To say ABC's Grey's Anatomy is going to be a lot different without leading man Patrick Dempsey would be an understatement. But as the medical drama moves into its first full season without McDreamy, the stars and producers behind the Shonda Rhimes medical drama are all looking forward to hitting the reset button.

"It feels a lot different. Every time we lose someone big — when we lost Sandra Oh — when we lose anybody — it's a big shift. But a show that runs this long, you welcome those big changes," leading lady Ellen Pompeo tells The Hollywood Reporter. "It makes everything feel so much different and that's what we're looking for in season 12. We're looking for things to not stay the same. They have to stay the same to some extent but you welcome change because that's what inspires the writers, that's what inspires the actors. Change is necessary for growth."

Pompeo, whose Meredith returned to work at Grey Sloan Memorial following a one-year time jump last season after Derek's (Dempsey) death, says she's committed to "doing the story justice" as an homage to dedicated fans and isn't approaching the role any differently heading into season 12.

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"I almost feel like Kobe Bryant every season — just because I have three [championship] rings — I don't have any Emmys — but because I have 12 seasons, I can't rest or get comfortable. You have to keep trying your hardest, running your fastest, working out your hardest, doing your best. You have to keep topping yourself," she says.

Rhimes, meanwhile, called Pompeo "the heart of the show" and noted she's more interested in bringing back the lighter tone of Grey's Anatomy's early days, which is among the biggest changes in store for season 12.

THR caught up with Rhimes, Pompeo, Caterina Scorsone (Amelia) and Kelly McCreary (Maggie) to discuss changes for season 12. Here are a few ways in which the drama will shift following the show's most depressing season ever.

1. It will be lighter. "We had a table read last week in which I have never heard the entire room laugh that much — I want to say since season one — the entire room was laughing and everybody broke into applause when we were done reading," Rhimes says. "It was a nice feeling to be so light again but in a way that didn't feel like we were trying so hard; it felt natural." Her goal was to recapture the early season banter and bring the fun back to the show. "I missed the banter and the fun of that. I missed their quickness and lightness," she adds. "Meredith being a widow, surprisingly, should be funny in some ways. She's been a woman who has been off the market forever and that humor of 'I'm dead inside, I'm not interested in men,' should be funny in a way. She should have some darker humor in that feeling."

2. Awkward living arrangements. Meredith has moved back into her mother's home and is sharing the space with sister-in-law Amelia and Maggie. "Right now it's very funny. Those three women are very different and don't have very much in common, which is fantastic," Rhimes says. "Meredith needs support right now and she is related to them so it's not the same as when she was living with Izzie (Katherine Heigl) and George (T.R. Knight) and liked them. She doesn't necessarily need to like them to love them and be in a house with them. It's a fascinating dynamic — it's family."

3. Callie and Arizona will both have new love interests. Rhimes says both characters, played by Sara Ramirez and Jessica Capshaw, respectively, will "definitely" have some new romances this season. "And some pretty exciting ones, too, which I think is going to be interesting," says Rhimes, who noted she's "intrigued" by what's happening with both characters individually and admits she still "loves them together." While Arizona — and fans — have expressed trepidation on if the bisexual Callie will go back to men following their split, Rhimes told THR that the "person Callie falls for and is in a relationship with is a woman." "That felt natural and it's what the story is about and how it plays out. I really tried to stay true to the idea that she's bisexual but it's literally what the story is."

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4. Callie's bisexuality will be further explored. While Callie's new love female interest is "very surprising," Rhimes said Callie's bisexuality will be addressed but it won't feel like the show is "telling an issue" story. "I like that we bring it up and I like that she has arguments about it. I like that Arizona always had a little bit of an issue with it, like, 'When are you going to go back to guys.' We're going to really try to deal with it and make it a thing. We'll be working it in but not as like an 'issue,' the way we never do issues and we'll work it in and have it be part of her character." To that point, Rhimes and Ramirez have spoken at length about the importance of Callie's bisexuality and using it as an opportunity to shed light on part of the LGBT community that tends to be underrepresented on the small screen. "Sara feels a lot of people don't take that seriously in the community," Rhimes says.

5. Arizona is going to find herself again. Though it's unclear if Arizona's famous roller shoes will return, Rhimes says the fun-loving character is going to experience some soul searching this season as she re-enters the dating community. "One of the hallmarks of this being a lighter season is a bit of Arizona's response [to Callie moving on] is fairly comic, which I love," she says. "I wanted to get back to the earlier seasons in which as I like to say, we're leaving the serious pain to the patients. Our characters have suffered enough. But also, Arizona is searching herself. We wanted to see her delve into and figure out what she wanted and needed. We're going to watch her try to find love, too."

6. Another time jump. Season 12 will pick up three months after the finale and bring April back to the hospital after re-enlisting. As for why she ultimately opted to skip forward a year in Meredith's journey, Rhimes revealed it was because she "needed there to be time to have passed for her to even be in a place where I felt like she could have a conversation."

7. Could Meredith find love again? It's unclear for now but Rhimes says that won't be the focus of what Meredith is doing come season 12. "I keep seeing these things saying that we're replacing McDreamy and Patrick is irreplaceable, that's not really the point. Meredith is on a journey. She's always been on a journey and I'm taking her on where the journey leads her and we'll see what that feels like," she says. Pompeo, meanwhile, says she is game to do what ever Rhimes has in mind. "I don't have to have expectations about what it should be, what it will be. All I have to do is convey what's on the page. I'm really lucky that's my only job," the actress says. As for new series regular Martin Henderson, Rhimes confessed that he won't arrive until the middle of season 12 and isn't sure what his character will be.

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8. Maggie's focus is on her "chosen" family. McCreary, whose Maggie learned of her adopted parents' divorce last season, says this season finds "everybody" with new footing after all of their individual traumas. "Maggie is carrying along the disillusionment and feeling of being unmoored but she's finding her footing again with her twisted sisters," McCreary says. The dynamic in the Grey house, however, is going to be quite interesting. "They're three different women with strong personalities who need each other. There are some hijinks, yelling and some truth telling." As for if viewers will ever meet Maggie's adoptive parents, no news on that front but McCreary has her dream castings in mind: Phylicia Rashad and Denzel Washington.

9. Amelia is "single, not dead." Scorsone says there's still some confusion — and "twitter-pated vibes" between Amelia and Owen (Kevin McKidd). "They are officially on the books 'friends' at this point but they are certainly not buddies [though] their pheromones would maybe disagree with their official relationship status," she says with a laugh. "She deserves a little bit of happy. With Ryan and Derek, she's had her fair share of tragic male loss [including her father]. Owen is fundamentally different than anyone Amelia has encountered before. He's out of the wheelhouse that she's comfortable with; he's an adult. He can equal her in tragedy and loss and yet he's persevering in the way that she is. There's a level of respect that she is surprised by. She definitely sees him as a person of substance."

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10. Amelia is going to redefine herself. "Derek was a father figure, the core person in her life, he was the only witness to her defining tragedy when they were children — losing their dad the way they lost him — he was her Paul McCartney to her John Lennon. They were competitive in a really creative and fruitful way. Her drive was very much fueled by his excellence. Losing Derek is going to spin her head around and cause her to have to redefine herself," Scorsone says. "Moving forward without this kind of foil that Derek always was for her, she's going to have to really find her feet on her own."

11. Everyone will experience a "redefinition and renaissance" — and there's actual laughter. To hear Scorsone tell it, "a lot has shifted this season" after the tragedies of season 11. "It was a depressing, dark, sad season. Inevitably, we'd have to get lighter this season. All of the characters are experiencing a redefinition and a renaissance and I feel like the show is, too. After going so dark, we're finding the humor. It's like when you have to laugh hysterically at a funeral — it couldn't get any sadder. The laughter had to come — and it has. There's a lot of levity on the set."

12. New sets. Scorsone says "even the sets are different" and there's a "lightness in the color scheme" as the relationships have all moved. "The constellation has shifted and people are living in different places. There's a lot of change now."

Grey's Anatomy season 12 premieres Thursday, Sept. 24 at 8 p.m. on ABC. What are you looking forward to seeing? Sound off in the comments section, below.