder* or winter depression or (season* adj5 (mood? or depress* or affective disorder* or affective symptom*))).ti,ab,id. (1721)
3 SIGH‐SAD.mp. (70)
4 1 or 2 or 3 (1791)
5 Psychopharmacology/ or Neuropsychopharmacology/ (9190)
6 "3340".cc. (76250)
7 exp Antidepressant Drugs/ (37978)
8 Neurotransmitter Uptake Inhibitors/ or exp serotonin norepinephrine reuptake inhibitors/ or exp serotonin reuptake inhibitors/ (13376)
9 exp Monoamine Oxidase Inhibitors/ (2227)
10 exp Tricyclic Antidepressant Drugs/ (6368)
11 (antidepress* or anti depress* or MAOI* or monoamine oxidase inhibit* or ((serotonin or norepinephrine or noradrenaline or nor epinephrine or nor adrenaline or neurotransmitt* or dopamine*) and (uptake or reuptake or re‐uptake)) or noradrenerg* or antiadrenergic or anti adrenergic or SSRI* or SNRI* or TCA* or tricyclic* or tetracyclic* or heterocyclic* or psychotropic* or second generation).mp. (84233)
12 Drug Therapy/ (134452)
13 (Agomelatine or Alaproclate or Amoxapine or Amineptine or Amitriptylin* or Amitriptylinoxide or Atomoxetine or Befloxatone or Benactyzine or Binospirone or Brofaromine or (Bupropion or Amfebutamone) or Butriptyline or Caroxazone or Cianopramine or Cilobamine or Cimoxatone or Citalopram or (Chlorimipramin* or Clomipramin* or Chlomipramin* or Clomipramine) or Clorgyline or Clovoxamine or (CX157 or Tyrima) or Demexiptiline or Deprenyl or (Desipramine* or Pertofrane) or Desvenlafaxine or Dibenzepin or Diclofensine or Dimetacrin* or Dosulepin or Dothiepin or Doxepin or Duloxetine or Desvenlafaxine or DVS‐233 or Escitalopram or Etoperidone or Femoxetine or Fluotracen or Fluoxetine or Fluvoxamine or (Hyperforin or Hypericum or St John*) or Imipramin* or Iprindole or Iproniazid* or Ipsapirone or Isocarboxazid* or Levomilnacipran or Lofepramine* or Lorpiprazole or (Lu AA21004 or Vortioxetine) or Lu AA24530 or (LY2216684 or Edivoxetine) or Maprotiline or Melitracen or Mepiprazole or Metapramine or Mianserin or Milnacipran or Minaprine or Mirtazapine or Moclobemide or Nefazodone or Nialamide or Nitroxazepine or Nomifensine or Norfenfluramine or Nortriptylin* or Noxiptilin* or Opipramol or Oxaflozane or Paroxetine or Phenelzine or Pheniprazine or Pipofezine or Pirlindole or Pivagabine or Pizotyline or Propizepine or Protriptylin* or Quinupramine or Reboxetine or Rolipram or Scopolamine or Selegiline or Sertraline or Setiptiline or Teciptiline or Thozalinone or Tianeptin* or Toloxatone or Tranylcypromin* or Trazodone or Trimipramine or (Tryptophan not depletion) or Venlafaxine or Viloxazine or Vilazodone or Vortioxetine or Viqualine or Zimelidine).ti,ab,id,hw. (39083)
14 or/5‐13 (206840)
15 clinical trials.sh. (11551)
16 (randomi#ed or randomi#ation or randomi#ing).ti,ab,id. (83338)
17 (RCT or at random or (random* adj3 (administ* or allocat* or assign* or class* or control* or crossover or cross‐over or determine* or divide* or division or distribut* or expose* or fashion or number* or place* or recruit* or split or subsitut* or treat*))).ti,ab,id. (99506)
18 (control* and (trial or study or group) and (placebo or waitlist* or wait* list* or ((treatment or care) adj2 usual))).ti,ab,id,hw. (28435)
19 ((single or double or triple or treble) adj2 (blind* or mask* or dummy)).ti,ab,id. (25785)
20 trial.ti. (29370)
21 placebo.ti,ab,id,hw. (39623)
22 treatment outcome.md. (20101)
23 treatment effectiveness evaluation.sh. (23786)
24 mental health program evaluation.sh. (2095)
25 or/15‐24 (191317)
26 4 and 14 and 25 (122)
27 (2011* or 2012* or 2013* or 2014* or 2015* or 2016* or 2017* or 2018* or 2019* or 2020*).yr,an. (1708381)
28 26 and 27 (31)
***************************
Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (2011‐June‐2016)
#1 (SIGH‐SAD or "seasonal affective disorder*" or "seasonal depression" or "seasonal mood disorder*" or "winter depression" or (season* NEAR (mood or depress* or affective disorder* or affective symptom*))) AND INREGISTER
#2 (antidepress* or "anti depress*" or MAOI* or "monoamine oxidase inhibit*" or ((serotonin or norepinephrine or noradrenaline or nor epinephrine or nor adrenaline or neurotransmitt* or dopamine*) and (uptake or reuptake or re‐uptake)) or noradrenerg* or antiadrenergic or "anti adrenergic" or SSRI* or SNRI* or TCA* or tricyclic* or tetracyclic* or heterocyclic* or psychotropic* or "second generation") AND INREGISTER
#3 (Agomelatine or Alaproclate or Amoxapine or Amineptine or Amitriptylin* or Amitriptylinoxide or Atomoxetine or Befloxatone or Benactyzine or Binospirone or Brofaromine or (Bupropion or Amfebutamone) or Butriptyline or Caroxazone or Cianopramine or Cilobamine or Cimoxatone or Citalopram or (Chlorimipramin* or Clomipramin* or Chlomipramin* or Clomipramine) or Clorgyline or Clovoxamine or (CX157 or Tyrima) or Demexiptiline or Deprenyl or (Desipramine* or Pertofrane) or Desvenlafaxine or Dibenzepin or Diclofensine or Dimetacrin* or Dosulepin or Dothiepin or Doxepin or Duloxetine or Desvenlafaxine or DVS‐233 or Escitalopram or Etoperidone or Femoxetine or Fluotracen or Fluoxetine or Fluvoxamine or (Hyperforin or Hypericum or "St John*") or Imipramin* or Iprindole or Iproniazid* or Ipsapirone or Isocarboxazid* or Levomilnacipran or Lofepramine* or Lorpiprazole or (Lu AA21004 or Vortioxetine) or Lu AA24530 or (LY2216684 or Edivoxetine) or Maprotiline or Melitracen or Mepiprazole or Metapramine or Mianserin or Milnacipran or Minaprine or Mirtazapine or Moclobemide or Nefazodone or Nialamide or Nitroxazepine or Nomifensine or Norfenfluramine or Nortriptylin* or Noxiptilin* or Opipramol or Oxaflozane or Paroxetine or Phenelzine or Pheniprazine or Pipofezine or Pirlindole or Pivagabine or Pizotyline or Propizepine or Protriptylin* or Quinupramine or Reboxetine or Rolipram or Scopolamine or Selegiline or Sertraline or Setiptiline or Teciptiline or Thozalinone or Tianeptin* or Toloxatone or Tranylcypromin* or Trazodone or Trimipramine or (Tryptophan not depletion) or Venlafaxine or Viloxazine or Vilazodone or Vortioxetine or Viqualine or Zimelidine) AND INREGISTER
#4 #2 OR #3
#5 #1 AND #4 (115)
Limited to 2011 onwards, n=14

N.B. The CCMDCTR is now an archived resource.  The rationale of maintaining a comprehensive specialised register was reviewed when the editorial group moved from the University of Bristol to the University of York in the summer of 2016. At this time the Group decided to  return to searching the medical and psychological literature directly, on a review‐by‐review basis.
***************************
Cochrane Register of Controlled Trials (CENTRAL) on the Cochrane Library (Issue 1 of 12, January 2020)
#1(SIGH‐SAD or "seasonal affective disorder" or "seasonal affective disorders" or "seasonal depression" or "seasonal mood disorder" or "seasonal mood disorders" or "winter depression" or (season* NEAR (mood or depress* or (affective next disorder*) or (affective next symptom*))))
#2 (antidepress* or (anti next depress*) or MAOI* or ("monoamine oxidase" next inhibit*) or ((serotonin or norepinephrine or noradrenaline or "nor epinephrine" or "nor adrenaline" or neurotransmitt* or dopamine*) and (uptake or reuptake or re‐uptake)) or noradrenerg* or antiadrenergic or "anti adrenergic" or SSRI* or SNRI* or TCA* or tricyclic* or tetracyclic* or heterocyclic* or psychotropic* or "second generation")
#3 (Agomelatine or Alaproclate or Amoxapine or Amineptine or Amitriptylin* or Amitriptylinoxide or Atomoxetine or Befloxatone or Benactyzine or Binospirone or Brofaromine or (Bupropion or Amfebutamone) or Butriptyline or Caroxazone or Cianopramine or Cilobamine or Cimoxatone or Citalopram or (Chlorimipramin* or Clomipramin* or Chlomipramin* or Clomipramine) or Clorgyline or Clovoxamine or (CX157 or Tyrima) or Demexiptiline or Deprenyl or (Desipramine* or Pertofrane) or Desvenlafaxine or Dibenzepin or Diclofensine or Dimetacrin* or Dosulepin or Dothiepin or Doxepin or Duloxetine or Desvenlafaxine or DVS‐233 or Escitalopram or Etoperidone or Femoxetine or Fluotracen or Fluoxetine or Fluvoxamine or (Hyperforin or Hypericum or "St John*") or Imipramin* or Iprindole or Iproniazid* or Ipsapirone or Isocarboxazid* or Levomilnacipran or Lofepramine* or Lorpiprazole or (Lu AA21004 or Vortioxetine) or Lu AA24530 or (LY2216684 or Edivoxetine) or Maprotiline or Melitracen or Mepiprazole or Metapramine or Mianserin or Milnacipran or Minaprine or Mirtazapine or Moclobemide or Nefazodone or Nialamide or Nitroxazepine or Nomifensine or Norfenfluramine or Nortriptylin* or Noxiptilin* or Opipramol or Oxaflozane or Paroxetine or Phenelzine or Pheniprazine or Pipofezine or Pirlindole or Pivagabine or Pizotyline or Propizepine or Protriptylin* or Quinupramine or Reboxetine or Rolipram or Scopolamine or Selegiline or Sertraline or Setiptiline or Teciptiline or Thozalinone or Tianeptin* or Toloxatone or Tranylcypromin* or Trazodone or Trimipramine or (Tryptophan not depletion) or Venlafaxine or Viloxazine or Vilazodone or Vortioxetine or Viqualine or Zimelidine)
#4 (#1 AND (#2 OR #3)
#5 SR‐DEPRESSN OR HS‐DEPRESSN
#6 (#4 NOT #5), n=59 (all years)
************************************************************************************************************

Appendix 2. Adverse events ‐  search strategy

P11: Second Generation Antidepressants for Seasonal Affective Disorder Adverse Events

Cross‐search of OVID MEDLINE, EMBASE, PsycINFO

1. SAFETY/

2. COMPLICATION/

3. DRUG SAFETY/

4. PATIENT SAFETY/

5. ADVERSE OUTCOME/

6. TREATMENT CONTRAINDICATION/

7. exp SIDE EFFECT/

8. exp "SIDE EFFECTS (treatment)"/

9. (safety or adverse or tolerability or tolerance or tolerat* or harm or harms or harmful or injur* or damage* or impair* complication* or risk or risks).tw.

10. (side effect* or treatment emergent or undesirable effect*).tw.

11. (suicid* or death*).mp.

12. ae.fs. [Adverese Effects ‐ MEDLINE; Adverse Drug Recation ‐ EMBASE]]

13. to.fs. [Toxicity – MEDLINE; Drug Toxicity ‐ EMBASE]

14. ct.fs. [Contraindications ‐ MEDLINE]

15. or/1‐14

16. SEASONAL AFFECTIVE DISORDER/

17. (seasonal affective disorder* or seasonal depression or seasonal mood disorder* or winter depression or (season* adj5 (mood or depress* or affective disorder* or affective symptom*))).tw.

18. or/16‐17

19. antidepress*.mp.

20. (agomelatine or bupropion or amfebutamone or brofaromine or citalopram or desvenlafaxine or duloxetine or escitalopram or fluoxetine or fluvoxamine or milnacipran or mirtazipine or nefazodone or paroxetine or reboxetine or sertraline or trazodone or venlafaxine or zimeldine or SSRI* or SNRI* or second generation).mp.

21. ((serotonin or norepinephrine or noradrenaline or neurotransmitter or monoamine or dopamine) and (uptake or reuptake or re‐uptake)).tw.

22. dt.fs. [Drug Therapy MEDLINE & EMBASE]

22. or/19‐22

23. 15 and 18 and 22

24. remove duplicates from 24

[Updated 21‐Feb‐2020, n=179]

Appendix 3. Searches to 2011

Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR)(previously known as the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR))

The CCDAN registers were searched (26 August 2011) using the following terms:

1. CCDANCTR‐Studies Register

Condition (alone) = “seasonal affective disorder” or “winter depression”

Records were screened for trials involving second‐generation antidepressants.

2. CCDANCTR‐References Register

Title, Abstract, Keywords = (“seasonal affective disorder*” or “seasonal depression” or “seasonal mood disorder*” or “winter depression” or "SAD")

AND

Title, Abstract, Keywords = (((serotonin or norepinephrine or noradrenaline or neurotransmitter or monoamine) and (uptake or reuptake or re‐uptake)) or SSRI* or SNRI* or agomelatine or brofaromine or bupropion or citalopram or desvenlafaxine or dopamin* or duloxetine or escitalopram or fluoxetine or fluvoxamine or maprotiline or milnacipran or mirtazipine or moclobemide or nefazodone or paroxetine or reboxetine or ritanserin or sertraline or trazodone or venlafaxine or viloxazine or zimeldine or 5‐hydroxytrypotophan or 5‐HT or antidepressant* or pharma* or medicat*)

At the time the CCMD/CCDAN maintained two clinical trials registers at their editorial base in Bristol, UK: a references register and a studies based register. The CCDANCTR‐References Register contained over 27,500 bibliographic references to completed or ongoing trials for the treatment or prevention of depression, anxiety and neurosis. Approximately 65% of the references had been tagged to individually coded trials held in the CCDANCTR‐Studies Register. Records were linked between the two registers through the use of unique Study ID tags. Coding of trials iwas based on the EU‐Psi coding manual, please contact CCDAN's Trials Search Co‐ordinator for further details. References to trials for inclusion in the Group's registers were collated from routine (weekly), generic searches of MEDLINE (1950‐), EMBASE (1974‐) and PsycINFO (1967‐); quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL) and review‐specific searches of additional databases (PSYNDEX, LILACS, AMED, CINAHL). Details of trials were also sourced from international trial registries, pharmaceutical industry trials registers, the handsearching of key journals, conference proceedings and other (non‐Cochrane) systematic reviews and meta‐analyses. Details of the generic search strategies which were used to inform the register can be found on the Group's website.

Data and analyses

Comparison 1. Fluoxetine versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Response (> 50% improvement on 29‐item HAM‐D SIGH‐SAD)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.2 Harm: overall adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 2. Fluoxetine versus light therapy.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Response (> 50% improvement on 24‐item HAM‐D SIGH‐SAD)	2	136	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.77, 1.24]
2.2 Remission (response plus end score 8 or less)	2	136	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.64, 1.30]
2.3 Harm: at least 1 treatment‐emergent adverse event	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4 Harm: agitation	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.5 Harm: sleep disturbance	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.6 Harm: palpitations	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Dilsaver 1992.

Study characteristics
Methods	Open‐label observational study, duration of study and treatment period: 5 weeks, single‐centre study in an outpatient clinic in the USA. Enrolment over 1 winter period (1 December to 28 February, year not specified).
Participants	N = 15, mean age was 33.9 years, 80% were female, suffering recurrent major depressive episodes with a seasonal pattern (DSM‐III‐R). No further eligibility criteria reported.
Interventions	Open‐label bupropion, 200 to 400 mg/day; no control group
Outcomes	The only outcome of interest for the purposes of this review was adverse events (this study did not fulfil our inclusion criteria for efficacy as it is not a randomised trial). The authors mentioned adverse events, but did not specify how and when adverse events were measured.
Notes	Supported by National Institute of Mental Health grant
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	"a consecutive series of 15 patients were treated with this agent" (Dilsaver 1992) This is an observational study with only 1 group.
Allocation concealment (selection bias)	High risk	"were all offered treatment with bupropion" (Dilsaver 1992) This is an open‐label study.
Incomplete outcome data (attrition bias) All outcomes	High risk	33% of participants had no efficacy measurement. Unclear for how many participants adverse events were measured (
Other bias	High risk	Additional 'Risk of bias' assessment as per Deeks 2003, see Table 3. This study contains a small number of participants, which is a likely source of bias. Only the intervention but not the outcomes of interest for this review (adverse events) is clearly specified.
Blinding of participants and personnel (performance bias) All outcomes	High risk	"were all offered treatment with bupropion" (Dilsaver 1992) This is an open‐label study.
Blinding of outcome assessment (detection bias) All outcomes	High risk	"were all offered treatment with bupropion" (Dilsaver 1992) This is an open‐label study.

Lam 1995.

Study characteristics
Methods	Randomised controlled trial (parallel design), study duration: 6 weeks, treatment duration 5 weeks (1‐week placebo wash‐out phase with exclusion of responders, then randomisation and a 5‐week treatment period). Multicentre study in 5 outpatient clinics in Canada. Enrolment over 2 years between 1991 and 1993 during winter seasons (15 October to 28 February)
Participants	N = 68, mean age in fluoxetine group 40.9 years (± 8.6), in placebo group 38.1 years (± 9.7), 66% female. Recurrent major depressive episodes with a seasonal pattern (DSM‐III‐R) was an inclusion criterion. Individuals were excluded in case of pregnancy or lactation, unstable convulsions or serious medical illness, serious active suicide risk, DSM‐III‐R diagnosis of organic mental disorder, alcohol or drug abuse, psychotic disorders, panic disorder, generalised anxiety disorder, bipolar disorder, use of psychotropic drugs, previous use of fluoxetine, use of heterocyclic antidepressants 7 days or monoamine oxidase inhibitors within 14 days prior study inclusion, current use of light therapy or psychotherapy.
Interventions	Fluoxetine (n = 36): 20 mg per day  Placebo (n = 32): 1 placebo pill per day
Outcomes	Response to treatment: greater than 50% improvement in baseline score as per the 29‐item SIGH‐SAD, 21‐item HAM‐D, and BDI, assessed at every visit (week 1, 2, 3, 4, 5) Adverse events, assessed at every visit (week 1, 2, 3, 4, 5)
Notes	Funded by Eli Lilly, Canada, Inc.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"eligible patients were randomly assigned to either fluoxetine, 20 mg daily, or an identical placebo capsule" (Lam 1995) Unclear what method of sequence generation was used
Allocation concealment (selection bias)	Unclear risk	This is not reported.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	The number of participants who did not complete the trial is not reported; however, the authors state that they conducted analyses "using the intention‐to‐treat last‐observation‐carried‐forward method" (Lam 1995)
Selective reporting (reporting bias)	Unclear risk	No study protocol is available; however, all of the outcomes that are described in the methods section are reported clearly and in detail.
Other bias	Low risk	None
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	This is unclear. The trial is described as being "double‐blind" (Lam 1995)
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	This is unclear. The trial is described as being "double‐blind" (Lam 1995)

Lam 2006.

Study characteristics
Methods	Randomised controlled trial, parallel design. Study duration: 9 weeks, treatment duration 8 weeks: 1‐week wash‐out of placebo responders with subsequent randomisation and an 8‐week treatment period. Multicentre trial in 4 outpatient clinics in Canada. Enrolment over 3 years during autumn/winter months (September 15 ‐ February 15) between 2000 and 2003.
Participants	N = 96. Mean age in light therapy group: 42.3 years (± 9.2), in fluoxetine group: 44.6 years (±11.3); 64.6% female in light therapy group, 68.6% female in fluoxetine group. Eligible individuals suffered recurrent major depressive episodes with a seasonal pattern according to the structured clinical interview for DSM‐IV and were aged 18 to 65 years.  Exclusion criteria were: pregnancy / lactation, serious suicidal risk, organic mental disorders, substance use within one year prior beginning of the study, other psychiatric disorders (e.g., schizophrenia, panic disorder), serious unstable medical illness, retinal disease, severe allergies or history of multiple drug adverse reactions, use of other psychotropic drugs, use of beta‐blockers, use of mood‐altering medications within 7 days of baseline, previous treatment with light therapy or fluoxetine, undergone psychotherapy 3 months prior to baseline, shift work, travelled south during protocol.
Interventions	Light therapy: 10,000 lux, 14 inches between screen and cornea for 30 minutes as soon as possible after waking (between 7:00 am and 8:00 am) with a placebo capsule Fluoxetine: 20 mg/day taken between 7:00 am and 8:00 am and placebo light box of 100 lux
Outcomes	Response: improvement of 50% or more on the 24‐item HAM‐D (consisting of the 17‐item HAM‐D scale, plus 7 atypical symptoms). Remission: clinical response plus an end score of 8 or less. Adverse events: captured using a predefined list of adverse events; both severity and frequency of treatment‐emergent adverse events were captured.
Notes	This is the Can‐SAD study, from which multiple publications have been produced, including Michalak 2007 on quality of life outcomes. This study was funded by a grant (CT62962) from the Canadian Institutes of Health Research  and a Canadian Institutes of Health Research /Wyeth Postdoctoral Fellowship Award to Dr Michalak. Light boxes were supplied by Uplift Technologies.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization codes were centrally computer generated and stratified by site in random blocks of 3–5" (Lam 2006)
Allocation concealment (selection bias)	Low risk	"Allocation concealment used opaque envelopes at each site that could only be opened after the unique subject number was entered in a master log" (Lam 2006)
Incomplete outcome data (attrition bias) All outcomes	Low risk	Light therapy: 16.7% dropouts; fluoxetine: 14.5% (calculated from Lam 2006)
Selective reporting (reporting bias)	Unclear risk	No study protocol available.
Other bias	Low risk	No other bias detected.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"In this study, the placebo light treatment was an identical light box fitted with a neutral density gel filter to reduce light exposure to 100 lux" (Lam 2006)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"The primary outcome measure was the 24‐item Hamilton depression scale score obtained by board‐certified psychiatrists blind to treatment assignment (the blind was maintained by having a separate research assistant managing the light device treatment and asking patients not to discuss side effects or specifics of treatment with the rater)." (Lam 2006)

Pjrek 2007.

Study characteristics
Methods	Open‐label observational study (drug surveillance), study duration and treatment period: 8 weeks. Single‐centre study at an outpatient clinic in Austria. Recruitment period between November 2005 and January 2006.
Participants	N=20, mean age: 40.8 years (± 13.4), 70% were female. Participants had SAD (DSM‐IV‐TR criteria) with a score of 20 or higher on the SIGH‐SAD, 29 items.  Patients with sub‐syndromal SAD or with psychiatric co‐morbidity were excluded, as well as patients who were suicidal, had severe physical illness, had received treatment wit psychotropic drugs during the last 2 weeks, treated with bright light therapy during the last 2 weeks, undergoing formal psychotherapy, or had known treatment resistance to SSRIs.
Interventions	Open‐label escitalopram, flexible dose 10 to 20 mg/day for 8 weeks
Outcomes	The only outcome of interest for the purposes of this review was adverse events (this study did not fulfil our inclusion criteria for efficacy as it is not a randomised trial). Adverse events were monitored at week 1, 2, 4, 6, and 8 using the UKU Side Effect Rating Scale.
Notes	Only the data for adverse events are reported in this review. This study was supported by an unrestricted grant from H. Lundbeck A / S.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	This is an observational study with only 1 group (Pjrek 2007)
Allocation concealment (selection bias)	High risk	This is an open‐label study (Pjrek 2007)
Incomplete outcome data (attrition bias) All outcomes	Low risk	2 out of 20 participants withdrew from the study at week 6 (10%). This level of attrition is unlikely to have resulted in a high risk of bias for the adverse events results of the study (Pjrek 2007)
Selective reporting (reporting bias)	Unclear risk	No protocol available.
Other bias	High risk	Additional 'Risk of bias' assessment as per Deeks 2003, see Table 4. This study contains a small number of participants, which is a likely source of bias.
Blinding of participants and personnel (performance bias) All outcomes	High risk	This is an open‐label study (Pjrek 2007)
Blinding of outcome assessment (detection bias) All outcomes	High risk	This is an open‐label study (Pjrek 2007)

Pjrek 2008.

Study characteristics
Methods	Open‐label observational study (drug surveillance), study and treatment duration: 8 weeks. Single‐centre study in 1 outpatient clinic in Austria. Recruitment during second week of October and the first week of December 2006.
Participants	N = 26, mean age 41.4 years (±12.6), 85% female. Participants were included if they had SAD (DSM‐IV‐TR criteria).  Exclusion reasons were: sub‐syndromal SAD, current psychiatric co‐morbidity, being suicidal or psychotic, severe physical illness, having already received treatment (medication, light therapy, psychotherapy) during this depressive episode, known treatment resistance.
Interventions	Open‐label duloxetine, flexible dose 60 to 120 mg/ day for 8 weeks
Outcomes	The only outcome of interest for the purposes of this review was adverse events (this study did not fulfil our inclusion criteria for efficacy as it is not a randomised trial). Adverse events were monitored at week 1, 2, 4, 6, and 8 using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale.
Notes	Only the data for adverse events are reported in this review. Dr Kasper has received research grants, consultancy fees, and lecture fees from a number of pharmaceutical companies in the area of CNS development. Dr Konstantinidis and Dr Winkler have received lecture fees from several pharmaceutical companies in the field. The authors of this study have been supported by various travel grants.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	This is an observational study with only 1 group (Pjrek 2008)
Allocation concealment (selection bias)	High risk	This is an open‐label study (Pjrek 2008)
Incomplete outcome data (attrition bias) All outcomes	High risk	6 out of 26 participants withdrew from the study (23%). This level of attrition is likely to have resulted in a high risk of bias for the adverse events results of the study (Pjrek 2008)
Selective reporting (reporting bias)	Unclear risk	No protocol available.
Other bias	High risk	Additional 'Risk of bias' assessment as per Deeks 2003, see Table 5. This study contains a small number of participants, which is a likely source of bias. Interpretation of the results is not accurate due to high attrition and use of "last observation carried forward" approach for missing data (Pjrek 2008)
Blinding of participants and personnel (performance bias) All outcomes	High risk	This is an open‐label study (Pjrek 2008)
Blinding of outcome assessment (detection bias) All outcomes	High risk	This is an open‐label study (Pjrek 2008)

Pjrek 2009.

Study characteristics
Methods	Open‐label observational study (drug surveillance). Pooled results of escitalopram (from Pjrek 2007) and reboxetine. Data presented here are for the reboxetine group. Study and treatment duration: 6 weeks. Single‐centre study at outpatient clinic in Austria. Recruitment period not specified.
Participants	N = 15, mean age 41.6 years (± 9.6), 86.7% female. Participants had SAD (DSM‐IV‐TR criteria).  Exclusion reasons: psychiatric comorbidtiy, severe somatic illness
Interventions	Open‐label reboxetine, 8 mg/day for 6 weeks
Outcomes	The only outcome of interest for the purposes of this review was adverse events (this study did not fulfil our inclusion criteria for efficacy as it is not a randomised trial). Adverse events were monitored at week 1, 2, 4, and 6 using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale.
Notes	Only the data for adverse events are reported in this review. The authors report no funding source for this study, although they have received multiple grants and research support as well as consultancy and advisory board payments.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	This is an observational study with only 1 group (Pjrek 2009)
Allocation concealment (selection bias)	High risk	This is an open‐label study (Pjrek 2009)
Incomplete outcome data (attrition bias) All outcomes	High risk	6 out of 26 participants withdrew from the study (23%). This level of attrition is likely to have resulted in a high risk of bias for the adverse events results of the study (Pjrek 2009)
Selective reporting (reporting bias)	Unclear risk	No protocol available.
Other bias	High risk	Additional 'Risk of bias' assessment as per Deeks 2003, see Table 6. This study contains a small number of participants, which is a likely source of bias. Interpretation of the results is not accurate due to high attrition and use of "last observation carried forward" approach for missing data (Pjrek 2009)
Blinding of participants and personnel (performance bias) All outcomes	High risk	This is an open‐label study (Pjrek 2009)
Blinding of outcome assessment (detection bias) All outcomes	High risk	This is an open‐label study (Pjrek 2009)

Ruhrmann 1998.

Study characteristics
Methods	Randomised controlled trial (parallel design), study duration: 6 weeks, treatment duration: 5 weeks (1 week of placebo, followed by 5 weeks of treatment), single‐centre trial, outpatient clinic, Germany. Enrolment ranged from 22 October to 5 February (year not specified).
Participants	N = 40 (42 were recruited to placebo phase, 40 moved on to the treatment phase of the study); mean age in bright‐light group: 39.4 years (± 11.0), in fluoxetine group: 41.9 (± 10.3); proportion of females: 78%. Participants had to fulfil criteria for major depression with a seasonal pattern (DSM‐III‐R).   Individuals were excluded if they were at serious suicidal risk, had concurrent clinically significant medical unstable illness, abnormalities in haematology or liver function, eye diseases, intake of reserpine, clonidine, alpha‐methyl‐dopa, or guanethidine, concomitant organic brain disease, history of seizures, drug or alcohol addiction or psychosis within the 6 months prior to study, use of monoamine oxidase inhibitors, anticonvulsants, or neuroleptics within 2 weeks prior to study or depot neuroleptics 4 weeks prior to study.
Interventions	Fluoxetine group (n = 20): fluoxetine 20 mg per day with dim light Bright‐light group (n = 20): light therapy 3000 lux, 2 hours per day (2 hours in the morning, 1 hour each in the morning and evening, or 2 hours in the evening) at a distance of 55 cm and a placebo capsule
Outcomes	Response to treatment: reduction of 21‐item HDRS (item 17 omitted) and the 7‐item supplement (SUPP) from the beginning of treatment to at least 50% at end of treatment Remission: a score reduction of 50% or higher, and (1) a score of 7 or less on the HDRS and on the HDRS‐Supplement for SAD; or (2) 2 or lower on the HDRS and 10 or lower on the HDRS‐Supplement for SAD at the end of treatment
Notes	This study was supported by a grant from Eli Lilly, Germany.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"were randomly assigned to the two treatment groups" (Ruhrmann 1998)
Allocation concealment (selection bias)	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	High risk	"During phase II, four BL patients (one responder, three non‐responders) and one FLU patient (a non‐responder) dropped out" (Ruhrmann 1998) Overall 12% attrition, unequal between groups: 20% (4/20) in the bright‐light group and 5% (1/20) in the fluoxetine group
Selective reporting (reporting bias)	Unclear risk	No protocol is available. All outcomes described in the methods section are reported in the results.
Other bias	Low risk	None
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"rater and patients blind to treatment conditions"; "treatment conditions were unknown to the patients" (Ruhrmann 1998)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"rater and patients blind to treatment conditions"; "all objective observer rating were done by one rater blind to study design and treatment conditions" (Ruhrmann 1998)

Shen 2005.

Study characteristics
Methods	Open‐label observational study, 8 weeks' study duration, 8‐week treatment period, single‐centre in Canada. Enrolment period not specified.
Participants	N = 12, but 2 participants withdrew before treatment and 1 after a few days of treatment, resulting in 9 analysed participants. All analysed participants met the DSM‐IV criteria for major depressive disorder and current major depressive episode with seasonal patterns studied. The mean age of the 9 participants was 45 years (range 35 to 58 years), 100% female. Participants had to be medically stable, not pregnant, and free of psychiatric medication in the 4 weeks before the study. Individuals who had sleep apnoea or periodic leg movements in sleep, or who were acutely suicidal or drug or alcohol dependent within the 12 months before the study, were excluded.
Interventions	Open‐label nefazodone (n = 9) for 8 weeks. Daily doses were 100 mg in week 1, 200 mg in week 2, 300 mg in week 3, 400 mg in weeks 4 to 8.
Outcomes	Adverse events (assessed with a self‐reported questionnaire at baseline, weeks 4 and 8) and insomnia (assessed with polysomnographic recordings at weeks 4 and 8). These safety outcomes were the only outcomes of interest for the purposes of this review (this study did not fulfil our inclusion criteria for efficacy as it is not a randomised trial).
Notes	Funding not reported.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	This is an observational study with only 1 group (Shen 2005)
Allocation concealment (selection bias)	High risk	This is an open‐label study (Shen 2005)
Incomplete outcome data (attrition bias) All outcomes	High risk	2 participants withdrew before taking any medication; 1 withdrew after one week; and another person was not analysed (33%). This level of attrition would have resulted in a high risk of bias for the adverse event results of the study (Shen 2005)
Selective reporting (reporting bias)	Unclear risk	No protocol available.
Other bias	High risk	Additional 'Risk of bias' assessment as per Deeks 2003, see Table 7. This study contains a small number of participants, which is a likely source of bias. Although the outcome insomnia is specified, a questionnaire was used for other adverse events, but details about the questionnaire and numerical results on adverse events are missing.
Blinding of participants and personnel (performance bias) All outcomes	High risk	This is an open‐label study (Shen 2005)
Blinding of outcome assessment (detection bias) All outcomes	High risk	This is an open‐label study (Shen 2005)

Abbreviations: BDI: Beck Depression Inventory, Can‐SAD: Canadian seasonal affective disorder; CNS: central nervous system; DSM‐II‐R: Diagnostic and Statistical Manual of Mental Disorders ‐ third edition ‐ revision; DSM‐IV: Diagnostic and Statistical Manual of Mental Disorders ‐ fourth edition; DSM‐IV‐TR: Diagnostic and Statistical Manual of Mental Disorders ‐ fourth edition ‐ text revision; HAM‐D: Hamilton Depression, mg: milligram; N = number of participants; SAD: Seasonal affective disorder; SIGH‐SAD: structured interview guide for Hamilton Depression Scale ‐ Seasonal Affective Disorder; SSRIs: selective serotonin reuptake inhibitor; UKU: Udvalg for Kliniske Undersogelser 

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
GlaxoSmithKline 2003	This is an 8‐week trial of participants with a history of SAD, but who were non‐depressed (score 7 or less on the HAMD‐17) at the beginning of the study. Participants were randomised to bupropion XL or placebo for the prevention of SAD, therefore this trial did not meet our inclusion criteria.
GlaxoSmithKline 2003a	This is an 8‐week trial of participants with a history of SAD, but who were non‐depressed (score 7 or less on the HAMD‐17) at the beginning of the study. Participants were randomised to bupropion XL or placebo for the prevention of SAD, therefore this trial did not meet our inclusion criteria.
GlaxoSmithKline 2004	This is an 8‐week trial of participants with a history of SAD, but who were non‐depressed (score 7 or less on the HAMD‐17) at the beginning of the study. Participants were randomised to bupropion XL or placebo for the prevention of SAD, therefore this trial did not meet our inclusion criteria.
Moscovitch 2004	The population did not meet our inclusion criteria. The trial included 187 participants with a DSM‐III‐R diagnosis of major depression or bipolar disorder with a seasonal pattern.
Partonen 1996	This is a 6‐week study of 183 participants with major depression who were randomised to 20 to 40 mg/day of fluoxetine or 300 to 450 mg/day of moclobemide. Results were presented separately for the 34 SAD participants in the trial; however, the comparator, moclobemide, did not meet our inclusion criteria.
Seo 2013	This study assessed the effect of bupropion hydrochloride extended‐release in participants with major depressive disorder with atypical features not specifically in patients with SAD.

DSM‐III‐R: Diagnostic and Statistical Manual of Mental Disorders, third edition, revised; HAMD‐17: Hamilton Depression Scale‐17 item version; SAD: seasonal affective disorder

Differences between protocol and review

None.

Contributions of authors

BNS supervised and co‐ordinated this review update. GG provided methodological advice. DW and BG provided a clinical perspective. BNS, KT, AC, TP, AS, and GG reviewed the abstracts and full texts. BNS performed data abstraction, which AC checked for accuracy and completeness. BNS conducted the 'Risk of bias' assessment for the newly included studies and updated the GRADE assessment, which KT checked for accuracy. All authors contributed to the writing of the review.

Sources of support

Internal sources

• Danube University Krems, Austria

  Home institution of the majority of authors of this review (BNS, AC, GG, TP).

External sources

• No sources of support supplied

Declarations of interest

Barbara Nussbaumer‐Streit: no conflict of interest
Kylie Thaler: no conflict of interest
Andrea Chapman: no conflict of interest
Thomas Probst: no conflict of interest
Dietmar Winkler: has received lecture fees from Angelini Pharmaceuticals, Lundbeck Pharmaceuticals, and Pro Mente Austria, and authorship honoraria from Medizin Medien Austria
Andreas Sönnichsen: no conflict of interest
Bradley Gaynes: no conflict of interest
Gerald Gartlehner: no conflict of interest

New search for studies and content updated (no change to conclusions)