Feeling anxious or depressed and want to get better? You have to really work at it and suffer through years of therapy and sometimes try lots of drugs. No pain, no gain, or so we’ve been told.
That would make a stoic happy, but as a psychiatrist — and an admittedly impatient one — I know that just because something feels bad doesn’t necessarily mean that it’s good for you. I’m pretty confident that people who are suffering prefer relief sooner rather than later and that if there was any way to make the treatment — be it psychotherapy or medication — more effective, they would gladly try it.
So I am cautiously optimistic that on Tuesday, the Food and Drug Administration approved esketamine, a nasal version of the drug ketamine, which appears to relieve depressive symptoms far faster than other antidepressants. There are risks: The drug is potentially addictive, heavy use can impair cognition, and it could induce a psychotic reaction in some patients. But if prescribed judiciously, esketamine should be a boon to the 25 percent of people with depression who fail to respond to current drugs.
I have been wondering if esketamine could be used for another purpose, too: to strengthen the effects of therapy. This is because it targets the neurotransmitter glutamate, which plays an important role in learning and memory.
There is intriguing neuroscience research that suggests that it may be possible to boost the efficacy of psychotherapy with drugs that share some of ketamine’s effects, somewhat the way athletes can enhance their performance with steroids.
A while back, I saw a young woman who had been mugged on her way home from work. She was pushed to the ground by an unseen assailant who stole her wallet and fled, leaving her shaken up but otherwise unharmed.
In the next few weeks, she become increasingly anxious when walking alone at night and had intrusive flashbacks of the assault during the day. Normally, you would lose this fear after being back on the street a few times and seeing that nothing traumatic happens. But she’d developed classic post-traumatic stress disorder, in which a previously safe situation provokes a persistent, and visceral, sense of danger.
She began exposure therapy with one of my colleagues in which she gradually confronted the situation she feared — a dark city street — alongside her therapist, who assured her that nothing terrible would happen. Like many people, she found this treatment upsetting and emotionally draining, but she stuck it out and eventually recovered.
What if we could use a drug to speed up a difficult treatment like that and make it more effective?
The psychologist JoAnn Difede and her colleagues at Weill Cornell Medical College, where I also work, addressed that question with a study in 2013 of 25 patients who developed PTSD after Sept. 11. They randomly assigned the participants to virtual reality exposure (12 weekly sessions of simulated attacks on the World Trade Center combined with patients’ recounting their traumatic experience in vivid detail) with either the drug d-cycloserine or a placebo.
Subjects who received exposure along with d-cycloserine showed faster and greater improvement in their PTSD and depressive symptoms, and the benefits persisted after six months of follow-up.
Of course, this was a very small study. A 2017 meta-analysis of 21 studies found that d-cycloserine was superior to a placebo in boosting the short-term effect of exposure-based therapy, though any long-term effects were less consistent. Studies of the drug in rodents have also found that it helps the animals recover from the fear of shocks much faster than a placebo.
How might this work? D-cycloserine is an antibiotic that, like ketamine, increases the activity of glutamate in key brain regions, which promotes connections between neurons. It seems to amp up the molecular machinery of learning. And psychotherapy is all about learning — to overcome fear and to better handle stress, among other lessons.
For decades, psychoanalysts were against medicating anxiety at all, because they believed it would interfere with the therapeutic process. Fortunately, those days are largely over. Many are now comfortable giving patients anti-anxiety benzodiazepines like Klonopin if they are having a hard time grappling with issues that arise in therapy. Treating excessive anxiety can allow patients to better face their pain and fears.
This research suggests we could be doing more to use drugs to turbocharge therapy.
The timing of drug and treatment is probably crucial. In one study, rats were trained to fear a particular context (cage) or a cue (white light) by pairing them with a mild shock. The animals then underwent fear-extinction therapy, either in one long session after receiving a benzodiazepine or in two sessions with the drug given in between. The latter group were more successful at getting over their fear, which suggests that some exposure therapy must precede the medication.
But maybe, with the help of the right drug, just a little therapy could go a long way.
One small study randomized 20 subjects with PTSD to receive just two sessions of therapy in addition to either MDMA (the party drug Ecstasy) or a placebo. Those who got MDMA had fewer PTSD symptoms and were more open and less “neurotic” than those who took a placebo at a two-month follow-up.
It’s not that surprising. MDMA is known to promote openness and lack of defensiveness, both of which might be conducive to attaining insights. Could that wisdom be as enduring as the kind acquired during months of therapy? It’s possible. After all, therapy and prescription drugs like antidepressants change the brain in surprisingly similar ways.