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Concept: Fluvoxamine

199

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

136

Cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) are both effective treatments for some patients with obsessive-compulsive disorder (OCD), yet little is known about the neurochemical changes related to these treatment modalities. Here, we used positron emission tomography and the α-[11C]methyl-L-tryptophan tracer to examine the changes in brain regional serotonin synthesis capacity in OCD patients following treatment with CBT or SSRI treatment. Sixteen medication-free OCD patients were randomly assigned to 12 weeks of either CBT or sertraline treatment. Pre-to-post treatment changes in the α-[11C]methyl-L-tryptophan brain trapping constant, K* (ml/g/min), were assessed as a function of symptom response, and correlations with symptom improvement were examined. Responders/partial responders to treatment did not show significant changes in relative regional tracer uptake; rather, in responders/partial responders, 12 weeks of treatment led to serotonin synthesis capacity increases that were brain-wide. Irrespective of treatment modality, baseline serotonin synthesis capacity in the raphe nuclei correlated positively with clinical improvement. These observations suggest that, for some patients, successful remediation of OCD symptoms might be associated with greater serotonergic tone.

Concepts: Positron emission tomography, Serotonin, Fluvoxamine, Antidepressant, Selective serotonin reuptake inhibitor, Major depressive disorder, Sertraline, Obsessive–compulsive disorder

72

Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD.Molecular Psychiatry advance online publication, 10 January 2017; doi:10.1038/mp.2016.232.

Concepts: Protein, Gene, Gene expression, Transcription, Action potential, Fluvoxamine, Selective serotonin reuptake inhibitor, Reuptake inhibitor

32

Serotonin reuptake inhibitors (SRIs), the first-line pharmacological treatment for obsessive-compulsive disorder (OCD), have two limitations: incomplete symptom relief and 2-3 months lag time before clinically meaningful improvement. New medications with faster onset are needed. Because converging evidence suggests a role for the glutamate system in the pathophysiology of OCD, we tested whether a single dose of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, could achieve rapid anti-obsessional effects. In a randomized, double-blind, placebo-controlled, crossover design, drug-free OCD adults (n=15) with near constant obsessions received two 40-minute intravenous infusions, one of saline and one of ketamine (0.5 mg/kg), spaced at least 1 week apart. The OCD visual analogue scale (OCD-VAS) and the Yale Brown Obsessive-Compulsive Scale (YBOCS) were used to assess OCD symptoms. Unexpectedly, ketamine’s effects within the crossover design showed significant (p<0.005) carryover effects (ie, lasting longer than 1 week). As a result, only the first-phase data were used in additional analyses. Specifically, those receiving ketamine (n=8) reported significant improvement in obsessions (measured by OCD-VAS) during the infusion compared with subjects receiving placebo (n=7). One week post-infusion, 50% of those receiving ketamine (n=8) met criteria for treatment response (35% Y-BOCS reduction) versus 0% of those receiving placebo (n=7). Rapid anti-OCD effects from a single intravenous dose of ketamine can persist for at least one week in some OCD patients with constant intrusive thoughts. This is the first randomized, controlled trial to demonstrate that a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an SRI and is consistent with a glutamatergic hypothesis of OCD.Neuropsychopharmacology accepted article preview online, 19 June 2013; doi:10.1038/npp.2013.150.

Concepts: Pharmacology, Clinical trial, Crossover study, Receptor antagonist, NMDA receptor, Fluvoxamine, Selective serotonin reuptake inhibitor, Obsessive–compulsive disorder

26

The extent to which clinicians adhere to international guidelines for the pharmacological management of obsessive-compulsive disorder (OCD) is unknown. We aimed to comprehensively map the patterns of prescription of psychotropic drugs for OCD patients (adults and children) at the Swedish national level and to compare these prescription patterns to best-practice recommendations in international guidelines. We linked the Swedish National Patient Register and the Swedish Prescribed Drug Register, which includes a record for all medications prescribed and dispensed in Sweden since July 2005. Of all active OCD cases in the Swedish National Patient Register between July 1st, 2005, and December 31st 2008 (N=10,523), 85% received at least one psychotropic drug. Most of the medicated adults and children with OCD (88%) received serotonin reuptake inhibitors (SRIs). Of all adults and children prescribed SRIs, 16% received sub-optimal doses. An additional 12% of all medicated patients were prescribed drugs that never included an SRI. Approximately 75% of the patients on SRIs received additional drugs (67% anxiolytics/hypnotics, 27% antipsychotics, 17% serotonin and norepinephrine reuptake inhibitors, 24% other antidepressants). Twelve percent of all medicated patients were at least ‘regular’ users, and 3% ‘heavy’ users of benzodiazepines. We also observed important variations in prescription practices according to patient’s gender, age, and comorbidity status. We conclude that a substantial number of OCD patients might benefit from changes in their prescriptions. Dissemination of best-practice prescription guidelines for OCD is a major educational goal for the future. Monitoring of these prescription patterns over time is warranted.

Concepts: Pharmacology, Drug, Opioid, Fluvoxamine, Antidepressant, Selective serotonin reuptake inhibitor, Tricyclic antidepressant, Recreational drug use

22

Initial evidences have shown that diabetes mellitus occurs concomitantly with obsessive-compulsive disorder (OCD) symptomatology. Serotonergic psychiatric therapy posits that serotonin is a central character in the management of OCD. Hence, it is worth investigating novel chemical entities affecting the serotonergic system for targeting OCD. An isoflavonoid phytoestrogen, genistein, has been recognized as of great pharmacological value especially for protecting neurodegeneration, depression (serotonin regulation), and diabetes. The effectiveness of genistein pretreatment on the symptoms of OCD in streptozotocin-induced diabetic mice is investigated in this study. We also evaluate the probable involvement of the serotonergic system.

Concepts: Nutrition, Diabetes mellitus, The Canon of Medicine, Obesity, Serotonin, Fluvoxamine, Selective serotonin reuptake inhibitor, Obsessive–compulsive disorder

10

To evaluate the effect of prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) on children’s behavioral, emotional, and social development by age 5 years, and over time since age 1.5 years.

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

8

Obsessive-compulsive disorder (OCD) in childhood and adolescence is an impairing condition, associated with a specific set of distressing symptoms incorporating repetitive, intrusive thoughts (obsessions) and distressing, time-consuming rituals (compulsions). This review considers current knowledge of causes and mechanisms underlying OCD, as well as assessment and treatment. Issues relating to differential diagnosis are summarised, including the challenges of distinguishing OCD from autism spectrum disorders and tic disorders in youth. The recommended treatments, namely cognitive behaviour therapy and serotonin reuptake inhibiting/selective serotonin reuptake inhibitor medications, are outlined along with the existing evidence-based and factors associated with treatment resistance. Finally, novel clinical developments that are emerging in the field and future directions for research are discussed.

Concepts: Psychology, Autism, Fluvoxamine, Selective serotonin reuptake inhibitor, Cognitive behavioral therapy, Tourette syndrome, Reuptake inhibitor, Obsessive–compulsive disorder

4

Selective serotonin reuptake inhibitors (SSRIs) may increase the risk for spontaneous intracranial hemorrhage (ICH), an effect that is in theory linked to the strength of inhibition of serotonin reuptake of an antidepressant. However, whether antidepressants that are strong inhibitors of serotonin reuptake actually increase the risk for ICH and the effect of concomitant use of antithrombotics are unknown.

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

4

Neuroscientists have been puzzled by the fact that acute administration of a selective serotonin reuptake inhibitor (SSRI) produces results that are, at times, compatible with either decreases or increases in serotonergic neurotransmission. Furthermore, the underlying cause of the delayed onset of antidepressant effects of SSRI treatment has remained obscure. It has recently been reported that serotonergic raphe neurons co-release glutamate and that serotonergic and glutamatergic components constitute a dual signal with behaviorally distinct effects. We discuss the consequences of these novel findings and propose a framework for understanding the controversial effects of acute SSRI administration. Furthermore, we suggest that the delayed remedial onset of SSRI treatment could be explained by an initial reduction of the glutamatergic component of the dual serotonergic signal.

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