Differences in Cerebral Distribution between Imipramine and Paroxetine via Membrane Transporters at the Rat Blood-Brain Barrier.

PURPOSE: The present study aimed to elucidate the transport properties of imipramine and paroxetine, which are the antidepressants, across the blood-brain barrier (BBB) in rats. METHODS: In vivo influx and efflux transport of imipramine and paroxetine across the BBB were tested using integration plot analysis and a combination of brain efflux index and brain slice uptake studies, respectively. Conditionally immortalized rat brain capillary endothelial cells, TR-BBB13 cells, were utilized to characterize imipramine and paroxetine transport at the BBB in vitro. RESULTS: The in vivo influx clearance of [3H]imipramine and [3H]paroxetine in rats was determined to be 0.322 mL/(min·g brain) and 0.313 mL/(min·g brain), respectively. The efflux clearance of [3H]imipramine and [3H]paroxetine was 0.380 mL/(min·g brain) and 0.126 mL/(min·g brain), respectively. These results suggest that the net flux of paroxetine, but not imipramine, at the BBB in vivo was dominated by transport to the brain from the circulating blood. The uptake of imipramine and paroxetine by TR-BBB13 cells exhibited time- and temperature-dependence and one-saturable kinetics with a Km of 37.6 µM and 89.2 µM, respectively. In vitro uptake analyses of extracellular ion dependency and the effect of substrates/inhibitors for organic cation transporters and transport systems revealed minor contributions to known transporters and transport systems and the difference in transport properties in the BBB between imipramine and paroxetine. CONCLUSIONS: Our study showed the comprehensive outcomes of imipramine and paroxetine transport at the BBB, implying that molecular mechanism(s) distinct from previously reported transporters and transport systems are involved in the transport.

Physiological tremor is suppressed and force steadiness is enhanced with increased availability of serotonin regardless of muscle fatigue.

Although there is evidence that 5-HT acts as an excitatory neuromodulator to enhance maximal force generation, it is largely unknown how 5-HT activity influences the ability to sustain a constant force during steady-state contractions. A total of 22 healthy individuals participated in the study, where elbow flexion force was assessed during brief isometric contractions at 10% maximal voluntary contraction (MVC), 60% MVC, MVC, and during a sustained MVC. The selective serotonin reuptake inhibitor, paroxetine, suppressed physiological tremor and increased force steadiness when performing the isometric contractions. In particular, a main effect of drug was detected for peak power of force within the 8-12 Hz range (P = 0.004) and the coefficient of variation (CV) of force (P < 0.001). A second experiment was performed where intermittent isometric elbow flexions (20% MVC sustained for 2 min) were repeatedly performed so that serotonergic effects on physiological tremor and force steadiness could be assessed during the development of fatigue. Main effects of drug were once again detected for peak power of force in the 8-12 Hz range (P = 0.002) and CV of force (P = 0.003), where paroxetine suppressed physiological tremor and increased force steadiness when the elbow flexors were fatigued. The findings of this study suggest that enhanced availability of 5-HT in humans has a profound influence of maintaining constant force during steady-state contractions. The action of 5-HT appears to suppress fluctuations in force regardless of the fatigue state of the muscle.NEW & NOTEWORTHY Converging lines of research indicate that enhanced serotonin availability increases maximal force generation. However, it is largely unknown how serotonin influences the ability to sustain a constant force. We performed two experiments to assess physiological tremor and force steadiness in unfatigued and fatigued muscle when serotonin availability was enhanced in the central nervous system. Enhanced availability of serotonin reduced physiological tremor amplitude and improved steadiness regardless of muscle fatigue.

Effect of Paroxetine-Mediated G-Protein Receptor Kinase 2 Inhibition vs Placebo in Patients With Anterior Myocardial Infarction: A Randomized Clinical Trial.

Importance: Left ventricular remodeling following acute myocardial infarction results in progressive myocardial dysfunction and adversely affects prognosis. Objective: To investigate the efficacy of paroxetine-mediated G-protein-coupled receptor kinase 2 inhibition to mitigate adverse left ventricular remodeling in patients presenting with acute myocardial infarction. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial was conducted at Bern University Hospital, Bern, Switzerland. Patients with acute anterior ST-segment elevation myocardial infarction with left ventricular ejection fraction (LVEF) of 45% or less were randomly allocated to 2 study arms between October 26, 2017, and September 21, 2020. Interventions: Patients in the experimental arm received 20 mg of paroxetine daily; patients in the control group received a placebo daily. Both treatments were provided for 12 weeks. Main Outcomes and Measures: The primary end point was the difference in patient-level improvement of LVEF between baseline and 12 weeks as assessed by cardiac magnetic resonance tomography. Secondary end points were changes in left ventricular dimensions and late gadolinium enhancement between baseline and follow-up. Results: Fifty patients (mean [SD] age, 62 [13] years; 41 men [82%]) with acute anterior myocardial infarction were randomly allocated to paroxetine or placebo, of whom 38 patients underwent cardiac magnetic resonance imaging both at baseline and 12 weeks. There was no difference in recovery of LVEF between the experimental group (mean [SD] change, 4.0% [7.0%]) and the control group (mean [SD] change, 6.3% [6.3%]; mean difference, -2.4% [95% CI, -6.8% to 2.1%]; P = .29) or changes in left ventricular end-diastolic volume (mean difference, 13.4 [95% CI, -12.3 to 39.0] mL; P = .30) and end-systolic volume (mean difference, 11.4 [95% CI, -3.6 to 26.4] mL; P = .13). Late gadolinium enhancement as a percentage of the total left ventricular mass decreased to a larger extent in the experimental group (mean [SD], -13.6% [12.9%]) compared with the control group (mean [SD], -4.5% [9.5%]; mean difference, -9.1% [95% CI, -16.6% to -1.6%]; P = .02). Conclusions and Relevance: In this trial, treatment with paroxetine did not improve LVEF after myocardial infarction compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03274752.

Development and evaluation of a physiologically based pharmacokinetic model to predict carvedilol-paroxetine metabolic drug-drug interaction in healthy adults and its extrapolation to virtual chronic heart failure patients for dose optimization.

Purpose: The metabolic drug-drug interactions (mDDIs) are one of the most important challenges faced by the pharmaceutical industry during the drug development stage and are frequently associated with labeling restrictions and withdrawal of drugs. The capacity of physiologically based pharmacokinetic (PBPK) models to absorb and upgrade with the newly available information on drug and population-specific parameters, makes them a preferred choice over the conventional pharmacokinetic models for predicting mDDIs.Method: A PBPK model capable of predicting the stereo-selective disposition of carvedilol after administering paroxetine by incorporating mechanism (time) based inhibition of CYP2D6 and CYP3A4 was developed by using the population-based absorption, distribution, metabolism and elimination (ADME) simulator, Simcyp®.Results: The model predictions for both carvedilol enantiomers were in close agreement with the observed PK data, as the ratios for observed/predicted PK parameters were within the 2-fold error range. The developed PBPK model was successful in capturing an increase in exposures of R and S-carvedilol, due to the time-based inhibition of CYP2D6 enzyme caused by paroxetine.Conclusion: The developed model can be used for exploring complex clinical scenarios, where multiple drugs are given concurrently, particularly in diseased populations where no clinical trial data is available.

Antidepressant action of transcranial direct current stimulation in olfactory bulbectomised adolescent rats.

BACKGROUND: Antidepressant drugs in adolescent depression are sometimes mired by efficacy issues and paradoxical effects. Transcranial direct current stimulation (tDCS) could represent an alternative. AIMS/METHODS: We tested the antidepressant action of prefrontal tDCS and paroxetine (20 mg/kg, intraperitoneal) in olfactory bulbectomised (OBX) adolescent rats. Using enzyme-linked immunosorbent assays and in situ hybridisation, we examined treatment-induced changes in plasma brain-derived neurotrophic factor (BDNF) and brain serotonin transporter (SERT) and 5-HT-1A mRNA. RESULTS: OBX-induced anhedonia-like reductions in sucrose preference (SP) correlated with open field (OF) hyperactivity. These were accompanied by decreased zif268 mRNA in the piriform/amygdalopiriform transition area, and increased zif268 mRNA in the hypothalamus. Acute paroxetine (2 days) led to a profound SP reduction, an effect blocked by combined tDCS-paroxetine administration. Chronic (14 days) tDCS attenuated hyperlocomotion and its combination with paroxetine blocked OBX-induced SP reduction. Correlations among BDNF, SP and hyperlocomotion scores were altered by OBX but were normalised by tDCS-paroxetine co-treatment. In the brain, paroxetine increased zif268 mRNA in the hippocampal CA1 subregion and decreased it in the claustrum. This effect was blocked by tDCS co-administration, which also increased zif268 in CA2. tDCS-paroxetine co-treatment had variable effects on 5-HT1A receptors and SERT mRNA. 5-HT1A receptor changes were found exclusively within depression-related parahippocampal/hippocampal subregions, and SERT changes within fear/defensive response-modulating brainstem circuits. CONCLUSION: These findings point towards potential synergistic efficacies of tDCS and paroxetine in the OBX model of adolescent depression via mechanisms associated with altered expression of BDNF, 5-HT1A, SERT and zif268 in discrete corticolimbic areas.

Comparing Medications for DSM-5 PTSD in Routine VA Practice.

OBJECTIVE: Fluoxetine, paroxetine, sertraline, topiramate, and venlafaxine have previously shown efficacy for posttraumatic stress disorder (PTSD). One prior study using US Department of Veterans Affairs (VA) medical records data to compare these agents found no differences in symptom reduction in clinical practice. The current study addresses several weaknesses in that study, including limited standardization of treatment duration, inability to account for prior treatment receipt, use of an outdated symptomatic assessment for PTSD, and lack of functional outcome. METHODS: A total of 834 VA outpatients were identified with DSM-5 clinical diagnoses of PTSD between October 2016 and March 2018 who initiated one of the medications and met prespecified criteria for treatment duration and dose, combined with baseline and endpoint DSM-5 PTSD Checklist (PCL-5) measurements. Twelve-week acute-phase changes in PCL-5 score and remission of PTSD symptoms were compared among patients receiving the different medications, as was use of acute psychiatric services in the subsequent 6-month continuation phase. RESULTS: In the acute phase, patients improved by a mean of 6.8-10.1 points on the PCL-5 and 0.0%-10.9% achieved remission of PTSD symptoms. Those taking venlafaxine were significantly more likely to achieve remission (P = .008 vs fluoxetine and P < .0001 vs paroxetine, sertraline, and topiramate). In the continuation phase, there were no differences in acute psychiatric care use between medications. Those who continued their medication were less likely to use acute psychiatric services (HR = 0.55; P = .03). CONCLUSIONS: There may be an advantage to venlafaxine over other agents in achieving acute-phase remission for DSM-5 PTSD in routine clinical practice, but this finding requires further study. Regardless of the agent chosen, medication cessation during the continuation phase is associated with a higher risk of acute psychiatric care use.

In search of a dose-response relationship in SSRIs-a systematic review, meta-analysis, and network meta-analysis.

OBJECTIVE: Recent meta-analyses on dose-response relationships of SSRIs are largely based on indirect evidence. We analyzed RCTs directly comparing different SSRI doses. METHOD: Systematic literature search for RCTs. Two raters independently screened articles and extracted data. Across SSRIs, doses defined as low, medium, and high doses, based on drug manufacturers' product monographs, were analyzed in pairwise random-effects meta-analyses and in a sensitivity network meta-analysis with regard to differences in antidepressive efficacy (primary outcome). We also analyzed all direct comparisons of different dosages of specific SSRIs. (Prospero CRD42018081031). RESULTS: Out of 5333 articles screened, we included 33. Comparisons of dosage groups (low, medium, and high) resulted in only small and clinically non-significant differences for SSRIs as a group, the strongest relating to medium vs low doses (SMD: -0.15 [95%-CI: -0.28; -0.01) and not sustained in a sensitivity analysis. Among different doses of specific SSRIs, no statistically significant trend emerged for efficacy at higher doses, but 60 mg/day fluoxetine are statistically significantly inferior to 20 mg/day. Paroxetine results are inconclusive: 10 mg/day are inferior to higher doses, but 30 and 40 mg/day are inferior to 20 mg/day. Meaningful effects cannot be ruled out for certain drugs and dosages, often investigated in only one trial. Dropout rates increase with dose-particularly due to side effects. Network meta-analyses supported our findings. CONCLUSIONS: There is no conclusive level I or level II evidence of a clinically meaningful dose-response relationship of SSRIs as a group or of single substances. High SSRI doses are not recommended as routine treatment.

Sustaining Circulating Regulatory T Cell Subset Contributes to the Therapeutic Effect of Paroxetine on Mice With Diabetic Cardiomyopathy.

BACKGROUND: G protein coupled receptor kinase 2 (GRK2) inhibitor, paroxetine, has been approved to ameliorate diabetic cardiomyopathy (DCM). GRK2 is also involved in regulating T cell functions; the potential modifications of paroxetine on the immune response to DCM is unclear.Methods and Results:DCM mouse was induced by high-fat diet (HFD) feeding. A remarkable reduction in the regulatory T (Treg) cell subset in DCM mouse was found by flow cytometry, with impaired cardiac function evaluated by echocardiography. The inhibited Treg differentiation was attributable to insulin chronic stimulation in a GRK2-PI3K-Akt signaling-dependent manner. The selective GRK2 inhibitor, paroxetine, rescued Treg differentiation in vitro and in vivo. Furthermore, heart function, as well as the activation of excitation-contraction coupling proteins such as phospholamban (PLB) and troponin I (TnI) was effectively promoted in paroxetine-treated DCM mice compared with vehicle-treated DCM mice. Blockade of FoxP3 expression sufficiently inhibited the proportion of Treg cells, abolished the protective effect of paroxetine on heart function as well as PLB and TnI activation in HFD-fed mice. Neither paroxetine nor carvedilol could effectively ameliorate the metabolic disorder of HFD mice. CONCLUSIONS: The impaired systolic heart function of DCM mice was effectively improved by paroxetine therapy, partially through restoring the population of circulating Treg cells by targeting the GRK2-PI3K-Akt pathway.

Effect of antidepressant drugs on the brain sphingolipid system.

BACKGROUND: Major depression is a common mood disorder and the central sphingolipid system has been identified as a possible drug target of this condition. Here we investigated the action of antidepressant drugs on sphingolipid levels in rat brain regions, plasma and in cultured mouse macrophages. METHODS: Two antidepressant drugs were tested: the serotonin reuptake inhibitor paroxetine and the noradrenaline reuptake inhibitor desipramine, either following acute or chronic treatments. Content of sphingosine and ceramide were analysed using LC-MS or HPLC-UV, respectively. This was from samples of brain, plasma and cultured mouse macrophages. Antidepressant-induced effects on mRNA expression for two key genes of the sphingolipid pathway, SMPD1 and ASAH1, were also measured by using quantitative real-time PCR. RESULTS: Chronic but not acute administration of paroxetine or desipramine reduced sphingosine levels in the prefrontal cortex and hippocampus (only paroxetine) but not in the striatum. Ceramide levels were also measured in the hippocampus following chronic paroxetine and likewise to sphingosine this treatment reduced its levels. The corresponding collected plasma samples from chronically treated animals did not show any decrease of sphingosine compared to the corresponding controls. Both drugs failed to reduce sphingosine levels from cultured mouse macrophages. The drug-induced decrease of sphingolipids coincided with reduced mRNA expression of two enzymes of the central sphingolipid pathway, i.e. acid sphingomyelinase (SMPD1) and acid ceramidase (ASAH1). CONCLUSIONS: This study supports the involvement of brain sphingolipids in the mechanism of action by antidepressant drugs and for the first time highlights their differential effects on brain versus plasma levels.

Effect of Paroxetine on the Neuropathic Pain: A Molecular Study.

Background: Neuropathic pain, due to peripheral nerve damage, has influenced millions of people living all over the world. It has been shown that paroxetine can relieve neuropathic pain. Recently, the role of certain proteins like brain-derived neurotrophic factor (BDNF), GABAA receptor, and K+-Cl- cotransporter 2 (KCC2) transporter in the occurrence of neuropathic pain has been documented. In the current study, the expression of these proteins affected by paroxetine was evaluated. Methods: Male Wistar rats were allocated into two main groups of pre- and post-injury. Rats in each main group received paroxetine before nerve injury and at day seven after nerve damage till day 14, respectively. The lumbar spinal cord of animals was extracted to assess the expression of target genes and proteins. Results: In the preventive study, paroxetine decreased BDNF and increased KCC2 and GABAA gene and protein expression, while in the post-injury paradigm, it decreased BDNF and increased KCC2 genes and protein expression. In this regard, an increase in the protein expression of GABAA was observed. Conclusion: It seems that paroxetine with a change in the expression of three significant proteins involved in neuropathic pain could attenuate this type of chronic pain.

Precision dosing-based optimisation of paroxetine during pregnancy for poor and ultrarapid CYP2D6 metabolisers: a virtual clinical trial pharmacokinetics study.

OBJECTIVE: Paroxetine has been demonstrated to undergo gestation-related reductions in plasma concentrations, to an extent which is dictated by the polymorphic state of CYP 2D6. However, knowledge of appropriate dose titrations is lacking. METHODS: A pharmacokinetic modelling approach was applied to examine gestational changes in trough plasma concentrations for CYP 2D6 phenotypes, followed by necessary dose adjustment strategies to maintain paroxetine levels within a therapeutic range of 20-60 ng/ml. KEY FINDINGS: A decrease in trough plasma concentrations was simulated throughout gestation for all phenotypes. A significant number of ultrarapid (UM) phenotype subjects possessed trough levels below 20 ng/ml (73-76%) compared to extensive metabolisers (EM) (51-53%). CONCLUSIONS: For all phenotypes studied, there was a requirement for daily doses in excess of the standard 20 mg dose throughout gestation. For EM, a dose of 30 mg daily in trimester 1 followed by 40 mg daily in trimesters 2 and 3 is suggested to be optimal. For poor metabolisers (PM), a 20 mg daily dose in trimester 1 followed by 30 mg daily in trimesters 2 and 3 is suggested to be optimal. For UM, a 40 mg daily dose throughout gestation is suggested to be optimal.

Cardiac autonomic tone, plasma BDNF levels and paroxetine response in newly diagnosed patients of generalised anxiety disorder.

Objective: The study examined the effect on cardiac autonomic tone via heart rate variability (HRV), brain derived neurotrophic factor (BDNF) in newly diagnosed generalised anxiety disorder (GAD) cases with paroxetine-controlled release (PX) CR intervention.Methods: Fifty GAD cases using DSM-5 criteria, matched with healthy controls (HC) were assessed with clinical measures (Hamilton Anxiety Scale (HAM-A), Clinical Global Impression- Severity Scale (CGI-Severity), General Health Questionnaire -12 (GHQ-12), HRV, plasma BDNF levels initially and 6 weeks postintervention with paroxetine CR.Results: HRV parameters were significantly lower in GAD vs HC at baseline for standard deviation of normal to normal intervals (SDNN) and proportion of differences in consecutive NN intervals that are longer than 50 ms (pNN50). Significantly higher plasma BDNF levels were noted between HC versus GAD at baseline. Postintervention HAM-A, CGI scores, GHQ-12 item scores showed significant reduction. Significant differences also noted in square root of mean squared difference of successive NN intervals (RMSSD), (SDNN), pNN50 and in plasma BDNF levels after intervention within GAD group. Significant negative correlation observed between HAM-A scores and SDNN parameter after taking PX CR in GAD.Conclusion: GAD showed cardiac autonomic dysfunction, lowered plasma BDNF levels and their improvement with paroxetine CR.Key messageGAD is associated with significantly lower HRV, suggestive of cardiac autonomic dysfunction and lowered plasma BDNF levels, an indicator of stress.Therapeutic intervention with Paroxetine in GAD patients showed clinically significant improvement reflecting restoration of the cardiac autonomic tone and BDNF levels, thus implying their role as potential biomarkers.

A Case Report of Serotonin Syndrome in a Patient on Selective Serotonin Reuptake Inhibitor (SSRI) Monotherapy.

INTRODUCTION: Paroxetine is a selective serotonin reuptake inhibitor (SSRI) with several indications, one of which is for depression. We present a case of probable paroxetine-induced serotonin syndrome. CASE SUMMARY: A 21-year-old female with a history of generalized anxiety disorder and major depression presented with increased depressive symptoms over several months while taking fluoxetine 20 mg daily. Fluoxetine was discontinued without taper and replaced with paroxetine 10 mg daily, along with hydroxyzine 50 mg twice daily as needed for anxiety. Within a week of starting the paroxetine, the patient reported increased anxiety, insomnia, and constant shaking. The paroxetine continued to be uptitrated over a 3-week period to a dose 30 mg due to unremitting depressive symptoms. One month later, the patient presented with tachycardia, generalized body aches, extreme fatigue, weakness, uncontrollable twitching, tremor, and hyperreflexia. A widespread burning sensation accompanied by random hot flashes without diaphoresis was also noted. Serotonin syndrome was diagnosed using the Hunters criteria. Paroxetine was discontinued, and the patient's physical symptoms resolved within a week. DISCUSSION: To date, only 5 cases of serotonin syndrome have been reported in patients receiving SSRI monotherapy at recommended therapeutic doses.

Paroxetine for the treatment of intractable and persistent cough in patients diagnosed with cancer.

INTRODUCTION: Intractable and persistent cough is experienced by more than a third of patients with advanced cancer, with a significant negative impact on quality of life. Pharmacological treatment has been of little help in some patients. Limited evidence suggests novel agents such as paroxetine may reduce cough severity. This retrospective study aimed to assess effectiveness and tolerability of paroxetine for the treatment of intractable cough in patients with cancer. METHODS: Single-centre medical record review of paroxetine use in patients with advanced malignancy and cough treated at an Australia tertiary referral cancer centre between 1 October 2012 and 1 October 2017. Data relating to cough type and severity, response and adverse events were extracted from medical records. Cough type was described as non-productive dry cough, productive chesty cough or cough exhibiting both non-productive and productive features (mixed cough). RESULTS: Overall, 24/34 patients (71%) experienced a major or moderate reduction in their cough severity after treatment with paroxetine. Nearly half (47%) described a major improvement and a quarter (24%) moderate improvement. Of the 34 patients, nearly half had a lung primary cancer (16/34, 47%) and nearly all (17/18) of those without lung cancer had lung metastases from another primary cancer. Patients with dry cough reported greater benefit from paroxetine. Of the 56% (19/34) of patients with non-productive dry cough, 80% (15/19) reported an improvement in symptoms post paroxetine. The remaining 15 patients, 44% of the group, presented with either a productive chesty cough (9/34, 27%) or mixed cough (6/34, 18%). Of these patients, 60% (9/15) reported an improvement in symptoms. Two thirds of patients were commenced on paroxetine 10 mg (22/34, 65%), with the remainder starting at 20 mg (14/34, 35%). CONCLUSION: Paroxetine may be an effective, novel, off-label treatment for intractable and persistent cough in patients with advanced cancer.

Dispensing patterns of selective serotonin reuptake inhibitors before, during and after pregnancy: a 16-year population-based cohort study from the Netherlands.

Management of mental illness in the perinatal period with antidepressants is controversial, since evidence emerged on potential harmful effects to the unborn child. However, over time, the dispensing of antidepressants in the perinatal period has increased. We examined perinatal dispensing patterns over time and the role of a recently issued guideline in this regard. We identified a 16-year cohort of 153,952 Dutch pregnancies with a delivery date between January 1999 and December 2014. Data included exposure to selective serotonin reuptake inhibitors (SSRIs) related to phases of pregnancy (preconception, pregnancy and delivery, post-delivery). The chi-square test for trends was used. With standard logistic regression, we explored the influence of patient characteristics on continuation of SSRIs during pregnancy. A persistent significant rise of dispensing rates in all phases was observed, with the largest increase during pregnancy (from 0.8% in 1999/2000 to 2.1% in 2013/2014, chi-square for trend = 141.735, p < 0.001). A substantial change of practice in terms of the SSRI used (less paroxetine) and the policy towards continuation into pregnancy (more continuation over time) was visible. Concomitant use of psycholeptics halved the probability of continuation of SSRIs (OR 0.50, 95%CI 0.43-0.55, p < 0.01). Dispensing rates of SSRIs steadily increased last 16 years, especially during pregnancy, caused by an increase in the proportion of women continuing their medication during pregnancy. In view of the demonstrated impact of uncertainty regarding effectiveness and safety of SSRIs in pregnancy, future research should involve more detailed outcome research of SSRIs as it is, and research into viable alternatives.

Efficacy and safety of lavender essential oil (Silexan) capsules among patients suffering from anxiety disorders: A network meta-analysis.

A systematic review and network-meta analysis (NMA) were performed to estimate significance of the anxiolytic effect of lavender essential oil taken as silexan capsules versus other comparators (i.e., placebo/paroxetine/lorazepam). The outcome of interest was Hamilton Anxiety Scale (HAMA). Weighted mean differences (WMD) were calculated to estimate the treatment effect at the confidence interval of 95%. League tables were generated using treatment effect, for all pairwise comparisons, where WMD < 0 favors the column-defining treatment. Five studies were identified with a total of 524 participants receiving treatment with silexan 80 mg and 121 participants taking silexan 160 mg. The NMA results indicated that consumption of silexan 160 mg resulted in higher decline of HAMA score [WMD -1.14 (-1.10, 3.39)] in comparison to silexan 80 mg, placebo [-2.20 (-4.64, 0.24)] and paroxetine [-1.24 (-5.34, 2.85)]. The effect of silexan 80 mg was observed to be same as that of paroxetine. Overall, silexan 160 mg was noticed to be a more efficient treatment giving significant decline in HAMA score across other comparators. However, no improvements in HAMA score was observed for the group receiving lorazepam 0.5 mg when compared to silexan 160 mg, silexan 80 mg, paroxetine 20 mg, and placebo.

Efficacy of Low-Dose Paroxetine for the Treatment of Hot Flushes in Surgical and Physiological Postmenopausal Women: Systematic Review and Meta-Analysis of Randomized Trials.

Background and Objectives: Hot flushes and sleep disturbances are the most common vasomotor symptoms (VMS) reported by postmenopausal women. Hormonal treatment is to date referred to as the gold standard approach but not suitable for all the patients. Alternative treatments are needed in case of a contraindication to menopausal hormone therapy (MHT), adverse side effects, and poor compliance. Paroxetine salt is the only nonhormonal medication approved by the US Food and Drug Administration for the management of VMS. Nonetheless, few trials with low consensus are available about this topic. In this review, we aimed to evaluate the efficacy of low-dose paroxetine therapy in the treatment of vasomotor hot flushes and night sleep disturbances in postmenopausal women. Materials and Methods: We performed an electronic search from the beginning of all databases to July 2019. All results were then limited to a randomized trial. Restrictions for language or geographic location were not utilized. Inclusion criteria were randomized clinical trials of physiological or surgical postmenopausal women experiencing hot flushes and sleep disturbances who were randomized to either low-dose paroxetine or placebo (i.e., formulations without active ingredients). The primary outcome evaluated was the mean weekly reduction of hot flushes. Results: Five randomized clinical trials, including 1482 postmenopausal women, were analyzed. Significant heterogeneity (I2 = 90%) between studies was noted. Hot flushes episodes were significantly reduced in the treatment arm compared to placebo (mean difference (MD) -7.97 [-10.51, -5.92] episodes/week). Results on the improvement on sleep were limited by being reported in only two studies; however, no significant reduction of night-time awakenings was observed (MD, -0.40 awakenings/night [-1.38, 0.58 CI]). Conclusions: Low-dose paroxetine is an effective treatment for vasomotor menopause symptoms, including hot flushes.

Basal Ganglia Calcification: A Case Report of Fahr Disease With Pure Psychiatric Symptoms.

Fahr disease, also known as familial idiopathic basal ganglia calcification, is a rare neurodegenerative disorder, the etiology of which remains unknown. Given its various presentations, Fahr disease is presumed to be underdiagnosed and its prevalence underestimated. We present a case of Fahr disease that presented mainly with pure psychiatric symptoms. Isolated psychiatric symptoms without neurological manifestations are rarely seen in patients diagnosed with Fahr disease. Psychiatrists should consider Fahr disease as a differential diagnosis in the evaluation of psychiatric illness.

Paroxetine, but not Vortioxetine, Impairs Sexual Functioning Compared With Placebo in Healthy Adults: A Randomized, Controlled Trial.

INTRODUCTION: Sexual dysfunction is prevalent among patients with depression, but assessment of treatment-emergent sexual dysfunction (TESD), a common side effect of antidepressants, can be confounded by the treatment of depressive symptoms in some patients. AIM: To evaluate sexual functioning in healthy volunteers administered vortioxetine compared with paroxetine, an antidepressant known to cause sexual dysfunction, and placebo. METHODS: This phase 4, multicenter, randomized, double-blind, placebo-controlled, 4-arm, fixed-dose, head-to-head study compared sexual functioning in healthy volunteers administered vortioxetine (10 and 20 mg once daily [QD]), paroxetine (20 mg QD), or placebo for 5 weeks. Approximately equal numbers of men and women ages 18-40 years with normal sexual functioning (self-reported Changes in Sexual Functioning Questionnaire Short-Form [CSFQ-14] score > 47 for men; > 41 for women) were enrolled. Two modified full analysis sets adjusting for treatment non-compliance were prespecified. MAIN OUTCOME MEASURE: The primary endpoint was change in CSFQ-14 total score for vortioxetine (10 and 20 mg) vs paroxetine after 5 weeks. Additional endpoints included CSFQ-14 change scores vs placebo, CSFQ-14 subscales, and patient global impression. RESULTS: Of the 361 subjects enrolled (mean age, 28.4 years), approximately 57% were white, 34% black/African American, and 4% Asian. Vortioxetine 10 mg was associated with significantly less TESD than paroxetine (mean difference, +2.74 points; P = .009). Although vortioxetine 20 mg was associated with numerically less TESD than paroxetine (mean difference, +1.05 points), this difference did not reach statistical significance. Non-compliance appeared to influence results, particularly the paroxetine and vortioxetine 20 mg arms. Paroxetine, but not vortioxetine, was associated with statistically significantly more TESD vs placebo. Vortioxetine also had better outcomes than paroxetine in the 3 phases and 5 dimensions of sexual functioning measured by CSFQ-14. CLINICAL IMPLICATIONS: These data establish that vortioxetine is associated with less TESD than paroxetine in healthy individuals, suggesting that vortioxetine may be a drug of choice in managing depressive disorders when sexual functioning is a concern. STRENGTHS & LIMITATIONS: Conducting the study in healthy adults mitigated the risk of an underlying condition (eg, depression) confounding the results. Assay sensitivity was demonstrated by statistically significant TESD with paroxetine vs placebo. The single comparator, paroxetine, and short study duration limit the generalizability of these results. CONCLUSION: Vortioxetine is associated with less TESD than paroxetine in healthy adults across all phases and dimensions of the sexual response cycle. Vortioxetine was not significantly different from placebo on sexual functioning; however, the difference was significant between paroxetine and placebo, validating study results. Jacobsen P, Zhong W, Nomikos G, et al. Paroxetine, but not Vortioxetine, Impairs Sexual Functioning Compared With Placebo in Healthy Adults: A Randomized, Controlled Trial. J Sex Med 2019; 16:1638-1649.

Influence of baseline severity on the effects of SSRIs in depression: an item-based, patient-level post-hoc analysis.

BACKGROUND: Reports claiming that antidepressants are effective only in patients with severe depression have affected treatment guidelines but these reports usually use a disputed measure of improvement, a decrease in the sum-score of the 17-item Hamilton Depression Rating Scale (HDRS-17), and are based on group-level rather than patient-level data. METHOD: In this item-based, patient-level, post-hoc analysis, we pooled data from all completed, acute-phase, placebo-controlled, industry-sponsored, HDRS-based trials of the SSRIs citalopram, paroxetine, or sertraline in adult major depression. Patient-level data were pooled and subjected to item-based post-hoc analyses to assess the effect of baseline severity of depression on the response to treatment as assessed with HDRS-17 sum score, the depressed mood item of the HDRS, a six-item HDRS subscale (HDRS-6), and the remaining 11 HDRS items not included in this subscale (non-HDRS-6). Patients were defined as having non-severe depression if they had a baseline HDRS-17 sum score of 18 points or less and as having severe depression if they had a score of 27 points or more. FINDINGS: Our study population consisted of 8262 patients from 28 placebo-controlled SSRI trials. Participants were treated with either citalopram (n=744), paroxetine (n=2981), sertraline (n=1202), fluoxetine (active-control group; n=754), or placebo (n=2581). 654 patients were defined as having non-severe depression and 1377 as having severe depression. Patients with non-severe and severe depression did not differ with respect to SSRI-induced decrease in depressed mood and other HDRS symptoms belonging to the HDRS-6 subscale. However, after exclusion of patients with rare extreme baseline values, a positive association was seen between severity and efficacy when using HDRS-17 sum score as the effect parameter. This result was largely due to a more pronounced response to treatment with respect to non-HDRS-6 items in patients with severe depression than in those with non-severe depression. This outcome could be explained by non-HDRS-6 items, more so than HDRS-6 items, being more severe and prevalent at baseline in severe than in non-severe cases; hence, less room was left for improvement in these areas in patients with non-severe depression. INTERPRETATION: The use of an outcome measure that includes symptoms that rate low at baseline in patients with non-severe depression might result in the interpretation that SSRIs are ineffective in these patients. With respect to alleviation of HDRS-6 items, SSRIs appear to be as effective in patients with non-severe depression as in those with severe depression. FUNDING: Swedish Medical Research Council, AFA Insurance, Swedish Brain Foundation, Sahlgrenska University Hospital (Avtal om Läkarutbildning och Forskning), Bertil Hållsten's Foundation, and Söderberg's Foundation.