Anything relating to Human-Plus, which gives a pilot cybernetic upgrades... but generally damages their mind in the process, and it's successor programs in the later games. You will usually have to fight or work with the pilots that went through this at least once a game. Some are Laughing Mad, some are Creepy Monotone, but they're all incredibly disturbing to listen to. One example is a re-made mission from the first game featured in Nexus, where a pilot begs you for help in attacking a train somehow related to the program. At the beginning, he's overly anxious. Once the train is destroyed He turns on you, saying in a monotone voice: "Everything, yes. I must. Destroy. Everything."
At the end of Nexus, your character accidentally releases a mob of kamakaze drones that attack the world.. It cuts to your AC on the roof of an enclosed city, where you try to fight the entire mob by yourself. The screen slowly fades to black as your AC keeps calling out damage warnings.
RD and Chief being seemly insane in AC 5. RD is seemly killed earlier on, but he is turned on you and suffers a major personality change in a matter of hours and is ready to kill his friends for no explainable reason. Chief, on the other hand, is an AI and, therefore, can't really be killed. He lives for battle and keeps coming back after seemly dying several time. He laughs madly every time you defeat him. Even when his AC explodes and is on fire, he pulls down a concrete support column and rushes you. Many of his attacks are one-hit-kills if you contacts with you just right. He just seems so happy while trying to beat your face in.
You later know that Armored Core V and Armored Core Verdict Day are continuation of Armored Core For Answer. Let thatsink in for a second...
Expanded material puts the control system used in NEXTs as this in an And I Must Scream fashion- the system requires the pilot's nervous system to be hardwired into the control pod, and removing the pilot will probably kill him.
The Bio-Weapons that occasionally show up throughout the series. The AMID As, in particular. Blecch...