Proton pump inhibitors, PPIs, are widely prescribed and sold globally. Although initially intended for time-limited treatment of acute disorders, such as gastric ulcers and esophagitis, PPIs are now commonly used for prolonged durations and are considered safe for over the counter access. Recent studies have raised concern over associations between PPI use and acute kidney injury, chronic kidney disease, end-stage renal disease, and electrolyte abnormalities. The growing concern over potentially serious adverse drug reactions warrants an evaluation of post marketing surveillance data. In this study of over ten million FDA Adverse Event Reporting System records, we provided evidence of kidney injury and electrolyte imbalances in an alarming number of patients taking PPIs. Additionally, we assessed differences between specific PPIs and observed significant electrolyte and renal abnormalities for each individual drug with varying magnitudes.

Proton-pump inhibitors, PPIs, are considered effective therapy for stomach acid suppression due to their irreversible inhibition of the hydrogen/potassium pump in the gastric parietal cells. They are widely prescribed and are considered safe for over-the-counter use. Recent studies have shown an association between PPI use and Alzheimer dementia, while others have disputed that connection. We analyzed over ten million United States Food and Drug Administration Adverse Event Reporting System reports, including over forty thousand reports containing PPIs, and provided evidence of increased propensity for memory impairment among PPI reports when compared to histamine-2 receptor antagonist control group. Furthermore, we found significant associations of PPI use with a wide range of neurological adverse reactions including, migraine, several peripheral neuropathies, and visual and auditory neurosensory abnormalities.

Tramadol is one of the most commonly used analgesics worldwide, classified as having a low abuse potential by U.S. Drug Enforcement Agency, and often recommended in pain management guidelines. Its pain-relieving mechanism of action is attributed to mild μ-opioid receptor agonism, serotonin and norepinephrine mediated nociception modulation, and N-methyl-D-aspartate receptor, NMDAR, antagonism. However, recent case reports and case-control studies have shown an association between tramadol use and hypoglycemia. The growing concern over increasing tramadol use and unexpected side effects warranted a further comparative and quantitative analysis of tramadol adverse reactions. In this study we analyzed over twelve million reports from United States Food and Drug Administration Adverse Event Reporting System and provided evidence of increased propensity for hypoglycemia in patients taking tramadol when compared to patients taking other opioids, serotonin-norepinephrine reuptake inhibitors, and drugs affecting NMDAR activity. Additionally, we identified that only methadone from the opioid cohort behaves similarly to tramadol and has an association with hypoglycemia.

Current therapeutic approaches to depression fail for millions of patients due to lag in clinical response and non-adherence. Here we provide new support for the antidepressant effect of an anesthetic drug, ketamine, by Inverse-Frequency Analysis of eight million reports from the FDA Adverse Effect Reporting System. The results of the examination of population scale data revealed that patients who received ketamine had significantly lower frequency of reports of depression than patients who took any other combination of drugs for pain. The analysis also revealed that patients who took ketamine had significantly lower frequency of reports of pain and opioid induced side effects, implying ketamine’s potential to act as a beneficial adjunct agent in pain management pharmacotherapy. Further, the Inverse-Frequency Analysis methodology provides robust statistical support for the antidepressant action of other currently approved therapeutics including diclofenac and minocycline.

The World Health Organization estimates the number of people suffering from depression to be over 264 million. Current monoamine transmission modulating therapeutics, even with proper adherence and acceptable tolerability, are not effective for nearly one third of the patients, leading clinicians to explore other therapeutic options such as electroconvulsive therapy, transcranial magnetic stimulation, ketamine infusions, and, more recently, glabellar botulinum toxin, BoNT, injections. The scale and mechanism of antidepressant action of BoNT is unclear and maybe hypothetically attributed to the disruption of proprioceptive facial feedback reinforcing negative emotions. Here we verify the antidepressant effect of botulinum toxin by analysis of over 40 thousand BoNT treatment reports out of thirteen million postmarketing safety reports in the FDA Adverse Event Reporting System, FAERS. The results of the analysis indicate that patients who received BoNT injections to treat hyperhidrosis, facial wrinkles, migraine prophylaxis, spasticity, and spasms, had a significantly lower number of depression reports when compared to patients undergoing different treatments for the same conditions. These findings suggest that the antidepressant effect of BoNT is significant, and, surprisingly, is observed for a broad range of injection sites.

Currently approved monoamine modulating antidepressant and anxiolytic pharmaceutics fail in over one third of patients due to delayed and variable therapeutic effect, adverse reactions preceding the therapeutic action, and adherence issues. Even with adequate adherence to the regimen and tolerability, one third of the patients do not respond to any class of antidepressants. There is a strong correlation between treatment resistant depression and increase in inflammatory cytokines in plasma and cerebrospinal fluid. Furthermore, epidemiological studies suggest that depression and anxiety are commonly comorbid with pain and inflammation. While a link between pain, inflammation and depression has been suggested it remains unclear which anti-inflammatory treatment may be beneficial to patients with depression and anxiety due to pain. Here, we analyzed 430,783 FDA adverse effect reports of patients treated for pain to identify potential antidepressant and anxiolytic effects of various anti-inflammatory medications. Patients treated for depression or patients taking any known antidepressants were excluded. The odds ratio analysis of 139,072 NSAID reports revealed that ketoprofen was associated with decreased reports of depression by a factor of 2.32 (OR 0.43 and 95% Confidence Interval [0.31, 0.59]) and decreased reports of anxiety by a factor of 2.86 (OR 0.35 [0.22, 0.56]), diclofenac with decreased depression reports by a factor of 2.22 (OR 0.45 [0.40, 0.49]) and anxiety by a factor of 2.13 (OR 0.47 [0.41, 0.54]), while naproxen decreased depression reports by a factor of 1.92 (OR 0.52 [0.49, 0.57]) and anxiety by a factor of 1.23 (OR 0.81 [0.75, 0.88]). Other NSAIDs did not exhibit any noticeable antidepressant and/or anxiolytic effect.