Serotonergic Antidepressants Research Articles

Majoon-E-Piyaz: A Potent Unani Formulation for Premature Ejaculation

Surʻat-e-Inzāl (Premature Ejaculation) is the most prevalent male sexual dysfunction affecting 25 - 40% global population of men. It is a universal disorder and is independent of age, social or marital status. It has a significant impact on both- patients and their partners, causing distress, anxiety and relationship difficulties affecting the quality of life. Several aetiologies have been proposed by various researchers which are not evidence-based but speculative. Accordingly the International Society for Sexual Medicine (ISSM) issued treatment guidelines for Premature Ejaculation (PE) recommending Serotonergic Antidepressants (SSRIs) and Local Anaesthetics (LA) for its management in modern medicine. However, these treatments were not actually developed for PE, and have limitations associated with their off-label use. Furthermore, nearly all the recommended drugs have a wider spectrum of adverse effects and serious drug interactions which sometimes could be fatal. On the other hand, centuries old Unani medicine offers a complete line of treatment for Surʻat-e-Inzāl based on traditional knowledge and experience. Unani physicians devised a large number of poly-herbal recipes which are still in vogue. Majoon-e-Piyaz (MP) is one of the compound Unani formulations which are in use for the treatment of premature ejaculation since centuries. This article is an attempt to summarize scientific investigations in support of the claim made by Unani physicians regarding Majoon-e-Piyaz (MP). 
 Keywords: Surʻat-e-Inzāl, Premature Ejaculation, Majoon-e-Piyaz, Unani Medicine

New-generation, non-SSRI antidepressants: Drug-drug interactions and therapeutic drug monitoring. Part 2: NaSSAs, NRIs, SNDRIs, MASSAs, NDRIs, and others.

After the development of "classical" tricyclic antidepressants and monoamine oxidase inhibitors, numerous other classes of antidepressant drugs have been introduced onto the market. The selective serotonin reuptake inhibitor class is the best-known one, but many others exist, usually identified by their mechanism of activity. In this second part of the review, focused on new-generation antidepressants not included among selective serotonin reuptake inhibitors, the following classes are considered: noradrenergic and selective serotonergic antidepressants; norepinephrine reuptake inhibitors; serotonin, norepinephrine and dopamine reuptake inhibitors; melatonergic agonists and selective serotonergic antagonists; norepinephrine and dopamine reuptake inhibitors; and so forth. These different mechanisms underlie tolerability and safety profiles that can be very different among the classes, with each one providing significant advantages and disadvantages in comparison with others. The main characteristics of the following antidepressants are described: mianserin, mirtazapine, setiptiline, reboxetine, viloxazine, teniloxazine, atomoxetine, nefazodone, agomelatine, bupropion, esketamine, and tianeptine. The paper is focused on their metabolism and interactions, but also includes brief notes on analytical methods useful for their therapeutic drug monitoring.

Sensory Neuron–Expressed TRPC4 Is a Target for the Relief of Psoriasiform Itch and Skin Inflammation in Mice

Psoriasis is an inflammatory skin disease associated with itch, which is a troublesome symptom with a few therapeutic options. TRPC4 is highly expressed in dorsal root ganglia (DRGs). Recently, we have revealed itch signaling in DRG neurons by which TRPC4 mediates itch to serotonergic antidepressants and demonstrated the antipruritic effect of the TRPC4 inhibitor ML204. However, the role of TRPC4 in acute and chronic itch is still largely unknown. Here, we have characterized the expression of TRPC4 in peptidergic DRG neurons and showed that acute itch induced by serotonin and histamine was attenuated in Trpc4-knockout mice and ML204-treated mice. We have also shown that silencing TRPC4 in DRG and its inhibition by intradermal injections were also effective in decreasing psoriatic itch after the repeated application of imiquimod, which is a preclinical model of psoriasis. Of clinical relevance, intradermal injections of ML204 in psoriasiform skin significantly reversed imiquimod-established chronic itch and cutaneous inflammation. Given that TRPC4 is expressed in human DRGs and a specific inhibitor is in clinical trials, our data not only expand our understanding of itch and psoriasis, but also reveal TRPC4 as a potential therapeutic target with considerable translational benefits.

Physiological effect of trazodone hydrochloride use for anxiety and sedation in rabbits (Oryctolagus cuniculus)

Oral sedation options for rabbits (Oryctolagus cuniculus) have remained limited despite the need for medications with anxiolytic effects during transportation and high stress procedures. Trazodone HCl (TZN), a serotonin modulator, is a commonly prescribed medication in humans to treat depression and anxiety. The efficacy of TZN use in rabbits was initially investigated in 2016 and found TZN to be successful in producing mild sedation, however the safety of the medication still needed to be determined. To identify the systemic effects of repeated TZN administration in rabbits, New Zealand white laboratory rabbits (n = 12) were given orally 40 mg/kg TZN every 12 hours (± 1 hour) for 28 days. A control group (n = 4) was used to monitor standard hematological fluctuations. Heart and respiratory rate were collected daily, and a physical examination was performed by a veterinarian every 7 days. Blood was collected for cell counts and serum chemistry analysis prior to and every 14 days during the experiment. No significant changes in heart or respiratory rate were noted throughout treatment (p = 0.201 and p = 0.984 respectively). Some fluctuations were noticed in blood serum chemistry and hematology results in both the experimental and control group, particularly in the liver and kidney values following 28 days of treatment. Serum alanine aminotransferase (ALT) between the blood draws of both groups was significantly elevated (p = 0.002), however the elevations were noticed in both the control and TZN treated animals (p = 0.597). A simmilar trend was noticed with alkaline phosphatase (ALP; p = 0.001 between blood draws, p = 0.428 between groups), creatinine (p < 0.0001 between blood draws, p = 0.340 between groups), and blood urea nitrogen (BUN) levels (p = 0.025 between blood draws, p = 0.343 between groups) indicating the changes overtime were not due to TZN treatment. All physiologic parameters tested remained within normal rabbit physiologic reference ranges. These results indicate TZN could be a viable option to provide mild sedation as needed and act as an alternative option to conventional treatments of behavioral problems. Future studies could be performed on dose range and safety among rabbits of varying age, sex, and breed.

The Effect of Lactobacillus casei Consumption in Improvement of Obsessive-Compulsive Disorder: an Animal Study.

Obsessive-compulsive disorder (OCD) is an important neuropsychiatric disorder worldwide. Common treatments of OCD include serotonergic antidepressants, which can cause potentially serious side effects. We assessed the effects of Lactobacillus casei (L. casei) Shirota consumption in an animal model of OCD. OCD-like symptoms were induced in rats by the chronic injection of the D2/D3 dopamine agonist quinpirole hydrochloride. Rats were classified into five groups of 6 rats. Four groups were injected chronically with quinpirole (0.5mg/kg, twice weekly for 5weeks). They were fed with L. casei Shirota (109CF/g, daily for 4weeks) (group 1), fluoxetine (10mg/kg, daily for 4weeks) (group 2), combination of L. casei Shirota and fluoxetine (group 3), and normal saline (positive control group). The last group did not receive dopamine agonist and was only injected with saline (negative control group). Expression levels of brain-derived neurotrophic factor (Bdnf), solute carrier family 6 member 4 (Slc6a4), and 5-hydroxytryptamine receptor type 2A (Htr2a) were assessed in orbitofrontal cortex tissues of all rats. Behavioral tests showed improvement of OCD signs in rats treated with L. casei Shirota, fluoxetine, and a combination of drugs. Quantitative PCR analysis showed a remarkable decrease in the expression of Bdnf and an increase in the expression of Htr2a in quinpirole-treated rats. After treatment with L. casei Shirota and fluoxetine, the expression level of Bdnf was increased remarkably, whereas Htr2a expression was decreased. The current study showed the effectiveness of L. casei Shirota in the treatment of OCD in a rat model. The beneficial effects of this probiotic are possibly exerted through the modulation of serotonin-related genes expression.

Fluoxetine exposure for more than 2 days decreases the neuronal plasticity mediated by CRMP2 in differentiated PC12 cells

BackgroundRecent studies indicate that antidepressants treatment restores neuronal plasticity. In contrast, some researchers claim that serotonergic antidepressants, including fluoxetine (FLU), may exacerbate neuronal plasticity, which is contradictory and rarely studied. Since almost those studies exposed cells with drugs for 1–2 days as treatment models of antidepressants, it is possible that FLU exposure for longer periods would have opposite effects on neuronal plasticity. ResultsIn the present study, we examined the effects of FLU exposure (up to 3 days) on the neuronal plasticity in differentiated PC12 cells. The cell viability shown a slight decrease at day 2 (93.5 ± 3.5 %), followed by a highly significant decrease at day 3(71.4 ± 4.4 %). As previously reported, neuronal plasticity was significantly upregulated by FLU exposure at day 1. However, the neurite length, activity-regulated cytoskeleton-associated protein (Arc) and c-Fos mRNA were inhibited with FLU exposure at day 3. Similarly, the expression of tubulin, which play important roles in the neuronal plasticity, was the same result. Furthermore, we found α-tubulin interacted with collapsing response mediator protein 2(CRMP2), which is related to neuronal plasticity, and the regulation of CRMP2 activity influenced the neurite length, Arc, c-Fos and tubulin expression. ConclusionsThe results demonstrated that neuronal plasticity was increased by FLU exposure at day 1, but exposure with FLU for more than 2 days had opposite effect on it. The reduction in neuronal plasticity with FLU exposure for more than 2 days might be involved in some aspects of the therapeutic effect of antidepressant on depression.

Mass Spectrometry-Based Rapid Quantitative Bioanalysis of Flibanserin: Pharmacokinetic and Brain Tissue Distribution Study in Female Rats.

Flibanserin (FLB) is the first United States Food and Drug Administration (USFDA) approved serotonin modulator recently marketed to treat acquired generalized women hypoactive sexual desire disorder. The scope of this study was to develop and validate a sensitive, selective and reliable ultra-performance liquid chromatography-mass spectroscopy/mass spectroscopy-based quantification method for FLB in rat plasma as well as brain tissue samples. The method includes a simple liquid-liquid sample extraction procedure. FLB was subjected to chromatographic separation using a poroshell C18 column with the mobile phase comprising a mixture of acetonitrile (ACN), 10mM ammonium acetate and acetic acid (90:10:0.1, v/v/v). Detection and quantification of FLB after positive electrospray ionization were carried out in selective ion monitoring mode. The fragment ions (m/z) of FLB (parent ion: 391.1741) and IS (parent ion: 448.1550) were monitored at 161.0704 and 285.0917, respectively. A linear response of FLB was observed over a concentration range of 2.5-600ng/mL in plasma and 5-500ng/mL in brain tissue homogenate. The intra- and inter-day precision and accuracy of the method met the acceptable limits specified in the USFDA bioanalytical method validation guideline. The analyte was found to be stable in benchtop, freeze-thaw, auto-injector and dry extract stability studies. The developed method was used to quantitate FLB in the plasma and brain tissue of a single-dose oral pharmacokinetic and brain tissue distribution study in female rats. Maximum FLB concentration in plasma and brain was achieved within an hour; however, the total amount of the drug that reached the brain was significantly less than in plasma. Rate of elimination of FLB from brain was also faster resulting in a lesser half-life in brain compared to the plasma.

A polygenic predictor of treatment-resistant depression using whole exome sequencing and genome-wide genotyping

Treatment-resistant depression (TRD) occurs in ~30% of patients with major depressive disorder (MDD) but the genetics of TRD was previously poorly investigated. Whole exome sequencing and genome-wide genotyping were available in 1209 MDD patients after quality control. Antidepressant response was compared to non-response to one treatment and non-response to two or more treatments (TRD). Differences in the risk of carrying damaging variants were tested. A score expressing the burden of variants in genes and pathways was calculated weighting each variant for its functional (Eigen) score and frequency. Gene-based and pathway-based scores were used to develop predictive models of TRD and non-response using gradient boosting in 70% of the sample (training) which were tested in the remaining 30% (testing), evaluating also the addition of clinical predictors. Independent replication was tested in STAR*D and GENDEP using exome array-based data. TRD and non-responders did not show higher risk to carry damaging variants compared to responders. Genes/pathways associated with TRD included those modulating cell survival and proliferation, neurodegeneration, and immune response. Genetic models showed significant prediction of TRD vs. response and they were improved by the addition of clinical predictors, but they were not significantly better than clinical predictors alone. Replication results were driven by clinical factors, except for a model developed in subjects treated with serotonergic antidepressants, which showed a clear improvement in prediction at the extremes of the genetic score distribution in STAR*D. These results suggested relevant biological mechanisms implicated in TRD and a new methodological approach to the prediction of TRD.

Efficacy and Safety of Lumateperone for Treatment of Schizophrenia

Individuals living with schizophrenia are affected by cardiometabolic, endocrine, and motor adverse effects of current antipsychotic medications. Lumateperone is a serotonin, dopamine, and glutamate modulator with the potential to treat schizophrenia with few adverse effects. To examine the efficacy and safety of lumateperone for the short-term treatment of schizophrenia. This randomized, double-blind, placebo-controlled, phase 3 clinical trial was conducted from November 13, 2014, to July 20, 2015, with data analyses performed from August 13 to September 15, 2015. Patients with schizophrenia who were aged 18 to 60 years and were experiencing an acute exacerbation of psychosis were enrolled from 12 clinical sites in the United States. Patients were randomized 1:1:1 (150 patients in each arm) to receive lumateperone tosylate, 60 mg; lumateperone tosylate, 40 mg (equivalent to 42 or 28 mg, respectively, of the active moiety lumateperone); or placebo once daily for 4 weeks. The prespecified primary efficacy end point was mean change from baseline to day 28 in the Positive and Negative Syndrome Scale (PANSS) total score vs placebo. The key secondary efficacy measure was the Clinical Global Impression-Severity of Illness (CGI-S) score. The PANSS subscale scores, social function, safety, and tolerability were also assessed. The study comprised 450 patients (mean [SD] age, 42.4 [10.2] years; 346 [77.1%] male; mean [SD] baseline PANSS score, 89.8 [10.3]; mean [SD] baseline CGI-S score, 4.8 [0.6]). In the prespecified modified intent-to-treat efficacy analysis (n = 435), 42 mg of lumateperone met the primary and key secondary efficacy objectives, demonstrating a statistically significant improvement vs placebo from baseline to day 28 on the PANSS total score (least-squares mean difference [LSMD], -4.2; 95% CI, -7.8 to -0.6; P = .02; effect size [ES], -0.3) and the CGI-S (LSMD, -0.3; 95% CI, -0.5 to -0.1; P = .003; ES, -0.4). For 28 mg of lumateperone, the LSMD from baseline to day 28 was -2.6 (95% CI, -6.2 to 1.1; P = .16; ES, -0.2) on the PANSS total score and -0.2 (95% CI, -0.5 to 0.0; P = .02; ES, -0.3) on the CGI-S. Both lumateperone doses were well tolerated without clinically significant treatment-emergent motor adverse effects or changes in cardiometabolic or endocrine factors vs placebo. Lumateperone demonstrated efficacy for improving the symptoms of schizophrenia and had a favorable safety profile. ClinicalTrials.gov identifier: NCT02282761.

Evaluating the Safe Use of Antidepressants in Older Adults: A Case-Based Approach

Depression in older adults is a mood disorder associated with physical and/or cognitive impairment. Though it may be present in a variety of settings, depression is a prominent health concern among long-term care and nursing facility residents. Pharmacologic therapy may be considered in patients with depression who have not responded to nonpharmacologic therapy or are experiencing considerable disability. There are a variety of commonly prescribed antidepressant drug options for this indication. Examples may include selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, or serotonin modulators. As the use of these agents continues in older adults, senior care pharmacists should be familiar with the evaluation of its safe and combined use (e.g., drug interactions, adverse effects).

Effect of serotonin modulation on dystrophin-deficient zebrafish.

ABSTRACTDuchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by mutation of the dystrophin gene. Pharmacological therapies that function independently of dystrophin and complement strategies aimed at dystrophin restoration could significantly improve patient outcomes. Previous observations have suggested that serotonin pathway modulation ameliorates dystrophic pathology, and re-application of serotonin modulators already used clinically would potentially hasten availability to DMD patients. In our study, we used dystrophin-deficient sapje and sapje-like zebrafish models of DMD for rapid and easy screening of several classes of serotonin pathway modulators as potential therapeutics. None of the candidate drugs tested significantly decreased the percentage of zebrafish exhibiting the dystrophic muscle phenotype in the short-term birefringence assay or lengthened the lifespan in the long-term survival assay. Although we did not identify an effective drug, we believe our data is of value to the DMD research community for future studies, and there is evidence that suggests serotonin modulation may still be a viable treatment strategy with further investigation. Given the widespread clinical use of selective serotonin reuptake inhibitors, tricyclic antidepressants and reversible inhibitors of monoamine oxidase, their reapplication to DMD is an attractive strategy in the field's pursuit to identify pharmacological therapies to complement dystrophin restoration strategies.

Serotonin Syndrome in a Patient Using Paroxetine and Bupropion

Serotonin syndrome is an important clinical condition that can occur after excessive central serotonergic activity, generally secondary to the use of combinations of antidepressants. Selective serotonin reuptake inhibitors and bupropion are frequently used in the treatment of major depression in clinical practice. Few cases of serotonin syndrome due to the use of serotonergic antidepressants and bupropion have been reported in the literature. The current case report presents a patient who underwent the serotonin syndrome after the administration of paroxetine and bupropion.

Pharmacogenomic Characterization in Bipolar Spectrum Disorders.

The holistic approach of personalized medicine, merging clinical and molecular characteristics to tailor the diagnostic and therapeutic path to each individual, is steadily spreading in clinical practice. Psychiatric disorders represent one of the most difficult diagnostic challenges, given their frequent mixed nature and intrinsic variability, as in bipolar disorders and depression. Patients misdiagnosed as depressed are often initially prescribed serotonergic antidepressants, a treatment that can exacerbate a previously unrecognized bipolar condition. Thanks to the use of the patient’s genomic profile, it is possible to recognize such risk and at the same time characterize specific genetic assets specifically associated with bipolar spectrum disorder, as well as with the individual response to the various therapeutic options. This provides the basis for molecular diagnosis and the definition of pharmacogenomic profiles, thus guiding therapeutic choices and allowing a safer and more effective use of psychotropic drugs. Here, we report the pharmacogenomics state of the art in bipolar disorders and suggest an algorithm for therapeutic regimen choice.

Higher S100B Levels Predict Persistently Elevated Anhedonia with Escitalopram Monotherapy Versus Antidepressant Combinations: Findings from CO-MED Trial.

Background: Elevated S100 calcium binding protein B (S100B) levels in systemic circulation may induce neuroinflammation and reflect greater blood–brain barrier (BBB) dysfunction. Neuroinflammation in patients with major depressive disorder (MDD), in turn, may reduce likelihood of improvement with serotonergic antidepressants. Methods: Levels of S100B were measured in plasma samples obtained prior to initiation of treatment with bupropion-plus-escitalopram, escitalopram-plus-placebo, or venlafaxine-plus-mirtazapine in participants of Combining Medications to Enhance Depression Outcomes trial (n = 153). Depression severity was measured with 16-item Quick Inventory of Depressive Symptomatology Self-Report and anhedonia was measured with 3 items of 30-item Inventory of Depressive Symptomatology. Differential changes in depression severity and anhedonia over acute-phase (baseline, weeks 1, 2, 4, 6, 8, 10, and 12) in the three treatment arms were tested with logS100B-by-treatment-arm interaction in mixed model analyses after controlling for age, gender, and body mass index. Results: There was a significant logS100B-by-treatment-arm interaction for anhedonia (F = 3.21; df = 2, 142; p = 0.04) but not for overall depression severity (F = 1.99; df = 2, 142; p = 0.14). Higher logS100B levels were associated with smaller reductions in anhedonia (effect size = 0.67, p = 0.047) in escitalopram monotherapy but not in the other two arms. Correlation coefficients of anhedonia severity averaged over acute-phase (including baseline) with baseline S100B levels were 0.57, −0.19, and 0.22 for escitalopram monotherapy, bupropion-plus-escitalopram and venlafaxine-plus-mirtazapine arms respectively. Conclusion: Higher baseline S100B levels in depressed patients resulted in poorer response to escitalopram monotherapy. Addition of bupropion, a dopaminergic antidepressant, partially mitigated this effect.

An Association of Serotonin with Pain Disorders and Its Modulation by Estrogens.

Ovarian hormones play an important role in pain perception, and are responsible, at least in part, for the pain threshold differences between the sexes. Modulation of pain and its perception are mediated by neurochemical changes in several pathways, affecting both the central and peripheral nervous systems. One of the most studied neurotransmitters related to pain disorders is serotonin. Estrogen can modify serotonin synthesis and metabolism, promoting a general increase in its tonic effects. Studies evaluating the relationship between serotonin and disorders such as irritable bowel syndrome, fibromyalgia, migraine, and other types of headache suggest a clear impact of this neurotransmitter, thereby increasing the interest in serotonin as a possible future therapeutic target. This literature review describes the importance of substances such as serotonin and ovarian hormones in pain perception and illustrates the relationship between those two, and their direct influence on the presentation of the aforementioned pain-related conditions. Additionally, we review the pathways and receptors implicated in each disorder. Finally, the objective was to stimulate future pharmacological research to experimentally evaluate the potential of serotonin modulators and ovarian hormones as therapeutic agents to regulate pain in specific subpopulations.

Selective serotonin reuptake inhibitors and Alzheimer's disease.

Given the failure to develop disease-modifying therapies for Alzheimer’s disease (AD), strategies aiming at preventing or delaying the onset of the disease are being prioritized. While the debate regarding whether depression is an etiological risk factor or a prodrome of AD rages on, a key determining factor may be the timing of depression onset in older adults. There is increasing evidence that untreated early-onset depression is a risk factor and that late-onset depression may be a catalyst of cognitive decline. Data from animal studies have shown a beneficial impact of selective serotonin reuptake inhibitors on pathophysiological biomarkers of AD including amyloid burden, tau deposits and neurogenesis. In humans, studies focusing on subjects with a prior history of depression also showed a delay in the onset of AD in those treated with most selective serotonin reuptake inhibitors. Paroxetine, which has strong anticholinergic properties, was associated with increased mortality and mixed effects on amyloid and tau deposits in mice, as well as increased odds of developing AD in humans. Although most of the data regarding selective serotonin reuptake inhibitors is promising, findings should be interpreted cautiously because of notable methodological heterogeneity between studies. There is thus a need to conduct large scale randomized controlled trials with long follow up periods to clarify the dose-effect relationship of specific serotonergic antidepressants on AD prevention.

Antidepressants: bleeding or thrombosis?

The contribution of depression to the pathogenesis of cardiovascular disease includes autonomic disturbances, endothelial dysfunction, inflammation, smoking, sedentary lifestyle, carbohydrate craving, and impaired fibrinolysis. There is evidence that serotonergic antidepressants (selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors) restore the fibrinolytic profile. Contrary to common belief, such antidepressants do not affect platelet aggregation induced by adenosine diphosphate or adrenaline but reduce platelet adhesion to collagen. Since platelet collagen receptor glycoprotein VI binds to fibrin, it is possible that fibrinolytic properties of serotonergic antidepressants could impair platelet adhesion to collagen. The profibrinolytic and antiplatelet properties of serotonergic antidepressants help explain the increased risk of gastrointestinal, intracranial, and surgical bleeding in patients using these medications. Studies evaluating the impact of antidepressants on thrombotic and cardiovascular risk have yielded contradictory results. Corroborating the hypothesis that serotonergic antidepressants have profibrinolytic and antiplatelet properties, some authors showed that these medications prevent both cardiovascular and thromboembolic events. Others showed an increased risk of ischemic stroke, cardiac events and thromboembolic disease. Silent brain infarction may present in some elders with depressive symptoms, so it is presumed that antidepressants are prescribed for subclinical stroke patients. Another explanation for the increased risk of cardiovascular and thromboembolic events reported by some authors in individuals taking antidepressants includes antidepressant side effects such as sedation and weight gain and depression comorbidities such as anxiety, obesity and hyperhomocysteinemia. In conclusion, we suggest that serotonergic antidepressants be considered weak anticoagulants. We also suggest that depressed patients with comorbidities increasing the risk of cardiovascular and thromboembolic disease be recommended to follow a balanced diet and engage in physical activity, such as daily walking.

Antidepressants in Spine Surgery: A Systematic Review to Determine Benefits and Risks.

Antidepressant drugs can be advantageous in treating psychiatric and non-psychiatric illnesses, including spinal disorders. However, spine surgeons remain unfamiliar with the advantages and disadvantages of the use of antidepressant drugs as a part of the medical management of diseases of the spine. Our review article describes a systematic method using the PubMed/Medline database with a specific set of keywords to identify such benefits and drawbacks based on 17 original relevant articles published between January 2000 and February 2018; this provides the community of spine surgeons with available cumulative evidence contained within two tables illustrating both observational (10 studies; three cross-sectional, three case-control, and four cohort studies) and interventional (seven randomized clinical trials) studies. While tricyclic antidepressants (e.g., amitriptyline) and duloxetine can be effective in the treatment of neuropathic pain caused by root compression, venlafaxine may be more appropriate for patients with spinal cord injury presenting with depression and/or nociceptive pain. Despite the potential associated consequences of a prolonged hospital stay, higher cost, and controversial reports regarding the lowering of bone mineral density in the elderly, antidepressants may improve patient satisfaction and quality of life following surgery, and reduce postoperative pain and risk of delirium. The preoperative treatment of preexisting psychiatric diseases, such as anxiety and depression, can improve outcomes for patients with spinal cord injury-related disabilities; however, a preoperative platelet function assay is advocated prior to major spine surgical procedures to protect against significant intraoperative blood loss, as serotonergic antidepressants (e.g., selective serotonin reuptake inhibitors) and bupropion can increase the likelihood of bleeding intraoperatively due to drug-induced platelet dysfunction. This comprehensive review of this evolving topic can assist spine surgeons in better understanding the benefits and risks of antidepressant drugs to optimize outcomes and avoid potential hazards in a spine surgical setting.

Novel multitarget 5-arylidenehydantoins with arylpiperazinealkyl fragment: Pharmacological evaluation and investigation of cytotoxicity and metabolic stability

On the basis of the structures of serotonin modulators or drugs (NAN-190, buspirone, aripiprazole) and phosphodiesterase 4 (PDE4) inhibitors (rolipram, RO-20-1724), a series of novel multitarget 5-arylidenehydantoin derivatives with arylpiperazine fragment was synthesized. Among these compounds, 5-(3,4-dimethoxybenzylidene-3-(4-(4-(2,3-dichlorophenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (13) and 5-(3-cyclopentyloxy-4-methoxybenzylidene-3-(4-(4-(2-methoxyphenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (18) were found to be the most promising showing very high affinity toward 5-HT1A and 5-HT7 receptors (Ki = 0.2–1.0 nM) but a negligible inhibitory effect on PDE4. The high affinity of the compounds for 5-HT1A and 5-HT7 receptors was further investigated by computer-aided studies. Moreover, compounds 13 and 18 showed no significant cytotoxicity in the MTT assay, but high clearance in the in vitro assay. In addition, these compounds behaved like 5-HT1A and 5-HT7 receptor antagonists and exhibited antidepressant-like activity, similar to the reference drug citalopram, in an animal model of depression.

Treatment of the obsessive-compulsive and bipolar disorders comorbidity: pharmacodynamic and pharmacokinetic evaluation

ABSTRACTIntroduction: The comorbidity between obsessive-compulsive disorder (OCD) and bipolar disorders (BDs) is a frequent and severe condition characterized by a chronic course, high suicidal risk and tendency towards chronicity and treatment non-response. It represents a real challenge to psychiatrists, while requiring a careful and appropriate therapeutic management consisting in the combination of serotonergic antidepressants (ADs), such as serotonin reuptake inhibitors (SRIs), with mood stabilizers. This combination, like any other, raises the problems related to drug interactions that may lead to pharmacokinetic and pharmacodynamic changes, resulting in the modification of the pharmacologic effect and safety profile of a given compound.Areas covered: The aim of the present paper was to review the literature on the pharmacokinetic and pharmacodynamic changes resulting from the interactions of the different drugs prescribed in the OCD-BD comorbidity.Expert opinion: The literature data on pharmacokinetic and pharmacodynamic changes due to interactions of drugs commonly prescribed in the treatment of the OCD-BD comorbidity are extremely limited, and the information is inferred by findings gathered in psychiatric patients suffering from other disorders. This represents a gap in psychopharmacology that should be filled by specific studies on this important topic.