Fluoxetine-induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15-deoxy-Δ12,14PGJ2

Major depressive disorder and other neuropsychiatric disorders are often managed with long-term use of antidepressant medication. Fluoxetine, an SSRI antidepressant, is widely used as a first-line treatment for neuropsychiatric disorders. However, fluoxetine has also been shown to increase the risk of metabolic diseases such as non-alcoholic fatty liver disease. Fluoxetine has been shown to increase hepatic lipid accumulation in vivo and in vitro. In addition, fluoxetine has been shown to alter the production of prostaglandins which have also been implicated in the development of non-alcoholic fatty liver disease. The goal of this study was to assess the effect of fluoxetine exposure on the prostaglandin biosynthetic pathway and lipid accumulation in a hepatic cell line (H4-II-E-C3 cells). Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes (Ptgs1, Ptgs2, and Ptgds), PPAR gamma (Pparg), and PPAR gamma downstream targets involved in fatty acid uptake (Cd36, Fatp2, and Fatp5) as well as production of 15-deoxy-Δ^12,14PGJ₂ a PPAR gamma ligand. The effects of fluoxetine to induce lipid accumulation were attenuated with a PTGS1 specific inhibitor (SC-560), whereas inhibition of PTGS2 had no effect. Moreover, SC-560 attenuated 15-deoxy-Δ^12,14PGJ₂ production and expression of PPAR gamma downstream target genes. Taken together these results suggest that fluoxetine-induced lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d-PGJ₂ and suggest a novel therapeutic target to prevent some of the adverse effects of fluoxetine treatment.     

Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants

This study demonstrated that distinct patterns of active behaviors are produced by antidepressants that selectively inhibit norepinephrine (NE) or serotonin (5-HT) uptake in the rat forced swimming test (FST). A behavior sampling technique was developed to score the active behaviors swimming, climbing and diving, as well as immobility. The rat's behavior was recorded at the end of each 5-s period during the test session. The sampling technique was both reliable, as demonstrated by test-retest reliability and inter-rater reliability, and valid, as shown by comparison to the timing of behavior durations. Five different antidepressant drugs which block monoamine uptake and two 5-HT_1A receptor agonists were shown to decrease immobility in the FST; however, they produced distinct patterns of active behaviors. The selective NE uptake inhibitors desipramine and maprotiline selectively increased climbing, whereas the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, sertraline and paroxetine selectively increased swimming. The 5-HT_1A receptor agonists 8-OH-DPAT and gepirone also selectively increased swimming. These results show that:1) SSRIs are not false negatives in the FST; 2) at least two behaviorally distinct processes occur in the FST; and 3) enhancement of NE neurotransmission may mediate climbing in the FST, whereas enhancement of 5-HT neurotransmission may mediate swimming.     

Moclobemide and specific serotonin re-uptake inhibitor combination treatment of resistant anxiety and depressive disorders

This retrospective study was undertaken with the objective of determining how effective and safe moclobemide, a specific and reversible inhibitor of monoamine oxidase-A (RIMA), is when used in combination with specific serotonin re-uptake inhibitors (SSRIs), in a clinical setting. A thorough chart review was done of all patients with affective and anxiety disorders seen at our centre who received combination treatment with moclobemide and an SSRI. Combination moclobemide-SSRI treatment demonstrated good efficacy in treating treatment-resistant patients. The combination treatment was well tolerated with very few drug interactions. Dosages should be started low, titrated slowly and carefully, and patients should be monitored closely.     

Lack of functional estrogen receptor beta influences anxiety behavior and serotonin content in female mice

Estrogen has been linked to the modulation of anxiety in females. Here we report results of anxiety tests conducted in female estrogen receptor beta (ERbeta) knockout (ERbetaKO) and wild-type (WT) mice. Ovariectomized (OVX) mice treated with chronic estradiol (E2) replacement did not behave differently on the elevated plus-maze when compared with OVX mice that did not experience hormone replacement. However, a genotype difference was noted; WT females were more likely to explore the distal portion of the open arm of the maze than ERbetaKO littermates. In addition, ERbetaKO female mice had significantly lower serotonin (5-HT) content than WT littermates in several brain regions including: the bed nucleus of the stria terminalis, preoptic area, and hippocampus. A similar trend was noted in the dorsal raphe nucleus. Dopamine content was reduced within the caudate putamen in ERbetaKO mice as compared to brains from WT animals. Thus, in the absence of functional ERbeta, regardless of the presence or absence of circulating E2 in plasma, female mice exhibited enhanced anxiety and decreased concentrations of 5-HT or dopamine in several brain regions. We hypothesize that ERbeta is required during development to modulate the effects of estrogen on anxiety and catecholamine concentrations in female mouse brains.     

Postbariatric hypoglycemia: symptom patterns and associated risk factors in the Longitudinal Assessment of Bariatric Surgery study

BackgroundPostbariatric hypoglycemia (PBH) can be a devastating complication for which current therapies are often incompletely effective. More information is needed regarding frequency, incidence, and risk factors for PBH.ObjectivesTo examine hypoglycemia symptoms following Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB) and baseline and in-study risk factors.SettingMulticenter, at 10 US hospitals in 6 geographically diverse clinical centers.MethodsA prospective, longitudinal cohort study of adults undergoing RYGB or LAGB as part of clinical care between 2006 and 2009 were recruited and followed until January 31, 2015, with baseline and annual postoperative research assessments. We analyzed baseline prevalence and post-operative incidence and frequency of self-reported hypoglycemia symptoms as well as potential preoperative risk factors.ResultsIn all groups, postoperative prevalence of hypoglycemia symptoms was 38.5%. Symptom prevalence increased postoperatively from 2.8%–36.4% after RYGB in patients without preoperative diabetes (T2D), with similar patterns in prediabetes (4.9%–29.1%). Individuals with T2D had higher baseline hypoglycemia symptoms (28.9%), increasing after RYGB (57.9%). Hypoglycemia symptoms were lower after LAGB, with 39.1% reported hypoglycemia symptoms at only 1 postoperative visit with few (4.0%) having persistent symptoms at 6 or more annual visits. Timing of symptoms was not restricted to the postprandial state. Symptoms of severe hypoglycemia were reported in 2.6–3.6% after RYGB. The dominant risk factor for postoperative symptoms was preoperative symptoms; additionally, baseline selective serotonin (SSRI) and serotonin-norepinephrine (SNRI) reuptake inhibitor use was also associated with increased risk in multivariable analysis. Weight loss and regain were not related to hypoglycemia symptom reporting.ConclusionHypoglycemia symptoms increase over time after RYGB, particularly in patients without diabetes. In a small percentage, symptoms can be persistent or severe and require hospitalization. Preoperative hypoglycemia symptoms and SSRI/SNRI use in RYGB patients without diabetes is associated with increased risk of symptoms.     

Acute fluoxetine treatment potentiates amphetamine hyperactivity and amphetamine-induced nucleus accumbens dopamine release: possible pharmacokinetic interaction

Amphetamine stimulates locomotor activity, in large part by activating central dopaminergic systems. Serotonin shares on overlapping distribution with dopamine and has been shown to modulate dopaminergic function and dopamine-mediated behaviors. The present study examined whether increasing serotonergic function, via the selective serotonin reuptake inhibitor fluoxetine, would alter the stimulatory effects of amphetamine on locomotor activity and dopamine overflow in the nucleus accumbens. In addition, the present study determined whether fluoxetine treatment would alter the metabolism of amphetamine. Results show that 5.0 mg/kg fluoxetine potentiated the locomotor activity induced by amphetamine (0.5–1.0 mg/ kg), and enhanced the increased dopamine overflow in the nucleus accumbens induced by amphetamine. Fluoxetine treatment also resulted in a higher concentration of amphetamine in the CNS. Together, these findings indicate that acute fluoxetine treatment potentiates the locomotor stimulating and dopamine activating effects of amphetamine. Further, the results indicate that fluoxetine potentiates the effects of amphetamine by decreasing the metabolism of amphetamine, probably through inhibition of cytochrome P450 isozymes. Received: 5 May 1998/Final version: 7 July 1998     

Acute Neurofunctional Effects of Escitalopram in Pediatric Anxiety: A Double-Blind,Placebo-Controlled Trial

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Innovations in CNS drug discovery: differentiating strategies to treat depression

Over the past two decades, the clinical management of depression has been revolutionized by the introduction of selective serotonin re-uptake inhibitors and serotonin/noradrenaline re-uptake inhibitors. However, despite this progress, several unmet medical needs remain. These challenges, which collectively represent the next frontier for antidepressant drug discovery, range from improving efficacy in treatment-resistant patients, to accelerating onset of therapeutic activity, to reducing deleterious side effects such as emesis or sexual dysfunction. The present review addresses some of the innovative approaches designed to create novel therapies that improve in one or more of these areas. Additionally, the authors propose that to discover truly novel disease-modifying agents we must improve our appreciation of disease etiology, pathophysiology and genetics. Therefore, while it is still very early in the characterization of these strategies – as well as our general understanding of disease progression – the next several years should allow sufficient time for one (or more) of these approaches to differentiate themselves from current therapies.     

Psychopharmacology and Cardiovascular Disease

This review discusses common mental health disorders and their associations with cardiovascular disease risks. Commonly found mental health disorders include depression, anxiety, and personality types. The link between depression and cardiovascular disease mortality has been established. Depression is also common in patients with heart failure. In addition to discussing psychological disorders, a review of psychotropic drugs is also included. Drugs are described for therapy for depression and anxiety, as well as associations with cardiovascular drug-drug interactions. Drug-drug interactions are more common and potentially dangerous in elderly patients, in whom the conditions often coexist. The most common drug-drug interactions involve the P450 system of enzymes.     

Selective serotonin re-uptake inhibitors and the risk of bleeding

Despite their safety, selective serotonin re-uptake inhibitors (SSRIs) are associated with bleeding. The authors critically reviewed the medical literature on SSRIs to identify subgroups of patients at risk of bleeding complications. The authors performed a literature search using MEDLINE from 1966 to 1st September 2004 using; ‘haemorrhage, serotonin uptake inhibitors and antidepressive agents’ as search terms and followed up on citations in each paper that was relevant to SSRI associated bleeding. The authors reviewed 7 retrospective analytical studies and 24 case reports of bleeding in 43 different people. Analytical studies support an association between SSRI consumption and upper gastrointestinal (GI) bleeding and perioperative bleeding. Little evidence links SSRI use with intracerebral haemorrhage. The risk of GI bleeding appeared to be highest among patients consuming SSRIs with NSAIDs. Combining aspirin or NSAIDs with SSRIs may further increase the risk of bleeding. Clinicians should caution patients about combining SSRIs with aspirin or NSAIDs. Pharmacotherapy to reduce the risk of GI bleeding should be consid-ered in high risk patients.