Could Ketamine Help Patients With Borderline Personality Disorder?

Can ketamine—which has demonstrated extraordinary promise in recent years as a fast-acting treatment for major depression and suicidal thinking—also help patients with borderline personality disorder (BPD)?

Sarah Fineberg, M.D., Ph.D., an instructor of psychiatry at Yale University and attending psychiatrist at the Connecticut Mental Health Center, believes the answer to this question may be yes. Fineberg is the principal investigator of an ongoing study, funded by the American Foundation for Suicide Prevention, that will look at the effectiveness of ketamine for reducing suicidality and improving social functioning in patients with BPD.

One of the most clinically challenging conditions, BPD is marked by a high degree of emotional lability, mood dysregulation, and social dysfunction. Evidence from functional magnetic resonance imaging has shown that patients with BPD have hyperactivity in limbic areas of the brain, especially the amygdala, and hypoactivity in the prefrontal cortex and related areas.

Past APA President John Oldham, M.D., an expert in BPD, has likened the amygdala of a patient with BPD to the engine of a car “running hot.” Such overactivity may explain why patients with BPD tend to be hypersensitive to stimuli and inclined to overinterpret or misinterpret social cues or facial expressions. The hypoactive prefrontal cortex, which should normally act like the brakes of a car, diminishes the patient’s capacity to reconsider or modulate aggressive impulses. “So with borderline patients, the engine is running hot, and the brakes don't work,” he said.

In an interview with Psychiatric News, Fineberg said her interest in ketamine was piqued by recent studies demonstrating the agent’s possible effectiveness in treating major depression and suicidal thinking, but also by animal research suggesting that ketamine may promote new connections between neurons.

“One of the things we are excited about is data from rodent models showing that within a day or two after infusion with ketamine, there appears to be an increase in neuroplasticity,” Fineberg said. “This suggests that there is a window in which new neural connections can be made.”

If ketamine, alone or as an adjunct to psychotherapy, could open a window of opportunity for the patient to change patterns of behavior that have proven to be socially disruptive, it could be a game changer, Fineberg said. “If we are able to find some success in that domain we hope to develop an intervention targeted at social change,” she said.

Fineberg noted that patients with BPD are also fifty times more likely than the general population to attempt or die by suicide. A landmark meta-analysis published in the American Journal of Psychiatry (AJP) last year found that a single infusion of ketamine appears to significantly reduce suicidal thoughts in depressed patients in as little as one day, with benefits lasting for up to one week.

No medications have been formally approved for the treatment of BPD, and studies show few BPD patients respond to selective serotonin reuptake inhibitors (SSRIs) and mood stabilizers. (Earlier this month, AJP published a study that found patients with BPD who took lamotrigine for 12 months reported similar symptoms on the Zanarini Rating Scale for Borderline Personality Disorder as those who took placebo for 12 months.)

Fineberg said available data suggest that more depressed individuals respond to ketamine than to traditional antidepressants. “Since people with BPD have little response to SSRIs, we hope that ketamine will also be more effective in BPD,” she said.

Fineberg’s study of ketamine in BPD will be a randomized, controlled trial with three arms consisting of 15 BPD patients in each arm: a control group receiving midazolam, a preoperative sedative; one active treatment group receiving an ultra-low dose of ketamine (0.25 mg/kg); and one active treatment group receiving the standard dose (0.50 mg/kg) of ketamine.

Patients in each of the study arms will receive one infusion and will be followed for a month. The primary outcome of interest is change in suicidal ideation; secondary outcomes include BPD symptoms, pain, and social functioning.

She said that the research will also seek to quantify social cognition and social functioning in the laboratory, drawing on the work of Reed Montague, Ph.D., and colleagues at Virginia Tech Research Institute. Montague and colleagues have developed computer games that require players to trust and cooperate with each other in order to win. These games offer researchers the opportunity to examine factors that promote or discourage cooperative, or “pro-social”, behavior.

At the APA Annual Meeting in New York next month, Fineberg will present preliminary data from the study and the clinical and basic research supporting use of ketamine in BPD during a symposium titled “Novel Approaches and New Directions in the Treatment of Borderline Personality Disorder.” This session will be held on Wednesday, May 9 in Room 1a21/22 of the Javits Convention Center.

Fineberg said the “buzz” surrounding ketamine has been extraordinary, but what is needed is solid data. Ketamine infusion centers are proliferating—few of which, if any, screen patients for personality disorders, she said. “This is a very hopeful area, but we need to proceed cautiously,” she said. ■