The analysis revealed general and specific co-occurrence patterns related to interventions for depression.
General Patterns in Intervention Co-occurrence
As shown in , the bipartite network visually represents the explicit relationships between the 968 depression trials and 279 interventions. Our analysis revealed four distinct general patterns in the network:
1. High Degree Placebo Hub. The placebo node is the largest node (connected to 559 or 57% of the trials), and centrally located. In addition to the placebo node, a few other intervention nodes have a high degree (e.g., Escitalopram is connected to 126 trials). However the majority of the intervention nodes have a low degree, resulting in a right-skewed intervention degree distribution (y=–10.11ln(x) + 40.464).
2. Concentric Rings of Nodes. There are four distinct concentric rings of nodes around the placebo node. Each ring is visible in the network layout, and quantitatively identified by the k-neighbors algorithm with colors based on their shortest distance to the placebo. These rings alternate between trials (black nodes) and interventions (colored nodes). The trial nodes in Ring-1 (black nodes) are connected directly to a placebo, and therefore represent placebo-controlled trials. The intervention nodes in Ring-2 (colored green) are connected to trial nodes in the first ring and therefore co-occur with a placebo; many of these nodes are also connected to trials in the third ring. The trial nodes in Ring-3 (colored black) represent trials that do not include a placebo, but have at least one intervention that has been tested in a placebo-controlled trial (green nodes in Ring-2). Finally, the intervention nodes in Ring-4 (colored red) are included in the trials in Ring-3, but have far fewer interventions compared to those in Ring-2.
3. Tendrils. There are tendrils (connected sequences of nodes with decreasing degree and terminating in a one degree node) that emanate from the network. These contain rare interventions that are a long distance from the placebo node, and have been pushed out to the periphery of the network. For example, Betaine is tested in only one trial, and is five steps removed from the placebo node.
4. Islands. There are 10 islands that are disconnected from the giant main network. These trial-intervention sets are disconnected from the rest of the trials as they include interventions that have neither a direct, nor an indirect connection, to a placebo.
Because distance from the placebo node appeared to be the main measure underlying the above network topologies, we calculated the Placebo Distance for each node, and plotted their distribution. The goal of generating the distribution was to relate this measure to the observed network topologies (rings, tendrils, and islands).
As shown in , Placebo Distances 1–4 corresponds to Ring-1 to Ring-4, Placebo Distances 5–6 correspond to tendrils, and Placebo Distances= infinity correspond to the trials and interventions in the islands. The distribution shows that there are 559 trials at Placebo Distance=1, and the remaining non-placebo trials have different profiles based on their complex relationship with interventions at different distances from the placebo. The Placebo Distance therefore provides a richer understanding of the complexities in no-placebo trials. This understanding could enable researchers to make sense of global trends in an entire domain, and identify specific categories of interventions and trials to target for close inspection. For example, tendrils in the network could be caused when interventions are abandoned by results from earlier trials, and replaced by new ones. Islands might exist because the interventions they contain have been tested against a placebo in another domain (e.g., a cardiac trial for impact on cardiovascular outcomes) but not tested against a placebo in the depression domain.
The distribution of 1246 Placebo Distances (excluding the distance of the placebo to itself), and their relationship to the trial (black) and intervention (colored) topologies identified in the network.
Specific Patterns in Intervention Co-occurrence
While the general patterns revealed how all depression interventions co-occurred across depression trials, the bipartite network in also revealed that all SSRI nodes (one of the 9 classes of antidepressants in the network) were all in Ring-3, whereas there were several nutritional supplements in Ring-5 and in the islands. We therefore analyzed how the specific subset of antidepressants and nutritional supplements co-occurred across trials.
shows a one-mode projection which represents how 33 antidepressants (colored nodes) and 51 natural supplements (black nodes) co-occur across trials. As shown, there is a tightly connected collection of colored nodes in the center of the network with no intermingling black nodes. This means that while antidepressants frequently co-occur in trials, they only infrequently co-occur with natural supplements. In fact, only 7 out of 51 natural supplements co-occur in trials with antidepressants, and in addition tend to be tested singly in independent trials. Furthermore, despite the high media and patient interest in St. John’s Wort (Hypericum Perforatum, pointed to by the right arrow) the network revealed that it has not been broadly tested for comparative efficacy.
The network also shows the relative low frequency of Tricyclic Antidepressants (TCAs) (white nodes), with Desipramine and Notriptyline being the most commonly tested. This is probably because they are more clinically tolerable compared to other TCAs.