Darkness Visible explores the central debates in treating depression. On one hand, many individuals with depression resist medication, believing their condition arises from their environment, spirit, or mind rather than their bodies. These people often opt for psychotherapy. On the other hand, a substantial portion of the medical community strongly advocates for pharmaceuticals, claiming depression is caused by chemical imbalances in the brain and that medication is the most effective treatment. Styron examines both sides, writing:

The intense and sometimes humorously exaggerated factionalism in modern psychiatry—the divide between proponents of psychotherapy and supporters of pharmacology—resembles the medical disputes of the eighteenth century (to bleed or not to bleed) and almost encapsulates the enigmatic nature of depression and the complexity of its treatment.

Styron never fully reconciles this conflict for himself, as he experiences both psychotherapy and antidepressants at various times. Although he "overcomes" the illness by the end of his story, he concludes with the thought that "the disease of depression remains a great mystery." For Styron, depression is as much a condition of the soul as it is of the mind. He compares those who have survived the "despair beyond despair" to poets who have journeyed from hell into the light of emotional well-being.

At its core, Darkness Visible explores themes of loss and the search for meaning. When depression engulfs him, he articulates feeling his ‘‘mind dissolving’’ and his brain overwhelmed by ‘‘anarchic disconnections.’’ He experiences a loss of voice, sexual desire, physical energy, and the ability to work, communicate, or love, even losing the ability to dream. All aspects that usually define human behavior and identity are severely impaired. He describes himself as living in a trance, unable to connect with the world in any significant way. This continuous decline pushes Styron to the edge of considering suicide, representing the ultimate loss of self. Styron investigates the link between suicide and depression, associating the deaths of friends and acquaintances with their struggles with depression or mood disorders. Reflecting on this, he believes that many of these deaths, including those of Abbie Hoffman, Primo Levi, and Albert Camus, might have been preventable with proper treatment for their depression. Styron suggests that meaning is found in the act of surviving and the bravery to confront a potentially meaningless world. He argues that cultivating meaning is primarily an act of human will. As he recovers, Styron begins to reclaim some of what he lost by writing about his illness. In trying to comprehend his experience with depression, he reflects on the loss of his mother during his childhood and speculates that his inadequate mourning of her death could have contributed to his adult mental health struggles.