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Concept: Selective serotonin reuptake inhibitor

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Objective To study serious harms associated with selective serotonin and serotonin-norepinephrine reuptake inhibitors.Design Systematic review and meta-analysis.Main outcome measures Mortality and suicidality. Secondary outcomes were aggressive behaviour and akathisia.Data sources Clinical study reports for duloxetine, fluoxetine, paroxetine, sertraline, and venlafaxine obtained from the European and UK drug regulators, and summary trial reports for duloxetine and fluoxetine from Eli Lilly’s website.Eligibility criteria for study selection Double blind placebo controlled trials that contained any patient narratives or individual patient listings of harms.Data extraction and analysis Two researchers extracted data independently; the outcomes were meta-analysed by Peto’s exact method (fixed effect model).Results We included 70 trials (64 381 pages of clinical study reports) with 18 526 patients. These trials had limitations in the study design and discrepancies in reporting, which may have led to serious under-reporting of harms. For example, some outcomes appeared only in individual patient listings in appendices, which we had for only 32 trials, and we did not have case report forms for any of the trials. Differences in mortality (all deaths were in adults, odds ratio 1.28, 95% confidence interval 0.40 to 4.06), suicidality (1.21, 0.84 to 1.74), and akathisia (2.04, 0.93 to 4.48) were not significant, whereas patients taking antidepressants displayed more aggressive behaviour (1.93, 1.26 to 2.95). For adults, the odds ratios were 0.81 (0.51 to 1.28) for suicidality, 1.09 (0.55 to 2.14) for aggression, and 2.00 (0.79 to 5.04) for akathisia. The corresponding values for children and adolescents were 2.39 (1.31 to 4.33), 2.79 (1.62 to 4.81), and 2.15 (0.48 to 9.65). In the summary trial reports on Eli Lilly’s website, almost all deaths were noted, but all suicidal ideation events were missing, and the information on the remaining outcomes was incomplete.Conclusions Because of the shortcomings identified and having only partial access to appendices with no access to case report forms, the harms could not be estimated accurately. In adults there was no significant increase in all four outcomes, but in children and adolescents the risk of suicidality and aggression doubled. To elucidate the harms reliably, access to anonymised individual patient data is needed.

Concepts: Epidemiology, Clinical trial, Medical statistics, Antidepressant, Selective serotonin reuptake inhibitor, Sertraline, Fluoxetine, Venlafaxine

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Individuals with a history of recurrent depression have a high risk of repeated depressive relapse or recurrence. Maintenance antidepressants for at least 2 years is the current recommended treatment, but many individuals are interested in alternatives to medication. Mindfulness-based cognitive therapy (MBCT) has been shown to reduce risk of relapse or recurrence compared with usual care, but has not yet been compared with maintenance antidepressant treatment in a definitive trial. We aimed to see whether MBCT with support to taper or discontinue antidepressant treatment (MBCT-TS) was superior to maintenance antidepressants for prevention of depressive relapse or recurrence over 24 months.

Concepts: Selective serotonin reuptake inhibitor, Bipolar disorder, Major depressive disorder, Bupropion, Sertraline, Mindfulness-based cognitive therapy

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An aversion to harming others is a core component of human morality and is disturbed in antisocial behavior [1-4]. Deficient harm aversion may underlie instrumental and reactive aggression, which both feature in psychopathy [5]. Past work has highlighted monoaminergic influences on aggression [6-11], but a mechanistic account of how monoamines regulate antisocial motives remains elusive. We previously observed that most people show a greater aversion to inflicting pain on others than themselves [12]. Here, we investigated whether this hyperaltruistic disposition is susceptible to monoaminergic control. We observed dissociable effects of the serotonin reuptake inhibitor citalopram and the dopamine precursor levodopa on decisions to inflict pain on oneself and others for financial gain. Computational models of choice behavior showed that citalopram increased harm aversion for both self and others, while levodopa reduced hyperaltruism. The effects of citalopram were stronger than those of levodopa. Crucially, neither drug influenced the physical perception of pain or other components of choice such as motor impulsivity or loss aversion [13, 14], suggesting a direct and specific influence of serotonin and dopamine on the valuation of harm. We also found evidence for dose dependency of these effects. Finally, the drugs had dissociable effects on response times, with citalopram enhancing behavioral inhibition and levodopa reducing slowing related to being responsible for another’s fate. These distinct roles of serotonin and dopamine in modulating moral behavior have implications for potential treatments of social dysfunction that is a common feature as well as a risk factor for many psychiatric disorders.

Concepts: Neurotransmitter, Serotonin, Mental disorder, Selective serotonin reuptake inhibitor, Morality, Dopamine, Antisocial personality disorder, Reuptake inhibitor

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Objectives To evaluate the risk of all cause mortality associated with initiating compared with not initiating benzodiazepines in adults, and to address potential treatment barriers and confounding related to the use of a non-active comparator group.Design Retrospective cohort study.Setting Large de-identified US commercial healthcare database (Optum Clinformatics Datamart).Participants 1:1 high dimensional propensity score matched cohort of benzodiazepine initiators, and randomly selected benzodiazepine non-initiators with a medical visit within 14 days of the start of benzodiazepine treatment (n=1 252 988), between July 2004 and December 2013. To address treatment barriers and confounding, patients were required to have filled one or more prescriptions for any medication in the 90 days and 91-180 days before the index date (ie, the date of starting benzodiazepine treatment for initiators and the date of the selected medical visit for benzodiazepine non-initiators) and the high dimensional propensity score was estimated on the basis of more than 300 covariates.Main outcome measure All cause mortality, determined by linkage with the Social Security Administration Death Master File.Results Over a six month follow-up period, 5061 and 4691 deaths occurred among high dimensional propensity score matched benzodiazepine initiators versus non-initiators (9.3 v 9.4 events per 1000 person years; hazard ratio 1.00, 95% confidence interval 0.96 to 1.04). A 4% (95% confidence interval 1% to 8%) to 9% (2% to 7%) increase in mortality risk was observed associated with the start of benzodiazepine treatment for follow-ups of 12 and 48 months and in subgroups of younger patients and patients initiating short acting agents. In secondary analyses comparing 1:1 high dimensional propensity score matched patients initiating benzodiazepines with an active comparator, ie, patients starting treatment with selective serotonin reuptake inhibitor antidepressants, benzodiazepine use was associated with a 9% (95% confidence interval 3% to 16%) increased risk.Conclusions This large population based cohort study suggests either no increase or at most a minor increase in risk of all cause mortality associated with benzodiazepine initiation. If a detrimental effect exists, it is likely to be much smaller than previously stated and to have uncertain clinical relevance. Residual confounding likely explains at least part of the small increase in mortality risk observed in selected analyses.

Concepts: Experimental design, Epidemiology, Actuarial science, Relative risk, Selective serotonin reuptake inhibitor, Statistical terminology, Benzodiazepine, Reuptake inhibitor

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The recent questioning of the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs) is partly based on the observation that approximately half of company-sponsored trials have failed to reveal a significant difference between active drug and placebo. Most of these have applied the Hamilton depression rating scale to assess symptom severity, the sum score for its 17 items (HDRS-17-sum) serving as effect parameter. In this study, we examined whether the negative outcomes of many SSRI trials may be partly caused by the use of this frequently questioned measure of response. We undertook patient-level post-hoc analyses of 18 industry-sponsored placebo-controlled trials regarding paroxetine, citalopram, sertraline or fluoxetine, and including in total 6669 adults with major depression, the aim being to assess what the outcome would have been if the single item depressed mood (rated 0-4) had been used as a measure of efficacy. In total, 32 drug-placebo comparisons were reassessed. While 18 out of 32 comparisons (56%) failed to separate active drug from placebo at week 6 with respect to reduction in HDRS-17-sum, only 3 out of 32 comparisons (9%) were negative when depressed mood was used as an effect parameter (P<0.001). The observation that 29 out of 32 comparisons detected an antidepressant signal from the tested SSRI suggests the effect of these drugs to be more consistent across trials than previously assumed. Further, the frequent use of the HDRS-17-sum as an effect parameter may have distorted the current view on the usefulness of SSRIs and hampered the development of novel antidepressants.Molecular Psychiatry advance online publication, 28 April 2015; doi:10.1038/mp.2015.53.

Concepts: Serotonin, Antidepressant, Selective serotonin reuptake inhibitor, Major depressive disorder, Sertraline, Fluoxetine, Paroxetine, Venlafaxine

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Hypothesised associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects (CHD), remain controversial. We investigated the putative teratogenicity of SSRI prescription in the 91 days either side of first day of last menstrual period (LMP).

Concepts: Serotonin, Fluvoxamine, Antidepressant, Selective serotonin reuptake inhibitor, Sertraline, Tricyclic antidepressant, Reuptake inhibitor, Fluoxetine

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Domestic violence in the perinatal period is associated with adverse obstetric outcomes, but evidence is limited on its association with perinatal mental disorders. We aimed to estimate the prevalence and odds of having experienced domestic violence among women with antenatal and postnatal mental disorders (depression and anxiety disorders including post-traumatic stress disorder [PTSD], eating disorders, and psychoses).

Concepts: Pregnancy, Childbirth, Selective serotonin reuptake inhibitor, Abnormal psychology, Posttraumatic stress disorder, Anxiety disorder, Anxiety disorders, Hypervigilance

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To estimate the association between prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and motor development in children considering the effect of maternal symptoms of anxiety and depression before, during and after pregnancy.

Concepts: Serotonin, Antidepressant, Selective serotonin reuptake inhibitor, Major depressive disorder, Sertraline, Tricyclic antidepressant, Reuptake inhibitor, Fluoxetine

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Adult neurogenesis in the hippocampal subgranular zone (SGZ) and the anterior subventricular zone (SVZ) is regulated by multiple factors, including neurotransmitters, hormones, stress, aging, voluntary exercise, environmental enrichment, learning, and ischemia. Chronic treatment with selective serotonin reuptake inhibitors (SSRIs) modulates adult neurogenesis in the SGZ, the neuronal area that is hypothesized to mediate the antidepressant effects of these substances. Layer 1 inhibitory neuron progenitor cells (L1-INP cells) were recently identified in the adult cortex, but it remains unclear what factors other than ischemia affect the neurogenesis of L1-INP cells. Here, we show that chronic treatment with an SSRI, fluoxetine (FLX), stimulated the neurogenesis of gamma-aminobutyric acid (GABA)ergic interneurons from L1-INP cells in the cortex of adult mice. Immunofluorescence and genetic analyses revealed that FLX treatment increased the number of L1-INP cells in all examined cortical regions in a dose-dependent manner. Furthermore, enhanced Venus reporter expression driven by the synapsin I promoter demonstrated that GABAergic interneurons were derived from retrovirally labeled L1-INP cells. In order to assess if these new GABAergic interneurons possess physiological function, we examined the their effect on apoptosis surrounding areas following ischemia. Intriguingly, the number of neurons expressing the apoptotic marker, active caspase-3, was significantly lower in adult mice pretreated with FLX. Our findings indicate that FLX stimulates the neurogenesis of cortical GABAergic interneurons, which might have, at least, some functions, including a suppressive effect on apoptosis induced by ischemia.Neuropsychopharmacology accepted article preview online, 4 January 2013; doi:10.1038/npp.2013.2.

Concepts: Nervous system, Neuron, Hippocampus, Neurogenesis, Serotonin, Antidepressant, Selective serotonin reuptake inhibitor, Subgranular zone