Serotonin Reuptake Inhibitor Class Research Articles

Escitalopram-induced hyponatremia

Escitalopram is an antidepressant belonging to the class of selective serotonin reuptake inhibitors. It is effective in the treatment of generalized anxiety and major depressive disorders. It also has an off-labeled use of treating mild agitation associated with dementia in non-psychotic patients. The most common adverse effects of escitalopram are a headache, fatigue, and diarrhea. Escitalopram-induced hyponatremia is rare; it is seen in elderly, especially in women. This is a rare case of escitalopram-induced hyponatremia which was observed in a 73-year-old female patient who was admitted, with complaints of increased tension and palpitation, in the psychiatry department. She also had a history of asthma for the past 30 years, a surgery done for carpel tunnel syndrome 6 years back and had no history of liver or renal disease. Tablet Nexito (escitalopram) 10 mg 1-0-0 was started as an antidepressant, and after 1 day, she developed fatigue due to hyponatremia which was evident from the laboratory values of sodium. The sodium level was found to be 122.3 mmol/l, the normal range is between 135 and 145 mmol/l. Hence, she was advised to include 2 g of salt in her diet. As she had hyponatremia, NS 3% was added, and also her dose of escitalopram was decreased to 5 mg OD, resulting in a gradual increase in the sodium level. This case showed a causality score of 8 according to Naranjo Scale and the causality to be probable.

Application of Mice Humanized for CYP2D6 to the Study of Tamoxifen Metabolism and Drug-Drug Interaction with Antidepressants.

Tamoxifen is an estrogen receptor antagonist used in the treatment of breast cancer. It is a prodrug that is converted by several cytochrome P450 enzymes to a primary metabolite, N-desmethyltamoxifen (NDT), which is then further modified by CYP2D6 to a pharmacologically potent secondary metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen). Antidepressants (ADs), which are often coprescribed to patients receiving tamoxifen, are also metabolized by CYP2D6 and evidence suggests that a drug–drug interaction between these agents adversely affects the outcome of tamoxifen therapy by inhibiting endoxifen formation. We evaluated this potentially important drug–drug interaction in vivo in mice humanized for CYP2D6 (hCYP2D6). The rate of conversion of NDT to endoxifen by hCYP2D6 mouse liver microsomes (MLMs) in vitro was similar to that of the most active members of a panel of 13 individual human liver microsomes. Coincubation with quinidine, a CYP2D6 inhibitor, ablated endoxifen generation by hCYP2D6 MLMs. The NDT-hydroxylation activity of wild-type MLMs was 7.4 times higher than that of hCYP2D6, whereas MLMs from Cyp2d knockout animals were inactive. Hydroxylation of NDT correlated with that of bufuralol, a CYP2D6 probe substrate, in the human liver microsome panel. In vitro, ADs of the selective serotonin reuptake inhibitor class were, by an order of magnitude, more potent inhibitors of NDT hydroxylation by hCYP2D6 MLMs than were compounds of the tricyclic class. At a clinically relevant dose, paroxetine pretreatment inhibited the generation of endoxifen from NDT in hCYP2D6 mice in vivo. These data demonstrate the potential of ADs to affect endoxifen generation and, thereby, the outcome of tamoxifen therapy.

Effects of paroxetine on intravaginal ejaculatory latency time in Egyptian patients with lifelong premature ejaculation as a function of serotonin transporter polymorphism.

Premature ejaculation (PE) is a common ejaculatory complaint. The estimated rates among Turkish men reached 20%, although the severest type of PE (lifelong PE) usually does not exceed 2.3%. This could be seen in line with two survey studies involving five nations. They revealed that 2.5% of men had an intravaginal ejaculation latency time of <1 min and 6% of <2 min. Rapid ejaculation may be treated pharmacologically with a variety of different medications that act either centrally or locally to delay ejaculation and subsequent orgasm. Antidepressants, particularly members of the selective serotonin reuptake inhibitor class, retard ejaculation significantly. Recently, it was postulated that men with lifelong PE might result from a combination of polymorphisms of the serotonergic transporter and receptors, and other neurotransmitters and/or receptors. Our findings augment the significant effect of paroxetine in delaying ejaculation in the responders (P<0.001). Meanwhile, the findings do not suggest a positive association between such response and serotonin transporter gene promoter polymorphism.

Abstract 3452: Antidepressant use and risk of central nervous system metastasis

Abstract CNS metastasis is the spread of a primary cancer to the CNS and occurs in up to 25% of cancer patients. Antidepressant therapy, used in 15-30% of cancer patients, affects the blood-brain barrier, potentially making patients more susceptible to CNS metastasis. This hypothesis is supported by an experimental study reporting increased CNS metastasis from breast cancer in mice receiving fluoxetine, an antidepressant in the class of selective serotonin reuptake inhibitors (SSRIs). However, no human studies have looked at this association. We conducted a case-control study to examine whether antidepressants, and specifically SSRIs, increased the relative odds of CNS metastasis. We identified cancer patients diagnosed with breast cancer, melanoma, and non-Hodgkin lymphoma (NHL) at one academic cancer center in Rochester, NY between 2005 and 2013. We ascertained 189 patients with CNS metastasis (cases) and 945 patients without CNS metastasis (controls). Cases of CNS metastasis were identified by the ICD-9 code 198.3 secondary malignant neoplasm of brain and spinal cord. Cases and controls were classified with regard to their antidepressant use based on medical chart review. Using multivariable logistic regression, we estimated the relative odds of CNS metastasis associated with ‘any antidepressant use’ (any antidepressant irrespective of class), ‘any SSRI use’ (SSRI use, nonexclusively), and ‘exclusive SSRI use’ (only SSRI use and no other class of antidepressant), all compared to ‘no antidepressant use’. Subset analyses were planned a priori for breast cancer and melanoma; subset analyses could not be conducted for NHL due to the small sample size. Both cases and controls had a median age of 53 years (range: 25-94 years and 15-89 years, respectively). The prevalence of ‘any antidepressant use’ was 28.6% in cases and 25.7% in controls, whereas SSRIs were used in 16.9% of cases and 15.6% of controls. Among all patients, ‘any SSRI use’ was not associated with CNS metastasis (odds ratio (OR) = 1.21; 95% confidence interval (CI) = 0.74, 1.97). However, among breast cancer patients, ‘any SSRI use’ was associated with a 1.73 times greater odds of CNS metastasis (95% CI = 0.75, 4.04). No consistent patterns of association were observed in the analyses of other cancer subsets or exposure measures. This was the first study to examine the association between antidepressant use and CNS metastasis. We did not observe clear patterns of association which may be due in part to the small sample size in many of our analyses. However, we believe that the increased odds in the breast cancer subset warrants further investigation as this is consistent with the animal research. Citation Format: Megan Herr, Nimish Mohile, Edwin van Wijngaarden, Edward Brown, David Q. Rich. Antidepressant use and risk of central nervous system metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3452.

Chronic fluoxetine treatment induces anxiolytic responses and altered social behaviors in medaka, Oryzias latipes

Medaka (Oryzias latipes) is a small freshwater teleost that is an emerging model system for neurobehavioral research and toxicological testing. The selective serotonin reuptake inhibitor class of antidepressants such as fluoxetine is one of the widely prescribed drugs, but little is known about the effects of these drugs on medaka behaviors. To assess the behavioral effects of fluoxetine, we chronically administrated fluoxetine to medaka adult fish and analyzed the anxiety-related and social behaviors using five behavioral paradigms (diving, open-field, light–dark transition, mirror-biting, and social interaction) with an automated behavioral testing system. Fish chronically treated with fluoxetine exhibited anxiolytic responses such as an overall increased time spent in the top area in the diving test and an increased time spent in center area in the open-field test. Analysis of socially evoked behavior showed that chronic fluoxetine administration decreased the number of mirror biting times in the mirror-biting test and increased latency to first contact in the social interaction test. Additionally, chronic fluoxetine administration reduced the horizontal locomotor activity in the open-field test but not the vertical activity in the diving test. These investigations are mostly consistent with previous reports in the other teleost species and rodent models. These results indicate that behavioral assessment in medaka adult fish will become useful for screening of effects of pharmaceutical and toxicological compounds in animal behaviors.

Synthesis, Characterization, Identification and Quantification of Sertraline Hydrochloride Related Impurities

Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class, is synthesized for commercial use as a drug substance in highly pure form. During the synthetic process development studies of Sertraline hydrochloride, an impurity was detected in the final product at levels ranging from 0.05% to 0.15% in Gas Chromatography (GC) method and its molecular weight was determined by LC-MS analysis. The impurity was identified as 4-(4-chlorophenyl)-3,4-dihydronaphthalen-1(2H)-ol impurity, synthesized and characterized, the process of its formation was discussed in detail. After qualification of impurity standard, it was used as a reference standard for development of quantification by High Performance Liquid Chromatography (HPLC) method.

Effect of Citalopram in Combination with Omega-3 on Depression in Post-menopausal Women: A Triple Blind Randomized Controlled Trial.

Depressive disorder is a common and disabling disorder that causes high rates of morbidity and mortality. Citalopram is an antidepressant drug, of the Selective Serotonin Reuptake Inhibitor (SSRI) class that has been used for geriatric depression since a long time ago. Prescription of omega-3 in geriatric depression has been increased recently; because of more favorable profile of their side effects. Some of the studies reported that omega-3 is effective in prevention or treatment of depressive disorders than Citalopram. However, there are contradictory studies too. This study aimed to investigate the effect of a combination of omega-3 and citalopram in the treatment of women with post-menopausal depression. This triple-blind randomized controlled trial was conducted on 60 women with post-menopausal depression who were referred to the Hamadan Fatemieh Hospital. After the participants completed the DSM-IV questionnaire and depression was confirmed by a psychiatrist, participants were assigned randomly into two-intervention and control groups. The patients in the control group received 20mg citalopram along with a placebo while patients in the intervention group received 20mg citalopram and 1g of omega-3. At baseline and at the end of the first, second, and fourth weeks, all of the participants answered the Beck's Depression Inventory (BDI). Descriptive statistics and t-test, repeated measures analysis of variance and Bonferroni post-hoc test was used to analyse the data. The depression score was 6.1±2.41 in intervention and 25.22±10.04 in control group, four weeks after intervention. A decreasing trend was observed in the mean depression scores of the intervention group during the study. Using repeated measures analysis of variance, a significant difference was observed between the mean depression scores of the two groups at the four measurement time-points (p<0.001). The mean depression scores of the intervention group were significantly lower than the control group either two weeks (p< 0.001) or four weeks after the treatments (p< 0.001). Using omega-3, can reduce the severity of depression in post-menopausal women.

In vivo investigation of escitalopram's allosteric site on the serotonin transporter

Escitalopram is a commonly prescribed antidepressant of the selective serotonin reuptake inhibitor class. Clinical evidence and mapping of the serotonin transporter (SERT) identified that escitalopram, in addition to its binding to a primary uptake-blocking site, is capable of binding to the SERT via an allosteric site that is hypothesized to alter escitalopram's kinetics at the SERT. The studies reported here examined the in vivo role of the SERT allosteric site in escitalopram action. A knockin mouse model that possesses an allosteric-null SERT was developed. Autoradiographic studies indicated that the knockin protein was expressed at a lower density than endogenous mouse SERT (approximately 10–30% of endogenous mouse SERT), but the knockin mice are a viable tool to study the allosteric site. Microdialysis studies in the ventral hippocampus found no measurable decrease in extracellular serotonin response after local escitalopram challenge in mice without the allosteric site compared to mice with the site (p=0.297). In marble burying assays there was a modest effect of the absence of the allosteric site, with a larger systemic dose of escitalopram (10-fold) necessary for the same effect as in mice with intact SERT (p=0.023). However, there was no effect of the allosteric site in the tail suspension test. Together these data suggest that there may be a regional specificity in the role of the allosteric site. The lack of a robust effect overall suggests that the role of the allosteric site for escitalopram on the SERT may not produce meaningful in vivo effects.

Adverse Events in Very Young Children Prescribed Psychotropic Medications: Preliminary Findings from an Acute Clinical Sample.

The present study used the Pediatric Adverse Events Rating Scale (PAERS) to provide a systematic assessment of adverse events (AEs) related to psychotropic medication use in a clinical sample of young children attending a specialized, early childhood partial hospital program. Study goals were as follows: 1) To describe the frequency and types of specific psychotropic medication-related AEs experienced by very young children (ages 3-7 years) in an acute clinical sample, and 2) to identify the psychotropic medication(s) and/or class(es) associated with the highest frequency of AEs. Participants were 158 children (118 males; ages 36-95 months, mean=66 months, SD=14.6 months) who presented to a hospital-based day treatment program for young children with severe emotional and behavioral problems, and were prescribed a psychotropic medication at any point during the hospitalization. Data on AEs related to psychotropic medication were collected using the PAERS from 2011 to 2014. The percentages of children who experienced one or more AEs attributed to a psychiatric medication ranged from 0 (sertraline, melatonin) to 41.2% (fluoxetine), with wide variability in the types AEs reported. The overall frequencies of events caused by a stimulant were similar across the two medications examined (21.4% and 27.7% for mixed amphetamine salts and methylphenidate, respectively), with mood-related difficulties and decreased appetite being the most common AEs reported. The frequencies of AEs caused by an α agonist were also similar across the two medications examined (9.8% and 17.2% for guanfacine and clonidine, respectively), with fatigue as the most commonly reported AE. With respect to the selective serotonin reuptake inhibitor (SSRI) class, there was a trend for fluoxetine to be associated with more AEs (41.2%) than sertraline (for which no AEs were reported). The most common AEs reported for fluoxetine were impulsivity and poor concentration. The data presented here support existing literature reporting differences in AEs between age groups. More rigorous studies are warranted to further examine the types and frequencies of AEs related to psychotropic medications in very young children.

Trazodone treatment protects neuronal-like cells from inflammatory insult by inhibiting NF-κB, p38 and JNK

Growing evidence suggests that alterations of the inflammatory/immune system contribute to the pathogenesis of major depression and that inflammatory processes may influence the antidepressant treatment response. Depressed patients exhibit increased levels of inflammatory markers in both the periphery and brain, and high co-morbidity exists between depression and diseases associated with inflammatory alterations. Trazodone (TDZ) is a triazolopyridine derivative that belongs to the class of serotonin receptor antagonists and reuptake inhibitors. Although the trophic and protective properties of classic antidepressants have extensively been exploited, the effects of TDZ remain to be fully elucidated. In this study, the pharmacological activities of TDZ on human neuronal-like cells were investigated under both physiological and inflammatory conditions. An in vitro inflammatory model was established using lipopolysaccharide (LPS) and tumour necrosis factor-α (TNF-α), which efficiently mimic the stress-related changes in neurotrophic and pro-inflammatory genes.Our results showed that TDZ significantly increased the mRNA expression of both brain-derived nerve factor (BDNF) and cAMP response element-binding protein (CREB) and decreased the cellular release of the pro-inflammatory cytokine interferon gamma (IFN-γ) in neuronal-like cells.In contrast, neuronal cell treatment with LPS and TNF-α decreased the expression of CREB and BDNF and increased the expression of nuclear factor kappa B (NF-κB), a primary transcription factor that functions in inflammatory response initiation. Moreover, the two agents induced the release of pro-inflammatory cytokines (i.e., interleukin-6 and IFN-γ) and decreased the production of the anti-inflammatory cytokine interleukin-10. TDZ pre-treatment completely reversed the decrease in cell viability and counteracted the decrease in BDNF and CREB expression mediated by LPS-TNF-α. In addition, the production of inflammatory mediators was inhibited, and the release of interleukin-10 was restored to control levels.Furthermore, the intracellular signalling mechanism regulating TDZ-elicited effects was specifically investigated. TDZ induced extracellular signal-regulated kinase (ERK) phosphorylation and inhibited constitutive p38 activation. Moreover, TDZ counteracted the activation of p38 and c-Jun NH2-terminal kinase (JNK) elicited by LPS-TNF-α, suggesting that the neuro-protective role of TDZ could be mediated by p38 and JNK.Overall, our results demonstrated that the protective effects of TDZ under inflammation in neuronal-like cells function by decreasing pro-inflammatory signalling and by enhancing anti-inflammatory signalling.

Multimodal functional and structural neuroimaging investigation of major depressive disorder following treatment with duloxetine.

BackgroundLongitudinal neuroimaging studies of major depressive disorder (MDD) have most commonly assessed the effects of antidepressants from the serotonin reuptake inhibitor class and usually reporting a single measure. Multimodal neuroimaging assessments were acquired from MDD patients during an acute depressive episode with serial measures during a 12-week treatment with the serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine.MethodsParticipants were medication-free MDD patients (n = 32; mean age 40.2 years) in an acute depressive episode and healthy controls matched for age, gender, and IQ (n = 25; mean age 38.8 years). MDD patients received treatment with duloxetine 60 mg daily for 12 weeks with an optional dose increase to 120 mg daily after 8 weeks. All participants had serial imaging at weeks 0, 1, 8, and 12 on a 3 Tesla magnetic resonance imaging (MRI) scanner. Neuroimaging tasks included emotional facial processing, negative attentional bias (emotional Stroop), resting state functional MRI and structural MRI.ResultsA significant group by time interaction was identified in the anterior default mode network in which MDD patients showed increased connectivity with treatment, while there were no significant changes in healthy participants. In the emotional Stroop task, increased posterior cingulate activation in MDD patients normalized following treatment. No significant group by time effects were observed for happy or sad facial processing, including in amygdala responsiveness, or in regional cerebral volumes. Reduced baseline resting state connectivity within the orbitofrontal component of the default mode network was predictive of clinical response. An early increase in hippocampal volume was predictive of clinical response.ConclusionsBaseline resting state functional connectivity was predictive of subsequent clinical response. Complementary effects of treatment were observed from the functional neuroimaging correlates of affective facial expressions, negative attentional bias, and resting state. No significant effects were observed in affective facial processing, while the interaction effect in negative attentional bias and individual group effects in resting state connectivity could be related to the SNRI class of antidepressant medication. The specificity of the observed effects to SNRI pharmacological treatments requires further investigation.Trial registrationRegistered at clinicaltrials.gov (NCT01051466).Electronic supplementary materialThe online version of this article (doi:10.1186/s12888-015-0457-2) contains supplementary material, which is available to authorized users.

Probable Association of an Attack of Bilateral Acute Angle-Closure Glaucoma With Duloxetine

To report a patient who had an attack of bilateral acute angle-closure glaucoma (ACG) probably associated with the use of duloxetine. The case reported here involves an 81-year-old Caucasian woman whose past ocular history was unremarkable except for high hyperopia and cataract. The patient developed ocular symptoms 2 days after starting duloxetine, a serotonin norepinephrine reuptake inhibitor (SNRI) and was diagnosed with acute ACG. The elevated intraocular pressure (IOP) was successfully lowered with medical treatment, and the patient was advised to discontinue duloxetine. She subsequently underwent laser iridotomy in both eyes, and her IOP remained adequately controlled. A score of 6 was obtained using the Naranjo adverse drug reaction probability scale, suggesting duloxetine as the probable cause of the attack of ACG in this patient. There are a few previous reports of acute ACG associated with venlafaxine, another member of the class of SNRIs. In addition, there are several reports of ACG associated with members of the related class of selective serotonin reuptake inhibitors (SSRIs)-namely, fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, and escitalopram. The mechanism responsible for the precipitation of ACG by members of these 2 classes of drugs is likely a result of mydriasis caused by their adrenergic effects, weak anticholinergic activities, or the increased levels of serotonin. Because the SNRIs, including duloxetine, and SSRIs are commonly used in the management of depression or chronic pain, caution is warranted with the use of these drugs in patients with risk factors for ACG.

5-HT1A/1B Receptors as Targets for Optimizing Pigmentary Responses in C57BL/6 Mouse Skin to Stress

Stress has been reported to induce alterations of skin pigmentary response. Acute stress is associated with increased turnover of serotonin (5-hydroxytryptamine; 5-HT) whereas chronic stress causes a decrease. 5-HT receptors have been detected in pigment cells, indicating their role in skin pigmentation. To ascertain the precise role of 5-HT in stress-induced pigmentary responses, C57BL/6 mice were subjected to chronic restraint stress and chronic unpredictable mild stress (CRS and CUMS, two models of chronic stress) for 21 days, finally resulting in abnormal pigmentary responses. Subsequently, stressed mice were characterized by the absence of a black pigment in dorsal coat. The down-regulation of tyrosinase (TYR) and tyrosinase-related proteins (TRP1 and TRP2) expression in stressed skin was accompanied by reduced levels of 5-HT and decreased expression of 5-HT receptor (5-HTR) system. In both murine B16F10 melanoma cells and normal human melanocytes (NHMCs), 5-HT had a stimulatory effect on melanin production, dendricity and migration. When treated with 5-HT in cultured hair follicles (HFs), the increased expression of melanogenesis-related genes and the activation of 5-HT1A, 1B and 7 receptors also occurred. The serum obtained from stressed mice showed significantly decreased tyrosinase activity in NHMCs compared to that from nonstressed mice. The decrease in tyrosinase activity was further augmented in the presence of 5-HTR1A, 1B and 7 antagonists, WAY100635, SB216641 and SB269970. In vivo, stressed mice received 5-HT precursor 5-hydroxy-l-tryptophan (5-HTP), a member of the class of selective serotonin reuptake inhibitors (fluoxetine; FX) and 5-HTR1A/1B agonists (8-OH-DPAT/CP94253), finally contributing to the normalization of pigmentary responses. Taken together, these data strongly suggest that the serotoninergic system plays an important role in the regulation of stress-induced depigmentation, which can be mediated by 5-HT1A/1B receptors. 5-HT and 5-HTR1A/1B may constitute novel targets for therapy of skin hypopigmentation disorders, especially those worsened with stress.

ISOLATION AND CHARACTERIZATION OF RELATED IMPURITY IN MILNACIPRAN HYDROCHLORIDE ACTIVE PHARMACEUTICAL INGREDIENT

Milnacipran hydrochloride is an antidepressant drug, belonging to a class of selective serotonin re-uptake inhibitors. Unknown impurity in active pharmaceutical ingredient and pharmaceutical formulation of Milnacipran hydrochloride was found to be 0.08% and 0.12%, respectively, by peak area, with sensitive, isocratic RP-HPLC method. As per revised guidelines of International Conference on Harmonization Q3A (R2) and Q3B (R2), impurity profiling should be done for drug substances and drug products to identify and characterize all the unknown impurities that are present at level above 0.05%. This unknown impurity was targeted and isolated by developed Prep-HPLC method. The isolated impurity is characterized as 1-phenyl-3-azabicyclo [3.1.0] hexan-2-one using spectroscopic techniques like FT-IR, Mass, and NMR. The origin of the impurity is also postulated by proposing the plausible mechanism of formation.

Trazodone as co-treatment for insomniac patients

Introduction Trazodone is an antidepressant belonging to the class of serotonin receptor antagonists and reuptake inhibitors. Trazodone is widely prescribed as a sleep aid, although it is indicated for depression, not insomnia. The aim of this study was to describe the usefulness of trazodone in the treatment of insomnia in our sleep unit. Materials and methods This retrospective cross-sectional study was conducted at a multidisciplinary sleep center (Hospital Universitario Araba) in Vitoria. Patients with insomnia treated with trazodone were analized. Average dose was 11.25±54.9mg (50–300mg). The quantify perceived insomnia severity were then assessed with the Insomnia Severity Index (ISI) questionnaire before and after taking trazodone. The use of benzodiazepine hypnotics, non- benzodiazepine hypnotics, antidepressants and other drugs were picked up on an average time of the intake for 6.1±4.4months. Results From December of 2011 to June of 2013, 166 patients were clinically diagnosed for insomnia, and 40 (24%) of them were started a treatment with trazodone or we added up more dose of it. 37.5% were men and mean age was 53.9±12.9. 33 (82.5%) had comorbid insomnia, and 50% associated with psyquiatric disorder. Compared to pre- treatment, trazodone improved scores on ISI ( p p =0.008). However, there was a increase in the number of non- benzodiazepine hypnotics taken. 13 patients (32.5%) discontinued the trazodone treatment because they did not perceive any benefit with treatment and/or they developed side effects. Conclusion In the group studied, the use of the trazodone could help to reduce the dose of benzodiazepine hypnotics taken. In some cases it could be possible to stop benzodiazepinas and to improve the sleep. One third of the patients discontinued the treatment of trazodone. More studies are necessary to demostrate the risk/benefit ratio for trazodone in insomnia. Acknowledgement All the people that made possible to develop this study.

Systematic meta-analysis of individual selective serotonin reuptake inhibitor medications and congenital malformations

It has been suggested that the commonly prescribed class of antidepressants selective serotonin reuptake inhibitors (SSRIs) are associated with birth defects. However, the teratogenic effect of individual SSRIs has not been previously compared using meta-analysis. To determine the strength of the association between individual SSRIs and major, minor, and cardiac malformation among infants born to women taking these medications. Electronic search of CINAHL, EMBASE, Medline, PsycINFO, and ISI Web of Science using the search terms (SSRI OR antidepressant) AND (obstetric outcome OR malformation OR birth outcome OR teratogen), supplemented by manual searching of published references and requests of primary researchers for unpublished data. There were 115 studies identified by electronic search and reviewed in full text, which yielded 16 papers reporting 36 data samples for major malformations, nine papers reporting 26 data samples for cardiac malformations, and four papers reporting seven data samples for minor malformations. Fluoxetine (OR 1.14, 95% CI 1.01-1.30) and paroxetine (OR 1.29, 95% CI 1.11-1.49) were associated with increased risk of major malformations. Paroxetine was associated with increased risk of cardiac malformations (OR 1.44, 95% CI 1.12-1.86). Sertraline and citalopram were not significantly associated with congenital malformation. Between-sample heterogeneity was low and a range of methodological considerations had no significant impact on effect size. There was little evidence of publication bias. Fluoxetine and paroxetine should be avoided in the first trimester and among those at risk of an unplanned pregnancy.

11C and 18F PET radioligands for the serotonin transporter (SERT)

The serotonin transporter (SERT) has been implicated in a variety of neuropsychiatric disorders including depression, anxiety, and suicide, and is the target of the selective serotonin reuptake inhibitor (SSRI) class of antidepressants. The availability of SERT-specific positron emission tomography (PET) radioligands will allow the SERT to be studied noninvasively in living subjects through PET imaging of the SERT and occupancy studies of SSRIs. Numerous diaryl sulfide and tropane derivatives have been developed and radiolabeled with (11) C or (18) F for imaging the SERT with PET.

In Utero Exposure of Venlafaxine: Impact on Maternal, Fetal, Neonatal Weight and Postnatal Growth in Rat Offspring

Venlafaxine (VEN), a newer antidepressant of serotonin and noradrenaline reuptake inhibitor (SNRI) class, is commonly used worldwide for clinical management of various forms of depression even during pregnancy. The maternal and fetal safety of this drug has not been established well so far due to lack of metanalysis studies in clinical settings and controlled investigations in rodents as well as availability of contradictory information. Therefore, present study has been planned to investigate the maternal toxicity in relation to food intake and body weight gain; fetal toxicity as fetal weight at GD-19 and neonatal weight at birth; and postnatal development/growth in young-adult rat offspring. In this study selected doses of VEN (25, 40 and 50 mg/kg) were administered to pregnant rats from GD 5–21 through gavage. These doses were equivalent to human therapeutic dose range (75–375 mg/day). Maternal food intake and body weight gain were found substantially reduced due to drug induced hypophagia. The fetal body weight at GD-19 as well as neonatal birth weight of VEN exposed offspring was found significantly deficient which could not reach up to the control level till 8 weeks as compared to control. This study concludes that prenatal exposure of VEN not only induced maternal weight loss and food intake deficit but also induced long-lasting impact on fetal as well as neonatal development and growth in young-adult offspring. Further, cautions are required for weighing the risks and benefits to both fetus and pregnant mothers before recommendation of SNRIs in general and VEN in particular.

Rediscovering trazodone for the treatment of major depressive disorder.

Trazodone is a triazolopyridine derivative that belongs to the class of serotonin receptor antagonists and reuptake inhibitors (SARIs). The drug is approved and marketed in several countries worldwide for the treatment of major depressive disorder (MDD) in adult patients. In clinical studies, trazodone has demonstrated comparable antidepressant activity to other drug classes, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and serotonin–noradrenaline (norepinephrine) reuptake inhibitors (SNRIs). Moreover, the SARI action of trazodone may overcome the tolerability issues that are often associated with second-generation antidepressants such as SSRIs (i.e. insomnia, anxiety and sexual dysfunction). Recent focus has been placed on the development of a new prolonged-release once-a-day formulation of trazodone (TzCOAD), which may provide improved tolerability over the conventional immediate-release formulation of trazodone. Clinical studies have led to the recent approval in the USA of TzCOAD (as Oleptro™; Angelini Labopharm LLC, Princeton, NJ, USA), which may see resurgence of interest in the drug for the management of patients with MDD. Although trazodone is approved for the treatment of depression, evidence supports the use of low-dose trazodone as an off-label hypnotic for the treatment of sleep disorders in patients with MDD. The most common adverse effects reported with trazodone are drowsiness (somnolence/sedation), headache, dizziness and dry mouth. Other events reported, albeit with low incidence, include orthostatic hypotension (particularly in elderly patients or those with heart disease), minimal anticholinergic activity, corrected QT interval prolongation and torsade de pointes, cardiac arrhythmias, and rare occurrences of priapism and suicidal ideation. Overall, trazodone is an effective and well tolerated antidepressant (SARI) with an important role in the current treatment of MDD both as monotherapy and as part of a combination strategy. Trazodone is effective in controlling a wide range of symptoms of depression, while avoiding the negative effects on sleep seen with SSRI antidepressants. The recently approved prolonged-release formulation should provide further optimization of this antidepressant and may be useful for enabling an appropriate therapeutic dose to be administered with improved patient compliance.

New Derivative Spectrophotometric Methods for the Determination of Fluoxetine - An Antidepressant Drug

Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. Two simple, rapid and sensitive first and second derivative spectrophotometric methods are developed for the determination of fluoxetine (FLX) in pharmaceutical dosage forms (capsules). The absorption minima was chosen (at 235 nm) in first order (Method A) and amplitude (229-238.5 nm) was selected in second order derivative spectral calculations. Fluoxetine follows Beer's law in the concentration range of 1-60 µg mL -1 (r 2 = 0.999) in first order as well as in second order (r 2 = 0.9994) derivative spectroscopy respectively. The proposed methods can be successfully applied for the determination of Fluoxetine in commercial brands of pharmaceutical formulations. No interferences were observed from the common excipients in the formulations. The methods were validated according to ICH guidelines.