-
Current Treatment Options in Oncology Mar 2022Preventing depression in cancer patients on long-term opioid therapy should begin with depression screening before opioid initiation and repeated screening during... (Review)
Review
Preventing depression in cancer patients on long-term opioid therapy should begin with depression screening before opioid initiation and repeated screening during treatment. In weighing the high morbidity of depression and opioid use disorder in patients with chronic cancer pain against a dearth of evidence-based therapies studied in this population, patients and clinicians are left to choose among imperfect but necessary treatment options. When possible, we advise engaging psychiatric and pain/palliative specialists through collaborative care models and recommending mindfulness and psychotherapy to all patients with significant depression alongside cancer pain. Medications for depression should be reserved for moderate to severe symptoms. We recommend escitalopram/citalopram or sertraline among selective serotonin reuptake inhibitors (SSRIs), or the serotonin and norepinephrine reuptake inhibitors (SNRIs) duloxetine, venlafaxine, or desvenlafaxine if patients have a significant component of neuropathic pain or fibromyalgia. Tricyclic antidepressants (TCAs) (consider nortriptyline or desipramine, which have better anticholinergic profiles) should be considered for patients who do not respond to or tolerate SSRI/SNRIs. Existing evidence is inadequate to definitively recommend methylphenidate or novel agents, such as ketamine or psilocybin, as adjunctive treatments for cancer-related depression and pain. Physicians who treat patients with cancer pain should utilize universal precautions to limit the risk of non-medical opioid use (non-medical opioid use). Patients should be screened for non-medical opioid use behaviors at initial consultation and at regular intervals during treatment using a non-judgmental approach that reduces stigma. Co-management with an addiction specialist may be indicated for patients at high risk of non-medical opioid use and opioid use disorder. Buprenorphine and methadone are indicated for the treatment of opioid use disorder, and while they have not been systematically studied for treatment of opioid use disorder in patients with cancer pain, they do provide analgesia for cancer pain. While an interdisciplinary team approach to manage psychological stress may be beneficial, this may not be possible for patients treated outside of comprehensive cancer centers.
Topics: Analgesics, Opioid; Cancer Pain; Depression; Humans; Neoplasms; Opioid-Related Disorders; Pain; Pain Management; Prescriptions; Selective Serotonin Reuptake Inhibitors; Serotonin and Noradrenaline Reuptake Inhibitors
PubMed: 35254595
DOI: 10.1007/s11864-022-00954-4 -
Frontiers in Pharmacology 2021-methyl-D-aspartate receptors (NMDARs) are an essential target for the analgetic action of tricyclic antidepressants (TCAs). Their therapeutic blood concentrations...
-methyl-D-aspartate receptors (NMDARs) are an essential target for the analgetic action of tricyclic antidepressants (TCAs). Their therapeutic blood concentrations achieve 0.5-1.5 μM, which, however, are insufficient to cause the open-channel block known as the only effect of TCAs on NMDARs. Whereas structures of amitriptyline (ATL), desipramine (DES), and clomipramine (CLO) are rather similar these compounds manifest different therapeutic profiles and side effects. To study structure-activity relationships of DES and CLO on NMDARs, we measured ICs as a function of extracellular calcium ([Ca]) and membrane voltage (V) of NMDAR currents recorded in cortical neurons. Here two components of TCA action on NMDARs are described, which could be characterized as the Ca-dependent inhibition and the open-channel block. DES demonstrated a profound Ca-dependent inhibition of NMDARs, while the CLO effect was weak. DES IC exhibited an e-fold change with a [Ca] shift of 0.59 mM, which is consistent with ATL. The Ca dependence of NMDAR inhibition by DES disappeared in BAPTA loaded neurons, suggesting that Ca acts from the inside. Since CLO differs from DES and ATL by the presence of Cl-atom in the structure, most likely, this is the atom which is responsible for the loss of pronounced [Ca] dependence. As for the NMDAR open-channel block, both DES and CLO were about 5-folds more potent than ATL due to their slow rates of dissociation either from open and closed states. DES demonstrated stronger V-dependence than CLO, suggesting a deeper location of the DES binding site within the ion pore. Because DES and CLO differ from ATL by the nitrogen-containing tricycle, presumably this moiety of the molecules determines their high-affinity binding with the NMDAR channel, while the aliphatic chain mono-methyl amino-group of DES allows a deep permeation in the channel. Thus, different structure-activity relationships of the Ca-dependent inhibition and V-dependent open-channel block of NMDARs by DES and CLO suggest that these processes are independent and most likely may represent an action on different molecular targets. The proposed model of TCA action on NMDARs predicts well the experimental values of ICs at physiological [Ca] and within a wide range of Vs.
PubMed: 35237149
DOI: 10.3389/fphar.2021.815368 -
Pharmaceutics Jan 2022A drug/proton-antiporter, whose the molecular structure is still unknown, was previously evidenced at the blood-brain barrier (BBB) by functional experiments. The...
A drug/proton-antiporter, whose the molecular structure is still unknown, was previously evidenced at the blood-brain barrier (BBB) by functional experiments. The computational method could help in the identification of substrates of this solute carrier (SLC) transporter. Two pharmacophore models for substrates of this transporter using the FLAPpharm approach were developed. The trans-stimulation potency of 40 selected compounds for already known specific substrates ([H]-clonidine) were determined and compared in the human brain endothelial cell line hCMEC/D3. Results. The two pharmacophore models obtained were used as templates to screen xenobiotic and endogenous compounds from four databases (e.g., Specs), and 45 hypothetical new candidates were tested to determine their substrate capacity. Psychoactive drugs such as antidepressants (e.g., imipramine, desipramine), antipsychotics/neuroleptics such as phenothiazine derivatives (chlorpromazine), sedatives anti-histamine-H drugs (promazine, promethazine, triprolidine, pheniramine), opiates/opioids (e.g., hydrocodone), trihexyphenidyl and sibutramine were correctly predicted as proton-antiporter substrates. The best performing pharmacophore model for the proton-antiporter substrates appeared as a good predictor of known substrates and allowed the identification of new substrate compounds. This model marks a new step in the characterization of this drug/proton-antiporter and will be of great use in uncovering its substrates and designing chemical entities with an improved influx capability to cross the BBB.
PubMed: 35213988
DOI: 10.3390/pharmaceutics14020255 -
Scientific Reports Feb 2022Psychostimulants have a paradoxical calming effect in the treatment of attention deficit hyperactivity disorder (ADHD), but their mechanism of action is unclear. Studies...
Psychostimulants have a paradoxical calming effect in the treatment of attention deficit hyperactivity disorder (ADHD), but their mechanism of action is unclear. Studies using dopamine (DA) transporter (DAT) knockout (KO) mice have suggested that the paradoxical calming effect of psychostimulants might occur through actions on serotonin (5-HT) neurotransmission. However, newer non-stimulant drugs, such as atomoxetine and guanfacine, suggest that targeting the norepinephrine (NE) system in the prefrontal cortex (PFC) might explain this paradoxical calming effect. Thus, we sought to clarify the mechanism of this paradoxical action of psychostimulants. Our ex vivo efflux experiments reveal that the NE transporter (NET) blocker desipramine elevates both norepinephrine (NE) and dopamine (DA), but not 5-HT levels, in PFC tissue slices from wild-type (WT) and DAT-KO, but not NET-KO mice. However, the 5-HT transporter (SERT) inhibitor fluoxetine elevates only 5-HT in all three genotypes. Systemic administration of desipramine or fluoxetine inhibits hyperactivity in DAT-KO mice, whereas local PFC infusion of desipramine alone produced this same effect. In contrast, pharmacological NE depletion and DA elevation using nepicastat also inhibits hyperactivity in DAT-KO mice. Together, these data suggest elevation of PFC DA and not NE or 5-HT, as a convergent mechanism for the paradoxical effects of psychostimulants observed in ADHD therapy.
Topics: Animals; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Dopamine; Dopamine Plasma Membrane Transport Proteins; Mice; Mice, Knockout; Prefrontal Cortex
PubMed: 35210489
DOI: 10.1038/s41598-022-07029-2 -
International Journal of Cancer Jul 2022Malignant brain tumors, such as glioblastoma multiforme (GBM) and brain metastases, continue to be an unmet medical challenge. Despite advances in cancer diagnostics and... (Review)
Review
Malignant brain tumors, such as glioblastoma multiforme (GBM) and brain metastases, continue to be an unmet medical challenge. Despite advances in cancer diagnostics and therapeutics, tumor cell colonization in the central nervous system renders most treatment options ineffective. This is primarily due to the selective permeability of the blood-brain barrier (BBB), which hinders the crossing of targeting agents into the brain. As such, repositioning medications that demonstrate anticancer effects and possess the ability to cross the BBB can be a promising option. Antidepressants, which are BBB-permeable, have been reported to exhibit cytotoxicity against tumor cells. Autophagy, specifically, has been identified as one of the common key mediators of antidepressant's antitumor effects. In this work, we provide a comprehensive overview of US Food and Drug Administration (FDA)-approved antidepressants with reported cytotoxic activities in different tumor models, where autophagy dysregulation was demonstrated to play the main part. As such, imipramine, maprotiline, fluoxetine and escitalopram were shown to induce autophagy, whereas nortriptyline, clomipramine and paroxetine were identified as autophagy inhibitors. Sertraline and desipramine, depending on the neoplastic context, were demonstrated to either induce or inhibit autophagy. Collectively, these medications were associated with favorable therapeutic outcomes in a variety of cancer cell models, including brain tumors.
Topics: Antidepressive Agents; Autophagy; Brain Neoplasms; Drug Repositioning; Glioblastoma; Humans
PubMed: 35179776
DOI: 10.1002/ijc.33965 -
BMC Neurology Feb 2022Bainbridge-Ropers syndrome is caused by monoallelic ASXL3 variants on chromosome 18. Clinical features include dysmorphic facies, developmental delay, intellectual...
BACKGROUND
Bainbridge-Ropers syndrome is caused by monoallelic ASXL3 variants on chromosome 18. Clinical features include dysmorphic facies, developmental delay, intellectual disability, autistic traits, hypotonia, failure to thrive, seizures and hyperventilation. Breath-holding spells with choreathetoid movements have been previously described.
CASE PRESENTATION
We describe an 11-year old boy who has daily intractable seizures reported since birth, developmental delay, autistic features and feeding difficulties. He was eventually found to have de novo, heterozygous pathogenic variant (c.1612G > T, p.E538*) in the ASXL3 gene. He has frequent episodes of breath-holding accompanied by dystonic posturing with right leg extension and head turning without ictal EEG correlate. The breath-holding spells have been refractory to several medication trials including iron supplementation, acetazolamide, and desipramine.
CONCLUSIONS
This case represents a more severe phenotype of Bainbridge-Ropers Syndrome than previously described with refractory breath-holding spells with dystonia, intractable epilepsy, and progressive cerebral/cerebellar atrophy. Breath-holding spells cause significant morbidity, are poorly understood, and have very limited treatment options.
Topics: Breath Holding; Child; Developmental Disabilities; Drug Resistant Epilepsy; Humans; Male; Phenotype; Transcription Factors
PubMed: 35172777
DOI: 10.1186/s12883-022-02573-w -
Frontiers in Psychiatry 2021Depression and post-traumatic stress disorder (PTSD) highly co-occur with alcohol use disorder (AUD). The comparative effects of noradrenergic vs. serotonergic...
Depression and post-traumatic stress disorder (PTSD) highly co-occur with alcohol use disorder (AUD). The comparative effects of noradrenergic vs. serotonergic antidepressants on drinking and depressive outcomes for those with AUD and co-occurring depression and/or PTSD are not well known. This study was an analysis of a randomized control trial of 128 patients with AUD who had co-occurring depression and/or PTSD. They were randomized to treatment with paroxetine vs. desipramine and naltrexone vs. placebo leading to four groups: paroxetine plus naltrexone, paroxetine plus placebo, desipramine plus naltrexone, and desipramine plus placebo. Outcomes were percent of drinking days, percent heavy drinking days, drinks per drinking day (Time Line Follow-back Method), and depressive symptoms (Hamilton Depression Scale). Groups compared were (1) depression without PTSD (depression group; = 35), (2) PTSD without depression (PTSD group; = 33), and (3) both depression and PTSD (comorbid group; = 60). There were no overall significant differences in drinking outcomes by medication in the entire sample, and no significant interaction when diagnostic groups were not considered. However, when diagnostic groups were included in the model, the interactions between time, diagnostic group, and medication (desipramine vs. paroxetine) were significant for percent drinking days ( = 0.042), and percent heavy drinking days ( = 0.036); paroxetine showed better drinking outcomes within the depression group, whereas desipramine showed better drinking outcomes in the PTSD and comorbid groups. Regarding depressive symptoms, paroxetine was statistically superior to desipramine in the total sample ( = 0.007), but there was no significant interaction of diagnostic group and medication. Naltrexone led to a decrease in craving but no change in drinking outcomes. The results of this study suggest that drinking outcomes may respond differently to desipramine and paroxetine depending on comorbid MDD and/or PTSD.
PubMed: 35058816
DOI: 10.3389/fpsyt.2021.768318 -
JCI Insight Feb 2022Adiponectin receptor 1 (ADIPOR1) is a lipid and glucose metabolism regulator that possesses intrinsic ceramidase activity. Mutations of the ADIPOR1 gene have been...
Adiponectin receptor 1 (ADIPOR1) is a lipid and glucose metabolism regulator that possesses intrinsic ceramidase activity. Mutations of the ADIPOR1 gene have been associated with nonsyndromic and syndromic retinitis pigmentosa. Here, we show that the absence of AdipoR1 in mice leads to progressive photoreceptor degeneration, significant reduction of electroretinogram amplitudes, decreased retinoid content in the retina, and reduced cone opsin expression. Single-cell RNA-Seq results indicate that ADIPOR1 encoded the most abundantly expressed ceramidase in mice and one of the 2 most highly expressed ceramidases in the human retina, next to acid ceramidase ASAH1. We discovered an accumulation of ceramides in the AdipoR1-/- retina, likely due to insufficient ceramidase activity for healthy retina function, resulting in photoreceptor death. Combined treatment with desipramine/L-cycloserine (DC) lowered ceramide levels and exerted a protective effect on photoreceptors in AdipoR1-/- mice. Moreover, we observed improvement in cone-mediated retinal function in the DC-treated animals. Lastly, we found that prolonged DC treatment corrected the electrical responses of the primary visual cortex to visual stimuli, approaching near-normal levels for some parameters. These results highlight the importance of ADIPOR1 ceramidase in the retina and show that pharmacological inhibition of ceramide generation can provide a therapeutic strategy for ADIPOR1-related retinopathy.
Topics: Animals; Ceramidases; DNA; DNA Mutational Analysis; Disease Models, Animal; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Receptors, Adiponectin; Retinal Cone Photoreceptor Cells; Retinal Diseases
PubMed: 35015730
DOI: 10.1172/jci.insight.156301 -
Biomedicine & Pharmacotherapy =... Feb 2022Depression is associated with thrombotic risk and arterial events, its proper management is strongly recommended in coronary artery disease (CAD) patients. We have...
Depression is associated with thrombotic risk and arterial events, its proper management is strongly recommended in coronary artery disease (CAD) patients. We have previously shown that the Brain-Derived Neurotrophic Factor (BDNF)Val66Met polymorphism, related to depression, is associated with arterial thrombosis in mice, and with an increased risk of acute myocardial infarction in humans. Herein, expanding the previous findings on BDNFVal66Met polymorphism, we show that desipramine, a norepinephrine reuptake-inhibitor, rescues behavioral impairments, reduces the arterial thrombosis risk, abolishes pathological coagulation and platelet hyper-reactivity, normalizes leukocyte, platelet, and bone marrow megakaryocyte number and restores physiological norepinephrine levels in homozygous knock-in BDNF Val66Met (BDNF) mice. The in vitro data confirm the enhanced procoagulant activity and the alpha-adrenergic receptor (α-ADR) overexpression found in BDNF mice and we provide evidence that, in presence of Met variant, norepinephrine is crucial to up-regulate procoagulant activity and to enhance platelet generation. The α-ADR antagonist rauwolscine rescues the prothrombotic phenotype in BDNF mice and reduces procoagulant activity and platelet generation in cells transfected with BDNF plasmid or exposed to pro-BDNF peptide. Finally, we show that homozygous BDNF CAD patients have hyper-reactive platelets overexpressing abundant α-ADR. The great proplatelet release from their megakaryocytes well reflects their higher circulating platelet number compared to BDNF patients. These data reveal an unprecedented described role of Met allele in the dysregulation of norepinephrine/α-ADR pathway that may explain the predisposition to arterial thrombosis. Overall, the development of α-ADR inhibitors might represent a pharmacological treatment for depression-associated thrombotic conditions in this specific subgroup of CAD patients.
Topics: Aged; Aged, 80 and over; Animals; Blood Coagulation; Brain-Derived Neurotrophic Factor; Coronary Artery Disease; Depression; Desipramine; Female; Humans; Male; Mice; Middle Aged; Norepinephrine; Polymorphism, Single Nucleotide; Receptors, Adrenergic, alpha-2; Thrombosis
PubMed: 34965503
DOI: 10.1016/j.biopha.2021.112557 -
Circulation Jan 2022Multiple pharmacogenomic studies have identified the synonymous genomic variant rs7853758 (G > A, L461L) and the intronic variant rs885004 in (solute carrier family 28...
BACKGROUND
Multiple pharmacogenomic studies have identified the synonymous genomic variant rs7853758 (G > A, L461L) and the intronic variant rs885004 in (solute carrier family 28 member 3) as statistically associated with a lower incidence of anthracycline-induced cardiotoxicity. However, the true causal variant(s), the cardioprotective mechanism of this locus, the role of and other solute carrier (SLC) transporters in anthracycline-induced cardiotoxicity, and the suitability of SLC transporters as targets for cardioprotective drugs has not been investigated.
METHODS
Six well-phenotyped, doxorubicin-treated pediatric patients from the original association study cohort were recruited again, and human induced pluripotent stem cell-derived cardiomyocytes were generated. Patient-specific doxorubicin-induced cardiotoxicity (DIC) was then characterized using assays of cell viability, activated caspase 3/7, and doxorubicin uptake. The role of in DIC was then queried using overexpression and knockout of in isogenic human-induced pluripotent stem cell-derived cardiomyocytes using a CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9). Fine-mapping of the locus was then completed after resequencing and an extended in silico haplotype and functional analysis. Genome editing of the potential causal variant was done using cytosine base editor. overexpression was done using a lentiviral plasmid-based transduction and was validated using stranded RNA-sequencing after ribosomal RNA depletion. Drug screening was done using the Prestwick Chemical Library (n = 1200), followed by in vivo validation in mice. The effect of desipramine on doxorubicin cytotoxicity was also investigated in 8 cancer cell lines.
RESULTS
Here, using the most commonly used anthracycline, doxorubicin, we demonstrate that patient-derived cardiomyocytes recapitulate the cardioprotective effect of the locus and that SLC28A3 expression influences the severity of DIC. Using Nanopore-based fine-mapping and base editing, we identify a novel cardioprotective single nucleotide polymorphism, rs11140490, in the locus; its effect is exerted via regulation of an antisense long noncoding RNA () that overlaps with Using high-throughput drug screening in patient-derived cardiomyocytes and whole organism validation in mice, we identify the SLC competitive inhibitor desipramine as protective against DIC.
CONCLUSIONS
This work demonstrates the power of the human induced pluripotent stem cell model to take a single nucleotide polymorphism from a statistical association through to drug discovery, providing human cell-tested data for clinical trials to attenuate DIC.
Topics: Animals; Cardiotoxicity; Disease Models, Animal; Doxorubicin; Genetic Variation; Genomics; Humans; Male; Mice
PubMed: 34874743
DOI: 10.1161/CIRCULATIONAHA.121.055801