An Overview of Degradation Strategies for Amitriptyline.

Antidepressant drugs play a crucial role in the treatment of mental health disorders, but their efficacy and safety can be compromised by drug degradation. Recent reports point to several drugs found in concentrations ranging from the limit of detection (LOD) to hundreds of ng/L in wastewater plants around the globe; hence, antidepressants can be considered emerging pollutants with potential consequences for human health and wellbeing. Understanding and implementing effective degradation strategies are essential not only to ensure the stability and potency of these medications but also for their safe disposal in line with current environment remediation goals. This review provides an overview of degradation pathways for amitriptyline, a typical tricyclic antidepressant drug, by exploring chemical routes such as oxidation, hydrolysis, and photodegradation. Connex issues such as stability-enhancing approaches through formulation and packaging considerations, regulatory guidelines, and quality control measures are also briefly noted. Specific case studies of amitriptyline degradation pathways forecast the future perspectives and challenges in this field, helping researchers and pharmaceutical manufacturers to provide guidelines for the most effective degradation pathways employed for minimal environmental impact.

Antidepressant discontinuation patterns and characteristics across sociodemographic groups in the United States.

BACKGROUND: While antidepressants are frequently used, less is known about contemporary discontinuation patterns, especially across different sociodemographic populations. METHODS: Patients 16-84 years initiating antidepressants between 2016 and 2019 within a large US health insurer were identified. The association between patient characteristics and time until antidepressant discontinuation was evaluated using adjusted Cox proportional hazard regression. RESULTS: Across 1,365,576 patients, mean time to discontinuation was 168.1 days (SD: 223.6). Men were more likely to discontinue than women (HR: 0.94, 95%CI: 0.94-0.94). Younger patients (16-24 years) were more likely to discontinue than older patients. Patients who were non-White (Asian HR: 1.33, 95%CI: 1.31-1.34; Black HR: 1.27, 95%CI: 1.27-1.28; Hispanic HR: 1.34, 95%:CI 1.34-1.35), with evidence of a substance use disorder (HR: 1.31, 95%CI: 1.27-1.35), or taking tricyclic antidepressants (HR:1.26, 95%CI: 1.25-1.27) were more likely to discontinue. LIMITATIONS: Information on reasons for discontinuation was not available, and wide standard deviations for the primary outcome were reported. The results may not be generalized to non-commercially insured beneficiaries. CONCLUSIONS: Discontinuation is common within the first 6 months of treatment but varies across populations, highlighting patients who may benefit from potential intervention.

Sustainable beeswax modified cellulose paper for the determination of tricyclic antidepressants in biofluids.

This article describes the synthesis of sorptive phases for bioanalysis based on the modification of cellulose paper with natural beeswax as sorbent, resulting in a substrate completely renewable and sustainable. The preparation of the sorptive phases consisted of the dissolution of beeswax in hexane, followed by its drop-casting on cellulose paper and subsequent evaporation of the solvent. The beeswax modification of paper renders it hydrophobic, enabling the extraction of the target analytes, i.e., imipramine, desipramine, amitriptyline and trimipramine, via hydrophobic interactions. The main variables affecting the extraction performance were investigated (e.g., pH, ionic strength, extraction time, eluent composition, agitation speed). The analytical workflow combines a straightforward sampling, simultaneous extraction of 30 samples in 1 h, and the rapid (<2 min) determination of the analytes via direct infusion mass spectrometry. The method provided limits of detection in the range 2.0 and 3.2 µg L-1, and the precision, expressed as relative standard deviation, was better than 5.4 % and 8.5 % for intra and inter-day analyses, respectively. The accuracy, in terms of relative recovery, ranged from 90 % to 121 % using saliva as model biofluid.

Association between depression, antidepressant use, and the incidence of atherosclerotic cardiovascular diseases.

OBJECTIVE: To examine the association between depression, the use of antidepressants, and atherosclerotic cardiovascular disease (ASCVD). METHODS: The South Korean national claims data was used. Among a nationally representative population, 273,656 subjects who had been diagnosed with depression and prescribed antidepressants ("DEP with antidepressants") and 78,851 subjects who had been diagnosed with depression but not prescribed antidepressants ("DEP without antidepressants") were identified to be eligible. Healthy controls (HCs) were 1:1 matched with DEP with antidepressants group for age and sex. We followed up on the occurrence of ASCVD including ischemic heart diseases and ischemic stroke. RESULTS: The risk of ASCVD was increased in the DEP with antidepressants group and decreased in the DEP without antidepressants group compared to HCs. Among those under antidepressants, tricyclic antidepressant users showed the highest risk of ASCVD compared to HCs. Among young adults, the risk of ASCVD was increased in both groups. CONCLUSION: The risk of ASCVD increased in depression patients taking antidepressants, while it decreased in depression patients not taking antidepressants. However, the relationship showed differences according to drug class and age group.

Nitrogen-containing heterocyclic compounds: A ray of hope in depression?

Depression is not similar to daily mood fluctuations and temporary emotional responses to day-to-day activities. Depression is not a passing problem; it is an ongoing problem. It deals with different episodes consisting of several symptoms that last for at least 2 weeks. It can be seen for several weeks, months, or years. At its final stage, or can say, in its worst condition, it can lead to suicide. Antidepressants are used to inhibit the reuptake of the neurotransmitters by some selective receptors, which increase the concentration of specific neurotransmitters around the nerves in the brain. Drugs that are currently being used for the management of various types of depression include selective serotonin reuptake inhibitors, tricyclic antidepressants, atypical antidepressants, serotonin, noradrenaline reuptake inhibitors, etc. In this review, we have outlined different symptoms, causes, and recent advancements in nitrogen-containing heterocyclic drug candidates for the management of depression. This article highlights the various structural features along with the structure-activity relationship (SAR) of nitrogen-containing heterocyclics that play a key role in binding at target sites for potential antidepressant action. The in silico studies were carried out to determine the binding interactions of the target ligands with the receptor site to determine the potential role of substitution patterns at core pharmacophoric features. This article will help medicinal chemists, biochemists, and other interested researchers in identifying the potential pharmacophores as lead compounds for further development of new potent antidepressants.

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.

Improved Pharmacokinetic and Pharmacodynamic Profile of Deuterium-Reinforced Tricyclic Antidepressants Doxepin, Dosulepin, and Clomipramine in Animal Models.

BACKGROUND AND OBJECTIVES: Doxepin, dosulepin, and clomipramine are tricyclic antidepressants (TCAs) that act as serotonin and noradrenaline reuptake inhibitors. The metabolites formed by N-dealkylation of these tricyclic antidepressants contribute to overall poor pharmacokinetics and efficacy. Deuteration of the methyl groups at metabolically active sites has been reported to be a useful strategy for developing more selective and potent antidepressants. This isotopic deuteration can lead to better bioavailability and overall effectiveness. The objective is to study the effect of site-selective deuteration of TCAs on their pharmacokinetic and pharmacodynamic profile by comparison with their nondeuterated counterparts. METHODS: In the current study, the pharmacokinetic profile and antidepressant behavior of deuterated TCAs were evaluated using the forced swim test (FST) and tail suspension test (TST), using male Wistar rats and male Swiss albino mice, respectively; additionally, a synaptosomal reuptake study was carried out. RESULTS: Compared with the nondeuterated parent drugs, deuterated forms showed improved efficacy in the behavior paradigm, indicating improved pharmacological activity. The pharmacokinetic parameters indicated increased maximum concentration in the plasma (Cmax), elimination half-life (t1/2), and area under the concentration-time curve (AUC)  in deuterated compounds. This can have a positive clinical impact on antidepressant treatment. Synaptosomal reuptake studies indicated marked inhibition of the reuptake mechanism of serotonin (5-HT) and norepinephrine. CONCLUSIONS: Deuterated TCAs can prove to be potentially better molecules in the treatment of neuropsychiatric disorders as compared with nondeuterated compounds. In addition, we have demonstrated a concept that metabolically active, site-selective deuteration can be beneficial for improving the pharmacokinetic and pharmacodynamic profiles of TCAs. A further toxicological study of these compounds is needed to validate their future clinical use.

Antidepressant deprescribing: State of the art and recommendations-A literature overview.

INTRODUCTION: In recent years, the consumption of antidepressants has arisen. However, deprescribing antidepressant therapy is very complicated. The aim of this study was to implement practical recommendations for the development of guidelines to be used for antidepressant deprescription in clinical practice. MATERIALS AND METHODS: The literature search has been conducted on March 13, 2023, using Scopus and PubMed databases. The following search string has been used: "antidepressants AND (deprescribing OR deprescription)". All studies reporting a deprescribing intervention for antidepressant medication, regardless of the study design, have been included. Studies that did not report antidepressant drug deprescription interventions and non-English-language papers have been excluded. RESULTS: From the literature search, a total of 230 articles have been extracted. Applying the exclusion criteria, 26 articles have been considered eligible. Most of the analyzed studies (16, 61%) have been carried out in the real world, 3 (11%) were RCTs, 5 (19%) were qualitative studies, in particular expert opinions, 1 (4%) was a literature review, and 1 (4%) was a post-trial observational follow-up of an RCT. In 8 out of 26 studies (31%), the analyzed antidepressants have been specified: 2 (8%) focused on anticholinergics, 2 (8%) on SSRIs, 3 (11%) on tricyclic antidepressants, and 1 (4%) on esketamine. Nineteen out of 26 studies (73%) did not stratify antidepressants by therapeutic class. The sample sizes analyzed in the studies ranged from a minimum of 4 patients to a maximum of 113,909, and 12 studies included geriatric age as an inclusion criterion. A patient's therapy review has been the main deprescribing intervention, and it has been identified in 14 (54%) articles. Interventions have been carried out by clinicians in 4 (15%) studies, general practitioners in 5 (19%) studies, nurses in 2 (8%) studies, pharmacists in 4 (15%) studies, multidisciplinary teams in 10 (38%) studies, and patients in 1 (4%) study. CONCLUSIONS: From the literature review, it emerged that there is no clear evidence useful to support clinicians in antidepressant deprescribing interventions.

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.

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.

G protein-biased LPAR1 agonism of prototypic antidepressants: Implication in the identification of novel therapeutic target for depression.

Prototypic antidepressants, such as tricyclic/tetracyclic antidepressants (TCAs), have multiple pharmacological properties and have been considered to be more effective than newer antidepressants, such as selective serotonin reuptake inhibitors, in treating severe depression. However, the clinical contribution of non-monoaminergic effects of TCAs remains elusive. In this study, we discovered that amitriptyline, a typical TCA, directly binds to the lysophosphatidic acid receptor 1 (LPAR1), a G protein-coupled receptor, and activates downstream G protein signaling, while exerting a little effect on ß-arrestin recruitment. This suggests that amitriptyline acts as a G protein-biased agonist of LPAR1. This biased agonism was specific to TCAs and was not observed with other antidepressants. LPAR1 was found to be involved in the behavioral effects of amitriptyline. Notably, long-term infusion of mouse hippocampus with the potent G protein-biased LPAR agonist OMPT, but not the non-biased agonist LPA, induced antidepressant-like behavior, indicating that G protein-biased agonism might be necessary for the antidepressant-like effects. Furthermore, RNA-seq analysis revealed that LPA and OMPT have opposite patterns of gene expression changes in the hippocampus. Pathway analysis indicated that long-term treatment with OMPT activated LPAR1 downstream signaling (Rho and MAPK), whereas LPA suppressed LPAR1 signaling. Our findings provide insights into the mechanisms underlying the non-monoaminergic antidepressant effects of TCAs and identify the G protein-biased agonism of LPAR1 as a promising target for the development of novel antidepressants.

Dispersive liquid-liquid microextraction (DLLME) for determination of tricyclic antidepressants in whole blood and plasma samples and analysis by liquid chromatography with diode array detector (LC-DAD).

Microextractions have been developed for the tricyclic antidepressants (TCAs) analysis in biological matrices, including dispersive liquid-liquid microextraction (DLLME). The proposed DLLME employed 490 µL of biological sample (whole blood or plasma), which were added 15 mg of NaCl, 10 µL of medazepam as internal standard (10 µg/mL) and 100 µL of 2 M NaOH. This mixture was homogenized by vortex (2800 rpm/10 s) and 400 µL of hexane (extractor solvent) with 600 µL of methanol (dispersing solvent) were added to the sample. After the vortex step (2800 rpm/5 s), an ultrasonic bath for 300 s was employed. Then, this content was centrifuged (10 min/10000 rpm), organic phase was collected and dried under air flow. After, 30 µL of the mobile phase was used for resuspension and 20 µL is injected into LC-DAD. This method was optimized and fully validated according to UNODC and SWGTOX guidelines, reaching limits of detection equivalent to analytical methodologies that employ mass spectrometry (MS). Also, it was applied in real cases involving suspected exposure to TCAs. So, the developed DLLME for the determination of TCAs in whole blood and plasma samples proved to be a simple, reliable, robust and reproducible method that can be used in toxicology and clinical laboratories.

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.

False-positive results for pheochromocytoma associated with norepinephrine reuptake blockade.

Measurements of plasma metanephrines and methoxytyramine provide a sensitive test for diagnosis of pheochromocytoma/paraganglioma. False-positive results remain a problem, particularly in patients taking norepinephrine reuptake-blocking drugs. Therefore, in this retrospective observational study, we measured plasma metanephrines and methoxytyramine in 61 patients taking norepinephrine reuptake blockers (tricyclic antidepressants or serotonin-norepinephrine reuptake inhibitors) and 17 others taking selective serotonin reuptake inhibitors, all without pheochromocytoma/paraganglioma. We highlight a singular case with strongly elevated plasma normetanephrine and methoxytyramine concentrations associated with norepinephrine reuptake blockade. Data were compared to results from 252 and 1804 respective patients with and without tumors. Plasma normetanephrine was 40% higher (P < 0.0001) in patients on norepinephrine reuptake blockers and methoxytyramine was 127% higher (P = 0.0062) in patients taking tricyclic antidepressants compared to patients not taking uptake blockers and without tumors. The corresponding false-positive rates rose (P < 0.0001) from 4.8% to 23.0% for normetanephrine and from 0.9% to 28.6% for methoxytyramine. Selective serotonin reuptake inhibitors did not increase plasma concentrations of metabolites. In the highlighted case, plasma normetanephrine and methoxytyramine were elevated more than six times above upper reference limits. A pheochromocytoma/paraganglioma, however, was excluded by functional imaging. All biochemical test results normalized after discontinuation of norepinephrine reuptake blockers. These findings clarify that norepinephrine reuptake blockers usually result in mild elevations of normetanephrine and methoxytyramine that, nevertheless, significantly increase the number of false-positive results. There can, however, be exceptions where increases in normetanephrine and methoxytyramine reach pathological levels. Such exceptions may reflect failure of centrally mediated sympathoinhibition that normally occurs with the norepinephrine reuptake blockade.

Development of Visible Spectrophotometric Methods for the Determination of Tricyclic Antidepressants Based on Formation of Molecular Complexes with p-Benzoquinones.

Tricyclic antidepressants are commonly employed in the management of major depressive disorders. The present work describes two visible (VIS) spectrophotometric techniques that utilize the formation of charge transfer complexes between four antidepressant compounds, namely, amitriptyline hydrochloride (AMI), imipramine hydrochloride (IMI), clomipramine hydrochloride (CLO), and trimipramine maleate (TRI) acting as electron donors and two p-benzoquinones, namely, p-chloranilic acid (pCA) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), serving as electron acceptors. The stoichiometry of the compounds produced exhibited a consistent 1:1 ratio in all instances, as established by Job's method. Molar absorptivities, equilibrium association constants, and several other spectroscopic properties were determined for all complexes. The developed spectrophotometric techniques were validated intra-laboratory and successfully applied for quantitative assessment of the four antidepressant active ingredients in several commercial pharmaceutical formulations. The methods are relatively simple, fast, and use readily available laboratory instrumentation, making them easily applicable by most quality control laboratories worldwide.

Antidepressants as Autophagy Modulators for Cancer Therapy.

Cancer is a major global public health problem with high morbidity. Depression is known to be a high-frequency complication of cancer diseases that decreases patients' life quality and increases the mortality rate. Therefore, antidepressants are often used as a complementary treatment during cancer therapy. During recent decades, various studies have shown that the combination of antidepressants and anticancer drugs increases treatment efficiency. In recent years, further emerging evidence has suggested that the modulation of autophagy serves as one of the primary anticancer mechanisms for antidepressants to suppress tumor growth. In this review, we introduce the anticancer potential of antidepressants, including tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs). In particular, we focus on their autophagy-modulating mechanisms for regulating autophagosome formation and lysosomal degradation. We also discuss the prospect of repurposing antidepressants as anticancer agents. It is promising to repurpose antidepressants for cancer therapy in the future.

Pharmacological treatments in panic disorder in adults: a network meta-analysis.

BACKGROUND: A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines. OBJECTIVES: To compare, via network meta-analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability. To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability. To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses. MAIN RESULTS: Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants. There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta-analysis. Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined. Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest. Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials. Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest. Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo. For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs. For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise. For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs. The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low. AUTHORS' CONCLUSIONS: In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes.

Chronic Pain Syndromes: Chronic Neuropathic Pain.

Neuropathic pain affects 7% to 10% of the population and has major effects on quality of life. It is defined as pain caused by a lesion or disease of the somatosensory nervous system and may be central or peripheral. Diagnostic testing may yield inconclusive or inconsistent results, so physicians often rely on clinical judgment based on the history and physical examination findings. Questionnaires and scoring systems can aid in diagnosis. Neuropathic pain is differentiated from other types of chronic pain by abnormal sensory symptoms, such as shooting pain, burning pain, or numbness. It is difficult to manage and can be accompanied by mood and sleep disturbances. Referral for psychotherapy may be useful for these patients. Nonpharmacotherapy options include mindfulness training, transcutaneous electrical nerve stimulation, and massage. Acupuncture also may be effective, but the data are mixed. Topical drugs (eg, lidocaine, capsaicin), gabapentinoids, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors are considered first-line drugs. Tramadol is considered a second-line drug, but may considered first-line for certain patients. For persistent pain, physicians can consider referring patients to a pain specialist for nerve blocks or other procedural interventions. Opioids may be considered for refractory pain, but their additional benefit has been shown to be modest compared with those of other treatments.

Assessment of psychotropic medications prescribing pattern in Gebretsadik Shawo General Hospital, South West Ethiopia.

Introduction: due to the widespread prescription of antipsychotic medications, their usage is cumulative. Evidence on the trends of medication use in Ethiopia and other parts of the world is lacking. The scant information on prescription trends and medication usage suggests that drug use is generally not sensible in both industrialized and emerging nations. So, the aim of this study was to assess the psychotropic medications prescribing pattern in Gebretsadik Shawo General Hospital, South West Ethiopia. Methods: from June 1st to July 31st, 2019, a cross-sectional study on prescriptions for psychiatric drugs was conducted at Gebretsadik Shawo General Hospital. Using systematic random sampling, prescription records were obtained from the pharmacy dispensing book. Version 21 of the statistical program for social science was used to code and analyze the data. Results: the study included 355 prescription records containing psychotropic drugs in total. The bulk of those taking the psychotropic medication were aged 20 to 49. The most often administered classes of drugs remained antipsychotic, followed by tricyclic antidepressants, antiepileptics, anxiolytics/sedatives, anticholinergic and selective serotonin reuptake inhibitors. The most often ordered antipsychotic medication, which included 102 (23.18%) medications, was chlorpromazine. Tricyclic antidepressants, which included 56 medicines (12.73%) and 24 medications (5.45%), included amitriptyline and imipramine. Conclusion: the results of this investigation showed that psychiatrists preferred traditional psychotropic medications, such as Antipsychotic tricyclic, antidepressants (TCAs) and phenothiazines, in high amounts possibly because these medications were readily available in this hospital and their prices suited patients' needs. Health care workers' interdisciplinary relationships and coherence would improve for the benefit of patients and services of higher quality.