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JMIR Public Health and Surveillance Jan 2024Drug-induced suicide (DIS) is a severe adverse drug reaction (ADR). Although clinical trials have provided evidence on DIS, limited investigations have been performed on... (Review)
Review
BACKGROUND
Drug-induced suicide (DIS) is a severe adverse drug reaction (ADR). Although clinical trials have provided evidence on DIS, limited investigations have been performed on rare ADRs, such as suicide.
OBJECTIVE
We aimed to systematically review case reports on DIS to provide evidence-based drug information.
METHODS
We searched PubMed to obtain case reports regarding DIS published until July 2021. Cases resulting from drugs that are no longer used or are nonapproved, substance use, and suicidal intentions were excluded. The quality of each case report was assessed using the CASE (Case Reports) checklist. We extracted data regarding demographics, medication history, suicide symptoms, and symptom improvement and evaluated the causality of DIS using the Naranjo score. Furthermore, to identify the potential suicidal risk of the unknown drugs, we compared the results of the causality assessment with those of the approved drug labels.
RESULTS
In 83 articles, we identified 152 cases involving 61 drugs. Antidepressants were reported as the most frequent causative drugs of DIS followed by immunostimulants. The causality assessment revealed 61 cases having possible, 89 cases having probable, and 2 cases having definite relationships with DIS. For approximately 85% of suspected drugs, the risk of suicidal ADRs was indicated on the approved label; however, the approved labels for 9 drugs, including lumacaftor/ivacaftor, doxycycline, clozapine, dextromethorphan, adalimumab, infliximab, piroxicam, paclitaxel, and formoterol, did not provide information about these risks.
CONCLUSIONS
We found several case reports involving drugs without suicide risk information on the drug label. Our findings might provide valuable insights into drugs that may cause suicidal ADRs.
Topics: Humans; Doxycycline; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Suicidal Ideation; Suicide; Case Reports as Topic
PubMed: 38289650
DOI: 10.2196/49755 -
Drug Metabolism and Disposition: the... Mar 2024Tree shrews are a nonprimate species used in a range of biomedical studies. Recent genome analysis of tree shrews found that the sequence identities and the numbers of...
Tree shrews are a nonprimate species used in a range of biomedical studies. Recent genome analysis of tree shrews found that the sequence identities and the numbers of genes of cytochrome P450 (CYP or P450), an important family of drug-metabolizing enzymes, are similar to those of humans. However, tree shrew P450s have not yet been sufficiently identified and analyzed. In this study, novel CYP2D8a and CYP2D8b cDNAs were isolated from tree shrew liver and were characterized, along with human CYP2D6, dog CYP2D15, and pig CYP2D25. The amino acid sequences of these tree shrew CYP2Ds were 75%-78% identical to human CYP2D6, and phylogenetic analysis showed that they were more closely related to human CYP2D6 than rat CYP2Ds, similar to dog and pig CYP2Ds. For tree shrew CYP2D8b, two additional transcripts were isolated that contained different patterns of deletion. The gene and genome structures of are generally similar in dogs, humans, pigs, and tree shrews. Tree shrew CYP2D8a mRNA was most abundantly expressed in liver, among the tissue types analyzed, similar to dog CYP2D15 and pig CYP2D25 mRNAs. Tree shrew CYP2D8b mRNA was also expressed in liver, but at a level 7.3-fold lower than CYP2D8a mRNA. Liver microsomes and recombinant protein of both tree shrew CYP2Ds metabolized bufuralol and dextromethorphan, selective substrates of human CYP2D6, but the activity level of CYP2D8a greatly exceeded that of CYP2D8b. These results suggest that tree shrew CYP2D8a and CYP2D8b are functional drug-metabolizing enzymes, of which CYP2D8a is the major CYP2D in liver. SIGNIFICANCE STATEMENT: Novel tree shrew CYP2D8a and CYP2D8b cDNAs were isolated from liver. Their amino acid sequences were 75%-78% identical to human CYP2D6. For CYP2D8b, two additional transcripts contained different patterns of deletion. Tree shrew CYP2D8a mRNA was abundantly expressed in liver, similar to dog CYP2D15 and pig CYP2D25 mRNAs. Recombinant tree shrew CYP2Ds catalyzed the oxidation of bufuralol and dextromethorphan. Tree shrew CYP2D8a and CYP2D8b are functional drug-metabolizing enzymes, of which CYP2D8a is the major CYP2D in liver.
Topics: Humans; Rats; Swine; Animals; Dogs; Cytochrome P-450 CYP2D6; Dextromethorphan; Tupaia; Tupaiidae; Phylogeny; Shrews; Cytochrome P-450 Enzyme System; Microsomes, Liver; RNA, Messenger; Ethanolamines
PubMed: 38262704
DOI: 10.1124/dmd.123.001603 -
Journal of Molecular Neuroscience : MN Jan 2024Hypothalamus is central to food intake and satiety. Recent data unveiled the expression of N-methyl-D-aspartate receptors (NMDAR) on hypothalamic neurons and their...
Hypothalamus is central to food intake and satiety. Recent data unveiled the expression of N-methyl-D-aspartate receptors (NMDAR) on hypothalamic neurons and their interaction with GABA and serotoninergic neuronal circuits. However, the precise mechanisms governing energy homeostasis remain elusive. Notably, in females, the consumption of progesterone-containing preparations, such as hormonal replacement therapy and birth control pills, has been associated with hyperphagia and obesity-effects mediated through the hypothalamus. To elucidate this phenomenon, we employed the progesterone-induced obesity model in female Swiss albino mice. Four NMDAR modulators were selected viz. dextromethorphan (Dxt), minocycline, d-aspartate, and cycloserine. Obesity was induced in female mice by progesterone administration for 4 weeks. Mice were allocated into 7 groups, group-1 as vehicle control (arachis oil), group-2 (progesterone + arachis oil), and group-3 as positive-control (progesterone + sibutramine); other groups were treated with test drugs + progesterone. Various parameters were recorded like food intake, thermogenesis, serum lipids, insulin, AST and ALT levels, organ-to-body weight ratio, total body fat, adiposity index, brain serotonin levels, histology of liver, kidney, and sizing of fat cells. Dxt-treated group has shown a significant downturn in body weight (p < 0.05) by a decline in food intake (p < 0.01), organ-to-liver ratio (p < 0.001), adiposity index (p < 0.01), and a rise in body temperature and brain serotonin level (p < 0.001). Dxt demonstrated anti-obesity effects by multiple mechanisms including interaction with hypothalamic GABA channels and anti-inflammatory and free radical scavenging effects, improving the brain serotonin levels, and increasing insulin release from the pancreatic β-cells.
Topics: Female; Mice; Animals; N-Methylaspartate; Receptors, N-Methyl-D-Aspartate; Serotonin; Progesterone; Peanut Oil; Obesity; Hypothalamus; Insulins; gamma-Aminobutyric Acid
PubMed: 38240858
DOI: 10.1007/s12031-023-02178-z -
American Journal of TherapeuticsMajor depressive disorder (MDD) affects millions of people and is the leading cause of disability worldwide. Patients report decreased quality of life and ability to...
BACKGROUND
Major depressive disorder (MDD) affects millions of people and is the leading cause of disability worldwide. Patients report decreased quality of life and ability to perform activities of daily living. It is estimated that the current standard of care, which includes pharmacologic therapy with a selective serotonin reuptake inhibitor, is effective in 40%-60%. Additional treatment options are warranted. The combination of dextromethorphan (DEX) and bupropion (BUP) (Auveulty) was approved for treatment in 2022. This unique combination offers an interesting mechanism of action and favorable onset of action for patients with MDD.
PHARMACODYNAMICS AND PHARMACOKINETICS
The mechanism of action of DEX-BUP when used in combination is unique. DEX is a noncompetitive N-methyl-d-aspartate receptor antagonist rapidly metabolized through the CYP450 2D6. BUP is an aminoketone and CYP2D6 inhibitor, which results in increased plasma levels of DEX through competitive CYP2D6 inhibition.
CLINICAL TRIALS
In a phase 2 clinical study, the efficacy of DEX-BUP was compared with BUP alone in patients with clinically diagnosed MDD. At baseline, participants had moderate-to-severe depression using the Montgomery-Asberg Depression Rating Scale (MADRS) and Clinical Global Impressions Severity (CGI-S) scales. There was a significant overall reduction in MADRS and CGI-S scores in the treatment group compared with the BUP monotherapy with improvement observed as early as week 1 of treatment. Later, a phase 3 study was conducted comparing DEX-BUP 45 mg/105 mg with placebo in patients with moderate-to-severe MDD. Similarly, MADRS and CGI-S scores were significantly reduced in the treatment group. Adverse effects were similar in all groups.
THERAPEUTIC ADVANCE
Clinical response to first line treatment options for MDD are reported to be 40%-60%. Availability of additional treatment options, particularly those with reduced time to efficacy, may improve overall treatment and patient quality of life. DEX-BUP is a combination option that has been shown to improve depression symptoms as early as 1 week after initiation.
Topics: Humans; Depressive Disorder, Major; Bupropion; Dextromethorphan; Activities of Daily Living; Quality of Life
PubMed: 38231578
DOI: 10.1097/MJT.0000000000001699 -
Journal of Biochemical and Molecular... Jan 2024The given investigation examined the neuroprotection role of 5-HT1b/1d agonist in reserpine induced Parkinson's disease (PD) in male Wistar rats. PD was induced in rats...
The given investigation examined the neuroprotection role of 5-HT1b/1d agonist in reserpine induced Parkinson's disease (PD) in male Wistar rats. PD was induced in rats by reserpine at 5 mg/kg ip for 3 days and thereafter the rats were provided with the following treatments for 4 days, zolmitriptan (ZLM) group (30 mg/kg ip); STD group (levodopa + carbidopa, 200 + 5 mg/kg ip); ZLM + GA group (zolmitriptan, 30 mg/kg ip and glutamic acid, 1.5 mg/kg); ZLM + DX group (zolmitriptan, 30 mg/kg ip and dextromethorphan, 20 mg/kg ip). All the groups were then assessed for cognitive and motor functions at the end of the protocol. Moreover, oxidative stress parameters and histopathological changes were observed in rats of all treatment groups. Deposition of α-synuclein in the brain tissue was observed by silver staining. Data of this investigation revealed that motor and cognitive functions were improved in the ZLM-treated group compared with the negative control group, which was observed to be reversed in ZLM + GA group. Treatment with ZLM ameliorated oxidative stress and histopathological changes in the brain tissue of PD rats. Further, ZLM reduced the deposition of α-synuclein in PD rats, which reversed in ZLM + GA-treated group. This study concludes by stating that 5-HT1b/1d agonist can prevent neurodegeneration and reduce oxidative stress in PD rats. The probable underlying mechanism of such an effect of 5-HT1b/1d agonist could be by regulating the deposition of α-synuclein and reducing the expression of NMDA receptor.
Topics: Male; Rats; Animals; Serotonin 5-HT1 Receptor Agonists; Parkinson Disease; alpha-Synuclein; Glutamic Acid; Reserpine; Rats, Wistar; Tryptamines; Oxazolidinones
PubMed: 38229316
DOI: 10.1002/jbt.23627 -
Journal of Clinical Psychopharmacology
Topics: Humans; Guaifenesin; Dextromethorphan; Antitussive Agents; Nephrolithiasis
PubMed: 38227627
DOI: 10.1097/JCP.0000000000001815 -
Hormone and Metabolic Research =... Mar 2024For treatment of type 1 diabetes mellitus, a combination of immune-based interventions and medication to promote beta-cell survival and proliferation has been proposed....
For treatment of type 1 diabetes mellitus, a combination of immune-based interventions and medication to promote beta-cell survival and proliferation has been proposed. Dextromethorphan (DXM) is an -methyl-D-aspartate receptor antagonist with a good safety profile, and to date, preclinical and clinical evidence for blood glucose-lowering and islet-cell-protective effects of DXM have only been provided for animals and individuals with type 2 diabetes mellitus. Here, we assessed the potential anti-diabetic effects of DXM in the non-obese diabetic mouse model of type 1 diabetes. More specifically, we showed that DXM treatment led to five-fold higher numbers of pancreatic islets and more than two-fold larger alpha- and beta-cell areas compared to untreated mice. Further, DXM treatment improved glucose homeostasis and reduced diabetes incidence by 50%. Our data highlight DXM as a novel candidate for adjunct treatment of preclinical or recent-onset type 1 diabetes.
Topics: Mice; Animals; Diabetes Mellitus, Type 2; Mice, Inbred NOD; Dextromethorphan; Receptors, N-Methyl-D-Aspartate; Diabetes Mellitus, Type 1; Insulin; Islets of Langerhans; Blood Glucose; Homeostasis
PubMed: 38168730
DOI: 10.1055/a-2236-8625 -
Psychedelic Medicine (New Rochelle,... Dec 2023N-methyl-D-aspartate receptor-mediated dissociatives and serotonergic hallucinogens are being increasingly used in therapeutic interventions that involve nonordinary...
RATIONALE
N-methyl-D-aspartate receptor-mediated dissociatives and serotonergic hallucinogens are being increasingly used in therapeutic interventions that involve nonordinary states of consciousness and may represent a unique mental health paradigm wherein pharmacologically induced experiences are conducive to psychological well-being.
OBJECTIVE
The aim of this study was to further understand how the phenomenological and health-promoting effects of high-dose dextromethorphan (DXM) compared to psilocybin in the same participants when administered under experimental conditions that are typical of therapeutic psychedelic trials.
METHODS
Single, acute oral doses of DXM (400 mg/70 kg), psilocybin (10, 20, 30 mg/70 kg), and inactive placebo were administered under double-blind and psychologically supportive conditions to 20 healthy participants with histories of hallucinogen use. Ratings of personal meaning, spiritual significance, psychological challenge, and psychological insight attributed to acute drug experiences were assessed 7 h (at session end) and 1 week after each drug administration. Persisting psychological effects were assessed 1 week after each drug administration.
RESULTS
High-dose DXM and psilocybin produced similar increases over placebo in ratings of drug experience that was predictive of psychological benefit at 1 week, even when expectancy effects were minimized. These effects tended to favor psilocybin in a dose-dependent manner and were limited by poor physical tolerability for DXM.
CONCLUSIONS
This analysis suggests the utility of exploring clinical applications of dissociatives that occur within the supportive contexts that are characteristic of psychedelic research and that prioritize the optimization of psychologically valuable drug experiences. This study was registered with ClinicalTrials.gov (NCT02033707).
PubMed: 38152462
DOI: 10.1089/psymed.2023.0035 -
Psychiatry and Clinical Neurosciences Mar 2024
Topics: Humans; Dextromethorphan; Electroencephalography
PubMed: 38145404
DOI: 10.1111/pcn.13634 -
Spectrochimica Acta. Part A, Molecular... Mar 2024A highly sensitive surface-enhanced Raman spectroscopy approach was established for the detection of dextromethorphan hydrobromide (DXM) utilizing nano CuO modified...
A highly sensitive surface-enhanced Raman spectroscopy approach was established for the detection of dextromethorphan hydrobromide (DXM) utilizing nano CuO modified silver nanoparticles (CuO@AgNPs) as substrate. Ultraviolet visible spectra (UV-vis), X-ray diffraction (XRD) and transmission electron microscopy (TEM) characterized the synthesized CuO@AgNPs. UV-vis and fourier transform infrared (FT-IR) were adopted to investigate the interaction between DXM and CuO@AgNPs. The optimal experimental conditions (the dosages of CuO@AgNPs and NaCl as well as mixing time) were explored. The enhancement factor (EF) was 1.71 × 10. The linear relationship between SERS intensity and the concentration of DXM in the range of 67 - 1000 nmol L was obtained as I = 25.81 c + 40398.77, and the limit of detection (LOD) was 2.12 nmol L (S/N = 3). The interference of K, Mg, Zn, Ca, Cu, Fe, glucose, HSA, L-tryptophan, soluble starch and ibuprofen were investigated. The method was successfully applied to test DXM in serum samples. The recovery was 99.06% - 101.51% with the relative standard deviation (RSD) of 0.74% - 3.87%.
Topics: Silver; Dextromethorphan; Metal Nanoparticles; Spectroscopy, Fourier Transform Infrared; Microscopy, Electron, Transmission
PubMed: 38134660
DOI: 10.1016/j.saa.2023.123798