I would use them as synonyms, but it all depends on the context of the sentence. En serio? and de verdad? Given both are questions I would assume are told in response to someone telling you a story and you use de verdad? And en serio? To show you find the story a little incredible and to demonstrate you are listening.

De verdad y en serio es prácticamente lo mismo no hay diferencia De verdad hiciste eso tu? En serio hiciste eso tu? Quiza en enserió seria como algo que crees menos tu

It depends how you use it, if you use it as an exclamation point there is no difference

Is " ¿ De verdad? ( pronounced "de verdá") And there is no difference between "¿De verdad? y ¿En serio? Significan lo mismo.

Hola! Saying "de verdad" is basically doubting a little bit about what the other person is saying. "Enserio" is the same. But, just if the person saying it is telling you this as a question, sometimes we also use "enserio" or "de verdad" as a way to "convince" the other person of what we are saying. Example: A) - Fui a comprar en el supermercado y me encontré con Pablo. B) - ¿De verdad? A) - Si, ¡enserio! Hope this helps!