Second-generation antidepressants for winter depression

Seasonal affective disorder (winter depression) is a type of depression that recurs in the autumn and lasts until the spring. It is similar to 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, are 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 for winter depression and how they compare to each other or to other types of therapy such as light therapy.

We found three trials with a total of 204 participants that looked at one SGA (fluoxetine) compared with placebo or light therapy. We did not find any trials on other SGAs. One trial (68 participants) compared fluoxetine with placebo. Fluoxetine appears to work better than placebo for winter depression, but we cannot say this with certainty due to the small numbers involved in the trial. Approximately the same number of participants in both groups experienced a side effect. We found two trials (with 136 participants in total) that compared fluoxetine with light therapy. When we combined the results of these two trials we found that there was no difference between the two groups: approximately 66 people out of 100 improved in both the fluoxetine and light therapy groups. We are unsure whether this summary result is correct because the trials are small and have some problems with their design as well as a high drop-out rate (many participants did not finish the trials).

About the same number of participants had side effects in the fluoxetine and light therapy groups. We found three additional studies that gave us information on the side effects of other SGAs (fluoxetine, escitalopram, duloxetine, and reboxetine), but we cannot compare the drugs directly. We can say that about 15% to 27% of people had to leave the studies early because of side effects and that 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 drugs which means that our confidence in the information on side effects is limited.

Authors' conclusions: 

Evidence for the effectiveness of SGAs is limited to one small trial of fluoxetine compared with placebo, which shows a non-significant effect in favour of fluoxetine, and two small trials comparing fluoxetine against light therapy, which suggest equivalence between the two interventions. The lack of available evidence precludes the ability to draw 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. Therefore the data we obtained on adverse effects is not robust and our confidence in the data is limited. Overall, up to 27% of participants treated with SGAs for SAD withdrew from the studies early due to adverse effects. The overall quality of evidence in this review is very low.

Read the full abstract...

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.


To assess the efficacy and safety of SGAs for the treatment of SAD in adults in comparison with placebo, light therapy, other SGAs or psychotherapy.

Search strategy: 

We searched the Cochrane Depression, Anxiety and Neuorosis Review Group's specialised register (CCDANCTR) on the 26 August 2011. The CCDANCTR contains reports of relevant randomised controlled trials from The Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date) and PsycINFO (1967 to date). In addition, we searched pharmaceutical industry trials registers via the Internet to identify unpublished trial data. Furthermore, we searched OVID MEDLINE, MEDLINE In-process, EMBASE and PsycINFO to 27July 2011 for publications on adverse effects (including non-randomised studies).

Selection criteria: 

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

Data collection and analysis: 

Two review authors screened abstracts and full-text publications against the inclusion criteria. Data abstraction and risk of bias assessment were conducted by one reviewer and checked for accuracy and completeness by a second. 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: 

For efficacy we included three randomised trials of between five and eight weeks duration with a total of 204 participants. For adverse effects we included two randomised trials and three observational (non-randomised) studies of five to eight weeks duration with a total of 225 participants. Overall, the randomised trials had low-to-moderate risk of bias, and the observational studies had a high risk of bias (due to small size and high attrition). The participants in the studies all met DSM (Diagnostic and Statistics Manual of Mental Disorders) criteria for SAD. The average age was approximately 40 years and 70% of the participants were female.

Results from one trial with 68 participants showed that fluoxetine was not significantly more effective than placebo in achieving clinical response (risk ratio (RR) 1.62, 95% confidence interval (CI) 0.92 to 2.83). The number of adverse effects were similar between the two groups.

We located two trials that contained a total of 136 participants for the comparison fluoxetine versus light therapy. Our meta-analysis of the results of the two trials 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), RR of remission 0.81 (95% CI 0.39 to 1.71). The number of adverse effects was similar in both groups.

Two of the three randomised trials and three non-randomised studies contained adverse effect data on 225 participants who received fluoxetine, escitalopram, duloxetine, reboxetine, light therapy or placebo. We were only able to obtain crude rates of adverse effects, so any interpretation of this needs to be undertaken with caution. Between 22% and 100% of participants who received a SGA suffered an adverse effect and between 15% and 27% of participants withdrew from the studies because of adverse effects.