If you have a raid array, a failed drive can greatly increase the startup time, and there may not be any indications without going into disk management, that a mirror drive isn't functioning.
Various games install AMD Dual Core Optimizer, even on Intel machines, and royally fuck things up. This particular bit of malware will take some light reading to properly remove it.
If MalwareBytes and NIS are on your system and running, that could be your problem as well. They "should" play nice, but you never know when an update to one will cause issues with the other, and conflicting antiviral software can have a diverse array of negative performance impacts. Competing real time scanning modes can easily duplicate the inconsistent performance issue.
You could also be having memory issues, run a memory checker. If you built a page file on a fragmented drive, the defrag didn't necessarily fix it.