Common questions and challenges
One of the most common questions asked by potential study participants and treatment providers is, “What do we do if ketamine works—what’s next?” Until recently, ketamine has been given only in the context of research studies. However, as evidence of its effects has continued to build along with data that suggest the drug is well-tolerated—despite concerns about unknown long-term effects, short duration of effects, and abuse potential—medical professionals with prescribing privileges have started offering the drug as an off-label treatment. Ketamine “boutique” clinics are opening across the country.
A current challenge is that most health insurance companies do not cover the high costs of off-label ketamine dosing. Patients for whom the medication is effective are concerned about how to continue treatment, especially if they do not have the finances for private-pay options. Similarly, health care providers are concerned about the options for those who respond to ketamine as well as for those who do not.
A consensus statement from the American Psychiatric Association Research Task Force on Novel Biomarkers and Treatments provides a good summary of the promise and limitations of off-label ketamine treatment.7 Although no clinical practice guidelines exist for the off-label administration of ketamine, the consensus statement offers an overview of appropriate training for prescribers, treatment setting and available facilities and resources (eg, blood pressure monitor, crash cart), and patient considerations (eg, safety eligibility such as cardiovascular risk factors or history of psychosis) as well as the challenges and limitations of the drug, including abuse potential, adverse-effect profile, and limited durability of effect (Figure 1).
A synaptic model of chronic stress pathology
Psychopharmacologic drug development and neuropsychiatry are undergoing a paradigm shift from the monoamine neurotransmitter systems toward the glutamatergic system and glutamate modulators for the treatment of stress-related psychopathology. Ketamine, a noncompetitive, high-affinity, N-methyl-d-aspartate receptor (NMDAR) antagonist, has served as the poster child for this new generation of research and drug development. Landmark preclinical and clinical studies that provided the first solid evidence of RAAD-like effects began an avalanche of research, including trials of ketamine and other glutamatergic drugs as well as those that support a glutamate- or synaptic-based hypothesis of chronic stress pathology (CSP).9-11
Early studies of SAADs altering NMDAR binding led to the hypothesis that the downregulation of NMDAR function may be a common pathway of antidepressant action.12 At the same time, we had the first evidence of gray matter volume loss in stress-related psychopathology, which appeared to parallel dendritic atrophy observed with chronic stress in rodents.13 These converging data suggested that downregulation of excess glutamate may exert antidepressant effects, which led to the question of whether ketamine’s RAAD effects may be due to the blockage of NMDARs and subsequent inhibition of glutamate neurotransmission.
In contrast to this inhibition model, mounting evidence also hinted at a neurotrophic hypothesis of stress-related psychopathology, in which chronic stress and depression are associated with a deficit in brain-derived neurotrophic factor (BDNF).14 Other findings suggested that administration of sub-anesthetic ketamine produces transient activation of glutamate neurotransmission. This α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor–dependent activation was found to increase BDNF levels and promote RAAD-like effects in rodent models.
Dr Averill is Clinical Research Psychologist, Clinical Neuroscience Division, Veterans Affairs National Center for PTSD, West Haven, CT; Associate Research Scientist, Department of Psychiatry, Yale School of Medicine, New Haven, CT; and Clinical Director, Emerge Research Program, Department of Psychiatry, Yale School of Medicine. Mr Averill is Neuroimaging & Technology Manager, Emerge Research Program, Clinical Neuroscience Division, Veterans Affairs National Center for PTSD, West Haven, CT and Department of Psychiatry, Yale University School of Medicine. Dr Abdallah is Assistant Professor of Psychiatry, Yale University School of Medicine, and Director of Neuroimaging, Clinical Neuroscience Division, Veterans Affairs National Center for PTSD.
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