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In November 1801, when Angelica was 17 years old, her oldest brother Philip Hamilton died of injuries resulting from a duel with George Eacker. The news of Philip's death precipitated a mental breakdown that left Angelica in a state described as "eternal childhood", and often unable even to recognize family members.

Angelica's nephew, psychiatrist Allan McLane Hamilton FRSE, described his aunt as an "invalid" and her condition as a type of "insanity". Dr. Hamilton wrote, "Upon receipt of the news of her brother's death in the Eacker duel, she suffered so great a shock that her mind became permanently impaired, and although taken care of by her devoted mother for a long time there was no amelioration in her condition."

Though the details of what occurred are not clear from a modern medical perspective, historian Ron Chernow similarly attributed the sudden and extreme deterioration of Angelica's mental health to her reaction to the death of Philip, with whom she had been very close. Other modern authors have described the mental health problem, which lasted for the rest of Angelica's life, without discussion of causation.

Despite her parents' best efforts to reach her, Angelica's condition only seemed to worsen. Her father had written his friend Charles Cotesworth Pinckney and asked him to send Angelica watermelons and three parakeets, as she was "very fond of birds". After visiting the Hamilton home, James Kent tactfully described Angelica as having "a very uncommon simplicity and modesty of deportment".

Don't know about anyone else but I'm crying right now....no joke.

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