Risk of dementia among antidepressant elderly users: A population-based cohort analysis in Spain.

The use of antidepressants with anticholinergic effects has been associated with an increased risk of dementia. However, the results published are contradictory. The aim of the study is to compare the risk of developing dementia in elderly who were prescribed tricyclic antidepressants (TCA) versus those who were prescribed selective serotonin reuptake inhibitors (SSRIs) and other antidepressants (OA). A prospective population-based cohort study was performed using the Spanish Database for Pharmacoepidemiological Research in Primary Care (BIFAP) data (from 2005 to 2018). The cohort study included 62,928 patients age ≥ 60 without dementia and with antidepressant long-term monotherapy. Patients were divided into exposure antidepressant groups based on ATC system [TCA, SSRIs users and OAs users]. The risk of dementia was calculated by Cox regression models, providing hazard ratios (HR) and 95 % confidence intervals. The Kaplan-Meier model was used for survival analysis. Chi2 test was used as association test. The results showed SSRI users had higher dementia risk than TCA users (HR = 1.864; 95%CI = 1.624-2.140). Moreover, OA users had also significant risk of dementia (HR = 2.103; 95%CI = 1.818-2.431). Several limitations are the variation of the trend in the prescription of antidepressants, the small number of patients that use some antidepressants, the lack of information related to the dose, or socioeconomic characteristics, the use of antidepressant drugs for other indications, or the therapeutic compliance. Our findings showed that older users of SSRI and OA have more risk of developing dementia than TCA elderly users. However, additional studies would be needed.

Neonatal Opioid Withdrawal Syndrome Following Prenatal Use of Supplements Containing Tianeptine.

Tianeptine is an opioid receptor agonist that is prescribed as an antidepressant in many countries. In the United States, tianeptine is not approved for medical use because of its potential for abuse and addiction. Nonetheless, products containing tianeptine are easily obtainable and are marketed as dietary supplements. There are increasing reports of adverse effects and fatal toxicities resulting from tianeptine use among adolescents and adults. This emerging public health threat could escalate the opioid epidemic and drive increased newborn perinatal exposure. The impact of in utero exposure to tianeptine has not been studied, and to our knowledge, the authors of only 1 report have documented possible neonatal effects. Here, we describe a case of chronic prenatal exposure to tianeptine in the setting of maternal dependence on dietary supplements. This infant developed signs of severe withdrawal shortly after birth that were refractory to treatment with oral phenobarbital but responded to subsequent oral morphine therapy. On further questioning, the mother revealed the use of a tianeptine-containing dietary supplement. We did not perform confirmatory toxicology testing because tianeptine is not assayed by usual urine drug screening tests. For infants with clinical signs of opioid withdrawal without known etiology, we suggest that the maternal interview should inquire about the use of neurotropic over-the-counter drugs.

Comparative Efficacy and Safety of Antidepressants for Patients with Chronic Back Pain: A Network Meta-Analysis.

Various antidepressants have introduced in clinical practice for pain management, but it is important to understand how to properly use them. We therefore performed a systematic review and network meta-analysis to compare and rank the efficacy and safety of antidepressants for patients with chronic back pain. We identified eligible randomized controlled trials (RCTs) that investigated the efficacy and safety of antidepressants for chronic back pain from PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov, searching from inception to May 2023. Six categories of antidepressants for the treatment of chronic back pain were included, and the surface under the cumulative ranking probabilities was applied to rank the treatment strategies. Overall, we selected 19 RCTs recruiting 2903 patients for the meta-analysis. Tricyclic antidepressants presented the best relative effects for relief in pain score (surface under the cumulative ranking, 84.4%). The results of pairwise comparison analyses found the use of serotonin-noradrenaline reuptake inhibitors (SNRIs) significantly reduced pain score and low disability score compared with placebo, irrespective of treatment duration. Noradrenaline-dopamine reuptake inhibitors (relative risk [RR], 2.80; 95% confidence interval [CI], 1.30-6.03; P = .008) and SNRIs (RR, 1.17; 95% CI, 1.07-1.27; P < .001) significantly increased the risk of adverse events. SNRIs were associated with an increased risk of withdrawal due to adverse events (RR, 2.37; 95% CI, 1.64-3.43; P < .001). This study found that antidepressants are more efficacious than placebos for treating chronic back pain, and tricyclic antidepressants are the most likely medications that lead to pain relief.

Antidepressant use and the risk of seizure: a meta-analysis of observational studies.

PURPOSE: The association between antidepressant use and the risk of seizures remains controversial. Therefore, this meta-analysis examined whether antidepressant use affects the risk of seizures. METHODS: To identify relevant observational studies, we conducted systematic searches in PubMed and Embase of studies published through May 2023. Random-effects models were used to estimate overall relative risk. RESULTS: Our meta-analysis included eight studies involving 1,709,878 individuals. Our results showed that selective serotonin reuptake inhibitors (SSRI) (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.32-1.66; P < 0.001) and selective noradrenalin reuptake inhibitors (SNRI) (OR 1.65, 95% CI 1.24-2.19; P = 0.001), but not tricyclic antidepressants (TCA) (OR 1.27, 95% CI 0.84-1.92; P = 0.249), were associated with an increased risk of seizures. Subgroup analyses revealed an OR of 2.35 (95% CI 1.7, 3.24; P < 0.001) among short-term (< 30 days) antidepressant users. CONCLUSIONS: The findings of this meta-analysis support an increased risk of seizures in new-generation antidepressant users, expanding previous knowledge by demonstrating a more pronounced risk in short-term users.

Novel hyperpigmentation pathophysiology following a prolonged course of imipramine therapy.

Imipramine is a tricyclic antidepressant typically reserved for patients with treatment-resistant mood disorders. A rare side effect of long-term use of imipramine is a slowly progressive melanin-associated, slate gray-blue hyperpigmentation of the skin in a photo-distributed pattern. We report a case of imipramine-induced hyperpigmentation developing 50 years after initiating imipramine therapy, whose lesions were essentially devoid of melanin on histopathological exam. This differs from all other reported cases of imipramine-induced hyperpigmentation in two notable respects. First, the time between initiating imipramine therapy and the onset of pigmentation changes was nearly 30 years longer than prior case reports. Second, the lack of melanin in our samples suggests a divergence from the hypothesized melanin-imipramine complex mechanism of hyperpigmentation. Instead, we propose a novel pathogenesis of imipramine-induced hyperpigmentation that is unrelated to melanin.

Nursing Implications for Tianeptine Use and Misuse.

ABSTRACT: Tianeptine is an atypical antidepressant that is not approved for use in the United States and has a significant potential for abuse. In recent years, illicit use and misuse of tianeptine have become increasingly common. Symptoms caused by illicit use and withdrawal from tianeptine have become an emerging public health concern. Nurses should be aware of serious or even fatal opiate-like intoxication or withdrawal symptoms, which may present in the absence of a positive urine drug screen or in cases where withdrawal does not follow expected patterns. The associated health effects of tianeptine exposure and misuse include neurologic, cardiovascular, and gastrointestinal symptoms, which manifest in a similar manner to opioid toxicity and opioid withdrawal syndrome. People who illicitly use or misuse tianeptine should be educated regarding the risks associated with this drug. In addition, nurses should promote screening, intervention, and referral to treatment for this and other substance use disorders. Nurses should also support efforts to control access to products containing tianeptine.

Tricyclic antidepressants induce liver inflammation by targeting NLRP3 inflammasome activation.

BACKGROUND: Idiosyncratic drug-induced liver injury (IDILI) is common in hepatology practices and, in some cases, lethal. Increasing evidence show that tricyclic antidepressants (TCAs) can induce IDILI in clinical applications but the underlying mechanisms are still poorly understood. METHODS: We assessed the specificity of several TCAs for NLRP3 inflammasome via MCC950 (a selective NLRP3 inhibitor) pretreatment and Nlrp3 knockout (Nlrp3-/-) BMDMs. Meanwhile, the role of NLRP3 inflammasome in the TCA nortriptyline-induced hepatotoxicity was demonstrated in Nlrp3-/- mice. RESULTS: We reported here that nortriptyline, a common TCA, induced idiosyncratic hepatotoxicity in a NLRP3 inflammasome-dependent manner in mildly inflammatory states. In parallel in vitro studies, nortriptyline triggered the inflammasome activation, which was completely blocked by Nlrp3 deficiency or MCC950 pretreatment. Furthermore, nortriptyline treatment led to mitochondrial damage and subsequent mitochondrial reactive oxygen species (mtROS) production resulting in aberrant activation of the NLRP3 inflammasome; a selective mitochondrial ROS inhibitor pretreatment dramatically abrogated nortriptyline-triggered the NLRP3 inflammasome activation. Notably, exposure to other TCAs also induced aberrant activation of the NLRP3 inflammasome by triggering upstream signaling events. CONCLUSION: Collectively, our findings revealed that the NLRP3 inflammasome may act as a crucial target for TCA agents and suggested that the core structures of TCAs may contribute to the aberrant activation of NLRP3 inflammasome induced by them, an important factor involved in the pathogenesis of TCA-induced liver injury. Video Abstract.

Mirtazapine-induced Acute Pancreatitis in Patients With Depression: A Systematic Review.

OBJECTIVE: Antidepressant-induced pancreatitis is a rare, albeit serious, adverse effect, with a frequency of occurrence that is not equally distributed among antidepressant drugs. The goal of this study was to investigate the association and causal relationship between mirtazapine treatment of patients with depression and pancreatitis. METHODS: The study was designed as a systematic review of the literature, accompanied by the description of a new case of mirtazapine-associated acute pancreatitis. RESULTS: Nine cases of mirtazapine-associated pancreatitis have been reported, involving 7 female patients and 2 male patients with a mean age of 46.4 years (range: 26 to 83 y of age). All of the patients were hospitalized, with an average length of stay of 16.2 days (range: 3 to 34 d). In 6 cases, "de-challenge" followed by improvement was reported. The patients for whom the outcome was reported (7 of 9) recovered completely. CONCLUSION: Although a rare adverse effect, mirtazapine-induced pancreatitis should be considered when patients taking mirtazapine report abdominal discomfort.

Doctors Speak: A Qualitative Study of Physicians' Prescribing of Antidepressants in Functional Bowel Disorders.

Tricyclic antidepressants (TCAs) are frequently prescribed for chronic functional pain disorders. Although the mechanism of action targets pain perception, treating patients with TCAs for disorders conceptualized as "functional" can promote stigmatization in these patients because it hints at psychological dimensions of the disorder. The goal of this study was to understand how physicians prescribe TCAs in the face of this challenge. We interviewed eleven gastroenterologists in tertiary care clinics specializing in functional gastrointestinal disorders, such as irritable bowel syndrome. We found that the physicians interviewed (1) were aware of the stigma attached to taking antidepressants for a medical condition, (2) emphasized biological, as opposed to psychological, mechanisms of action, (3) while focusing on biological mechanisms, they nevertheless prescribed TCAs in a way that is highly attentive to the psychology of expectations, making specific efforts to adjust patients' expectations to be realistic and to reframe information that would be discouraging and (4) asked patients to persist in taking TCAs despite common and, at times, uncomfortable side effects. In this context of shared decision making, physicians described nuanced understanding and behaviours necessary for treating the complexity of functional disorders and emphasized the importance of a strong patient-provider relationship.

Antidepressant Use and Risk of Myocardial Infarction: A Longitudinal Investigation of Sex-Specific Associations in the HUNT Study.

OBJECTIVE: Antidepressants are thought to affect the risk of cardiovascular disease, although the nature of the association is unclear. Men and women have unique cardiovascular risk factors, and sex differences in depression as well as the efficacy of antidepressants are important to consider. We examined whether antidepressant use was associated with risk of having a myocardial infarction (MI) and whether this association was sex-specific. METHODS: Data from The Trøndelag Health Study were used, gathered from a population in Norway ( N = 31,765), collected from 1995 to 2008. These data were combined with the Norwegian Cause of Death Registry and the Norwegian Prescription Database. We performed logistic regression models to examine the association of antidepressant use on risk of having a fatal or nonfatal MI, adjusting for depression, anxiety, diabetes, systolic blood pressure, cholesterol, waist-hip ratio, smoking, age, and sex. Results are presented as odds ratios (ORs) and 95% confidence intervals in parentheses. RESULTS: The results indicated that antidepressant use was associated with a reduced risk of having MI at a later date (OR = 0.49 [0.38-0.64]). Although this association was somewhat stronger for women (OR = 0.46 [0.31-0.68]) compared with men (OR = 0.53 [0.37-0.75]), analysis did not identify a sex-specific association of antidepressant use on MI. Follow-up analyses on different subtypes of antidepressants showed that both selective serotonin reuptake inhibitor and tricyclic antidepressant were associated with a reduced risk of MI. CONCLUSIONS: In this population study, the use of antidepressants was associated with a reduced risk of MI. This association was stronger for women, although we detected no interaction between sex and antidepressant use in terms of reduced risk of MI. Although limitations apply regarding causality, especially concerning a dose-response relationship, the results suggest that antidepressant use might reduce the risk of MI among both men and women.

Risk of cardiovascular events according to the tricyclic antidepressant dosage in patients with chronic pain: a retrospective cohort study.

PURPOSE: We aimed to examine the risk of cardiovascular adverse events by tricyclic antidepressant (TCA) dosage among patients with chronic pain. METHODS: A retrospective cohort study was conducted using a nationwide sample cohort. Among patients aged ≥ 18 years with a chronic pain diagnosis and no history of cardiovascular events, we extracted users and non-users of TCAs through 1:1 propensity score matching. TCA users were categorized into three groups according to the mean defined daily dose (DDD): very low doses (< 0.15 DDD), low doses (0.15-0.34 DDD), and traditional doses (≥ 0.34 DDD). A 6-month follow-up was conducted with an intention-to-treat approach. We examined the hazard ratio of cardiovascular adverse events using Cox proportional hazards analysis. RESULTS: In total, 16,660 matched patients were followed up (8330 TCA users and 8330 non-users). TCA use did not significantly increase cardiovascular adverse events (hazard ratio [HR] 1.12, 95% confidence interval [CI] 0.94-1.33). Low-dose (0.15-0.34 DDD) TCAs (HR 1.37, 95% CI 1.08-1.74), particularly low-dose (0.15-0.34 DDD) nortriptyline (HR 2.11, 95% CI 1.44-3.08), was associated with an increased risk of cardiovascular adverse events. Administration of TCAs at the traditional dose (≥ 0.34 DDD) increased the risk of ischemic stroke (HR 2.08, 95% CI 1.11-3.88). CONCLUSION: Close monitoring of patients on long-term, low-dose use of TCAs should be conducted to avoid an increase in the cumulative dose, which increases the risk of cardiovascular adverse events.

[The use of antidepressants for the treatment of chronic pain: a focus on elderly patients.]

A possible tool to improve the efficacy and safety of managing elderly and senile patients with chronic pain may be the use of adjuvant analgesics, in particular, antidepressants. Available clinical data indicate the possibility of using antidepressants as an alternative to opioid analgesics and non-steroidal anti-inflammatory drugs. The review includes the analysis of the comparative characteristics and peculiarities of prescribing tricyclic antidepressants, selective serotonin and norepinephrine reuptake inhibitors, and selective serotonin reuptake inhibitors as painkillers in elderly patients. Recommendations are given on the use of various representatives of the antidepressant group in elderly patients with various types of pain, aimed at minimizing possible adverse drug reactions and improving the quality of life of this category of patients.

Oral Manifestations of Psychotropic Drugs on the Oral Cavity: Observational Study.

AIM: This study aims to detect the prevalence of oral manifestations in patients with psychiatric disorders on psychotropic medications. MATERIALS AND METHODS: A total of 46 patients above the age of 18 years who have been diagnosed with psychiatric illness and under psychotropic medications were included in this study. Thorough case history and oral findings were recorded. Patients with already existing systemic illness and other oral manifestations were excluded from this study. RESULTS: Out of 46 patients, 34 patients presented with oral manifestations such as xerostomia, sialorrhea, geographic tongue, candidiasis, and burning mouth syndrome, secondary to the use of psychotropic medications. The oral manifestations were significantly higher in the patients under antipsychotics (80.0%), selective serotonin reuptake inhibitor (66.7%), antiepileptics (55.6%), antidepressants (44.4%), benzodiazepine (44.4%), and tricyclic antidepressants (13.7%). CONCLUSION: The commonly used psychotropic medications to treat patients with psychiatric illnesses such as selective serotonin reuptake inhibitor, tricyclic antidepressants, antidepressants, and benzodiazepines exhibited several oral manifestations. However, long-term use of these medications seems to cause oral changes. CLINICAL SIGNIFICANCE: Awareness among psychiatrists about oral changes associated with the use of psychotropic medication will assist them to make necessary modifications in the prescriptions. Dental practitioners will be able to recognize these changes early in the course of the condition and provide appropriate treatment.

Respiratory Effects of the Atypical Tricyclic Antidepressant Tianeptine in Human Models of Opioid-induced Respiratory Depression.

BACKGROUND: Animal data suggest that the antidepressant and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor modulator tianeptine is able to prevent opioid-induced respiratory depression. The hypothesis was that oral or intravenous tianeptine can effectively prevent or counteract opioid-induced respiratory depression in humans. METHODS: Healthy male and female volunteers participated in two studies that had a randomized, double blind, placebo-controlled, crossover design. First, oral tianeptine (37.5-, 50-, and 100-mg doses with 8 subjects) pretreatment followed by induction of alfentanil-induced respiratory depression (alfentanil target concentration, 100 ng/ml) was tested. Primary endpoint was ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg (V̇E55). Next, the ability of four subsequent and increasing infusions of intravenous tianeptine (target tianeptine plasma concentrations 400, 1,000, 1,500, and 2,000 ng/ml, each given over 15 min) to counteract remifentanil-induced respiratory depression was determined in 15 volunteers. Ventilation was measured at isohypercpania (baseline ventilation 20 ± 2 l/min). The primary endpoint was minute ventilation during the 60 min of tianeptine versus placebo infusion. RESULTS: Alfentanil reduced V̇E55 to 13.7 (95% CI, 8.6 to 18.8) l/min after placebo pretreatment and to 17.9 (10.2 to 25.7) l/min after 50-mg tianeptine pretreatment (mean difference between treatments 4.2 (-11.5 to 3.0) l/min, P = 0.070). Intravenous tianeptine in the measured concentration range of 500 to 2,000 ng/ml did not stimulate ventilation but instead worsened remifentanil-induced respiratory depression: tianeptine, 9.6 ± 0.8 l/min versus placebo 15.0 ± 0.9 l/min; mean difference, 5.3 l/min; 95% CI, 2.5 to 8.2 l/min; P = 0.001, after 1 h of treatment. CONCLUSIONS: Neither oral nor intravenous tianeptine were respiratory stimulants. Intravenous tianeptine over the concentration range of 500 to 2000 ng/ml worsened respiratory depression induced by remifentanil.

Risk of Falls Associated with Long-Acting Benzodiazepines or Tricyclic Antidepressants Use in Community-Dwelling Older Adults: A Nationwide Population-Based Case-Crossover Study.

BACKGROUND: Falls are common in older adults and increase in recent years. This study aimed to examine the risk of falls associated with long-acting benzodiazepines (BZDs) or tricyclic antidepressants (TCAs) use in community-dwelling older adults. METHODS: A nationwide population-based case-crossover design was used. We screened information on 6,370,275 fall or fall fracture cases among community-dwelling elderly patients from the database of the national health insurance data warehouse in South Korea. We extracted the data of elderly patients who visited the hospital for a fall and were diagnosed with the first fall or fall fracture after prescription of long-acting BZDs (n = 1805) or TCAs (n = 554). The study used conditional logistic regression analysis to analyze the associations and stratified analysis by gender and age group to control for their confounding effects. RESULTS: Risk of falls or fall fractures increased by more than two times after taking long-acting BZDs (odds ratio [OR] = 2.16; 95% confidence interval [CI] = 1.85-2.52) or TCAs (OR = 2.13; 95% CI = 1.62-2.83). The longer the prescription period of both, the higher the risk of falls or fall fractures was (≥49 days for long-acting BZDs vs. ≥ 56 days for TCAs). CONCLUSIONS: Long-acting BZDs or TCAs should be avoided or prescribed for a shorter duration based on these adverse effects. Health care providers should focus on fall prevention practices in older adults who take such drugs.

COVID-19 Prognosis in Association with Antidepressant Use.

INTRODUCTION: Various subtypes of severe acute respiratory syndrome coronavirus 2 and variations among immune systems in different ethnicities need to be considered to understand the outcomes of coronavirus disease 2019 (COVID-19). This study aimed to provide evidence for the association between the use of antidepressants and the severity of COVID-19. METHODS: We used the National Health Information Data-COVID database. Patients with one or more prescriptions of any antidepressant were selected as the exposure group. Detailed analyses were performed to determine the type of medication associated with the prognosis. RESULTS: The use of selective serotonin reuptake inhibitors (SSRIs) was associated with a lower risk of severe outcomes of COVID-19, whereas the use of tricyclic antidepressants (TCAs) increased the risk of poor prognosis of COVID-19. Detailed analyses showed that escitalopram was significantly associated with better clinical outcomes, and nortriptyline was linked to more severe COVID-19 outcomes. CONCLUSION: This study revealed an association between antidepressants and COVID-19 prognosis. SSRIs were significantly associated with a lower risk of severe outcomes, whereas TCAs were related to the poor prognosis of COVID-19.

Central Neuropathic Pain Syndromes: Current and Emerging Pharmacological Strategies.

Central neuropathic pain is caused by a disease or lesion of the brain or spinal cord. It is difficult to predict which patients will develop central pain syndromes after a central nervous system injury, but depending on the etiology, lifetime prevalence may be greater than 50%. The resulting pain is often highly distressing and difficult to treat, with no specific treatment guidelines currently available. This narrative review discusses mechanisms contributing to central neuropathic pain, and focuses on pharmacological approaches for managing common central neuropathic pain conditions such as central post-stroke pain, spinal cord injury-related pain, and multiple sclerosis-related neuropathic pain. Tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and gabapentinoids have some evidence for efficacy in central neuropathic pain. Medications from other pharmacologic classes may also provide pain relief, but current evidence is limited. Certain non-pharmacologic approaches, neuromodulation in particular, may be helpful in refractory cases. Emerging data suggest that modulating the primary afferent input may open new horizons for the treatment of central neuropathic pain. For most patients, effective treatment will likely require a multimodal therapy approach.

Imipramine-Induced Cutaneous and Iris Hyperpigmentation: A Case Report and Literature Review.

Objective: To describe a novel case of imipramine-induced hyperpigmentation and characterize the literature pertaining to imipramine-induced hyperpigmentation to this point.Data Sources: PubMed and Google Scholar were searched through July 2021 utilizing various combinations of imipramine, discoloration, and hyperpigmentation. The references of initial articles were searched for more case reports and imipramine-related literature. Also, articles that cited the references identified in the literature search were reviewed using Google Scholar. Only articles published in English were included.Study Selection: A total of 19 cases of imipramine-induced hyperpigmentation were found in 15 publications to date. All cases were included to determine the variation in clinical presentations of this rare condition.Data Extraction: The case reports were reviewed in their entirety for information concerning patient demographic, clinical presentation, histologic findings on biopsy, and treatment options for imipramine-induced hyperpigmentation.Results: This presentation, to our knowledge, represents the third case of imipramine-induced iris hyperpigmentation, the first case of iris hyperpigmentation occurring in a blue-eyed individual, and the first report to include pictures of the hyperpigmented irides. A novel proposed pathophysiologic mechanism is also provided.Conclusions: Imipramine is a tricyclic antidepressant with a rare side effect of cutaneous and iris hyperpigmentation. Granular dermal deposits in microscopy appear to be the cause of this discoloration. Treatment primarily focuses on discontinuing imipramine or laser therapy.