Here are some simple tips when you're trying to decide what you should be optimizing for between unique open rate and unique clickthrough rate.
If you're ONLY testing subject lines or main subject lines and secondary subject lines, chose Open Rate.
If your variations are limited to what's in the message once a user opens it, choose Clickthrough Rate. That includes variations that have different layouts, graphics, CTAs, copy, colors, etc.
If you're testing both subject lines AND body-level variations, you should probably default to Clickthrough Rate. This often a good choice if you don't time to run multiple experiments on that campaign step.
Depending on what you're testing and personal preference it may make sense to actually separate out the subject line experiments from the body-level experiments. You can run one and then switch over to the other.