Table 3.
Modified GRADE ratings for each study and the overall rating of strength of evidence.
| Study | Unified statistical analysis on original data | Confounding by antidepressant use adequately excluded (where effect found)* | Outcomes of interest pre-specified | Consistent results (or heterogeneity adequately addressed if present) | Little likelihood of publication bias (in funnel plots or tests) | Large sample (>500 for non-genetic and >10,000 for genetic) | Certainty of evidence | Overall certainty of domain |
|---|---|---|---|---|---|---|---|---|
| Serotonin and 5HIAA: case (depression) vs. healthy control studies comparing concentration of serotonin in plasma and CSF | ||||||||
| Huang et al., 2020 | 1 | 1 | 1 | 0 | 1 | 1 | Moderate certainty evidence of no effect (lowered serotonin explained by antidepressants) | Moderate certainty evidence of no effect |
| Ogawa et al., 2018 | 0 | N/A | 1 | 1 | 1 | 1 | Moderate certainty evidence of no effect | |
| Pech et al., 2018 | 0 | N/A | 1 | 1 | 0 | 1 | Low certainty evidence of no effect | |
| Receptors: case (depression) vs. healthy control studies comparing 5-HT1 receptor binding | ||||||||
| Nikolaus et al., 2016 | 0 | 0 | 0 | 0 | 0 | 0 | Very low certainty evidence of increased serotonin activity | Very low certainty evidence of increased serotonin activity |
| Wang et al., 2016 | 0 | 0 | 1 | 0 | 0 | 0 | Very low certainty evidence of increased serotonin activity | |
| Serotonin transporter (SERT): case (depression) vs. healthy control studies comparing SERT binding | ||||||||
| Nikolaus et al., 2016 | 0 | 0 | 0 | 0 | 0 | 0 | Very low certainty evidence of increased serotonin activity | Very low certainty evidence of increased serotonin activity |
| Kambeitz & Howes., 2015 | 0 | 0 | 1 | 1 | 0 | 1 | Very low certainty evidence of increased serotonin activity | |
| Gryglewski et al., 2014 | 0 | 0 | 1 | 1 | 0 | 1 | Very low certainty evidence of increased serotonin activity | |
| Tryptophan depletion studies: effect of acute tryptophan depletion (ATD) on mood in healthy volunteers; healthy volunteers with family history of depression; drug-free patients with MDD in remission | ||||||||
| Ruhe et al., 2007 | 0 | 0 | 1 | 1 | 0 | 0 | Very low certainty evidence of no effect for people with no family history of depression. Very low certainty evidence of lowered serotonin activity in those with a family history and people with depression in remission. | Very low certainty evidence of no effect or lowered serotonin activity in vulnerable populations |
| Fusar-Poli et al., 2006 | 0 | N/A | 1 | 0 | 0 | 0 | Very low certainty evidence of lowered serotonin activity | |
| SERT gene: association between SERT gene and depression | ||||||||
| Border et al., 2019 | 1 | N/A | 1 | N/A | 1 | 1 | High certainty evidence of no effect of the SERT gene | High certainty evidence of no effect for SERT gene |
| Culverhouse et al., 2018 | 1 | N/A | 1 | 1 | 1 | 1 | High certainty evidence of no effect of the SERT gene | |
| Oo et al., 2016 | 0 | N/A | 0 | 1 | 1 | 0 | Very low certainty evidence of an effect for SERT gene | |
| Gatt et al., 2015 | 0 | N/A | 0 | 0 | 0 | 0 | Very low certainty evidence of an effect for SERT gene | |
| Kiyohara & Yoshimasu, 2010 | 0 | N/A | 1 | 0 | 1 | 0 | Very low certainty evidence of an effect for SERT gene | |
| Gene-stress interaction | ||||||||
| Border et al., 2019 | 1 | N/A | 1 | N/A | 1 | 1 | High certainty evidence of no effect for gene-stress interaction | High certainty evidence of no effect for gene-stress interaction |
| Bleys et al., 2018 | 0 | N/A | 1 | 0 | 1 | 1 | Low certainty evidence of an effect for gene-stress interaction | |
| Culverhouse et al., 2018 | 1 | N/A | 1 | 1 | 1 | 1 | High certainty evidence of no effect for gene-stress interaction | |
| Sharpley et al., 2014 | 0 | N/A | 1 | 0 | 1 | 1 | Low certainty evidence of an effect for gene-stress interaction | |
| Karg et al., 2011 | 0 | N/A | 1 | 0 | 1 | 1 | Low certainty evidence of an effect for gene-stress interaction | |
N/A not applicable
*Where no effect found or where prior use of medication is not relevant (as in genetic studies), item was rated as ‘not applicable’.