Brain Repair: The Ketamine Combo Treatment for Depression and Chronic Pain
Matt and psychiatrist Jon Berner discussed the potential of rapamycin and ketamine for treating severe depression and chronic pain, focusing on their impact on microglia and brain inflammation. They touch on how microglia, a type of immune cell found in the central nervous system that help protect the brain against infections, clear debris, and respond to injuries, shifts from an inflammatory to a reparative state in response to rapamycin and ketamine treatment. They also dive into clinical case studies of ketamine and rapamycin combinations and the complicated topic of how regulatory reform and AI collaboration might advance medical innovation.
Jon has been in solo psychiatric practice at Woodinville Psychiatric in Washington since 1997. He spent several years working at the Monroe Correctional Complex, a Washington State Department of Corrections prison. His specialties include brain disorders, particularly bipolar and psychotic illnesses, complex pain, addiction, and "undiagnosed" neuropsychiatric syndromes, and other general psychiatric disorders such as anxiety and depression. Jon has published multiple scientific papers about various topics in the realm of mood disorders and treatments for them. He holds an M.D and a PhD in neuroscience from the University of California, Los Angeles and a B.A. in psychology from Harvard University.
Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!
Rapamycin and ketamine hold significant promise for addressing neurodegenerative disease, neuropsychiatric disorders, and inflammatory driven pathologies, both alone and in conjunction. Optimal use of these medications requires identification of biomarkers which specify dose requirements and predict clinical effectiveness of each intervention on an individual level. This study, which Jon co authored, measured a biomarker of mTOR activity (phosphorylated S70S6K or pS6K) in the blood of 27 women with psychiatric disease and found that baseline levels of pS6K predicted clinical effectiveness of ketamine and rapamycin—and interestingly enough, also body size features like height, pupil distance, and head size in relation to body. Although the cohort size was small and randomized-controlled trials are needed for validation, this study sheds light on a simple assay that may provide a cost-effective solution for the personalized prescription of putative gerotherapeutic interventions that hold promise to extend healthspan and enhance quality of life.
Depression is an extremely heterogeneous disease that can be classified into different subtypes based on biological drivers, experiential risk factors and clinical manifestations. Ketamine has been shown to be strikingly effective for remedying many cases of treatment-resistant depression, but research on the optimization of ketamine utilization towards specific, responsive subtypes of depression is sparse. This retrospective study used metabolomics and machine learning to analyze the metabolomic signatures of 29 treatment-resistant depression patients’ cerebrospinal fluid. The machine learning model utilized 151 metabolites to define two subtypes of patients that may have different biological drivers of depression, thus requiring differential treatment regimens. One subtype was characterized by markers associated with a glial hyper-inflammatory phenotype and the second subtype was characterized by markers associated with mitochondrial dysfunction. Interestingly, the mitochondrial dysfunction phenotype of depression was more strongly associated with responsiveness to ketamine treatment. The authors even go on to suggest in this paper that such sub-typing based on metabolomic signatures may allow for the more precise selection of FDA-approved drugs tailored towards an individual’s unique aging signature (“ageotype”) – the advent of personalized longevity medicine.
A growing body of real-world data demonstrates that low-dose rapamycin administration substantially improves pain symptoms in individuals afflicted with varying types of pain. This case study chronicles the treatment history of one of Jon Berner’s patients, a woman suffering with debilitating complex regional pain syndrome following a series of car accidents. She struggled for 16 years taking anti-depressants, opioids, benzodiazepines, spinal cord stimulator and other interventional modalities to resolve her pain and these interventions brought her little relief of symptoms and long-term disability associated with suicidal behavior. When she started taking Ketamine and rapamycin dual therapy, her pain reduced significantly days after administration. After 10 months of administration, her pain decreased by 50%, she increased the number of daily steps she could take from 400 to 14k steps a day and reduced the number of medications she was taking. The mechanism of action underlying how rapamycin and ketamine synergize to reduce pain is unknown, but Jon Berner and colleagues hypothesize that the chronic pain is likely driven by a nervous system component including glial hyperactivation and neural inflammation which has been demonstrated to be mitigated by both drugs in mouse models.
Sub-analgesic doses of ketamine have demonstrated remarkable efficacy for ameliorating treatment-resistant depression, but the mechanism of how these doses work is not well understood. Ketamine is often thought of as an experiential medicine, but emerging research suggests that it has some very real effects on the molecular reprogramming of cells of the immune and nervous system, specifically reprogramming cellular profiles into a more anti-inflammatory state oriented towards tissue repair. This study demonstrated that patients with major depressive disorder had increased plasma levels of pro-inflammatory cytokines (IL-12 and IL-16) and monocytes than individuals without depression. Further, the authors conducted in vitro and in vivo mouse studies and demonstrated that ketamine binds to N-methyl-D-aspartate receptors on immune cells in the spleen and brain to activate mTOR signaling and shift the ratio of macrophages towards the M2c type (anti-inflammatory/tissue repair). Although this study only provided a snapshot of the state of inflammatory mediators within the body, it adds to a growing body of evidence explaining how a single dose of ketamine may reprogram immune signaling to support rapid and sustained antidepressant effects in individuals with treatment resistant depression.
Mitochondrial complex I activity in microglia sustains neuroinflammation - PMC
Hyperactivation of microglia is a feature of chronic neurological diseases like multiple sclerosis and neurodegenerative disease. It can be characterized as a state of sustained inflammation within the central nervous system. This research study uses a multi-omics approach to characterize the catalysts of the “molecular forest fire” of inflammation initiated in the brain in several different model systems and pathological contexts. The research group found a shift towards disease-associated, hyper-inflammatory microglia with increased mitochondrial complex I activity, reverse electron transport and the production of reactive oxygen species and oxidative stress. Further, blocking mitochondrial complex I (e.g. with metformin) in hyper-inflammatory microglia protects the nervous system from neurotoxic damage and improves functional outcomes in an animal disease model.
Few people would opt in for electroconvulsive therapy (ECT) as a first choice to treat their depression. Nevertheless, ECT has long been considered one of the most efficacious interventions for treatment-resistant depression. Ketamine is a more recent contender.
This large, randomized study compared the effectiveness of ECT to sub-anesthetic doses of IV ketamine over 3 weeks for individuals with treatment-resistant depression. Compared to the ECT group, more responders in the ketamine group (55.4% vs 32.3%) demonstrated an improvement of greater than 50% on the standardized depression scale, and a greater percentage of individuals experienced complete remission (32.3% vs 20%) after just 3 weeks of treatment. Further, individuals in the ketamine group performed better in memory assessments post-treatment compared to the ECT group. The study also included a 6-month follow up period on responders and found that relapse occurred in only 34.5% of ketamine patients compared to 56.3% of ECT patients. This suggests that just 6 sessions of ketamine treatment over 3 weeks was superior to ECT for treatment-resistant depression and had sustained effects that lasted at least 6 months post-treatment.
