Amitriptyline

Hepatocellular carcinoma (HCC) is one of the most lethal human cancers. The search for targeted treatments has been hampered by the lack of relevant animal models for the genetically diverse subsets of HCC, including the 20-40% of HCCs that are defined by activating mutations in the gene encoding β-catenin. To address this chemotherapeutic challenge, we created and characterized transgenic zebrafish expressing hepatocyte-specific activated β-catenin. By 2 months post fertilization (mpf), 33% of transgenic zebrafish developed HCC in their livers, and 78% and 80% of transgenic zebrafish showed HCC at 6 and 12 mpf, respectively. As expected for a malignant process, transgenic zebrafish showed significantly decreased mean adult survival compared to non-transgenic control siblings. Using this novel transgenic model, we screened for druggable pathways that mediate β-catenin-induced liver growth and identified two c-Jun N-terminal kinase (JNK) inhibitors and two antidepressants (one tricyclic antidepressant, amitriptyline, and one selective serotonin reuptake inhibitor) that suppressed this phenotype. We further found that activated β-catenin was associated with JNK pathway hyperactivation in zebrafish and in human HCC. In zebrafish larvae, JNK inhibition decreased liver size specifically in the presence of activated β-catenin. The β-catenin-specific growth-inhibitory effect of targeting JNK was conserved in human liver cancer cells. Our other class of hits, antidepressants, has been used in patient treatment for decades, raising the exciting possibility that these drugs could potentially be repurposed for cancer treatment. In support of this proposal, we found that amitriptyline decreased tumor burden in a mouse HCC model. Our studies implicate JNK inhibitors and antidepressants as potential therapeutics for β-catenin-induced liver tumors.

The cuprizone animal model, also known as the toxic demyelination model, is a well-reproducible model of demyelination- and remyelination in mice, and has been useful in studying important aspect of human demyelinating diseases, including multiple sclerosis. In this study, we investigated the role of acid sphingomyelinase in demyelination and myelin repair by inducing acute and chronic demyelination with 5- or 12-week cuprizone treatment, followed by a 2-week cuprizone withdrawal phase to allow myelin repair. Sphingolipids, in particular ceramide and the enzyme acid sphingomyelinase, which generates ceramide from sphingomyelin, seem to be involved in astrocyte activation and neuronal damage in multiple sclerosis. We used immunohistochemistry to study glial reaction and oligodendrocyte distribution in acid sphingomyelinase deficient mice and wild-type C57BL/6J littermates at various time intervals after demyelination and remyelination. Axonal injury was quantified using amyloid precursor protein and synaptophysin, and gene expression and protein levels were measured using gene analysis and Western blotting, respectively. Our results show that mice lacking acid sphingomyelinase had a significant increase in myelin recovery and a significantly higher oligodendrocyte cell count after 2 weeks remyelination compared to wild-type littermates. Detrimental astroglial distribution was also significantly reduced in acid sphingomyelinase deficient animals. We obtained similar results in experiments using amitriptyline to inhibit acid sphingomyelinase. These findings suggest that acid sphingomyelinase plays a significant role in myelin repair, and its inhibition by amitriptyline may constitute a novel therapeutic approach for multiple sclerosis patients.

ObjectiveThe aim of this paper is to critically re-appraise the published trials assessing amitriptyline for migraine prophylaxis.MethodsWe report our methods and results following the Preferred Reporting Items for Systematic Reviews (PRISMA), by searching MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov for randomized trials of pharmacologic treatments for migraine prophylaxis. We included randomized trials that compared amitriptyline with placebo for migraine prophylaxis in adults. Our outcomes of interest were informed by the Outcome Set for preventive intervention trials in chronic and episodic migraine (COSMIG) and include the proportion of patients who experience a 50% or more reduction in migraine days per month, migraine days per month, and adverse events leading to discontinuation. We assessed risk of bias by using a modified Cochrane RoB 2.0 tool and the certainty of evidence by using the GRADE approach.ResultsOur search yielded 10.826 unique records, of which three trials (n = 622) were eligible for data synthesis and analysis. We found moderate certainty evidence that amitriptyline increases the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo (relative risk: 1.60 (95% CI 1.17 to 2.19); absolute risk difference: 165 more per 1,000 (95% CI 47 more to 327 more). We found moderate certainty evidence that amitriptyline increases the proportion of patients who discontinue due to adverse events compared to placebo (risk difference: 0.05 (95% CI 0.01 to 0.10); absolute risk difference: 50 more per 1,000 (95% CI 10 more to 100 more).ConclusionsOur meta-analysis showed that amitriptyline may have a prophylactic role in migraine patients, however these results are far from robust. This warrants further large-scale research to evaluate the role of amitriptyline in migraine prevention.

ImportanceFibromyalgia (FM) is a chronic pain condition associated with substantial quality-of-life impairments and economic burden. Although multiple pharmacologic options are recommended in clinical guidelines, the relative cost-effectiveness of off-label amitriptyline compared with FDA-approved treatments remains poorly defined due to a scarcity of direct economic comparisons and the use of heterogenous outcome measures in the extant literature.ObjectiveTo evaluate the cost-effectiveness of pregabalin, duloxetine, and milnacipran compared with amitriptyline in adults with moderate to severe FM.Design, setting, and participantsDecision analytical model using a Markov cohort state transition model to estimate lifetime costs and quality-adjusted life-years (QALYs) for each investigated pharmacologic strategy. Model inputs included treatment-specific transition probabilities, utility values, and direct and indirect costs for each health state, which were derived from published sources. The simulated cohort reflected adults (aged ≥18 years) with moderate to severe FM. Data were analyzed between September 2024 and February 2025.ExposureAmitriptyline (25-100 mg), pregabalin (150, 300, 450, and 600 mg), duloxetine (60 and 120 mg), and milnacipran (100 and 200 mg), evaluated from US health care payer and societal perspectives.Main outcomes and measuresExpected lifetime cost, QALYs, incremental cost-effectiveness ratios (ICERs), and incremental net monetary benefit (iNMB) at willingness-to-pay (WTP) thresholds of $50 000, $100 000, and $150 000 per QALY.ResultsThe simulated cohort included predominantly women (94.4%), had a mean (SD) age of 48.4 (10.4) years, and was parameterized using demographic distributions derived from published FM populations. From the US health care payer perspective, duloxetine 120 mg was associated with increased QALYs versus amitriptyline at slightly higher cost (ICER, $1536 per QALY), while pregabalin 450 mg was dominated by duloxetine 120 mg. When societal costs were considered, duloxetine 120 mg and pregabalin 450 mg were cost saving relative to amitriptyline. Amitriptyline remained both more effective and less costly than milnacipran, lower doses of pregabalin and duloxetine, and no treatment. At a $100 000 WTP threshold, iNMB for duloxetine 120 mg was $40 375 from the health care payer perspective and $70 063 from the societal perspective; for pregabalin 450 mg, iNMB was $21 211 and $40 190 for the health care payer and societal perspectives, respectively.Conclusions and relevanceIn this decision analytical model, duloxetine 120 mg was the preferred strategy across perspectives; pregabalin 450 mg was economically favorable relative to amitriptyline only when societal costs were included. Amitriptyline provided greater net benefit than milnacipran and the lower doses of pregabalin and duloxetine. These findings may help inform the selection of value-based treatments for moderate to severe FM.