Inclusion Scenarios and Conformational Flexibility of the SSRI Paroxetine as Perceived from Polymorphism of β-Cyclodextrin–Paroxetine Complex

Depression, a global mental health problem, is prevalent during the coronavirus disease 2019 (COVID-19) pandemic and can be efficiently treated by selective serotonin reuptake inhibitors (SSRIs). Our study series aims at forwarding insights on the β-cyclodextrin (β-CD)–SSRI inclusion complexes by X-ray crystallography combined with density functional theory (DFT) calculation. Here, we report a new crystal form (II) of the 1:1 β-CD–paroxetine (PXT) complex, which is inspired by the reported 2:1 β-CD–PXT complex (crystal form I), reflecting an elusive phenomenon of the polymorphism in CD inclusion complexes. The β-CD–PXT polymorphism stems from the PXT conformational flexibility, which is defined by torsion angles κ, ε around the -CH2–O- group bridging the A- and C–D-rings, of which those of PXT in I and II are totally different. While PXT (II) in an open V-shaped conformation that has the B-ring shallowly inserted in the β-CD cavity, PXT (I) in a closed U-shaped structure is mostly entirely embedded in the β-CD dimeric cavity, of which the A-ring is deeply inserted in the main β-CD cavity. However, PXT molecules in both crystal forms are similarly maintained in the CD cavity via host–guest N–H···O5/O6 H-bonds and C/O–H···π(B/C) interactions and β-CDs have similar 3D arrangements, channel (II) vs. screw-channel (I). Further theoretical explorations on the β-CD–PXT thermodynamic stabilities and the PXT conformational stabilities based on their potential energy surfaces (PESs) have been completed by DFT calculations. The 2:1 β-CD–PXT complex with the greater presence of dispersion interactions is more energetically favorable than the unimolar complex. Conversely, whereas free PXT, PXT (II) and PXT in complex with serotonin transporter are more energetically stable, PXT (I) is least stable and stabilized in the β-CD cavity. As SSRIs could lessen the COVID-19 severity, the CD inclusion complexation not only helps to improve the drug bioavailability, but also promotes the use of antidepressants and COVID-19 medicines concurrently.

Granisetron Augmentation of Sertraline in Obsessive-Compulsive Disorder: A Double-Blind Placebo-Controlled, Randomized Clinical Trial

Background: Medications currently recommended for the treatment of Obsessive-Compulsive Disorder (OCD) usually relieve the severity of symptoms by as much as 20–30%, and satisfactory treatment is obtained in 40–60% of patients with OCD. Nevertheless, the remaining symptoms continue to impair the patients’ function. Therefore, it is necessary to investigate possible strategies to improve the mitigation of symptoms.In this study, the main objective was to examine and investigate the effectiveness of granisetron, which is a serotonin 5-hydroxytryptamine receptor type 3 (5-HT3) antagonist, as an adjunct therapy to selective serotonin reuptake inhibitors, for the purpose of ameliorating OCD symptoms. Methods: fifty-eight patients diagnosed with OCD, based on Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria, who had a Yale-Brown obsessive-compulsive scale (Y-BOCS) score of more than 21 were recruited in a double-blinded, parallel-group, placebo-controlled, clinical trial of 10 weeks to receive either granisetron (1 mg twice daily) and sertraline (100 mg daily initially followed by 200 mg daily after week 4) or placebo and sertraline. The primary outcome was OCD symptoms measured by the Y-BOCS.Results: Y-BOCS total score significantly dropped in both groups (28.9 to 17.7 for granisetron and 27.5 to 19.3 for placebo group with a slightly greater drop for granisetron group), while the granisetron group experienced a significantly greater reduction in obsession scores (Greenhouse-Geisser F(2.32,97.57)=4.52,p-value=0.01). Moreover, in comparison with the placebo group, the proportion of the patients showing complete response was considerably higher among the granisetron group (P-value <0.01). No major adverse effects were observed in any of the groups. Conclusion: The results suggest that granisetron augmentation of sertraline may increase the rate of response in patients with moderate to severe non-refractory OCD. Further studies are suggested in this regard.Trial registration: The trial was registered at the Iranian Registry of Clinical Trials on 27/03/2019 (www.irct.ir; IRCT ID: IRCT20170123032145N3).

Efficacy and Safety of Citalopram Compared to Atypical Antipsychotics on Agitation in patients with BPSD

Background: The psychomotor agitation of the behavioural and psychological symptoms of dementia (BPSD) is one of the common issues in aged care facilities, leading to the poor functional and medical consequences. Psychotropic interventions are the preferred choice of treatment, but which medication should be the prescribers first preference? This review aims to compare pharmacological interventions for psychomotor agitation, judging them according to their effectuality and justifiability profiles. This is to be achieved by retrieving information from Randomised Control Trials (RCTs) and systematic reviews. Objectives: This review evaluates evidence from RCTs, systematic reviews, and meta-analyses of BPSD patients who have taken agitation treatments. Assessing the efficacy of selective serotonin reuptake inhibitors (SSRI) and antipsychotic treatments when compared to each other for the purpose of improving agitation outcomes. Methods: This review includes RCT that compared one or more active ingredient medications with another medication or with a placebo, along with systematic reviews comparing citalopram (SSRI) with antipsychotics such as quetiapine, olanzapine, and risperidone. Studies were extracted by searching and accessing databases, such as PubMed, OVID, and Cochrane with restrictions of date from 2000 to 2021 and English language. Conclusion: There is still limited studies of SSRIs for the treatment of agitation in BPSD. SSRIs such as citalopram were associated with a reduction in symptoms of agitation, and lower risk of adverse effects compared to antipsychotics. Future studies are required to assess the long-term safety and efficacy of SSRI treatments for agitation in BPSD.

When to Choose Paroxetine Treatment in Skin-Picking Disorder: A Case Report

Skin picking disorder (SPD) characterized by repetitive compulsive scratching in the absence of a primary skin disease is strongly associated with psychiatric comorbidities, including obsessive-compulsive disorder (OCD) and depression (MDD). Selective serotonin reuptake inhibitors (SSRIs) have been used in the treatment of SPD with variable success. Nevertheless, the optimum treatment choice for SPD is an issue for clinicians. This case report presents a 32-year-old female SPD patient treated with four-week paroxetine monotherapy. Based upon the clinical interview and standardized questionnaires, the patient was diagnosed with OCD with depressive features and Skin Picking Disorder. In addition to symptom severity scales, quantitative electroencephalography (qEEG) was also applied. Paroxetine treatment was started (titrated from 5 to 40 mg/day) and doubled each week. After four-week paroxetine monotherapy, OCD symptoms were diminished, and skin lesions were completely regressed leaving solely post inflammatory hyperpigmentation. Post-treatment qEEG assessment also showed a normalization of frontal alpha power and amplitude asymmetry. It can be concluded that if OCD includes SPD with abnormal EEG patterns; then the treatment success using paroxetine will be very high.

The sociodemographic and clinical profile of patients with major depressive disorder receiving SSRIs as first-line antidepressant treatment in European countries

Introduction Due to favorable antidepressant (AD) efficacy and tolerability, selective-serotonin reuptake inhibitors (SSRIs) are consistently recommended as substances of first choice for the treatment of major depressive disorder (MDD) in international guidelines. However, little is known about the real-world clinical correlates of patients primarily prescribed SSRIs in contrast to those receiving alternative first-line ADs. Methods These secondary analyses are based on a naturalistic, multinational cross-sectional study conducted by the European Group for the Study of Resistant Depression at ten research sites. We compared the socio-demographic and clinical characteristics of 1410 patients with primary MDD, who were either prescribed SSRIs or alternative substances as first-line AD treatment, using chi-squared tests, analyses of covariance, and logistic regression analyses. Results SSRIs were prescribed in 52.1% of MDD patients who showed lower odds for unemployment, current severity of depressive symptoms, melancholic features, suicidality, as well as current inpatient treatment compared to patients receiving alternative first-line ADs. Furthermore, patients prescribed SSRIs less likely received add-on therapies including AD combination and augmentation with antipsychotics, and exhibited a trend towards higher response rates. Conclusion A more favorable socio-demographic and clinical profile associated with SSRIs in contrast to alternative first-line ADs may have guided European psychiatrists’ treatment choice for SSRIs, rather than any relevant pharmacological differences in mechanisms of action of the investigated ADs. Our results must be cautiously interpreted in light of predictable biases resulting from the open treatment selection, the possible allocation of less severely ill patients to SSRIs as well as the cross-sectional study design that does not allow to ascertain any causal conclusions.

The Role of Natural Products in Treatment of Depressive Disorder

Depressive disorder is one of the most common psychiatric syndromes that, if left untreated, can cause many disturbances in a person's functions. Numerous factors are involved in depression, including inflammation, brain-derived neurotrophic factor (BDNF), GABAergic system, hypothalamic–pituitary–adrenal (HPA) Axis, monoamine neurotransmitters (serotonin (5-HT), noradrenaline, and dopamine). Common treatments for depression are selective serotonin reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors, but these drugs have several side effects such as anxiety, diarrhea, constipation, weight loss, and sexual dysfunctions. These agents only reduce the symptoms and temporarily reduce the rate of cognitive impairment associated with depression. As a result, extensive research has recently been conducted on the potential use of antidepressant and sedative herbs. According to the available data, herbs used in traditional medicine can be significantly effective in reducing depression, depressive symptoms and improving patients' performance. The present study provides a summary of biomarkers and therapeutic goals of depression and shows that natural products such as saffron or genipin, have antidepressant effects. Some of the useful natural products and their mechanisms were evaluated. Data on various herbs and natural isolated compounds reported to prevent and reduce depressive symptoms is also discussed.

Effect of Low and High Doses of Two Selective Serotonin Reuptake Inhibitors on Pregnancy Outcomes and Neonatal Mortality

Selective serotonin reuptake inhibitors (SSRI) are the most common antidepressant used by pregnant women; however, they have been associated with adverse pregnancy outcomes and perinatal morbidity in pregnant women and animal models. We investigated the effects of two SSRI, fluoxetine and sertraline, on pregnancy and neonatal outcomes in mice. Wild-type mice were treated daily with low and high doses of fluoxetine (2 and 20 mg/kg) and sertraline (10 and 20 mg/kg) from the day of detection of a vaginal plug until the end of lactation (21 days postpartum). Pregnancy rate was decreased only in the high dose of fluoxetine group. Maternal weight gain was reduced in the groups receiving the high dose of each drug. Number of pups born was decreased in the high dose of fluoxetine and low and high doses of sertraline while the number of pups weaned was decreased in all SSRI-treated groups corresponding to increased neonatal mortality in all SSRI-treated groups. In conclusion, there was a dose-dependent effect of SSRI on pregnancy and neonatal outcomes in a non-depressed mouse model. However, the distinct placental transfer of each drug suggests that the effects of SSRI on pup mortality may be mediated by SSRI-induced placental insufficiency rather than a direct toxic effect on neonatal development and mortality.