Reflections on 2017: Blame it on the Ketamine?


Whether or not the advent of a new Gregorian or lunar New Year (the Year of the Dog starts 16 February) is important to you, most of us, however atavistically, attach significance to arbitrary markers of the passage of time. As this New Year lurched to its feet I found myself reflecting on the past year and what it held for psychology and mental health.

One of the most significant developments of the past year has been the continued exodus of pharmaceutical firms from the mental health marketplace. Last week, the pharmaceutical manufacturer Pfizer announced that it was suspending research activities into new drugs to treat Alzheimer’s disease and Parkinson’s disease in spite of the fact that currently 40 million people around the world have Alzheimer’s—a figure expected to more than double in the next 30 years. This announcement follows the failure of yet another drug addressing the underlying neuropathology of the disease. Since the early 2000s, over 100 new drugs aimed at either the pathophysiology of Alzheimer’s disease or managing its symptoms have failed in clinical trials—a rate far higher than seen with other diseases.

In many ways, this is not surprising. Dementia is a complex spectrum of disorders that remain poorly understood. Multifactorial in origin and protean in symptom manifestation, it resembles other chronic mental disorders, although the neuropathology of illnesses such as schizophrenia or bipolar disorder remains even more elusive than that for dementia.

But Pfizer’s abandonment of the field signals a further retreat by big PHRMA from the development of drugs for mental disorders. While several drugs for mental disorders were approved by the FDA in 2017, almost all of these were variations on drugs already in the marketplace—repackaged forms of amphetamine or methyphenidate for ADHD and one very controversial long acting antipsychotic, which I will discuss shortly. In 2017, Eli Lilly, another pharmaceutical manufacturer that had previously made huge investments in drugs for mental illness, had one drug for schizophrenia in clinical trials. Like Pfizer, Lilly had also invested heavily in the development of drugs for dementia, and has largely abandoned the search for more effective antidepressants or antipsychotics.

In fact, only one entirely new drug was brought onto the mental health marketplace last year. This drug (valbenazine, tradename Ingrezza) does not target the primary symptoms of a mental disorder, rather, it addresses the most pernicious and feared side effect of antipsychotic treatment, tardive dyskinesia. Valbenazine works by inhibiting the action of a presynaptic transporter that is specific for dopamine, the VMAT2 transporter. This prevents the release of dopamine into the synaptic cleft. Since tardive dyskinesia, while still poorly understood, is believed to result from heightened sensitivity of post-synaptic dopamine receptors, a mechanism to selectively block the release of dopamine may be of assistance. Phase III clinical trials have shown some modest benefit for patients with tardive dyskinesia (most of whom continued to take antipsychotics), leading to its approval by the FDA as a “breakthrough” drug.

In 2017, drug development was otherwise marked by minor tweaks to two main classes of drugs: long-acting antipsychotics, which are the primary income generator for pharmaceutical firms in this market, since most of the second generation agents are now generic, and in repackaging long acting amphetamine (Mydayis) and methylphenidate (Contempla, a long-acting, orally disintegrating tablet).

More controversially, 2017 saw the approval of a “digital pill”—a form of the antipsychotic aripiprazole called Abilify MyCite. This tablet contains an electronic sensor, which, when paired with a sensing device that adheres to the patient’s abdomen, transmits data to a smartphone or cloud-based tracking system confirming that the pill was taken. Benignly, this development can be viewed as an electronic helper to remind patients if they have taken a dose. In my view, the host of ethical questions and practical questions that surround the electronic monitoring of drug ingestion, particularly when some patients may be court-ordered to take antipsychotics, raises far more concerns than any supposed benefits of this new system. Clinically, there seem to be obvious contraindications for those patients with active paranoid delusional symptoms.

2017 did bring a few positive developments in dealing with substance abuse. Drug manufacturers, instead of making more and more potent forms of opioids, are turning their attention to delayed release preparations that make misuse more difficult. Also, opiate antagonists are becoming more widely available, though some that have been demonstrated to be important adjuncts in helping opiate dependent patients, like the partial agonist buprenorphine, still have numerous, generally politically driven, restrictions on availability.

Operating outside the sphere of FDA approval, another troubling development in psychopharmacology has been gathering steam over the past several years: the use of subanesthetic doses of the dissociative anesthetic (and rather frightening drug of abuse) ketamine for treating depression. After almost two decades of investigation the clinical data are not convincing (one small randomized clinical trial published in late 2017 did demonstrate some efficacy in reducing suicidal ideation on standardized scales), ketamine clinics have been springing up around the country. The exact number is difficult to ascertain, though there may be as many as a thousand such clinics. Since ketamine is not FDA indicated for depression or suicidal ideation, none of these clinics accept insurance reimbursement. More troubling is that the vast majority of these clinics appear not to have any mental health staff, and the drug is being administered for a wide range of mental conditions, for which little to no evidence of efficacy exists. The drug is administered intravenously, often by anesthesiologists with no mental health training, generally on a weekly basis. While the bona fides of most ketamine clinics must be questioned, there is one potential development on this front. Several years ago, the FDA gave breakthrough therapy status to an intranasal formulation of the drug, and a small preclinical trial for this formulation has demonstrated positive results in a drug company funded trial. Whether ketamine will emerge as a definitive treatment for mental disorders is uncertain. In the meantime, patients should be cautioned against seeking expensive and unapproved therapies.

When faced with a mass withdrawal from drugs for mental disorders, even the most determined optimist cannot call the development glass half-full. It is, we must admit, essentially empty. This leaves us with two essential questions: why has this stampede for the exits occurred, and where does this leave the field?

The lesson taught as a result of the failure of the “Decade of the Brain” of the 1990s has not been learned. There are no pharmacological cures for mental disorders. Pharmaceutical interventions may ameliorate patient distress, and may assist in making some of the more onerous symptoms of a mental disorder more bearable to patients. These are obvious benefits, and these benefits alone justify the use of many pharmacological interventions. But curative agents they are not. Although this fact is acknowledged by most prescribers, there remains an unfortunate tendency to employ drugs as if they were curative. More often than not, the only treatment that a depressed patient in America gets is an antidepressant pill, in spite of our knowledge that this is not likely to be effective in most patients who take it. Effective psychological treatments are simply not offered. This is not a failure of psychiatry or the pharmaceutical industry, although much of the blame can be laid at the feet of reimbursement structures that prefer short-term, mechanistic interventions.

It is a failure, in many respects, of psychology. Psychology, no more than psychiatry, has no magic cures in our treatment bag. Psychological interventions for chronic mental disorders are no more curative than are pills—but like pills, they can ameliorate symptoms. Unlike pills, they can, when well applied, provide patients with skills to more effective manage a chronic, lifelong condition. But have we as a profession done what is needed to make these treatments more widely available?  Have we as a profession effectively engaged regulators and policy makers so that the benefits of non-pharmacological treatments are better appreciated, and more widely accessible? The answer to these questions is, not surprisingly, no. Ketamine clinics and other unproven interventions that promise easy fixes for long-term debilitating disorders will always exist. We as a profession need to take a hard look at how we train future psychologists and how forcefully we advocate for treatments of proven benefit, lest we become complicit in a system that denies most citizens access to the type of care that will be truly beneficial to them.

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